Hydroxydiphenylethane compound ointment as well as application and preparation method thereof

Abstract

The invention discloses a hydroxydiphenylethane compound solution type ointment as well as application and a preparation method thereof, and the hydroxydiphenylethane compound solution type ointment comprises the following components in percentage by weight: 0.001%-3% of an active component hydroxydiphenylethane 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 hydroxydiphenylethane compound ointment provided by the invention 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, the face and the like.

Description

Hydroxydiphenylethane compound ointment and its use and preparation method Technical Field

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

[0002] Ointments are homogeneous, semisolid topical preparations made by mixing a drug substance with an oily or water-soluble matrix. 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 state of the drug substance in the matrix, ointments can be categorized as solution ointments or suspension ointments.

[0003] The most widely used ointment base is petrolatum base. Due to the limited solubility of drugs in petrolatum, 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 API 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-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 product quality.

[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] Despite the various technical advantages of solution-type ointments, 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 solubilizer dosage is insufficient, the drug approaches saturation solubility, which may cause crystallization of the drug due to changes in the external environment or 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, selecting appropriate excipients to prepare a homogeneous solution-type ointment presents a huge technical challenge.

[0006] Diphenylethane compounds can undergo a variety of substitution reactions on their two benzene rings, resulting in a variety of pharmacological activities, including anti-tumor, anticoagulant, and anti-inflammatory activities, depending on the substituents. However, research on diphenylethane compounds in the areas of skin diseases and cosmetics is limited. Korean patent application KR20150004221A discloses an androgen receptor antagonist with a diphenylethane structure, which may be used to treat conditions such as hair loss and acne, but the patent does not address topical formulations. Chinese patent application CN108366938B discloses a biaromatic vitamin D receptor agonist with a diphenylethane structure and provides a cosmetic composition with potential anti-wrinkle applications. This composition differs significantly from the ointment formulation in this patent, and the active ingredient lacks phenolic hydroxyl substitution, eliminating the need to address compound instability. Chinese patent application CN103483158B discloses a class of diphenylethane compounds that can be used to treat immune diseases or inflammation. The patent also provides a topical cream composition that demonstrated excellent edema suppression and inflammation reduction in a TPA-induced mouse skin edema model. However, such compounds have extremely poor solubility, and the compositions disclosed in the patents use high concentrations of propylene glycol and ionic surfactants, which are irritating to the skin.

[0007] On the other hand, diphenylethane derivatives containing hydroxyl groups are highly susceptible to photodegradation, causing changes in product color and performance under light. This photostability limits their use in skin disease treatments and cosmetics. Photoprotectants are often added to formulations to improve the photostability of pharmaceutically active molecules. Based on their mechanism, photoprotectants can be categorized as UV blockers and UV absorbers. The former, such as titanium dioxide and zinc oxide, offer excellent protection but typically require large dosages, and the presence of solid powders can affect the skin feel of the formulation. The latter, such as octyl salicylate, exhibits some transdermal absorption and can be allergenic or acne-causing. These photoprotectants are widely used in sunscreen cosmetics, but fewer are suitable for pharmaceutical formulations, and their dosage is limited.

[0008] Summary of the Invention

[0009] Technical Problems to be Solved by the Invention

[0010] Most commercially available ointments for poorly soluble drugs are suspension ointments. Developing homogeneous, stable solution ointments presents numerous technical challenges. Choosing the right excipients and optimizing their dosage—enabling them to dissolve the drug without crystallization, penetrate the skin efficiently in a molecular state, and avoid compromising transdermal absorption due to reduced thermodynamic activity—remains a process of trial and error, accumulating experience.

[0011] Many drugs have multiple clinical strengths, intended for different populations or disease conditions. To achieve optimal clinical results, formulations and / or processes must be tailored to each strength. Solution-based ointments require optimized dosages of solubilizers and penetration enhancers for optimal transdermal absorption. This often consumes significant resources and time. Furthermore, direct testing of drug solubility in formulations is difficult, and there is a lack of systematic, scientific methods to guide formulation optimization.

[0012] In view of the above technical problems, the purpose of the present invention is to develop a solution-type ointment suitable for hydroxydiphenylethane compounds, screen suitable solubilizers and penetration enhancers, and establish a mathematical model that can predict the solubility of drugs in multi-component systems. The optimal prescription ratio can be selected according to the dosage of the active ingredient to prepare a uniform and stable external preparation with good drug release and transdermal performance.

[0013] Furthermore, hydroxydiphenylethane compounds are unstable to light and heat and are easily oxidized and degraded under light. The colored quinone degradation products can also cause skin discoloration. Therefore, they require light shielding during use and cannot be used on areas exposed to light, such as the head and face. However, the head and face are prone to many skin diseases, which limits the clinical applicability of hydroxydiphenylethane active ingredients and affects patient compliance. Another object of the present invention is to provide a hydroxydiphenylethane compound topical composition that has good light stability, does not require light shielding during use, and is suitable for use on the head / face.

[0014] Technical solutions to technical issues

[0015] In order to solve the above technical problems, the present invention provides a solution-type ointment of hydroxydiphenylethane compounds, 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, and can be used on affected areas exposed to light such as the head and face.

[0016] The hydroxydiphenylethane compound solution type ointment provided by the present invention comprises:

[0017] 0.001 wt% to 3 wt% of an active ingredient hydroxydiphenylethane compound and the remainder an ointment base;

[0018] The ointment base comprises vaseline and / or liquid paraffin, medium chain triglycerides, and isopropyl palmitate and / or isopropyl myristate.

[0019] The inventors have found through research that in the solution-type ointment system of the present invention, the active ingredient hydroxydiphenylethane compounds exhibit pharmacological effects such as anti-inflammatory and soothing effects within a concentration range of 0.001 wt% to 3 wt%, and are feasible for drug development.

[0020] Wherein, the hydroxydiphenylethane compound is selected from 1,2-bis(3,5-dihydroxy-4-isopropylphenyl)ethane, 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, 1-(3,5-dihydroxy-4-ethylphenyl)-2-phenylethane, 1,2-bis(3,5-dihydroxy-4-ethylphenyl)ethane, 1-(3,5-dihydroxy-4-butylphenyl)-2-phenylethane, 1,2-bis(3,5-dihydroxy-4-butylphenyl)ethane, preferably 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol.

[0021] 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 (PG) being preferred.

[0022] 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 5-17% by weight; if the formulation size is 1-3% by weight, the total amount is preferably 13%-25% by weight.

[0023] In the hydroxydiphenylethane 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.

[0024] 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.

[0025] In the solution-type ointment of the present invention, the saturated solubility of the drug in the composition can be predicted by the following mathematical model:

[0026] Saturated solubility (%) = 0.445829*A + 0.032300*B - 0.000599*C + 0.008112*A*B - 0.003841*A*C; where A, B, and C represent the medium-chain triglyceride content (%), isopropyl myristate and / or isopropyl palmitate content (%), and hydrocarbon compound content (%), respectively, and A+B+C = 100. Therefore, when the amount of the active ingredient does not exceed 0.445829×A+0.032300×B-0.000599×C+0.008112×A×B-0.003841×A×C, a better solution-type ointment can be prepared. In practical applications, a drug content not exceeding 1.2 times the saturated solubility is also acceptable. From the perspective of minimizing the risk of drug precipitation, it is preferred that the drug content is no higher than 90% × - saturated solubility.

[0027] In the solution-type ointment of the present invention, the hydroxydiphenylethane compound content is 0.005% to 2% by weight, the antioxidant content is 0.01% to 1% by weight, more preferably the hydroxydiphenylethane 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%.

[0028] In the solution-type ointment of the present invention, the active ingredient exists in a non-crystalline form in the ointment.

[0029] The solution-type ointment of the present invention contains substantially no water or contains less than 2% by weight of water.

[0030] The hydroxydiphenylethane compound ointment of the present invention can be used on the skin of the whole body, especially on the head and / or face.

[0031] The present invention also provides a method for preparing a hydroxydiphenylethane compound ointment, which is characterized in that the active ingredient hydroxydiphenylethane 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.

[0032] Beneficial technical effects

[0033] The present invention discloses a solution-type ointment of a hydroxydiphenylethane compound. The composition creatively utilizes a compound system of medium-chain triglycerides and isopropyl palmitate and / or isopropyl myristate. Medium-chain triglycerides not only have a good solubilizing effect on 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, which has extremely poor solubility, but also stabilize the entire ointment system, thereby preparing a homogeneous, stable solution-type ointment. Isopropyl myristate not only interacts with stratum corneum lipids to promote transdermal absorption of the drug, but also forms a reservoir in the skin, continuously and slowly releasing the drug.

[0034] 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 can be compounded with hydroxydiphenylethane compounds to form a homogeneous ointment in a hydrocarbon ointment base, in which the active pharmaceutical ingredient (hereinafter sometimes referred to as API) exists in a non-crystalline dissolved state. Through research, it was discovered that the ratio of hydroxydiphenylethane compounds in this compounded system exists in a dissolved form, that is, the mathematical relationship between the amount of hydroxydiphenylethane compounds used and the amount of medium-chain triglycerides, isopropyl palmitate / isopropyl myristate, and hydrocarbon compounds used. Only when this mathematical relationship is met can a solution-type ointment be formed.

[0035] According to the preferred dosage and ratio of the present invention, the drug in the composition can be dissolved in the ointment base in molecular form. Even after being stored at 5°C for three months, even high concentrations of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol do 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.

[0036] In addition, the present invention also solves the problem of light instability of hydroxydiphenylethane compounds. The antioxidant selected in the composition effectively protects the active substance, allowing this type of compound to be used on parts of the body directly exposed to light, such as the head and / or face, and there is no need to deliberately avoid light during use, thereby expanding the scope of use of this type of compound and improving patient compliance. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] FIG1 is a contour plot showing a visual expression of the solubility prediction equation for 2-isopropyl-5-(2′-phenylethyl)-1,3-benzenediol.

[0038] FIG2 is a three-dimensional graph showing a visual expression of the solubility prediction equation for 2-isopropyl-5-(2′-phenylethyl)-1,3-benzenediol.

[0039] FIG3 shows the results of the light stability test of the cream formulation of Control Example 1.

[0040] FIG4 shows the results of a light stability test of the ointment of Example 10 of the present invention.

[0041] FIG5 shows a polarizing microscope photograph (a) of the solution-type ointment of Example 15 of the present invention and a polarizing microscope photograph (b) of the non-solution-type ointment of Comparative Example 4.

[0042] FIG6 shows the in vivo exposure of the ointments of Example 16 (solid line) and Example 17 (dashed line) of the present invention after topical administration. DETAILED DESCRIPTION

[0043] In the present invention, the compound 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, sometimes also referred to as 1-(3,5-dihydroxy-4-isopropylphenyl)-2-phenylethane, has the following structural formula.

[0044]

[0045] Example

[0046] 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 the feasibility of the invention. The examples do not limit the invention, and the scope of protection of the present invention is not limited to the following examples.

[0047] 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.

[0048] In the present invention, white petrolatum, liquid paraffin, medium-chain triglycerides, isopropyl palmitate, isopropyl myristate, propylene glycol, cetyl alcohol, glyceryl mono- and distearate, Tween 80, purified water, butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E (VE), propyl gallate (PG), and 2-ethylhexyl salicylate (OSAL) are commercially available products.

[0049] Preparation of hydroxydiphenylethane compound ointment

[0050] The preparation method is as follows: Heat and melt a hydrocarbon compound (e.g., vaseline or a mixture of vaseline and liquid paraffin), stir well, and keep warm for later use. In a separate suitable container, weigh the required amounts of medium-chain triglycerides, isopropyl palmitate, and / or isopropyl myristate, stir and heat to the desired temperature, then add the active ingredient, a hydroxydiphenylethane compound (if an antioxidant is used in the ointment, add the antioxidant at the same time), stir to dissolve, then pour in the melted vaseline and liquid paraffin, stir well, and cool to room temperature.

[0051] Example 1 Screening of solubilizers and penetration enhancers

[0052] The saturated solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol in different excipients was determined, and it was found that Span 80 (solubility 3%), 10% glycerol (solubility = 0.00007%), water (solubility = 0.0008%), 20% ethanol (solubility = 0.02%), and light liquid paraffin (solubility = 0.01%) could not dissolve an effective dose of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, and therefore a solution-type ointment could not be prepared. The excipients that were unexpectedly found to provide good solubility were medium chain triglycerides (solubility = 27%), isopropyl palmitate (solubility = 23%), isopropyl myristate (solubility = 27%), polyethylene glycol 400 (solubility = 30%), diethylene glycol monoethyl ether (solubility = 52%), propylene glycol (solubility = 30%), propylene glycol monolaurate (solubility = 30%), and polysorbate 80 (solubility = 17%).

[0053] The above-mentioned excipients that can provide good solubility were further used in combination with hydrocarbon compounds (light liquid paraffin) and 1% of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol to investigate the physical stability of the resulting ointment. Liquid paraffin has similar properties to vaseline, so liquid paraffin was used instead of solid vaseline to carry out the prescription screening experiment. All components were stirred evenly at room temperature, and the test sample was obtained after high-speed homogenization. After standing overnight, the sample was observed to see if it was stratified. The results showed that common API solvents, propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether, polysorbate 80, propylene glycol monolaurate, etc., did not have good compatibility with the API in the hydrocarbon compound matrix, and stratification would occur, and a solution-type ointment could not be formed. The specific prescription and results are shown in Table 1:

[0054] Table 1 Screening of solubilizers and penetration enhancers

[0055]

[0056] An unexpected discovery was that an ointment system composed of isopropyl palmitate and medium-chain triglycerides (Formulation 9 in Table 1) was stable and did not delaminate. Even when the drug dosage was increased to 5% (correspondingly, the amount of liquid paraffin in Formulation 9 in Table 1 was reduced by 4%), the resulting ointment system remained stable over the long term. Polarizing microscopic observation of the ointment revealed no drug crystals, indicating that the drug was present in the ointment in a non-crystalline molecular state.

[0057] Example 2 Solubility Prediction Model and Optimization of Dosages of Isopropyl Myristate and Medium Chain Triglycerides

[0058] By designing different formulations and conducting a series of experimental studies, we developed a mathematical model that can predict the saturated solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol in multi-component ointments. The method is as follows:

[0059] Experimental variables A, B, and C were set to represent the medium-chain triglyceride content (%), isopropyl myristate content (%), and light liquid paraffin content (%), respectively. (For ease of experimental design and operation, light liquid paraffin was used to represent all hydrocarbon compounds.) Based on the maximum safe use amount of excipients (FDA IID database), the variable ranges were set as follows: 0 < A ≤ 20, 0 < B ≤ 20. Based on preliminary experimental results (medium-chain triglycerides are more important for API dissolution and system stability) and the requirements for ointment viscosity and skin feel, the constraints were set as follows: A > B; A + B ≤ 25%; A + B + C = 100%.

[0060] Based on the variable range and constraints, a total of 20 experimental recipes were designed. After the components were mixed uniformly in the appropriate proportions, an excess of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol was added. The mixture was stirred overnight at room temperature. The supernatant was centrifuged, filtered, and diluted. The saturated solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol was then tested. The component ratios and experimental results for each experimental recipe are shown in Table 2.

[0061] Table 2 DOE test of solubility of API in preparation

[0062]

[0063] The saturated solubility (%) of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol was used as the dependent variable and A, B, and C as the independent variables. A three-variable quadratic equation was fitted to the data in Table 2 (the quadratic term was removed), and the fitting equation of saturated solubility was obtained, that is, saturated solubility (%) = 0.445829×A + 0.032300×B - 0.000599×C + 0.008112×A×B - 0.003841×A×C [where A, B, and C represent the content of medium-chain triglycerides (%), the content of isopropyl myristate / isopropyl palmitate (%), and the content of white petrolatum / liquid paraffin (%), respectively]. The p-value of the fitting equation was less than 0.0001 (the closer the p-value is to 0, the more the equation can represent the law of the data), and the regression coefficient (R 2 ) value is 0.9932(R 2 The closer the value is to 1, the better the equation represents the data pattern) and 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 2 and 2.

[0064] The accuracy of the prediction equation was verified by examining the saturated solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol in various ratios of medium-chain triglycerides, isopropyl myristate, and light liquid paraffin. The results, shown in Table 3, demonstrate that the equation accurately predicts the solubility of the API in various ratios of excipients. In practical applications, the drug content is within an acceptable range of no more than 1.2 times the saturated solubility, that is, 120%×(0.445829×A+0.032300×B-0.000599×C+0.008112×A×B-0.003841×A×C). Preferably, when the content of the active ingredient in the preparation is not higher than 0.445829×A+0.032300×B-0.000599×C+0.008112×A×B-0.003841×A×C, a better solution-type ointment can be prepared. It is further preferred that the content of the active ingredient in the preparation is not higher than 90% of the saturated solubility, that is, the content of the active ingredient in the preparation is not higher than 90%×(0.445829×A+0.032300×B-0.000599×C+0.008112×A×B-0.003841×A×C).

[0065] Table 3. Validation of the solubility prediction equation for 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol

[0066]

[0067] Preliminary experimental results indicate that to produce an ointment with satisfactory viscosity and skin feel, the combined amount of medium-chain triglycerides and isopropyl myristate should account for less than 30% of the ointment formulation, and optimally, less than 25%. Furthermore, the drug's saturated solubility increases with the combined amount of medium-chain triglycerides and isopropyl myristate, and medium-chain triglycerides are more effective at solubilizing the drug than isopropyl myristate. Preliminary experiments revealed that the ratio of medium-chain triglycerides to isopropyl myristate should be no less than 1:4, otherwise the solubility decreases significantly; optimally, the amount of medium-chain triglycerides should be no less than that of isopropyl myristate (no less than 1:1). Therefore, model constraints were set based on the preliminary experimental results. As shown in Table 3, the saturated solubility predicted by the above equation can easily determine the required medium-chain triglyceride and isopropyl myristate concentrations for formulations of different strengths. For example, to prepare a 0.5% concentration of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol solution ointment, when A (medium chain triglyceride content) is 3% and B (isopropyl myristate content) is at least ≥4.93%, solve the equation 0.5 = 0.445829 × 3 + 0.032300 × B - 0.000599 × (100-3-B) + 0.008112 × 3 × B - 0.003841 × 3 × (100-3-B), B = 4.93%.

[0068] Example 3-7 In vitro drug release of different formulations

[0069] The configuration specification is 1%, containing different proportions of medium chain triglycerides, isopropyl myristate and liquid paraffin 2-isopropyl-5-(2'-phenylethyl)-1,3-diol ointment. Artificial simulated skin (supplier: Millipore) was used with 0.5% sodium lauryl 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 4.

[0070] Table 4 Release rate and cumulative drug release of ointments with different prescriptions

[0071]

[0072] The results of the investigation found that an increase in the amount of medium-chain triglycerides would slow down the release rate of the drug. However, medium-chain triglycerides play an important role in maintaining the physical stability of the ointment matrix, and the minimum amount required is to maintain the ointment matrix from precipitation and stratification. Preliminary experimental results show that when the ratio of medium-chain triglycerides to isopropyl myristate is not less than 1:4, the solubility of the drug in the ointment matrix is ​​better, and no precipitation occurs in the ointment matrix. The higher the ratio of medium-chain triglycerides to isopropyl myristate, the better the solubilization effect of the prescription, but the drug release rate will also decrease. As can be seen from Table 4, the total amount of medium-chain triglycerides and isopropyl myristate in Examples 3-6 is similar. When the ratio of the two increases from 1.2:1 to 5:1, the drug release rate increases from 125.95 μg / cm 2 *h 1 / 2 Reduced to 90.55 μg / cm 2 *h 1 / 2 The cumulative drug release decreased from 488.9 μg to 340.04 μg. In particular, when the ratio of medium-chain triglycerides to isopropyl myristate exceeded 3:1, the drug release rate and cumulative drug release began to decline significantly. Therefore, the preferred ratio of medium-chain triglycerides to isopropyl myristate is between 1:4 and 3:1.

[0073] Comparing Example 3 with Example 7, the ratio of medium chain triglycerides to isopropyl myristate was the same, but the total amount of the latter, 27.53%, was higher than that of the former, 21.22%. When the total amount increased from 21.22% to 27.53%, the drug release rate increased from 125.95 μg / cm 2 *h 1 / 2 Reduced to 93.9 μg / cm 2 *h 1 / 2 , the cumulative drug release decreased from 488.90 μg to 360.95 μg. Therefore, when the formulation can completely dissolve the API and does not cause phase separation in 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.

[0074] When preparing a 1% ointment, if the MCT:IPM ratio is 1:1, the amount of MCT and IPM is at least 5.35%; if the MCT:IPM ratio is 1:4, the amount of MCT is at least 2.6%, and the corresponding amount of IPM is at least 10.4%; if the MCT:IPM ratio is 3:1, the amount of MCT is at least 7.35%, and the corresponding amount of IPM is at least 2.45%.

[0075] More preferably, when preparing a 1% ointment, if the MCT:IPM ratio is 1:1, the amount of MCT and IPM is at least 6.41%; if the MCT:IPM ratio is 1:4, the amount of MCT is at least 3.4%, and the corresponding amount of IPM is at least 13.6%; if the MCT:IPM ratio is 3:1, the amount of MCT is at least 8.85%, and the corresponding amount of IPM is at least 2.95%.

[0076] Therefore, when preparing a 1% cream, the total amount of medium chain triglycerides and isopropyl myristate is at least 13%, preferably 17%, and a stable solution-type ointment can be prepared with an MCT:IPM ratio in the range of 1:4-3:1.

[0077] When preparing a 3% cream, if the MCT:IPM ratio is 1:1, the amount of MCT and IPM is at least 10.55%; if the MCT:IPM ratio is 1:4, the amount of MCT is at least 5.67%, and the corresponding amount of IPM is at least 22.68%; if the MCT:IPM ratio is 1:2, the amount of MCT is at least 7.93%, and the corresponding amount of IPM is at least 15.86%; if the MCT:IPM ratio is 3:1, the amount of MCT is at least 14.67%, and the corresponding amount of IPM is at least 4.89%.

[0078] More preferably, when preparing a 3% cream, if the MCT:IPM ratio is 1:1, the amount of MCT and IPM is at least 11.23%; if the MCT:IPM ratio is 1:4, the amount of MCT is at least 6.05%, and the corresponding amount of IPM is at least 24.2%; if the MCT:IPM ratio is 1:2, the amount of MCT is at least 8.32%, and the corresponding amount of IPM is at least 16.64%; if the MCT:IPM ratio is 3:1, the amount of MCT is at least 15.63%, and the corresponding amount of IPM is at least 5.21%.

[0079] Therefore, when preparing a 3% cream, if the total amount of medium-chain triglycerides and isopropyl myristate is 30%, a stable solution-type ointment can be prepared with an MCT:IPM ratio in the range of 1:4-3:1. More preferably, if the total amount of medium-chain triglycerides and isopropyl myristate is 25%, a stable solution-type ointment can be prepared with an MCT:IPM ratio in the range of 1:2-3:1.

[0080] Examples 8-13 Ointments containing different antioxidants

[0081] 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointments containing different antioxidants were prepared according to the prescriptions shown in Table 5.

[0082] Table 5. Ointments containing different antioxidants

[0083]

[0084]

[0085] Comparative Example 1

[0086] A 3,5-dihydroxy-4-isopropyldiphenylethane control cream without antioxidant was prepared according to the following table:

[0087] Table 6. 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol control cream (Control Example 1)

[0088]

[0089] Comparative Example 2

[0090] A control ointment of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol containing the commonly used photoprotective agent isooctyl salicylate was prepared according to the table below.

[0091] Table 7. Ointments containing 2-ethylhexyl salicylate

[0092]

[0093] Investigating the effect of antioxidants on light stability

[0094] Color changes of Examples 8-13 and control preparations under illumination

[0095] 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol is light-sensitive and easily degrades upon exposure to light, generating colored substances that can cause skin discoloration. Exposure to light can also reduce the active ingredient content in the formulation, affecting efficacy. Parallel light exposure experiments were conducted on the ointments of Examples 8-13 of the present invention, along with an antioxidant-free cream (Control Example 1) and an ointment containing the commonly used light protectant isooctyl salicylate (Control Example 2).

[0096] Take equal amounts of the above samples and spread them 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 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).

[0097] Figures 33(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 4(a) and (b) are photographs of the appearance changes of Example 10 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 cream sample of Control Example 1 changed from milky white to dark yellow. The color of the ointment containing the light protection agent isooctyl salicylate (Control Example 2) also changed from slightly yellow to light brown, with a significant change (omitted in the figure). The degree of color change of Examples 8-13 containing antioxidants was significantly lower than that of Control Examples 1 and 2, with no obvious color change (omitted in the figure). The ointment preparation of Example 10 performed best, with almost no color change, as shown in Figure 4.

[0098] It can be seen from this that the light stability of the ointment of the present invention is significantly better than that of a cream without an antioxidant and an ointment containing the common antioxidant isooctyl salicylate, which greatly improves the light resistance of the preparation and greatly reduces the problem of darkening of the preparation on the skin surface and the problem of reduced content caused by light, thus solving a major clinical limitation problem that similar preparations are prohibited from being used on the head and face in the instructions.

[0099] Effects of different types and contents of antioxidants on active substances and related substances

[0100] Take equal amounts of samples of Examples 8-12 containing different types and amounts of antioxidants, Example 13 without antioxidants, and Control Example 2 containing the light protection agent isooctyl salicylate, and spread them flat in glass transparent containers of the same size. Place them in a light box with a light intensity of LUX 5000 + 84 μw / cm 2 / h, and the content of active substance and related substances in the preparation were measured on day 0, day 4 and day 12. The results are shown in Table 8 and Table 9, respectively.

[0101] Table 8 Changes in the content of active substances

[0102] Type of antioxidant Content at 0 day (%) Content at 4 day (%) Content at 12 day (%) Example 8 0.5% BHT 100.0 97.5 69.2 Example 9 0.5% VE 98.8 97.5 17.0 Example 100.1% PG 99.4 98.6 98.3 Example 11 0.5% BHT + 0.05% PG 98.8 97.2 80.6 Example 12 0.2% BHT + 0.1% PG 101.4 105.8 100.2 Example 13 Ointment without antioxidant 96.7 78.1 4 1.9 Control 25% OSAL 95.5 82.9 11.7

[0103] Table 9 Related substances produced by different antioxidants

[0104]

[0105] *Only report related substances ≥0.05%, “-”: related substance content less than 0.05%, “ND”: not detected

[0106] As shown in Tables 8 and 9, Example 13, which lacks an antioxidant, exhibits a significant decrease in active substance content upon exposure to light. Example 10, which contains propyl gallate, maintains its active substance content unchanged after 12 days of light exposure. The active substance content in the other antioxidant formulations all decreases to some extent. The formulation containing butylated hydroxytoluene and vitamin E, while showing minimal degradation after 4 days of light exposure, exhibits significant degradation after 12 days. Example 13, which lacks an antioxidant, exhibits a complex impurity profile upon light degradation, with secondary or even multiple degradation of the active substance. In addition to the primary degradation impurity with a relative retention time of 0.89, numerous low-level chromatographic peaks and impurities lacking UV absorption are present. The addition of propyl gallate alters the degradation pathway of the active substance, significantly reducing secondary degradation. Example 11, containing 0.5% butylated hydroxytoluene and 0.05% propyl gallate, exhibits superior light stability to Example 8, which contains only 0.5% butylated hydroxytoluene, but exhibits weaker light protection than Example 10, which contains 0.1% propyl gallate.

[0107] Examples 14-15 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointment of different specifications

[0108] Isopropyl myristate was replaced with isopropyl palmitate, and 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointments of different strengths were prepared according to the prescription in Table 10.

[0109] Table 10 Different specifications of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointment

[0110]

[0111] Light stability of ointments of different specifications

[0112] The ointments of Examples 14 and 15 were subjected to a light stability test according to the aforementioned method. The results showed that after 12 days of light exposure, the color of the ointments of Examples 14 and 15 remained almost unchanged, and the content of the active ingredient remained unchanged. The antioxidant selected by the present invention can effectively protect 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol of different specifications.

[0113] Physical stability of ointments of different specifications

[0114] The ointments of Example 15 and Control Example 4 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 5. In Example 15 (Figure 5a), according to the present invention, the dosage ratio of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, isopropyl palmitate, and medium-chain triglycerides was used. No API crystallization was observed in the formulation under a polarizing microscope. After 3 months of storage at 5°C, 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol remained completely dissolved in the ointment base in molecular form, without precipitation of crystals (the bright spots in Figure 5a are the crystalline phase of white petrolatum, not drug crystals). In contrast, the amount of isopropyl palmitate and medium-chain triglycerides in Control Example 4 ( FIG. 5 b ) does not meet the ratio of the present invention (when preparing a 3% cream, the total amount of isopropyl palmitate (isopropyl myristate) and medium-chain triglycerides is 13-25%). Under a polarizing microscope, a large number of short rod-shaped drug crystals can be seen in the resulting preparation, indicating that 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol has crystallized and precipitated, and a solution-type ointment cannot 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. The present invention provides a new method for optimizing the prescription ratio of preparations of different specifications, which greatly saves the time for prescription development and stability studies.

[0115] Examples 16-17

[0116] 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointment was prepared according to the formulation shown in Table 11. The in vivo exposure of the different strengths of the formulation was investigated using the SD rat model. The day before application, hair was removed from both sides of the animal's spine using electric clippers. Cellophane was placed in the groove of a blank plaster patch and placed over the depilated area on the animal's back. The patch was secured with medical tape. The skin application area was 4 × 4 cm. 2 (The corresponding amount is: 1.6g / kg).

[0117] Table 11

[0118]

[0119] As shown in Figure 6, when Examples 16 and 17 were applied to rat skin, active drug was detectable in the blood 2 hours after administration. The 24-hour AUCs for the 0.3% and 1% formulations were 48 ng / ml*h and 182 ng / ml*h, respectively. This demonstrates that the formulations have good transdermal properties, with the drug being continuously and slowly released from the ointment base and penetrating the skin, maintaining the required therapeutic blood concentration after 24 hours.

[0120] 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 hydroxydiphenylethane compound, comprising: 0.001% to 3% by weight of an active ingredient hydroxydiphenylethane 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 5-17% by weight; when the ointment preparation specification is 1-3% by weight, the total amount is 13%-25% by weight.

3. The solution-type ointment according to claim 1, wherein the hydroxydiphenylethane compound is selected from 1,2-bis(3,5-dihydroxy-4-isopropylphenyl)ethane, 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, 1-(3,5-dihydroxy-4-ethylphenyl)-2-phenylethane, 1,2-bis(3,5-dihydroxy-4-ethylphenyl)ethane, 1-(3,5-dihydroxy-4-butylphenyl)-2-phenylethane, and 1,2-bis(3,5-dihydroxy-4-butylphenyl)ethane, preferably 2-isopropyl-5-(2'-phenylethyl)-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 weight percentage of the active ingredient does not exceed 1.2×(0.445829×A+0.032300×B-0.000599×C+0.008112×A×B-0.003841×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×(0.445829×A+0.032300×B−0.000599×C+0.008112×A×B−0.003841×A×C)%.

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

9. The solution-type ointment according to claim 1, wherein the content of the hydroxydiphenylethane 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.

10. The solution-type ointment according to claim 1, wherein the ointment does not contain water or contains less than 2% by weight of water.

11. The solution-type ointment according to any one of claims 1 to 10, for use on skin all over the body, especially on the head and / or face.

12. The method for preparing the hydroxydiphenylethane compound ointment according to any one of claims 1 to 10, characterized in that: The active ingredient hydroxydiphenylethane 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.

Images