A kind of crisaborole aerosol and preparation method thereof

Abstract

This application relates to the field of external-use medicines and specifically discloses a crisaborole aerosol and its preparation method. The crisaborole aerosol comprises crisaborole, a solvent, a non-aqueous solvent, a latent solvent, a film-forming agent, and a propellant. The composition comprises, by weight, 0.01% to 3.0% crisaborole, 20% to 60% non-aqueous solvent, 0.5% to 5.0% latent solvent, 0.1% to 5.0% film-forming agent, and 20% to 50% propellant. The solvent contains 10% to 30% water. A water-based aerosol, in particular, offers advantages over alcohol-based aerosols in terms of environmental friendliness, safety, and low irritation, as well as good stability and excellent skin penetration.

Description

Technical Field

[0001] The present application relates to the field of external medicine, and more specifically, to a crisaborole aerosol and a preparation method thereof. Background Art

[0002] Atopic dermatitis (AD) is a common disease worldwide that can occur at any age, usually before the age of five. It typically presents in three stages: infancy, childhood, and adulthood, with acute, subacute, and / or chronic skin manifestations occurring in each stage.

[0003] Atopic dermatitis is a long-lasting, chronic disease with periodic exacerbations, and may be accompanied by symptoms such as asthma or allergic rhinitis. The etiology and pathogenesis of atopic dermatitis are not yet fully understood, but it is generally believed to be caused by the stimulation and interaction of various internal and external factors, including genetic, immune, and environmental factors.

[0004] Criborole is a phosphodiesterase 4 (PDE4) inhibitor. PDE4 is an enzyme involved in controlling the activity of inflammatory cells. PDE4 participates in the production of inflammatory factors such as IL-4 / 5 / 10 / 13 and prostaglandin PGE2 in inflammatory cells by controlling the degradation of cyclic adenosine monophosphate. It exerts its effect by inhibiting PDE4 activity and improving the body's inflammatory response.

[0005] Currently, crisaborole has poor water solubility and typically requires dissolution in alcoholic solvents or the addition of a cosolvent. The original crisaborole cream used propylene glycol as a solvent. Compared to creams, aerosols offer the advantages of ease of use, precise dosing, and good clinical compliance. However, the sole use of alcohol as a solvent in aerosols can cause dry skin due to its high volatility. It is also unstable during storage due to its volatility and poses safety concerns during use, requiring it to be kept away from sources of ignition. Summary of the Invention

[0006] The present invention provides a crisaborole aerosol and a preparation method thereof, in particular a water-based aerosol. Compared with alcohol-based aerosols, the water-based aerosol has the advantages of being environmentally friendly, safe, and less irritating, and has good stability and excellent skin penetration performance.

[0007] When the invention is used, the greasy feeling problem of creams is avoided, skin dryness caused by alcohol-based aerosols is avoided, and the use feeling is good.

[0008] In a first aspect, the present disclosure provides a crisaborole aerosol, comprising a solvent, a non-aqueous solvent, a latent solvent, a film-forming agent, and a propellant;

[0009] Calculated by weight percentage, the present invention comprises 0.01% to 3.0% of crisaborole, 20% to 60% of non-aqueous solvent, 0.5% to 5.0% of latent solvent, 0.1% to 5.0% of film-forming agent, and 20% to 50% of propellant; and the solvent contains 10% to 30% of water.

[0010] Crisaborole has poor water solubility and usually needs to be dissolved in alcohol solvents or added with latent solvents. By adding solvents and non-aqueous solvents, the solvent can contain more water, thereby reducing skin dryness during the use of the aerosol, thereby alleviating the problem of alcohol solvents easily causing skin dryness and certain irritation due to their high volatility, and further reducing irritation in the treatment of atopic dermatitis.

[0011] Preferably, the non-aqueous solvent is one or more of ethanol, isopropanol, and glycerol.

[0012] Preferably, the latent solvent is one or more of polyethylene glycol, phenoxyethanol, propylene glycol, and diisopropyl adipate.

[0013] Preferably, the film-forming agent is one or more of polyvinyl pyrrolidone, hydroxypropyl methylcellulose, and polyvinyl alcohol.

[0014] Preferably, the propellant is one or more selected from HFA, HFO, and butane.

[0015] Preferably, it also includes one or more of antioxidants and metal chelating agents.

[0016] Preferably, the aerosol is an aqueous aerosol.

[0017] In a second aspect, the present disclosure provides a method for preparing a crisaborole aerosol, comprising the following preparation steps:

[0018] S1: Premix solution: stir the prescribed amount of the solvent and the non-aqueous solvent evenly, add the latent solvent and the other excipients, dissolve them completely to obtain a solution, add the film-forming agent, and then add the crisaborole, stirring to dissolve;

[0019] S2: Filling: Add the premixed solution into the tank, install the valve system and seal it, pour the propellant into the pressure-resistant container, and if the airtightness test is qualified, the cleborole aerosol is obtained.

[0020] The aqueous aerosol of crisaborole has the characteristics of good feeling when used, avoiding skin dryness, and being safe and effective.

[0021] In summary, this application has the following beneficial effects:

[0022] 1. The solvent added in this application has a relatively high water content, so that the aerosol can maintain moisture on the skin surface during use. The drug aerosol has the advantages of small dosage, uniform distribution, fast effect, good effect, and convenience. External use avoids irritation to the wound surface, and the dosage can be controlled by a quantitative valve, with fast effect and localized effect.

[0023] 2. The crisaborole in this application has poor water solubility and usually needs to be dissolved in an alcohol solvent or a latent solvent. By adding a solvent and a non-aqueous solvent, the solvent can contain more water, thereby reducing skin dryness during use of the aerosol, thereby alleviating the problem of skin dryness and irritation caused by alcohol solvents due to their high volatility, and further reducing irritation in the treatment of atopic dermatitis;

[0024] 3. The preparation method of the present application is relatively simple. The aqueous aerosol of crisaborole has the characteristics of good feel when used, avoiding skin dryness, and being safe and effective.

[0025] It should be understood that the foregoing general description and the following detailed description are merely exemplary and explanatory and are not intended to limit the scope of protection of the present disclosure. DETAILED DESCRIPTION

[0026] The present application is further described in detail below with reference to the examples. It is particularly noted that if no specific conditions are specified in the following examples, the reactions are carried out according to conventional conditions or the conditions recommended by the manufacturer. Unless otherwise specified, the raw materials used in the following examples can be obtained from common commercial sources.

[0027] Example

[0028] Example 1

[0029] Raw materials content% Criborole 0.4 Isopropyl alcohol 47.6 polyethylene glycol 200 1.5 water 11.9 BHT 0.1 PVP30 1.0 DME 37.5 total 100

[0030] Preparation method: Add the prescribed amount of isopropyl alcohol, water and polyethylene glycol to the container, stir evenly, add BHT to dissolve, then add polyvinyl pyrrolidone, add crisaborole after complete dissolution, stir evenly, add the solution to the tank, install the valve system and seal it, and pour DME into the pressure-resistant container to obtain the product.

[0031] Example 2:

[0032] Raw materials content% Criborole 0.9 ethanol 28.15 water 28.15 Phenoxyethanol 0.25 Propylene glycol 1.5 Propyl gallate 0.05 PVP30 1.0 DME 40 total 100

[0033] Preparation method: Add the prescribed amount of ethanol, water, propylene glycol and phenoxyethanol into the container, stir evenly, add propyl gallate to dissolve, then add polyvinyl pyrrolidone, add crisaborole after complete dissolution, stir evenly, add the solution into the tank, install the valve system and seal it, and pour DME into the pressure-resistant container to obtain the product.

[0034] Comparative Example

[0035] Comparative Example 1

[0036] The crisaborole aerosol was prepared according to the method of Example 2, except that the crisaborole was a non-aqueous aerosol. The preparation formula was as follows:

[0037] Raw materials content% Criborole 2.0 ethanol 15.4 Propylene glycol 1.5 BHT 0.10 Eudragit RS100 1.0 HFA 80 total 100

[0038] Preparation method: Add the prescribed amount of ethanol and propylene glycol to a container, add BHT to dissolve, then add polyethyl acrylate-methyl methacrylate-trimethylaminoethyl methacrylate chloride Eudragit RS100 and dissolve it completely, then add crisaborole and stir evenly, add the solution to the tank, install the valve system and seal it, and pour HFA into the pressure-resistant container to obtain the product.

[0039] Comparative Example 2 Take the commercially available crisaborole cream (Sultanamine) as comparative example 2

[0040] (1) Properties:

[0041] The crisaborole aerosol prepared in Examples 1, 2 and Comparative Example 1 was sprayed on the skin and its shape and drying time were observed.

[0042]

[0043] Conclusion: The crisaborole aqueous aerosol of the present invention is a colorless and transparent solution. When sprayed on the skin, it does not cause drying and has relatively low irritation.

[0044] (2) Stability:

[0045] The crisaborole aqueous aerosol prepared in Examples 1 and 2 and Comparative Examples 1 and 2 were stored at a high temperature of 40° C. for 2 weeks and 4 weeks, and their stability was examined.

[0046] preparation 0 days Criborole content after 2 weeks of storage (%) Criborole content after 4 weeks of storage (%) Example 1 98.37 98.05 97.68 Example 2 99.50 98.81 98.52 Comparative Example 1 99.25 97.46 96.33 Comparative Example 2 98.53 97.56 96.81

[0047] preparation 0 days Purity of crisaborole after 2 weeks of storage Purity of crisaborole after 4 weeks of storage (%) Example 1 99.42 98.75 98.44 Example 2 99.61 99.04 98.98 Comparative Example 1 99.86 98.64 97.73 Comparative Example 2 99.51 99.14 99.10

[0048] Conclusion: The crisaborole aqueous aerosol of the present invention still maintains good stability at a high temperature of 40°C and is substantially free of degradation.

[0049] (3) Examples 1 and 2 and Comparative Examples 1 and 2 were subjected to in vitro skin penetration experiments.

[0050] Experiment: Ex vivo human skin was used as a permeation membrane, and drugs were administered in the supply pool. Samples were taken from the receptor fluid every 3 hours to detect the crisaborole content. After 24 hours of penetration, the cumulative amount of the drug in the epidermis and dermis was calculated as a proportion of the administered dose.

[0051] preparation Percentage of 24-hour epidermal drug accumulation Percentage of cumulative dermal drug volume in 24 hours Comparative Example 2 5.30％ 6.36％ Comparative Example 1 6.83％ 8.52％ Example 1 12.00％ 10.95％ Example 2 10.94％ 8.79％

[0052] Conclusion: Compared with the original cream, the cumulative amount of drugs in the epidermis and dermis of the crisaborole aqueous aerosol prepared in this application is significantly higher than that of the latter, and the effect of drug delivery by aerosol is better than that of cream.

[0053] The above description is merely an exemplary embodiment of the present disclosure, but the scope of protection of the present disclosure is not limited thereto. Any changes or substitutions that can be easily conceived by a person skilled in the art within the technical scope disclosed in the present disclosure should be included in the scope of protection of the present disclosure. Therefore, the scope of protection of the present disclosure should be based on the scope of protection of the claims.

Claims

1. A crisaborole aerosol, characterized in that: It is made of the following components in percentage by mass: Preparation method: Add the prescribed amount of isopropyl alcohol, water and polyethylene glycol to a container, stir evenly, add BHT to dissolve, then add polyvinyl pyrrolidone, add crisaborole after complete dissolution, stir evenly, add the solution to the tank, install the valve system and seal it, and pour DME into the pressure-resistant container to obtain the product; or Preparation method: Add the prescribed amount of ethanol, water, propylene glycol and phenoxyethanol into the container, stir evenly, add propyl gallate to dissolve, then add polyvinyl pyrrolidone, add crisaborole after complete dissolution, stir evenly, add the solution into the tank, install the valve system and seal it, and pour DME into the pressure-resistant container to obtain the product.

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