Hydroxydiphenylethane compound ointment, its use and preparation method

Abstract

The present invention provides a solution-type ointment of a hydroxydiphenylethane compound, its uses, and its preparation method. The ointment contains 0.001% to 3% by weight of the active ingredient hydroxydiphenylethane compound, 0.01% to 1% by weight of an antioxidant, and the remaining ointment matrix. The ointment matrix contains petrolatum and / or liquid paraffin, a medium-chain triglyceride, and isopropyl palmitate and / or isopropyl myristate. The hydroxydiphenylethane ointment of the present invention has excellent drug solubility and transdermal absorbability, good photostability, and does not require light protection during use, so it can be used on areas exposed to light, such as the head and face.

Description

[Technical Field]

[0001] The present invention relates to a topical composition of a hydroxydiphenylethane compound, particularly a solution-type ointment formulation suitable for a poorly soluble and photolabile hydroxydiphenylethane compound, as well as its uses and preparation method.

[0002] Ointments are homogeneous, semi-solid topical preparations made by mixing active pharmaceutical ingredients with an oily or water-soluble matrix. They are one of the most widely used topical preparations. Ointments form a closed barrier on the skin surface, providing excellent moisturizing effects. They are particularly suitable for skin diseases such as atopic dermatitis, where the skin barrier is damaged. Depending on the dispersion state of the active pharmaceutical ingredients in the matrix, ointments can be divided into solution-type ointments and suspension-type ointments.

[0003] The most widely used ointment matrix is ​​petrolatum. Due to the limited solubility of drugs in petrolatum, most commercially available ointments are suspension ointments. However, in suspension ointments, the active ingredient (API) is uniformly dispersed in the matrix in the form of a fine powder. Only a small amount of the API dissolved in the matrix can penetrate the skin, while the majority of the suspended API particles cannot diffuse into the skin. Therefore, it is impossible to achieve higher intradermal drug concentrations, the API exerts its effect more slowly, and more of the API that does not penetrate the skin is wasted. Different batches of active ingredient powders can have slight differences in particle size distribution, moisture content, and particle morphology, which can lead to batch variations in ointments and affect clinical efficacy and safety. Furthermore, polycrystalline drugs can undergo crystal transformation during manufacturing and storage, which not only poses significant challenges to the manufacturing process but also potentially affects product quality.

[0004] In solution-type ointments, the active ingredient is dissolved or co-dissolved in the matrix or matrix components, eliminating the need for a dissolution process to convert the active ingredient from powder to molecular form for percutaneous absorption. Molecular active ingredients can diffuse better from the matrix and penetrate the skin. The batch-to-batch variation of solution-type ointments is relatively small, making them suitable for quality control and clinical use of ointments.

[0005] Although solution-based ointments have many technical advantages, many commonly used solubilizers and penetration enhancers, such as propylene glycol, polyethylene glycol, diethylene glycol monomethyl ether, and ethanol, are mutually insoluble in the ointment matrix. Furthermore, the amount of solubilizer is crucial for the preparation of solution-based ointments. Insufficient solubilizer content can lead to the drug approaching its saturated solubility, potentially resulting in drug crystallization during changes in external conditions or prolonged storage. Excessive solubilizer content can lead to excessive drug solubility in the formulation, resulting in the drug remaining in the formulation and inhibiting its penetration into the skin. Therefore, selecting the appropriate auxiliary ingredients for preparing a homogeneous solution-based ointment poses significant technical challenges.

[0006] The two benzene rings of diphenylethane compounds undergo various substitution reactions, and different substituents can result in various pharmacological activities, such as antitumor, anticoagulant, and anti-inflammatory. There has been little research on diphenylethane compounds in the fields of skin diseases and cosmetics. Patent document KR20150004221A discloses an androgen receptor antagonist having a diphenylethane structure, which may be used for related diseases such as hair loss and acne, but this patent document does not concern its topical formulation. Patent document CN108366938B discloses a diaromatic vitamin D receptor agonist having a diphenylethane structure and provides a cosmetic composition that can be used for anti-wrinkle purposes. This composition differs significantly from the ointment formulation of the present invention in that the active ingredient does not have a phenolic hydroxyl group substitution, eliminating the need to address the issue of compound instability. Patent document CN103483158B discloses a group of diphenylethane compounds that can be used to treat immune diseases or inflammation, and also provides a topical cream composition that shows good effects in suppressing edema and reducing inflammation in a TPA-induced mouse skin edema model. However, such compounds have extremely poor solubility, and the compositions disclosed in this patent document 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, resulting in changes in the color and performance of products made from these compounds. This photoinstability limits their application in skin diseases and cosmetics. Photoprotectors are typically added to formulations to improve the photostability of active pharmaceutical molecules. Photoprotectors can be divided into UV blockers and UV absorbers based on their mechanism of action. The former, such as titanium dioxide and zinc oxide, provide strong protection but typically require large dosages and are solid powders that affect the skin feel of the formulation. The latter, such as octyl salicylate, have some degree of transdermal absorption and often cause allergies and acne. While these photoprotectors are widely used in sunscreen cosmetics, there are few suitable photoprotectors for pharmaceutical formulations, and their use is limited. Summary of the Invention [Problem to be solved by the invention]

[0008] Most commercially available ointments for poorly soluble drugs are suspension-type ointments, and there are many technical challenges in developing a homogeneous and stable solution-type ointment. How to select appropriate auxiliary ingredients and optimize their dosage so that the drug dissolves without crystallization, penetrates the skin well in molecular form, and does not affect the transdermal absorption of the drug due to reduced thermodynamic activity requires continuous trial and error and accumulated experience.

[0009] Many drugs have multiple clinical specifications for different populations and different pathologies. To achieve the best clinical efficacy, the formulation and manufacturing process must be tailored to meet these different specifications. For solution-type ointments, the dosage of solubilizers and penetration enhancers must be optimized to achieve optimal transdermal drug absorption. This often requires significant resources and time. Direct testing of the solubility of the active pharmaceutical ingredient in the formulation is difficult, and there is a lack of systematic and scientific methods to guide formulation optimization.

[0010] In view of the above technical problems, the objective of the present invention is to provide a solution-type ointment suitable for hydroxydiphenylethane compounds, screen suitable solubilizers and penetration enhancers, and establish a mathematical model for predicting the solubility of drug substances in multi-component systems. By selecting the optimal formulation ratio according to the dose of the active ingredient, it is possible to prepare a uniform and stable topical formulation with good drug release and transdermal performance.

[0011] In addition, hydroxydiphenylethane compounds are unstable to light and heat and are easily oxidatively decomposed by light irradiation. Furthermore, colored quinone decomposition products may cause skin pigmentation. Therefore, light must be shielded during use, and the composition cannot be used on areas exposed to light, such as the head or face. However, because the head and face are prone to skin diseases, the clinical application range of hydroxydiphenylethane as an active ingredient is limited, affecting patient compliance. Another object of the present invention is to provide a topical hydroxydiphenylethane compound composition that is photostable, does not require light shielding during use, and can be applied to the head or face. [Means for solving the problem]

[0012] In order to solve the above technical problems, the present invention provides a hydroxydiphenylethane compound solution-type ointment that can sufficiently dissolve the active ingredient in the ointment matrix by providing an optimal combination and ratio of auxiliary ingredients according to the concentration of the active ingredient, thereby imparting good active ingredient release properties and transdermal absorbability, and that can be used on affected areas exposed to light, such as the head and face.

[0013] The hydroxydiphenylethane compound solution-type ointment provided by the present invention contains 0.001% by weight to 3% by weight of a hydroxydiphenylethane compound as an active ingredient, and the remainder is an ointment matrix, which contains petrolatum and / or liquid paraffin, a medium-chain triglyceride, and isopropyl palmitate and / or isopropyl myristate.

[0014] Through research, the present inventors have found that in the solution-type ointment system of the present invention, the active ingredient hydroxydiphenylethane compound exhibits pharmacological effects such as anti-inflammatory and sedative effects at a concentration range of 0.001% by weight to 3% by weight, and can be used as a drug.

[0015] Here, 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, and preferably 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol.

[0016] The solution-type ointment of the present invention further contains an antioxidant, which is one or more oil-soluble antioxidants selected from propyl gallate, butylated hydroxyanisole, and dibutylhydroxytoluene, preferably propyl gallate (PG).

[0017] In the solution-type ointment of the present invention, the total amount of medium-chain triglyceride, isopropyl palmitate, and isopropyl myristate is 2 to 30% by weight, preferably 5 to 25% by weight. When the formulation specification is 1% by weight or less, the total amount is preferably 5 to 17% by weight, and when the formulation quantity is 1 to 3% by weight, the total amount is preferably 13 to 25% by weight.

[0018] In the hydroxydiphenylethane compound ointment of the present invention, the blending amount of isopropyl palmitate and / or isopropyl myristate is 0.5 to 15% by weight, preferably 2 to 15% by weight, more preferably 4 to 12% by weight.

[0019] In the solution-type ointment of the present invention, the ratio of medium-chain triglyceride to isopropyl palmitate and / or isopropyl myristate is 1:4 to 3:1, preferably 1:2 to 2:1, and more preferably 1:1 to 2:1.

[0020] 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: 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 (%), the isopropyl myristate and / or isopropyl palmitate content (%), and the hydrocarbon compound content (%), respectively, and A + B + C = 100. Therefore, a better solution-type ointment can be prepared if the active ingredient content does not exceed 0.445829 × A + 0.032300 × B - 0.000599 × C + 0.008112 × A × B - 0.003841 × A × C. In practice, it is acceptable for the active ingredient content to not exceed 1.2 times the saturated solubility. From the viewpoint of minimizing the risk of precipitation as much as possible, the content of the active ingredient is preferably 90% x saturated solubility or less.

[0021] In the solution-type ointment of the present invention, the content of the hydroxydiphenylethane compound is 0.005% by weight to 2% by weight, the content of the antioxidant is 0.01% by weight to 1% by weight, and more preferably the content of the hydroxydiphenylethane compound is 0.005% by weight to 1% by weight, the content of the antioxidant is 0.02% by weight to 0.5% by weight, and the content of the ointment matrix is ​​97.5% by weight to 99.97% by weight.

[0022] In the solution-type ointment of the present invention, the active ingredient is present in the ointment in amorphous form. The solution-type ointment of the present invention is substantially free of water or contains less than 2% by weight of water.

[0023] The hydroxydiphenylethane compound ointment of the present invention can be applied to the skin of the whole body, particularly to the head and / or face.

[0024] The present invention also provides a method for preparing a hydroxydiphenylethane compound ointment, in which the hydroxydiphenylethane compound as an active ingredient (together with an antioxidant, if any) is added to a medium-chain triglyceride, isopropyl myristate and / or isopropyl palmitate, and the mixture is heated and stirred to dissolve, and then added to molten petrolatum and / or liquid paraffin, stirred uniformly, and cooled to room temperature to obtain an ointment.

[0025] Technical effects This invention discloses a solution-type ointment containing a hydroxydiphenylethane compound. It creatively utilizes a composition of medium-chain triglycerides with isopropyl palmitate and / or isopropyl myristate. The medium-chain triglycerides not only have a good solubilizing effect on the poorly soluble 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, but also stabilize the entire ointment system, allowing for the preparation of a uniform and stable solution-type ointment. Isopropyl myristate not only interacts with stratum corneum lipids to promote percutaneous absorption of the active pharmaceutical ingredient, but also forms a reservoir in the skin, allowing for sustained and slow release of the active pharmaceutical ingredient.

[0026] In the prior art, medium-chain triglycerides and isopropyl palmitate / isopropyl myristate are used only as the oil phase of emulsions or as general transdermal penetration enhancers. Unlike the prior art, the present inventors have discovered that by blending these two auxiliary ingredients with a hydroxydiphenylethane compound, a homogeneous ointment can be formed in a hydrocarbon ointment matrix, and the active pharmaceutical ingredient (API) is present in the ointment in an amorphous dissolved form. Through their investigations, the present inventors have discovered a ratio law for the dissolved state of the hydroxydiphenylethane compound in a formulation system, i.e., a mathematical relationship between the amount of the hydroxydiphenylethane compound and the amounts of the medium-chain triglycerides, isopropyl palmitate / isopropyl myristate, and hydrocarbon compound. When this mathematical relationship is satisfied, a solution-type ointment is formed.

[0027] The preferred amounts and ratios of the active ingredients in the composition allow the active ingredient to dissolve in the ointment matrix in a molecular form, and even after storage at 5°C for 3 months, high concentrations of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol do not crystallize. Meanwhile, the composition maintains high thermodynamic properties and active ingredient release rate. Even at low active ingredient concentrations, good transdermal absorption is maintained, allowing the active ingredient to be effectively released from the ointment matrix, penetrate the stratum corneum barrier, and reach the required therapeutic concentration at the site of action.

[0028] Furthermore, the present invention also solves the problem of photoinstability of hydroxydiphenylethane compounds. Because the antioxidant used in the composition can effectively protect the active ingredient, this type of compound can be used on areas directly exposed to light, such as the head and / or face, without the need to intentionally avoid light during use, thus broadening the scope of use of this type of compound and improving patient compliance. [Brief explanation of the drawings]

[0029] [Figure 1]FIG. 1 is a contour plot showing the solubility prediction equation for 2-isopropyl-5-(2′-phenylethyl)-1,3-benzenediol in a visual representation format. [Figure 2] 1 is a three-dimensional graph showing the solubility prediction equation for 2-isopropyl-5-(2′-phenylethyl)-1,3-benzenediol in a visual representation format. [Figure 3] 1 shows the results of a photostability test of the ointment formulation of Comparative Example 1. [Figure 4] 1 shows the results of a photostability test of the ointment of Example 10 of the present invention. [Figure 5] 1 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. [Figure 6] 1 shows the internal exposure when the ointments of Example 16 (solid line) and Example 17 (dashed line) of the present invention are topically administered. DETAILED DESCRIPTION OF THE INVENTION

[0030] In the present invention, the compound 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol is also called 1-(3,5-dihydroxy-4-isopropylphenyl)-2-phenylethane and is a compound having the following structural formula:

[0031] [ka] Example The present invention will be described in detail with reference to the following examples. The examples provide detailed implementation methods and steps to fully disclose and demonstrate that the present invention can be carried out. The examples do not represent the limitations of the present invention, and the protection scope of the present invention is not limited to the following examples.

[0032] In the examples of this specification, experimental methods for which specific conditions are not specified are generally carried out according to conditions commonly used in the art or according to conditions recommended by the manufacturer. In the present invention, unless otherwise specified, "parts" means parts by weight, and "%" means % by weight. In the present invention, unless otherwise specified, "not less than," "not more than," and "within" mean that the numerical values ​​themselves are included.

[0033] In the present invention, commercially available products such as white petrolatum, liquid paraffin, medium-chain triglycerides, isopropyl palmitate, isopropyl myristate, propylene glycol, cetyl alcohol, mono- and diglycerides of stearic acid (also simply referred to as glyceryl stearate), TWEEN 80, purified water, dibutylhydroxytoluene (BHT), butylated hydroxyanisole (BHA), vitamin E (VE), propyl gallate (PG), and 2-ethylhexyl salicylate (also referred to as isooctyl salicylate) (OSAL) can be used.

[0034] Preparation of hydroxydiphenylethane compound ointment The preparation method is as follows: a hydrocarbon compound (e.g., petrolatum or a mixture of petrolatum and liquid paraffin) is heated to melt, stirred until homogenous, and kept warm for later use. The required amount of medium-chain triglyceride, isopropyl palmitate, and / or isopropyl myristate is weighed into a separate suitable container, stirred and heated to the required temperature, and then the active ingredient, a hydroxydiphenylethane compound (if an antioxidant is used in the ointment, the antioxidant is also added at the same time). After stirring to dissolve, the mixture is poured into the melted petrolatum and liquid paraffin, stirred, and cooled to room temperature to obtain the ointment.

[0035] Example 1 Screening of solubilizers and penetration enhancers The present inventors measured the saturated solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol in various different adjuvants and found that an effective amount of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol could not be dissolved in Span 80 (solubility 3%), 10% glycerol (solubility = 0.00007%), water (solubility = 0.0008%), 20% ethanol (solubility = 0.02%), or light liquid paraffin (solubility = 0.01%), and therefore a solution-type ointment could not be prepared. The inventors have unexpectedly found that 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%) are adjuvants that can provide good solubility.

[0036] The above-mentioned adjuvants, which provide good solubility, were further combined with a hydrocarbon compound (light liquid paraffin) and a 1% dose of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, and the physical stability of the resulting ointment was examined. Because liquid paraffin has properties similar to petrolatum, it was used instead of solid petrolatum in formulation screening experiments. All ingredients were uniformly stirred at room temperature and then homogenized at high speed to obtain test samples. After allowing to stand overnight, the samples were observed for stratification. Results showed that common API solvents, such as propylene glycol, polyethylene glycol 400, diethylene glycol monoethyl ether, polysorbate 80, and propylene glycol monolaurate, had poor compatibility with the API in the hydrocarbon compound matrix, resulting in stratification and preventing the formation of a solution-type ointment. The specific formulations and results are shown in Table 1:

[0037] [Table 1]

[0038] The ointment system composed of isopropyl palmitate and medium-chain triglycerides (Formulation 9 in Table 1) unexpectedly turned out to be stable and not to form layers. In this system, even when the content of the active ingredient was increased up to 5% (correspondingly, in Formulation 9 of Table 1, the content of liquid paraffin was decreased by 4%), the prepared ointment system was stable for a long time. When the fine structure of the ointment was observed with a polarizing microscope, no crystals of the active ingredient were observed, indicating that the active ingredient existed in the ointment in an amorphous molecular state.

[0039] Example 2 Solubility prediction model and optimization of the blending amounts of isopropyl myristate and medium-chain triglycerides By designing a plurality of different formulations and conducting a series of experimental studies, a mathematical model for predicting the saturation solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol in a multi-component ointment was summarized. The method is as follows.

[0040] The experimental variables A, B, and C were set as medium-chain triglycerides (%), isopropyl myristate (%), and light liquid paraffin (%) respectively (for the convenience of experimental design and operation, light liquid paraffin was used as a representative of all hydrocarbon compounds). According to the maximum safe dosages of auxiliary components (FDA IID database), the ranges of the variables were set as follows: 0 < A ≤ 20, 0 < B ≤​​​​

[0042] [Table 2]

[0043] The saturated solubility (%) of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol was used as the dependent variable, and A, B, and C were used as independent variables. The data in Table 2 were fitted with a three-element quadratic equation (removing the quadratic terms) to obtain the following fitted equation for saturated solubility: saturated solubility (%) = 0.445829 x A + 0.032300 x B - 0.000599 x C + 0.008112 x A x B - 0.003841 x A x C (where A, B, and C represent the medium-chain triglyceride content (%), isopropyl myristate / isopropyl palmitate content (%), and white petrolatum / liquid paraffin content (%), respectively). The p-value of the fitted equation was less than 0.0001 (the closer the p-value is to 0, the better the equation represents the data regularity), and the regression coefficient (R 2 ) value is 0.9932 (R 2 The closer the value is to 1, the better the formula can represent the data rules, and the better the fit. Figures 1 and 2 show the 3D spatial surface diagram of the prediction formula and its 2D spatial projection (contour plot).

[0044] The saturated solubility of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol in a solution of medium-chain triglycerides, isopropyl myristate, and light liquid paraffin at different ratios was investigated, and the accuracy of the prediction formula was verified. The results are shown in Table 3. This prediction formula can accurately predict the solubility of API in various ratios of auxiliary ingredients. In practice, the content of the API is allowed to be within 1.2 times the saturated solubility, i.e., within the range of 120% × (0.445829 × A + 0.032300 × B - 0.000599 × C + 0.008112 × A × B - 0.003841 × A × C). Preferably, a superior solution-type ointment can be prepared when the content of the active ingredient in the formulation is not more than 0.445829×A+0.032300×B−0.000599×C+0.008112×A×B−0.003841×A×C. Furthermore, it is preferred that the content of the active ingredient in the formulation is not more than 90% of its saturated solubility, i.e., the content of the active ingredient in the formulation is not more than 90%×(0.445829×A+0.032300×B−0.000599×C+0.008112×A×B−0.003841×A×C).

[0045] [Table 3]

[0046] Preliminary experiments showed that to prepare an ointment with satisfactory viscosity and skin feel, the combined amount of medium-chain triglycerides and isopropyl myristate should be 30% or less, preferably 25% or less, of the ointment formulation. Furthermore, the saturated solubility of the active ingredient increased with increasing combined amount of medium-chain triglycerides and isopropyl myristate, and the solubilizing effect of medium-chain triglycerides was superior to that of isopropyl myristate. Preliminary experiments also showed that the ratio of medium-chain triglycerides to isopropyl myristate must be 1:4 or greater; otherwise, solubility would be significantly reduced. Preferably, the amount of medium-chain triglycerides should not be less than that of isopropyl myristate (i.e., not less than 1:1). Therefore, model constraints were set according to the results of the preliminary experiments. As shown in Table 3, the concentrations of medium-chain triglycerides and isopropyl myristate required for different amounts of formulation can be easily determined according to the saturated solubility predicted by the above formula. For example, to prepare a 0.5% 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol solution ointment, if A (medium-chain triglyceride content) is 3%, B (isopropyl myristate content) must be at least 4.93%. Therefore, solving the equation 0.5 = 0.445829 x 3 + 0.032300 x B - 0.000599 x (100 - 3 - B) + 0.008112 x 3 x B - 0.003841 x 3 x (100 - 3 - B), we obtain B = 4.93%.

[0047] Examples 3-7 In vitro drug release of different formulations 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointments containing different proportions of medium-chain triglycerides, isopropyl myristate, and liquid paraffin were prepared in a 1% amount. Using StraM® artificial skin (supplied by Millipore) and 0.5% sodium dodecyl sulfate solution as the receptor medium, the in vitro release rate and cumulative release amount of different formulations within 9 hours were investigated. The formulations investigated and the results are shown in Table 4.

[0048] [Table 4]

[0049] The results of the study showed that increasing the dosage of medium-chain triglyceride slowed the release rate of the active ingredient. However, since medium-chain triglyceride plays an important role in maintaining the physical stability of the ointment matrix, its dosage must be at least sufficient to maintain the stability without precipitation or stratification from the ointment matrix. Preliminary experimental results showed that when the ratio of medium-chain triglyceride to isopropyl myristate is 1:4 or higher, the active ingredient dissolves better in the ointment matrix and does not precipitate from the ointment matrix. The higher the ratio of medium-chain triglyceride to isopropyl myristate, the better the solubilization effect of the formulation, but the slower the active ingredient release rate. As shown in Table 4, when the total dosage of medium-chain triglyceride and isopropyl myristate in Examples 3 to 6 was similar, increasing the ratio of the two components from 1.2:1 to 5:1 increased the active ingredient release rate to 125.95 μg / cm. 2 *h 1 / 2 to 90.55 μg / cm 2 *h 1 / 2 and the cumulative drug release amount decreases from 488.9 μg to 340.04 μg. In particular, when the ratio of medium-chain triglyceride to isopropyl myristate exceeds 3:1, the drug release rate and cumulative drug release amount begin to decrease significantly. Therefore, the preferred ratio of medium-chain triglyceride to isopropyl myristate is 1:4 to 3:1.

[0050] Comparing Example 3 and Example 7, the ratios of medium-chain triglyceride and isopropyl myristate were the same, but the total amount of the latter was 27.53%, which was higher than the former's 21.22%. When the total amount increased from 21.22% to 27.53%, the drug release rate was 125.95 μg / cm 2 *h 1 / 2 to 93.9 μg / cm 2 *h 1 / 2and the cumulative API release decreases from 488.90 μg to 360.95 μg. Therefore, the total amount of medium-chain triglyceride and isopropyl myristate should be kept as low as possible to achieve the highest possible API release rate and amount, as long as the ratio in the formulation allows complete dissolution of the API and does not cause separation from the ointment matrix.

[0051] When preparing a 1% ointment, if the MCT:IPM ratio is 1:1, the amounts of MCT and IPM are 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%, and 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%.

[0052] More preferably, when preparing a 1% ointment, when the MCT:IPM ratio is 1:1, the amount of MCT and IPM is at least 6.41%, when 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%, and when 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%.

[0053] Therefore, when preparing a 1% ointment, a stable solution-type ointment can be prepared when the total amount of medium-chain triglycerides and isopropyl myristate is at least 13%, preferably 17%, and the MCT:IPM ratio is in the range of 1:4 to 3:1.

[0054] When preparing a 3% ointment, when the ratio of MCT:IPM is 1:1, the amounts of MCT and IPM are at least 10.55%, when the ratio of MCT:IPM is 1:4, the amount of MCT is at least 5.67% and the corresponding amount of IPM is at least 22.68%, when the ratio of MCT:IPM is 1:2, the amount of MCT is at least 7.93% and the corresponding amount of IPM is at least 15.86%, and when the ratio of MCT:IPM is 3:1, the amount of MCT is at least 14.67% and the corresponding amount of IPM is at least 4.89%.

[0055] More preferably, when preparing a 3% ointment, when the MCT:IPM ratio is 1:1, the amount of MCT and IPM is at least 11.23%, when 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%, when 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%, and when 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%.

[0056] Therefore, when preparing a 3% ointment, 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 to 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 to 3:1.

[0057] Examples 8-13 Ointments containing different antioxidants 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointments containing different antioxidants were prepared according to the formulations shown in Table 5.

[0058] [Table 5]

[0059] Comparative Example 1 A comparative ointment containing no antioxidant, 3,5-dihydroxy-4-isopropyldiphenylethane, was prepared according to the following table.

[0060] [Table 6]

[0061] Comparative Example 2 A 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol comparative ointment containing the commonly used photoprotectant isooctyl salicylate was prepared according to the table below.

[0062] [Table 7]

[0063] Examination of the effect of antioxidants on photostability Color change of Examples 8 to 13 and comparative preparations under light irradiation 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol is sensitive to light and easily decomposes upon exposure to light to produce colored substances, which can easily cause skin pigmentation. Light exposure also reduces the content of active ingredients in the formulation, affecting the therapeutic effect. Parallel light exposure experiments were conducted on the ointments of Examples 8 to 13 of the present invention, an ointment containing no antioxidant (Comparative Example 1), and an ointment containing isooctyl salicylate, a commonly used photoprotectant (Comparative Example 2).

[0064] Equal amounts of the above sample were taken and spread evenly in a light-transmitting glass container of the same size, and the measured value was LUX5000+84μw / cm 2 The specimens were placed in a light box with a light intensity of 1 / h, and samples for observation were collected on days 0, 4 (simulating 4 hours of sunlight exposure outdoors on a sunny summer day), and 12 (ICH photostability test conditions).

[0065] Figures 3(a) and (b) are photographs showing the changes in appearance of the ointment formulation of Comparative Example 1 after 0 and 12 days of light irradiation, respectively. Figures 4(a) and (b) are photographs showing the changes in appearance of Example 10 of the present invention after 0 and 12 days of light irradiation, respectively. After being left in a light box for 12 days, the color of the ointment sample of Comparative Example 1 changed from milky white to deep yellow. The color of the ointment (Comparative Example 2) containing the photoprotectant isooctyl salicylate also changed significantly from pale yellow to pale brown (not shown). The degree of color change in Examples 8 to 13, which contain antioxidants, was significantly lower than that of Comparative Examples 1 and 2, and no clear color change was observed (not shown). As shown in Figure 4, the ointment formulation of Example 10 showed almost no color change and was the most favorable.

[0066] The photostability of the ointment of the present invention has been found to be significantly superior to that of ointments containing no antioxidant or that containing the common antioxidant isooctyl salicylate. The present invention significantly improves the light resistance of the formulation, significantly alleviating the problems of darkening of the color depth and content loss of the formulation on the skin surface caused by light exposure, and resolving the major clinical limitation that the same type of formulation is prohibited from being used on the head and face as specified in the instructions.

[0067] Effects of different antioxidant types and contents on active substances and related substances Equal amounts of samples were taken from Examples 8 to 12 containing antioxidants of different types and amounts, Example 13 containing no antioxidant, and Comparative Example 2 containing isooctyl salicylate as a light protectant, and spread evenly in light-transmitting glass containers of the same size. 2 The formulations were placed in a light box with a light intensity of 0 / h. The contents of active and related substances in the formulations were measured on days 0, 4, and 12. The results are shown in Tables 8 and 9, respectively.

[0068] [Table 8]

[0069] [Table 9]

[0070] As shown in Tables 8 and 9, the active substance content of Example 13, which did not contain an antioxidant, decreased significantly upon exposure to light. The active substance content of Example 10, which contained propyl gallate, remained unchanged after 12 days of exposure. However, the active substance content of the formulations containing other antioxidants decreased to some extent. In particular, the formulation containing dibutylhydroxytoluene and vitamin E showed little degradation after 4 days of exposure to light, but degraded significantly after 12 days of exposure. The spectrum of photodegradation impurities in Example 13, which did not contain an antioxidant, was complex, with the active substance degraded twice or multiple times. In addition to the main degradation impurity with a relative retention time of 0.89, there were many impurities with low abundance chromatographic peaks and no UV absorption. The addition of propyl gallate to the formulation changed the degradation pathway of the active substance, significantly reducing secondary degradation. The light stability of Example 11, which contains 0.5% dibutylhydroxytoluene and 0.05% propyl gallate, is better than that of Example 8, which contains only 0.5% dibutylhydroxytoluene, but is weaker than the light protection effect of Example 10, which uses 0.1% propyl gallate.

[0071] Examples 14-15 Various amounts of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointment Various amounts of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointments were prepared according to the formulations in Table 10, substituting isopropyl palmitate for isopropyl myristate.

[0072] [Table 10]

[0073] Photostability of different amounts of ointment The ointments of Examples 14 and 15 were subjected to photostability testing according to the method described above. The results showed that after 12 days of exposure to light, the color of the ointments of Examples 14 and 15 hardly changed, and the content of the active substance also remained unchanged. The antioxidant selected according to the present invention can effectively protect different amounts of 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointment.

[0074] Physical stability of different amounts of ointment The ointments of Example 15 and Comparative Example 4 were stored at a low temperature of 5°C. After three months, the microstructure of the ointments and the dissolution of the active ingredient were observed under a polarized light microscope. The results are shown in Figure 5. Example 15 (Figure 5a) shows a formulation obtained by preparing 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol, isopropyl palmitate, and a medium-chain triglyceride in the proportions specified in the present invention. No crystals of the API were observed in the formulation under a polarized light microscope. Even after three months of storage at 5°C, 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol remained completely dissolved in the ointment matrix in molecular form without any crystalline precipitation (the bright spots in Figure 5a are the crystalline phase of the white petrolatum, not the crystals of the active ingredient). In contrast, in Comparative Example 4 (Figure 5b), the dosage of isopropyl palmitate and medium-chain triglycerides did not meet the ratios specified in the present invention (when preparing a 3% ointment, the total amount of isopropyl palmitate (isopropyl myristate) and medium-chain triglycerides was 13-25%). The resulting formulation contained numerous short, rod-shaped crystals of the active ingredient, as confirmed by polarized light microscopy. This indicated that 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol had crystallized and precipitated, making it impossible to successfully prepare a solution-type ointment. These results further demonstrate that a stable solution-type ointment can be prepared by optimizing the blending ratio range of isopropyl palmitate (and / or isopropyl myristate) and medium-chain triglycerides according to the present invention. The present invention provides a new method for optimizing the blending ratio of different amounts of formulations, significantly shortening the time required for formulation development and stability studies.

[0075] Examples 16-17 2-Isopropyl-5-(2'-phenylethyl)-1,3-benzenediol ointment was prepared according to the formulation shown in Table 11. The internal exposure of different formulations was investigated using an SD rat model. The day before application, the hair on both sides of the spine of the animal's back was removed with an electric clipper, and drug-impregnated cellophane was placed in the groove of a blank plaster patch, which was then placed over the bald area on the animal's back and secured in place with medical tape. The area of ​​the skin where the drug was applied was 4 x 4 cm. 2 (corresponding amount: 1.6g / kg).

[0076] [Table 11]

[0077] As shown in Figure 6, when the ointments of Examples 16 and 17 were applied to rat skin, the active ingredients were detected 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 indicated that the formulations had good transdermal absorption performance, with the active ingredient being continuously and slowly released from the ointment matrix and penetrating the skin, and the therapeutically required blood drug concentration being maintained even after 24 hours.

[0078] The protection content of the present invention is not limited to the above examples. Any modifications and substitutions that can be thought of by those skilled in the art without departing from the spirit and scope of the concept of the present invention are included in the present invention, and the protection scope 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 matrix, and the remainder being an ointment matrix, the ointment matrix comprises a hydrocarbon compound, a medium-chain triglyceride, and isopropyl palmitate and / or isopropyl myristate, and the weight ratio of the medium-chain triglyceride to the isopropyl palmitate and / or isopropyl myristate is 1:4 to 3:1; the hydrocarbon compound is selected from petrolatum, liquid paraffin, or a mixture thereof; A solution-type ointment of a hydroxydiphenylethane compound, wherein the total amount of the medium-chain triglyceride and isopropyl palmitate and / or isopropyl myristate is 5 to 25% by weight.

2. The solution-type ointment according to claim 1, wherein the total amount of the medium-chain triglyceride and isopropyl palmitate and / or isopropyl myristate is 5 to 17% by weight when the amount of the ointment formulation is 1% by weight or less, and the total amount is 13 to 25% by weight when the amount of the ointment formulation is 1 to 3% by weight.

3. The solution-type ointment according to claim 1, wherein the hydroxydiphenylethane compound is 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, or 1,2-bis(3,5-dihydroxy-4-butylphenyl)ethane, and preferably 2-isopropyl-5-(2'-phenylethyl)-1,3-benzenediol.

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

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

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

7. the weight percent of the active ingredient does not exceed 1.2 x (0.445829 x A + 0.032300 x B - 0.000599 x C + 0.008112 x A x B - 0.003841 x A x C)%, where A, B, and C represent the medium chain triglyceride content (%), the isopropyl myristate and / or isopropyl palmitate content (%), and the hydrocarbon compound content (%), respectively, and A + B + C = 100; 2. The solution-type ointment of claim 1, wherein the weight percent of the active ingredient preferably does not exceed 0.9 x (0.445829 x A + 0.032300 x B - 0.000599 x C + 0.008112 x A x B - 0.003841 x A x C)%.

8. 2. A solution-type ointment according to claim 1, wherein the active ingredient is present in the ointment in amorphous form.

9. 2. The solution-type ointment according to claim 1, wherein the content of the hydroxydiphenylethane compound is 0.005% by weight to 2% by weight, the content of the antioxidant is 0.01% by weight to 1% by weight, and the remainder is an ointment matrix.

10. 2. The solution-type ointment according to claim 1, wherein the ointment is water-free or contains less than 2% by weight of water.

11. The solution-type ointment according to any one of claims 1 to 10, which is used on the skin of the whole body, particularly the head and / or face.

12. 11. A method for preparing a solution-type ointment of a hydroxydiphenylethane compound according to any one of claims 1 to 10, characterized in that the hydroxydiphenylethane compound as an active ingredient and the antioxidant are added to a mixed solution of a medium-chain triglyceride, isopropyl myristate and / or isopropyl myristate, the solution is heated and stirred to dissolve, the solution is then added to a hydrocarbon compound that has been preheated and melted, the mixture is stirred until homogenous, and the mixture is cooled to room temperature.

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