An oteracil topical composition

Abstract

The present application belongs to the field of pharmaceutical preparations, and relates to an oteracil outside use composition. The oteracil outside use composition comprises a therapeutically effective amount of oteracil or a pharmaceutically acceptable salt thereof, at least one methanolic penetration enhancer, a pharmaceutically acceptable topical carrier, and a dosage form of a solution, a lotion or a liniment. The pharmaceutical composition of the present application has a high drug loading, a high methanolic permeation rate and a large methanolic retention amount, solves the problem that the fungi attached to the nail plate cannot be killed due to the thickening, hardness and compactness of the keratin protein of the nail plate of the patient with onychomadesis, has a fast effect, is safe and reliable, and has a great market development prospect.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical preparations and relates to the formulation composition and application of an octaconazole topical composition. Background Technology

[0002] Oteseconazole (VT-1161) is a novel oral antifungal drug belonging to the triazole class of compounds. It exerts its antifungal effect by inhibiting fungal cytochrome P450 enzyme (CYP51A1), thus interfering with fungal cell membrane synthesis. Oteseconazole is currently available in capsule form and is used to treat severe vulvovaginal candidiasis (VVC). Furthermore, the "Chinese Guidelines for the Diagnosis and Treatment of Onychomycosis (2021 Edition)" mentions that oteseconazole, as a novel oral antifungal drug, has shown good efficacy and safety against onychomycosis and is expected to become a new treatment option for onychomycosis in the future.

[0003] Onychomycosis is a fungal infection of the nails or toenails and surrounding tissues. It is one of the most common nail diseases, accounting for the vast majority of nail infections. Because one of its main symptoms is nail discoloration (usually grayish-white, yellow, or brown), it is commonly referred to as "fungal nail infection" in everyday life. While oral medications for onychomycosis are highly effective, they may have some impact on liver function, therefore they should be used under the guidance of a doctor and liver function should be monitored regularly. Topical medications are convenient to use, have high safety profiles, and are well-tolerated by patients. However, because the keratin in the nail plate of onychomycosis patients is thickened, hardened, and dense, it is a difficult obstacle to drug penetration. Therefore, topical medications for onychomycosis need to have good nail penetration and retention rates to be effective. Summary of the Invention

[0004] In order to overcome the above-mentioned technical problems existing in the field, the present invention provides an octaconazole topical composition, which has a high drug loading capacity, high nail permeability, and large nail retention, thus solving the problem that fungi attached to the nail plate cannot be killed due to the thickening, hardening and densification of keratin in patients with onychomycosis.

[0005] The present invention achieves the above-mentioned objectives by adopting the following technical solution:

[0006] One embodiment provides a pharmaceutical composition characterized by comprising: (a) a therapeutically effective amount

[0007] (a) octaconazole or a pharmaceutically acceptable salt thereof; (b) at least one nail penetration enhancer; (c) a pharmaceutically acceptable topical carrier;

[0008] In optional embodiments, the pharmaceutical composition is a topical solution, lotion, or liniment.

[0009] In an alternative embodiment, the mass percentage of octaconazole in the composition is 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 5.5%, 6.0%, 6.5%, 7.0%, 7.5%, 8.0%, 8.5%, 9.0%, 9.5%, 10.0%, 10.5%, 11.0%, 11.5%, 12.0%, 12.5%, 13.0%, 13.5%, 14.0%, 14.5%, 15.0%, 15.5%, 16.0%, 16.5%, 17.0%, 17.5%, 18.0%, 18.5%, 19.0%, 19.5%, or 20.0%, preferably 10% to 20%.

[0010] In an optional embodiment, the penetration enhancer is selected from one or more of urea, salicylic acid, azone, menthol, ethyl oleate, and diisopropyl adipate. Diisopropyl adipate is preferred, and its mass percentage in the composition can be 1.0%, 1.5%, 2.0%, 2.5%, 3.0%, 3.5%, 4.0%, 4.5%, 5.0%, 6%, 7%, 8%, 9%, or 10%, preferably 1-5%, more preferably 5%.

[0011] In an optional embodiment, the topical carrier comprises a solvent system consisting of volatile and non-volatile solvents, accounting for 65%-75% by mass of the composition. The solvent system may include one or more of anhydrous ethanol, polyethylene glycol 400, diethylene glycol monoethyl ether, and polyethylene glycol glycerol caprylate.

[0012] In an alternative embodiment, the composition may further comprise an emollient, preferably a cyclomethyl silicone.

[0013] In an optional embodiment, the composition comprises 10-20% octaconazole, 1-10% diisopropyl adipate, 5-15% diethylene glycol monoethyl ether, 15-25% polyethylene glycol 400, 30-50% anhydrous ethanol and 5-15% cyclomethyl silicone, the percentages being by weight.

[0014] In an optional embodiment, the composition comprises 15% octaconazole, 5% diisopropyl adipate, 10% diethylene glycol monoethyl ether, 20% polyethylene glycol 400, 40% anhydrous ethanol and 10% cyclomethyl silicone, the percentages being by weight.

[0015] The present invention also provides the use of the above-described pharmaceutical composition in the preparation of a topical medicament for treating onychomycosis.

[0016] Compared to existing technologies, this invention offers the following advantages: It formulates octaconazole into a topical octaconazole composition, allowing it to directly target the affected nail site in the treatment of onychomycosis, facilitating drug release and penetration into the nail plate to exert its therapeutic effect. Furthermore, this composition boasts a high drug loading capacity, stable formulation, rapid onset of action, and safety, making it highly promising for market development.

[0017] Diisopropyl adipate is a versatile fine chemical product widely used in pharmaceuticals, fragrances, and daily chemical products, serving as an emulsifier, lubricant, solubilizer, and plasticizer. This invention unexpectedly discovered that diisopropyl adipate, as a nail penetration enhancer in topical octaconazole compositions, has significant advantages in increasing the depth and speed of penetration of the active pharmaceutical ingredient into the nail, thereby improving drug bioavailability and enhancing therapeutic efficacy. While improving penetration, diisopropyl adipate may also exhibit lower irritation and toxicity, reducing damage and side effects to the nail and surrounding tissues. This has important clinical significance for patients who use nail care products long-term or undergo antifungal treatment. Detailed Implementation

[0018] The formulation disclosed in this application uses an anhydrous polymorph of octconazole (melting point approximately 103°C). Detailed descriptions of the properties of the anhydrous form of octconazole are found in patent document US10414751, the entire contents of which are incorporated herein by reference.

[0019] The present invention will be explained below with reference to embodiments. Those skilled in the art will understand that the following embodiments are for illustrative purposes only and should not be considered as limiting the scope of the invention. Where specific techniques or conditions are not specified in the embodiments, they are performed according to the techniques or conditions described in the literature in the field or according to the product instructions. Reagents or instruments whose manufacturers are not specified are all conventional products that can be obtained commercially.

[0020] Example 1: Composition Formulation Screening

[0021] Weigh out the prescribed amount of solvent, stir and mix, then add octaconazole, stir to dissolve, add the methyl penetration enhancer and emollient, and stir until homogeneous. The APIs listed in Table 1 are all anhydrous polymorphs of octaconazole.

[0022] Table 1. Composition Formulation Screening Table (Proportions in the table are by mass percentage)

[0023]

[0024]

[0025]

[0026] Example 2: Transdermal Test

[0027] In vitro transdermal dermal permeation experiments were conducted on prescriptions 1-7, with multiple sampling points.

[0028] The specific procedure for the in vitro transdermal diffusion assay was as follows: The prepared formulation sample was subjected to transdermal diffusion using 40% ethanol as the release medium. The toenail used for diffusion was a bovine toenail, 0.5 mm thick, from a 1-year-old infant. The instrument used was a transdermal diffusion apparatus (manufacturer: LOGAN), with a rotation speed of 600 rpm, a medium volume of 12 ml, and a temperature of 32℃. Samples were collected completely at 4h, 12h, 24h, 48h, and 72h, and analyzed by liquid chromatography.

[0029] The calculation formula is as follows:

[0030]

[0031] Table 2 Results of in vitro permeability

[0032]

[0033] Example 3: Intra-acid retention study:

[0034] A study on intrathyroidal retention was conducted on prescriptions 1-7, with multiple sampling points.

[0035] Specific procedures: Cut several toenail samples into small pieces, place them in centrifuge tubes, add 1.5 ml of methanol (diluent), shake for 1 min each, then place the samples in an ultrasonic water bath and sonicate for 20 min. Remove the samples, shake them, and filter the supernatant into a sample vial for liquid chromatography analysis.

[0036] The calculation formula is as follows:

[0037]

[0038] Table 3 Results of methanogenic retention over 72 hours

[0039] Prescription number Intramyotrophic lateral sclerosis (mg / cm²) Prescription 1 0.132 Prescription 2 0.078 Prescription 3 0.050 Prescription 4 0.035 Prescription 5 0.012 Prescription 6 0.014 Prescription 7 0.240

[0040] Conclusion: Studies on nail penetration and retention in different formulations showed that for formulations 2, 5, and 6, nail penetration and retention increased with the increasing proportion of diisopropyl adipate in the formulation (1%, 3%, and 5%, respectively). Formulation 2, compared to other formulations, exhibited both partial retention within the nail bed and penetration into the subungual space. Formulation 1, lacking diisopropyl adipate, primarily retained within the nail bed and did not penetrate into the subungual space. Formulation 4 showed less intraungual retention compared to formulation 1, with no penetration into the subungual space. Formulation 7 showed virtually no penetration into the subungual space, remaining mainly within the nail bed.

[0041] Example 4: Drug Loading of Formulation

[0042] Table 4 Results of Drug Loading Study

[0043]

[0044] Conclusion: 20% of the active pharmaceutical ingredient can be dissolved in the formulation, and the product has a good appearance with no crystal precipitation.

[0045] Example 5: Study on influencing factors of prescription 2

[0046] The effects of high-temperature (60°C) storage for 10 days, 30 days, and light exposure on the formulation content are as follows:

[0047] Table 5. Study on influencing factors of prescription 2

[0048] Prescription / Conditions 0-day content Content after 10 days at 60 degrees Celsius Content after 30 days at 60 degrees Celsius Content after 30 days of light exposure Prescription 2 99.94 % 100.42 % 102.01 % 100.02 %

[0049] Conclusion: The influencing factors of the optimized formulation 2 were studied. After being placed under high temperature and light conditions for 30 days, its content did not change significantly.

Claims

1. A pharmaceutical composition, characterized in that... Include: (a) A therapeutically effective amount of octaconazole or a pharmaceutically acceptable salt thereof; (b) At least one methyl penetration enhancer; (c) Pharmaceutically acceptable topical carriers.

2. The composition according to claim 1, characterized in that... The pharmaceutical composition is a topical solution, lotion, or liniment.

3. The composition according to claim 1, characterized in that... The octaconazole in the composition is 1%-20% by mass, preferably 10%-15%.

4. The pharmaceutical composition according to any one of claims 1 to 3, characterized in that... The methyl penetration enhancer is selected from one or more of the following: urea, salicylic acid, menthol, and diisopropyl adipate.

5. The pharmaceutical composition according to claim 4, characterized in that... The methyl penetration enhancer is diisopropyl adipate, and its mass percentage in the composition is 1%-5%, preferably 5%.

6. The composition according to claim 1, characterized in that... The topical carrier comprises a solvent system consisting of volatile and non-volatile solvents, accounting for 65%-75% by mass of the composition.

7. The composition according to claim 6, characterized in that... The solvent system comprises one or more of anhydrous ethanol, polyethylene glycol 400, diethylene glycol monoethyl ether, and polyethylene glycol glycerol caprylate.

8. The composition according to claim 1, characterized in that... It further contains emollients.

9. The composition according to claim 8, characterized in that... The emollient is cyclomethyl silicone.

10. The composition according to claim 1, characterized in that... It contains 10-20% octaconazole, 1-5% diisopropyl adipate, 5-15% diethylene glycol monoethyl ether, 15-25% polyethylene glycol 400, 30-50% anhydrous ethanol and 5-15% cyclomethyl silicone, the percentages are by mass.

11. The composition according to claim 10, characterized in that... It contains 15% octaconazole, 5% diisopropyl adipate, 10% diethylene glycol monoethyl ether, 20% polyethylene glycol 400, 40% anhydrous ethanol and 10% cyclomethyl silicone, the percentages are by weight.

12. Use of any of the pharmaceutical compositions of claims 1-11 in the preparation of a topical medicament for treating onychomycosis.

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