Composition for treating of rhinitis comprising Angelica gigas extracts and indirubin

Abstract

The present invention relates to a composition for treating psoriasis or rhinitis comprising an Angelica gigas extract and an indirubin concentrate, and more specifically, to a composition for treating psoriasis or rhinitis that is particularly effective in treating rhinitis accompanied by atopic dermatitis, psoriasis, etc., comprising 0.01 to 5 w / v% Angelica gigas extract and 0.01 to 5 w / v% indirubin concentrate.

Description

Technology Field

[0001] The present invention relates to a composition for treating rhinitis comprising Angelica gigas extract and indirubin concentrate. Background Technology

[0002] Rhinitis refers to inflammation of the nasal mucosa; histopathologically, it is an exudative inflammation, among which purulent and allergic inflammations are frequently observed. In either case, it is characterized by the exudation of fluid components from blood vessels, edema, cellular exudation, and hypersecretion.

[0003] There are various types of rhinitis depending on their causes and symptoms, such as acute rhinitis (common cold), chronic rhinitis, and allergic rhinitis. However, they are generally classified into four types based on their causes and symptoms: infectious rhinitis, hypersensitive non-infectious rhinitis, irritant rhinitis, and others, as follows: 1) acute or chronic infectious rhinitis, 2) hypersensitive non-infectious rhinitis such as allergic rhinitis, non-allergic rhinitis, rhinorrhea, congestive rhinitis, and dryness, 3) irritant rhinitis caused by physical, chemical, radioactive, etc. 4) other atrophic rhinitis.

[0004] Infectious rhinitis can be divided into acute rhinitis, which presents with short-term symptoms known as the common cold, and chronic rhinitis. Infectious chronic paranasal sinusitis, characterized by lesions in the nasal cavity centered around the ethmoid sinus and middle nasal passage, is also included in infectious rhinitis. Among infectious rhinitis, acute rhinitis is primarily composed of the common cold caused by infections such as viral infections, but simple acute rhinitis is also frequently observed. Acute viral rhinitis (common cold) is characterized by symptoms such as runny nose, nasal congestion, postnasal drip (nasal secretions flowing down into the throat), cough, and mild fever. To relieve nasal congestion, vasoconstrictors such as phenylephrine nasal sprays or pseudoephedrine oral medications are used. However, the use of sprays needs to be limited to within 3 to 4 days due to side effects such as nasal congestion, and while antihistamines are effective in suppressing runny nose, they may cause drowsiness.

[0005] Factors that trigger simple acute rhinitis include hypersensitivity or inflammatory responses caused by dust, exhaust fumes, tobacco, and air pollution, as well as temperature changes, dryness, and humidity. Symptoms begin with sneezing and include olfactory dysfunction due to nasal obstruction and excessive runny nose. The nasal mucosa becomes congested and swollen, but usually heals within ten days. In the presence of a bacterial infection, symptoms worsen accompanied by fever and can progress to sinusitis or chronic rhinitis over time. Symptomatic treatment is commonly used, involving the use of antipyretics, analgesics, antitussives, and anti-inflammatory drugs; antibiotics are used if a bacterial infection is present. Additionally, maintaining psychological stability and warmth is helpful.

[0006] Chronic rhinitis is generally accompanied by chronic sinusitis. There are three pathological conditions of chronic rhinitis, referred to as chronic simple rhinitis, chronic hypertrophic rhinitis, and atrophic rhinitis, respectively. Chronic simple rhinitis is a condition in which the nasal mucosa becomes chronically swollen as a result of repeated episodes of acute rhinitis. The symptoms of chronic simple rhinitis are generally identical to those of chronic hypertrophic rhinitis, including nasal obstruction, excessive rhinorrhea, olfactory dysfunction, and headaches. However, it differs from chronic hypertrophic rhinitis in that the swelling of the nasal mucosa is improved by vasoconstrictors. While conservative treatments such as topical medications or the use of anti-inflammatory drugs are performed, the most important aspect of treatment is the elimination of the underlying cause.

[0007] Mixed (nasal hypersensitivity) rhinitis typically presents with a combination of various symptoms, such as runny nose, nasal congestion, and sneezing. House dust, house dust mites, mold, various bacteria, volatile irritants, leaves, pollen, grass, and animal hair are the causative agents of allergic rhinitis. Allergic rhinitis, a type I allergic disease, is often accompanied by allergic predispositions such as a history of allergies, complications, and a family history, and is characterized by focal mast cell and eosinophilia, elevated serum-specific IgE levels, and increased non-specific mucosal hypersensitivity.

[0008] Among non-allergic rhinitis, essential rhinitis is a type of chronic rhinitis that has symptoms similar to allergic rhinitis but refers to rhinitis in which no clear antigen is recognized.

[0009] Rhinitis is a chronic disease that generally causes difficulty breathing accompanied by the main symptoms of runny nose and nasal congestion, and involves inflammation and swelling of the nasal mucosa, which interferes with daily life.

[0010] Generally, drugs used in drug therapy can be classified into groups such as steroids, histamine receptor antagonists, chemical mediator release inhibitors, thromboxane A2 receptor antagonists, thromboxane A2 synthesis inhibitors, leukotriene antagonists, and Th2 cytokine inhibitors. Steroids or histamine receptor antagonists are frequently used as treatments for moderate allergic rhinitis, and steroids and histamine receptor antagonists are used in combination for severe cases.

[0011] Major disadvantages of nasal spray steroids include local side effects such as nasal burning, irritation, dryness, and epistaxis; furthermore, long-term use of steroids can lead to reduced efficacy and unavoidable risks of infection. Antihistamines suppress allergic symptoms but have drawbacks, such as drying out the nasal mucosa and causing drowsiness. Additionally, while allergen desensitization is effective against hypersensitivity reactions, it has the disadvantage of requiring low-dose injections over a long period. Therefore, there is a demand for the development of new rhinitis treatments that are highly effective, have few side effects, and have a low recurrence rate in patients with rhinitis.

[0012] Meanwhile, cytokines associated with allergic inflammatory diseases reduce the proliferation rate of skin keratinocytes and interfere with the matrix formation of the dermis, thereby slowing down the healing rate of damaged skin and causing skin aging and inflammatory skin diseases such as atopic dermatitis and psoriasis.

[0013] In particular, among skin diseases related to inflammation and immune abnormalities, psoriasis is a relatively common skin disease affecting 1–2% of the global population. It is a chronic disease characterized by various clinical symptoms and repeated cycles of exacerbation and remission. Although the exact cause of psoriasis is unknown, it is currently considered an autoimmune disease. Specifically, the hypothesis that psoriatic lesions develop through interactions between cells such as keratinocytes in the epidermis and T cells and fibroblasts in the dermis is accepted (Nickoloff, BJ, 1999). In addition, recent studies have confirmed that keratinocytes play an important role in the development of psoriasis by revealing that they secrete TNF-α and IL-8, which mediate the onset of psoriasis, by activating the NF-κB (nuclear factor-κB) signaling pathway through TLRs (toll-like receptors), and report that psoriasis treatments can be developed through the immunomodulatory function of keratinocytes (Li, ZJ, et al., 2013).

[0014] To date, steroids and other agents used to maintain skin moisture and regulate inflammatory responses of the immune system have been commonly used to treat inflammatory skin diseases, including psoriasis. However, these treatment methods have the disadvantage of only temporarily alleviating symptoms or causing side effects when used in excessive amounts. Therefore, there is a need for research on the development of natural-derived treatments for skin inflammatory diseases that have high pharmacological effects and low side effects to address these issues.

[0015] Accordingly, the inventors completed the present invention in the process of researching a treatment for allergic inflammation, rhinitis associated with non-allergic inflammation, psoriasis, etc., using a substance derived from natural products.

[0016] Angelica gigas Nakai is a biennial perennial herb belonging to the Apiaceae family that has long been known for its beneficial effects on coldness in the limbs and lower back, menstrual irregularities or menstrual cramps, hysteria, menopausal disorders, headaches, and anemia. Recently, it has been reported that the bioactive components of Angelica gigas, such as decursin, decursinol angelate, and decursinol, have effects such as analgesic effects, protection against neurotoxicity, prevention of dementia, treatment of sepsis, and antioxidant properties.

[0017] Qing Dynasty Polygonum tinctorium Indigo is an annual herbaceous plant of the Polygonaceae family, also known as *Jokdae*. The blue dye extracted from the leaves of the indigo plant is used as a dye for special fabrics and is also used as an analgesic and antidote. Indigo, the representative compound of the blue dye, is isolated from the indigo plant, and indirubin is known to have anticancer activity against cancer cell lines.

[0018] Korean Published Patent No. 10-2019-0041130, a prior art invention, describes an immune-enhancing composition for the prevention and treatment of immune diseases such as allergic rhinitis, atopic dermatitis, and psoriasis, containing Angelica gigas extract and decursin and decursinol angelate isolated therefrom as active ingredients; however, it does not describe the synergistic effect of the Angelica gigas extract and indirubin in the treatment of rhinitis according to the present invention. Korean Published Patent No. 10-2017-0133497 describes that a purified extract containing indirubin can be used for psoriasis and inflammatory skin conditions; however, it also does not describe the synergistic effect of the Angelica gigas extract and indirubin in the treatment of rhinitis according to the present invention.

[0019] In addition, the non-patent prior art Jeong, HJ, et al. (2014) describes that an inhibitory effect was observed when an extract of Polygonum tinctorium was applied to an allergic rhinitis mouse model. However, in that the extract was prepared by extracting the Polygonum tinctorium with distilled water at 80°C for 3 hours, filtering, freeze-drying, and then grinding it into a powder, it differs from the present invention, which establishes and utilizes a method for extracting water-insoluble indirubin. Prior art literature

[0020] Korean Published Patent No. 10-2019-0041130, Immunostimulating composition containing fermented Angelica gigas extract as an active ingredient, published on April 22, 2019. Korean Registered Patent No. 893779, Method for extracting Angelica gigas extract having a scavenging effect on harmful reactive oxygen species, registered on April 9, 2009. Korean Registered Patent No. 1171434, Discovery and improvement of isatin-producing enzyme and method for producing natural indirubin by grafting the same with beta-glucosidase, registered on July 30, 2012. Korean Published Patent No. 10-2017-0133497, Extract from Indigo Naturalis and method for preparing the same, published on December 5, 2017. Korean Registered Patent No. 1728799, Solubilization of poorly soluble active pharmacological components using ethanol and alkaline amino acids Method for manufacturing a homogeneous solution formulation, Registered April 14, 2017. Korean Registered Patent No. 1717672; Injectable or ophthalmic formulation formed into a homogeneous solution by solubilizing a poorly soluble active pharmacological component, and method for manufacturing the same, Registered March 13, 2017. Korean Registered Patent No. 995891; Extracts of *Angelica gigas* and *Angelica dahurica* containing decursin and decursinol angelate, which have lipid metabolism improving effects, as active ingredients, and method for extracting the same, Registered November 16, 2010. Korean Published Patent No. 10-2019-0142601; Injectable or ophthalmic formulation indirubin solubilized using glacial acetic acid and polyoxy-35-castor oil, and method for manufacturing the same, Published December 27, 2019.

[0021] Kim, K.M., et al., Oral Acute and Subacute Toxicity Studies of Decursin and Decursinol Angelate of Angelica gigas Nakai, Molecular and Cellular Toxicology (2009), 5(2):153-159Kim, K.M., et al., Absorption, Distribution, Metabolism, and Excretion of Decursin and Decursinol Angelate from Angelica gigas Nakai, J. Microbiol. Biotechnol. (2009), 19(12), 1569-1572Hwang B.M., et al., Decursin inhibits UVB-induced MMP expression in human dermal fibroblasts via regulation of Nuclear factor-kB, Int. J. Mol. Med (2013), 31(2):477-83Lee, Y.J., et al., Preventive effect of Angelica gigas Nakai extract oral administration on dry eye syndrome, APJ (2018), 03, 369-375Kim, K.M., et al., The Preventive Effect of Bacillus polyfermenticus KJS-2 and Angelica gigas Nakai Extract on Triton WR-1339-induced Hyperlipidemia JLS (2018), 8, 101-107Jeong, H.J., et al., Inhibition of IL-32 and TSLP production through the attenuation of caspase-1 activation in an animal model of allergic rhinitis by Naju Jjok (Polygonum tinctorium), Int. j. Mol. Med. (2014), 33, 142-150Nickoloff BJ, et al., Injection of Pre-Psoriatic Skin with CD4+ T Cells Induces Psoriasis, The American Journal of Pathology (1999), 155(1), 145-158Jing Li, et al., Toll-like receptors as therapeutic targets for autoimmune connective tissue diseases, Pharmacology & Therapeutics, (2013), 138(3), 441-451. The problem to be solved

[0022] The objective of the present invention is to provide a composition for treating psoriasis and rhinitis containing Angelica gigas extract and indirubin.

[0023] Another objective of the present invention is to provide a composition for treating psoriasis and rhinitis containing Angelica gigas extract and indirubin, which can maximize the therapeutic effect on rhinitis by mixing Angelica gigas extract and indirubin in a certain ratio. means of solving the problem

[0024] The present invention relates to a composition for treating psoriasis or rhinitis comprising Angelica gigas extract and indirubin.

[0025] The above composition for treating psoriasis or rhinitis is characterized by containing at least 70 w / w% of decursin, decursinol angelate, and decursinol in the Angelica gigas extract. Additionally, the above composition for treating psoriasis or rhinitis is characterized by containing 0.01 to 5 w / v% Angelica gigas extract and 0.01 to 5 w / v% indirubin concentrate.

[0026] The above composition for treating psoriasis or rhinitis is

[0027] Korean angelica extract is,

[0028] (1) A step of washing Angelica gigas, drying it to a moisture content of 15 w / v% or less relative humidity, crushing it into 1 mm pieces, and mixing it with 50~90% ethanol to obtain a supernatant;

[0029] (2) A step of concentrating the above supernatant by evaporating and drying it;

[0030] (3) A step of dissolving the above concentrated extract in 60 w / v% ethanol, removing the undissolved portion by filtration, and then adding an equal volume of purified water to collect the precipitate by centrifugation; and

[0031] (4) a step of purifying the precipitate by adding hot water, shaking to settle it, discarding the supernatant, and repeating this operation three times to obtain a product containing 70 w / w% or more of Decursin, Decursinol angelate, and Decursinol; the product is manufactured by a manufacturing method comprising: (4) a step of adding hot water to the precipitate, shaking to settle it, discarding the supernatant, and repeating this operation three times; and (4) a step of purifying the product containing 70 w / w% or more of Decursinol, Decursinol angelate, and Decursinol.

[0032] Indirubin concentrate is,

[0033] (a) A step of mixing crushed indigo with glacial acetic acid;

[0034] (b) a step of filtering the above mixture to obtain a filtrate;

[0035] (c) a step of adding purified water to the above filtrate to precipitate indirubin and centrifuging at 10,000 rpm for 20 minutes to collect the precipitate; and

[0036] (d) a step of adding ethanol to the precipitate to dissolve it and centrifuging to remove the precipitate; can be manufactured by a manufacturing method comprising this step.

[0037] The present invention will be described in detail below.

[0038] The Angelica gigas extract of the present invention is characterized by containing 70 w / w% or more of decursin, decursinol angelate, and decursinol. The decursin, decursinol angelate, and decursinol are physiologically active components of Angelica gigas and are pyranocoumarin derivatives. The purification rate of the decursin, decursinol angelate, and decursinol of the present invention may be 50% or more. Preferably, it is 70% or more. The composition for treating psoriasis or rhinitis may include a mixture in which the Angelica gigas extract and indirubin concentrate are mixed in a weight ratio of 1 to 5:1 to 5, and preferably, a weight ratio of 1 to 3:1 to 3 is preferred. Outside the range of the above compositional ratios, for example, in the case of a compositional ratio of Angelica gigas extract to indirubin concentrate of 1:6 or 6:1, the therapeutic effect on psoriasis or rhinitis may be low, or it may take a long time for symptom relief.

[0039] The above composition for treating psoriasis or rhinitis may include the above Angelica gigas extract, indirubin concentrate, and pharmaceutically acceptable excipients.

[0040] The above composition for treating psoriasis or rhinitis may be added in an amount preferably 0.001 to 50% by weight, more preferably 0.001 to 40% by weight, and most preferably 0.01 to 10% by weight, based on the total weight of the pharmaceutical composition.

[0041] The above pharmaceutical composition may be formulated and used in the form of oral formulations such as powders, granules, tablets, capsules, suspensions, emulsions, syrups, liquids, and aerosols, as well as external preparations, suppositories, and sterile injectable solutions, according to conventional methods. Carriers, excipients, and diluents that may be included in the above pharmaceutical composition include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, acacia gum, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, microcrystalline cellulose, polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oil. When formulating, the product is prepared using diluents or excipients such as commonly used fillers, fillers, binders, humectants, disintegrants, surfactants, sweeteners, and acidifiers. Solid dosage forms for oral administration include tablets, pills, powders, granules, and capsules, and these solid dosage forms are prepared by mixing at least one excipient, for example, starch, calcium carbonate, sucrose or lactose, gelatin, etc., with the solubilized decursinol of the present invention. In addition to simple excipients, lubricants such as magnesium stearate and talc are also used. Liquid dosage forms for oral administration include suspensions, liquid formulations, emulsions, and syrups, and may include various excipients, for example, humectants, sweeteners, flavorings, preservatives, and acidifiers, in addition to commonly used simple diluents such as water and liquid paraffin. Preparations for parenteral administration include sterile aqueous solutions, non-aqueous solvents, suspensions, emulsions, lyophilized preparations, and suppositories. As non-aqueous solvents and suspensions, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable esters such as ethyl oleate may be used. As bases for suppositories, witepsol, macrogol, tween-61, cacao oil, laurin oil, glycerogelatin, etc. may be used.

[0042] When the pharmaceutical composition of the present invention is applied as an external agent, the external agent may be prepared in one formulation selected from the group consisting of ointments, gels, creams, lotions, liquids, powders, or sprays.

[0043] The dosage of the pharmaceutical composition of the present invention will vary depending on the age, gender, and weight of the subject to treatment, the specific disease or pathological condition to be treated, the severity of the disease or pathological condition, the route of administration, and the judgment of the prescriber. The determination of the dosage based on these factors is within the level of a person skilled in the art, and generally, the dosage ranges from 0.01 mg / kg / day to approximately 500 mg / kg / day. A preferred dosage is 0.1 mg / kg / day to 200 mg / kg / day, and a more preferred dosage is 1 mg / kg / day to 200 mg / kg / day. Administration may be performed once a day or divided into several doses. The above dosage does not limit the scope of the present invention in any way.

[0044] The pharmaceutical composition of the present invention can be administered to mammals, such as rats, livestock, and humans, via various routes. Any mode of administration is expected, for example, oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine or intrathecal injection, and topical application. Since the decursinol of the present invention has minimal toxicity and side effects, it is a drug that can be safely used for long-term preventive purposes. Effects of the invention

[0045] The present invention provides a composition for treating rhinitis containing Angelica gigas extract and indirubin concentrate, which can maximize the therapeutic effect on rhinitis by mixing Angelica gigas extract and indirubin concentrate in a certain ratio. This contributes to the development of a new rhinitis treatment that is not only effective and safe for rhinitis patients but also has a low recurrence rate and fewer side effects such as drowsiness, dryness, irritation, nasal burning, and epistaxis. Specific details for implementing the invention

[0046] Preferred embodiments of the present invention will be described in detail below. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the content introduced herein is provided to be thorough and complete and to sufficiently convey the concept of the present invention to those skilled in the art.

[0047] <Preparation of Angelica gigas extract>

[0048] Purified Angelica gigas was obtained in accordance with Korean Patent Registration No. 10-0893779.

[0049] Korean angelica extract is,

[0050] (1) A step of washing Angelica gigas, drying it to a moisture content of 15 w / v% or less relative humidity, crushing it into 1 mm pieces, and mixing it with 50~90% ethanol to obtain a supernatant;

[0051] (2) A step of concentrating the above supernatant by evaporating and drying it;

[0052] (3) A step of dissolving the above concentrated extract in 60 w / v% ethanol, removing the undissolved portion by filtration, and then adding an equal volume of purified water to collect the precipitate by centrifugation; and

[0053] (4) A step of purifying the precipitate by adding hot water, shaking it to settle, discarding the supernatant, and repeating this operation three times to obtain a product containing 70 w / w% or more of Decursin, Decursinol angelate, and Decursinol; the product can be manufactured by a manufacturing method including the above steps.

[0054] The raw material, Angelica gigas, was finely ground to 40 mesh or less and dried to a moisture content of 5% or less. Two to four times the amount of the ground Angelica gigas was added to medicinal alcohol or ethanol (hereinafter referred to as 'ethanol') and extracted sufficiently for more than 12 hours, and the resulting product was filtered and concentrated.

[0055] 1 liter of 95% ethanol was added per 1 kilogram of the above concentrate to dissolve the main component, and the mixture was left at -20°C for 10 hours to remove the precipitate by centrifugation, and the supernatant was obtained. This supernatant was then evaporated and dried. The dried material was dissolved in 60 v / v% ethanol until completely dissolved; any material that did not dissolve in 60 v / v% ethanol was removed by centrifugation, and the supernatant was evaporated and dried. The dried material was dissolved in ethanol of 95 v / v% or higher, and the supernatant was taken to obtain the Angelica gigas extract. HPLC analysis of the Angelica gigas extract confirmed that it contained 90 w / w% or more of decursin, decursinol, and decursinol angelate.

[0056] Preparation of Indirubin Concentrate

[0057] 10 g of indigo was taken, 100 ml of ethanol was added, and the mixture was stirred thoroughly to dissolve it. The resulting liquid was then filtered using filter paper to obtain a filtrate. It is known that this extract contains indigo and indirubin in a ratio of approximately 4:1. However, this indigo ethanol extract contains a large amount of indigo, which has no medicinal effect, so the medicinal effect is not effectively exerted. Therefore, the inventors conducted experiments with various solvents to purify indirubin.

[0058] As a result of using various solvents and extraction methods to isolate structurally similar indirubin from indigo, the inventors confirmed that indigo is not soluble in glacial acetic acid, but indirubin is effectively soluble, and established a method for preparing an indirubin concentrate as follows.

[0059] Indirubin concentrate is,

[0060] (a) A step of mixing crushed indigo with glacial acetic acid;

[0061] (b) a step of filtering the above mixture to obtain a filtrate;

[0062] (c) a step of adding purified water to the above filtrate to precipitate indirubin and centrifuging at 10,000 rpm for 20 minutes to collect the precipitate; and

[0063] (d) a step of adding ethanol to the precipitate to dissolve it and centrifuging to remove the precipitate; can be manufactured by a manufacturing method comprising this step.

[0064] A more detailed look at this is as follows.

[0065] i) 10 g of indigo was added to 100 ml of glacial acetic acid and mixed by stirring thoroughly. ii) The mixture was filtered using filter paper to obtain the first filtrate. During filtration, Whatman filters No. 2 and No. 4 were stacked and used. iii) 15 ml of glacial acetic acid was dispensed onto the filter paper once more to obtain the second filtrate. This solution was combined with the first filtrate, and 1,000 ml of distilled water was added and centrifuged at 10,000 rpm for 20 minutes to obtain a precipitate. iv) 60 ml of 95% ethanol was added to the precipitate to dissolve it, and the precipitate was removed by centrifugation. The supernatant was taken, and the ethanol was volatilized using a rotary concentrator to obtain an indirubin concentrate. HPLC analysis of the concentrate confirmed that it contained more than 50 w / w% indirubin.

[0066] <Preparation of Gel Formulations Containing Angelica gigas Extract and / or Indirubin Concentrate>

[0067] A gel formulation containing the Angelica gigas extract and / or indirubin concentrate obtained above was prepared. To solubilize and homogenize the poorly soluble pharmacological components, the method of the inventors' prior patent, Korean Patent Registration No. 1717672, was used.

[0068] 600 g of PEG 4,000 and 1,400 g of PEG 400 were mixed and dissolved by applying heat. A solution of 6 g of Lysine HCl, 16 g of Tween 80, 4 g of Span, and 1.6 g of Polyvinylpyrrolidone (K30) dissolved in 100 ml of purified water was added to the mixture of PEG 4,000 and PEG 400 and mixed. The temperature was adjusted to approximately 50°C, and 4 g of Sorbic acid was added to prepare a gel composition. Subsequently, the Angelica gigas extract and / or indirubin concentrate obtained above were mixed in the ratios shown in Table 1 below, dissolved in ethanol, added to the gel composition prepared above, mixed uniformly, and cooled to complete a gel formulation containing the Angelica gigas extract and / or indirubin concentrate. A control group was prepared by adding the same amount of solvent to the gel composition.

[0069] Angelica gigas extract (w / w%) Indirubin concentrate (w / w%) control group 0.0 0.0 Preparation 1 0.0 0.6 Preparation 2 0.1 0.5 Formulation 3 0.2 0.4 Preparation 4 0.3 0.3 Preparation 5 0.4 0.2 Formulation 6 0.5 0.1 Preparation 7 0.6 0.0

[0070] <Effects of Korean Angelica Extract and / or Indirubin Concentrate on Rhinitis in an Allergic Rhinitis Mouse Model>

[0071] The rhinitis-inducing effects of the Angelica gigas extract and / or indirubin concentrate obtained above were confirmed in an allergic rhinitis mouse model. Six-week-old female BALB / c mice (Charles River Laboratories, Inc., Wilmington, Massachusetts, USA) were maintained under pathogen-free conditions, and then sensitized on days 1, 5, and 14 by intraperitoneal (ip) injection of 100 μg OVA emulsified in 20 mg aluminum hydroxide (Sigma). Preparations 1 to 7 of the combinations in Table 1 above were administered intranasally to the mice. One day later, 1.5 mg OVA was administered to the mice, and nasal symptoms were evaluated by counting the number of nasal rubs occurring over a 10-minute period.

[0072] As a result, it was confirmed that the number of nose rubs decreased compared to the control group for all formulations 1 to 7, but formulations 2 to 6 showed a significantly greater decrease in the number of nose rubs than formulations 1 and 7, and formulation 4 was the most effective.

[0074] <Effect of Gel Preparations Containing Angelica gigas Extract and / or Indirubin Concentrate on Rhinitis>

[0075] From January 2018 to December 2019, a gel formulation with the composition shown in Table 1 was applied to six patients with psoriasis and rhinitis at two Korean medicine clinics in the Busan area, and their symptoms were evaluated. The rhinitis evaluation stage was classified into four levels by combining the daily frequency of sneezing, the frequency of nose blowing, the degree of nasal obstruction, and the degree of impairment to daily life, as shown in Table 2 below; symptoms other than rhinitis were recorded individually. Since the symptoms and severity of rhinitis varied among the subjects, the formulation was applied according to the individual's condition.

[0076] Type / Degree normal Rhinitis Stage 1 Rhinitis Stage 2 Rhinitis Stage 3 Rhinitis Stage 4 Sneezing (daily average) 0 1~5 times 6~10 times Episodes 11~20 21 times or more Nasal congestion (number of times blowing nose per day) 0 1~5 times 6~10 times Episodes 11~20 21 times or more Nasal obstruction 0 No mouth breathing, but nasal obstruction There is occasional mouth breathing, but nasal obstruction is severe. Mouth breathing persists for a considerable amount of time and nasal obstruction is very severe. Completely blocked all day Degree of impairment in daily life 0 No major issues Between rhinitis stage 1 and rhinitis stage 3 Suffering to the point where I cannot focus on work Completely impossible

[0077] Case 1 (Woman in her 30s)

[0078] The patient had stage 2 rhinitis and generalized psoriasis. Psoriasis had developed on almost every part of the body from head to toe, and there were areas where the skin had scabbed over due to drug abuse. Additionally, the patient suffered from severe allergic rhinitis and itching throughout the body. After applying a gel containing 0.3 w / w% Angelica gigas extract and 0.3 w / w% indirubin concentrate, improvement was observed on almost all parts of the body after 90 days; the scabs disappeared, leaving only a few scar-like marks, and the patient was completely healed after 12 months. However, slight redness was observed on the inner elbow area, and all other symptoms disappeared.

[0079] Case 2 (Male in his 50s)

[0080] A single preparation of 0.3 w / w% Angelica gigas extract was applied for one week to a male in his 50s with the surname Kang living in Busan, who was a patient with stage 2 rhinitis. While the treatment was being applied, the condition was effective and the patient recovered from stage 2 rhinitis to stage 1 rhinitis; however, when use was stopped, the condition recurred and returned to stage 2 rhinitis. In other words, the single preparation of 0.3 w / w% Angelica gigas extract was effective for rhinitis, but it was difficult to achieve a complete cure or sustain the effect.

[0081] Case 3 (Male in his 30s)

[0082] Patient with rhinitis-induced or allergic rhinitis, stage 2 rhinitis, severe nasal congestion upon waking in the morning.

[0083] As a result of applying a gel formulation containing 0.3 w / w% Angelica gigas extract and 0.3 w / w% indirubin concentrate, sneezing disappeared from the first day of application and rhinorrhea disappeared from the second day. It was continued for 4 weeks (28 days) before discontinuation, and after observing for 2 months, no further symptoms appeared. The condition recovered from stage 2 rhinitis to normal.

[0084] Case 4 (Male in his 20s)

[0085] Patient with rhinitis-induced allergic rhinitis, stage 3 rhinitis, reported severe nasal congestion upon waking in the morning, which interfered with learning and caused distress.

[0086] As a result of applying a gel formulation containing 0.3 w / w% Angelica gigas extract and 0.3 w / w% indirubin concentrate, nasal congestion disappeared starting from the first day, 2 hours after application, and rhinorrhea disappeared starting from the second day. The treatment was discontinued after 4 weeks (28 days), and after observing the patient for 2 months, no further symptoms appeared. The condition recovered from stage 3 rhinitis to normal.

[0087] Case 5 (Woman in her 30s)

[0088] Patients with rhinitis-induced or allergic rhinitis, stage 3 rhinitis, severe nasal congestion and sneezing upon waking in the morning.

[0089] As a result of applying a gel formulation containing 0.3 w / w% Angelica gigas extract and 0.3 w / w% indirubin concentrate, nasal congestion disappeared from the first day of application, and rhinorrhea disappeared from the second day. Use was discontinued after 4 weeks (28 days), and there were no symptoms even after 6 months. The condition recovered from stage 3 rhinitis to normal.

[0090] Case 6 (Woman in her 20s)

[0091] Allergic rhinitis, rhinitis stage 1, severe nasal congestion upon waking in the morning.

[0092] As a result of applying a gel formulation containing 0.3 w / w% Angelica gigas extract and 0.3 w / w% indirubin concentrate, nasal congestion disappeared starting from the first day of application, and use was discontinued after 4 weeks (28 days), with no symptoms remaining even after 6 months. The condition recovered from stage 1 rhinitis to normal.

[0093] The above case is shown in Table 3.

[0094] example symptoms Treatment Time of treatment or duration of treatment result 1 Generalized psoriasis, generalized itching, severe allergic rhinitis Angelica gigas extract 0.3w / w% indirubin concentrate 0.3w / w% (Preparation 6) 3 months Improvement of all body parts 12 months Only the inside of the elbow is red, and the rest of the symptoms have disappeared (complete cure) 2 Rhinitis Stage 2 Korean Angelica extract 0.3w / w% (Preparation 1) 1 week Recurrence occurs if recovery treatment is stopped at stage 1 rhinitis. 3 Rhinorrhea, Allergic Rhinitis, Stage 2 Rhinitis, Severe nasal congestion upon waking in the morning Angelica gigas extract 0.3w / w% indirubin concentrate 0.3w / w% (Preparation 6) 1 day The sneezing disappeared 2 days Discontinued use 4 weeks after rhinorrhea disappeared, observed 2 months later with no recurrence (complete cure) 4 Rhinorrhea, Allergic Rhinitis, Stage 3 Rhinitis, Severe nasal congestion upon waking in the morning, Interference with learning, Indicates distress Angelica gigas extract 0.3w / w% indirubin concentrate 0.3w / w% (Preparation 6) 1 day Nasal congestion disappears 2 hours after application 2 days Discontinued use 4 weeks after rhinorrhea disappeared, observed 2 months later with no recurrence (complete cure) 5 Rhinorrhea, Allergic Rhinitis, Stage 3 Rhinitis, Severe nasal congestion upon waking in the morning, Accompanied by sneezing Angelica gigas extract 0.3w / w% indirubin concentrate 0.3w / w% (Preparation 6) 1 day Nasal congestion disappears 2 days Discontinued use 4 weeks after rhinorrhea disappeared, observed 6 months later with no recurrence (complete cure) 6 Allergic Rhinitis Stage 1: Severe nasal congestion upon waking in the morning Angelica gigas extract 0.3w / w% indirubin concentrate 0.3w / w% (Preparation 6) 1 day Nasal congestion disappears Discontinuation of use after 4 weeks, observation after 6 months showed no recurrence (complete cure)

[0095] Based on the above cases, the efficacy and formulation characteristics of single or combination preparations of Angelica gigas extract and indirubin concentrate are summarized in Table 4 below. As shown in Table 4, Angelica gigas extract and indirubin concentrate showed consistent effects in rhinitis and psoriasis when used as single agents, respectively, and when used as a combination, they showed clinically superior therapeutic effects compared to when used as single agents.

[0096] Formulation effect Single preparations (Preparations 1, 7) - Treatment efficacy observed. - Approximately 50% complete cure after 4 weeks of use (recurrence within 6 months) Combination preparations (Preparations 3, 4, 5, 6) - Very good treatment efficacy. - Approximately 80% cure rate after 4 weeks of use (no recurrence within 6 months)

[0098] <Formulation Example 1. Pharmaceutical Formulation>

[0099] Formulation Example 1-1. Preparation of Tablets

[0100] A mixture of 42.8 mg of Angelica gigas extract and 150 mg of indirubin concentrate according to the present invention was mixed with 175.9 g of lactose, 180 g of potato starch, and 32 g of colloidal silica. A 10% gelatin solution was added to this mixture, followed by grinding and passing the mixture through a 14-mesh sieve. The mixture was dried, and 160 g of potato starch, 50 g of active ingredient, and 5 g of magnesium stearate were added to it to form a tablet.

[0101] Example 1-2. Preparation of Injectable Preparations

[0102] 100 ml was prepared by dissolving 21.4 mg of the Angelica gigas extract and 75 mg of the mixture of indirubin concentrate, 0.6 g of sodium chloride, and 0.1 g of ascorbic acid in distilled water. This solution was placed in a bottle and sterilized by heating at 20°C for 30 minutes.

[0103] <Preparation Example 2. Preparation of a Health Functional Food>

[0104] Preparation Example 2-1. Preparation of a health functional food

[0105] The present invention was prepared as granules by mixing 42.8 mg of Angelica gigas extract and 150 mg of indirubin concentrate mixture, an appropriate amount of vitamin mixture, 70 μg of vitamin A acetate, 1.0 mg of vitamin E, 0.13 mg of vitamin B1, 0.15 mg of vitamin B2, 0.5 mg of vitamin B6, 0.2 μg of vitamin B12, 10 mg of vitamin C, 10 μg of biotin, 1.7 mg of nicotinamide, 50 μg of folic acid, 0.5 mg of calcium pantothenate, an appropriate amount of mineral mixture, 1.75 mg of ferrous sulfate, 0.82 mg of zinc oxide, 25.3 mg of magnesium carbonate, 15 mg of monopotassium phosphate, 55 mg of disodium phosphate, 90 mg of potassium citrate, 100 mg of calcium carbonate, and 24.8 mg of magnesium chloride, but it can be prepared by modifying it into various formulations depending on the use. In addition, the composition ratio of the above vitamin and mineral mixture may be arbitrarily modified, and the above ingredients may be mixed and manufactured according to a conventional method for manufacturing health functional foods.

[0106] Preparation Example 2-2. Preparation of a health functional beverage

[0107] A beverage was prepared by mixing 42.8 mg of the Angelica gigas extract and 150 mg of the indirubin concentrate mixture of the present invention, 0.1 g of citric acid, 100 g of fructooligosaccharide, and 900 g of purified water, and stirring, heating, filtering, sterilizing, and refrigerating according to a conventional beverage preparation method.

Claims

Claim 1 A nasal administration gel formulation for treating allergic rhinitis or rhinorrhea, comprising an Angelica gigas extract and an indirubin concentrate, wherein the Angelica gigas extract comprises 70 w / w% or more of decursin, decursinol angelate, and decursinol, the indirubin concentrate comprises 50 w / w% or more of indirubin, and the Angelica gigas extract and the indirubin concentrate are included in a weight ratio of 1:

1. Claim 2 delete Claim 3 delete Claim 4 delete Claim 5 delete Claim 6 delete Claim 7 delete Claim 8 delete

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