A topical composition containing an HMG-CoA inhibitor and methods of making and using the same

Abstract

The application relates to the field of pharmaceutical preparations, in particular to an external composition containing an HMG-CoA inhibitor and a preparation method and application thereof. The composition comprises an inner oil phase, an inner water phase and an outer water phase, wherein the inner oil phase contains an HMG-CoA inhibitor, an oily solvent, a polar cosolvent and an emulsifier, the inner water phase comprises a surfactant and water, and the outer water phase comprises a thickening agent and water. Through reasonable combination of the oily solvent and the thickening agent, the composition has good physical and chemical stability, good transdermal property and is suitable for the prevention or treatment of skin diseases.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical formulations, specifically to a topical composition containing an HMG-CoA inhibitor, its preparation method, and its application. Background Technology

[0002] Statins block the mevalonate metabolic pathway by inhibiting hydroxymethylglutaryl-CoA (HMG-CoA) reductase. This pathway plays a crucial role in skin lipid synthesis, keratinocyte differentiation, and inflammation regulation. Simvastatin, an HMG-CoA reductase inhibitor, is widely used orally for the treatment of hypercholesterolemia and the prevention of cardiovascular disease. Recent studies have found that topical application of simvastatin can improve skin lipid metabolism, has anti-inflammatory properties, and promotes skin barrier repair. Therefore, developing simvastatin into a topical formulation has significant clinical application value.

[0003] Porokeratosis is an inflammatory keratinization disorder characterized by monogenic inheritance, clinically manifesting as hyperkeratotic papules and plaques. Some patients experience severe itching, and long-term lesions carry a high risk of malignant transformation. Current research suggests that mutations in genes related to the mevalonate metabolic pathway are closely associated with the pathogenesis of porokeratosis. Statins, as HMG-CoA reductase inhibitors, act upstream in this pathway, inhibiting the production of abnormal metabolites. Their combined use with cholesterol has been shown to have therapeutic potential for porokeratosis.

[0004] However, simvastatin is a lipid-soluble drug, susceptible to degradation by environmental factors such as moisture, temperature, and light, posing challenges to its stability, solubility, and skin permeability in topical formulations. Conventional topical formulation systems often struggle to balance drug solubility, long-term stability of the emulsion system, and skin tolerability, leading to decreased efficacy or inconsistent formulation quality, thus affecting clinical application. Furthermore, topical formulations must also meet appropriate spreadability and skin comfort, placing higher demands on formulation design and manufacturing processes.

[0005] Therefore, developing a topical formulation with stable simvastatin content, good transdermal properties, long-term storage stability, and good skin tolerance has become an urgent technical problem to be solved. Summary of the Invention

[0006] To address the above problems, a first aspect of the present invention provides a pharmaceutical composition comprising simvastatin and pharmaceutical excipients.

[0007] In some embodiments, the composition is in the form of a topical preparation.

[0008] In some embodiments, the composition is in the form of a cream, ointment, gel, or paste.

[0009] In some preferred embodiments, the composition is in the form of a cream.

[0010] In some embodiments, the present invention provides a topical composition comprising an inner oil phase, an inner aqueous phase, and an outer aqueous phase; the inner oil phase comprising an active ingredient, an oily solvent, and a polar co-solvent; the active ingredient comprising an HMG-CoA inhibitor or a combination of an HMG-CoA inhibitor and cholesterol; and the polar co-solvent being isopropanol.

[0011] In some embodiments, the inner oil phase further includes an emulsifier; and / or the inner aqueous phase includes a surfactant and water; and / or the outer aqueous phase includes a thickener and water.

[0012] In some embodiments, the HMG-CoA inhibitor comprises one, two, or more of the following: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitavastatin, cerivastatin, mevastatin, simvastatinic acid, lovastatinic acid, mevastatinic acid, and / or a pharmaceutically acceptable salt, ester, prodrug, solvate, hydrate, polymorph, or isomer thereof.

[0013] Preferably, the HMG-CoA inhibitor comprises one, two, or more of the following: simvastatin, simvastatinic acid, and / or a pharmaceutically acceptable salt thereof; More preferably, the HMG-CoA inhibitor is simvastatin.

[0014] In some embodiments, the active ingredient comprises a combination of an HMG-CoA inhibitor and cholesterol. Cholesterol helps regulate skin barrier function and can be used in combination with an HMG-CoA inhibitor.

[0015] In some embodiments, the oily solvent is selected from one, two or more of the following: medium-chain triglycerides, diisopropyl adipate, isopropyl myristate, caprylic / capric triglycerides, ethyl oleate, oleyl alcohol, liquid paraffin, and polydimethylsiloxane.

[0016] Preferably, the oily solvent comprises a combination of medium-chain triglycerides and diisopropyl adipate.

[0017] In some embodiments, the emulsifier is selected from one, two or more of the following: polyoxyethylene 35 hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, stearic acid alkyl oxy 40 ester, polycetol 1000, Tween 80, Span 60; preferably, the emulsifier is polyoxyethylene hydrogenated castor oil; more preferably, the emulsifier is polyoxyethylene 40 hydrogenated castor oil.

[0018] In some embodiments, the thickener is selected from one, two or more of the following: xanthan gum, carbomer, hydroxyethyl cellulose, sodium carboxymethyl cellulose; preferably, the thickener is xanthan gum.

[0019] In some embodiments, the surfactant is a nonionic surfactant; preferably, the surfactant is poloxamer; more preferably, the poloxamer is poloxamer 188.

[0020] In some embodiments, the weight percentage of each component is based on the total weight of the composition as follows: HMG-CoA inhibitor: 0.01-15%; preferably, 0.05-10%; more preferably, 0.1-5%; further preferably, 0.5-2%; most preferably, 2%; Specifically, the weight percentage of the HMG-CoA inhibitor can be any one of 0.01%, 0.05%, 0.1%, 0.2%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.5%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, or 15%, or a range between any two values.

[0021] When the composition contains cholesterol: the amount used is 0.1-8%; preferably, 0.5-5%; more preferably, 1-3%; further preferably, 1.5-2.5%; most preferably, 2%; Specifically, the weight percentage of cholesterol can be any one of 0.1%, 0.2%, 0.5%, 0.8%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.2%, 2.5%, 2.8%, 3%, 3.5%, 4%, 5%, 6%, 7%, or 8%, or a range between any two values.

[0022] Total weight of oily solvent: 30-90%; preferably, 40-85%; more preferably, 50-80%; further preferably, 65-75%; most preferably, 70%; Specifically, the total weight percentage of the oily solvent can be any one of 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 68%, 70%, 72%, 75%, 78%, 80%, 85%, 90%, or a range between any two values.

[0023] Emulsifier: 0.1-5%; preferably, 0.2-3%; more preferably, 0.5-2%; further preferably, 0.8-1.5%; most preferably, 1%; Specifically, the weight percentage of the emulsifier can be any one of 0.1%, 0.2%, 0.3%, 0.5%, 0.6%, 0.8%, 0.9%, 1%, 1.1%, 1.2%, 1.5%, 1.8%, 2%, 2.5%, 3%, 4%, 5%, or a range between any two values.

[0024] Isopropanol: 1-15%; preferably, 2-12%; more preferably, 3-10%; further preferably, 4-8%; most preferably, 6%; Specifically, the weight percentage of isopropanol can be any one of 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, or 15%, or a range between any two values.

[0025] Surfactant: 0.1-3%; preferably, 0.2-2%; more preferably, 0.4-1.5%; even more preferably, 0.5-1%; most preferably, 0.8%; Specifically, the weight percentage of the surfactant can be any one or a range between any two of the following values: 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 1.2%, 1.5%, 1.8%, 2%, 2.5%, and 3%.

[0026] Thickener: 0.01-3%; preferably, 0.05-2%; more preferably, 0.1-1%; further preferably, 0.2-0.4%; most preferably, 0.3%; Specifically, the weight percentage of the thickener can be any one of 0.01%, 0.02%, 0.05%, 0.08%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.5%, 0.6%, 0.8%, 1%, 1.5%, 2%, 2.5%, 3%, or a range between any two values.

[0027] The water content in the internal aqueous phase is: 1-40%; preferably, 5-25%; more preferably, 10-20%; even more preferably, 12-16%; and most preferably, 15%. Specifically, the weight percentage of water in the internal aqueous phase can be any one of the following values ​​or a range between any two values: 1%, 2%, 5%, 8%, 10%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 20%, 22%, 25%, 30%, 35%, and 40%.

[0028] The remainder is external water phase water, added up to 100%.

[0029] In some preferred embodiments, the oily solvent comprises a combination of medium-chain triglycerides and diisopropyl adipate. The weight ratio of the medium-chain triglycerides to diisopropyl adipate is greater than 6:1, more preferably (10-15):1, and most preferably 13:1.

[0030] In some preferred embodiments, the oily solvent comprises a combination of medium-chain triglycerides and diisopropyl adipate. Based on the total weight of the composition, the weight percentage of diisopropyl adipate is 3-7%, and the weight percentage of the medium-chain triglycerides is 50-85%, preferably 60-70%.

[0031] In some more preferred embodiments, the composition comprises 0.5-2% simvastatin and 2% cholesterol; the inner oil phase comprises 65-75% oily solvent, 0.8-1.5% emulsifier and polar cosolvent; the inner aqueous phase comprises 0.6-0.9% surfactant and 12-16% water; and the outer aqueous phase comprises 0.2-0.4% thickener and water to 100%.

[0032] Furthermore, the oily solvent comprises medium-chain triglycerides and diisopropyl adipate, wherein the weight ratio of medium-chain triglycerides to diisopropyl adipate is (10-15):1, and / or the weight percentage of diisopropyl adipate is 3-7%; and / or the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and / or the polar cosolvent is isopropanol, and / or the weight percentage of the polar cosolvent is 6%; and / or the surfactant is poloxamer; and / or the thickener is xanthan gum.

[0033] In some embodiments, the pH of the composition is 5.0-6.5, preferably 5.5-6.5. This pH range is beneficial for the stability of the HMG-CoA inhibitor and is gentle on the skin.

[0034] Specifically, the pH of the composition can be any one of 5.0, 5.2, 5.5, 5.7, 6.0, 6.2, 6.4, 6.5 or a range between any two values.

[0035] The reagent used to adjust the pH is an acidic solvent or an alkaline solvent.

[0036] The acidic solvent is selected from one or more inorganic or organic acids. The inorganic acids include, but are not limited to, hydrochloric acid, sulfuric acid, phosphoric acid, and nitric acid; the organic acids include, but are not limited to, citric acid, acetic acid, lactic acid, and tartaric acid. Preferably, the acid is hydrochloric acid.

[0037] The alkaline solvent is selected from one or more inorganic or organic bases. The inorganic bases include, but are not limited to, sodium hydroxide, potassium hydroxide, calcium hydroxide, sodium carbonate, sodium bicarbonate, and ammonia; the organic bases include, but are not limited to, triethylamine and pyridine. Preferably, the base is sodium hydroxide.

[0038] As a second aspect of the invention, a stable simvastatin topical composition is provided, characterized in that the composition comprises: The inner oil phase includes 0.5-2% simvastatin, optionally 2% cholesterol, 65-75% oily solvent, 0.8-1.5% emulsifier and polar co-solvent; The internal aqueous phase consists of 0.6-0.9% surfactant and 12-16% water; The external aqueous phase includes 0.2-0.4% thickener, with water added to bring the total to 100%.

[0039] In some embodiments, the oily solvent comprises a medium-chain triglyceride and diisopropyl adipate, wherein the weight ratio of the medium-chain triglyceride to diisopropyl adipate is (10-15):1, and / or the weight percentage of the diisopropyl adipate is 3-7%; and / or the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and / or the polar cosolvent is isopropanol, and / or the weight percentage of the polar cosolvent is 6%; and / or the surfactant is poloxamer; and / or the thickener is xanthan gum.

[0040] In some embodiments, the compositions of the present invention are stable, and after accelerated degradation for 6 months at 25±2°C and 60±5% relative humidity, the content of simvastatin decreases by no more than 8%; and / or the simvastatin content in the dermis is ≥5μg / g and the cumulative penetration amount in 24h is ≥100μg / cm² after skin application.

[0041] As a third aspect of the invention, a medicament is provided, the medicament comprising the composition described in any one of the first or second aspects above.

[0042] In some embodiments, the dosage form of the drug is a cream, ointment, or gel, preferably a cream.

[0043] In some implementations, the drug is used to treat or prevent skin diseases.

[0044] In some implementations, the skin disease is selected from one, two, or more of the following: keratosis, seborrheic dermatitis, acne, atopic dermatitis, eczema, psoriasis, skin barrier dysfunction-related diseases, xanthoma, CHILD syndrome, vitiligo, or inflammatory skin diseases.

[0045] In some embodiments, the drug is used to treat or prevent one, two, or more of porokeratosis, keratosis pilaris, actinic keratosis, seborrheic keratosis, palmoplantar keratosis, and other skin keratinization disorders; most preferably, the drug is used to treat or prevent porokeratosis.

[0046] As a fourth aspect of the present invention, the present invention provides a method for preparing the above-described composition, the method comprising the following steps: a) An HMG-CoA inhibitor and optionally added cholesterol are dissolved in an oily solvent, an optional emulsifier, and isopropanol as a polar co-solvent to form an inner oil phase; b) Dissolve the surfactant in water to form an internal aqueous phase; c) The inner oil phase is added to the inner aqueous phase, and the primary emulsion is prepared by emulsification; d) Add the external aqueous phase to the pre-emulsion from step c), stir and mix thoroughly, then add the thickener, stir until completely dissolved, and the product is obtained.

[0047] As a fifth aspect of the invention, the invention provides the use of the above-described composition in the preparation of a medicament for treating or preventing skin diseases.

[0048] In some implementations, the skin disease is selected from one or more of the following: keratosis, atopic dermatitis, seborrheic dermatitis, acne, eczema, psoriasis, skin barrier dysfunction-related diseases, xanthoma, CHILD syndrome, vitiligo, or inflammatory skin diseases.

[0049] In some embodiments, the drug is used to treat or prevent one, two, or more of porokeratosis, keratosis pilaris, actinic keratosis, seborrheic keratosis, palmoplantar keratosis, and other skin keratinization disorders; most preferably, the drug is used to treat or prevent porokeratosis.

[0050] Compared with the prior art, the present invention has the following beneficial effects: 1. This invention utilizes a specific ternary solvent system, namely medium-chain triglyceride / diisopropyl adipate / isopropanol system, to discover that using isopropanol as the core polar co-solvent and controlling the dosage of diisopropyl adipate within the range of 3-7% can improve the stability of the drug.

[0051] 2. The composition of the present invention uses xanthan gum as a thickener. Xanthan gum has the best compatibility with simvastatin and can inhibit drug degradation to the greatest extent.

[0052] 3. The composition of this invention exhibits thixotropy and good spreadability, providing a comfortable feel on the skin, and is stable without stratification during centrifugation. This composition can efficiently enrich simvastatin in target skin tissues while reducing systemic absorption, improving local efficacy, and reducing side effects. Attached Figure Description

[0053] Figure 1 This is an HPLC chromatogram of the determination of impurities in simvastatin cream.

[0054] Figure 2 The figure shows the results of the thixotropic ring experiment of xanthan gum.

[0055] Figure 3 The figure shows the experimental results of the thixotropic ring of Carbomer 980.

[0056] Figure 4 The figure shows the experimental results of thixotropic rings of hydroxyethyl cellulose.

[0057] Figure 5 The figure shows the results of the thixotropic ring experiment of hydroxypropyl cellulose. Detailed Implementation

[0058] I. Definition The simvastatin described in this application, chemically named (1S,3R,7S,8S,8aR)-1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl]-1-naphthol, CAS number 79902-63-9, is a pharmaceutical-grade raw material and can be obtained through commercial channels. Its function is as the active ingredient of this composition to achieve the pharmacological effects of treating or preventing skin diseases.

[0059] The pharmaceutical excipients described in this application refer to pharmaceutical-grade materials other than simvastatin that have functions such as assisting in shaping, stabilizing active ingredients, and regulating dosage form characteristics in the composition. These include, but are not limited to, cholesterol, oily solvents, emulsifiers, thickeners, polar solubilizers, purified water, etc., mentioned in the claims of this application. All excipients comply with the pharmaceutical excipient standards of the Pharmacopoeia of the People's Republic of China, have no obvious toxic side effects, and do not affect the pharmacological activity of simvastatin.

[0060] The cholesterol described in this application is pharmaceutical grade cholesterol, which can act as a lipid carrier to help simvastatin dissolve in oily systems, regulate the fluidity and stability of the inner oil phase, and enhance the compatibility of the composition with the skin, promoting the skin penetration of the active ingredients.

[0061] The oily solvent described in this application refers to an organic solvent or lipid substance that can dissolve lipid-soluble components such as simvastatin and cholesterol and meets pharmaceutical standards. Its function is to construct an inner oil phase, improve the solubility of lipid-soluble active ingredients, and enhance the stability of the composition.

[0062] The polar cosolvents described in this application refer to pharmaceutical excipients that have a certain polarity and can assist active ingredients such as simvastatin in dissolving in the inner oil phase, thereby improving the solubility and stability of the active ingredients.

[0063] The thickener described in this application refers to a pharmaceutical excipient that can increase the viscosity of the composition (external aqueous phase), improve the texture of the formulation, prevent the components from settling and separating, and enhance the application feel.

[0064] The composition described in this application is a double emulsion system, wherein: the inner oil phase is the core oil phase region of the composition, containing simvastatin, cholesterol, oily solvents, polar cosolvents, and emulsifiers. It is the main dissolution and carrying region of simvastatin, responsible for encapsulating the active ingredient and controlling its release rate; the inner aqueous phase is the aqueous phase region encapsulated within the inner oil phase, containing surfactants to improve the solubility and stability of the active ingredient; and the outer aqueous phase is the outermost aqueous phase region of the double emulsion system, containing thickeners and purified water, used to adjust the viscosity and stability of the composition, improve the application feel, and protect the internal oil and aqueous phase structures from damage.

[0065] The topical preparations described in this application refer to dosage forms that are directly applied or placed on the skin surface for local pharmacological effects, and are not used for oral administration, injection, or other routes of administration. Their core characteristic is that they can form an effective concentration on the skin, reducing adverse reactions caused by systemic absorption. This application preferably uses creams or ointments.

[0066] II. Examples The technical solutions in the embodiments of the present invention will be clearly and completely described below. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0067] Unless otherwise specified, all raw materials used in the examples in this specification are pharmaceutical grade or commercially available products.

[0068] Example 1: Formulation and General Preparation Method prescription: Table 1. Components and Dosage of the Formulation Preparation method: Simvastatin cream is manufactured using a two-step emulsification process.

[0069] a) Weigh out the prescribed amounts of diisopropyl adipate, medium-chain triglycerides, isopropanol, and polyoxyethylene 40 hydrogenated castor oil, stir and dissolve until clear, and set aside; then add the prescribed amounts of simvastatin and cholesterol to the aforementioned solvent, heat or not heat, stir and dissolve until clear, forming the inner oil phase, and set aside. b) Add the prescribed amount of poloxamer 188 to purified water 1, stir until dissolved and clear, forming the inner aqueous phase; c) The inner oil phase is slowly added to the inner aqueous phase while continuously stirring, and the initial emulsion is prepared by emulsification; d) Add purified water 2 to the colostrum in step c), stir and mix well, then add the prescribed amount of xanthan gum, stir until completely dissolved, and adjust the pH value to 5.0~6.5 to obtain the final product.

[0070] Example 2: Preliminary screening of solvent systems for simvastatin Experimental objective: Simvastatin has poor stability and mainly undergoes three degradation pathways: oxidative polymerization, transesterification, and hydrolysis. It is necessary to screen for suitable solvents that can solve the stability problem.

[0071] Experimental methods: (1) Solubility: Add excess simvastatin to the solvent and sonicate for 30 min. If there is a completely dissolved sample, continue to add simvastatin and sonicate for 30 min. Then, place the sample at room temperature overnight and perform content detection.

[0072] (2) Melting point and whether it contains exposed hydroxyl groups: judged based on the structure of the solvent and literature.

[0073] Experimental results: Based on initial screening, medium-chain triglycerides and diisopropyl adipate were selected as non-polar solvents. However, it was found that using only medium-chain triglycerides (different types of medium-chain triglycerides showed no significant difference in effectiveness) and diisopropyl adipate as solvents resulted in problems such as agglomeration, wall adhesion, and uneven content of active ingredients, which could not be completely dissolved even with heating and ultrasonication. Therefore, a binary solvent system using only medium-chain triglycerides and diisopropyl adipate is still insufficient to meet the drug loading requirements of the formulation. To address this, this invention found that using a ternary solvent system, such as introducing a polar co-solvent, can improve the solubility of simvastatin, and propylene carbonate, isopropanol, isosorbide dimethyl ether, ethanol, or ethyl acetate were selected as candidate co-solvents.

[0074] Example 3: Determination of Polar Co-solvents Experimental methods: Screening was conducted by changing the type of polar cosolvent. Except for the type of cosolvent, the types and contents of the other components were consistent with those of Formulation 1 described in Example 1, and the preparation method was also the same as in Example 1.

[0075] (1) Stability testing method The stability sampling conditions are shown in Table 2, and the specific sampling time is shown in the test results table.

[0076] Table 2. Stability Layout Conditions Chromatographic conditions: Column: Octadecylsilane-bonded silica gel (YMC Triart ExRs C18, 250 × 4.6 mm, 3 μm, or a column with equivalent performance); Mobile phase: 0.1% phosphoric acid as mobile phase A, methyl tert-butyl ether: acetonitrile = 6:94 (V:V) as mobile phase B, and methanol as mobile phase C, with gradient elution according to Table 3; Flow rate: 0.8 ml / min; Detection wavelength: 238 nm; Column temperature: 40 ℃; Injection tray temperature control: 8 ℃; Injection volume: 10 μl.

[0077] Table 3. Gradient elution table Preparation of the test solution: Weigh approximately 0.25 g of the sample accurately and place it in a 20 ml volumetric flask. Add 2 ml of water and shake vigorously to disperse it completely. Gradually dilute to the mark with acetonitrile, shake well, and filter through a 0.22 μm hydrophobic PTFE membrane. Discard 0.5 ml of the initial filtrate and collect the subsequent filtrate.

[0078] Preparation of reference solution: Accurately weigh 12.5 mg of simvastatin reference standard, place it in a 50 ml volumetric flask, dissolve it with an appropriate amount of acetonitrile, dilute to the mark, and shake well.

[0079] Figure 1 This is a typical high-performance liquid chromatogram of simvastatin preparations.

[0080] (2) Methods for observing droplet size and microstructure The particle size and particle size distribution were determined according to the method for determination of particle size and particle size distribution (Chinese Pharmacopoeia 2025 Edition, Part IV, General Chapter 0982, Method I).

[0081] Using a syringe needle, pick up a sample the size of a needle tip and spot it onto a clean glass slide. Cover with a coverslip and press with a 200g weight for 30 seconds to ensure the sample is evenly spread. Observe the prepared slide under a microscope with 10x objective and 10x eyepiece using transmitted light. Select three fields of view for each slide and prepare two parallel slides.

[0082] Experimental results: Table 4 shows the experimental results of screening different polarity cosolvents. The results indicate that isopropanol, ethanol, propylene carbonate, isosorbide dimethyl ether, and ethyl acetate can all prevent the active ingredient from crystallizing. However, 6% isopropanol showed the best stability for the formulation, with impurity content significantly lower than other polarity cosolvents.

[0083] Table 4. Experimental results of cosolvents with different polarities Note 1: d represents day, M represents month.

[0084] Note 2: Because cholesterol has a stable chemical structure, the stability study mainly focuses on the characterization of simvastatin.

[0085] Example 4: Determination of the amount of ternary solvent system Simvastatin is a highly lipid-soluble drug that is also sensitive to environmental factors. Its stability and transdermal properties in topical formulations largely depend on the chosen solvent system. A suitable solvent system not only needs to ensure sufficient drug solubility to prevent precipitation but also should inhibit degradation reactions during storage while minimizing skin irritation. Therefore, this embodiment systematically compares the solubility and stability of simvastatin by constructing different combinations of oil phase and co-solvent, thereby screening for a solvent system that can maintain complete drug dissolution while exhibiting good stability, providing a foundation for subsequent formulation development.

[0086] Experimental methods: The focus was on screening the dosage of diisopropyl adipate. Except for medium-chain triglycerides and diisopropyl adipate, the types and contents of the other components were consistent with those of Formulation 1 described in Example 1, and the preparation method was also the same as in Example 1.

[0087] The stability testing method, droplet size, and microstructure observation method are the same as in Example 3.

[0088] Table 5. Experimental design for formulations using different amounts of diisopropyl adipic acid. Table 6. Experimental effects of different dosages of diisopropyl adipate Note 1: d represents day, M represents month.

[0089] Note 2: Because cholesterol has a stable chemical structure, the stability study mainly focuses on the characterization of simvastatin.

[0090] Table 6 shows that the stability of simvastatin decreases with increasing diisopropyl adipate content in the formulation. Therefore, it is necessary to control the amount of diisopropyl adipate in the formulation. Based on the above experiments, the preferred amount of diisopropyl adipate in the formulation is 3-7%.

[0091] Example 5: Thickener Screening Experimental objective: Thickeners can enhance the stability of emulsion systems by increasing the viscosity of the continuous phase, while also affecting the rheological and coating properties of the formulation. Therefore, by comparing the rheological profiles of different thickener systems, thickeners suitable for the system of this invention are screened.

[0092] Experimental methods: The comparison was made by changing the type of thickener. Except for the type and amount of thickener, the types and contents of the other components were consistent with those of Formulation 1 described in Example 1, and the preparation method was also the same as that in Example 1.

[0093] Table 7. Types and Dosages of Thickeners 1-4 (1) Method for observing droplet size and microstructure: Microscopic observation was performed according to the method described in Example 3.

[0094] (2) Method for determining rheological curves: Take an appropriate amount of the sample to be tested onto the Peltier and perform the test according to the test parameters shown in Table 8: Table 8. Relevant Detection Parameters Experimental results: from Figure 2-5 As can be seen from the results in Table 9, all the thickeners tested maintained the physical stability of the cream and did not have an adverse effect on the rheological properties of the cream. All formulations were pseudoplastic fluids with shear-thinning rheological characteristics.

[0095] However, different polymeric thickeners have a significant impact on the stability of simvastatin. Among the screened polymeric thickeners, xanthan gum showed the best compatibility with simvastatin and could maximally inhibit drug degradation. Therefore, xanthan gum was selected as the thickener for this invention.

[0096] Table 9. Results of centrifugal and accelerated stability of different thickeners Note: Because cholesterol has a stable chemical structure, stability studies mainly focus on the characterization of simvastatin.

[0097] Example 6: Study on transdermal effect Experimental methods: Transdermal absorption of three different formulations from Example 1 was compared, using a drug application area of ​​1.77 cm². 2 A Franz diffusion cell with a receiving volume of 7 mL was used, with the skin of Bama miniature pigs (one month old) as the osmotic barrier, at a concentration of 15 mg / cm³. 2The drug was applied at a dose of approximately 26.6 mg. The receiving medium consisted of a solution of 0.9% NaCl, 0.10% polyoxyethylene 20 oil ether, and 0.01% gentamicin sulfate. An in vitro transdermal test was conducted at a temperature of 32℃ and a rotation speed of 600 rpm, with n=6. Sampling times were 3, 6, 9, 12, 16, 20, and 24 hours. After the transdermal test, any residual ointment on the pigskin was wiped away with a cotton swab. The epidermis and dermis were then separated, and the concentrations of simvastatin in the active epidermal and dermal layers were determined by grinding and extraction.

[0098] Table 10 shows the results of the transdermal absorption experiment: Table 10. Transdermal absorption and retention of different formulation strengths In vitro transdermal experiments showed that simvastatin, at concentrations ranging from 0.5% to 2%, could accumulate at high concentrations in the dermis, the target site for drug action. Furthermore, in vitro pharmacodynamic data for simvastatin reported in the literature (https: / / www.drugfuture.com / pmda / interview / 270072_2189016F1028_1_38) indicate that simvastatin's IC50... 50 The concentration range is 0.5–60 ng / g, which is far less than the drug's exposure level in the dermis. Therefore, the drug strength range for simvastatin is 0.5–2%.

[0099] Example 7: Preparation of existing ointments 1-3 Preparation of ointment 1 in the prior art Experimental methods: Simvastatin-cholesterol ointment was prepared according to the preparation method in patent CN 112791049 A: Table 11. Prescription of Ointment 1 in the Prior Art Oil phase preparation: Weigh stearic acid, cetearyl alcohol, liquid paraffin, butylated hydroxytoluene, and white petrolatum according to the proportions in Table 11. Heat to 70°C, stir until homogeneous, and dissolve and clarify. Add cholesterol and stir at 500 rpm until clear.

[0100] Preparation of active phase: Weigh simvastatin, add hexanediol, propylene glycol, and polyoxypropylene octadecyl ether, sonicate to dissolve and clarify, then heat to 70°C for later use.

[0101] Mixing: Add the active phase to the oil phase, keep warm at 70°C, stir at 700 rpm for 10 min, observe the state, stir at 700 rpm and cool down to 25°C to obtain the prior art ointment 1.

[0102] Preparation of ointment 2 in the prior art Experimental methods: Cream prepared according to patent CN 120078712 A: Table 12. Prescription of Ointment 2 in the Prior Art According to the proportions in Table 12, stearic acid, cetearyl alcohol, polycetol 1000, and polysorbate 80 were added to a mixture of propylene glycol, benzyl alcohol, oleyl alcohol, and isopropyl myristate (weight ratio 30:2:5:5), heated to 70°C, and stirred at 500–1000 rpm until clear.

[0103] Add 2% simvastatin and cholesterol raw materials, stir well and set aside.

[0104] Heat the aqueous phase to 70°C, add the oil phase to the aqueous phase, and homogenize by stirring at 4000 rpm for 10 min. Observe the state. After homogenization, stir at 600 rpm to cool down to 25°C.

[0105] The samples were stored at room temperature, and the simvastatin content and impurity changes were detected after 7 days and 30 days, respectively.

[0106] Preparation of Cream 3 in the Existing Technology Experimental methods: Cream prepared according to patent CN 110368358 B: Table 13. Prescription of Ointment 3 in the Prior Art Oil phase: Stearic acid, cholesterol, glyceryl monostearate, and light liquid paraffin are heated and melted according to the proportions in Table 13. Ethylparaben is added, stirred and dissolved, and kept at about 80°C.

[0107] Aqueous phase: Boil distilled water, add sodium dodecyl sulfate, simvastatin, and glycerin, grind evenly, and keep warm at about 80°C.

[0108] Add the oil phase to the aqueous phase and stir for 15-20 min. Add triethanolamine and laurocapram and stir at 600 rpm to cool to 25°C.

[0109] Example 8: Stability Experiment Verification The stability of the prior art ointments 1-3 in Example 7 and the formulation 1 of Example 1 was verified by a stability test. The self-made simvastatin cream and the prior art simvastatin cream were compared under the conditions of 40℃ / 75%RH. The test results are detailed in Table 14.

[0110] Table 14. Stability Test Results Note: Because cholesterol has a stable chemical structure, stability studies mainly focus on the characterization of simvastatin.

[0111] According to the stability test results in Table 14, under the conditions of 40℃ / 75%RH, the active ingredient content of the existing ointments 1-3 can still be maintained at about 65-69% within 5 days. However, after 10 days, the active ingredient rapidly degrades, and the content drops to 15.6-33.9% respectively. This shows that the existing formulations have insufficient stability in long-term storage and cannot meet the shelf life requirements.

[0112] In contrast, the formulation of Formula 1 still showed an active ingredient content of over 95% after 30 days in short-term stability testing. Therefore, its designed internal oil phase, internal aqueous phase, and external aqueous phase system, as well as optimized oily solvents and emulsification systems, help to significantly improve the stability of simvastatin in the formulation and effectively address the problem of rapid degradation of active ingredients in existing technologies, thus providing a feasible solution for developing long-term stable topical formulations.

[0113] Example 9: Sensory Testing Study Sensory testing was conducted on Formula 1 and existing ointments 1-3 to evaluate clinical patient acceptance of the different formulations. The evaluation method adopted the Standard Guide for Two Sensory Descriptive Analysis Approaches for Skin Creams and Lotions (ASTM E1490-11) published by the American Society for Testing and Materials (ASTM). Volunteers were recruited to conduct sensory testing on Formula 1 and existing ointments 1-3.

[0114] Table 15. Results of Sensory Testing Studies The experimental results are shown in the table above. Existing ointment 1 is an ointment base; the high viscosity and greasiness caused by petrolatum are severe, and the formulation has poor spreadability, making it difficult to apply. Existing ointment 2 is a cream, but the large amount of propylene glycol in the formula brings greasiness and skin irritation. Existing ointment 3 uses excessive amounts of glyceryl monostearate, resulting in an overly thick formulation with poor spreadability, and the use of laurocapram increases the drug's irritation to the skin. Formula 1 is the simvastatin cream of this invention, which retains the wetting ability of a cream, has low viscosity, low greasiness, good spreadability, and low skin irritation.

[0115] Example 10: Stability Experiment Study Experimental methods: The stability test method is the same as in Example 3.

[0116] Experimental results: As shown in the table below, the simvastatin composition of the present invention can significantly improve the stability of simvastatin in formulations. After investigation of influencing factors and accelerated testing, the content of the active ingredient can be kept stable at over 90%. In long-term testing, the content changes little after 24 months of storage, which can meet the shelf life requirements of pharmaceuticals.

[0117] Table 16. Test results of stability experiment Note 1: The sum of the content and total impurities within 102% is within the normal detection error range.

[0118] Note 2: Because cholesterol has a stable chemical structure, the stability study mainly focuses on the characterization of simvastatin.

[0119] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A topical composition, characterized in that, The composition comprises an internal oil phase, an internal aqueous phase, and an external aqueous phase; The internal oil phase includes active ingredients, oily solvents, and polar co-solvents; The active ingredient includes an HMG-CoA inhibitor or a combination of an HMG-CoA inhibitor and cholesterol; The polar cosolvent is isopropanol.

2. The composition according to claim 1, characterized in that, The HMG-CoA inhibitors include one, two, or more of the following: atorvastatin, fluvastatin, lovastatin, pravastatin, rosuvastatin, simvastatin, pitavastatin, cerivastatin, mevastatin, simvastatin acid, lovastatin acid, mevastatin acid, and / or their pharmaceutically acceptable salts, esters, prodrugs, solvates, hydrates, polymorphs, or isomers.

3. The composition according to claim 1, characterized in that, The HMG-CoA inhibitors include one, two, or more of the following: simvastatin, simvastatin acid, and / or a pharmaceutically acceptable salt thereof.

4. The composition according to claim 1, characterized in that, The HMG-CoA inhibitor is simvastatin.

5. The composition according to claim 1, characterized in that, Based on the total weight of the composition, the total weight percentage of the oily solvent is 30-90%; And / or the oily solvent includes one, two or more of the following: medium-chain triglycerides, diisopropyl adipate, isopropyl myristate, caprylic / capric triglycerides, ethyl oleate, oleyl alcohol, liquid paraffin, and polydimethylsiloxane.

6. The composition according to claim 1, characterized in that, The total weight percentage of the oily solvent is 40-85%; and / or the oily solvent comprises a combination of medium-chain triglycerides and diisopropyl adipate.

7. The composition according to claim 5, characterized in that, The total weight percentage of the oily solvent is 50-80%; and / or the weight ratio of the medium-chain triglyceride to diisopropyl adipate is greater than 6:1; and / or based on the total weight of the composition, the weight percentage of diisopropyl adipate is 3-7%, and the weight percentage of the medium-chain triglyceride is 50-85%.

8. The composition according to claim 5, characterized in that, The total weight percentage of the oily solvent is 65-75%; and / or the weight ratio of the medium-chain triglyceride to diisopropyl adipate is (10-15):1; and / or the weight percentage of the medium-chain triglyceride is 60-70%.

9. The composition according to claim 5, characterized in that, The total weight percentage of the oily solvent is 70%; and / or the weight ratio of the medium-chain triglyceride to diisopropyl adipate is 13:

1.

10. The composition according to claim 1, characterized in that, The inner oil phase further includes an emulsifier; and / or the inner aqueous phase includes a surfactant and water; and / or the outer aqueous phase includes a thickener and water.

11. The composition according to claim 10, characterized in that, The thickener includes one, two, or more of the following: xanthan gum, carbomer, hydroxyethyl cellulose, and sodium carboxymethyl cellulose; And / or the emulsifiers include one, two or more of the following: polyoxyethylene hydrogenated castor oil, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 hydrogenated castor oil, stearic acid alkyl oxy 40 ester, polycetol 1000, Tween 80, Span 60. And / or the surfactant is a nonionic surfactant.

12. The composition according to claim 10, characterized in that, The thickener is xanthan gum; and / or the emulsifier is polyoxyethylene hydrogenated castor oil; and / or the surfactant is poloxamer.

13. The composition according to claim 10, characterized in that, The emulsifier is polyoxyethylene 40 hydrogenated castor oil; and / or the poloxamer is poloxamer 188.

14. The composition according to claim 10, characterized in that, Based on the total weight of the composition The HMG-CoA inhibitor has a weight percentage of 0.01-15%; And / or when the composition contains cholesterol, the weight percentage of cholesterol is 0.1-8%; And / or the emulsifier is 0.1-5% by weight; And / or the weight percentage of the isopropanol is 1-15%; And / or the surfactant is 0.1-3% by weight; And / or the thickener is 0.01-3% by weight; And / or the weight percentage of water in the internal aqueous phase is 1-40%; The remainder is external water phase water, added up to 100%.

15. The composition according to claim 10, characterized in that, Based on the total weight of the composition The HMG-CoA inhibitor has a weight percentage of 0.05-10%; And / or when the composition contains cholesterol, the cholesterol content is 0.5-5% by weight; And / or the emulsifier is 0.2-3% by weight; And / or the weight percentage of the isopropanol is 2-12%; And / or the surfactant is 0.2-2% by weight; And / or the thickener is 0.05-2% by weight; And / or the weight percentage of water in the internal aqueous phase is 5-25%; The remainder is external water phase water, added up to 100%.

16. The composition according to claim 10, characterized in that, Based on the total weight of the composition The HMG-CoA inhibitor has a weight percentage of 0.1-5%; And / or when the composition contains cholesterol, the weight percentage of cholesterol is 1-3%; And / or the emulsifier is 0.5-2% by weight; And / or the weight percentage of the isopropanol is 3-10%; And / or the surfactant comprises 0.4-1.5% by weight; And / or the thickener is 0.1-1% by weight; And / or the weight percentage of water in the internal aqueous phase is 10-20%; The remainder is external water phase water, added up to 100%.

17. The composition according to claim 10, characterized in that, Based on the total weight of the composition The HMG-CoA inhibitor has a weight percentage of 0.5-2%; And / or when the composition contains cholesterol, the weight percentage of cholesterol is 1.5-2.5%; And / or the weight percentage of the emulsifier is 0.8-1.5%; And / or the weight percentage of the isopropanol is 4-8%; And / or the surfactant is 0.5-1% by weight; And / or the thickener is 0.2-0.4% by weight; And / or the weight percentage of water in the internal aqueous phase is 12-16%; The remainder is external water phase water, added up to 100%.

18. The composition according to claim 10, characterized in that, Based on the total weight of the composition The HMG-CoA inhibitor is 2% by weight; And / or when the composition contains cholesterol, the weight percentage of cholesterol is 2%; And / or the emulsifier is 1% by weight; And / or the isopropanol is 6% by weight; And / or the surfactant comprises 0.8% by weight; And / or the thickener is 0.3% by weight; And / or the weight percentage of water in the internal aqueous phase is 15%; The remainder is external water phase water, added up to 100%.

19. The composition according to claim 10, characterized in that, The composition comprises 0.5-2% simvastatin and 2% cholesterol; the inner oil phase comprises 65-75% oily solvent, 0.8-1.5% emulsifier and polar cosolvent; the inner aqueous phase comprises 0.6-0.9% surfactant and 12-16% water; the outer aqueous phase comprises 0.2-0.4% thickener and water to 100%.

20. The composition according to claim 19, characterized in that, The oily solvent comprises medium-chain triglycerides and diisopropyl adipate, wherein the weight ratio of medium-chain triglycerides to diisopropyl adipate is (10-15):1, and / or the weight percentage of diisopropyl adipate is 3-7%; and / or the emulsifier is polyoxyethylene 40 hydrogenated castor oil; and / or the weight percentage of the polar cosolvent is 6%; and / or the surfactant is poloxamer; and / or the thickener is xanthan gum.

21. The composition according to claim 1, characterized in that, The pH of the composition is 5.0-6.

5.

22. A stable topical simvastatin composition, characterized in that, The composition contains: The inner oil phase includes 0.5-2% simvastatin, optionally 2% cholesterol, 65-75% oily solvent, 0.8-1.5% emulsifier and polar co-solvent; The internal aqueous phase consists of 0.6-0.9% surfactant and 12-16% water; The external aqueous phase includes 0.2-0.4% thickener, with water added to bring the total to 100%.

23. The composition according to claim 22, characterized in that, The oily solvent comprises medium-chain triglycerides and diisopropyl adipate, wherein the weight ratio of medium-chain triglycerides to diisopropyl adipate is (10-15):1, and / or the weight percentage of diisopropyl adipate is 3-7%; The emulsifier is polyoxyethylene 40 hydrogenated castor oil; The polar co-solvent is isopropanol, and / or the polar co-solvent has a weight percentage of 6%; The surfactant is poloxamer; And / or the thickener is xanthan gum.

24. The composition according to any one of claims 1-23, wherein after accelerated degradation for 6 months at 25±2°C and 60±5% relative humidity, the content of simvastatin decreases by no more than 8%; and / or the simvastatin content in the dermis is ≥5μg / g and the cumulative penetration amount in 24h is ≥100μg / cm² after skin application.

25. A method for preparing the composition according to any one of claims 1-24, characterized in that, Includes the following steps: a) An HMG-CoA inhibitor and optionally added cholesterol are dissolved in an oily solvent, an optional emulsifier, and isopropanol to form an inner oil phase; b) Dissolve the surfactant in water to form an internal aqueous phase; c) The inner oil phase is added to the inner aqueous phase, and the primary emulsion is prepared by emulsification; d) Add water to the external aqueous phase into the pre-emulsion from step c), stir and mix evenly, then add the thickener, stir and dissolve completely to obtain the final product.

26. Use of the composition according to any one of claims 1-24 in the preparation of a medicament for treating or preventing skin diseases.

27. A medicament comprising the composition according to any one of claims 1-24.

28. The medicament according to claim 27, characterized in that, The dosage form of the drug is cream, ointment, or gel.

29. The medicament according to claim 27, characterized in that, The drug is used to treat or prevent skin diseases.

30. The use according to claim 26, characterized in that, The skin disease is selected from one, two or more of the following: keratosis, atopic dermatitis, seborrheic dermatitis, acne, eczema, psoriasis, skin barrier dysfunction-related diseases, xanthoma, CHILD syndrome, vitiligo or inflammatory skin disease.

31. The use according to claim 26, characterized in that, The drug is used to treat or prevent one, two, or more of the following: porokeratosis, keratosis pilaris, actinic keratosis, seborrheic keratosis, palmoplantar keratosis, and abnormal skin keratinization.

32. The use according to claim 26, characterized in that, The drug is used to treat or prevent porokeratosis.

33. The medicament according to claim 29, characterized in that, The skin disease is selected from one, two or more of the following: keratosis, atopic dermatitis, seborrheic dermatitis, acne, eczema, psoriasis, skin barrier dysfunction-related diseases, xanthoma, CHILD syndrome, vitiligo or inflammatory skin disease.

34. The medicament according to claim 27, characterized in that, The drug is used to treat or prevent one, two, or more of the following: porokeratosis, keratosis pilaris, actinic keratosis, seborrheic keratosis, palmoplantar keratosis, and abnormal skin keratinization.

35. The medicament according to claim 27, characterized in that, The drug is used to treat or prevent porokeratosis.

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