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WO2025185660A1 - Pommade cutanée de simvastatine à l'état moléculaire à charge de médicament élevée, sa préparation et son utilisation - Google Patents

Pommade cutanée de simvastatine à l'état moléculaire à charge de médicament élevée, sa préparation et son utilisation

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Publication number
WO2025185660A1
WO2025185660A1 PCT/CN2025/080783 CN2025080783W WO2025185660A1 WO 2025185660 A1 WO2025185660 A1 WO 2025185660A1 CN 2025080783 W CN2025080783 W CN 2025080783W WO 2025185660 A1 WO2025185660 A1 WO 2025185660A1
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WO
WIPO (PCT)
Prior art keywords
simvastatin
ointment
drug
skin
parts
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Pending
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PCT/CN2025/080783
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English (en)
Chinese (zh)
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WO2025185660A8 (fr
Inventor
赵锡龙
唐星
张宁
宗琦文
李�杰
马琳
杨舟
李鹏
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Beijing Merson Pharmaceutical Technology Development Co Ltd
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Beijing Merson Pharmaceutical Technology Development Co Ltd
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Publication of WO2025185660A1 publication Critical patent/WO2025185660A1/fr
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Pending legal-status Critical Current
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/06—Ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders

Definitions

  • the present disclosure relates to the field of medical technology, and in particular to a high-drug-loading molecular simvastatin skin ointment and its preparation and application.
  • Autosomal recessive ichthyosis is a heterogeneous group of nonsyndromic ichthyoses characterized by erythematous, keratotic, and scaly skin. Clinical manifestations and severity vary widely. They are caused by mutations in genes encoding enzymes involved in cholesterol synthesis, leading to impaired synthesis of the end product cholesterol and accumulation of toxic lipid metabolic intermediates.
  • moisturizers and topical keratolytics are the preferred treatment options for autosomal recessive ichthyosis. These agents can improve skin barrier function and promote desquamation. However, these treatments are associated with significant and numerous side effects, necessitating the development of safe, effective, and patient-friendly pharmacological agents.
  • Vitiligo is an acquired, localized or generalized skin depigmentation disorder caused by the functional loss or decrease in number of melanocytes in the skin. To date, its etiology and pathogenesis remain largely unexplained. International and domestic analyses suggest that the pathogenesis of vitiligo is multifactorial, primarily involving genetics, immunity, oxidative stress, and melanocyte self-destruction. Due to this lack of clarity, no single treatment method has been found that is consistently effective and minimizes side effects.
  • Oxidative stress in melanocytes can induce local inflammatory responses and innate immune responses, leading to melanocyte destruction and is considered a key pathogenic factor in the development and progression of vitiligo.
  • Simvastatin possesses antioxidant properties and has demonstrated protective effects in a variety of oxidative stress-related diseases, protecting vitiligo melanocytes from oxidative stress damage.
  • Simvastatin is a synthetic product of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors fermented from Aspergillus terreus. It is a white or off-white crystalline powder. It is easily soluble in ethanol, acetone or acetonitrile, but insoluble in water. It belongs to BCS Class II drugs. At the same time, in the presence of water, the lactone ring of simvastatin will be hydrolyzed into hydroxy acid.
  • HMG-CoA hydroxymethylglutaryl coenzyme A reductase inhibitors fermented from Aspergillus terreus. It is a white or off-white crystalline powder. It is easily soluble in ethanol, acetone or acetonitrile, but insoluble in water. It belongs to BCS Class II drugs. At the same time, in the presence of water, the lactone ring of simvastatin will be hydrolyzed into hydroxy acid.
  • Patent CN110368358A discloses a preparation method of simvastatin external preparation for treating autosomal recessive ichthyosis and xanthomas, which is made from the following weight ratio of raw materials and excipients: simvastatin 25-500g, stearic acid 550-600g, glyceryl monostearate 300-350g, light liquid paraffin 100-110ml, ethyl hydroxybenzoate 4-6g, glycerol 600-650g, sodium lauryl sulfate 8-12g, triethanolamine 8-12ml, laurocapram 20-30ml, water is supplemented to 5000g.
  • Patent CN112791049 A discloses a method for preparing simvastatin ointment for treating vitiligo.
  • the raw materials include 1-6% simvastatin, 2-2.5% triethanolamine, 3.5-4.5% glycerol, 2-2.5% soft soap, 0.2-0.4% ethylparaben, 20-30% vaseline, 3-5% anhydrous lanolin, 20-30% octadecyl alcohol, 3-5% stearic acid, and the balance is distilled water.
  • the preparation method separately prepares an aqueous phase and an oil phase, adds the aqueous phase to the oil phase, heats to 40-45°C, and stirs to form an emulsion to obtain simvastatin ointment.
  • the preparation method is very cumbersome, difficult to scale up production, and has poor transdermal effect.
  • the water involved in the preparation process can easily degrade simvastatin, making it difficult to prepare as a drug, greatly reducing the therapeutic effect, lowering the drug accumulation concentration, and extending the treatment cycle.
  • the present invention aims to provide a highly drug-loaded molecular simvastatin skin ointment, its preparation, and use. By administering the drug via application, the adverse side effects of oral simvastatin can be effectively avoided, significantly enhancing its safety. Furthermore, the present invention utilizes an anhydrous preparation and storage process, and the drug is dissolved in the matrix in molecular form, which not only increases the drug's solubility but also its retention in the skin, significantly improving its efficacy.
  • a molecular simvastatin ointment for skin use with a high drug loading content comprises simvastatin as an active ingredient and a pharmaceutically acceptable non-aqueous semisolid material.
  • the simvastatin ointment for skin use comprises simvastatin as an active ingredient and a basic matrix composition;
  • the basic matrix composition comprises a basic matrix, a solubilizer, a consistency regulator and a stabilizer.
  • the simvastatin skin ointment is prepared from the following raw materials in the following weight ratios:
  • the basic matrix composition is selected from one or more of white petrolatum, yellow petrolatum, solid paraffin, vegetable oil, stearic acid and beeswax.
  • the solubilizing agent is selected from one or more of Tween-80, Span-80 and phospholipids.
  • the consistency regulator is selected from one or more of anhydrous lanolin and liquid paraffin.
  • the stabilizer is selected from one or more of glyceryl monostearate, cholesterol and caprylic/capric triglyceride.
  • the present disclosure further provides a method for preparing simvastatin skin ointment:
  • the basic matrix composition i.e., the solubilizer, stabilizer, consistency regulator and basic matrix are mixed, heated to 60-90° C. to melt, cooled to 30-50° C. after melting, simvastatin is added to the basic matrix composition, stirred evenly and cooled to room temperature to obtain simvastatin ointment.
  • the present disclosure also provides use of the aforementioned simvastatin skin ointment in treating autosomal recessive ichthyosis and vitiligo.
  • the present disclosure also provides the use of the aforementioned simvastatin skin ointment in the preparation of a medicament for treating autosomal recessive ichthyosis and vitiligo.
  • the disclosed simvastatin skin ointment has a high drug loading capacity, with simvastatin molecularly dispersed in the matrix, resulting in improved stability and significantly enhanced efficacy.
  • Conventional simvastatin topical preparations can have a maximum drug loading of 3%, but the disclosed ointment can increase the drug loading to 5%, allowing for a higher concentration of simvastatin in the preparation and improving efficacy.
  • the preparation process of the invention is simple and easy to produce in large quantities.
  • the simvastatin skin ointment disclosed herein contains a reverse micelle structure. Cholesterol and phospholipids can self-assemble to form reverse micelles in non-aqueous solutions, enhancing drug stability and the solubility of weakly polar drugs. When used as a transdermal drug delivery vehicle, the reverse micelle system can promote transdermal transport and enhance drug absorption.
  • FIG1 shows the in vitro release test results of Test Example 1.
  • FIG2 shows the in vitro permeation test results of Test Example 2.
  • FIG3 shows a thin layer chromatogram of the stability of the preparation of Test Example 3.
  • FIG4 shows the drug efficacy study of Test Example 4 - changes in skin and fur color before and after administration.
  • FIG5A shows the HE-stained pathological section of the blank group in the drug efficacy study of Test Example 4. ...
  • FIG5B shows the HE-stained pathological sections of the drug efficacy study of the model group of Test Example 4.
  • FIG5B shows the HE-stained pathological sections of the model group of Test Example 4.
  • FIG5C shows the efficacy study of the UV group of Test Example 4 - HE-stained pathological sections.
  • FIG5D shows the HE-stained pathological section of the drug efficacy study of the natural recovery group of Test Example 4.
  • FIG5E shows the HE-stained pathological section of the low-dose+UV group efficacy study of Test Example 4.
  • FIG5E shows the HE-stained pathological section of the low-dose+UV group.
  • FIG5F shows the HE-stained pathological section of the efficacy study of the medium dose + UV group of Test Example 4.
  • FIG5G shows the HE-stained pathological section of the high-dose+UV group efficacy study of Test Example 4.
  • FIG5H shows the efficacy study of the tacrolimus group in Test Example 4 - HE-stained pathological sections.
  • FIG6 shows the results of a single skin irritation test of Test Example 5.
  • FIG. 7 shows the results of multiple skin irritation experiments in Test Example 5.
  • FIG8 is a graph showing the differential scanning calorimetry (DSC) results of Test Example 6.
  • DSC differential scanning calorimetry
  • FIG. 9 shows the therapeutic effect of Test Example 1 on autosomal recessive ichthyosis.
  • FIG. 10 shows the therapeutic effect of vitiligo in Test Example 2 after 80 days of treatment.
  • Figure 11 shows the thin layer chromatogram of phospholipid-modified simvastatin nanocrystals of Comparative Example 3
  • the articles “a” and “an” refer to one or more than one (ie, to at least one) of the grammatical object to which the article refers.
  • an element means one element or more than one element.
  • the term “about” refers to and encompasses a specified value and a range greater than or less than that value. In certain embodiments, the term “about” can refer to a variation of ⁇ 0.1%, ⁇ 0.5%, ⁇ 1%, ⁇ 2%, ⁇ 3%, ⁇ 4%, ⁇ 5%, ⁇ 6%, ⁇ 7%, ⁇ 8%, ⁇ 9%, or ⁇ 10%. In certain embodiments, where applicable, the term “about” refers to a specified value ⁇ one standard deviation of that value.
  • Simvastatin is a semisynthetic derivative/analog of lovastatin. While insoluble in water, simvastatin is soluble in polar organic solvents. For lipid-soluble drugs, solubility must be addressed when formulating them into pharmaceutical formulations. However, due to simvastatin's readily hydrolyzed nature, carrier solubilization technology is preferred to address this poor solubility issue.
  • Reverse micelles have attracted considerable attention as a novel drug carrier for drug delivery and solubility enhancement. Unlike traditional micelles, reverse micelles possess a relatively low internal polarity, which facilitates the solubility and stabilization of non-polar or hydrophobic drugs. This property enables reverse micelles to effectively enhance the solubility of hydrophobic drugs, thereby increasing their bioavailability.
  • reverse micelles provides a "refuge"-like environment, allowing hydrophobic drugs to exist stably within it. This environment reduces interactions between drug molecules, thereby reducing aggregation and precipitation during drug delivery. Furthermore, this sanctuary effect of reverse micelles protects drugs from environmental influences, such as enzymatic degradation.
  • reverse micelles as drug carriers, can improve drug solubility by changing the physical state of the drug, such as from a crystalline to an amorphous state. Furthermore, reverse micelles can stabilize drug molecules through interactions with drug molecules, such as hydrogen bonds and hydrophobic interactions, thereby increasing their solubility in physiological environments.
  • reverse micelles as drug carriers have been shown to significantly improve the solubility and bioavailability of hydrophobic drugs. This advantage makes reverse micelles promising for future drug delivery systems, providing new strategies and tools for improving drug solubility, stability, and bioavailability.
  • This structure can increase drug stability and bioavailability. Upon contact with body fluids, it transforms into a liquid crystal structure, retarding drug dissolution and thus achieving sustained-release drug delivery. It also has particular advantages as a carrier for transdermal drug delivery systems, promoting transdermal drug transport, enhancing drug stability, and reducing skin irritation.
  • Materials commonly used to form reverse micelle structures include anionic surfactants, cationic surfactants, nonionic surfactants and amphoteric surfactants.
  • Anionic surfactants This type of surfactant has good foaming properties and can quickly produce a large amount of foam. The foam is large and stable and not easy to break. It has little irritation to the skin and eyes, good biodegradability, strong antistatic properties, and is easy and safe to use.
  • Cationic surfactants This type of surfactant has good bactericidal, antistatic and softening properties, but it is highly irritating, easily soluble in water, and has poor oxidation resistance, and can generally only be used as a detergent.
  • Non-ionic surfactants These surfactants are resistant to strong electrolytes, hard water, acids and alkalis. They are colorless, odorless, non-toxic, non-irritating, and non-allergenic. They have excellent wetting, cleaning, rust prevention, and softening properties, and are particularly miscible with various solvents.
  • Amphoteric surfactants contain both anionic and cationic hydrophilic groups within the same molecule. Their greatest characteristic is their ability to both donate and accept protons. They exhibit excellent emulsification and dispersibility during use.
  • the reverse micelle structure in the preparation utilizes a solubilizing agent (one or more of Tween-80, Span-80, and phospholipids) and a stabilizer (one or more of glyceryl monostearate, cholesterol, and caprylic/capric triglyceride) to self-assemble into reverse micelles in a non-aqueous solution.
  • the solubilizing agent and stabilizer are dissolved in a non-aqueous solution such as yellow vaseline, stirred at high temperature to mix them evenly, and then cooled and added to the basic matrix composition.
  • the reverse micelle system can enhance the stability of the drug and increase the solubility of weakly polar drugs. When used as a transdermal drug delivery carrier, the skin retention can be greatly increased, thereby enhancing the transdermal absorption of the drug.
  • simvastatin is almost insoluble in yellow vaseline and liquid paraffin. After adding phospholipids and cholesterol, the drug can exist in the form of molecules, forming reverse micelles, which significantly improves the solubility.
  • the present invention prepares a simvastatin skin ointment with high drug loading, high drug accumulation in the skin, easy penetration, rapid onset and significant efficacy.
  • the present disclosure provides a high-drug-loaded molecular simvastatin skin ointment, comprising simvastatin as an active ingredient and a pharmaceutically acceptable non-aqueous semi-solid material.
  • a non-aqueous semi-solid material including a base matrix, a solubilizer, a consistency regulator, and a stabilizer.
  • the non-aqueous semi-solid material includes a basic matrix, a solubilizer, a consistency regulator, a stabilizer, etc. or a combination thereof.
  • the simvastatin ointment for skin use comprises simvastatin as an active ingredient and a basic matrix composition;
  • the basic matrix composition comprises a basic matrix, a solubilizer, a consistency regulator and a stabilizer.
  • the simvastatin skin ointment is prepared from the following raw materials in the following weight ratios:
  • simvastatin 0.5-5 parts of simvastatin, 5-30 parts of solubilizer, 0.5-5 parts of stabilizer, 5-20 parts of consistency regulator, and 40-89 parts of basic matrix.
  • the basic matrix composition is selected from one or more of white petrolatum, yellow petrolatum, solid paraffin, vegetable oil, stearic acid and beeswax.
  • the solubilizing agent is selected from one or more of Tween-80, Span-80 and phospholipids.
  • the consistency regulator is selected from one or more of anhydrous lanolin and liquid paraffin.
  • the stabilizer is selected from one or more of glyceryl monostearate, cholesterol and caprylic/capric triglyceride.
  • the present disclosure further provides a method for preparing simvastatin skin ointment:
  • the basic matrix composition i.e., the solubilizer, stabilizer, consistency regulator and basic matrix are mixed, heated to 60-90° C. to melt, cooled to 30-50° C. after melting, simvastatin is added to the basic matrix composition, stirred evenly and cooled to room temperature to obtain simvastatin ointment.
  • the present disclosure also provides use of the aforementioned simvastatin skin ointment in treating autosomal recessive ichthyosis and vitiligo.
  • the present disclosure also provides use of the aforementioned simvastatin skin ointment in the preparation of a medicament for treating autosomal recessive ichthyosis and vitiligo.
  • simvastatin skin ointment provided by the present invention and the raw materials and excipients used in its application can all be purchased from the market.
  • 125 parts of Tween-80, 25 parts of glyceryl monostearate, 50 parts of anhydrous lanolin and 275 parts of white vaseline were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin were added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • Span-80 25 parts of Span-80, 25 parts of cholesterol, 100 parts of liquid paraffin, 118 parts of beeswax and 207 parts of vegetable oil were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin was added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • phospholipid 125 parts of phospholipid, 25 parts of caprylic/capric triglyceride, 50 parts of liquid paraffin, 175 parts of solid paraffin and 100 parts of vegetable oil were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin was added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • 125 parts of Tween-80, 25 parts of glyceryl monostearate, 50 parts of anhydrous lanolin and 275 parts of yellow vaseline were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin were added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • phospholipid 125 parts of phospholipid, 15 parts of glyceryl monostearate, 50 parts of liquid paraffin and 285 parts of yellow vaseline were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin were added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • Span-80 Weigh 50 parts of Span-80, 25 parts of glyceryl monostearate, 50 parts of anhydrous lanolin and 350 parts of white vaseline, mix them, heat to 85°C to melt, and then cool to 45°C after melting. Add 25 parts of simvastatin to the molten phase, stir evenly, and then cool to room temperature to obtain a simvastatin skin ointment.
  • phospholipid 125 parts of phospholipid, 2.5 parts of cholesterol, 50 parts of liquid paraffin and 297.5 parts of white vaseline were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin was added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • 125 parts of Tween-80, 25 parts of glyceryl monostearate, 50 parts of anhydrous lanolin and 275 parts of stearic acid were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin was added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • phospholipid 125 parts of phospholipid, 25 parts of cholesterol, 50 parts of liquid paraffin and 275 parts of yellow vaseline were weighed and mixed, heated to 85°C to melt, and then cooled to 45°C. 25 parts of simvastatin were added to the molten phase, stirred evenly, and cooled to room temperature to obtain a simvastatin skin ointment.
  • simvastatin skin ointment prepared in Examples 1-9 was subjected to an in vitro release test as follows:
  • the preparations prepared in Examples 1 to 9 can all be slowly released from the preparations and can meet the expected release requirements of the preparations.
  • a 0.004 g portion of the ointment formulation from Example 9 was precisely weighed and evenly applied to pigskin and ratskin mounted in a Franz diffusion cell for transdermal permeation testing.
  • 2 ml of the receiving medium was collected at 0.5, 1, 2, 4, 6, 8, 10, 12, and 24 hours, and fresh receiving medium was added.
  • the initial filtrate was filtered through a 0.45 ⁇ m microporous membrane, and the peak area was determined by high-performance liquid chromatography.
  • the 24-hour cumulative permeation rate was 13.45% for pigskin vs. 27.8% for ratskin.
  • the final skin retention was greater in pigskin than in ratskin: 35.7% for pigskin vs. 11.4% for ratskin.
  • the experimental results are shown in Figure 2.
  • Example 9 The sample prepared in Example 9 was placed under accelerated conditions (30 ⁇ 2°C, relative humidity 65 ⁇ 5%) for 3 months. The properties, content uniformity and related substances were used as key indicators. The results are shown in Table 3 below:
  • Example 9 The sample prepared in Example 9 was placed under long-term stability conditions (5°C ⁇ 3°C) for 6 months, with properties, content uniformity and related substances as key indicators. The results are shown in Table 4 below:
  • Example 9 Three batches of samples prepared in Example 9 were placed under accelerated conditions (30 ⁇ 2°C, relative humidity 65 ⁇ 5%), and the drug stability was observed using TLC. The results are shown in Figure 3.
  • 1 represents simvastatin
  • 2 represents simvastatin acid
  • 3 represents the preparation of Example 9 at 0 months
  • 4 represents the preparation of Example 9 at 1 month
  • 5 represents the preparation of Example 9 at 3 months.
  • Test Example 4 Pharmacodynamic Study of High-Drug-Loaded Molecular Simvastatin Skin Ointment
  • mice 40 mice were randomly divided into 8 groups, 5 mice in each group, and numbered within each group. They were divided into blank control group, vitiligo model group, natural recovery group, UV group, low-dose + UV group, medium-dose + UV group, high-dose + UV group, and tacrolimus + UV group.
  • Dosage method C57BL/6 mice were selected and the animals were allowed to adapt to the environment for 3 days. On the 4th day, 2 ⁇ 2 square centimeters of dorsal hair were removed from each mouse with a depilatory cream, and modeling was started 24 hours later. The modeling period was 50 days.
  • the blank control group was coated with 0.5 ml/day of sterile distilled water; the model control group, natural recovery group, UV group, low dose + UV group, medium dose + UV group, high dose + UV group, tacrolimus + UV group were smeared on the test area with 3% hydroquinone glycerol solution (1 g of glycerol and 3 g of hydroquinone dissolved in 100 mL of deionized water), with a dose of 100 mg/kg ⁇ d, bid; starting from the 30th day, the tacrolimus group applied a thin layer of the ointment of Example 9 to the mouse skin, gently rubbed it evenly, and completely covered it, twice a day in the morning and evening, plus UV therapy twice a week; UV group: UV therapy twice a week The initial dose was 350 mj/cm2, adjusted based on the presence of erythema or varicella.
  • the dose was increased by 50 mj/cm2 the next time. If skin damage was observed, the dose was temporarily discontinued the next time.
  • the low-dose + UV group 10 mg/kg was applied to the mouse skin and evenly spread once daily, followed by UV phototherapy twice weekly.
  • the medium-dose + UV group 18 mg/kg was applied to the mouse skin and evenly spread once daily, followed by UV phototherapy twice weekly.
  • the high-dose + UV group 25 mg/kg was applied to the mouse skin and evenly spread once daily, followed by UV phototherapy twice weekly. Skin images were taken every other day. Changes in mouse skin color were closely observed throughout the experiment. The results are shown in Figure 4.
  • Each animal was sacrificed by collecting blood from its orbital cavity. The blood was kept at 4°C for 3 h and then centrifuged at 3500 r/min in a refrigerated centrifuge at 4°C for 10 min. The serum of each mouse was drawn and the tyrosinase (TYR) content, cholinesterase (CHE) activity and malondialdehyde (MDA) content of each group were determined by ELISA using a microplate reader according to the instructions of the kit.
  • TLR tyrosinase
  • CHE cholinesterase
  • MDA malondialdehyde
  • simvastatin skin ointment has a therapeutic effect on the hydroquinone-induced vitiligo model, with better therapeutic effect and faster recovery compared with the tacrolimus group.
  • Japanese white rabbits were subjected to a skin irritation test using a self-comparison method using the left and right skin sides of the same rabbit. Twenty-four hours before the experiment, hair was removed along both sides of the spine. The depilated area was 3 cm ⁇ 3 square centimeters, and no skin damage was allowed to ensure adequate drug-skin contact.
  • the low-dose, medium-dose, and high-dose groups of the simvastatin skin ointment of Example 9 were applied to the intact skin on the left side of the spine at a thickness of approximately 1 mm. An equal amount of a blank formulation was applied to the right side and covered with gauze. Twelve hours later, the application site was cleaned with warm physiological saline. The application site was observed for erythema, edema, and other conditions 24, 48, and 72 hours after drug withdrawal, and the experimental results were recorded.
  • the pre-experimental treatment process was the same as that of the single-dose skin irritation experiment.
  • the low-dose, medium-dose and high-dose simvastatin topical preparations were applied to the depilated area on the left side of the spine with a thickness of about 1 mm, and the same amount of blank preparation was applied to the right side and wrapped with gauze.
  • the medication was used once a day for seven consecutive days.
  • the medication site was cleaned with warm saline the next day.
  • the erythema and edema of the medication site were observed 24 hours, 48 hours and 72 hours after stopping the medication.
  • Irritation scores were calculated using the evaluation method in Table 6. The average value was then calculated and evaluated according to the following evaluation criteria: Non-irritant: 0-0.49; Mild Irritation: 0.50-2.99; Moderate Irritation: 3.00-5.99; Severe Irritation: 6.00-8.00.
  • the low and medium dose groups of simvastatin skin ointment did not show irritation phenomena such as erythema and edema.
  • the high dose group had a mild erythema reaction with total scores of 0, 0, and 0.3 respectively, indicating that in the single skin irritation experiment, the low, medium, and high doses of simvastatin skin ointment were non-irritating to intact skin.
  • DSC Differential scanning calorimetry
  • Each sample is dynamically scanned at a heating rate of 10°C/min under a nitrogen flow, and the scanning temperature range is -20°C-160°C.
  • pure simvastatin shows a sharp exothermic peak at 140.3°C.
  • Test Example 1 Efficacy trial for autosomal recessive ichthyosis
  • the formula composition of the 2% preparation is: 125 parts phospholipid, 25 parts cholesterol, 50 parts liquid paraffin, 290 parts yellow vaseline and 10 parts simvastatin
  • the prescription composition of the 4% preparation is: 125 parts of phospholipids, 25 parts of cholesterol, 50 parts of liquid paraffin, 280 parts of yellow vaseline and 20 parts of simvastatin.
  • Test method 2% simvastatin ointment was given for the first month, followed by 4% simvastatin skin ointment for external use. Apply it twice a day, applying a thin layer and massaging.
  • Figures 9-1(a), 9-2(a), and 9-3(a) show the skin lesions before treatment;
  • Figures 9-1(b), 9-2(b), and 9-3(b) show the effects of 2% simvastatin skin ointment for one month. While the study drug was effective, the local lesions remained stubborn.
  • Figures 9-1(c), 9-2(c), and 9-3(c) show the effects of 4% simvastatin skin ointment for three months, showing accelerated improvement and significant regression of stubborn lesions.
  • the simvastatin skin ointment can significantly improve the symptoms of autosomal recessive ichthyosis after treatment.
  • the prepared 4% simvastatin skin ointment is more effective than the prepared 2% simvastatin ointment.
  • simvastatin skin ointment prepared in Example 9 was subjected to a drug efficacy test to investigate the efficacy of the ointment on vitiligo.
  • Trial subject One patient clinically diagnosed with vitiligo was recruited.
  • the trial drug was applied topically twice daily, with massage, and supplemented with narrow-band ultraviolet B phototherapy for 80 days. Patients and evaluators evaluated the efficacy and safety of the treatment.
  • the simvastatin liposome preparation for external use is prepared using a thin film dispersion method, which involves dissolving simvastatin in an organic solvent, evaporating the solvent, and leaving a thin film of the drug. This film is then added to an appropriate amount of water and ultrasonically or stirred to form liposomes.
  • the prepared simvastatin liposomes were subjected to a storage stability test. Specifically, three batches of samples were placed at room temperature (25 ⁇ 2°C, relative humidity 65 ⁇ 5%) for 10 days, with properties and content as key indicators. The results are shown in Table 9:
  • simvastatin liposome composite external preparation water and a surfactant (Tween 80) were mixed at 45°C to obtain an aqueous phase; simvastatin was dissolved in a medium-chain oil at 45°C, phospholipids and cholesterol were added thereto, and the mixture was stirred to obtain an oil phase; the aqueous phase was slowly injected into the oil phase in a 60°C water bath and the mixture was stirred for 45 minutes; the mixed liquid was sheared at 10,000 rpm for 3 minutes, and then allowed to stand for defoaming after shearing; the defoamed solution was circulated once at 500 bar and 6 times at 800 bar to obtain a final emulsion.
  • a surfactant Teween 80
  • the prepared simvastatin liposomal emulsion composite external preparation was subjected to a shelf stability test. Specifically, three batches of samples were placed at room temperature (25 ⁇ 2°C, relative humidity 65 ⁇ 5%) for 10 days. The properties and content were used as key indicators. The results are shown in Table 10:
  • the prepared phospholipid-modified simvastatin nanocrystal topical preparation was subjected to a shelf stability test. Specifically, three batches of samples were placed at room temperature (25 ⁇ 2°C, relative humidity 65 ⁇ 5%) for 10 days. Properties and content were used as key indicators. The results are shown in Table 11:
  • Table 11 Stability test results of phospholipid-modified simvastatin nanocrystals for external use
  • 1 represents simvastatin
  • 2 represents simvastatin acid
  • 3 represents nanocrystals (stored at room temperature for 5 days)
  • 4 represents phospholipid-modified nanocrystals (stored at room temperature for 5 days).
  • Thin layer board GF254 silicone prefabricated board
  • Color developer iodine vapor color development
  • Control solution Dissolve 0.05 g of simvastatin in 5 ml of methanol and shake well.
  • Test solution Take 1 ml of simvastatin nanocrystals and dilute it to 5 ml with methanol; take 1.5 ml of phospholipid-modified simvastatin nanocrystals and dilute it to 5 ml with methanol.
  • Simvastatin acid solution Take 0.02g of simvastatin and place it in a 50ml volumetric flask. Add 5ml of a mixed solution of 0.2mol/L sodium hydroxide solution and acetonitrile (1:1) and shake to dissolve it. Let it stand for 5 minutes. After neutralization with dilute hydrochloric acid, add methanol to dilute to the scale to obtain a simvastatin acid solution containing open-ring degradation products.

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Abstract

La présente divulgation concerne une pommade cutanée de simvastatine à l'état moléculaire à charge de médicament élevée et son procédé de préparation. La pommade comprend de la simvastatine et une composition de matrice basique. La composition de matrice basique comprend une matrice basique, un solubilisant, un régulateur de consistance, un stabilisant et similaire. Selon la pommade de la présente divulgation, la simvastatine est présente de manière stable dans la composition de matrice basique sous la forme de molécules. Le phospholipide et le cholestérol, en tant que solubilisant et stabilisant, sont autoassemblés dans une solution non aqueuse pour former une structure micellaire inverse, ce qui permet d'améliorer la stabilité d'un médicament. Par ailleurs, la solubilité d'un médicament à faible polarité est augmentée au moyen du système micellaire inverse, de sorte que la quantité de rétention cutanée peut être fortement augmentée lorsque le système micellaire inverse est utilisé en tant que véhicule d'administration percutanée, ce qui permet d'améliorer l'absorption percutanée du médicament. La formulation de la présente divulgation est facile à préparer, présente une bonne stabilité à la conservation, une charge de médicament élevée, une quantité d'accumulation de médicament élevée dans la peau, pénètre facilement et a un effet rapide, ce qui permet d'éviter les effets secondaires provoqués par la simvastatine orale.
PCT/CN2025/080783 2024-03-05 2025-03-05 Pommade cutanée de simvastatine à l'état moléculaire à charge de médicament élevée, sa préparation et son utilisation Pending WO2025185660A1 (fr)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110368358A (zh) * 2019-09-02 2019-10-25 上海交通大学医学院附属新华医院 一种辛伐他汀的外用制剂及其应用
CN112791049A (zh) * 2021-04-02 2021-05-14 中国人民解放军空军军医大学 一种治疗白癜风的辛伐他汀软膏制备方法及其应用

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110368358A (zh) * 2019-09-02 2019-10-25 上海交通大学医学院附属新华医院 一种辛伐他汀的外用制剂及其应用
CN112791049A (zh) * 2021-04-02 2021-05-14 中国人民解放军空军军医大学 一种治疗白癜风的辛伐他汀软膏制备方法及其应用

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