The present invention relates to a composition for preventing, improving or treating psoriasis containing immunomodulator and glucosamine.
Psoriasis is an immune-mediated autoimmune skin disease induced by chronic inflammatory cell infiltration in the skin and dysregulation of epidermal keratinocytes. Histologically, psoriasis is characterized by epidermal thickening and scaling, and hyperproliferative parakeratosis in skin biopsies. The mechanism by which psoriasis is induced has not yet been fully elucidated, and has been reported to be related to interactions between inflammatory cytokines and immune cell infiltration. A recent study demonstrated that T helper 17 (Th17) cells and Th17-mediated cytokines, such as IL-17A, IL-22 and IL-23, induced psoriasis.
Common treatments for psoriasis include topical and internal medications and phototherapy. In topical treatments, steroids, coal tar, anthralin, vitamin D3 and analogs thereof, retinoids, sunlight, and the like are used. These topical treatments have side effects of skin thinning, stretch marks, burns, irritation, and photosensitivity. In addition, steroids may induce tolerance and affect subsequent steroid therapies. Phototherapy involves the administration of psoralen in combination with ultraviolet B or A, which may promote skin aging and increase skin cancer incidence.
In addition, the most severe psoriasis is treated with immunomodulators, such as cyclosporine, which is currently the most commonly used medication. However, careful observation is needed because nephrotoxicity or hypertension may occur upon long-term use of cyclosporine. Therefore, to administer cyclosporine, approved as a therapeutic agent for long-term treatment of psoriasis, it is important to develop treatment methods capable of effectively treating psoriasis while reducing the administration dose. Thus, studies on such methods have been made, but there are no known effective treatment methods yet.
The present invention was made to solve the above problem. The present inventors developed a method of effectively treating psoriasis. As a result, it was confirmed that co-administration of cyclosporine and glucosamine remarkably improved the effectiveness of anti-psoriasis treatment while reducing the administration dose of cyclosporine. Based on these findings, the present invention was completed.
Thus, the present invention is directed to providing a pharmaceutical composition for preventing or treating psoriasis and a cosmetic composition for improving psoriasis, containing cyclosporine and glucosamine as active ingredients.
However, the technical problem to be solved by the present invention is not limited to the above-mentioned problem, and other problems not mentioned herein can be clearly understood by those skilled in the art from the following description.
One aspect of the present invention provides a pharmaceutical composition for preventing or treating psoriasis and a cosmetic composition for improving psoriasis, containing cyclosporine and glucosamine as active ingredients.
In one embodiment of the present invention, the cyclosporine and glucosamine may be contained in a weight ratio of 1:5 to 1:2000.
In another embodiment of the present invention, the cyclosporine may be cyclosporine A.
Another aspect of the present invention provides a pharmaceutical composition for enhancing the effectiveness of anti-psoriasis treatment, which is used in combination with an anti-psoriasis agent, wherein the pharmaceutical composition contains glucosamine and the anti-psoriasis agent is cyclosporine.
In one embodiment of the invention, the composition and the anti-psoriasis agent may be administered simultaneously, separately or sequentially.
Still another aspect of the present invention provides a method of treating psoriasis, the method including a step of co-administering cyclosporine and glucosamine to an individual.
Yet another aspect of the present invention provides a method of enhancing the effectiveness of anti-psoriasis treatment, the method including a step of co-administering cyclosporine and glucosamine to an individual.
Cyclosporine, an immunomodulator, is difficult to administer for a long time due to side effects thereof, and when the administration of cyclosporine is discontinued, lesions tend to deteriorate to an original state thereof. However, according to the present invention, the co-administration of cyclosporine and glucosamine, even when the dose of cyclosporine is reduced, can exert a far superior effect on the treatment or improvement of psoriasis than the administration of cyclosporine and glucosamine alone.
Hereinafter, the present invention is described in detail.
The present invention provides a composition for preventing, improving or treating psoriasis containing cyclosporine and glucosamine as active ingredients, the composition including a pharmaceutical composition and a cosmetic composition.
According to the present invention, when cyclosporine, approved as a therapeutic agent for psoriasis, is administered in combination with glucosamine, the effectiveness of anti-psoriasis treatment is remarkably improved while reducing the administration dose of cyclosporine, thereby reducing the side effects of cyclosporine.
In the present invention, “cyclosporine” is an immunomodulator which suppresses in vivo immune responses, and cyclosporine A is preferably used, without being limited thereto.
In the present invention, “glucosamine” is produced through decomposition of chitosan, one of the main components of saltwater crab and shrimp exoskeletons. The main components of saltwater crab and shrimp exoskeletons are chitin and chitosan. Chitin is composed of 2-acetylamino-2-deoxy-β-D-glucose (N-acetylglucosamine), and chitosan is poly (β-(1,4)-glucosamine), a polysaccharide produced by deacetylation of chitin. Glucosamine may be represented by Formula 1 below.
In the present invention, glucosamine derivatives may be used instead of glucosamine. “Glucosamine derivatives” may be represented by Formula 2 below, wherein the hydrogen atoms of the hydroxyl groups of glucosamine may be substituted with acyl or alkyl compounds.
In Formula 2, R is an acyl group having 2 to 18 carbon atoms or a straight or branched chain alkyl group having 1 to 5 carbon atoms, and is preferably an acyl group, such as an acetyl propionyl, butyryl, pentanoyl, hexanoyl, heptanoyl, octanoyl, nonanoyl, decanoyl, undecanoyl, lauryl, tridecanoyl, myristyl, pentadecanoyl, palmitoyl, margaryl or stearyl group, or an alkyl group, such as a methyl, ethyl, propyl, butyl, pentyl, isopropyl, isobutyl or sec-butyl group.
In addition, glucosamine or glucosamine derivatives used in the present invention may be contained in the pharmaceutical composition of the present invention in the form of a pharmaceutically acceptable salt depending on the use of the pharmaceutical composition. For example, the salt form includes sulfates of glucosamine or glucosamine derivatives, hydrochlorides of glucosamine or glucosamine derivatives, maleates of glucosamine or glucosamine derivatives, and the like, without being limited thereto. A preferred salt form is a sulfate of glucosamine or glucosamine derivatives.
In the composition according to the present invention, cyclosporine and glucosamine are preferably contained in a weight ratio of 1:5 to 1:2000, more preferably 1:5 to 1:500, and most preferably 1:5 to 100.
The composition according to the present invention may be formulated into oral preparations, such as powders, granules, tablets, capsules, suspensions, emulsions, syrups and aerosols, and sterile injectable solutions, suppositories and preparations for percutaneous administration according to conventional methods. Examples of carriers, excipients and diluents that may be contained in the composition may include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia rubber, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil. The composition may be formulated using diluents or excipients, such as fillers, extenders, binders, wetting agents, disintegrants and surfactants, when the diluents or excipients are required.
The composition according to the present invention is preferably formulated into a solid preparation for oral administration. The solid preparation for oral administration may include tablets, pills, powders, granules, capsules, and the like. The solid preparation may be formulated by mixing one or more excipients, for example, starch, calcium carbonate, sucrose or lactose, gelatin, and the like, as active ingredients. In addition to excipients, lubricants such as magnesium stearate and talc may also be used.
In addition, the composition according to the present invention is preferably formulated into a liquid preparation for oral administration. The liquid preparation for oral administration may include suspensions, liquids for internal use, emulsions, syrups, and the like. In addition to commonly used inert diluents, for example, purified water, ethanol and liquid paraffin, the liquid preparation may include various excipients, for example, wetting agents, sweeteners, flavoring agents, preservatives, and the like.
In addition, the composition according to the present invention may be formulated into a preparation for parenteral administration. The preparation for parenteral administration may include sterilized aqueous solutions, non-aqueous solvents, suspensions, emulsions, freeze-dried preparations, and suppositories. As the sterilized aqueous solutions, suitable buffers such as Hank's solution and Ringer's solution or physically buffered saline may be used. As non-aqueous solvents and suspensions, vegetable oils such as propylene glycol, polyethylene glycol and olive oil and injectable esters such as ethyl oleate may be used. When required, preservatives, stabilizers, wetting agents or emulsifying agents, and salts and/or buffers for controlling osmotic pressure may be used. In the case of suppositories, Witepsol, macrogol, Tween 61, cacao butter, laurinum, glycerogelatin, and the like may be used as common base compounds of suppositories.
When the composition of the present invention is administered to patients, the total daily usage of the composition may be determined by prescription within the scope of medical judgment. To determine a therapeutically effective dose for a particular patient, various factors including whether other agents are used, age, body weight, general health status, sex, diet, administration time, administration route, secretion rate of a composition and treatment period and similar factors well known in the medical field are preferably taken into consideration.
Preferably, cyclosporine is co-administered with glucosamine in an amount of 0.025 to 2.9 mg/kg, and the number of doses may be appropriately adjusted depending on a patient's skin condition and may be from one to three times per day. In addition, cyclosporine may be taken in combination with glucosamine up to a maximum dose of 5 mg/kg depending on the condition of skin lesions.
In addition, the composition according to the present invention may be formulated into an external preparation for application to the skin, a cosmetic preparation or the like. The external preparation for application to the skin may include ointments, plasters, sprays, suspensions, emulsions, creams, gels, and the like.
In addition to the above-described active ingredients, the cosmetic composition according to the present invention, when required, may be compounded with various ingredients (e.g., water-soluble components, powder components, oils, surfactants, moisturizers, viscosity controlling agents, preservatives, antioxidants, perfumes, pigments, and the like) generally used in external preparations for application to the skin, provided that the effect of the composition of the present invention is not deteriorated.
The formulation of the cosmetic composition of the present invention may be arbitrarily selected, and may be formulated into conventional forms such as skin ointments, essences, whitening creams, lotions, emulsions, packs, general lotions, skin milks, creams, serums, cosmetic soaps, softening lotions, medicated lotions, hair tonics, body cleansers, and oil gels. The cosmetic composition of the present invention may additionally contain one or more additives selected from the group consisting of oils, water, surfactants, moisturizers, thickeners, chelating agents, pigments, preservatives and perfumes, and is preferably formulated into softening lotions, nutritional lotions, nutritional creams, massage creams, nutritional serums, essences, and packs.
By applying the cosmetic composition of the present invention to a skin inflammation site, psoriasis may be alleviated and improved. The amount of application may be appropriately adjusted depending on the inflammation site of a patient, and the rate of application may be one to five times per day.
As another aspect of the present invention, the present invention provides a pharmaceutical composition for enhancing the effectiveness of anti-psoriasis treatment containing glucosamine, which is used in combination with cyclosporine, an anti-psoriasis agent. The composition and the anti-psoriasis agent may be administered simultaneously, separately or sequentially.
Hereinafter, preferred examples of the present invention are described to facilitate understanding of the present invention. However, the following examples are provided only for the purpose of easier understanding of the present invention, and the present invention is not limited by the following examples.
8-week-old female C57BL/6 mice were purchased from Orient Bio (Seongnam, Korea). Mice were acclimated for a week before performing experiments and maintained in experimental animal facilities at the Dongguk University School of Medicine. All studies were approved by the Animal Care and Use Committee of Dongguk University Hospital.
Glucosamine (Glu) and cyclosporine A (CsA) were purchased from Sigma-Aldrich Co. (St. Louis, Mo., USA) and Chong Kun Dang Pharm. (Seoul, Korea), respectively. In addition, IMQ cream (5%) (Aldara) was purchased from Dong-A Pharm.
IMQ cream (5%) (Aldara; 3M Health Care, UK) was used to induce psoriasis-like skin symptoms in C57BL/6 mice.
More specifically, hair on the backs of C57BL/6 mice was shaved off using an electric razor and then treated with a depilatory (Niclean, Ildong, Korea). For all other groups except a normal group, 62.5 mg of IMQ cream was applied daily to the shaved back area for 14 days.
On the seventh day after the first sensitization, mice were divided into several groups, and glucosamine and cyclosporine A were administered at various doses, individually or in combination. On the other hand, the normal group as a negative control group was treated only with a vehicle cream (petrolatum).
The degree of (1) erythema, (2) scaling and (3) thickening was scored as 0 (none), 1 (mild), 2 (moderate) and 3 (severe). A cumulative dermatitis score (erythema+scaling+thickening) indicates the severity of psoriasis in back skin (scale: 0-9).
To measure cytokine levels in blood serum, mouse blood serum was collected 24 hours after the final administration and stored at −70° C. until analysis. To measure cytokine levels in the skin tissues, the back skin of mice was removed and stored at −80° C. Thereafter, the skin tissues were homogenized using a Bullet Blender™ Blue (Next Advance, Averill Park, N.Y.) at 4° C. to obtain supernatants, and the supernatants were stored at −30° C. IL-17A, IL-22, IL-23, and TNF-α concentrations in the blood serum and the skin tissues of mice were measured using the Mouse IL-17A Quantikine ELISA Kit (R&D Systems, Minneapolis, Minn., USA), IL-22, IL-23 and TNF-α ELISA kits (eBioscience, San Diego, Calif., USA). Meanwhile, ELISA was performed according to the manufacturer's instructions.
Mouse back skin which was fixed with paraformaldehyde and paraffin-embedded was sliced and stained with hematoxylin and eosin (H&E). Based on histological findings, several representative symptoms of psoriasis (epidermal thickening, stratum corneum and inflammatory cell infiltration) were assessed in the epidermis or dermis in a blind manner.
Single-cell suspensions prepared from spleens were stained with FITC-anti-CD4 (GK1.5) and PE-anti-CD25 (280406) (R&D Systems, Minneapolis, Minn., USA), and incubated in a PBS solution containing 2% FBS at 4° C. for 30 minutes under dark conditions. After incubation, the samples were washed twice and analyzed using CellQuest software (Becton Dickinson).
Glucosamine (100, 200, 300 and 400 mg/kg) and cyclosporine A (10, 20, and 40 mg/kg) were orally administered to the psoriasis-like mouse model described in Example 1-3 at different doses for 7 days, respectively. Then, according to the method described in Example 1-4, several representative symptoms were measured using cumulative scores (erythema+scaling+thickening), and the results are shown in
As shown in
Thus, in the following examples, experiments were conducted with low doses of glucosamine (300 mg/kg) and cyclosporine A (10 and 20 mg/kg).
Low doses of glucosamine (300 mg/kg) and cyclosporine A (10 and 20 mg/kg) are orally co-administered to the psoriasis-like mouse model described in Example 1-3 once a day for a week. According to the method described in Example 1-4, clinical skin scores were determined and the results are shown in
As shown in
To evaluate the effect of co-administration of glucosamine and cyclosporine A (CsA) on psoriasis treatment, the following experiments were conducted to measure changes in immune responses.
That is, after low doses of glucosamine (300 mg/kg) and cyclosporine A (10 and 20 mg/kg) were administered to the psoriasis-like mouse model described in Example 1-3, alone or in combination, according to the method described in Example 1-5, the levels of cytokines (IL-17A, IL-22, IL-23 and TNF-α) were measured in blood serum samples and skin samples, and the results are shown in
As shown in
After low doses of glucosamine (300 mg/kg) and cyclosporine A (20 mg/kg) were administered to the psoriasis-like mouse model described in Example 1-3, alone or in combination, according to the method described in Example 1-6, H&E staining for back skin samples was performed, and the results are shown in
As shown in
In addition, after low doses of glucosamine (300 mg/kg) and cyclosporine A (20 mg/kg) were administered alone or in combination, the epidermal thicknesses of back skin samples was measured, and the results are shown in
As shown in
Previous studies reported that the size and weight of the spleen significantly increased in an IMQ-induced psoriasis mouse model. Accordingly, after low doses of glucosamine (300 mg/kg) and cyclosporine A (20 mg/kg) were administered to the psoriasis-like mouse model described in Example 1-3, alone or in combination, mice were sacrificed and spleens were removed to determine the size and weight of each spleen, and the results are shown in
As shown in
After low doses of glucosamine (300 mg/kg) and cyclosporine A (20 mg/kg) were administered to the psoriasis-like mouse model described in Example 1-3, alone or in combination, according to the method described in Example 1-7, the number of CD4+ CD25+ Treg cells was measured, and the results are shown in
As shown in
The aforementioned description of the present invention is provided by way of example and those skilled in the art will understood that the present invention can be easily changed or modified into other specified forms without departing from the technical spirit or essential characteristics of the present invention. Therefore, it should be understood that the aforementioned examples are only provided by way of example and not provided to limit the present invention.
Number | Date | Country | Kind |
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1020140175935 | Dec 2014 | KR | national |
Filing Document | Filing Date | Country | Kind |
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PCT/KR2015/010162 | 9/25/2015 | WO | 00 |