Pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis

Abstract

Disclosed is a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis. The pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment comprises: a phosphodiesterase-4 inhibitor including at least one of a phosphodiesterase-4 inhibitory component or a pharmaceutically acceptable salt thereof; and an active ingredient including at least one of octenidine or an octenidine salt, wherein the phosphodiesterase-4 inhibitory component may include at least one among roflumilast, dipamilast, and tanimilast.

Description

Pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis

[0001] The present disclosure relates to a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis.

[0002] Among skin diseases, psoriasis and atopic dermatitis, both systemic skin diseases, are prime examples of diseases whose incidence has increased significantly due to industrial development and climate change. While numerous treatments are currently available for psoriasis and atopic dermatitis, their effectiveness remains low, leaving patients suffering from unbearable itching and skin inflammation.

[0003] Psoriasis is a chronic, non-contagious skin disease characterized by redness and thickening of the skin due to excessive keratin production. Psoriasis is a chronic autoimmune disease that occurs when the immune system, which should be attacking external microorganisms or irritants, attacks the skin itself.

[0004] Currently, molecular biological mediators that induce excessive immune responses include inflammatory cytokines such as Tumor Necrosis Factor-alpha (TNF-α), Interleukin-17A (IL-17A), Interleukin-23 (IL-23), and Interleukin-33 (IL-33). Among these, Interleukin-17A and Interleukin-23 have the greatest effect on psoriasis.

[0005] Topical treatments for psoriasis (e.g., topical treatments) include vitamin D derivatives, steroids, and combinations of vitamin D derivatives and steroids. These drugs mainly promote differentiation of normal cells, inhibit proliferation of keratinocytes, anti-inflammation, and control itching.

[0006] Meanwhile, atopic dermatitis affects 15-20% of children and 1-3% of adults worldwide, and is a chronic, intractable inflammatory skin disease characterized by itching, skin redness, lichenification, and skin infections. In skin affected by atopic dermatitis, various subtypes of T cells, such as Th2 (T helper 2), Th22, and Th17 cells, increase, resulting in damage to the skin barrier.

[0007] Additionally, in skin affected by atopic dermatitis, Thymic Stromal Lymphopoietin (TSLP) is secreted, which activates Th2 cells and releases interleukin-4 (IL-4), interleukin-5 (IL-5), interleukin-13 (IL-13), and interleukin-31 (IL-31). Among these, interleukin-4 and interleukin-13 have the greatest effect on atopic dermatitis.

[0008] Topical medications for atopic dermatitis include calcineurin inhibitors (e.g., tacrolimus, pimecrolimus, etc.), steroids (e.g., betamethasone, desonide, etc.), antihistamines (e.g., hydroxyzine, diphenhydramine, etc.), and antibiotics (e.g., azithromycin, mupirocin, etc.).

[0009] Additionally, fungi that cause inflammatory skin diseases include Staphylococcus aureus, Candida albicans, and Malassezia sympodialis.

[0010] However, a number of adverse effects (e.g., skin atrophy, growth retardation, malignant tumors, lymphopenia, vomiting, abdominal pain, nephrotoxicity, osteoporosis, avascular necrosis, hypertension, headache, bacterial and viral infections, etc.) that appear in drugs and therapies for the treatment of psoriasis and atopic dermatitis are widely reported as side effects.

[0011] Therefore, there is an urgent need for a treatment for psoriasis and atopic dermatitis that suppresses itching, prevents infection by various pathogens, effectively restores damaged skin barriers, and has no side effects.

[0012] The present inventor has made diligent efforts to develop a pharmaceutical composition that effectively sterilizes bacteria in inflamed areas of psoriasis and atopic dermatitis, improves the stability of pharmaceutical preparations used for psoriasis and atopic dermatitis, and further enhances the inhibitory effect against inflammatory cytokines that cause psoriasis and atopic dermatitis, and has thus completed the present invention.

[0013] [Prior Art Literature]

[0014] [Non-patent literature]

[0015] 1. Lee Young-ae, "Psoriasis and Dry Skin," BRIC View 2020-T03, January 9, 2020.

[0016] 2. Gam Seong-gyun, “Key players in atopic dermatitis and new drug development,” Korean Pharmaceutical Journal, May 21, 2020.

[0017] The technical idea of ​​the present disclosure is to solve the above-described problems, and provides a technology for a pharmaceutical composition having an excellent therapeutic effect on systemic skin diseases.

[0018] In addition, the technical idea of ​​the present disclosure provides a technology for a pharmaceutical composition having an excellent effect of sterilizing bacteria that cause diseases such as psoriasis and atopic dermatitis.

[0019] In addition, the technical idea of ​​the present disclosure provides a technology for a pharmaceutical composition with improved storage stability.

[0020] In addition, the technical idea of ​​the present disclosure provides a technology for a pharmaceutical composition having an excellent inhibitory effect on inflammatory cytokines that cause psoriasis and atopic dermatitis.

[0021] And, the technical idea of ​​the present disclosure provides a pharmaceutical composition for preventing or treating psoriasis.

[0022] In addition, the technical idea of ​​the present disclosure provides a pharmaceutical composition for preventing or treating atopic dermatitis.

[0023] Additionally, the technical idea of ​​the present disclosure provides a use for preventing or treating psoriasis and atopic dermatitis.

[0024] And, the technical idea of ​​the present disclosure provides a method for preventing or treating psoriasis by applying a pharmaceutical composition to an affected area.

[0025] In addition, the technical idea of ​​the present disclosure provides a method for preventing or treating atopic dermatitis by applying a pharmaceutical composition to an affected area.

[0026] The problems to be solved by the present invention are not limited to the problems described above, and other technical problems not mentioned will be clearly understood by those skilled in the art to which the present invention pertains from the contents described below.

[0027] In order to achieve this purpose, as one embodiment of the present invention, a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis comprises: a phosphodiesterase-4 inhibitor comprising at least one of a phosphodiesterase-4 (PDE-4) inhibitor and a pharmaceutically acceptable salt thereof; and an active ingredient comprising at least one of octenidine and an octenidine salt; wherein the phosphodiesterase-4 inhibitor may comprise at least one of roflumilast, difamilast, and tanimilast.

[0028] Additionally, the content of the phosphodiesterase-4 inhibitor may be 0.01 to 5 wt% based on the total weight of the composition.

[0029] In addition, the phosphodiesterase-4 inhibitor may further include at least one of roflumilast N-oxide, lotamilast, apremilast, orismilast, crisaborole, and rolipram.

[0030] In addition, the pharmaceutically acceptable salt of the phosphodiesterase-4 inhibitory component may include at least one selected from an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt of the phosphodiesterase-4 inhibitory component.

[0031] In addition, the content of the active ingredient is 0.01 to 8 wt% based on the total weight of the composition, and the octenidine salt may include at least one selected from an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt of the octenidine.

[0032] In addition, the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis further comprises a crystal growth inhibitor comprising isopentyldiol and propylene carbonate in a weight ratio of 2:1, and the content of the crystal growth inhibitor may be 1 to 30 wt% based on the total weight of the composition.

[0033] In addition, the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may further include an additive including at least one of a solvent, a moisturizer, a penetrant, a surfactant, an antioxidant, a chelating agent, a pH regulator, and a viscosity regulator.

[0034] Additionally, the pH of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be 2 to 10.

[0035] And, the density of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be 0.1 to 2 g / cm3.

[0036] Additionally, the surface tension of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be 1 to 75 dyn / cm.

[0037] Additionally, the moisture content of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be 0.1 to 95 wt%.

[0038] In addition, the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may have any one formulation selected from among solutions, ointments, lotions, creams, gels, emulsions, suspensions, sticks, plasters, patches, wet compresses, microcapsules, cleansers, liposomes, and sprays.

[0039] Meanwhile, another embodiment of the present invention may include a use for manufacturing a drug for preventing or treating psoriasis and atopic dermatitis.

[0040] The solutions to the above-described problems are merely exemplary and should not be construed as limiting the scope of the present invention. In addition to the exemplary embodiments described above, additional embodiments may exist, as described in the drawings and detailed description of the invention.

[0041] As described above, the various embodiments of the present invention not only exhibit excellent preventive and therapeutic effects against psoriasis and atopic dermatitis, but also exhibit high medication compliance due to their outstanding antibiotic effects. That is, the various embodiments of the present invention exhibit superior inhibitory effects against inflammatory cytokines compared to single-component PDE-4 inhibitor formulations, and the pharmaceutical composition exhibits excellent stability.

[0042] Furthermore, according to various embodiments of the present invention, the composition of the present invention exhibits a significantly superior bactericidal effect compared to single-component formulations of existing PDE-4 inhibitors. That is, the pharmaceutical composition according to various embodiments of the present invention has an excellent bactericidal effect against Gram-positive bacteria (e.g., Staphylococcus aureus), yeast, fungi, etc.

[0043] In addition, according to various embodiments of the present invention, the preparation is preserved in a good condition, has an excellent sterilizing effect on the inflamed area, and shows an enhanced inhibitory effect on inflammatory cytokines. That is, the pharmaceutical composition according to various embodiments of the present invention has an improved sterilizing effect compared to the existing single-component preparation of a PDE-4 inhibitor, and thus has a superior therapeutic effect on skin diseases, and can significantly improve the storage stability of the preparation compared to the existing single preparation containing only a PDE-4 inhibitor.

[0044] In addition, according to various embodiments of the present invention, the storage stability of the pharmaceutical composition is excellent even when stored at 45°C for 4 weeks.

[0045] The effects according to various embodiments of the present invention are not limited to the effects mentioned above, and other effects not mentioned will be clearly understood by those skilled in the art from the description of the claims.

[0046] Figure 1 is a graph showing the results of an inhibitory effect experiment on IL-17A and IL-23 according to Control Example 1 and Manufacturing Example 1.

[0047] Figure 2 is a graph showing the results of an inhibitory effect experiment on IL-4 and IL-13 according to Control Example 1 and Manufacturing Example 1.

[0048] A preferred embodiment of the present invention will be described in more detail with reference to the attached drawings, but technical parts already known will be omitted or compressed for the sake of brevity.

[0049] It should be noted that references in this specification to “one” or “an” embodiment of the invention are not necessarily to the same embodiment, but rather mean at least one.

[0050] In the examples below, singular expressions include plural expressions unless the context clearly indicates a different meaning.

[0051] In the following examples, terms such as “include” or “have” mean that a feature or component described in the specification is present, and do not preclude the possibility that one or more other features or components may be added.

[0052] As used herein, the term “prevention” means any act of inhibiting or delaying the occurrence, spread or recurrence of a disease by administering a pharmaceutical composition according to various embodiments of the present invention.

[0053] As used herein, the term “treatment” means any action by which the symptoms of a disease are improved or beneficially changed by administration of a pharmaceutical composition according to various embodiments of the present invention.

[0054] As used herein, the term “administration” means providing an active ingredient to a subject by any suitable method.

[0055] The term "subject" as used herein includes, but is not limited to, mammals including humans, guinea pigs, monkeys, cows, horses, sheep, pigs, chickens, turkeys, quails, cats, dogs, mice, rats or rabbits, and preferably may be humans.

[0056] As used herein, the term "pharmaceutically acceptable" means physiologically acceptable and does not typically cause allergic reactions such as urticaria, gastrointestinal upset, dizziness or similar reactions when administered to humans.

[0057] As used herein, the term "salt" means an acid addition salt formed by a pharmaceutically acceptable free acid. Accordingly, a pharmaceutically acceptable salt means a salt commonly used in the pharmaceutical industry, for example, an inorganic ionic salt prepared with calcium, potassium, sodium or magnesium, etc.; an inorganic acid salt prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; an organic acid salt prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid, etc. Sulfonate salts made with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid or naphthalenesulfonic acid; amino acid salts made with glycine, arginine or lysine; or amine salts made with trimethylamine, triethylamine, ammonia, pyridine or picoline; etc.; However, the types of salts meant in this specification are not limited by these listed salts.

[0058] In this specification, the term "density" refers to a value indicating mass per unit volume, generally expressed in units of g / cm3. The density described in this specification It can be measured by a surface tension meter (Easy Dyne surface tension meter model K20) sold by the company.

[0059] As used herein, the term "moisture content" refers to the moisture content contained in a pharmaceutical composition, expressed as a percentage. The moisture content described herein is measured by the Karl Fischer titration method, and a Metrohm 901 KF Titrando moisture meter can be used for the measurement.

[0060] As used herein, the term "surface tension", generally expressed in units of dyn / cm, means the force required to increase the unit area of ​​a liquid surface or the unit area of ​​an interface between two liquids or between a liquid and a gas. The surface tension described herein is De Nuy ring surface tension method (Du) using a surface tensiometer (Easy Dyne surface tensiometer model K20) sold by It is measured by the Ring Method.

[0061] A pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment may include a phosphodiesterase-4 inhibitor and an active ingredient. In one embodiment, the phosphodiesterase-4 inhibitor may include at least one of a phosphodiesterase-4 inhibitor and a pharmaceutically acceptable salt thereof.

[0062] In one embodiment, the phosphodiesterase-4 inhibitor component may include at least one of roflumilast, dipamilast, tanimilast, roflumilast N-oxide, rotamialast, apremilast, orismilast, crisaborole, and rolipram.

[0063] In one embodiment, the chemical name of roflumilast (CAS registration number: 162401-32-3) is 3-(cyclopropylmethoxy)-N-(3,5-dichloro-4-pyridinyl)-4-(difluoromethoxy)benzamide.

[0064] The molecular formula of roflumilast is C 17 H 14 It is Cl2F2N2O3 (molecular weight: 403.2 g / mol, melting point: 158℃) and is a white powder. The structural formula of roflumilast can be represented by the following chemical formula 1.

[0065] [Chemical Formula 1]

[0066]

[0067] Roflumilast is an inhibitory component that inhibits phosphodiesterase-4, which increases the level of intracellular cyclic adenosine monophosphate (cAMP) in immune cell endothelial cells and keratinocytes, thereby reducing the expression of inflammatory cytokines, making it effective in treating psoriasis, an inflammatory skin disease.

[0068] In one embodiment, the pharmaceutically acceptable salt of the phosphodiesterase-4 inhibitor can include at least one selected from an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt of the phosphodiesterase-4 inhibitor. For example, when the phosphodiesterase-4 inhibitor is roflumilast, the roflumilast salt can include at least one from an inorganic ionic salt of roflumilast, an inorganic acid salt of roflumilast, an organic acid salt of roflumilast, a sulfonate salt of roflumilast, an amino acid salt of roflumilast, and an amine salt of roflumilast.

[0069] In one embodiment, the content of the phosphodiesterase-4 inhibitor may be 0.01 to 5 wt% based on the total weight of the composition. As a specific example, the content of the phosphodiesterase-4 inhibitor is 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 %, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt% or 5 wt%. In addition, the content of the phosphodiesterase-4 inhibitor can be in a range of one or more of the above values ​​and one or less of the above values.

[0070] For example, the content range of the phosphodiesterase-4 inhibitor is 0.01 wt% to 5 wt%, 0.01 wt% to 2 wt%, 0.05 wt% to 1.5 wt%, 0.1 wt% to 2 wt%, 0.5 wt% to 2 wt%, 0.01 wt% to 0.5 wt%, 0.5 wt% to 5 wt%, 0.01 wt% to 1 wt%, 1 wt% to 2 wt%, 1.5 wt% to 3 wt%, 2.5 wt% to 4 wt%, 3.5 wt% to 5 wt%, 4 wt% to 5 wt%, 1 wt% to 5 wt%, 2 wt% to 4 wt%, 1 wt% to 3 wt%, 3 wt% to 5 wt%, 0.01 wt% to 0.05 wt%, 0.1 wt% to It can be prepared in the range of 0.5 wt%, 0.5 wt% to 1 wt%, or 0.1 wt% to 3 wt%.

[0071] In addition, the content of the phosphodiesterase-4 inhibitor may be applied as one or more of the above values, or may be applied as one or less of the above values. For example, the content of the phosphodiesterase-4 inhibitor may be applied as 0.01 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, or 4 wt% or less, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, or 0.05 wt% or less.

[0072] In one embodiment, the amount of the phosphodiesterase-4 inhibitor is not limited to the examples described above, and may be applied in an amount effective for the prevention or treatment of psoriasis and atopic dermatitis. The level of the amount effective for the prevention or treatment of psoriasis and atopic dermatitis may be determined based on factors including the type and severity of the patient's disease, the activity and sensitivity of the drug, the time of administration, the route of administration, the excretion rate, the duration of treatment, concurrent medications, and other factors well known in the medical field. Taking all of the above factors into account, it is important to administer an amount that achieves the maximum effect with the minimum amount without causing side effects, and this can be readily determined by those skilled in the art.

[0073] In one embodiment, the active ingredient may be at least one of an antifungal ingredient and an antibacterial ingredient. For example, the active ingredient may be an ingredient that exhibits bactericidal activity against Staphylococcus aureus, Candida albicans, Malassezia sympodialis, and the like. In one specific embodiment, the active ingredient may include at least one of octenidine and an octenidine salt.

[0074] In one embodiment, the structural formula of octenidine (CAS registration number: 71251-02-0) can be represented by the following chemical formula 2. The molecular formula of octenidine is C 36 H 62 It is N4 and has a molecular weight of 550.9. Octenidine has antibacterial activity and is effective in killing bacteria and fungi.

[0075] [Chemical Formula 2]

[0076]

[0077] In one embodiment, the octenidine salt is a pharmaceutically acceptable salt of octenidine, which may include at least one selected from an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt, and an amine salt of octenidine.

[0078] For example, pharmaceutically acceptable salts of octenidine include inorganic ionic salts prepared with calcium, potassium, sodium or magnesium, etc.; inorganic salts prepared with hydrochloric acid, nitric acid, phosphoric acid, hydrobromic acid, iodic acid, perchloric acid or sulfuric acid, etc.; organic salts prepared with acetic acid, trifluoroacetic acid, citric acid, maleic acid, succinic acid, oxalic acid, benzoic acid, tartaric acid, fumaric acid, mandelic acid, propionic acid, lactic acid, glycolic acid, gluconic acid, galacturonic acid, glutamic acid, glutaric acid, glucuronic acid, aspartic acid, ascorbic acid, carbonic acid or vanillic acid, etc.; sulfonic salts prepared with methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salicylic acid, p-toluenesulfonic acid or naphthalenesulfonic acid, etc.; amino acid salts prepared with glycine, arginine or lysine, etc.; Or amine salts prepared with trimethylamine, triethylamine, ammonia, pyridine or picoline; etc.; but the types of octenidine salts are not limited by these listed salts.

[0079] As a specific example, a pharmaceutically acceptable salt of octenidine may be octenidine dihydrochloride. Octenidine dihydrochloride (CAS registration number: 70775-75-6) is a white or light yellow powder and is a pyridine compound.

[0080] The chemical name of octenidine dihydrochloride is N-octyl-1-[10-(4-octyliminopyridin-1-yl)decyl]pyridin-4-imine dihydrochloride. The molecular formula of octenidine dihydrochloride is C 36 H 64 Cl2N4 (molecular weight: 623.84, melting point: 215∼217℃). The structural formula of octenidine dihydrochloride can be expressed by the following chemical formula 3.

[0081] [Chemical Formula 3]

[0082]

[0083] In one specific example, octenidine dihydrochloride exhibits excellent bactericidal effects by strongly adsorbing to the cell surface of anionic bacteria, binding to phospholipids and anionic polysaccharides in the cell membrane, and impairing cell function, causing plasma membrane leakage and inhibiting mitochondrial function. Furthermore, octenidine dihydrochloride exhibits excellent anti-inflammatory properties by inhibiting Langerhans gland cell activation and suppressing the secretion of inflammatory cytokines.

[0084] Psoriasis is an inflammatory skin disease caused by the expression of inflammatory cytokines (e.g., TNF-α, IL-17A, IL-23, IL-33, etc.), which are molecular biological mediators that induce an excessive immune response. Of these, IL-17A and IL-23 have the greatest impact. The main pathogens causing infections in psoriasis include Staphylococcus aureus and Candida albicans.

[0085] Atopic dermatitis is an inflammatory skin disease caused by the secretion of lymphopoietin from the thymic stroma, which activates Th2 cells to release IL-4, IL-5, IL-13, and IL-31. Among these, IL-4 and IL-13 have the greatest effect. The main pathogens causing infections caused by atopic dermatitis include Staphylococcus aureus and Malassezia sympodialis.

[0086] A pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment can strongly kill bacteria and fungi through a complex antibacterial action, and thus its effect shows a much better antibiotic effect than a single preparation containing only a PDE-4 inhibitory component, and can significantly improve the effect of preventing and treating inflammatory skin diseases.

[0087] In one embodiment, the content of the active ingredient may be 0.01 to 8 wt% based on the total weight of the composition. As a specific example, the content of the active ingredient is 0.01 wt%, 0.02 wt%, 0.03 wt%, 0.04 wt%, 0.05 wt%, 0.06 wt%, 0.07 wt%, 0.08 wt%, 0.09 wt%, 0.1 wt%, 0.2 wt%, 0.3 wt%, 0.4 wt%, 0.5 wt%, 0.6 wt%, 0.7 wt%, 0.8 wt%, 0.9 wt%, 1 wt%, 1.1 wt%, 1.2 wt%, 1.3 wt%, 1.4 wt%, 1.5 wt%, 1.6 wt%, 1.7 wt%, 1.8 wt%, 1.9 wt%, 2 wt%, 2.1 wt%, 2.2 wt%, 2.3 wt%, 2.4 wt%, 2.5 wt%, 2.6 wt%, 2.7 wt%, 2.8 wt%, 2.9 wt%, 3 wt%, 3.1 wt%, 3.2 wt%, 3.3 wt%, 3.4 wt%, 3.5 wt%, 3.6 wt%, 3.7 wt%, 3.8 wt%, 3.9 wt%, 4 wt%, 4.1 wt%, 4.2 wt%, 4.3 wt%, 4.4 wt%, 4.5 wt%, 4.6 wt%, 4.7 wt%, 4.8 wt%, 4.9 wt%, 5 wt%, 5.1 wt%, 5.2 wt%, 5.3 wt%, 5.4 wt%, 5.5 wt%, 5.6 wt%, 5.7 wt%, 5.8 wt%, 5.9 wt%, 6 %, 6.1 wt%, 6.2 wt%, 6.3 wt%, 6.4 wt%, 6.5 wt%, 6.6 wt%, 6.7 wt%, 6.8 wt%, 6.9 wt%, 7 wt%, 7.1 wt%, 7.2 wt%, 7.3 wt%, 7.4 wt%, 7.5 wt%, 7.6 wt%, 7.7 wt%, 7.8 wt%, 7.9 wt% or 8 wt%. In addition, the content of the active ingredient can be in a range of one or more of the above values ​​and one or less of the above values.

[0088] For example, the content range of the active ingredient can be set to be 0.01 wt% to 3 wt%, 0.05 wt% to 2.5 wt%, 0.1 wt% to 3 wt%, 0.5 wt% to 2.5 wt%, 1 wt% to 2 wt%, 1 wt% to 3 wt%, 2 wt% to 4 wt%, 3 wt% to 5 wt%, 4 wt% to 6 wt%, 5 wt% to 7 wt%, 6 wt% to 8 wt% or 0.01 wt% to 8 wt%.

[0089] In addition, the content of the active ingredient may be applied as one or more of the above values, or may be applied as one or less of the above values. For example, the content of the active ingredient may be applied as 0.01 wt% or more, 0.1 wt% or more, 0.5 wt% or more, 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, or 7 wt% or less, 8 wt% or less, 7 wt% or less, 6 wt% or less, 5 wt% or less, 4 wt% or less, 3 wt% or less, 2 wt% or less, 1 wt% or less, 0.9 wt% or less, 0.8 wt% or less, 0.7 wt% or less, 0.6 wt% or less, 0.5 wt% or less, 0.4 wt% or less, 0.3 wt% or less, 0.2 wt% or less, 0.1 wt% or less, or 0.05 wt% or less. In one embodiment, the content of the active ingredient is not limited to the above-described examples, and may be applied in an amount effective for the prevention or treatment of psoriasis and atopic dermatitis.

[0090] A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis according to one embodiment may further comprise a crystal growth inhibitor. In one embodiment, the crystal growth inhibitor may inhibit the crystallization of a specific component included in the pharmaceutical composition. For example, the crystal growth inhibitor may prevent at least one of the phosphodiesterase-4 inhibitor and the active ingredient included in the composition from precipitating into crystals.

[0091] In one embodiment, the content of the crystal growth inhibitor may be 1 to 30 wt% based on the total weight of the composition. As a specific example, the content of the crystal growth inhibitor is 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, 3 wt%, 3.5 wt%, 4 wt%, 4.5 wt%, 5 wt%, 5.5 wt%, 6 wt%, 6.5 wt%, 7 wt%, 7.5 wt%, 8 wt%, 8.5 wt%, 9 wt%, 9.5 wt%, 10 wt%, 10.5 wt%, 11 wt%, 11.5 wt%, 12 wt%, 12.5 wt%, 13 wt%, 13.5 wt%, 14 wt%, 14.5 wt%, 15 wt%, 15.5 wt%, 16 wt%, 16.5 wt%, 17 wt%, 17.5 wt%, 18 wt%, 18.5 %, 19 wt%, 19.5 wt%, 20 wt%, 20.5 wt%, 21 wt%, 21.5 wt%, 22 wt%, 22.5 wt%, 23 wt%, 23.5 wt%, 24 wt%, 24.5 wt%, 25 wt%, 25.5 wt%, 26 wt%, 26.5 wt%, 27 wt%, 27.5 wt%, 28 wt%, 28.5 wt%, 29 wt%, 29.5 wt% or 30 wt%. In addition, the content of the crystal growth inhibitor can be in a range of one or more of the above values ​​and one or less of the above values.

[0092] For example, the content range of the crystal growth inhibitor can be set to be 1 wt% to 30 wt%, 1 wt% to 25 wt%, 1 wt% to 20 wt%, 1 wt% to 10 wt%, 10 wt% to 30 wt%, 10 wt% to 20 wt%, 5 wt% to 20 wt%, 5 wt% to 30 wt%, 15 wt% to 30 wt%, 15 wt% to 20 wt%, 20 wt% to 30 wt%, 25 wt% to 30 wt%, 5 wt% to 10 wt%, 5 wt% to 15 wt%, 1 wt% to 5 wt%, or 12 wt% to 30 wt%.

[0093] And, the content of the crystal growth inhibitor may be applied as one or more of the above values, or may be applied as one or less of the above values. For example, the content of the crystal growth inhibitor may be applied as 1 wt% or more, 2 wt% or more, 3 wt% or more, 4 wt% or more, 5 wt% or more, 6 wt% or more, 7 wt% or more, 8 wt% or more, 9 wt% or more, 10 wt% or more, 15 wt% or more, or 30 wt% or less, 25 wt% or less, 20 wt% or less, 15 wt% or less, or 10 wt% or less.

[0094] According to one specific example, the crystal growth inhibitor may include isopentyldiol and propylene carbonate. In one specific example, the weight ratio of isopentyldiol to propylene carbonate may be 2:1. If the weight ratio between isopentyldiol and propylene carbonate exceeds 2:1, the storage stability of the composition may be reduced, crystals may precipitate or sediment may occur during storage of the composition, and there is a concern that this may negatively affect the physical properties of the composition.

[0095] According to one embodiment, a pharmaceutical composition may use isopentyldiol and propylene carbonate in a weight ratio of 2:1 as a crystal growth inhibitor when stored at a low temperature (e.g., -15°C) in an amount of 1 to 30 wt% based on the total weight of the composition.

[0096] A pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment may further include an additive. In one embodiment, the additive may include at least one of a solvent, a moisturizer, a penetrant, a surfactant, an antioxidant, a chelating agent, a pH adjusting agent, and a viscosity adjusting agent.

[0097] In one embodiment, the solvent may include at least one of an organic solvent, water for injection (WFI), purified water, and saline. The organic solvent may include at least one selected from the group consisting of alkanes, alkenes, alcohols, esters, ketones, and ether solvents. For example, the organic solvent may include at least one of ethanol, isopropyl alcohol, dimethyl sulfoxide, acetone, and ethyl acetate. According to one embodiment, ethanol, isopropyl alcohol, dimethyl sulfoxide, purified water, and the like may be used as the solvent. In one embodiment, the content of the solvent may be from 1 wt% to 90 wt% (e.g., 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, 80 wt%, 85 wt%, or 90 wt%) based on the total weight of the composition.

[0098] In one embodiment, a moisturizer is an additive that supplies moisture to the stratum corneum of the skin or prevents excessive skin dryness. According to one embodiment, the moisturizer may include at least one selected from the group consisting of isoamyl laurate, propylene glycol, glycerin, polyethylene glycol 400, sorbitol, hyaluronic acid, and mixtures thereof. Preferably, isoamyl laurate, polyethylene glycol 400, hyaluronic acid, etc. may be used as the moisturizer. In one embodiment, the content of the moisturizer may be from 1 wt% to 60 wt% (e.g., 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, or 60 wt%) based on the total weight of the composition.

[0099] In one embodiment, a penetrant is a substance added to enhance the therapeutic effect by increasing the penetration ability of a drug into the skin. According to one embodiment, the penetrant may include at least one selected from the group consisting of diisopropyl adipate, diethyl sebacate, oleyl oleate, capric / caprylic triglyceride, 2-methyl-1,3-propanediol, and mixtures thereof. Preferably, diisopropyl adipate, oleyl oleate, capric / caprylic triglyceride, etc. may be used as the penetrant. In one embodiment, the content of the penetrant may be from 1 wt% to 80 wt% (e.g., 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, 30 wt%, 35 wt%, 40 wt%, 45 wt%, 50 wt%, 55 wt%, 60 wt%, 65 wt%, 70 wt%, 75 wt%, or 80 wt%) relative to the total weight of the composition.

[0100] In one embodiment, the surfactant may include at least one selected from the group consisting of Poloxamer 407, Poloxamer 188, Sorbitan monolaurate, Sorbitan monooleate, Sorbitan trioleate, Polyglycerol-10-laurate, Polysorbate 80, and mixtures thereof. Preferably, Poloxamer 407, Sorbitan trioleate, Polyglycerol-10-laurate, Polysorbate 80, etc. may be used as the surfactant. In one embodiment, the content of the surfactant may be from 1 wt% to 30 wt% (e.g., 1 wt%, 5 wt%, 10 wt%, 15 wt%, 20 wt%, 25 wt%, or 30 wt%) relative to the total weight of the composition.

[0101] In one embodiment, the antioxidant may include at least one selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisol (BHA), ascorbic acid, tocopherol, ferulic acid, propyl gallate, cysteine, sodium sulfite, and mixtures thereof. Preferably, butylhydroxytoluene, ascorbic acid, tocopherol, cysteine, and the like may be used as the antioxidant. In one embodiment, the content of the antioxidant may be from 0.001 wt% to 3 wt% (e.g., 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt% or 3 wt%) relative to the total weight of the composition.

[0102] In one embodiment, the chelating agent is a metal ion sequestering agent that binds to and inactivates oxygen, nitrogen, or various metal ions. According to one embodiment, the chelating agent may include at least one selected from the group consisting of pentasodium pentetate, glutamic acid, methylglycine, disodium EDTA, tetrasodium EDTA, and mixtures thereof. Preferably, pentasodium pentetate, disodium ethylenediaminetetraacetic acid, tetrasodium ethylenediaminetetraacetic acid, etc. may be used as the chelating agent. In one embodiment, the content of the chelating agent may be from 0.001 wt% to 3 wt% (e.g., 0.001 wt%, 0.005 wt%, 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, or 3 wt%) relative to the total weight of the composition.

[0103] In one embodiment, the pH adjusting agent may include at least one selected from the group consisting of hydrochloric acid, phosphoric acid, pentetic acid, acetic acid, citric acid, succinic acid, lactic acid, malic acid, tartaric acid, triethanolamine, sodium hydroxide, sodium citrate, calcium citrate, diisopropylamine, and mixtures thereof. Preferably, pentetic acid, citric acid, tartaric acid, sodium hydroxide, or sodium citrate may be used to adjust the pH range of the composition to a range of 2 or more and 10 or less (e.g., 2, 3, 4, 5, 6, 7, 8, 9, or 10). In one embodiment, the content of the pH adjuster may be from 0.01 wt% to 3 wt% (e.g., 0.01 wt%, 0.05 wt%, 0.1 wt%, 0.5 wt%, 1 wt%, 1.5 wt%, 2 wt%, 2.5 wt%, or 3 wt%) relative to the total weight of the composition.

[0104] In one embodiment, the viscosity modifier may include at least one selected from the group consisting of sodium alginate, carboxymethyl cellulose, sodium polyacrylate, pectin, gelatin, hydroxypropylmethyl cellulose, dextrin, povidone, and mixtures thereof. Preferably, carboxymethyl cellulose, sodium polyacrylate, hydroxypropylmethyl cellulose, povidone, or the like may be used as the viscosity modifier. Depending on the viscosity of the pharmaceutical composition, the viscosity modifier may or may not be added to the composition.

[0105] The excipients of the pharmaceutical composition according to one embodiment may be ingredients commonly used in the art, and examples thereof are included in the literature (Raymond C. Rowe. Handbook of Pharmaceutical Excipients 7th edition). In addition, the aforementioned types of additives, such as solvents, moisturizers, penetrants, surfactants, antioxidants, chelating agents, pH regulators, and viscosity regulators, may be manufactured by adding them in various compositions depending on the intended use and conditions, and, if necessary, the use of at least some of the types of additives may be omitted, or other types of known ingredients may be additionally used.

[0106] In one embodiment, a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be implemented in the form of a solution containing 0.01 to 5 wt% of roflumilast, 0.01 to 8 wt% of octenidine dihydrochloride, 1 to 90 wt% of a solvent (e.g., ethanol, dimethyl sulfoxide), 1 to 60 wt% of a moisturizer (e.g., polyethylene glycol 400), 1 to 80 wt% of a penetrant (e.g., diisopropyl adipate), 1 to 30 wt% of a surfactant, 0.001 to 3 wt% of an antioxidant, 0.001 to 3 wt% of a chelating agent, 0.01 to 3 wt% of a pH regulator (e.g., citric acid), and 1 to 30 wt% of a crystal growth inhibitor (a weight ratio of isopentyl diol and propylene carbonate of 2:1).

[0107] In another embodiment, a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be implemented in the form of a solution containing 0.01 to 5 wt% of difamilast, 0.01 to 8 wt% of octenidine dihydrochloride, 1 to 90 wt% of a solvent (e.g., ethanol, dimethyl sulfoxide), 1 to 60 wt% of a moisturizer (e.g., polyethylene glycol 400), 1 to 80 wt% of a penetrant (e.g., diisopropyl adipate), 1 to 30 wt% of a surfactant, 0.001 to 3 wt% of an antioxidant, 0.001 to 3 wt% of a chelating agent, 0.01 to 3 wt% of a pH regulator (e.g., citric acid), and 1 to 30 wt% of a crystal growth inhibitor (a weight ratio of isopentyl diol and propylene carbonate of 2:1).

[0108] In another embodiment, a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be implemented in the form of a solution containing 0.01 to 5 wt% of tanimilast, 0.01 to 8 wt% of octenidine dihydrochloride, 1 to 90 wt% of a solvent (e.g., ethanol, dimethyl sulfoxide), 1 to 60 wt% of a moisturizer (e.g., polyethylene glycol 400), 1 to 80 wt% of a penetrant (e.g., diisopropyl adipate), 1 to 30 wt% of a surfactant, 0.001 to 3 wt% of an antioxidant, 0.001 to 3 wt% of a chelating agent, 0.01 to 3 wt% of a pH regulator (e.g., citric acid), and 1 to 30 wt% of a crystal growth inhibitor (a weight ratio of isopentyl diol and propylene carbonate of 2:1).

[0109] Meanwhile, the pH of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment may be 2 to 10. As a specific example, the pH of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be prepared as 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5, 6, 6.5, 7, 7.5, 8, 8.5, 9, 9.5, or 10. In addition, the pH of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment may be in a range of one or more of the above values ​​and one or less of the above values. For example, the pH range of the pharmaceutical composition can be set to be 2 to 10, 3 to 9, 4 to 8, 5 to 7, 4 to 9, 4 to 10, 5 to 9.5, 6 to 8 or 7 to 8.

[0110] The density of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment may be 0.1 to 2 g / cm3. As a specific example, the density of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be applied as 0.1 g / cm3, 0.2 g / cm3, 0.3 g / cm3, 0.4 g / cm3, 0.5 g / cm3, 0.6 g / cm3, 0.7 g / cm3, 0.8 g / cm3, 0.9 g / cm3, 1 g / cm3, 1.1 g / cm3, 1.2 g / cm3, 1.3 g / cm3, 1.4 g / cm3, 1.5 g / cm3, 1.6 g / cm3, 1.7 g / cm3, 1.8 g / cm3, 1.9 g / cm3 or 2 g / cm3.

[0111] Additionally, in one embodiment, the density of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be in a range of one or more of the above values ​​and one or less of the above values. For example, the density range of the pharmaceutical composition can be set to be in the range of 0.1 g / cm3 to 2 g / cm3, 0.4 g / cm3 to 1 g / cm3, 0.8 g / cm3 to 1.5 g / cm3, 1.2 g / cm3 to 1.7 g / cm3, 1 g / cm3 to 2 g / cm3, 1.5 g / cm3 to 2 g / cm3, 0.5 g / cm3 to 2 g / cm3, 0.8 g / cm3 to 2 g / cm3, 1.2 g / cm3 to 1.8 g / cm3, 1.5 g / cm3 to 1.7 g / cm3 or 1.5 g / cm3 to 2 g / cm3.

[0112] In one embodiment, the surface tension of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be 1 to 75 dyn / cm. As a specific example, the surface tension of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is 1 dyn / cm, 2 dyn / cm, 3 dyn / cm, 4 dyn / cm, 5 dyn / cm, 6 dyn / cm, 7 dyn / cm, 8 dyn / cm, 9 dyn / cm, 10 dyn / cm, 11 dyn / cm, 12 dyn / cm, 13 dyn / cm, 14 dyn / cm, 15 dyn / cm, 16 dyn / cm, 17 dyn / cm, 18 dyn / cm, 19 dyn / cm, 20 dyn / cm, 21 dyn / cm, 22 dyn / cm, 23 dyn / cm, 24 dyn / cm, 25 dyn / cm, 26 dyn / cm, 27 dyn / cm, at 25°C. 28dyn / cm, 29dyn / cm, 30dyn / cm, 31dyn / cm, 32dyn / cm, 33dyn / cm, 34dyn / cm, 35dyn / cm, 36dyn / cm, 37dyn / cm, 38dyn / cm, 39dyn / cm, 40dyn / cm, 41dyn / cm, 42dyn / cm, 43dyn / cm, 44dyn / cm, 45dyn / cm, 46dyn / cm, 47dyn / cm, 48dyn / cm, 49dyn / cm, 50dyn / cm, 51dyn / cm, 52dyn / cm, 53dyn / cm, 54dyn / cm, 55dyn / cm, 56dyn / cm, 57dyn / cm, It can be applied as 58dyn / cm, 59dyn / cm, 60dyn / cm, 61dyn / cm, 62dyn / cm, 63dyn / cm, 64dyn / cm, 65dyn / cm, 66dyn / cm, 67dyn / cm, 68dyn / cm, 69dyn / cm, 70dyn / cm, 71dyn / cm, 72dyn / cm, 73dyn / cm, 74dyn / cm or 75dyn / cm.

[0113] Additionally, the surface tension of the pharmaceutical composition according to one embodiment may be in a range of one or more of the above values ​​and one or less of the above values. For example, the surface tension range of the pharmaceutical composition may be 1 dyn / cm to 75 dyn / cm, 5 dyn / cm to 60 dyn / cm, 10 dyn / cm to 50 dyn / cm, 15 dyn / cm to 65 dyn / cm, 20 dyn / cm to 60 dyn / cm, 10 dyn / cm to 40 dyn / cm, 15 dyn / cm to 30 dyn / cm, 25 dyn / cm to 55 dyn / cm, 30 dyn / cm to 50 dyn / cm, 41 dyn / cm to 50 dyn / cm, 42 dyn / cm to 50 dyn / cm, 43 dyn / cm to 50 dyn / cm, 44 dyn / cm to 50 dyn / cm, 45 dyn / cm to 50 dyn / cm, 41 dyn / cm to It can be provided in the range of 45 dyn / cm, 41 dyn / cm to 44 dyn / cm, 41 dyn / cm to 43 dyn / cm or 50 dyn / cm to 75 dyn / cm.

[0114] In one embodiment, the moisture content of a pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is measured by the Karl Fischer method, and the moisture content of the composition measured by the Karl Fischer method may be 0.1 to 95 wt%. As a specific example, the moisture content of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, 20%, 21%, 22%, 23%, 24%, 25%, 26%, 27%, 28%, 29%, 30%, 31%, 32%, 33%, 34%, 35%, 36%, 37%, 38%, 39%, 40%, 41%, 42%, 43%, 44%, 45%, 46%, 47%, 48%, 49%, 50%, 51%, 52%, 53%, 54%, 55%, 56%, 57%, 58%, 59%, 60%, 61%, 62%, 63%, 64%, 65%, 66%, 67%, 68%, 69%, 70%, 71%, 72%, 73%, 74%, 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, It can be applied at 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95%.

[0115] In addition, the moisture content of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis may be in a range of one or more of the above values ​​and one or less of the above values. For example, the moisture content of the pharmaceutical composition may be in a range of 0.1 to 95%, 0.5 to 90%, 0.1 to 80%, 1 to 70%, 2 to 5%, 3 to 5%, 5 to 85%, 7 to 60%, 8 to 55%, 9 to 50%, 10 to 45%, 10 to 20%, 10 to 15%, 10 to 13%, 15 to 40%, or 20 to 35%.

[0116] A pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis according to one embodiment may be prepared in any one formulation selected from among a solution, an ointment, a lotion, a cream, a gel, an emulsion, a suspension, a stick, a plaster, a patch, a cataplasma, a microcapsule, a cleaning agent, a liposomal drug, and a spray.

[0117] Pharmaceutical compositions according to various embodiments of the present invention can be manufactured by mixing the aforementioned components according to conventional methods, and since heating and cooling processes are not required, the convenience and economy of process control can be improved. If necessary, a phosphodiesterase-4 inhibitor and the active ingredient can be added according to the addition ratio, and a stock solution using ethanol and dimethyl sulfoxide as solvents can be first prepared, and then other components can be additionally mixed to prepare a solution.

[0118] The present invention is described in more detail below through specific manufacturing examples. The following manufacturing examples are merely examples intended to aid understanding of the present invention and are not intended to limit or restrict the scope of the present invention.

[0119] Preparation of solutions according to Control Examples 1 to 3 and Manufacturing Examples 1 to 9

[0120] A solution containing a phosphodiesterase-4 inhibitor and octenidine dihydrochloride was prepared according to the respective components and compositions listed in Tables 1, 2, and 3 below. The content of each component listed in Tables 1 to 3 represents the weight % of the entire solution. At room temperature (25℃), ethanol and dimethyl sulfoxide were added to three preparation containers, and phosphodiesterase-4 inhibitors (roflumilast, dipamilast, tanimilast) were added to each preparation container and dissolved. Then, octenidine dihydrochloride, polyethylene glycol 400, diisopropyl adipate, isopentyldiol, propylene carbonate, poloxamer 407, butylhydroxy toluene, disodium ethylenediamine tetraacetic acid, and citric acid were added in sequence to each preparation container, and purified water was added so that the total weight of the solution became 100 wt%, and then filtered through a 0.45 μm filter to prepare a transparent solution. As a result of measuring the pH, density, surface tension and moisture content of the manufactured solution, the pH was within the range of 4 to 8, the density was within the range of 0.8 to 1 g / cm3, the surface tension (25°C) was within the range of 35 to 55 dyn / cm, and the moisture content was within the range of 1 to 10 wt%.

[0121] Composition Example of manufacturing (weight%) Control Example 1 Example 1 Example 2 Example 3 Roflumilast 0.500.500.015.00 Octenidine dihydrochloride-0.108.000.01 Ethanol 20.0020.0020.0020.00 Dimethyl sulfoxide 20.0020.0020.0020.00 Polyethylene glycol 400 10.0010.0010.0010.00 Diisopropyl adipate 10.0010.0010.0010.00 Isopentyl diol 20.0020.0020.0020.00 Propylene carbonate 10.0010.0010.0010.00 Poloxamer 4071.001.001.001.00 Butylhydroxytoluene 0.010.010.010.01 Disodium ethylenediaminetetraacetic acid 0.010.010.010.01 Citric acid 0.100.100.100.10 Purified water 8.388.280.873.87 Total (weight%) 100.00100.00100.00100.00

[0122] Composition Example of manufacturing (weight%) Control Example 2 Example 4 Example 5 Example 6 Dipamilast 0.50 0.50 0.01 5.00 Octenidine dihydrochloride-0.10 8.00 0.01 Ethanol 20.00 20.00 20.00 20.00 20.00 Dimethyl sulfoxide 20.00 20.00 20.00 20.00 Polyethylene glycol 400 10.00 10.00 10.00 10.00 Diisopropyl adipate 10.00 10.00 10.00 10.00 Isopentyl diol 20.00 20.00 20.00 20.00 Propylene carbonate 10.00 10.00 10.00 10.00 Poloxamer 4071.001.001.001.00 Butylhydroxytoluene 0.010.010.010.01 Disodium ethylenediaminetetraacetic acid 0.010.010.010.01 Citric acid 0.100.100.100.10 Purified water 8.388.280.873.87 Total (weight%) 100.00100.00100.00100.00

[0123] Composition Example of manufacturing (weight%) Control Example 3 Example 7 Example 8 Example 9 Tanimilast 0.500.500.015.00 Octenidine dihydrochloride-0.108.000.01 Ethanol 20.0020.0020.0020.00 Dimethyl sulfoxide 20.0020.0020.0020.00 Polyethylene glycol 400 10.0010.0010.0010.00 Diisopropyl adipate 10.0010.0010.0010.00 Isopentyl diol 20.0020.0020.0020.00 Propylene carbonate 10.0010.0010.0010.00 Poloxamer 4071.001.001.001.00 Butylhydroxytoluene 0.010.010.010.01 Disodium ethylenediaminetetraacetic acid 0.010.010.010.01 Citric acid 0.100.100.100.10 Purified water 8.388.280.873.87 Total (weight%) 100.00100.00100.00100.00

[0124] Test Example 1. Susceptibility Test for Antibacterial Activity Evaluation

[0125] Typically, clinical treatment outcomes can be predicted through antimicrobial susceptibility testing. The test strains subject to the susceptibility test for antimicrobial activity evaluation are Staphylococcus aureus, Candida albicans, and Malassezia sympodialis, which are causative agents of atopic dermatitis and psoriasis. To evaluate the antimicrobial activity against the three microorganisms mentioned above, this experiment was conducted using the tube dilution technique. The antimicrobial activity evaluation was performed by calculating the minimum growth inhibitory concentration (MIC) for each microorganism. 90; The results of comparing Control Examples 1 to 3 and Manufacturing Examples 1 to 9 as Minimum Inhabiton Concentration (MIGC) are as shown in Tables 4, 5, and 6 below. The minimum growth inhibition concentration test was conducted according to the CLSI (Clinical and Laboratory Standards Institute) standards, with Staphylococcus aureus, a Gram-positive bacterium, using the CLS I M07-A10:2015 test method, and with Candida albicans and Malassezia sympodialis, a yeast, using the CLS I M27-A3:2008 test method.

[0126] 1) Pre-culture of test bacteria

[0127] ① Staphylococcus aureus: Inoculated onto TSA (Typical Soy Agar) medium and cultured at 35±2℃ for 16 to 24 hours.

[0128] ②Candida albicans, Malassezia sympodialis: Inoculated onto Sabouraud Dextrose Agar (SDA) medium and cultured at 35±2℃ for 20 to 24 hours.

[0129] 2) Preparation of test bacterial solution and spore suspension

[0130] ① Staphylococcus aureus: 1×10 6 The solution was diluted in Cation-Adjusted Muller-Hinton Broth (CAMHB) medium to CFU / ml and used as a test bacterial solution.

[0131] ②Candida albicans, Malassezia sympodialis: After buffering 0.165 mol / L of 3-N-morpholinopropane sulfonic acid (MOPS: 3-N-morpholinopropane sulfonic acid) in RPMI 1640 medium (RPMI1640, Gibco), a spore suspension of 5.0×10² to 2.5×10³ CFU / ml was prepared and used as a test bacterial solution.

[0132] 3) Inoculation of test bacteria solution

[0133] ① Staphylococcus aureus: 1 ml of the test bacteria solution was inoculated into each tube containing the test solution at each concentration. A tube containing 2 ml of the solution (Control Examples 1-3, Preparation Examples 1-9) on CAMHB medium was used as a negative control group, and a tube containing 1 ml of the solution (Control Examples 1-3, Preparation Examples 1-9) and 1 ml of the test bacteria solution on CAMHB medium was used as a positive control group. The tubes that had been treated with the test bacteria solution were cultured at 35±2℃ for 16-24 hours.

[0134] ②Candida albicans, Malassezia sympodialis: 0.9 ml of the test bacteria solution was inoculated into each well containing the test solution at each concentration. A well containing 1.0 ml of the solution (Control Examples 1 to 3, Preparation Examples 1 to 9) in RPM 1640 medium buffered with MOPS 0.165 mol / L was used as a negative control group, and a well containing 0.1 ml of the solution (Control Examples 1 to 3, Preparation Examples 1 to 9) and 0.9 ml of the test bacteria solution in RPM 1640 medium buffered with MOPS 0.165 mol / L was used as a positive control group. The tubes that had been treated with the test bacteria solution were cultured at 35±2℃ for 24 to 48 hours.

[0135] 4) Judging the results

[0136] After incubation, the minimum concentration at which no bacterial growth occurred was considered the minimum growth inhibitory concentration. After incubation, no bacterial growth should be observed in the negative control group, and bacterial growth should be observed in the positive control group. The results obtained using the above antibacterial activity test method are presented in Tables 4, 5, and 6.

[0137] Minimum growth inhibitory concentration (MIC) 90 , ㎍ / ml) Control Example 1 Preparation Example 1 Preparation Example 2 Preparation Example 3 Staphylococcus aureus (S. aureus) ATCC 65380.160.030.020.06 Candida albicans (C. albicans) ATCC 102310.260.050.030.09 Malassezia sympodialis (M. sympodialis) ATCC 421320.190.030.020.07

[0138] Minimum growth inhibitory concentration (MIC) 90 , ㎍ / ml) Control Example 2 Preparation Example 4 Preparation Example 5 Preparation Example 6 Staphylococcus aureus (S. aureus) ATCC 65380.280.050.030.11 Candida albicans (C. albicans) ATCC 102310.320.060.040.12 Malassezia sympodialis (M. sympodialis) ATCC 421320.180.030.020.07

[0139] Minimum growth inhibitory concentration (MIC) 90 , ㎍ / ml) Control Example 3 Preparation Example 7 Preparation Example 8 Preparation Example 9 Staphylococcus aureus (S. aureus) ATCC 65380.260.050.030.10 Candida albicans (C. albicans) ATCC 102310.360.070.040.15 Malassezia sympodialis (M. sympodialis) ATCC 421320.240.050.030.09

[0140] As can be seen from the results in Tables 4, 5, and 6 above, the compositions according to Preparation Examples 1 to 9 showed significantly increased antibacterial activity against Staphylococcus aureus, Candida albicans, and Malassezia symphodialis compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. The antibacterial activity of Preparation Examples 1 to 3 was 2.7 to 8 times higher than that of Control Example 1 against Staphylococcus aureus, 2.9 to 8.7 times higher than that of Control Example 1 against Candida albicans, and 2.7 to 9.5 times higher than that of Malassezia symphodialis. The antibacterial activity of Preparation Examples 4 to 6 was 2.6 to 9.3 times higher than that of Control Example 2 against Staphylococcus aureus, 2.7 to 8 times higher than that of Candida albicans, and 2.6 to 9 times higher than that of Malassezia symphodialis.

[0141] The antibacterial activity of Manufacturing Examples 7 to 9 was 2.6 to 8.7 times higher than the antibacterial activity against Staphylococcus aureus of Control Example 3, 2.4 to 9 times higher than the antibacterial activity against Candida albicans, and 2.7 to 8 times higher than the antibacterial activity against Malassezia sympodialis. Therefore, the pharmaceutical compositions according to Manufacturing Examples 1 to 9 showed good susceptibility test results against the causative agents of psoriasis and atopic dermatitis, and thus can be expected to show excellent clinical treatment results.

[0142] Test Example 2. Storage Stability Evaluation

[0143] Each sample from Control Examples 1 to 3 and Manufacturing Examples 1 to 9 was taken in an amount of 10 ml and placed in a 20 ml vial, sealed hermetically, and stored at 45°C for 4 weeks. The UV-visible absorption spectra of the samples at the beginning and after 4 weeks at 45°C were measured. That is, the absorbance was measured at 500 nm using a spectrophotometer (Mega-800, Scinco, Korea), and the results are shown in Table 7 below.

[0144] [Absorbance at 500 nm] After 4 weeks of initial sample preparation Control Example 10.046 ± 0.000 20.049 ± 0.000 3 Manufactured Example 10.074 ± 0.000 10.075 ± 0.000 2 Manufactured Example 20.092 ± 0.000 30.094 ± 0.000 2 Manufactured Example 30.122 ± 0.000 40.126 ± 0.000 1 Control Example 20.041 ± 0.000 10.044 ± 0.000 2 Manufactured Example 40.053 ± 0.000 10.054 ± 0.000 2 Manufactured Example 50.134 ± 0.000 20.137 ± 0.000 3 Manufactured Example 60.176 ± 0.00020.182 ± 0.0001Control 30.061 ± 0.00030.065 ± 0.0001Manufactured 70.063 ± 0.00020.064 ± 0.0002Manufactured 80.172 ± 0.00030.175 ± 0.0001Manufactured 90.181 ± 0.00050.186 ± 0.0003

[0145] As described in Table 7, the solutions of Preparation Examples 1 to 9 showed improved stability compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. In the 500 nm absorbance measured after 4 weeks, Control Example 1 showed an absorbance increase of about 7%, whereas Preparation Examples 1 to 3 showed an increase of about 1 to 3%, Control Example 2 showed an absorbance increase of about 7%, whereas Preparation Examples 4 to 6 showed an increase of about 2 to 3%, and Control Example 3 showed an absorbance increase of about 7%, whereas Preparation Examples 7 to 9 showed an increase of about 2 to 3%. Therefore, it can be seen that the compositions of Preparation Examples 1 to 9 showed superior stability compared to Control Examples 1 to 3 even after 4 weeks at 45°C.

[0146] Test Example 3. Evaluation of the ability to suppress inflammatory cytokines

[0147] The ability to suppress inflammatory cytokines for Control Examples 1 to 3 and Manufacturing Examples 1 to 9 was evaluated using the method described below.

[0148] (1) Ability to suppress cytotoxicity and inflammatory cytokines in keratinocytes

[0149] Keratinocytes (HaCaT) were purchased from the Korean Cell Line Bank (Seoul, Korea). Keratinocytes were cultured in DMEM (Dulbecco's Modified Eagle Medium; Gibco BRL., USA) containing 10% heat-inactivated fetal bovine serum (HIFBS; Gibco BRL., USA) and 1% penicillin / streptomycin (penicillin 100 IU / ml, streptomycin 100 μg / ml; Thermo Fisher Scientific) at 37°C in an incubator with 5% CO₂ for 24 h.

[0150] ① Cytotoxicity assessment (MTT Assay)

[0151] 1×10 cultured keratinocytes 6100 μl was dispensed into a 96-well plate at cells / ml and cultured for 24 hours under 37°C, 5% CO₂ conditions. The medium was removed, and 100 μl of DMEM medium and 100 μl of sample (control examples 1-3, preparation examples 1-9) were added to each well and cultured for 24 hours. After 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) solution (0.5 mg / ml, Sigma Aldrich, St. Louis, MO, USA) was added to each well and cultured for 4 more hours to reduce MTT, and the supernatant was removed. Afterwards, 100 μl of dimethyl sulfoxide (DMSO) was dispensed into each well and mixed for 1 hour, and then the absorbance was measured at 540 nm using an ELISA microplate reader (Enzyme-Linked Immunosorbent Assay microplate reader; Bio-Rad model 680, Bio-Rad Laboratories INC., Tokyo, Japan). The cell viability was calculated as the percentage of the absorbance of the sample-added group compared to the absorbance of the sample-free group, and the results are shown in Table 8.

[0152] * Cell viability (%) = (absorbance of sample added group / absorbance of sample-free group) × 100

[0153] ② Ability to suppress inflammatory cytokines

[0154] Keratinocytes were seeded at 5 × 10 per well in a 96-well plate. 5The cells were seeded and cultured for 24 hours, and the supernatant was washed with phosphate-buffered saline (PBS). To induce an immune response in keratinocytes, 10 ng / ml of TNF-α (Tumor Necrosis Factor-α) and 10 ng / ml of IFN-γ (Interferon-γ) were added to DMEM medium without HIFBS, and 100 μg / ml of Control Examples 1 to 3 and Preparation Examples 1 to 9 were added to each well. After 24 hours of culture, the concentrations of IL-17A and IL-23 in the supernatant of keratinocytes were measured using an ELISA kit (MAX DELUXE; BioLegend, USA).

[0155] Briefly, ELISA plates were coated with 100 μl of diluted (1x) capture antibody and incubated at 4°C for 24 h, washed four times with washing buffer (0.05 v / v% Tween-20 mixed in PBS), and then 200 μl of blocking buffer (3 w / v% bovine serum albumin mixed in Tris-buffered saline, pH 7.6) was added, incubated with shaking at room temperature for 1 h, and then washed four times with washing buffer. IL-17A and IL-23 standards were diluted to a concentration range of 0 to 1,000 pg / ml, 100 μl each was added to the wells of an ELISA plate, incubated with shaking at room temperature for 2 hours, and washed four times. 100 μl of the detection antibody was added, incubated with shaking at room temperature for 1 hour, and washed four times. 100 μl of Avidin-HRP (Horseradish peroxidase) reagent (1:1,000) was then added, incubated with shaking at room temperature for 30 minutes, and washed five times. Finally, 100 μl of TMB (3,3',5,5'-Tetramethyl benzidine) substrate solution was added, and the mixture was incubated in the dark for 30 minutes. After adding 100 μl of stop solution (2 N H2SO4), the absorbance was measured at 450 nm within 15 minutes using a microplate reader (Bio TeK Instruments, Inc. Vermont, USA), and the inhibitory concentration of each cytokine was listed in Table 8.

[0156] Sample cytotoxicity (cell viability%) Cytokine inhibitory activity (pg / ml) IL-17AIL-23 Control Example 110076.784.3 Manufacturing Example 110121.222.4 Manufacturing Example 29916.617.5 Manufacturing Example 310030.834.5 Control Example 210080.687.5 Manufacturing Example 410121.423.1 Manufacturing Example 510018.320.2 Manufacturing Example 610227.531.8 Control Example 310083.680.2 Manufacturing Example 710024.222.7 Manufacturing Example 810021.419.5 Manufacturing Example 99935.336.7

[0157] As can be seen from the results in Table 8, the compositions of Preparation Examples 1 to 9 showed significantly increased inhibitory effects on IL-17A and IL-23 compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. The inhibitory effects of Preparation Examples 1, 2, and 3 increased 2.5 to 4.6 times for IL-17A and 2.4 to 4.8 times for IL-23 compared to Control Example 1. The inhibitory effects of Preparation Examples 4, 5, and 6 increased 2.9 to 4.4 times for IL-17A and 2.8 to 4.3 times for IL-23 compared to Control Example 2. The inhibitory effects of Preparation Examples 7, 8, and 9 increased 2.4 to 3.9 times for IL-17A and 2.2 to 4.1 times for IL-23 compared to Control Example 3. Therefore, the pharmaceutical compositions of Manufacturing Examples 1 to 9 exhibit good inhibitory effects on the major cytokines (IL-17A, IL-23) that cause psoriasis, and thus, it can be predicted that they will show excellent clinical treatment results.

[0158] (2) Ability to suppress cytotoxicity and inflammatory cytokines in mast cells

[0159] Mast cells (HMC-1: Human Mast Cell-1) were purchased from the Korea Cell Line Bank (Seoul, Korea). Mast cells were cultured in IMDM (Iscove's Modified Dulbecco's Medium, Gibco BRL, USA) containing 10% heat-inactivated fetal bovine serum (HIFBS; Gibco BRL, USA) and 1% penicillin / streptomycin (penicillin 100 IU / ml, streptomycin 100 μg / ml; Thermo Fisher Scientific) at 37°C in a 5% CO2 incubator for 24 h.

[0160] ① Cytotoxicity assessment (MTT Assay)

[0161] Cultured mast cells were 1×10 6 100 μl was dispensed into a 96-well plate at cells / ml and cultured for 24 hours under 37°C, 5% CO₂ conditions. The medium was removed, and 100 μl of DMEM medium and 100 μl of sample (control examples 1-3, preparation examples 1-9) were added to each well and cultured for 24 hours. After 24 hours, 10 μl of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) solution (0.5 mg / ml, Sigma Aldrich, St. Louis, MO, USA) was added to each well and cultured for 4 more hours to reduce MTT, and the supernatant was removed. Afterwards, 100 μl of DMSO was dispensed into each well, mixed for 1 hour, and the absorbance was measured at 540 nm using an ELISA microplate reader (Bio-Rad model 680, Bio-Rad Laboratories INC., Tokyo, Japan). Cell viability was calculated as the percentage of the absorbance of the sample-added group compared to the absorbance of the sample-free group, and the results are shown in Table 9.

[0162] * Cell viability (%) = (absorbance of sample added group / absorbance of sample-free group) × 100

[0163] ② Ability to suppress inflammatory cytokines

[0164] Mast cells were seeded at 5×10 per well in a 96-well plate. 5 After seeding with a cell line and culturing for 24 hours, 20 nM of PMA (Phorbol 12-myristate 13 acetate) and 1 μM of calcium ionophore (Calcium ionophore A23187) were added to each well, and simultaneously, Control Examples 1 to 3 and Manufacturing Examples 1 to 9 were treated at a concentration of 100 μg / ml each, and then cultured for 8 hours in an incubator at 37°C and 5% CO2 conditions. After the culture was completed, the culture solution was centrifuged (2,000 rpm, 5 minutes) and the supernatant was collected. To confirm the concentration of each cytokine (IL-4, IL-13) contained in the supernatant using an ELISA kit (LEGEND MAX; BioLegend, USA), the absorbance was measured at 450 nm using an ELISA microplate reader (Bio-Rad model 680, Bio-Rad Laboratories INC., Tokyo, Japan), and the inhibitory concentration of each cytokine is shown in Table 9.

[0165] Sample cytotoxicity (cell viability%) Cytokine inhibitory power (pg / ml) IL-4 IL-13 Control Example 11002.95.2 Manufacturing Example 11000.91.6 Manufacturing Example 21000.71.2 Manufacturing Example 31011.02.0 Control Example 21002.57.6 Manufacturing Example 41010.82.4 Manufacturing Example 51010.62.0 Manufacturing Example 6991.02.7 Control Example 31002.76.2 Manufacturing Example 71000.91.9 Manufacturing Example 8990.71.5 Manufacturing Example 91011.12.6

[0166] As can be seen from the results in Table 9, the compositions of Preparation Examples 1 to 9 showed significantly increased inhibitory effects on IL-4 and IL-13 compared to Control Examples 1 to 3 that did not contain octenidine dihydrochloride. The inhibitory effects of Preparation Examples 1, 2, and 3 increased 2.9 to 4.1 times for IL-4 and 2.6 to 4.3 times for IL-13 compared to Control Example 1. The inhibitory effects of Preparation Examples 4, 5, and 6 increased 2.5 to 4.2 times for IL-4 and 2.8 to 3.8 times for IL-13 compared to Control Example 2. The inhibitory effects of Preparation Examples 7, 8, and 9 increased 2.5 to 3.9 times for IL-4 and 2.4 to 4.1 times for IL-13 compared to Control Example 3. Therefore, since the pharmaceutical compositions of Manufacturing Examples 1 to 9 exhibit good inhibitory effects on the major cytokines (IL-4, IL-13) that cause atopic dermatitis, it can be predicted that they will also show excellent therapeutic results clinically. Fig. 1 is a graph showing the results of the inhibitory effects test on IL-17A and IL-23 according to Control Example 1 and Manufacturing Example 1. Referring to Fig. 1, it can be seen that the composition according to Manufacturing Example 1 has a better inhibitory effect on IL-17A and IL-23 than Control Example 1. Fig. 2 is a graph showing the results of the inhibitory effects test on IL-4 and IL-13 according to Control Example 1 and Manufacturing Example 1. Referring to Fig. 2, it can be seen that the composition according to Manufacturing Example 1 has a better inhibitory effect on IL-4 and IL-13 than Control Example 1.

[0167] Test Example 4. Evaluation of the ability to suppress crystal precipitation during low-temperature storage

[0168] In order to evaluate the ability to suppress crystal precipitation during low-temperature storage, solutions containing PDE-4 inhibitors and octenidine dihydrochloride were prepared according to the components and formulations in Tables 10, 11, and 12 as follows. Ethanol was added to a preparation container at room temperature (25°C), and roflumilast, dipamilast, and tanimilast were added to each preparation container and dissolved. Then, octenidine dihydrochloride, polyethylene glycol 400, diisopropyl adipate, isopentyl diol, propylene carbonate, butyl hydroxy toluene, disodium ethylenediamine tetraacetic acid, and citric acid were added in sequence to each preparation container, and purified water was added so that the total weight of the solution became 100 wt%, and then filtered through a 0.45 μm filter to prepare a transparent solution. Each of the above manufactured samples was added at 10 ml per 20 ml vial and stored in a low-temperature freezer at -15°C for 2 weeks. The crystal and precipitate formation status of each sample was observed with the naked eye at room temperature (25°C), and the results are shown in Table 13.

[0169] Composition Example of manufacturing (weight%) Control Example 4 Example 10 Example 11 Example 12 Roflumilast 0.50 0.50 0.50 0.50 0.50 Octenidine dihydrochloride 0.100 100 100 100 100 100 10 Ethanol 20.00 20.00 20.00 20.00 Polyethylene glycol 400 10.00 10.00 10.00 10.00 Diisopropyl adipate 10.00 10.00 10.00 10.00 Isopentyl diol-10.00 20.00 30.00 Propylene carbonate-10.00 10.00 10.00 Butyl hydroxy toluene 0.01 0.01 0.01 Disodium ethylenediamine tetrahydrate Acetic acid 0.010.010.010.01Citric acid 0.100.100.100.10Purified water 59.2839.2829.2819.28Total (weight%) 100.00100.00100.00100.00

[0170] Composition Example of manufacturing (weight%) Control Example 5 Example 13 Example 14 Example 15 Dipamilast 0.50 0.50 0.50 0.50 Octenidine dihydrochloride 0.100 100 100 100 100 100 100 10 Ethanol 20.00 20.00 20.00 20.00 Polyethylene glycol 400 10.00 10.00 10.00 10.00 Diisopropyl adipate 10.00 10.00 10.00 10.00 Isopentyl diol-10.00 20.00 30.00 Propylene carbonate-10.00 10.00 10.00 Butylhydroxytoluene 0.01 0.01 0.01 Disodium ethylenediamine tetrahydrate Acetic acid 0.010.010.010.01Citric acid 0.100.100.100.10Purified water 59.2839.2829.2819.28Total (weight%) 100.00100.00100.00100.00

[0171] Manufacturing example (weight%) Composition Control example 6 Manufacturing example 16 Manufacturing example 17 Manufacturing example 18 Tanimilast 0.50 0.50 0.50 0.50 0.50 Octenidine dihydrochloride 0.100 100 100 100 100 100 10 Ethanol 20.00 20.00 20.00 20.00 Polyethylene glycol 400 10.00 10.00 10.00 10.00 Diisopropyl adipate 10.00 10.00 10.00 10.00 Isopentyl diol-10.00 20.00 30.00 Propylene carbonate-10.00 10.00 10.00 Butylhydroxytoluene 0.01 0.01 0.01 Disodium ethylenediamine tetrahydrate Acetic acid 0.010.010.010.01Citric acid 0.100.100.100.10Purified water 59.2839.2829.2819.28Total (weight%) 100.00100.00100.00100.00

[0172] Comparative Example 4 Manufacturing Example 10 Manufacturing Example 11 Manufacturing Example 12 Crystal / precipitate → Yes Crystal / precipitate → Yes Crystal / precipitate → No Crystal / precipitate → Yes Comparative Example 5 Manufacturing Example 13 Manufacturing Example 14 Manufacturing Example 15 Crystal / precipitate → Yes Crystal / precipitate → Yes Crystal / precipitate → No Crystal / precipitate → Yes Comparative Example 6 Manufacturing Example 16 Manufacturing Example 17 Manufacturing Example 18 Crystal / precipitate → Yes Crystal / precipitate → Yes Crystal / precipitate → No Crystal / precipitate → Yes

[0173] Referring to the results in Table 13, in the case of Manufacturing Examples 11, 14, and 17, in which the weight ratio of isopentyl diol and propylene carbonate as crystal growth inhibitors was 2:1 and the content of the crystal growth inhibitor was 30 wt% based on the total weight of the composition, it was confirmed that no crystal precipitation phenomenon occurred even after storage at -15°C for 2 weeks. As described above, according to various embodiments of the present invention, not only is the preventive and therapeutic effect on psoriasis and atopic dermatitis excellent, but also it has high medication compliance due to its excellent antibiotic effect.

[0174] Furthermore, according to various embodiments of the present invention, the compositions of the present invention exhibit significantly superior bactericidal effects compared to single-component formulations of existing PDE-4 inhibitors. That is, the pharmaceutical compositions according to various embodiments of the present invention have excellent bactericidal effects against Gram-positive bacteria, yeast, fungi, etc.

[0175] And, according to various embodiments of the present invention, the preparation is preserved in a good state, has an excellent sterilizing effect on the inflamed area, and shows an improved inhibitory effect on inflammatory cytokines.

[0176] In addition, according to various embodiments of the present invention, the storage stability of the pharmaceutical composition is excellent even when stored at 45°C for 4 weeks.

[0177] As described above, the present invention has been specifically described by way of examples. However, since the above-described examples are merely preferred examples of the present invention, the present invention should not be understood as being limited to the above-described examples, and the scope of the present invention should be understood by the claims described below and their equivalents.

Claims

1. A phosphodiesterase-4 inhibitor comprising at least one of a phosphodiesterase-4 inhibitory component and a pharmaceutically acceptable salt thereof; and An active ingredient comprising at least one of octenidine and an octenidine salt; The above phosphodiesterase-4 inhibitory component is characterized in that it comprises at least one of roflumilast, dipamilast, and tanimilast. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

2. In paragraph 1, The content of the above phosphodiesterase-4 inhibitor is characterized in that it is 0.01 to 5 wt% based on the total weight of the composition. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

3. In paragraph 1, The above phosphodiesterase-4 inhibitory component is characterized in that it further comprises at least one of roflumilast N-oxide, rotamialast, apremilast, orismilast, crisaborole, and rolipram. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

4. In paragraph 1, The pharmaceutically acceptable salt of the phosphodiesterase-4 inhibitory component includes at least one selected from the group consisting of an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt and an amine salt of the phosphodiesterase-4 inhibitory component. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

5. In paragraph 1, The content of the above active ingredient is 0.01 to 8 wt% based on the total weight of the composition, The above octenidine salt is characterized in that it comprises at least one selected from the group consisting of an inorganic ionic salt, an inorganic acid salt, an organic acid salt, a sulfonate salt, an amino acid salt and an amine salt of the above octenidine. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

6. In paragraph 1, The pharmaceutical composition for preventing or treating the above psoriasis and atopic dermatitis Further comprising a crystal growth inhibitor comprising isopentyldiol and propylene carbonate in a weight ratio of 2:1; The content of the above crystal growth inhibitor is characterized in that it is 1 to 30 wt% with respect to the total weight of the composition. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

7. In paragraph 1, The pharmaceutical composition for preventing or treating the above psoriasis and atopic dermatitis characterized in that it further comprises an additive including at least one of a solvent, a moisturizer, a penetrant, a surfactant, an antioxidant, a chelating agent, a pH regulator and a viscosity regulator; A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

8. In paragraph 1, The pH of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is characterized by being 2 to 10. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

9. In paragraph 1, The density of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is characterized by being 0.1 to 2 g / cm3. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

10. In paragraph 1, The surface tension of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is characterized by being 1 to 75 dyn / cm. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

11. In paragraph 1, The moisture content of the pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is characterized by being 0.1 to 95 wt%. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

12. In paragraph 1, The pharmaceutical composition for preventing or treating psoriasis and atopic dermatitis is characterized in that it has a formulation selected from among solutions, ointments, lotions, creams, gels, emulsions, suspensions, sticks, plasters, patches, wet compresses, microcapsules, detergents, liposomes, and sprays. A pharmaceutical composition for the prevention or treatment of psoriasis and atopic dermatitis.

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