An external ointment preparation for preventing radioactive skin damage and a method for preparing the same

Abstract

This application relates to the field of pharmaceutical technology, and in particular to a topical ointment formulation and its preparation method. The formulation uses Sonicate as the active ingredient, combined with petrolatum, liquid paraffin, a solubilizing and penetration-enhancing system, and emulsifiers as excipients, to form an O / W type cream, an oil-based or water-soluble ointment. The preparation process employs a low-temperature dosing method at 40°C to ensure drug activity and inhibit crystallization. This application achieves high-concentration retention in local skin tissue through topical administration, significantly reducing radiation damage scores and pathological damage, while resulting in extremely low systemic plasma exposure, avoiding the systemic toxicity of oral administration, and providing a safe and efficient means for the clinical prevention and treatment of radiation-induced skin damage.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a topical ointment preparation, its preparation method, and its application. Background Technology

[0002] Radiation-induced skin injury is the most common dose-limiting adverse reaction during radiotherapy for malignant tumors, with an extremely high incidence rate in clinical practice, severely impacting patient prognosis. Ionizing radiation induces epidermal cell apoptosis, triggers an inflammatory cascade in the dermis, and causes microvascular damage and fibrosis, leading to symptoms such as erythema, edema, desquamation, erosion, ulceration, and even necrosis. This not only significantly reduces patients' quality of life but also often results in radiotherapy interruption due to severe skin damage, directly affecting the overall treatment outcome of the tumor. Currently, clinical prevention and treatment of radiation-induced skin injury mainly rely on symptomatic supportive measures such as moisturizers, corticosteroids, or antibiotic ointments. These methods only alleviate surface symptoms and cannot block the occurrence and progression of radiation damage at the molecular level. Clinically, there is still a lack of targeted and effective preventive drugs, indicating a significant unmet medical need.

[0003] Soniadiazole, a highly selective receptor inhibitor, blocks abnormal SHH signaling pathway transduction by binding to and inhibiting the SMO receptor. Studies have shown that this signaling pathway plays a central regulatory role in tissue regeneration and cell proliferation and participates in the pathological process of tissue damage caused by ionizing radiation; therefore, inhibiting the relevant receptor can effectively reduce radiation-induced skin tissue damage. However, currently, the only commercially available Soniadiazole formulation worldwide is an oral capsule, and its approved indication is limited to basal cell carcinoma. Oral administration makes the drug highly susceptible to systemic adverse reactions such as muscle spasms, myalgia, hair loss, and taste disturbances after systemic absorption. Furthermore, due to its metabolism depending on specific enzymes, there is a serious risk of drug interactions. More importantly, oral administration cannot precisely concentrate the drug in the local skin tissue treated with radiation, resulting in a less than ideal effect in preventing and treating radiation-induced skin damage, making it difficult to balance local efficacy with systemic safety.

[0004] In the development of topical formulations of Soniadegavir, the drug's molecules exhibit strong hydrophobicity and high lipophilicity, resulting in extremely low solubility in water and sensitivity to light and heat. This presents several technical bottlenecks. First, the drug is difficult to disperse stably in the ointment matrix, and crystallization easily occurs with prolonged storage. Second, conventional high-temperature preparation processes easily lead to drug degradation and inactivation, making it difficult to guarantee the stability of the formulation. Furthermore, existing technologies struggle to precisely control the drug's transdermal behavior, failing to effectively achieve the core objectives of high retention in skin tissue and low exposure in systemic circulation. Currently, there is no technical solution for Soniadegavir ointment formulations specifically for the prevention and treatment of radiation-induced skin damage. There is a lack of clearly quantifiable formulation ratios, reproducible preparation processes, and sufficient in vivo pharmacodynamic validation data. Therefore, developing a topical Soniadegavir ointment formulation that can achieve local targeted drug delivery, reduce systemic toxicity, possess stable physicochemical properties, and demonstrate clear preventive and therapeutic effects is of significant practical importance and application value for the clinical prevention and treatment of radiation-induced skin damage. Summary of the Invention

[0005] This invention addresses the technical shortcomings of existing technologies, such as the oral administration route of Sonidegib, the high risk of side effects due to systemic distribution, the difficulty in achieving effective therapeutic concentrations in radiation-damaged skin, the lack of targeted intervention for radiation-induced skin damage, the extreme lipophilicity and poor thermal stability of Sonidegib itself, and the tendency for crystallization and degradation in conventional matrices. This invention provides a topical ointment formulation and its preparation method.

[0006] The technical problem to be solved by this invention is to construct a topical formulation that is stable, has high transdermal absorption efficiency and strong local targeting through specific prescription compatibility and process optimization, so as to achieve deep penetration and long-term retention of Sonicep in skin tissue, while reducing the proportion of the drug entering the systemic blood circulation, thereby effectively inhibiting the pathological process of radiation-induced skin damage and avoiding systemic toxic side effects.

[0007] To solve the above-mentioned technical problems, the present invention adopts the following technical solution: This invention provides a topical ointment formulation in which the active ingredient is Sonicet, chemically named N-(6-((2S,6R)-2,6-dimethylmorpholino)pyridin-3-yl)-2-methyl-4'-(trifluoromethoxy)-[1,1'-biphenyl]-3-carboxamide. The formulation comprises any one of an O / W cream, an oil-based ointment, or a water-soluble ointment.

[0008] The O / W type cream comprises, by weight percentage: 0.01%-1.0% of Sonicet, 10%-35% of oil phase matrix, 1.5%-10% of emulsifier, 5%-20% of solubilizing and penetration-enhancing system, 5%-20% of moisturizer, 0.3%-1.5% of preservative and stabilizing system, and the balance being purified water.

[0009] The oil phase matrix is ​​composed of petrolatum, liquid paraffin, and stearic acid in a mass ratio of (1-5):(0.5-2):(1-3). The petrolatum forms a semi-solid sealing film in the formulation, providing physical shielding and retaining skin moisture; the liquid paraffin adjusts the spreadability and applicability of the formulation; and the stearic acid acts as an auxiliary emulsifying component and provides suitable consistency.

[0010] The emulsifier is composed of glyceryl monostearate, triethanolamine, and polysorbate 80 in a mass ratio of (1-3):(1-4):(0.5-2). During emulsification, triethanolamine reacts with stearic acid to form sodium stearate soap in situ, which, together with glyceryl monostearate and polysorbate 80, constructs a highly stable multi-emulsification system, inhibiting droplet coalescence during storage.

[0011] The solubilizing and penetration-enhancing system comprises dimethyl sulfoxide, laurocapram, and propylene glycol. Dimethyl sulfoxide acts as the primary solvent, responsible for completely dissolving the highly lipophilic Sinedig molecules and carrying them across the stratum corneum. Laurocapram increases the diffusion coefficient of drug molecules by interfering with the arrangement of the lipid bilayer of the stratum corneum. Propylene glycol acts as a co-solvent, maintaining the drug in a saturated dissolved state on the skin surface after water evaporation and preventing drug crystallization.

[0012] The moisturizing agent includes glycerin and disodium ethylenediaminetetraacetate (EDTA-2Na). The glycerin increases the osmotic pressure of the aqueous phase, maintaining a moist environment for damaged skin; the EDTA-2Na acts as a chelating agent, complexing metal ions in the aqueous phase and inhibiting the oxidative degradation of drug molecules.

[0013] The corrosion-stabilizing system includes ethyl p-hydroxybenzoate and phenoxyethanol, which are used to inhibit microbial growth and maintain the chemical stability of the formulation at room temperature.

[0014] Furthermore, the present invention provides a preferred O / W type cream formulation, which, based on 100% of the total mass of the preparation, comprises the following components: 0.125% Sonicate, 10% Vaseline, 5% liquid paraffin, 3% glyceryl monostearate, 7% stearic acid, 3.5% triethanolamine, 1% polysorbate 80, 0.1% EDTA-2Na, 2% laurocapram, 3% dimethyl sulfoxide, 0.1% ethylparaben, 0.4% phenoxyethanol, 8% glycerin, 5% propylene glycol, and the balance being distilled water.

[0015] This invention also provides an oily ointment formulation, wherein the oily ointment is composed of a pre-dissolved solution of Sonicepidoxime and a pharmaceutical-grade petrolatum base. The pre-dissolved solution of Sonicepidoxime includes Sonicepidoxime, dimethyl sulfoxide, polyethylene glycol 400 (PEG400), polysorbate 80, and physiological saline. The oily ointment, through the high occlusive properties of petrolatum, forms an artificial barrier on the surface of radiation-damaged skin, reducing transdermal water loss and promoting the passive diffusion of drug molecules into the deep dermal tissue.

[0016] This invention also provides a water-soluble ointment formulation, wherein the ointment uses pharmaceutical-grade polyethylene glycol 400 and polyethylene glycol 3350 in a 1:1 mass ratio as a base, and anhydrous ethanol as the initial solubilizer for Sonidazole. The water-soluble base has good hydrophilicity and washability, and is suitable for radiation dermatitis wounds with exudate.

[0017] This invention further provides a method for preparing the above-mentioned O / W type cream formulation. This method solves the technical difficulties of Sinedig's easy degradation upon heating and easy crystallization in a cold matrix through strict temperature control and drug addition sequence. The specific steps are as follows: S1. Aqueous phase preparation: Mix glycerol, EDTA-2Na, triethanolamine, ethylparaben, polysorbate 80 and purified water, heat to 80-85℃, melt at a constant temperature and stir evenly to obtain a clear and transparent aqueous solution.

[0018] S2. Oil phase preparation: Mix petrolatum, liquid paraffin, stearic acid, glyceryl monostearate, and phenoxyethanol, heat to 75-80℃, melt at a constant temperature and stir evenly to obtain a uniform and transparent oil phase liquid.

[0019] S3. Emulsification into a paste: Under constant temperature of 80℃, the aqueous phase obtained in step S1 is slowly added to the oil phase obtained in step S2. The emulsifier is turned on and homogenized at a speed of 10000-15000 rpm for 5-10 minutes. Then, the speed is switched to 300 rpm for low-speed stirring to form a preliminary emulsion system. The temperature is then lowered to 50-55℃ to obtain a blank cream matrix.

[0020] S4. Low-Temperature Drug Addition: Accurately weigh SonicDysyl and completely dissolve it in a mixed solvent of dimethyl sulfoxide, propylene glycol, and laurocapram to form a concentrated drug solution. Once the blank cream matrix from step S3 has cooled to 40°C, add the concentrated drug solution dropwise into the matrix.

[0021] S5. Homogenization and Curing: Under constant temperature of 40℃, use a homogenizer to continuously stir at a speed of 200~300rpm for 15-20 minutes to make the Sonidage molecules evenly distributed in the cream droplets. Then, let it cool naturally to room temperature to obtain a white to off-white fine cream.

[0022] In the above preparation method, the 40°C low-temperature drug addition process in step S4 is crucial for maintaining drug activity. Because the sinedipropionate (Sinedipropion) molecule contains amide bonds and biphenyl structures, it is prone to hydrolysis or oxidation when exposed to temperatures above 80°C for extended periods. By introducing a pre-dissolved drug solution before the matrix semi-solidifies and when the temperature drops to 40°C, uniform drug dispersion in the matrix is ​​ensured, while thermal degradation is avoided. Simultaneously, pre-dissolution treatment with solvents such as dimethyl sulfoxide inhibits crystallization of drug molecules during matrix cooling, ensuring the physical stability of the formulation.

[0023] This invention also provides the application of Sonicet in the preparation of drugs for preventing and treating radiation-induced skin damage. Radiation-induced skin damage encompasses acute and chronic skin damage induced by ionizing radiation such as X-rays, gamma rays, and electron beams. Specifically, the ointment formulation of this invention is applied to the skin surface of the irradiated area before receiving radiotherapy.

[0024] The technical principle behind this application lies in the fact that Sinedig, a potent Smoothened (SMO) receptor inhibitor, can cross the stratum corneum barrier and enter the germinal layer and dermis after being administered through the skin. During radiation damage, ionizing radiation abnormally activates the Hedgehog (Hh) signaling pathway, leading to the release of pro-inflammatory factors, abnormal apoptosis of basal cells, and dysfunction of dermal fibroblasts. The formulation of this invention maintains a high concentration of Sinedig in local tissues, precisely binding to and blocking the SMO receptor, thereby inhibiting the activation of downstream GLI transcription factors. This process effectively downregulates the expression of inflammatory mediators such as IL-6 and TNF-α, reduces radiation-induced increases in microvascular permeability, and protects the proliferative capacity of epidermal stem cells, thus blocking the cascade reaction of radiation-induced skin damage at the molecular level.

[0025] The beneficial effects of this invention are reflected in the following aspects: First, it achieves a balance between local targeted drug delivery and systemic safety. This invention delivers SonicDydira directly to the radiation-damaged skin through a topical ointment formulation, resulting in a significantly higher drug concentration in the skin tissue compared to oral administration.

[0026] Secondly, it solves the problem of stability and dispersibility of extremely poorly soluble drugs. The dimethyl sulfoxide-lauryl azelazone-propylene glycol synergistic solubilizing and permeation-enhancing system constructed in this invention utilizes the stepwise dissolution effect of polar and non-polar solvents to uniformly encapsulate Sonicep in the inner oil phase or interfacial layer of O / W cream in a molecular state. Furthermore, the chemical structural integrity of the drug is protected by a low-temperature dosing process, ensuring the stability of clinical efficacy.

[0027] Third, it exhibits significant and dose-dependent preventive and therapeutic effects. In pharmacodynamic studies of a mouse model of radiation-induced skin injury (a single high-dose irradiation of 30 Gy), the Sinedig ointment provided by this invention demonstrated excellent protective capabilities. The low-dose group (1 mg / kg) significantly delayed the onset of skin erythema; the high-dose group (10 mg / kg) maintained a skin injury score below 1.0 throughout the observation period (only showing mild redness), and no obvious dry desquamation, wet desquamation, or ulceration was observed.

[0028] Fourth, the formulation has good clinical applicability. The O / W type cream matrix provided by this invention has excellent spreadability, is non-greasy and easily absorbed after application, and has an extremely low radiation absorption coefficient during radiotherapy, thus not producing an additional skin surface dose enhancement effect. Furthermore, the oil-based and water-soluble matrix solutions provided by this invention offer diverse options for skin lesions at different clinical stages, meeting the needs of comprehensive management from early erythema prevention to later wound repair.

[0029] In summary, this invention, through scientific formulation design and a unique low-temperature drug delivery process, has successfully developed a topical ointment formulation of Sonideji with stable physicochemical properties, definite efficacy, and high safety. This formulation fills the gap in targeted therapy drugs for radiation-induced skin damage, provides important technical support for improving the quality of life of cancer radiotherapy patients and ensuring the smooth implementation of radiotherapy plans, and has broad prospects for clinical translation.

[0030] Furthermore, in order to enable those skilled in the art to implement the present invention, the specific experimental verification process and results of the formulation of the present invention in preventing and treating radiation-induced skin damage are described in detail below.

[0031] In the pharmacodynamic evaluation, C57BL / 6J mice were used as experimental animals. After hair removal on their backs, a 3cm×3cm irradiation area was exposed. One hour before irradiation, the corresponding dose of SonicDig ointment or blank petroleum jelly base was applied to the hair-removed area. 60 A radiation-induced skin injury model was established by single-dose local irradiation of the hairless area on the back of mice with Coγ rays. The experiment was divided into a blank control group (no irradiation + blank cream), a matrix group (irradiation + blank cream), a low-dose Sinedazole group (irradiation + 1 mg / kg cream), a medium-dose Sinedazole group (irradiation + 5 mg / kg cream), and a high-dose Sinedazole group (irradiation + 10 mg / kg cream).

[0032] The administration regimen was as follows: the first dose was administered 1 hour before irradiation. Morphological changes in the irradiated skin area of ​​the mice were observed and recorded weekly.

[0033] The experimental results showed that mice in the matrix group began to develop obvious skin erythema 2-3 weeks after irradiation, reaching the peak of damage around week 3, manifested as severe moist desquamation and focal ulceration. In contrast, all dose groups of Sonicep showed varying degrees of protective effect. Among them, the high-dose group (10 mg / kg) showed the most outstanding performance, with its skin damage score remaining at a low level throughout, and only slight hyperemia observed on the skin surface, without desquamation or ulceration.

[0034] In summary, the Sinedig ointment formulation provided by this invention has a scientifically sound composition, good drug stability, and enables targeted local drug delivery, effectively exerting the drug's activity. This formulation exhibits excellent preventative and therapeutic effects against radiation-induced skin damage, with definite efficacy and high safety, providing a highly efficient and safe novel treatment method for the clinical prevention and treatment of radiation-induced skin damage. Attached Figure Description

[0035] Figure 1 This is a trend graph showing the change in the degree of skin damage over time in mice of different treatment groups within 6 weeks after a single high-dose irradiation of 30 Gy in the experiment of this invention. The latter three groups represent the degree of damage at doses of 1 mg / kg, 5 mg / kg, and 10 mg / kg, respectively. Figure 2 The image shows the appearance of the Sondega ointment formulation based on pharmaceutical petrolatum in an embodiment of the present invention. The leftmost image is an oily ointment, the middle image is an O / W type cream, and the rightmost image is a water-soluble ointment. Figure 3 This is a trend graph showing the change of skin damage severity score over time in an embodiment of the present invention; Figure 4 This is a skin scoring table according to an embodiment of the present invention. Detailed Implementation

[0036] The invention will be more readily understood by referring to the following detailed description of preferred embodiments and included examples. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. In case of conflict, the definitions in this specification shall prevail.

[0037] As used herein, the terms “prepared from” and “comprising” are synonymous. The terms “comprising,” “including,” “having,” “containing,” or any other variations thereof, as used herein, are intended to cover non-exclusive inclusion. For example, a composition, step, method, article, or apparatus that includes the listed elements is not necessarily limited to those elements, but may include other elements not expressly listed or elements inherent to such composition, step, method, article, or apparatus.

[0038] The conjunction "composed of..." excludes any unspecified elements, steps, or components. If used in a claim, this phrase makes the claim closed, excluding materials other than those described, except for associated conventional impurities. When the phrase "composed of..." appears in a clause of the body of a claim rather than immediately following it, it limits only the elements described in that clause; other elements are not excluded from the claim as a whole.

[0039] When a quantity, concentration, or other value or parameter is expressed as a range, a preferred range, or a range defined by a series of upper and lower preferred values, this should be understood as specifically disclosing all ranges formed by any pair of any upper or preferred value with any lower or preferred value, regardless of whether the range is disclosed individually. For example, when the range “1 to 5” is disclosed, the described range should be interpreted as including the ranges “1 to 4”, “1 to 3”, “1 to 2”, “1 to 2 and 4 to 5”, “1 to 3 and 5”, etc. When numerical ranges are described herein, unless otherwise stated, the range is intended to include its endpoints and all integers and fractions within that range.

[0040] The singular form includes the plural objects of discussion unless the context clearly indicates otherwise. "Optional" or "any one" means that the matter or event described thereafter may or may not occur, and the description includes both the possibility that the event occurs and the possibility that the event does not occur.

[0041] Approximate terms used in the specification and claims to modify quantities indicate that the invention is not limited to that specific quantity, but also includes acceptable modifications close to that quantity that do not alter the relevant essential function. Correspondingly, the use of "about," "approximately," etc., to modify a numerical value means that the invention is not limited to that precise value. In some instances, approximate terms may correspond to the precision of the instrument used to measure the value. In this application's specification and claims, scope definitions can be combined and / or interchanged, unless otherwise stated, these scopes include all subscopes contained therein.

[0042] Furthermore, the indefinite articles “a” and “an” preceding the elements or components of this invention do not impose any limitation on the quantity requirement (i.e., the number of times) of the elements or components. Therefore, “an” or “a” should be interpreted as including one or at least one, and the singular form of an element or component also includes the plural form, unless the quantity clearly refers to the singular form.

[0043] Example 1: The Sonidegib ointment formulation of this invention has Sonidegib as its core active ingredient. Sonidegib is a highly selective smoothed receptor inhibitor. In practical applications, radiation-induced skin damage is often accompanied by disruption of the epidermal barrier, dermal inflammatory infiltration, and microvascular damage. This invention's formulation, applied topically, allows drug molecules to cross the stratum corneum and penetrate deep into the skin tissue, blocking the abnormal activation of the Hedgehog signaling pathway and thus inhibiting the inflammatory cascade response in skin cells.

[0044] In a preferred embodiment of the present invention, the Soniceji ointment formulation adopts an O / W type cream dosage form. The optimized formulation components, by mass percentage, are: Soniceji 0.125%, petrolatum 10%, liquid paraffin 5%, glyceryl monostearate 3%, stearic acid 7%, triethanolamine 3.5%, polysorbate 80 1%, EDTA-2Na 0.1%, laurocapram 2%, dimethyl sulfoxide 3%, ethylparaben 0.1%, phenoxyethanol 0.4%, glycerin 8%, propylene glycol 5%, and the balance being distilled water. In this formulation system, petrolatum and liquid paraffin together constitute the oil phase framework, forming a semi-closed lipid film on the skin surface, thereby increasing the drug partition coefficient by increasing skin hydration. Stearic acid and triethanolamine undergo a saponification reaction during emulsification, generating sodium stearate soap in situ. This soap acts as the main emulsifier, synergistically with the nonionic emulsifier polysorbate 80, significantly reducing the oil-water interfacial tension and forming uniformly distributed droplets. The ternary penetration-enhancing system composed of dimethyl sulfoxide, laurocapram, and propylene glycol effectively improves the transdermal rate of SonicDysgene by altering the arrangement of lipids in the stratum corneum, ensuring that the drug reaches the effective concentration required to prevent radiation damage in the dermis.

[0045] The preparation method provided in this embodiment of the invention for the above-mentioned O / W type cream formulation includes the following steps.

[0046] S1. Preparation of aqueous phase: Weigh distilled water, glycerol, propylene glycol, triethanolamine, polysorbate 80, EDTA-2Na, ethylparaben, and phenoxyethanol according to the prescribed amounts, place them in a reaction dish, and raise the temperature to 80 to 85°C using a water bath until all solid components are completely dissolved and the liquid is clear. Then maintain this temperature for later use.

[0047] S2. Oil phase preparation: Weigh out the following amounts according to the prescription: petrolatum, liquid paraffin, glyceryl monostearate, stearic acid, and laurocapram. Place them in an oil phase container and heat them in a water bath to 75-80°C to completely melt the solid oils such as petrolatum, forming a homogeneous and transparent liquid oil phase. Keep the liquid at a constant temperature for later use.

[0048] S3. Emulsification into a paste: Under constant temperature and stirring conditions, the high-temperature aqueous phase obtained in step S1 is slowly and continuously added to the oil phase obtained in step S2 in a flowing manner. During the addition process, the system temperature is maintained at 80℃, and homogenization is carried out using an emulsifier at a speed of 10000-15000 rpm for 5-10 minutes, followed by switching to low-speed stirring at 300 rpm. During this process, the aqueous phase and oil phase undergo a phase transition under the action of the emulsifier, forming a uniform milky white semi-solid paste, which is the blank cream base.

[0049] S4. Low-Temperature Drug Addition and Homogenization: This is the core step to ensure the stability of Sinemet. The blank cream matrix obtained in step S3 is cooled in a water bath while maintaining low-speed stirring. When the matrix temperature drops to 40°C, the Sinemet active pharmaceutical ingredient solution, pre-dissolved in the prescribed amount of dimethyl sulfoxide, is added dropwise to the matrix. Under constant temperature of 40°C, homogenization is performed using a homogenizer at a speed of 200-300 rpm for 15-20 minutes. Since Sinemet is relatively sensitive to heat, adding it at 40°C effectively avoids drug degradation caused by high temperature. At the same time, the matrix at 40°C still has good fluidity, ensuring the microscopic uniform distribution of drug molecules in the matrix, thereby preventing local crystallization of the drug during the cooling process.

[0050] S5. Cooling and Curing: The homogenized cream with added medicine is naturally cooled to room temperature (20-25°C) under stirring. During this process, the viscosity of the cream gradually increases, eventually forming a smooth, glossy Sonideji cream product, which is then stored in a light-proof, sealed container.

[0051] In another embodiment of the invention, a topical ointment formulation of Sonicegan with pharmaceutical petrolatum as the single matrix is ​​provided. This formulation is particularly suitable for patients with radiation-induced skin damage characterized by dryness and severe desquamation. The preparation process first involves the preparation of a pre-dissolved Sonicegan solution. Under light-protected conditions, 10 mg of Sonicegan powder is dissolved in 250 μL of dimethyl sulfoxide and vortexed until completely dissolved; subsequently, 1 mL of PEG400 and 125 μL of polysorbate 80 are added sequentially and vortexed until homogeneous; finally, 1.25 mL of physiological saline is added to prepare a 5 mg / mL Sonicegan pre-dissolved concentrate. In preparing the ointment, pharmaceutical petrolatum is gently heated until completely melted, and then, according to the required dosage (e.g., 1 mg / kg, 5 mg / kg, or 10 mg / kg), the corresponding volume of the pre-dissolved solution is added to the petrolatum matrix, which has cooled to near room temperature. The drug is then thoroughly stirred to achieve uniform dispersion in the oil matrix. Figure 2 As shown, the Sonic Vaseline ointment prepared by this invention exhibits a uniform and delicate semi-solid texture, with no visible particles, and has excellent skin spreadability.

[0052] In another embodiment of the invention, a water-soluble ointment with pharmaceutical-grade polyethylene glycol (PEG) as a single matrix was developed for patients with minor exudation or lipoallergy. The formulation uses a 1:1 mass ratio of PEG400 and PEG3350. PEG400 provides lubricity and solubility, while PEG3350 provides suitable consistency. In preparation, the two PEG components are first melted and mixed in a 60°C water bath, then cooled before adding an ethanol solution of Sonicet. Anhydrous ethanol serves not only as a solvent for the drug but also as an aid in penetration. This formulation exhibits good hydrophilicity, is easily washed off with water after application, and does not impede the drainage of wound exudate, thus maintaining a clean wound environment.

[0053] To verify the efficacy of the formulation of this invention in preventing and treating radiation-induced skin damage, a systematic in vivo pharmacodynamic validation experiment was conducted in this embodiment. The experiment used male C57BL / 6J mice, and... 60 Mouse backs were irradiated with a single dose of 30 Gy of Co-γ rays. The experiment was divided into five groups: a blank control group (no irradiation and only a blank base applied); a model control group (30 Gy irradiation and blank petroleum jelly base applied); a low-dose group (1 mg / kg); a medium-dose group (5 mg / kg); and a high-dose group (10 mg / kg).

[0054] The administration process began 1 hour before irradiation, with 200 μL of the corresponding concentration of Sonicoge ointment evenly applied to the irradiated area. The observation period after irradiation lasted for 6 weeks.

[0055] Combined with appendix Figure 1 Analysis of the experimental results showed that the blank control group maintained a score of 0 throughout the observation period, indicating that the skin remained in a normal physiological state. The model control group developed significant skin erythema and desquamation starting in the second week after irradiation, with the score rapidly increasing, manifesting as large-area wet desquamation and exudation. In stark contrast, skin damage in the drug-treated groups was significantly suppressed. The low-dose and medium-dose groups showed peak scores not exceeding 2 points, with mild skin erythema; the high-dose group exhibited the strongest protective effect, with a score not exceeding 1 point throughout the 6-week observation period, showing no significant skin redness, wet desquamation, or necrosis, and normal hair growth was observed. This result demonstrates that the formulation of this invention, through local administration, can reduce the severity of radiation-induced skin damage in a dose-dependent manner.

[0056] Regarding safety, the formulation of this invention exhibited excellent local tolerability. During a continuous 6-week administration period, no non-radiation-related redness, swelling, itching, or allergic reactions occurred at the administration site. Throughout the experiment, mice in all treatment groups showed stable weight gain, good mental status, and no deaths or cachexia due to drug absorption occurred, suggesting that topical administration allows Sonicep to remain primarily in the skin tissue, thus avoiding systemic toxicity common with oral administration, such as elevated serum creatine kinase, muscle spasms, and liver damage.

[0057] In practical clinical applications, the formulation of this invention can be used as a routine adjuvant drug for radiotherapy of malignant tumors. For patients receiving radiotherapy to the head and neck, chest, or pelvis, applying the formulation of this invention before the start of radiotherapy can serve as a preventative intervention, significantly increasing the skin's tolerance threshold to radiation.

[0058] Furthermore, the formulation of this invention has good scalability. In addition to the petrolatum and PEG matrix mentioned in the above embodiments, Soniadi can be combined with skin-repairing components such as hyaluronic acid and ceramides, or prepared into gels or patches with long-acting release properties, depending on clinical needs. Regardless of the dosage form, as long as the core technology involves using Soniadi topically to block the Hh pathway to prevent radiation-induced skin damage, it falls within the scope of protection of this invention.

[0059] In summary, this invention, through formulation optimization and process improvement of Sinedegare topical ointment, has successfully developed a drug for preventing and treating radiation-induced skin damage that exhibits strong local targeting, high stability, definite efficacy, and good safety. This invention not only solves the physicochemical challenges in Sinedegare formulation development but also, through rigorous in vivo experiments, demonstrates its significant advantages in reducing radiation-induced skin damage scores and protecting skin tissue structure, providing a novel technical approach and reliable drug selection for clinical radiotherapy protection.

[0060] The implementation of the formulation of this invention will significantly improve the quality of life of radiotherapy patients, reduce treatment costs, and has significant social and economic benefits.

[0061] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the present invention as claimed. The scope of protection of this invention is defined by the appended claims and their equivalents.

Claims

1. A topical ointment formulation, characterized in that, The active ingredient of the formulation is Sonicet, whose chemical name is N(6((2S,6R)2,6-dimethylmorpholino)pyridinyl)2-methyl-4'(trifluoromethoxy)[1,1'-biphenyl]3-formamide; the formulation includes any one of O / W cream, grease ointment or water-soluble ointment.

2. The topical ointment formulation according to claim 1, characterized in that, The O / W type cream, by weight percentage, comprises: 0.01%~1.0% of Sonicate, 10%~35% of oil phase matrix, 1.5%~10% of emulsifier, 5%~20% of solubilizing and penetration-enhancing system, 5%~20% of humectant, 0.3%~1.5% of preservative and stabilizing system, and the balance being purified water.

3. The topical ointment formulation according to claim 2, characterized in that, The oil phase matrix is ​​composed of petrolatum, liquid paraffin, and stearic acid in a mass ratio of (1~5):(0.5~2):(1~3).

4. The topical ointment formulation according to claim 2, characterized in that, The emulsifier is composed of glyceryl monostearate, triethanolamine, and polysorbate 80 in a mass ratio of (1~3):(1~4):(0.5~2).

5. A topical ointment formulation according to claim 2, characterized in that, The solubilizing and penetration-enhancing system includes dimethyl sulfoxide, laurocapram, and propylene glycol; the humectant includes glycerin and disodium EDTA; and the preservative and stabilizing system includes ethylparaben and phenoxyethanol.

6. The topical ointment formulation according to claim 2, characterized in that, The components of the low-dose Sonicetine dosing group, calculated based on 100% of the total mass of the preparation, are as follows: Sonicetine 0.125%, petrolatum 10%, liquid paraffin 5%, glyceryl monostearate 3%, stearic acid 7%, triethanolamine 3.5%, polysorbate 80 1%, disodium EDTA 0.1%, laurocapram 2%, dimethyl sulfoxide 3%, ethylparaben 0.1%, phenoxyethanol 0.4%, glycerol 8%, propylene glycol 5%, and the balance being distilled water.

7. The topical ointment formulation according to claim 1, characterized in that, The greasy ointment is composed of a pre-dissolved solution of Sonica and a pharmaceutical petrolatum base; the pre-dissolved solution of Sonica includes Sonica, dimethyl sulfoxide, polyethylene glycol 400, polysorbate 80 and physiological saline.

8. The topical ointment formulation according to claim 1, characterized in that, The water-soluble ointment uses pharmaceutical grade polyethylene glycol 400 and polyethylene glycol 3350 in a 1:1 mass ratio as a base, and anhydrous ethanol as the initial solubilizer for Sonid.

9. A method for preparing a topical ointment formulation as described in claim 2, characterized in that, Includes the following steps: S1. Preparation of aqueous phase: Mix glycerol, disodium EDTA, triethanolamine, ethyl p-hydroxybenzoate, polysorbate 80 and purified water, heat to 80~85℃, melt at constant temperature and stir evenly to obtain an aqueous solution; S2. Preparation of oil phase: Mix petrolatum, liquid paraffin, stearic acid, glyceryl monostearate, and phenoxyethanol, heat to 75~80℃, melt at a constant temperature and stir evenly to obtain oil phase liquid; S3. Emulsification into a paste: Under constant temperature of 80℃, the aqueous phase obtained in step S1 is added to the oil phase obtained in step S2, and the mixture is homogenized and emulsified at a speed of 10000~15000 rpm for 5~10 minutes. Then, the mixture is stirred at a speed of ~300 rpm and cooled to 50~55℃ to obtain a blank cream base. S4. Low-temperature drug addition: Dissolve Sonicid in a mixed solvent of dimethyl sulfoxide, propylene glycol and laurocapram to form a concentrated drug solution; When the blank cream matrix in step S3 has cooled to ~40℃, the concentrated drug solution is added to the matrix; S5. Homogeneous curing: Under constant temperature of 40℃, stir continuously at a speed of 200~300rpm for 15~20 minutes, then cool to room temperature.

10. The method for preparing a topical ointment formulation according to claim 9, characterized in that, In step S4, Sonicaji is completely dissolved in dimethyl sulfoxide under light-protected conditions, followed by the sequential addition of propylene glycol and laurocapram, mixed evenly, and then added to a blank cream base at 40°C.

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