Pimerolimus composition of low-viscosity power law fluid and application of pimerolimus composition

Abstract

The invention relates to the fields of medicines and skin medicines, in particular to a pimerolimus composition of a low-viscosity power law fluid and application of the pimerolimus composition. The invention provides a pimerolimus-containing composition, which contains pimerolimus, a rheology modifier and a thickener, and at normal temperature, the viscous modulus of the composition is greater than the elastic modulus of the composition.

Description

Technical Field

[0001] The present invention relates to the fields of medicine and skin medication, and in particular to a pimecrolimus composition of a low-viscosity power-law fluid and applications thereof. Background Art

[0002] Pimecrolimus is an immunosuppressive drug of the calcineurin inhibitor class. 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-dioxa-4-azatricyclo[22.3.1.04.9]octacos-18-ene-2,3,10,16-tetraone. Its structural formula is:

[0003]

[0004] Pimecrolimus cream, developed by Novartis and marketed as Elidel, was first launched in the US in 2001, in the EU in 2002, and in China in 2005. It is approved for use in non-immunocompromised patients aged three months or older with mild to moderate atopic dermatitis. It has demonstrated a potent immunosuppressive effect in vitro and is effective in improving various skin inflammatory symptoms.

[0005] The dosage form of pimecrolimus cream has certain defects, which limit the clinical efficacy of pimecrolimus. Patent CN100335063C discloses the formula of Novartis' pimecrolimus cream. The formula uses a large amount of solid oil to increase the physical stability of the pimecrolimus composition, but this increased physical stability limits the transdermal penetration of the drug. In a clinical study of pimecrolimus cream (clinical number: ASMW205), 55% of the subjects voluntarily withdrew from the clinical trial due to poor clinical results. This may be because the overall high viscosity of pimecrolimus cream limits the skin penetration process of pimecrolimus cream, affecting the clinical efficacy of the drug.

[0006] Patent CN117462492A discloses a method for promoting the transdermal delivery of pimecrolimus using nanoemulsion technology to enhance transdermal absorption of pimecrolimus. However, this nanoemulsion's transdermal enhancement method can result in systemic exposure of pimecrolimus to plasma, compromising safety. Literature reports indicate that pimecrolimus can cause immunosuppression and lymphoproliferative toxicity in vivo, as well as severe immunosuppressive activity.

[0007] At the same time, due to its greasy feel and high viscosity, the cream is not suitable for application on hairy areas; when applied to the nose and face, it will also feel too greasy, causing discomfort to the patient. This limits the application of pimecrolimus in diseases of the nose, face, and hairy areas. Dermatologist Julia and others summarized the advantages, disadvantages, and applicable scope of different topical dosage forms. For exudative skin diseases such as seborrheic dermatitis that are prone to occur in hairy areas, it is clinically recommended to use lotions as drug carriers. Emulsions as drug carriers have the following advantages: a. The viscosity of the emulsion is low, and the drug solution has the characteristics of spontaneous flow, which is suitable for application and can be easily applied to the skin surface and hairy areas; b. During the use of the emulsion, the evaporation of water will bring a cool skin feeling to the applied area, improving the greasy feeling caused by seborrheic dermatitis.

[0008] In short, the design of the dosage form is very important for drugs. The choice of the dosage form of pimecrolimus cream directly affects its effectiveness and safety. A more optimized dosage form of pimecrolimus still needs to be developed clinically. Summary of the Invention

[0009] The present invention provides a composition containing pimecrolimus, which contains a rheology modifier that imparts power-law fluid characteristics, exhibiting a viscous modulus greater than an elastic modulus at room temperature, exhibiting a tendency to spontaneous flow and facilitating application. The composition also contains a thickener, which enhances its stability and forms a reticular gel structure within the composition, thereby controlling its permeation rate. The composition provided by the present invention improves the delivery of the formulation, ensuring high epidermal retention and low dermal exposure of pimecrolimus, thereby enhancing its effectiveness and safety.

[0010] Specifically, the present invention provides the following technical solutions:

[0011] In a first aspect, the present invention provides a pimecrolimus-containing composition, comprising pimecrolimus, a rheology modifier, and a thickener.

[0012] Preferably, at room temperature, the viscous modulus of the composition is greater than its elastic modulus, and the composition exhibits low viscosity, power-law fluid characteristics, and has spontaneous flow properties.

[0013] 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.

[0014] 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, 1000; preferably, 50-500 cp; preferably, 100-400 cp; more preferably, 100-200 cp.

[0015] Preferably, the composition does not undergo stratification or demulsification when centrifuged at 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.

[0016] Preferably, the composition is an emulsion.

[0017] Preferably, the composition is a power-law fluid.

[0018] Preferably, the composition comprises 0.05-10% pimecrolimus by weight, specifically 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%, 10%.

[0019] Preferably, the composition comprises 0.1-5% by weight of pimecrolimus.

[0020] Preferably, the composition comprises 0.5-2% by weight of pimecrolimus.

[0021] Preferably, the composition comprises 0.75-1%, 0.75-0.8% or 0.8-1% pimecrolimus by weight.

[0022] Preferably, the composition comprises 0.75%, 0.8% or 1% pimecrolimus by weight.

[0023] Preferably, the rheology modifier is a fatty acid or an ester thereof with a carbon chain length between 12 and 14, specifically including a fatty acid or an ester thereof with a carbon chain length of 12, 13 or 14.

[0024] Preferably, the rheology modifier comprises lauric acid or its esters, myristic acid or its esters.

[0025] Preferably, the ester of lauric acid includes 2-ethylhexyl laurate, butyl laurate, ethyl laurate, methyl laurate, glyceryl laurate, polyethylene glycol laurate, sorbitan laurate, polyoxyethylene sorbitan laurate, and cholesterol laurate.

[0026] Preferably, the ester of myristic acid includes one or more of glyceryl myristate, cetyl myristate, stearyl myristate, methyl myristate, ethyl myristate, butyl myristate, isopropyl myristate, octyl myristate, isostearyl myristate, propylene glycol myristate, and phenylethyl myristate.

[0027] Preferably, the rheology modifier is isopropyl myristate.

[0028] Preferably, the weight percentage of the rheology modifier 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%.

[0029] Preferably, the weight percentage of the rheology modifier is 1-10%; preferably, 3-8%; preferably, 4-6%; preferably, 5%.

[0030] Preferably, the weight percentage of the 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%.

[0031] Preferably, the weight percentage of the isopropyl myristate is 1-10%; preferably, 3-8%; preferably, 4-6%; preferably, 5%.

[0032] Preferably, the thickener comprises xanthan gum, guar gum, hydroxypropyl guar gum, gum arabic, tragacanth gum, galactan, carob gum, karaya gum, sodium alginate, carbomer and locust bean gum.

[0033] Preferably, the thickening agent is xanthan gum.

[0034] Preferably, the weight percentage of the thickener is 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%.

[0035] Preferably, the weight percentage of the thickener is 0.05-1%; preferably, 0.1-0.5%; preferably, 0.2-0.4%; preferably, 0.3%.

[0036] Preferably, the weight percentage of the xanthan gum is 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%.

[0037] Preferably, the weight percentage of the xanthan gum is 0.05-1%; preferably, 0.1-0.5%; preferably, 0.2-0.4%; preferably, 0.3%.

[0038] Preferably, the composition further comprises an emulsifier.

[0039] Preferably, the emulsifier is an agent with an HLB value between 10-20.

[0040] Preferably, the emulsifier includes polysorbate 80 (Tween 80), cetomacrogol 1000, polyoxyethylene-21 stearyl ether, Tween 20, polyethylene glycol-12 hydroxystearate, and polyethylene glycol-20 hydroxystearate.

[0041] Preferably, the weight percentage of the emulsifier is 0.1-10%, 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%, 5%, 5.5%, 6%, 6.5%, 7%, 7.5%, 8%, 8.5%, 9%, 9.5%, 10%.

[0042] Preferably, the weight percentage of the emulsifier is 0.5-5%; preferably, 1-3%; preferably, 2%.

[0043] Preferably, the emulsifier is a combination of polysorbate 80 and cetomacrogol 1000.

[0044] Preferably, the weight percentage of polysorbate 80 is 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%.

[0045] Preferably, the weight percentage of the polysorbate 80 is 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0046] Preferably, the weight percentage of the cetomacrogol 1000 is 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%.

[0047] Preferably, the weight percentage of the cetomacrogol 1000 is 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0048] Preferably, the composition further comprises a preservative.

[0049] Preferably, the preservative comprises one or more of benzyl alcohol, methylparaben, ethylparaben, propylparaben, butylparaben, citric acid, dimethylaminoethanol, benzalkonium chloride, benzalkonium bromide and cetrimide.

[0050] Preferably, the preservative is benzyl alcohol.

[0051] Preferably, the weight percentage of the preservative is 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%.

[0052] Preferably, the weight percentage of the preservative is 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0053] Preferably, the weight percentage of the benzyl alcohol is 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%.

[0054] Preferably, the weight percentage of the benzyl alcohol is 0.3-3%; preferably, 0.5-2%; preferably, 1%.

[0055] Preferably, the pH of the composition is 4.5-6.5.

[0056] Preferably, the composition further comprises a pH adjuster.

[0057] 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.

[0058] 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.

[0059] 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.

[0060] Preferably, the pH adjuster is citric acid and sodium hydroxide.

[0061] Specifically, the citric acid is anhydrous citric acid.

[0062] Preferably, the weight percentage of the 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%.

[0063] Preferably, the weight percentage of the anhydrous citric acid is 0.01-0.1%; preferably, 0.03-0.08%; preferably, 0.05%.

[0064] Preferably, the weight percentage of the sodium hydroxide is 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%.

[0065] Preferably, the weight percentage of the sodium hydroxide is 0.008-0.05%; preferably, 0.01-0.03%; preferably, 0.02%.

[0066] Preferably, the composition also comprises a skin soothing agent.

[0067] 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.

[0068] Preferably, the skin soothing agent is a combination of allantoin and sodium hyaluronate.

[0069] Preferably, the weight percentage of allantoin is 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%.

[0070] Preferably, the weight percentage of the allantoin is 0.05-1%; preferably, 0.1-0.5%; preferably, 0.2%.

[0071] Preferably, the weight percentage of the sodium hyaluronate is 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%.

[0072] Preferably, the weight percentage of the sodium hyaluronate is 0.005-0.05%; preferably, 0.008-0.02%; preferably, 0.01%.

[0073] Preferably, the composition further comprises an oil phase agent.

[0074] Preferably, the oil phase agent includes one or more of mono- and distearic acid glyceryl, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, and medium chain triglycerides.

[0075] Preferably, the oil phase agent is a combination of mono- and distearic acid glyceryl, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, and medium chain triglycerides.

[0076] Preferably, the weight percentage of the oil phase agent is 5-60%; preferably, 20-50%; preferably, 25-40%; preferably, 35.5%.

[0077] Preferably, the weight percentage of the mono- and distearic glyceryl is 0.5%.

[0078] Preferably, the weight percentage of the hexadecanol is 1%.

[0079] Preferably, the weight percentage of the stearyl alcohol is 1%.

[0080] Preferably, the weight percentage of the propylene glycol is 8%.

[0081] Preferably, the weight percentage of the oleyl alcohol is 10%.

[0082] Preferably, the weight percentage of the medium chain triglycerides is 15%.

[0083] Preferably, the composition comprises one or more of the following substances: pimecrolimus, benzyl alcohol, glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, rheology modifiers, polysorbate 80, cetomacrogol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum and water.

[0084] Preferably, the composition consists of the following substances: pimecrolimus, benzyl alcohol, glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, rheology modifier, polysorbate 80, cetomacrogol 1000, xanthan gum and water.

[0085] Preferably, the composition is composed of the following substances: 0.75%-1% pimecrolimus, 4-6% isopropyl myristate, 0.2-0.4% xanthan gum, 1% benzyl alcohol, 0.5% mono- and distearic acid glyceryl, 1% cetyl alcohol, 1% stearyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium chain triglycerides, 1% polysorbate 80, 1% cetomacrogol 1000 and water.

[0086] Preferably, the composition consists of the following substances: pimecrolimus, benzyl alcohol, glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, rheology modifier, polysorbate 80, cetomacrogol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum and water.

[0087] Preferably, the composition is composed of 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% mono- and distearic glyceryl, 1% cetyl alcohol, 1% stearyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium chain triglycerides, 1% polysorbate 80, 1% cetomacrogol 1000, 0.01% sodium hyaluronate, 0.05% anhydrous citric acid, 0.02% sodium hydroxide and water.

[0088] Preferably, the epidermal retention of the composition 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 drug content in the dermis.

[0089] Preferably, the composition is retained in the epidermis in an amount of 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.

[0090] Preferably, the drug content of the composition in the dermis is less than 15 μg / g, 10 μg / g, 5 μg / g, 4 μg / g or 3 μg / g.

[0091] Preferably, the composition has a systemic exposure AUC 0～24h Less than 15 μg·h / cm 2 , 10μg·h / cm 2 , 9μg·h / cm 2 or 8 μg·h / cm 2 Some of the above excipients 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 limiting or restrictive in any way.

[0092] On the other hand, the present invention also provides a method for preparing the aforementioned pimecrolimus-containing composition, the method comprising the following steps:

[0093] i) Oil phase preparation: one or more of the rheology modifier, emulsifier, preservative and oil phase reagent are heated and dissolved until clear, and then pimecrolimus is added and dissolved until clear;

[0094] ii) Water phase preparation: Add thickener and skin soothing agent to purified water and dissolve until clear;

[0095] iii) Mixing: Add the oil phase to the water phase and stir homogeneously;

[0096] iv) pH adjustment: adjust the pH to 4.5-6.5 using a pH adjuster;

[0097] v) Cooling: Cool to room temperature.

[0098] Preferably, the vacuum degree during stirring in step iii) is not less than -0.06 MPa.

[0099] On the other hand, the present invention also provides use of the aforementioned pimecrolimus-containing composition in the preparation of a medicament for treating and / or preventing skin manifestations of inflammatory skin diseases and / or immune-mediated diseases.

[0100] Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma.

[0101] Preferably, the immune-mediated diseases include alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus.

[0102] Preferably, the immune-mediated disease is seborrheic dermatitis.

[0103] In another aspect, the present invention also provides a method for treating and / or preventing inflammatory skin diseases and / or skin manifestations of immune-mediated diseases, comprising administering an effective amount of the aforementioned composition to a subject.

[0104] Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma.

[0105] Preferably, the immune-mediated diseases include alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus.

[0106] Preferably, the immune-mediated disease is seborrheic dermatitis.

[0107] In another aspect, the present disclosure provides the aforementioned composition for use in treating and / or preventing inflammatory skin diseases and / or cutaneous manifestations of immune-mediated diseases.

[0108] Preferably, the inflammatory skin diseases include dermatomyositis, vitiligo, ichthyosis vulgaris, photoallergic sensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma.

[0109] Preferably, the immune-mediated diseases include alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia and lupus erythematosus.

[0110] Preferably, the immune-mediated disease is seborrheic dermatitis.

[0111] Compared with the prior art, the present invention has the following beneficial effects:

[0112] The pimecrolimus composition provided by the present invention, containing a rheology modifier and a thickener, exhibits a tendency to flow spontaneously and is easy to apply clinically. The active ingredient, pimecrolimus, is highly retained in the epidermis while having reduced exposure in the dermis and in the body. The pimecrolimus composition is highly effective and safe, exhibits excellent therapeutic effects, and complies with the basic theory of pharmacoeconomics. It is particularly suitable for exudative diseases of the nose, face, and hairy areas. Results from an animal model showed that skin inflammation subsided in guinea pigs with seborrheic dermatitis after treatment with pimecrolimus emulsion, and pathological sections showed no nuclear infiltration. BRIEF DESCRIPTION OF THE DRAWINGS

[0113] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments consistent with the specification and, together with the description, serve to explain the principles of the specification.

[0114] Figure 1 Shown are the skin appearances of guinea pigs in each group before and after treatment.

[0115] Figure 2 The effect scores of each group before and after treatment are shown.

[0116] Figure 3 Shown are the pathological sections of each group stained with HE after treatment.

[0117] Figure 4 Masson-stained pathological sections of each group after treatment are shown.

[0118] Figure 5 Shown are the changes in body weight of guinea pigs in each group during the experiment. DETAILED DESCRIPTION

[0119] To make the objectives, technical solutions, and advantages of the present disclosure more clearly understood, the present disclosure is further described in detail below through specific examples. It is apparent that the described examples are only a portion of the embodiments of the present disclosure, and not all of them. All other implementations derived by persons of ordinary skill in the art based on the embodiments of the present disclosure without creative effort are intended to fall within the scope of protection of the present disclosure.

[0120] The present disclosure may be implemented in other specific forms without departing from the essential attributes of the present disclosure. It should be understood that, without conflict, any and all embodiments of the present disclosure may be combined with the technical features of any other embodiment or multiple other embodiments to obtain additional embodiments. The present disclosure includes additional embodiments obtained by such combinations.

[0121] (I) Definitions and Explanations

[0122] In order to make it easier to understand the present disclosure, certain technical and scientific terms are specifically defined below. In the present disclosure, unless otherwise indicated, the scientific and technical terms used in the present disclosure have the meanings commonly understood by those skilled in the art. It should be understood that the present disclosure is not limited to specific methods, reagents, compounds, compositions or biological systems, and of course, the above can be changed. In addition, the protein and nucleic acid chemistry, molecular biology, cell and tissue culture, microbiology, immunology related terms and laboratory procedures used in the present disclosure are all terms and routine procedures widely used in the corresponding fields. It should also be understood that the terms used in the present disclosure are only for the purpose of describing specific embodiments and are not intended to be limiting.

[0123] In the present disclosure, the conjunction term “and / or” between multiple elements is intended to include both the meanings of “and” and “or”.

[0124] In the present disclosure, the terms "comprises," "includes," "has," and "contains," and any variations thereof, are intended to cover non-exclusive inclusions. The terms are intended to be open ended, specifying the presence of any stated features, elements, integers, steps, or components, but not excluding the presence or addition of one or more other features, elements, integers, steps, components, or groups thereof. Thus, the term "comprising" encompasses the more restrictive terms "consisting of" and "consisting essentially of." In the present disclosure, the term "comprising" indicates that various ingredients may be used together in the mixture or composition of the present disclosure.

[0125] In this disclosure, the disclosure of all ranges should be deemed to be a disclosure of all subranges and all point values ​​within the range. All point values ​​are independently combinable. Since these ranges are continuous, they include every value between the minimum and maximum values. It should also be understood that any numerical range cited in this application is intended to include all subranges within that range. For example: the disclosure of 0.05-10% should be deemed to also disclose ranges such as 0.05%-0.55%, 0.7%-0.8%, 1.4%-10%, and also discloses 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%, 10% and other point values.

[0126] In the present disclosure, the term "pimecrolimus" is an immunosuppressive drug of the calcineurin inhibitor class, whose 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-dioxa-4-azatricyclo[22.3.1.04.9]octacos-18-ene-2,3,10,16-tetraone, and its structural formula is:

[0127]

[0128] In the present disclosure, the term "composition" refers to a preparation containing pimecrolimus and may contain other auxiliary ingredients such as rheology modifiers and thickeners. These ingredients work together to improve clinical compliance, increase the retention of the drug in the epidermis of the skin, and enhance the efficacy and safety of pimecrolimus.

[0129] In the present disclosure, the term "weight percent" or "%" means percent by weight (w / w).

[0130] In this disclosure, the term "cp" or "centipoise" is a commonly used unit of viscosity (dynamic viscosity), which is a measure of a fluid's resistance to flow.

[0131] In this disclosure, the term "Pa" or "Pascal" is a unit of pressure, where 1 Pa is equal to the pressure generated by a force of 1 Newton acting uniformly and vertically on an area of ​​1 square meter.

[0132] In this disclosure, the terms "elastic modulus (usually represented by G', also known as storage modulus)" and "viscous modulus (usually represented by G", also known as loss modulus)" are used to characterize the deformation response characteristics of a material under stress, and can be measured by a rheometer.

[0133] In this disclosure, the term "power-law fluid" is a type of non-Newtonian fluid in which the shear stress (τ) is proportional to the shear rate (γ · ) satisfies the power law relationship: τ = K·γ^n; where K is the viscosity coefficient, or power law coefficient, which reflects the viscosity of the fluid; n is the power law exponent, which characterizes the non-Newtonian characteristics of the fluid.

[0134] In this disclosure, the term "emulsifier" refers to a compound used to mix the oil phase and aqueous phase components. The HLB value of the emulsifier required for the pimecrolimus-containing composition of the present invention is generally between 10 and 20, and the HLB value of 10-20 specifically includes 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20. Preferably, the emulsifier is a combination of polysorbate 80 and cetomacrogol 1000, which can maintain the stability of the emulsion droplets and prevent the merging and aggregation of the emulsion droplets.

[0135] In the present disclosure, the term "Hydrophile-Lipophile Balance (HLB)" is a quantitative indicator that measures the relative strength of the hydrophilicity and lipophilicity of a surfactant.

[0136] In the present disclosure, the term "pH adjuster" refers to a chemical substance used to adjust the pH of a product. An appropriate pH value helps ensure product stability and skin adaptability, and avoids irritation or damage to the skin.

[0137] In the present disclosure, term "thickening agent" refers to a composition added to the preparation to increase its viscosity, such as xanthan gum. Xanthan gum has been added to the composition containing pimecrolimus of the present invention, and can, without significantly increasing viscosity, under the premise of not changing the rheological characteristics of the preparation, the viscosity of the composition is limited to 50-500cp, and the composition with this viscosity still has the rheological characteristics of a power-law fluid, and under centrifugal conditions (5000rpm, 30min), stratification will not occur. In addition, the addition of xanthan gum can also control the transdermal release process of the active ingredient. Xanthan gum has formed a reticular gel structure in the preparation, and this structure has stable thixotropic properties, can limit the speed of the active ingredient penetrating the stratum corneum, and the active ingredient is enriched in the epidermis, reduces the exposure in the dermis and the body, and plays a targeted effect.

[0138] In this disclosure, the term "preservative" refers to a chemical substance, such as benzyl alcohol, used to inhibit the growth of microorganisms such as bacteria and mold. Preservatives ensure that a product remains stable and safe during storage and use.

[0139] In the present disclosure, the term "normal temperature" refers to a natural temperature without the need for additional temperature control, which may be 4-40°C, preferably 25±5°C.

[0140] In this disclosure, the term "skin manifestation" refers to signs or conditions of abnormal appearance, structure, or function of a subject's skin due to various physiological or pathological factors or external stimuli. In this disclosure, the term "skin" includes not only the skin tissue covering the body surface, but also the appendages (such as nails and hair) and mucosal tissues that are closely related to its structure and function. Specifically, this disclosure is directed to signs or conditions of abnormal skin caused by inflammatory skin diseases and / or immune-mediated diseases.

[0141] In this disclosure, the terms "treat," "treat," and "prevent," "alleviate," and are intended to mean delaying the development of a disease, preventing the development of a disease, and / or reducing the severity of symptoms that will develop or are expected to develop. Thus, these terms include ameliorating existing disease symptoms, preventing additional symptoms, ameliorating or preventing potential metabolic causes of symptoms, inhibiting the disorder or disease, e.g., arresting the development of the disorder or disease, alleviating the disorder or disease, causing the disorder or disease to regress, alleviating the symptoms caused by the disease or disorder, or halting the symptoms of the disease or disorder.

[0142] In the present disclosure, the term "subject" includes confirmed patients, but the "subject" does not need to have any special identity to the hospital, clinic or research facility (such as being a confirmed patient, research participant, etc.). The amount of the 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 mode and frequency of treatment, and the judgment of the prescribing physician. The frequency of administration can also depend on the pharmacodynamic effect on arterial oxygen partial pressure. However, the most preferred dosage can be adjusted according to the individual subject, as understood by those skilled in the art and can be determined without excessive experimentation. This generally includes adjusting the standard dose (for example, if the patient has a low body weight, then reducing the dose).

[0143] In the present disclosure, the terms "subject", "object", "individual" or "patient" are used interchangeably herein and specifically include mammals and non-mammals. In one embodiment of the present disclosure, the mammal is a human.

[0144] In the present disclosure, the term "effective amount" or "effective dose" refers to the amount of pimecrolimus and / or the amount of the composition described in the present disclosure that can produce a therapeutic effect on humans and / or animals and can be accepted by humans and / or animals. For example, a drug therapeutically or pharmaceutically effective amount refers to the amount of pimecrolimus and / or the amount of the aforementioned composition required to produce the desired therapeutic effect, and the therapeutic effect can be reflected by the results of clinical trials, model animal studies and / or in vitro studies. The pharmaceutically effective amount depends on several factors, including but not limited to: characteristic factors of the treatment subject (such as the height, weight, gender, age and medication history of the treatment subject), and the severity of the disease. In a specific embodiment of the present disclosure, the "effective amount" refers to an amount sufficient to inhibit, slow down or prevent the deterioration of the skin manifestations of skin diseases and immune-mediated diseases in the subject.

[0145] (II) Detailed technical plan

[0146] For purposes of clarity and conciseness, features are described herein as part of the same or separate embodiments; however, it will be understood that the scope of the present disclosure may include embodiments having a combination of all or some of the described features.

[0147] Example 1: Preparation of pimecrolimus microemulsion gel

[0148] Preparation of pimecrolimus microemulsion gel by the method of reference patent CN117462492A:

[0149] Step 1. First, a high-pressure homogenization method is used to prepare a pimecrolimus microemulsion. In terms of weight percentage, 1% of the pimecrolimus raw material is first added to a mixed oil of 20% ethanol, medium-chain triglycerides and isopropyl myristate (volume ratio is 1:1:2), and stirred at 500-1000 rpm until clear; then 6% Tween 60 and 2% Span 60 are added, stirred evenly, and purified water is added to 100%; high-speed shear dispersion (10000 rpm / 30 min) is performed to prepare colostrum, and the colostrum particle size is about 1-100 μm; the prepared colostrum is then homogenized three times using a high-pressure homogenizer (homogenization pressure 800 bar) to prepare a microemulsion;

[0150] Step 2: Add 0.5% hydroxyethyl cellulose (HEC) to the pimecrolimus microemulsion prepared in step 1, and stir slowly until it is completely dissolved.

[0151] Example 2: Preparation of pimecrolimus emulsion

[0152] Table 1. Pimecrolimus emulsion prescription

[0153]

[0154] The formulations of pimecrolimus emulsions 1-4 are shown in Table 1, where the numbers in Table 1 represent the weight percentages (% w / w) of the respective ingredients. The rheology modifiers of emulsions 1-4 are selected from decanoic acid, palmitic acid, or isopropyl myristate, respectively. The carbon chain length of decanoic acid is 10, the carbon chain length of palmitic acid is 16, and the carbon chain length of isopropyl myristate is 14, all of which are purchased from Zhejiang Wumei Biotechnology Co., Ltd. Pimecrolimus emulsions 1-4 were prepared using a homogeneous emulsification method according to Table 1. The specific configuration method is as follows:

[0155] Step 1, oil phase preparation: heat the rheology modifier (decanoic acid, palmitic acid or isopropyl myristate), oleyl alcohol, benzyl alcohol, medium chain triglycerides, propylene glycol, glyceryl mono- and distearate, cetomacrogol 1000, cetyl alcohol, octadecanol, and polysorbate 80 to 70±5°C, stir and dissolve until clear, and set aside; then add pimecrolimus, stir and dissolve until clear, and set aside;

[0156] Step 2, aqueous phase preparation: add xanthan gum, allantoin, and sodium hyaluronate to purified water, stir and dissolve until clear, and heat to 70±5℃ for later use;

[0157] Step 3: Mixing: Add the oil phase to the water phase and stir homogeneously. The vacuum degree should not be lower than -0.06Mpa.

[0158] Step 4, pH adjustment: Use anhydrous citric acid and sodium hydroxide to adjust the pH to 4.5-6.5,

[0159] Step 5: Cooling: Turn on the cooling water, stir and cool to room temperature to obtain emulsion 1-4.

[0160] Example 3: Viscosity, modulus and rheological curve detection

[0161] 1. Viscosity determination method:

[0162] The equipment used was a Brookfield DV2T viscometer with an SC4-18 rotor, a test temperature of 25°C, a constant temperature time of 10 minutes, a measuring speed of 80 rpm, a running time of 120 seconds, and a collection time of 10 seconds.

[0163] 2. Determination method of rheological curve:

[0164] The rheological curve was measured using the HA-10 rheometer from TA Company, USA. The test mode was the rotation test CR mode, ramp scanning, logarithmic coordinates, the fixture was a 40 mm stainless steel plate, the test temperature was 25 ° C, the holding time was 60 seconds, the shear time was 240 seconds, the shear range was 1000~0.01, and the gap was 0.5 mm.

[0165] 3. Determination method of modulus:

[0166] The modulus was determined using an HA-10 rheometer from TA Company, USA. The test mode was oscillation test control CF mode with continuous change. The fixture was a 40 mm stainless steel plate. The test temperature was 25 °C, the holding time was 60 s, the strain was 1.0%, the angular frequency was 100-0.1 rad / s, and the gap was 0.5 mm.

[0167] According to the above method, the microemulsion gels, emulsions 1-4 and commercially available creams ( The results are shown in Table 2.

[0168] Table 2. Viscosity, modulus and rheological curve test results

[0169]

[0170] Viscosity is a key quality attribute of emulsions. Excessively high viscosity can affect patient compliance with the drug and hinder application. Excessively low viscosity can affect drug stability, potentially leading to sedimentation and demulsification during the stability period. An appropriate viscosity ensures both drug stability and clinical compliance. A composition with a viscosity between 50 and 500 cp exhibits excellent drug stability and strong clinical compliance.

[0171] The formulation characteristics of the composition are emulsions, and it is a non-Newtonian fluid in rheology. When the rheological curve of the composition is a power-law fluid, the rheological curve characteristics of the drug are pseudoplastic fluids with no yield stress, that is, the consistency of the drug will become thinner during the application process, making it easier to apply. When the application stops, the drug will spontaneously recover and present a certain consistency, adhering to the lesion site, thereby protecting the lesion site and curing the disease.

[0172] According to the results shown in Table 2, emulsions 1, 3, 4, and the microemulsion gel all exhibited a viscous modulus greater than an elastic modulus. The opposite was true for emulsion 2 and the commercial cream, where the viscous modulus was less than the elastic modulus. This result suggests that the modulus of the product reverses when the carbon chain length of the rheology modifier is ≤14, with the viscous modulus exceeding the elastic modulus. A formulation with a viscous modulus greater than the elastic modulus exhibits spontaneous flow, making it easier to apply during clinical use, particularly to the nose, face, and hairy areas. It is suitable for the treatment of seborrheic dermatitis of the nose and face. According to the second law of thermodynamics, the state of matter tends to develop toward increasing entropy. When the viscous modulus exceeds the elastic modulus, the drug's ability to penetrate the skin increases.

[0173] Example 4: Centrifugal stability and long-term stability studies

[0174] The microemulsion gel, emulsion and commercially available cream prepared in Examples 1 and 2 were subjected to a centrifugal stability study (5000 rpm, 30 min).

[0175] Table 3. Centrifugal stability of pimecrolimus emulsions with different rheology modifiers

[0176]

[0177] The experimental results, shown in Table 3, show that Emulsions 1 and 4 separated into separate layers after centrifugation, were unstable, and failed to meet shelf stability requirements. According to Stokes's law of sedimentation, emulsion droplets are in a thermodynamically unstable state within the system, making them susceptible to sedimentation and aggregation during long-term storage. The addition of a rheology modifier significantly reduced the viscosity of the formulation, negatively impacting shelf life. However, the addition of xanthan gum formed a networked gel system within the system, slowing the coalescence and sedimentation of the droplets, thereby increasing viscosity and enhancing formulation stability.

[0178] Example 5: In vitro transdermal studies

[0179] The microemulsion gel and emulsion prepared in Examples 1 and 2 were compared with the commercially available pimecrolimus cream for transdermal absorption. 2 The receiving cell volume was 8 mL, and the skin of Bama miniature pigs (one month old) was used as the permeation barrier. The concentration of 10 mg / cm 2 The drug was applied in an amount of about 17.7 mg, and the receiving solution was normal saline for in vitro transdermal testing, wherein the temperature was set at 32°C, the rotation speed was 600 rpm, and n = 6. Samples were taken at 1, 2, 4, 8, 12, and 24 hours.

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

[0181] Table 4. Summary and comparison of transmittance

[0182]

[0183]

[0184] Note: AUC 0-24h The area under the plasma concentration-time curve from 0 to 24 hours

[0185] The results showed that compared with the commercially available pimecrolimus cream and pimecrolimus microemulsion gel, the pimecrolimus composition (emulsion 3) after adding rheology modifier and thickener could target and enrich pimecrolimus in the epidermis (p < 0.05), with epidermal retention ≥ 20 μg / g, dermal drug content ≤ 10 μg / g, and systemic exposure AUC 0-24h≤10 μg·h / cm 2 , significantly reducing drug exposure in the dermis (Table 4).

[0186] Example 6: Transdermal study of pimecrolimus emulsions of different strengths

[0187] In order to further study the transdermal effect of pimecrolimus of different specifications, the pimecrolimus content was changed according to the composition formula of emulsion 3 in Table 1, and pimecrolimus emulsions with pimecrolimus contents of 0.75%, 0.8% and 1% were prepared (formulation see Table 5) for in vitro release and in vitro transdermal studies.

[0188] Table 5. Prescriptions of different specifications of pimecrolimus emulsion

[0189] Raw materials Emulsion 3 (Specification: 0.75%) Emulsion 3 (Specification: 0.8%) Emulsion 3 (Specification: 1.0%) Pimecrolimus 0.75 0.8 1 Benzyl alcohol 1 1 1 Glyceryl mono- and distearate 0.5 0.5 0.5 Cetyl alcohol 1 1 1 Octadecanol 1 1 1 Propylene glycol 8 8 8 Oleyl alcohol 10 10 10 Medium-chain triglycerides 15 15 15 Rheology modifiers 5 / Isopropyl myristate 5 / Isopropyl myristate 5 / Isopropyl myristate Polysorbate 80 1 1 1 Cetomacrogol 1000 1 1 1 Allantoin 0.2 0.2 0.2 Sodium hyaluronate 0.01 0.01 0.01 Anhydrous citric acid 0.05 0.05 0.05 Sodium hydroxide 0.02 0.02 0.02 Xanthan gum 0.3 0.3 0.3 purified water Add to 100 Add to 100 Add to 100

[0190] The in vitro release study method refers to the "Technical Guidelines for In Vitro Release (IVRT) and In Vitro Transdermal (IVPT) Studies of Topically Acting Chemical Generic Drugs (Trial)" issued by the CDE and the "In Vitro Release (IVRT) Study of Topical Drug Products Submitted in ANDA Applications" issued by the FDAOGD Office. The release medium is 50% ethanol-0.9% saline.

[0191] The three release curves were compared for similarity using the Mann-Whitney U test. The results showed that the release rates of Emulsion 3 (strength: 0.75%), Emulsion 3 (strength: 0.8%), and Emulsion 3 (strength: 1.0%) were consistent at a 90% confidence interval (Tables 6 and 7). Additionally, in vitro transdermal testing was performed, and the results are shown in Table 8.

[0192] Table 6. Similarity of release curves of 0.8% and 1.0%

[0193]

[0194] Table 7. Similarity of release curves of 0.75% and 1.0%

[0195]

[0196] Table 8. Transmission rate of different emulsions

[0197]

[0198] Example 7: Study on the dosage of rheology modifier and thickener in emulsion 3

[0199] The rheology modifier and thickener in Emulsion 3 were isopropyl myristate and xanthan gum, respectively. The amounts of isopropyl myristate and xanthan gum were screened in this example. The contents of isopropyl myristate and xanthan gum in Emulsion 3 and Emulsions 5-8 are shown in Table 9. The pimecrolimus content was 0.75%. All other ingredients were identical to the formulation of Emulsion 3 in Table 1.

[0200] Table 9. Rheology modifier and thickener dosage study

[0201] preparation Lotion 5 Lotion 6 Lotion 3 Lotion 7 Lotion 8 Isopropyl myristate dosage / % 4 6 5 5 5 Xanthan gum dosage / % 0.3％ 0.3％ 0.3％ 0.2％ 0.4％

[0202] Emulsion 3 and Emulsions 5-8 were prepared according to the method described in Example 2, and their viscosity, modulus, and rheological curves were tested according to the method described in Example 3. The results showed that when the amount of xanthan gum was between 0.2% and 0.4% and the amount of isopropyl myristate was between 4% and 6%, the compositions maintained power-law fluid characteristics, with low viscosity and a viscous modulus greater than the elastic modulus (Table 10).

[0203] Table 10. Viscosity, modulus and rheological curve test results

[0204]

[0205] Example 8: Treatment of seborrheic dermatitis

[0206] 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 pharmacodynamic and safety studies on guinea pigs.

[0207] Animal grouping and medication regimen are shown in Table 11, and evaluation criteria are shown in Table 12. Forty-eight 5-week-old male guinea pigs were purchased and routinely raised for one week. Marked groups were divided into groups of 6 + 2 mice (2 spare) per group. Guinea pigs transfected with Malassezia were used as the model for the animal experiment, and medication was administered twice daily. The specific modeling method was:

[0208] Step 1: Bacterial culture: Malassezia furfur was inoculated on a specific culture medium for two consecutive passages, and then a single colony was picked and cultured in a liquid culture medium; the fungal count was adjusted to 1x10 8 CFU / mL and added 5% olive oil for mixing;

[0209] Step 2: Modeling: Use a razor to shave one side of the guinea pig's back into a 5cmx5cm area, remove the hair with a depilatory cream, disinfect it, and then use sandpaper to polish the depilatory area until punctate bleeding occurs. 7 The bacterial suspension was applied to the polished area for 7 consecutive days until white bran-like scales and light red spots appeared in the modeling area inoculated with Malassezia. The modeling was successful and classified according to the severity.

[0210] Step 3. Identification of successful modeling: Clinical appearance scoring (scaly, erythematous papules, hair loss, etc.) of the mouse skin seborrheic dermatitis experimental animals.

[0211] Table 11. Animal groups and medication regimens

[0212]

[0213] Table 12. Evaluation criteria

[0214]

[0215] After 10 days of treatment, the symptoms of the model group did not improve significantly, and the pathological features were significant, indicating that the guinea pigs did not recover on their own during the treatment period, and the model was effective ( Figure 1 , guinea pig skin appearance before and after treatment in the model group); the emulsion group and the microemulsion gel group had significant therapeutic effects on seborrheic dermatitis (p < 0.05), while the commercial cream group had no significant effect (p > 0.05). This may be because pimecrolimus cream is a pseudoplastic fluid with elastic modulus > viscous modulus and low transdermal permeability, so the therapeutic effect was not significant during the treatment, and the effect was similar to that of the blank emulsion group ( Figure 1-2 ).

[0216] The results of HE-stained pathological sections showed that the model group had abnormal thickening of the stratum corneum, acanthosis hyperplasia, increased number of melanocytes, inflammatory cell infiltration, cell clustering, and follicular plugs. The above pathological conditions in the emulsion group and microemulsion gel group were relatively improved, while the blank emulsion group and commercial cream group had weaker improvements (e.g. Figure 3 HE-stained pathological sections as shown).

[0217] The results of Masson staining of pathological sections showed that the model group had obvious epidermal hyperplasia, and the collagen fibers were unevenly distributed and arranged in disorder; the blank group still had obvious hyperplasia, and the collagen fibers were more evenly distributed than the model group. The emulsion group and microemulsion gel group had significantly less hyperplasia than the blank emulsion group and the commercial cream group, and the collagen fibers were more evenly distributed (such as Figure 4 Masson-stained pathological sections as shown).

[0218] In terms of safety, the weight of guinea pigs in each group was measured during the experiment. Figure 5 The results showed that, with the exception of the microemulsion gel group, the weight of the guinea pigs in the other groups steadily increased. However, the guinea pigs in the microemulsion gel group experienced a significant weight loss during the dosing period, became less active, and two of the guinea pigs died on the sixth day of dosing. This result suggests that the microemulsion gel is highly toxic to guinea pigs, likely due to the microemulsion gel's high permeability and the high exposure in the guinea pigs.

[0219] In summary, in terms of pharmacodynamics, both the emulsion and microemulsion gel groups demonstrated superior efficacy compared to the commercially available cream. This may be due to the improved permeability of the emulsion and microemulsion gel groups compared to the emulsion group, enabling the delivery of a greater amount of the active ingredient into the epidermis. However, differences emerged between the emulsion and microemulsion gel groups in terms of safety. While the microemulsion gel group exhibited a high permeability, it lacked a targeted effect, resulting in the active ingredient penetrating into the guinea pigs and causing significant in vivo exposure. This led to weight loss, behavioral limitations, and the death of two guinea pigs during treatment. In contrast, the emulsion group, due to the controlled release effect of the reticular gel provided by xanthan gum, targeted the active ingredient to the epidermis, with minimal exposure to the dermis and the body, resulting in greater safety.

Claims

1. A composition containing pimecrolimus, comprising pimecrolimus, a rheology modifier and a thickener, wherein the weight percentage of the pimecrolimus is 0.05-10%, and the viscous modulus of the composition is 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; preferably, 50-500 cp; more preferably, 100-200 cp; Preferably, the composition is centrifuged at 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 without stratification or demulsification; Preferably, the composition is an emulsion; Preferably, the composition is a power-law fluid; Preferably, the weight percentage of pimecrolimus is 0.1-5%; preferably, 0.75-1%, 0.75-0.8% or 0.8-1%; more preferably, 0.75%, 0.8%, 1%; Preferably, the rheology modifier is a fatty acid or an ester thereof having a carbon chain length between 12 and 14; Preferably, the rheology modifier comprises lauric acid or its ester, myristic acid or its ester; preferably, the rheology modifier is isopropyl myristate; Preferably, the weight percentage of the rheology modifier is 0.5-20%; preferably, 4-6%; preferably, 5%; Preferably, the weight percentage of the 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, galactan, carob gum, karaya gum, sodium alginate, carbomer and locust bean gum; Preferably, the thickener is xanthan gum; Preferably, the weight percentage of the thickener is 0.01-2%; preferably, 0.2-0.4%; preferably, 0.3%; Preferably, the weight percentage of the xanthan gum is 0.01-2%; preferably, 0.2-0.4%; preferably, 0.3%.

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

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

6. The composition according to any one of claims 1 to 5, wherein the pH is 4.5 to 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 comprises 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%; preferably, 0.05%; Preferably, the weight percentage of the sodium hydroxide is 0.005-0.1%; preferably, 0.02%.

7. The composition of any one of claims 1 to 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 agents are allantoin and sodium hyaluronate; Preferably, the weight percentage of allantoin is 0.01-2%; preferably, 0.2%; Preferably, the weight percentage of the sodium hyaluronate is 0.001-0.1%; preferably, 0.01%.

8. The composition according to any one of claims 1 to 7, further comprising an oil phase agent; Preferably, the oil phase agent includes one or more of mono- and distearic acid glyceryl, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, and medium chain triglycerides; Preferably, the oil phase agent is glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, and medium chain triglycerides; Preferably, the weight percentage of the oil phase agent is 5-60%; preferably, 35.5%; Preferably, the weight percentage of the mono- and distearic glyceryl is 0.5%; Preferably, the weight percentage of the hexadecanol is 1%; Preferably, the weight percentage of the stearyl alcohol is 1%; Preferably, the weight percentage of the propylene glycol is 8%; Preferably, the weight percentage of the oleyl alcohol is 10%; Preferably, the weight percentage of the medium chain triglycerides is 15%; Preferably, the composition comprises one or more of the following substances: pimecrolimus, benzyl alcohol, glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, rheology modifier, polysorbate 80, cetomacrogol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum and water; Preferably, the composition consists of the following substances: Pimecrolimus, benzyl alcohol, glyceryl mono- and distearate, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, rheology modifier, polysorbate 80, cetomacrogol 1000, xanthan gum, and water; Preferably, the composition is composed of the following substances: 0.75%-1% pimecrolimus, 4-6% isopropyl myristate, 0.2-0.4% xanthan gum, 1% benzyl alcohol, 0.5% mono- and distearic acid glyceryl, 1% cetyl alcohol, 1% stearyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium chain triglycerides, 1% polysorbate 80, 1% cetomacrogol 1000 and water; Preferably, the composition is composed of the following substances: pimecrolimus, benzyl alcohol, mono- and distearic glyceryl, cetyl alcohol, stearyl alcohol, propylene glycol, oleyl alcohol, medium chain triglycerides, rheology modifier, polysorbate 80, cetomacrogol 1000, allantoin, sodium hyaluronate, anhydrous citric acid, sodium hydroxide, xanthan gum and water; Preferably, the composition is composed of 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% mono- and distearic acid glyceryl, 1% cetyl alcohol, 1% stearyl alcohol, 8% propylene glycol, 10% oleyl alcohol, 15% medium chain triglycerides, 1% polysorbate 80, 1% cetomacrogol 1000, 0.01% sodium hyaluronate, 0.05% anhydrous citric acid, 0.02% sodium hydroxide and water; Preferably, the epidermal retention amount of the composition 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 drug content in the dermis; Preferably, the composition has an epidermal retention of 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 drug content of the composition in the dermis is less than 15 μg / g, 10 μg / g, 5 μg / g, 4 μg / g or 3 μg / g; Preferably, the composition has a systemic exposure AUC 0～24h Less than 15 μg·h / cm 2 , 10μg·h / cm 2 , 9μg·h / cm 2 or 8 μg·h / cm 2 .

9. A method for preparing a composition according to any one of claims 1 to 8, comprising the steps of: i) Oil phase preparation: one or more of the rheology modifier, emulsifier, preservative and oil phase reagent are heated and dissolved until clear, and then pimecrolimus is added and dissolved until clear; ii) Water phase preparation: Add thickener and skin soothing agent to purified water and dissolve until clear; iii) Mixing: Add the oil phase to the water phase and stir homogeneously; iv) pH adjustment: adjust the pH to 4.5-6.5 using a pH adjuster; v) Cooling: cooling to room temperature; Preferably, the vacuum degree during stirring in step iii) is not less than -0.06 MPa.

10. Use of the composition according to any one of claims 1 to 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, photoallergic sensitivity, cutaneous T-cell lymphoma, acne, and autoimmune diseases such as chronic rheumatoid arthritis and scleroderma; Preferably, the immune-mediated diseases include: Alopecia areata, psoriasis, atopic dermatitis, contact dermatitis and other eczematous dermatitis, seborrheic dermatitis, lichen planus, pemphigus, bullous pemphigoid, epidermolysis bullosa, urticaria, angioedema, vasculitis, erythema, cutaneous eosinophilia, and lupus erythematosus; Preferably, the immune-mediated disease is seborrheic dermatitis.

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