Power law fluid pimecrolimus composition having low viscosity, and use thereof

Abstract

The present invention relates to the pharmaceutical field and the field of skin medication, and specifically relates to a power law fluid pimecrolimus composition having low viscosity, and the use thereof. The present invention provides a pimecrolimus-containing composition, comprising pimecrolimus, a rheology modifier, and a thickener. At room temperature, the viscous modulus of the composition is greater than the elastic modulus thereof.

Description

A pimecrolimus composition for low-viscosity power-law fluids and its applications

[0001] Cross-reference to related applications

[0002] This application claims the benefit of Chinese patent application CN202510999085.7, filed on July 18, 2025; the entire contents of which are incorporated herein by reference. Technical Field

[0003] This invention relates to the fields of medicine and dermatological drugs, specifically to a low-viscosity power-law fluid pimecrolimus composition and its application. Background Technology

[0004] Pimecrolimus is an immunosuppressive drug belonging to the class of calcineurin inhibitors. Its chemical name is (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxo-4-azatricyclo[22.3.1.04.9]octadec-18-ene-2,3,10,16-tetraone, and its structural formula is:

[0005] Pimecrolimus cream, developed by Novartis and marketed under the brand name Elidel, was first launched in the United States in 2001, in the European Union in 2002, and later entered the Chinese market in 2005. It is approved for use in patients with mild to moderate atopic dermatitis lasting 3 months or longer without immunodeficiency. It exhibits very strong immunosuppressive activity in vitro and can effectively improve various skin inflammatory symptoms.

[0006] The formulation of pimecrolimus cream has certain limitations, thus restricting its clinical efficacy. Patent CN100335063C discloses Novartis's pimecrolimus cream formulation, which uses a large amount of solid oils to increase the physical stability of the pimecrolimus composition. However, this increased physical stability limits the transdermal penetration of the drug. In a clinical study of pimecrolimus cream (Clinical Study No.: ASMW205), 55% of the participants voluntarily withdrew from the clinical trial due to poor clinical efficacy. This may be because the overall viscosity of pimecrolimus cream is relatively high, limiting its skin penetration and affecting the drug's clinical efficacy.

[0007] Patent CN117462492A discloses a method for promoting the transdermal absorption of pimecrolimus by using nanoemulsion technology. However, this transdermal enhancement method using nano-formulations can lead to systemic exposure in the body, exposing pimecrolimus to plasma and affecting safety. Literature reports that pimecrolimus can cause immunosuppressive and lymphoproliferative disorders in vivo, as well as severe immunosuppressive activity.

[0008] Meanwhile, creams, due to their greasiness and high viscosity, are unsuitable for application to hairy areas; when applied to the nose and face, their excessive greasiness can cause discomfort to patients. This limits the application of pimecrolimus in diseases of the nose, face, and hairy areas. Dermatologists Julia et al. summarized the advantages, disadvantages, and applicable scope of different topical formulations. For exudative skin diseases like seborrheic dermatitis that commonly occur in hairy areas, emulsions are clinically recommended as drug carriers. Emulsions offer the following advantages as drug carriers: a. Emulsions have low viscosity, allowing the drug to flow spontaneously, making them suitable for application and easy to apply to the skin surface and areas with abundant hair; b. During application, the evaporation of water from the emulsion provides a cooling sensation, reducing the greasiness associated with seborrheic dermatitis.

[0009] In conclusion, dosage form design is crucial for drugs. The choice of dosage form for pimecrolimus cream directly affects its efficacy and safety, and further optimized pimecrolimus dosage forms still need to be developed in clinical practice. Summary of the Invention

[0010] This invention proposes a pimecrolimus-containing composition, which includes a rheology modifier to give the composition power-law fluid characteristics, with a viscosity modulus greater than its elastic modulus at room temperature, exhibiting a tendency for spontaneous flow and easy application. The composition also contains a thickener to improve its stability and form a network gel structure within the composition, allowing for control of the penetration rate. The composition provided by this invention improves the delivery of the formulation, resulting in high epidermal retention and low dermal exposure of pimecrolimus, thus enhancing the efficacy and safety of the medication.

[0011] Specifically, the present invention provides the following technical solutions:

[0012] In a first aspect, the present invention provides a composition containing pimecrolimus, wherein pimecrolimus, a rheology modifier, and a thickener are contained.

[0013] Preferably, at room temperature, the viscosity modulus of the composition is greater than its elastic modulus, and the composition exhibits low viscosity, power-law fluid characteristics, and spontaneous flow properties.

[0014] Preferably, the viscous modulus of the composition is at least 1.1 times, at least 1.2 times, at least 1.3 times, at least 1.4 times, at least 1.5 times, at least 1.6 times, at least 1.7 times, at least 1.8 times, at least 1.9 times, at least 2 times, at least 2.1 times, at least 2.2 times, or at least 2.3 times its elastic modulus.

[0015] Preferably, the composition has a viscosity of 10-1000 cp at room temperature; specifically including 10, 50, 100, 150, 200, 300, 400, 500, 600, 700, 800, 900, and 1000; preferably, 50-500 cp; preferably, 100-400 cp; more preferably, 100-200 cp.

[0016] Preferably, the composition does not exhibit stratification or demulsification when centrifuged at speeds of 2000 rpm, 3000 rpm, 4000 rpm, 5000 rpm, 6000 rpm, 7000 rpm, 8000 rpm or higher for 5 min, 10 min, 15 min, 20 min, 25 min, 30 min or longer.

[0017] Preferably, the composition is an emulsion.

[0018] Preferably, the composition is a power-law fluid.

[0019] Preferably, the composition comprises 0.05-10% pimecrolimus by weight, specifically including 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, and 10%.

[0020] Preferably, the composition comprises 0.1-5% pimecrolimus by weight.

[0021] Preferably, the composition comprises 0.5-2% pimecrolimus by weight.

[0022] Preferably, the composition comprises pimecrolimus in a weight percentage of 0.75-1%, 0.75-0.8%, or 0.8-1%.

[0023] Preferably, the composition comprises pimecrolimus in a weight percentage of 0.75%, 0.8%, or 1%.

[0024] Preferably, the rheology modifier is a fatty acid or its ester with a carbon chain length between 12 and 14, specifically including fatty acids or their esters with a carbon chain length of 12, 13 or 14.

[0025] Preferably, the rheology modifier includes lauric acid or its ester, myristic acid or its ester.

[0026] Preferably, the esters of lauric acid include 2-ethylhexyl laurate, butyl laurate, ethyl laurate, methyl laurate, glyceryl laurate, polyethylene glycol laurate, sorbitan laurate, polyoxyethylene sorbitan laurate, and cholesterol laurate.

[0027] Preferably, the ester of myristic acid includes one or more of the following: glyceryl myristicate, cetyl myristicate, stearyl myristicate, methyl myristicate, ethyl myristicate, butyl myristicate, isopropyl myristicate, octyl myristicate, isostearyl myristicate, propylene glycol myristicate, and phenethyl myristicate.

[0028] Preferably, the rheology modifier is isopropyl myristate.

[0029] Preferably, the rheology modifier has a weight percentage of 0.5-20%, specifically including 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, and 20%.

[0030] Preferably, the rheology modifier has a weight percentage of 1-10%; preferably, 3-8%; preferably, 4-6%; preferably, 5%.

[0031] Preferably, the weight percentage of isopropyl myristate is 0.5-20%, specifically including 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%, 10.5%, 11%, 11.5%, 12%, 12.5%, 13%, 13.5%, 14%, 14.5%, 15%, 15.5%, 16%, 16.5%, 17%, 17.5%, 18%, 18.5%, 19%, 19.5%, and 20%.

[0032] Preferably, the weight percentage of isopropyl myristate is 1-10%; preferably, 3-8%; preferably, 4-6%; preferably, 5%.

[0033] Preferably, the thickener includes xanthan gum, guar gum, hydroxypropyl guar gum, gum arabic, tragacanth gum, galactomannan, long bean gum, black privet gum, sodium alginate, carbomer, and locust bean gum.

[0034] Preferably, the thickener is xanthan gum.

[0035] Preferably, the thickener has a weight percentage of 0.01-2%, specifically including 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, and 2%.

[0036] Preferably, the thickener has a weight percentage of 0.05-1%; preferably, 0.1-0.5%; preferably, 0.2-0.4%; preferably, 0.3%.

[0037] Preferably, the xanthan gum has a weight percentage of 0.01-2%, specifically including 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, and 2%.

[0038] Preferably, the xanthan gum has a weight percentage of 0.05-1%; preferably, 0.1-0.5%; preferably, 0.2-0.4%; preferably, 0.3%.

[0039] Preferably, the composition further comprises an emulsifier.

[0040] Preferably, the emulsifier is a reagent with an HLB value between 10 and 20.

[0041] Preferably, the emulsifier includes polysorbate 80 (Tween 80), polycetol 1000, polyoxyethylene-21 stearyl ether, Tween 20, polyethylene glycol-12 hydroxystearate, and polyethylene glycol-20 hydroxystearate.

[0042] Preferably, the emulsifier has a weight percentage of 0.1-10%; specifically, it includes 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, and 10%.

[0043] Preferably, the emulsifier has a weight percentage of 0.5-5%; preferably, 1-3%; preferably, 2%.

[0044] Preferably, the emulsifier is a combination of polysorbate 80 and polycetol 1000.

[0045] Preferably, the polysorbate 80 has a weight percentage of 0.1-5%, specifically including 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0046] Preferably, the polysorbate 80 has a weight percentage of 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0047] Preferably, the polycetool 1000 has a weight percentage of 0.1-5%, specifically including 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0048] Preferably, the polycetool 1000 has a weight percentage of 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0049] Preferably, the composition further comprises a preservative.

[0050] Preferably, the preservative includes one or more of benzyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben, citric acid, dimethylaminoethanol, benzalkonium chloride, benzalkonium bromide, and cetrimonium bromide.

[0051] Preferably, the preservative is benzyl alcohol.

[0052] Preferably, the preservative has a weight percentage of 0.1-5%, specifically including 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0053] Preferably, the preservative has a weight percentage of 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0054] Preferably, the benzyl alcohol has a weight percentage of 0.1-5%, specifically including 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, and 5%.

[0055] Preferably, the benzyl alcohol has a weight percentage of 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0056] Preferably, the pH of the composition is 4.5-6.5.

[0057] Preferably, the composition further comprises a pH adjuster.

[0058] Preferably, the pH adjuster comprises a weak acid or its salt, and / or a salt of an alkali metal or alkaline earth metal.

[0059] Preferably, the weak acid or its salt includes one or more of citric acid or its salt, carbonic acid or its salt, succinic acid or its salt, phosphoric acid or its salt, boric acid or its salt, citric acid or its salt, acetic acid or its salt, tartaric acid or its salt, and hydrochloric acid or its salt.

[0060] Preferably, the alkali metal or alkaline earth metal salt includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate.

[0061] Preferably, the pH adjuster is citric acid and sodium hydroxide.

[0062] Specifically, the citric acid is anhydrous citric acid.

[0063] Preferably, the weight percentage of anhydrous citric acid is 0.005-0.5%, specifically including 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, and 0.5%.

[0064] Preferably, the weight percentage of the anhydrous citric acid is 0.01-0.1%; preferably, 0.03-0.08%; preferably, 0.05%.

[0065] Preferably, the sodium hydroxide has a weight percentage of 0.005-0.1%, specifically including 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, and 0.1%.

[0066] Preferably, the sodium hydroxide has a weight percentage of 0.008-0.05%; preferably, 0.01-0.03%; preferably, 0.02%.

[0067] Preferably, the composition further comprises a skin soothing agent.

[0068] Preferably, the skin soothing agent includes one or more of sodium hyaluronate, allantoin, aloe vera, pantothenic acid and its derivatives (such as ethyl panthenol), bisabolol, and dipotassium glycyrrhizate.

[0069] Preferably, the skin soothing agent is a combination of allantoin and sodium hyaluronate.

[0070] Preferably, the allantoin content is 0.01-2% by weight, specifically including 0.01%, 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.6%, 0.65%, 0.7%, 0.75%, 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.05%, 1.1%, 1.15%, 1.2%, 1.25%, 1.3%, 1.35%, 1.4%, 1.45%, 1.5%, 1.55%, 1.6%, 1.65%, 1.7%, 1.75%, 1.8%, 1.85%, 1.9%, 1.95%, and 2%.

[0071] Preferably, the allantoin has a weight percentage of 0.05-1%; preferably, 0.1-0.5%; preferably, 0.2%.

[0072] Preferably, the sodium hyaluronate has a weight percentage of 0.001-0.1%, specifically including 0.001%, 0.005%, 0.01%, 0.015%, 0.02%, 0.025%, 0.03%, 0.035%, 0.04%, 0.045%, 0.05%, 0.055%, 0.06%, 0.065%, 0.07%, 0.075%, 0.08%, 0.085%, 0.09%, 0.095%, and 0.1%.

[0073] Preferably, the sodium hyaluronate has a weight percentage of 0.005-0.05%; preferably, 0.008-0.02%; preferably, 0.01%.

[0074] Preferably, the composition further comprises an oil phase reagent.

[0075] Preferably, the oil phase reagent includes one or more of mono- and di-stearyl glycerides, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, and medium-chain triglycerides.

[0076] Preferably, the oil phase reagent is a combination of mono- and di-stearate glyceryl esters, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, and medium-chain triglycerides.

[0077] Preferably, the oil phase reagent has a weight percentage of 5-60%; preferably, 20-50%; preferably, 25-40%; preferably, 35.5%.

[0078] Preferably, the weight percentage of the mono- and di-stearyl glycerides is 0.5%.

[0079] Preferably, the hexadecyl alcohol has a weight percentage of 1%.

[0080] Preferably, the octadecyl alcohol has a weight percentage of 1%.

[0081] Preferably, the propylene glycol has a weight percentage of 8%.

[0082] Preferably, the oleyl alcohol has a weight percentage of 10%.

[0083] Preferably, the medium-chain triglyceride has a weight percentage of 15%.

[0084] Preferably, the composition comprises one or more of the following substances: pimecrolimus, benzyl alcohol, glyceryl monostearate and distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, medium-chain triglycerides, rheology modifier, polysorbate 80, polycetol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum, and water.

[0085] Preferably, the composition comprises the following substances: pimecrolimus, benzyl alcohol, glyceryl monostearate and distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, medium-chain triglycerides, rheology modifier, polysorbate 80, polycetol 1000, xanthan gum and water.

[0086] Preferably, the composition comprises: 0.75%-1% pimecrolimus, 4-6% isopropyl myristate, 0.2-0.4% xanthan gum, 1% benzyl alcohol, 0.5% glyceryl mono- and di-stearates, 1% cetyl alcohol, 1% octadecyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium-chain triglycerides, 1% polysorbate 80, 1% polycetol 1000, and water.

[0087] Preferably, the composition comprises the following substances: pimecrolimus, benzyl alcohol, glyceryl monostearate and distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, medium-chain triglycerides, rheology modifier, polysorbate 80, polycetol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum, and water.

[0088] Preferably, the composition comprises the following substances: 0.75%-1% pimecrolimus, 4-6% isopropyl myristate, 0.2-0.4% xanthan gum, 0.2% allantoin, 1% benzyl alcohol, 0.5% glyceryl mono- and di-stearates, 1% cetyl alcohol, 1% octadecyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium-chain triglycerides, 1% polysorbate 80, 1% polycetol 1000, 0.01% sodium hyaluronate, 0.05% anhydrous citric acid, 0.02% sodium hydroxide, and water.

[0089] Preferably, the amount of the composition retained in the epidermis is at least 5 μg / g, 10 μg / g, 15 μg / g, 20 μg / g, 21 μg / g, 22 μg / g, 23 μg / g, or 24 μg / g higher than the amount of drug in the dermis.

[0090] Preferably, the amount of the composition retained in the epidermal layer is at least 5 μg / g, 10 μg / g, 15 μg / g, 20 μg / g, 21 μg / g, 22 μg / g, 23 μg / g, 24 μg / g, 25 μg / g, 26 μg / g, 27 μg / g, or 28 μg / g.

[0091] Preferably, the composition contains less than 15 μg / g, 10 μg / g, 5 μg / g, 4 μg / g, or 3 μg / g in the dermis.

[0092] Preferably, the composition has an AUC when the system is exposed. 0～24h Less than 15 μg·h / cm 2 10 μg·h / cm 2 9 μg·h / cm 2 or 8 μg·h / cm 2 .

[0093] Some of the excipients described above may have more than one function in the composition. For example, an excipient may be both a solvent and a penetration enhancer, or both a solvent and a carrier. The above classification of excipients should not be construed as any form of limitation or constraint.

[0094] On the other hand, the present invention also provides a method for preparing the aforementioned pimecrolimus-containing composition, the method comprising the following steps:

[0095] i) Oil phase preparation: Dissolve one or more of the rheology modifier, emulsifier, preservative and oil phase reagent by heating until clear, then add pimecrolimus and dissolve until clear;

[0096] ii) Aqueous phase preparation: Add thickener and skin soothing agent to purified water and dissolve until clear;

[0097] iii) Mixing: Add the oil phase to the aqueous phase and stir homogenously;

[0098] iv) pH adjustment: Adjust the pH to 4.5-6.5 using a pH adjuster;

[0099] v) Cool down: Cool down to room temperature.

[0100] Preferably, the vacuum degree during stirring in step iii) is not lower than -0.06 MPa.

[0101] On the other hand, the present invention also provides the use of the aforementioned pimecrolimus-containing compositions in the preparation of medicaments for treating and / or preventing skin manifestations of inflammatory skin diseases and / or immune-mediated diseases.

[0102] Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma.

[0103] Preferably, the immune-mediated diseases include: alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus.

[0104] Preferably, the immune-mediated disease is seborrheic dermatitis.

[0105] On the other hand, the present invention also provides a method for treating and / or preventing skin manifestations of inflammatory skin diseases and / or immune-mediated diseases, the method comprising administering an effective amount of the aforementioned composition to a subject.

[0106] Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma.

[0107] Preferably, the immune-mediated diseases include: alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus.

[0108] Preferably, the immune-mediated disease is seborrheic dermatitis.

[0109] On the other hand, this disclosure provides the aforementioned compositions for treating and / or preventing skin manifestations of inflammatory skin diseases and / or immune-mediated diseases.

[0110] Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma.

[0111] Preferably, the immune-mediated diseases include: alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus.

[0112] Preferably, the immune-mediated disease is seborrheic dermatitis.

[0113] Compared with the prior art, this disclosure has the following beneficial effects:

[0114] The pimecrolimus composition containing rheology modifiers and thickeners provided by this invention exhibits a spontaneous flow tendency, making it easy to apply clinically. The active ingredient, pimecrolimus, shows high retention in the epidermis while its exposure in the dermis and throughout the body is reduced. This pimecrolimus composition demonstrates high efficacy and safety, exhibiting excellent therapeutic effects that align with basic pharmacoeconomic principles, and is particularly suitable for exudative diseases of the nose, face, and hairy areas. Animal model results show that in guinea pigs with seborrheic dermatitis treated with pimecrolimus emulsion, skin inflammation subsided, and pathological sections showed no nuclear infiltration.

[0115] Unless they contradict each other, the details mentioned in the pharmaceutical compositions, cassettes, methods of preparation of pharmaceutical compositions, uses, and treatment methods disclosed herein shall be applied in the same manner. Attached Figure Description

[0116] To more clearly illustrate the technical solutions in the specific embodiments of this disclosure or the prior art, the accompanying drawings used in the description of the specific embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of this disclosure. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort. The accompanying drawings are incorporated in and constitute a part of this specification, illustrating embodiments consistent with this specification, and are used together with the specification to explain the principles of this specification.

[0117] Figure 1 shows the skin appearance of guinea pigs in each group before and after treatment.

[0118] Figure 2 shows the effect scores of each group before and after treatment.

[0119] Figure 3 shows the HE-stained pathological sections of each group after treatment.

[0120] Figure 4 shows the Masson-stained pathological sections of each group after treatment.

[0121] Figure 5 shows the weight changes of each group of guinea pigs during the experiment. Detailed Implementation

[0122] In this invention, unless otherwise stated, the scientific and technical terms used herein have the meanings commonly understood by those skilled in the art. Furthermore, the related terms and laboratory procedures used herein are all widely used terms and routine procedures in the respective fields. To better understand this invention, definitions and explanations of related terms are provided below.

[0123] In the description herein, references to “some embodiments,” “some implementations,” or “some implementation schemes” describe a subset of all possible embodiments. However, it is understood that “some embodiments” may be the same subset or different subsets of all possible embodiments and may be combined with each other without conflict.

[0124] I. Terms and Definitions

[0125] To facilitate understanding of this disclosure, certain technical and scientific terms are specifically defined below. In this disclosure, unless otherwise stated, the scientific and technical terms used have meanings commonly understood by those skilled in the art. It should be understood that this disclosure is not limited to specific methods, reagents, compounds, compositions, or biological systems, and variations thereof are certainly possible. Furthermore, the protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, and immunology-related terms and laboratory procedures used in this disclosure are all widely used terms and routine procedures in their respective fields. It should also be understood that the terminology used in this disclosure is for the purpose of describing specific embodiments only and is not intended to be limiting.

[0126] In this disclosure, the conjunction term "and / or" between multiple elements means that it includes both the meaning of "and" and "or".

[0127] In this disclosure, the terms “comprising,” “including,” “having,” and “containing,” and any variations thereof, are intended to cover non-exclusive inclusion. The term is intended to be open-ended to specify the presence of any of the stated features, elements, integers, steps, or components, but does not exclude the presence or addition of one or more other features, elements, integers, steps, components, or groups thereof. Therefore, the term “comprising” includes the more restrictive terms “consisting of” and “substantially consisting of”. In this disclosure, the term “containing” indicates that various ingredients may be used together in mixtures or compositions of this disclosure.

[0128] In this disclosure, all ranges are to be considered as disclosures of all subranges and all point values ​​within the range. All point values ​​can be combined independently. Since these ranges are continuous, they include every numerical value between the minimum and maximum values. It should also be understood that any numerical range referenced in this application is intended to include all subranges within that range. For example, the disclosure of 0.05-10% should be considered as also disclosing ranges such as 0.05%-0.55%, 0.7%-0.8%, 1.4%-10%, etc., and also disclosing ranges such as 0.05%, 0.1%, 0.15%, 0.2%, 0.25%, 0.3%, 0.35%, 0.4%, 0.45%, 0.5%, 0.55%, 0.65%, 0.7%, 0.75%, etc. Point values ​​of 0.8%, 0.85%, 0.9%, 0.95%, 1%, 1.1%, 1.2%, 1.3%, 1.4%, 1.5%, 1.6%, 1.7%, 1.8%, 1.9%, 2%, 2.5%, 3%, 3.5%, 4%, 4.5%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, and 10%.

[0129] In this disclosure, the term "pimecrolimus" refers to a calcineurin inhibitor, an immunosuppressive drug of the class of calcineurin inhibitors, with the chemical name (1R,9S,12S,13R,14S,17R,18E,21S,23S,24R,25S,27R)-12-[(1E)-2-[(1R,3R,4S)-4-chloro-3-methoxycyclohexyl]-1-methylvinyl]-17-ethyl-1,14-dihydroxy-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxo-4-azatricyclo[22.3.1.04.9]octadec-18-ene-2,3,10,16-tetraone, and its structural formula is:

[0130] In this disclosure, the term "composition" refers to a formulation containing pimecrolimus and possibly other excipients such as rheology modifiers and thickeners, which work together to improve clinical compliance, increase drug retention in the epidermal layer of the skin, and enhance the efficacy and safety of pimecrolimus.

[0131] In this disclosure, the terms "weight percentage" or "%" mean weight percentage (w / w).

[0132] In this disclosure, the term “cp” or “centipoise” is a commonly used unit of viscosity (dynamic viscosity), which measures a fluid’s ability to resist flow.

[0133] In this disclosure, the term “Pa” or “Pascal” is a unit of pressure, 1 Pa equal to the pressure produced by a force of 1 Newton acting uniformly and perpendicularly on an area of ​​1 square meter.

[0134] In this disclosure, the terms "elastic modulus (usually denoted by G', also known as storage modulus)" and "viscosity modulus (usually denoted by G', also known as loss modulus)" are used to characterize the deformation response of a material under stress and can be measured by a rheometer.

[0135] In this disclosure, the term "power-law fluid" refers to a class of non-Newtonian fluids whose shear stress (τ) is proportional to the shear rate. Satisfies the power law relationship: Wherein, K is the consistency coefficient, or power-law coefficient, which reflects the viscosity of the fluid; n is the power-law exponent, which characterizes the non-Newtonian properties of the fluid.

[0136] In this disclosure, the term "emulsifier" refers to a compound used to mix oil and aqueous phase components. The HLB value of the emulsifier required in the pimecrolimus-containing compositions of the present invention is typically between 10 and 20, specifically including 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Preferably, the emulsifier is a combination of polysorbate 80 and polycetyl 1000, which maintains droplet stability and inhibits droplet aggregation.

[0137] In this disclosure, the term "Hydrophile-Lipophile Balance (HLB)" is a quantitative indicator that measures the relative strength of the hydrophilicity and lipophilicity of a surfactant.

[0138] In this disclosure, the term "pH adjuster" refers to a chemical substance used to adjust the acidity or alkalinity of a product. An appropriate pH value helps ensure the stability of the product and the skin's adaptability, avoiding irritation or damage to the skin.

[0139] In this disclosure, the term "thickener" refers to a component added to a formulation to increase its viscosity, such as xanthan gum. The pimecrolimus-containing compositions of this invention incorporate xanthan gum, which limits the viscosity of the composition to 50-500 cp without significantly increasing viscosity or altering the rheological characteristics of the formulation. Compositions with this viscosity still exhibit power-law fluid rheological characteristics and do not show stratification under centrifugation conditions (5000 rpm, 30 min). Furthermore, the addition of xanthan gum can control the transdermal release process of the active ingredient. Xanthan gum forms a network-like gel structure in the formulation, which has stable thixotropic properties, limiting the rate at which the active ingredient penetrates the stratum corneum, enriching the active ingredient in the epidermis, reducing exposure in the dermis and throughout the body, and thus achieving a targeted effect.

[0140] In this disclosure, the term "preservative" refers to a chemical substance, such as benzyl alcohol, used to inhibit the growth of microorganisms like bacteria and mold. Preservatives ensure that products remain stable and safe during storage and use.

[0141] In this disclosure, the term "normal temperature" refers to the natural temperature that does not require additional temperature control, specifically 4-40°C, preferably 25±5°C.

[0142] In this disclosure, the term "skin manifestation" refers to the signs or conditions of abnormal appearance, structure, or function of a subject's skin due to various physiological, pathological factors, or external stimuli. In this disclosure, the term "skin" includes not only the skin tissue covering the body surface but also appendages (such as nails and hair) and mucous membranes closely related to its structure and function. Specifically, this disclosure addresses the signs or conditions of abnormal skin caused by inflammatory skin diseases and / or immune-mediated diseases.

[0143] In this disclosure, the term "treatment" is synonymous with the terms "prevention" and "mitigation," and is intended to indicate delaying the development of a disease, preventing the development of a disease, and / or reducing the severity of said symptoms that will develop or are expected to develop. Therefore, these terms include improving existing disease symptoms, preventing additional symptoms, improving or preventing the underlying metabolic cause of symptoms, inhibiting a disorder or disease, for example, preventing the development of a disorder or disease, alleviating a disorder or disease, regressing a disorder or disease, reducing symptoms caused by a disease or disorder, or stopping the symptoms of a disease or disorder.

[0144] In this disclosure, the term "subject" includes confirmed patients, but the "subject" does not need to have any special status in relation to the hospital, clinic, or research facility (e.g., as a confirmed patient, research participant, etc.). The amount of drug administered can depend on the subject being treated, the subject's age, health status, sex, and weight, the type of concurrent treatment (if any), the severity of the condition, the nature of the desired effect, the manner and frequency of treatment, and the prescribing physician's judgment. The frequency of administration can also depend on the pharmacodynamic effect on arterial oxygen partial pressure. However, the optimal dose can be adjusted for individual subjects, as understood by those skilled in the art and determined without tolerance experiments. This typically involves adjusting the standard dose (e.g., reducing the dose if the patient is underweight).

[0145] In this disclosure, the terms “subject,” “object,” “individual,” or “patient” are used interchangeably to specifically include mammals and non-mammals. In one embodiment of this disclosure, the mammal is a human.

[0146] In this disclosure, the term "effective amount" or "effective dose" refers to an amount of pimecrolimus and / or the composition described in this disclosure that is therapeutically effective in humans and / or animals and is acceptable to humans and / or animals. For example, a therapeutically or pharmaceutically effective amount refers to the amount of pimecrolimus and / or the aforementioned composition required to produce the desired therapeutic effect, which can be reflected by the results of clinical trials, animal model studies, and / or in vitro studies. A pharmaceutically effective amount depends on several factors, including but not limited to: characteristic factors of the treatment subject (such as the subject's height, weight, sex, age, and medication history) and the severity of the disease. In specific embodiments of this disclosure, the "effective amount" refers to an amount sufficient to inhibit, slow down, or prevent the worsening of skin manifestations of dermatitis and immune-mediated diseases in the subject.

[0147] II. Examples

[0148] To make the objectives, technical solutions, and advantages of this disclosure clearer, the disclosure will be described in further detail below. The described embodiments should not be regarded as limitations on this disclosure. All other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of this disclosure.

[0149] The raw materials and equipment used in the specific embodiments of this disclosure are all known products, obtained by purchasing commercially available products or by using disclosed methods.

[0150] Example 1: Preparation of pimecrolimus microemulsion gel

[0151] Pimecrolimus microemulsion gel was prepared according to the method of patent CN117462492A:

[0152] Step 1: First, pimecrolimus microemulsion was prepared using a high-pressure homogenization method. By weight percentage, 1% pimecrolimus active pharmaceutical ingredient was added to a mixture of 20% ethanol, medium-chain triglycerides, and isopropyl myristate (volume ratio 1:1:2), and stirred at 500-1000 rpm until clear. Then, 6% Tween 60 and 2% Span 60 were added, stirred evenly, and purified water was added to 100%. The mixture was then dispersed at high-speed shear (10000 rpm / 30 min) to obtain a pre-emulsion with a particle size of approximately 1-100 μm. The pre-emulsion was then homogenized three times using a high-pressure homogenizer (homogenization pressure 800 bar) to obtain a microemulsion.

[0153] Step 2: Add 0.5% hydroxyethyl cellulose (HEC) to the pimecrolimus microemulsion prepared in Step 1, and stir slowly until completely dissolved.

[0154] Example 2: Preparation of pimecrolimus emulsion

[0155] Table 1. Pimecrolimus Emulsion Formula

[0156] The formulations of pimecrolimus emulsions 1-4 are shown in Table 1. The numbers in Table 1 represent the weight percentage (%w / w) of each component. The rheology modifiers for emulsions 1-4 were caprylic acid, palmitic acid, or isopropyl myristate, respectively. The carbon chain length of caprylic acid was 10, that of palmitic acid was 16, and that of isopropyl myristate was 14. All were purchased from Zhejiang Wumart Biotechnology Co., Ltd. Pimecrolimus emulsions 1-4 were prepared according to Table 1 using a homogenization emulsification method. The specific preparation method is as follows:

[0157] Step 1, Oil phase preparation: Heat the rheology modifier (capric acid, palmitic acid, or isopropyl myristate), oleyl alcohol, benzyl alcohol, medium-chain triglycerides, propylene glycol, glyceryl mono- and di-stearate, polycetol 1000, cetyl alcohol, octadecyl alcohol, and polysorbate 80 to 70±5℃ and stir until dissolved and clear. Set aside. Then add pimecrolimus and stir until dissolved and clear. Set aside.

[0158] Step 2, Aqueous phase preparation: Add xanthan gum, allantoin, and sodium hyaluronate to purified water and stir until dissolved and clear. Heat to 70±5℃ for later use.

[0159] Step 3, Mixing: Add the oil phase to the aqueous phase, stir homogenously, and maintain a vacuum degree of not less than -0.06 MPa;

[0160] Step 4, pH adjustment: Adjust the pH to 4.5-6.5 using anhydrous citric acid and sodium hydroxide.

[0161] Step 5, Cooling: Turn on the cooling water and stir to cool down to room temperature to obtain emulsion 1-4.

[0162] Example 3: Determination of viscosity, modulus and rheological profiles

[0163] 1. Viscosity measurement method:

[0164] The equipment used was a Bollerfeld DV2T viscometer with an SC4-18 rotor. The test temperature was 25℃, the constant temperature time was 10 min, the measuring speed was 80 rpm, the running time was 120 seconds, and the data acquisition time was 10 seconds.

[0165] 2. Methods for determining rheological curves:

[0166] The rheological curves were determined using a HA-10 rheometer from TA Instruments, Inc. (USA). The test mode was rotational test CR mode, ramp scan, logarithmic coordinates, and the fixture was a 40mm stainless steel plate. The test temperature was 25℃, the holding time was 60 seconds, the shearing time was 240 seconds, the shearing range was 1000~0.01, and the gap was 0.5mm.

[0167] 3. Methods for determining modulus:

[0168] Modulus was determined using a HA-10 rheometer from TA Instruments, USA. The test mode was oscillating test control CF mode with continuous variation. The fixture was a 40mm stainless steel plate. The test temperature was 25℃, the holding time was 60 seconds, the strain was 1.0%, the angular frequency was 100~0.1rad / s, and the gap was 0.5mm.

[0169] The microemulsion gels, emulsions 1-4, and commercially available creams prepared in Examples 1-2 were processed according to the above methods. The product (manufacturer: Viatris; batch number: 330158) was tested. The test results are shown in Table 2.

[0170] Table 2. Results of viscosity, modulus, and rheological curve tests.

[0171] Viscosity is a key quality attribute of emulsions. Excessive viscosity can affect patient compliance and make application difficult; conversely, insufficient viscosity can compromise drug stability, potentially leading to sedimentation or emulsion breakdown during the stability period. A suitable viscosity ensures both drug stability and clinical compliance. When the viscosity of the composition is in the range of 50–500 cp, the drug exhibits good stability and strong clinical compliance.

[0172] The formulation of the composition is an emulsion, and rheologically it is a non-Newtonian fluid. When the rheological curve of the composition is a power-law fluid, the rheological curve of the drug is a pseudoplastic fluid without yield stress. That is, the consistency of the drug will become thinner during the application process, making it easier to apply. When the application is stopped, the drug will spontaneously recover and exhibit a certain consistency, adhering to the lesion site, thereby protecting the lesion site and curing the disease.

[0173] According to the results shown in Table 2, emulsions 1, 3, 4, and the microemulsion gel all have a viscous modulus > elastic modulus, while emulsion 2 and the commercially available cream have the opposite, with a viscous modulus < elastic modulus. This indicates that the modulus of the product will reverse when the carbon chain length of the rheology modifier is ≤14, resulting in a viscous modulus > elastic modulus. When the viscous modulus of the formulation is > elastic modulus, it exhibits spontaneous flow characteristics, making it easy to apply in clinical use, especially for the nose, face, and hairy areas, suitable for the treatment of nasofacial seborrheic dermatitis. According to the second law of thermodynamics, the evolution of the state of matter tends towards entropy increase; when the viscous modulus > elastic modulus, the transdermal penetration ability of the drug also increases.

[0174] Example 4: Centrifugal Stability and Long-Term Stability Study

[0175] The microemulsion gels, emulsions, and commercially available creams prepared in Examples 1 and 2 were subjected to centrifugal stability studies (5000 rpm, 30 min).

[0176] Table 3. Centrifugal stability of pimecrolimus emulsions with different rheology modifiers

[0177] The experimental results are shown in Table 3. The results indicate that emulsions 1 and 4 separated into layers after centrifugation, demonstrating instability and failing to meet shelf-life stability requirements. According to Stokes' law of sedimentation, emulsion droplets are in a thermodynamically unstable state within the system, making them prone to sedimentation and aggregation during long-term storage. The addition of rheology modifiers significantly reduced the viscosity of the formulation, which is detrimental to shelf life; however, the addition of xanthan gum formed a network gel system, slowing down droplet coalescence and sedimentation, thus increasing viscosity and improving formulation stability to some extent.

[0178] Example 5: In vitro transdermal study

[0179] The microemulsion gels and emulsions prepared in Examples 1 and 2 were compared with commercially available pimecrolimus cream in terms of transdermal absorption, using a drug application area of ​​1.77 cm². 2 A Franz diffusion cell with a receiving volume of 8 mL was used, with the skin of Bama miniature pigs (one month old) as the osmotic barrier, at a concentration of 10 mg / cm³. 2The drug was applied at a dose of approximately 17.7 mg, and the receiving solution was physiological saline for in vitro transdermal testing. The temperature was set at 32℃, the rotation speed at 600 rpm, and n=6. Samples were taken at 1, 2, 4, 8, 12, and 24 hours.

[0180] After the transdermal test, the pigskin was heated in a 60°C oven for 2 minutes, and then the skin was gently rubbed with surgical forceps until the epidermis and dermis separated. The concentrations of pimecrolimus in the epidermis and dermis were then measured, and the results are shown in Table 4.

[0181] Table 4. Summary and Comparison of Transmission Amount

[0182] Note: AUC 0-24h Area under the plasma drug concentration-time curve from 0 to 24 hours

[0183] The results showed that, compared with commercially available pimecrolimus cream and pimecrolimus microemulsion gel, the pimecrolimus composition (emulsion 3) with added rheology modifier and thickener could target and enrich pimecrolimus in the epidermis (p < 0.05), with an epidermal retention of ≥ 20 μg / g and a dermal drug content ≤ 10 μg / g, and a systemic exposure AUC of ≤ 10 μg / g. 0-24h ≤10μg·h / cm 2 This significantly reduces drug exposure in the dermis (Table 4).

[0184] Example 6: Transdermal Study of Pimecrolimus Emulsions of Different Specifications

[0185] To further investigate the transdermal effects of pimecrolimus of different specifications, the pimecrolimus content was changed according to the composition of emulsion 3 in Table 1, and pimecrolimus emulsions with pimecrolimus contents of 0.75%, 0.8% and 1% were prepared (formulations are shown in Table 5) for in vitro release and in vitro transdermal studies.

[0186] Table 5. Formulations of pimecrolimus emulsions in different specifications

[0187] The in vitro release study method followed the "Technical Guidelines for In Vitro Release (IVRT) and In Vitro Transdermal (IVPT) Studies of Topically Effective Generic Chemical Drugs" issued by the CDE and the "In Vitro Release (IVRT) Studies of Topical Drug Products Submitted in ANDA Applications" issued by the FDA OGD Office. The release medium was 50% ethanol-0.9% physiological saline.

[0188] The similarity of the three release curves was compared using the Mann-Whitney U test. The results showed that the release rates of emulsion 3 (specification: 0.75%) and emulsion 3 (specification: 0.8%) were consistent with those of emulsion 3 (specification: 1.0%) within the 90% confidence interval (Tables 6 and 7). In addition, the results of the in vitro transdermal assay are shown in Table 8.

[0189] Table 6. Similarity of release curves for 0.8% and 1.0%

[0190] Table 7 shows the similarity of release curves for 0.75% and 1.0%.

[0191] Table 8. Permeability of Emulsions of Different Specifications

[0192] Example 7: Study on the dosage of rheology modifier and thickener in emulsion 3

[0193] The rheology modifier and thickener in emulsion 3 are isopropyl myristate and xanthan gum, respectively. In this embodiment, the dosage of isopropyl myristate and xanthan gum was screened. The contents of isopropyl myristate and xanthan gum in emulsion 3 and emulsions 5-8 are shown in Table 9. The pimecrolimus content is 0.75%, and the other components are the same as those in the formulation of emulsion 3 in Table 1.

[0194] Table 9. Study on the dosage of rheology modifiers and thickeners

[0195] After preparing emulsions 3 and 5-8 according to the method described in Example 2, their viscosity, modulus, and rheological profiles were tested according to the method described in Example 3. The results showed that when the amount of xanthan gum was 0.2-0.4% and the amount of isopropyl myristate was 4-6%, the compositions were able to maintain power-law fluid characteristics, with low viscosity and viscous modulus > elastic modulus (Table 10).

[0196] Table 10. Results of viscosity, modulus, and rheological curve tests.

[0197] Example 8: Treatment of seborrheic dermatitis

[0198] The emulsion 3 (specification: 0.75%) prepared in Example 6, the microemulsion gel prepared in Example 1, and a commercially available cream were selected for animal pharmacodynamics and safety studies in guinea pigs.

[0199] Animal grouping and medication regimens are shown in Table 11, and evaluation criteria are shown in Table 12. Forty-eight 5-week-old male guinea pigs were purchased and fed routinely for one week. They were then labeled and grouped, with 6+2 mice per group (2 spares). Malassezia-transfected guinea pigs were used as the animal model for the experiment, and the medication was administered twice daily. The specific modeling method was as follows:

[0200] Step 1, Bacterial Culture: Malassezia f. furfur was inoculated onto a specific culture medium and passaged twice. Single colonies were then picked and cultured in liquid medium. Fungal counts were performed, adjusting the medium to 1x10⁻⁶. 8 CFU / mL, and mix with 5% olive oil;

[0201] Step 2, Modeling: Shave a 5cm x 5cm area on one side of the guinea pig's back with a razor. Remove hair with depilatory cream, then disinfect. Next, sand the depilated area until pinpoint bleeding occurs. Collect 5 x 10 cm samples. 7 The bacterial suspension was applied to the polished area and continued for 7 days until white, bran-like scales appeared on the inoculated Malassezia model area, which turned into light red spots. The areas were then classified according to their severity, indicating that the modeling was successful.

[0202] Step 3: Successful model establishment assessment: Clinical appearance score of mouse seborrheic dermatitis experimental animals (scales, erythematous papules, hair loss, etc.).

[0203] Table 11. Animal grouping and medication regimen

[0204] Table 12. Evaluation Criteria

[0205] After 10 days of treatment, the model group showed no significant improvement in symptoms and significant pathological features, indicating that the guinea pigs did not experience spontaneous remission during treatment and the model was effective (Figure 1, skin appearance of guinea pigs before and after treatment in the model group). The emulsion group and the microemulsion gel group both showed significant efficacy in treating seborrheic dermatitis (p < 0.05), while the commercially available cream group did not show significant efficacy (p > 0.05). This may be because pimecrolimus cream is a pseudoplastic fluid with an elastic modulus > viscous modulus and low transdermal penetration, so its efficacy was not significant during treatment and was similar to that of the blank emulsion group (Figures 1-2).

[0206] HE-stained pathological sections showed that the model group exhibited pathological phenomena such as abnormal thickening of the stratum corneum, acanthosis, increased number of melanocytes, inflammatory cell infiltration, clumped arrangement of cells, and follicular plugs. The above-mentioned pathological conditions in the emulsion group and microemulsion gel group were relatively improved, while the improvement in the blank emulsion group and the commercially available cream group was weak (as shown in HE-stained pathological sections in Figure 3).

[0207] Masson-stained pathological sections showed that the model group had significant epidermal hyperplasia with uneven and disordered collagen fiber distribution; the blank group still had significant hyperplasia, but the collagen fiber distribution was more uniform than that of the model group; the emulsion group and microemulsion gel group had significantly less hyperplasia and more uniform collagen fiber distribution than the blank emulsion group and the commercially available cream group (as shown in Figure 4, Masson-stained pathological sections).

[0208] Regarding safety, the weight of guinea pigs in each group was measured during the experiment. The results, as shown in Figure 5, indicate that, except for the microemulsion gel group, the weight of guinea pigs in other groups steadily increased. The guinea pigs in the microemulsion gel group experienced significant weight loss during the administration period, and their activity decreased; two mice died on the sixth day after administration. These results suggest that the microemulsion gel is highly toxic to guinea pigs, possibly due to its excessive permeability and high exposure within the guinea pig's body.

[0209] In summary, from a pharmacodynamic perspective, both the emulsion and microemulsion gel groups showed superior efficacy compared to commercially available creams. This is likely because the emulsion and microemulsion gel groups had better permeability than the emulsion group, enabling them to deliver a larger amount of active ingredients into the epidermis. However, differences emerged in safety between the emulsion and microemulsion gel groups. While the microemulsion gel group had a large permeation volume, it lacked targeted delivery, leading to the active ingredients penetrating into the guinea pigs and causing significant in vivo exposure. This resulted in weight loss, behavioral limitations, and the deaths of two guinea pigs during treatment. In contrast, the emulsion group, due to the controlled-release effect of the xanthan gum's network gel, targeted and concentrated the active ingredients in the epidermis, with less exposure in the dermis and the rest of the body, resulting in greater safety.

Claims

1. A composition containing pimecrolimus, comprising pimecrolimus, a rheology modifier and a thickener, wherein the pimecrolimus is present in a weight percentage of 0.05-10%, and the composition has a viscous modulus greater than its elastic modulus at room temperature.

2. The composition of claim 1, wherein the viscous modulus is at least 1.1 times, at least 1.5 times, or at least 2 times the elastic modulus; Preferably, the composition has a viscosity of 10-1000 cp at room temperature; more preferably, 50-500 cp; more preferably, 100-200 cp. Preferably, the composition does not exhibit stratification or demulsification when centrifuged at speeds of 2000 rpm, 3000 rpm, 4000 rpm, 5000 rpm, 6000 rpm, 7000 rpm, 8000 rpm or higher for 5 min, 10 min, 15 min, 20 min, 25 min, 30 min or longer. Preferably, the composition is an emulsion; Preferably, the composition is a power-law fluid; Preferably, the pimecrolimus content is 0.1-5% by weight; more preferably, 0.75-1%, 0.75-0.8%, or 0.8-1%; more preferably, 0.75%, 0.8%, or 1%. Preferably, the rheology modifier is a fatty acid or its ester with a carbon chain length between 12 and 14. Preferably, the rheology modifier includes lauric acid or its ester, myristic acid or its ester; preferably, the rheology modifier is isopropyl myristate. Preferably, the rheology modifier has a weight percentage of 0.5-20%; preferably, 4-6%; preferably, 5%. Preferably, the weight percentage of isopropyl myristate is 0.5-20%; preferably, 4-6%; preferably, 5%.

3. The composition according to claim 1 or 2, wherein the thickener comprises one or more of xanthan gum, guar gum, hydroxypropyl guar gum, gum arabic, tragacanth gum, galactomannan, long bean gum, black privet gum, sodium alginate, carbomer and locust bean gum; Preferably, the thickener is xanthan gum; Preferably, the thickener has a weight percentage of 0.01-2%; preferably, 0.2-0.4%; preferably, 0.3%. Preferably, the xanthan gum has a weight percentage of 0.01-2%; preferably, 0.2-0.4%; preferably, 0.3%.

4. The composition according to any one of claims 1-3, further comprising an emulsifier; Preferably, the emulsifier is a reagent with an HLB value between 10 and 20; Preferably, the emulsifier comprises one or more of polysorbate 80, polycetol 1000, polyoxyethylene-21 stearyl ether, Tween 20, polyethylene glycol-12 hydroxystearate, and polyethylene glycol-20 hydroxystearate. Preferably, the emulsifier has a weight percentage of 0.1-10%; more preferably, 2%. Preferably, the emulsifier is polysorbate 80 and polycetol 1000; Preferably, the polysorbate 80 has a weight percentage of 0.1-5%; preferably, 1%. Preferably, the polycetrol 1000 has a weight percentage of 0.1-5%; preferably, 1%.

5. The composition according to any one of claims 1-4, further comprising a preservative; Preferably, the preservative includes one or more of benzyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben, citric acid, dimethylaminoethanol, benzalkonium chloride, benzalkonium bromide and cetrimonium bromide. Preferably, the preservative is benzyl alcohol; Preferably, the preservative has a weight percentage of 0.1-5%; more preferably, 1%. Preferably, the benzyl alcohol has a weight percentage of 0.1-5%; more preferably, 1%.

6. The composition according to any one of claims 1-5, wherein the pH is 4.5-6.5; Preferably, the composition further comprises a pH adjuster; Preferably, the pH adjuster comprises a weak acid or a salt thereof, and / or a salt of an alkali metal or an alkaline earth metal; Preferably, the weak acid or its salt includes one or more of citric acid or its salt, carbonic acid or its salt, succinic acid or its salt, phosphoric acid or its salt, boric acid or its salt, citric acid or its salt, acetic acid or its salt, tartaric acid or its salt, and hydrochloric acid or its salt. Preferably, the alkali metal or alkaline earth metal salt includes one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate. Preferably, the pH adjuster is citric acid and sodium hydroxide; Specifically, the citric acid is anhydrous citric acid; Preferably, the weight percentage of the anhydrous citric acid is 0.005-0.5%; more preferably, 0.05%. Preferably, the sodium hydroxide has a weight percentage of 0.005-0.1%; more preferably, 0.02%.

7. The composition according to any one of claims 1-6, further comprising a skin soothing agent; Preferably, the skin soothing agent includes one or more of sodium hyaluronate, allantoin, aloe vera, pantothenic acid or its derivatives, bisabolol, and dipotassium glycyrrhizate; Preferably, the skin soothing agent is allantoin and sodium hyaluronate; Preferably, the allantoin content is 0.01-2% by weight; more preferably, 0.2%. Preferably, the sodium hyaluronate has a weight percentage of 0.001-0.1%; more preferably, 0.01%.

8. The composition according to any one of claims 1-7, further comprising an oil phase reagent; Preferably, the oil phase reagent includes one or more of mono- and di-stearate glycerides, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, and medium-chain triglycerides; Preferably, the oil phase reagent is glyceryl monostearate or distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, or medium-chain triglycerides; Preferably, the oil phase reagent has a weight percentage of 5-60%; more preferably, 35.5%. Preferably, the weight percentage of the mono- and di-stearyl glycerides is 0.5%; Preferably, the hexadecyl alcohol has a weight percentage of 1%; Preferably, the octadecyl alcohol has a weight percentage of 1%; Preferably, the propylene glycol has a weight percentage of 8%. Preferably, the oleyl alcohol content is 10% by weight; Preferably, the medium-chain triglyceride has a weight percentage of 15%; Preferably, the composition comprises one or more of the following substances: pimecrolimus, benzyl alcohol, glyceryl monostearate and distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, medium-chain triglycerides, rheology modifier, polysorbate 80, polycetol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum, and water; Preferably, the composition consists of: Pimecrolimus, benzyl alcohol, glyceryl monostearate and distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, medium-chain triglycerides, rheology modifier, polysorbate 80, polycetol 1000, xanthan gum and water; Preferably, the composition comprises: 0.75%-1% pimecrolimus, 4-6% isopropyl myristate, 0.2-0.4% xanthan gum, 1% benzyl alcohol, 0.5% glyceryl mono- and di-stearates, 1% cetyl alcohol, 1% octadecyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium-chain triglycerides, 1% polysorbate 80, 1% polycetol 1000, and water; Preferably, the composition comprises the following substances: pimecrolimus, benzyl alcohol, glyceryl monostearate and distearate, cetyl alcohol, octadecanol, propylene glycol, oleyl alcohol, medium-chain triglycerides, rheology modifier, polysorbate 80, polycetol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum, and water. Preferably, the composition comprises the following substances: 0.75%-1% pimecrolimus, 4-6% isopropyl myristate, 0.2-0.4% xanthan gum, 0.2% allantoin, 1% benzyl alcohol, 0.5% glyceryl mono- and di-stearates, 1% cetyl alcohol, 1% octadecanol, 8% propylene glycol, 10% oleyl alcohol, 15% medium-chain triglycerides, 1% polysorbate 80, 1% polycetol 1000, 0.01% sodium hyaluronate, 0.05% anhydrous citric acid, 0.02% sodium hydroxide, and water; Preferably, the amount of the composition retained in the epidermis is at least 5 μg / g, 10 μg / g, 15 μg / g, 20 μg / g, 21 μg / g, 22 μg / g, 23 μg / g or 24 μg / g higher than the amount of drug in the dermis. Preferably, the amount of the composition retained in the epidermal layer is at least 5 μg / g, 10 μg / g, 15 μg / g, 20 μg / g, 21 μg / g, 22 μg / g, 23 μg / g, 24 μg / g, 25 μg / g, 26 μg / g, 27 μg / g, or 28 μg / g; Preferably, the composition contains less than 15 μg / g, 10 μg / g, 5 μg / g, 4 μg / g, or 3 μg / g in the dermis. Preferably, the composition has a systemic exposure AUC 0～24h less than 15 pg-h / cm 2 , 10 pg-h / cm 2 , 9 pg-h / cm 2 , or 8 pg-h / cm 2 .

9. A method for preparing the composition according to any one of claims 1-8, the method comprising the following steps: i) Oil phase preparation: Dissolve one or more of the rheology modifier, emulsifier, preservative and oil phase reagent by heating until clear, then add pimecrolimus and dissolve until clear; ii) Aqueous phase preparation: Add thickener and skin soothing agent to purified water and dissolve until clear; iii) Mixing: Add the oil phase to the aqueous phase and stir homogenously; iv) pH adjustment: Adjust the pH to 4.5-6.5 using a pH adjuster; v) Cooling: Cooling down to room temperature; Preferably, the vacuum degree during stirring in step iii) is not lower than -0.06 MPa.

10. Use of the composition according to any one of claims 1-8 in the preparation of a medicament for treating and / or preventing skin manifestations of inflammatory skin diseases and / or immune-mediated diseases; Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma; Preferably, the immune-mediated disease comprises: Alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus; Preferably, the immune-mediated disease is seborrheic dermatitis.

11. A method for treating and / or preventing skin manifestations of inflammatory skin diseases and / or immune-mediated diseases, the method comprising administering to a subject an effective amount of the composition according to any one of claims 1-8; Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma; Preferably, the immune-mediated disease comprises: Alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus; Preferably, the immune-mediated disease is seborrheic dermatitis.

12. The composition according to any one of claims 1-8, used for the treatment and / or prevention of skin manifestations of inflammatory skin diseases and / or immune-mediated diseases; Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photosensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma; Preferably, the immune-mediated disease comprises: Alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, bullous epidermolysis, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus; Preferably, the immune-mediated disease is seborrheic dermatitis.

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