US20170209519A1 - Pharmaceutical composition for treating or alleviating autoimmune-related diseases and method for treating or alleviating autoimmune-related diseases - Google Patents

Pharmaceutical composition for treating or alleviating autoimmune-related diseases and method for treating or alleviating autoimmune-related diseases Download PDF

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US20170209519A1
US20170209519A1 US15/416,304 US201715416304A US2017209519A1 US 20170209519 A1 US20170209519 A1 US 20170209519A1 US 201715416304 A US201715416304 A US 201715416304A US 2017209519 A1 US2017209519 A1 US 2017209519A1
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pharmaceutical composition
extract
related diseases
autoimmune
tsao
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Kuo-Kuei Huang
I-Horng Pan
Meng-Nan Lin
Jir-mehng Lo
Jennline Sheu
Pei-Ru Liau
Yi-Cheng Cheng
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Industrial Technology Research Institute ITRI
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Industrial Technology Research Institute ITRI
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Assigned to INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE reassignment INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CHENG, Yi-cheng, HUANG, KUO-KUEI, LIAU, PEI-RU, LIN, Meng-nan, LO, JIR-MEHNG, PAN, I-HORNG, SHEU, Jennline
Publication of US20170209519A1 publication Critical patent/US20170209519A1/en
Assigned to INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE reassignment INDUSTRIAL TECHNOLOGY RESEARCH INSTITUTE ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: LIN, PEI-HSIN
Priority to US16/698,502 priority patent/US11510957B2/en
Priority to US17/977,541 priority patent/US20230061259A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/88—Liliopsida (monocotyledons)
    • A61K36/906—Zingiberaceae (Ginger family)
    • A61K36/9064—Amomum, e.g. round cardamom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/11—Aldehydes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A61K9/0024—Solid, semi-solid or solidifying implants, which are implanted or injected in body tissue
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2236/00—Isolation or extraction methods of medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicine
    • A61K2236/30—Extraction of the material
    • A61K2236/33—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones
    • A61K2236/333—Extraction of the material involving extraction with hydrophilic solvents, e.g. lower alcohols, esters or ketones using mixed solvents, e.g. 70% EtOH

Definitions

  • the technical field relates to pharmaceutical compositions for treating or alleviating autoimmune-related diseases.
  • immune system Under a normal physiological condition, immune system can be regarded as the defense army of the body. When immune system detects the invasion of bacteria, virus, or other foreign materials, it will produce antibodies and attack these foreign materials. However, when immune system is disorder and no longer be able to accurately distinguish between the enemy and the self, the defense army will attack their own tissues or organs, and trigger the so-called “Autoimmune disease”.
  • the prevalence of suffering from autoimmune disease is about 5% of the global population.
  • the type of autoimmune disease ranges from single organ disease (such as Hashimoto's thyroiditis) to systemic diseases (such as systemic lupus erythematosus, referred to SLE).
  • SLE systemic lupus erythematosus
  • the pathological features of autoimmune disease include that a large number of abnormal infiltration lymphocytes can be found in the inflammatory tissues or organs, and the autoantibody can be detected in the blood of the patient.
  • MS multiple sclerosis
  • MS it usually occurs in the ancestors of the Caucasian race from Northern Europe, and the residents of high latitudes are more likely to suffer from MS.
  • interleukin such as IL-17
  • T helper cells T helper cells
  • the main drugs used to treat autoimmune diseases include non-steroidal anti-inflammatory drugs, steroids, immune-modulators, and immune-suppressive agents.
  • these drugs are known to have the risk of side effects, and somehow they may interact with each other.
  • the new generation of therapeutic drugs are developed to adopt immuno-target therapy, which designs biological agents targeting for specific immune messages or molecules in autoimmune diseases, and these biological agents can accurately target abnormal immune molecules, but will not hurt the normal cells.
  • the disclosure provides a pharmaceutical composition for treating or alleviating autoimmune-related diseases, comprising: an extract of Amomum tsao - ko as an effective ingredient and a pharmaceutically acceptable carrier or salt.
  • the disclosure also provides a pharmaceutical composition for treating or alleviating autoimmune-related diseases, comprising: a compound as an effective ingredient and a pharmaceutically acceptable carrier or salt, wherein the compound is vanillin, tsaokoin, or a combination thereof.
  • the disclosure also provides a method of treating or alleviating autoimmune-related diseases, comprising: administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises an extract of Amomum tsao - ko as an effective ingredient and a pharmaceutically acceptable carrier or salt.
  • the disclosure provides a method of treating or alleviating autoimmune-related diseases, comprising: administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a compound as an effective ingredient and a pharmaceutically acceptable carrier or salt, wherein the compound is vanillin, tsaokoin, or a combination thereof.
  • FIG. 1 shows the effect of Amomum tsao - ko extract HE-06 on TNF- ⁇ secretion in LPS-induced acute inflammatory BALB/c mouse model. ** represents p value is less than 0.01;
  • FIG. 2A shows that Amomum tsao - ko extract HE-06 exhibits the effect on delaying the progression of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mouse model, in which the results were obtained through daily observation and recording for 14 consecutive days, and the scoring criteria of the progression is based on Ataxia score and EAE score which have been recognized in literature.
  • EAE experimental autoimmune encephalomyelitis
  • FIG. 2B-2C show the effects of the extracts, 2015-0803-2 and 2015-0909-2, on the progression of EAE mouse model, respectively.
  • 2015-0803-2 and 2015-0909-2 are the further extracts of Amomum tsao - ko extract HE-06 and obtained through the toxicity-attenuating steps, and both 2015-0803-2 and 2015-0909-2 extracts are administered with a dose of 250 mg/kg.
  • *** represents p value is less than 0.001;
  • FIG. 3A-3E show the effects of active fractional interval (I) of Amomum tsao - ko extract HE-06 on EAE acute inflammatory mouse model, including delaying the development of EAE progression, improving EAE disorders, improving demyelination of the cervical spine, and reducing the incidence of demyelination and axonal swelling in the entire spinal cord, respectively.
  • * represents p value is less than 0.05
  • ** represents p value is less than 0.01
  • *** represents p value is less than 0.001;
  • FIG. 4A-4C show the effects of active fractional interval (II) of Amomum tsao - ko extract HE-06 on inhibition of TNF- ⁇ secretion in LPS-induced acute inflammatory mouse model, delaying the progression of EAE mouse model, and slowing down the skin inflammatory conditions of IMQ-induced psoriasis-like dermatitis, respectively.
  • * represents p value is less than 0.05
  • ** represents p value is less than 0.01
  • *** represents p value is less than 0.001;
  • FIG. 5A-5D show the effects of active ingredient Tsaokoin (TK) of Amomum tsao - ko extract HE-06 on inhibiting IL-17 secretion of induced EL4 lymphoma cells, inhibiting TNF- ⁇ secretion in LPS-induced acute inflammatory mouse model, delaying the progression of EAE mouse model, and slowing down the skin inflammatory conditions of IMQ-induced psoriasis-like dermatitis, respectively.
  • * represents p value is less than 0.05
  • ** represents p value is less than 0.01
  • *** represents p value is less than 0.001.
  • the disclosure provides a pharmaceutical composition for treating or alleviating autoimmune-related diseases, which comprises an effective amount of an extract of Amomum tsao - ko (hereinafter referred to as A. tsao - ko ) as a main effective ingredient and a pharmaceutically acceptable carrier or salt.
  • A. tsao - ko an extract of Amomum tsao - ko (hereinafter referred to as A. tsao - ko ) as a main effective ingredient and a pharmaceutically acceptable carrier or salt.
  • A. tsao - ko is belong to evergreen perennial herb of Zingiberaceae cardamom genus, with a height of 2.5 to 3 meters and grown in forest humid zone of tropical and subtropical. Otherwise, the origin of A. tsao - ko is distributed in Yunnan of China and Southeast Asia, and its artificial cultivation history has been 200 years.
  • A. tsao - ko can also be used as seasonings because of its whole plant having spicy flavor.
  • A. tsao - ko can be considered as both food and medicine material.
  • the above-mentioned extract of A. tsao - ko is extracted from the root, stem, leaf, flower, fruit, seed, bark or a combination thereof.
  • the above-mentioned extract of A. tsao - ko can be extracted from the fruit of A. tsao - ko.
  • the above-mentioned extract of A. tsao - ko is obtained from performing an extraction with an organic solvent.
  • the said organic solvent may comprise alcohol, ester, alkane, haloalkane, or a combination thereof, but it is not limited thereto.
  • the above-mentioned alcohol may be C1-C12 alcohols (for example, methanol, ethanol, propanol, isopropanol, n-butanol, 2-butanol, t-butanol, 1,3-butanediol, 1,4-butanediol, pentanol, isoamyl alcohol, 2,3-pentanediol, 2,4-pentanediol, cyclopentanol, hexanol, cyclohexanol, heptanol, octanol, nonanol, decanol, hendecanol, dodecanol, etc.), the above-mentioned esters may be C2-C5 acid esters (for example, ethyl acetate, propyl acetate, amyl acetate, amyl propionate, etc.), the above-mentioned alkanes may be
  • the above-mentioned extract of A. tsao - ko can be obtained from performing an extraction with alcohol solvent.
  • the extract of A. tsao - ko can be obtained from performing an extraction by alcohol solvent with the concentration of ranging from 50 to 95%.
  • the concentration of the alcohol solvent utilized to perform the extraction of A. tsao - ko can be 50-60%, 60-70%, 70-80%, 80-90%, or 90-95%.
  • the concentration of the alcohol solvent utilized to perform the extraction of A. tsao - ko can be 95% alcohol solvent.
  • the weight of A. tsao - ko which would be used this time is calculated first, and the extraction is then carried out by the proportion of which a volume of the organic solvent is 3-10 times the weight of A. tsao - ko .
  • the volume of the organic solvent can be 3-7 times the weight of A. tsao - ko .
  • the volume of the organic solvent can be 5 times the weight of A. tsao - ko .
  • the extraction is performed an extraction temperature of 10 to 35° C. and an extraction time of 3 to 10 days.
  • the extraction temperature can be 20 to 30° C. and the extraction time can be 5 to 8 days.
  • the extraction temperature can be 25° C. and the extraction time can be 7 days.
  • the extraction of the extract of A. tsao - ko is further performed with a shaking mode, including horizontal shaking, vertical shaking, rotate shaking, 3D-nutating shaking, seesaw shaking, ultrasonic shaking or a combination thereof, but it is not limited thereto.
  • the extract of A. tsao - ko obtained by the preceding extraction process is still passed through a suction filtration step and the resulting filtrate is considered as the test substance of the extract of A. tsao - ko , hereinafter referred to as HE-06.
  • the extraction of the above-mentioned extract of A. tsao - ko HE-06 further comprises a distillation step.
  • the extraction of the above-mentioned extract of A. tsao - ko HE-06 still comprises a heating reflux step with a low polarity solvent.
  • the pharmaceutical composition comprising the above-mentioned extract of A. tsao - ko HE-06 as an effective ingredient has the effect on inhibiting cytokine secretion, and the said cytokine includes IL-17, TNF- ⁇ , and a combination thereof, but it is not limited thereto.
  • the pharmaceutical composition comprising the above-mentioned extract of A. tsao - ko HE-06 as an active ingredient can be used for treating or alleviating autoimmune-related diseases.
  • the said treating or alleviating autoimmune-related diseases can include, but is not limited to, alleviating the syndrome of the autoimmune-related diseases or slowing down the progress of the autoimmune-related diseases.
  • the said autoimmune-related diseases can include Multiple Sclerosis (MS), neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), demyelination-related neuritis, Ankylosing spondylitis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis (RA), Crohn's disease, Juvenile idiopathic arthritis (JIA), Ulcerative Colitis (UC), and a combination thereof, but it is not limited thereto.
  • the pharmaceutical composition comprising the above-mentioned extract of A. tsao - ko HE-06 as an effective ingredient can be used for treating or alleviating Multiple Sclerosis.
  • the pharmaceutical composition comprising the above-mentioned extract of A. tsao - ko HE-06 as an effective ingredient may be administered orally, non-orally, parenterally by an inhalation spray, or via an implanted reservoir.
  • the parenteral method may comprise subcutaneous, intracutaneous, intravenous, intramuscular, intra-articular, intra-arterial, intrasynovial, intrasternal, intrathecal, and intralesional injection or infusion techniques, but it is not limited thereto.
  • An oral composition can comprise, but is not limited to, tablets, capsules, emulsions, aqueous suspensions, dispersions and solutions.
  • the pharmaceutical composition can be administered by oral or subcutaneous injection. It is also possible to administer with multi-dose thereof in a suitable period according to the pharmacological routine method for determining the course of administration to which the patient is applied.
  • the pharmaceutical composition comprising the above-mentioned extract of A. tsao - ko HE-06 as an effective ingredient further comprises a pharmaceutically acceptable carrier or salt well known in the art and added in appropriate proportion.
  • the pharmaceutically acceptable carrier may include, but is not limited to, a solvent, a dispersion medium, a coating, an antibacterial and antifungal agent, or an isotonic and absorption delaying agent, etc. which is compatible to pharmaceutical administration.
  • the pharmaceutical composition can be formulated into dosage forms for different administration routes utilizing conventional methods.
  • the pharmaceutically acceptable salt may include, but is not limited to, inorganic cation salt, such as alkali metal salts such as sodium salt, potassium salt or amine salt, such as alkaline-earth metal salt such as magnesium salt or calcium salt, such as the salt containing bivalent or quadrivalent cation such as zinc salt, aluminum salt or zirconium salt.
  • the pharmaceutically acceptable salt may also comprise organic salt, such as dicyclohexylamine salt, methyl-D-glucamine, and amino acid salt such as arginine, lysine, histidine, or glutamine.
  • a method of treating or alleviating autoimmune-related diseases comprises administering a pharmaceutical composition to a subject in need thereof, and the pharmaceutical composition comprises an extract of A. tsao - ko as an effective ingredient and a pharmaceutically acceptable carrier or salt.
  • the said subject can include mammals, such as rat, dog, cat, horse, sheep, pig, monkey, ape, etc., especially human.
  • a pharmaceutical composition for treating or alleviating autoimmune-related diseases in which the pharmaceutical composition comprises a compound as an effective ingredient and a pharmaceutically acceptable carrier or salt, and the compound is vanillin, tsaokoin, or a combination thereof.
  • the above-mentioned extract of A. tsao - ko , HE-06 is further extracted with a distillation step to remove the portion of essential oil. Then, a step of heating and refluxing with a low polarity solvent is performed to reduce the toxicity and extract the active ingredient therein.
  • the said low polarity solvent can include petroleum ether, C4-C9 linear alkanes (such as n-Hexane), n-Heptane, C4-C9 cycloalkanes, unsaturated benzene, esters, ketones, and a combination thereof, but it is not limited thereto.
  • the pharmaceutical composition comprising vanillin, tsaokoin or a combination thereof as an effective ingredient has the effect on inhibiting cytokine secretion, and the cytokine includes IL-17, TNF- ⁇ , and a combination thereof, but it is not limited thereto.
  • the pharmaceutical composition comprising vanillin, tsaokoin or a combination thereof as an effective ingredient can be can be used for treating or alleviating autoimmune-related diseases.
  • the said treating or alleviating autoimmune-related diseases can include, but is not limited to, alleviating autoimmune-related diseases or slowing down autoimmune-related diseases.
  • the said autoimmune-related diseases can include Multiple Sclerosis (MS), neuromyelitis optica (NMO), acute disseminated encephalomyelitis (ADEM), demyelination-related neuritis, Ankylosing spondylitis, Psoriasis, Psoriatic arthritis, Rheumatoid arthritis (RA), Crohn's disease, Juvenile idiopathic arthritis (JIA), Ulcerative Colitis (UC), and a combination thereof, but it is not limited thereto.
  • the pharmaceutical composition comprising vanillin, tsaokoin or a combination thereof as an effective ingredient can be used for treating or alleviating Multiple Sclerosis.
  • the pharmaceutical composition comprising vanillin, tsaokoin or a combination thereof as an effective ingredient may be administered orally, non-orally, parenterally by an inhalation spray, or via an implanted reservoir.
  • an inhalation spray or via an implanted reservoir.
  • composition comprising vanillin, tsaokoin or a combination thereof as an effective ingredient further comprises a pharmaceutically acceptable carrier or salt well known in the art and added in appropriate proportion.
  • a pharmaceutically acceptable carrier or salt well known in the art and added in appropriate proportion.
  • a method of treating or alleviating autoimmune-related diseases comprises administering a pharmaceutical composition to a subject in need thereof, wherein the pharmaceutical composition comprises a compound as an effective ingredient and a pharmaceutically acceptable carrier or salt, wherein the compound is vanillin, tsaokoin, or a combination thereof.
  • the pharmaceutical composition comprises a compound as an effective ingredient and a pharmaceutically acceptable carrier or salt, wherein the compound is vanillin, tsaokoin, or a combination thereof.
  • the fruit of A. tsao - ko was taken as the medicinal material. After cleaning and drying, the fruit of A. tsao - ko was initially crushed by herbs crusher.
  • Example 2 The Extract of A. tsao - Ko HE-06 can Inhibit IL-17 Secretion
  • EL4 cell line is murine lymphoma cell purchased from Bioresource Collection and Research Center (referred to as BCRC) and cultured in RPMI 1640 medium which contains 10% Fetal Bovine Serum (referred to as FBS), 1.5 g Sodium bicarbonate, 1 mM Sodium pyruvate, 1 ⁇ non-essential amino acids (referred to as NEAA), and 0.5 mM 2-Mecaptoethanol (referred to as 2-ME).
  • FBS Fetal Bovine Serum
  • NEAA non-essential amino acids
  • 2-ME 2-Mecaptoethanol
  • EL4 lymphoma cells were seeded into 96-well plate by 1 ⁇ 10 5 cells per well and 10 ⁇ l of the extract of A. tsao - ko HE-06 was added to each well and incubated at 37° C. in 5% CO 2 cell incubator for 1 hour. Then, Phorbol-12-myristate-13-acetate (referred to as PMA or TPA) and Ionomycin were added to be the stimulants that induce activation of lymphoma cells, in which the final concentration of PMA was 10 ng/ml and the final concentration of Ionomycin was 5 ng/ml, and additional 18 hours incubation was executed. In the above test, the group of adding both PMA (final concentration of 10 ng/ml) and Ionomycin (final concentration of 5 ng/ml) was considered as the control group.
  • PMA or TPA Phorbol-12-myristate-13-acetate
  • Ionomycin were added to be the stimulants that induce activation of lymphom
  • the cell-containing 96-well plate was centrifuged at 1200 rpm for 5 minutes and the supernatant was collected and transferred to the new 96-well plate.
  • 5 ⁇ l MTT of 5 mg/ml was added to the cells in original 96-well plate and 1 hour incubation of 37° C. and 5% CO 2 in cell incubator was executed to generate crystal violet.
  • 150 ⁇ l DMSO was then added to dissolve the crystal violet and the absorbance of 570 nm was measured to assess the cell viability.
  • mouse IL-17 ELISA kit As for the supernatant in new 96-well plate, mouse IL-17 ELISA kit (R&D, DY421E) was used to detect the IL-17 secretion, and the foregoing IL-17 amount in supernatant represents the IL-17 amount secreted by the cells.
  • the detection results of IL-17 secretion were first normalized by the control group as 100%, and IC 50 of the extract of A. tsao - ko HE-06 on inhibiting IL-17 secretion was calculated. The results were shown in Table 1.
  • the blood of SD rats was collected by means of sapheneous vein sampling and then placed in EDTA-containing centrifuge tubes (the final concentration of EDTA was 2 mg/ml) as well as mixed homogeneously. Then about 4-fold the total volume of blood and EDTA of red blood cell lysate (ACK Lysis Buffer or Red Blood Cell Lysis Buffer) was added to break the red blood cells. The reaction was carried out at 37° C. water bath for 5 minutes, and then about 4-fold the total volume of blood, EDTA and erythrocyte lysate of buffer (PBS buffer) was added and the supernatant was removed by centrifugation at 3000 rpm for 5 minutes. The foregoing step of breaking the red blood cells was repeated twice, and then centrifugation was performed to obtain the precipitated part, namely PBL. Thereafter the appropriate volume of RPMI cell culture medium was added for culture.
  • ACK Lysis Buffer or Red Blood Cell Lysis Buffer red blood cell lysate
  • PBL cells were seeded into 96-well plate by 2 ⁇ 10 5 cells per well and 10 ⁇ l of the extract of A. tsao - ko HE-06 was added to each well and incubated in 37° C. and 5% CO 2 cell incubator for 1 hour. Then, (final concentration of 10 ng/ml) and Ionomycin (final concentration of 5 ng/ml) were added to be the stimulants that induce activation of lymphoma cells, and additional 48 hours incubation was executed. In the above test, the group of adding both PMA (final concentration of 10 ng/ml) and Ionomycin (final concentration of 5 ng/ml) was considered as the control group.
  • the cell-containing 96-well plate was centrifuged at 3000 rpm for 5 minutes and the supernatant was collected and transferred to the new 96-well plate.
  • 5 ⁇ l AlamarBlue was added to the cells in original 96-well plate and additional 4 hours incubation of 37° C. and 5% CO 2 in cell incubator was executed. Then, the cell viability was assessed by ELISA reader to measure the absorbance of excitation light at 560 nm as well as the emitting light at 590 nm.
  • rat IL-17 ELISA kit (eBioscience, 88-7170) was used to detect the IL-17 secretion.
  • the detection results of IL-17 secretion were first normalized by the control group as 100%, and IC 50 of the extract of A. tsao - ko HE-06 on inhibiting IL-17 secretion was calculated. The results were also shown in Table 1.
  • IC 50 is the HE-06 concentration causing 50% IL-17 secretion inhibition.
  • IC 50 ( ⁇ g/ml) Test sample EL4 PBL HE-06 27.9 9.9
  • Example 3 The Extract of A. tsao - Ko HE-06 can Inhibit TNF- ⁇ Secretion
  • mice The 6-8 weeks BALB/c male mice were purchased from BioLASCO Taiwan Co., Ltd. In addition to make the feeding condition meeting with national experimental animal guidelines, the batch of mice were marked, sub-cage and weighing soon after acquisition. Then, these mice were placed to the quarantine room of general area for a week of quarantine work. During the quarantine period, observation of mobility and environmental adaptability was performed, and after assessment to be normal, these mice were transferred into the feeding area for experimental implementation.
  • mice were free to obtain adequate food and drinking water. Due to abundant basic references and related data have been established for this laboratory animal strain, it is applicable to inflammatory functional assessment test. The experimental methods established in the following inflammatory models have been approved by the IACUC Committee of ITRI.
  • mice were weighed and grouped so that the average body weight of each group was not significantly different. Then the mice were fasted for 2 to 4 hours but regular drinking water was still supplied. LPS stimulation, and the control group was given the same volume of solvent. After administration, the clinical symptoms of the mice were observed and recorded. Thereafter, LPS stimulation (about 0.25 ml/mouse) was conducted by IP injection. In which, the mice in experimental group were administered orally with the extract of A. tsao - ko HE-06 2 hours before LPS stimulation, and the mice in control group were administered with the same volume of solvent. After administration, the clinical symptoms of the mice were observed and recorded.
  • mice were euthanized by excessive CO 2 and the whole blood was collected by cardiac puncture blood sampling. Next, the plasma was collected after centrifugation at 6000 rpm and 4° C. for 10 minutes and then TNF- ⁇ secretion were analyzed.
  • the TNF- ⁇ secretion in plasma was analyzed according to the following procedure shown in Duoset® ELISA kit. First, 100 ⁇ l of the Capture Antibody mixture solution was added to each well of the 96-well plate at room temperature to cover the surface of each well overnight. After that, the mixture solution was dried and washed with 300 ⁇ l Wash Buffer per well three times. Next, 200 ⁇ l of Block buffer was added at room temperature for 1 hour, and the previous wash step was repeated. Thereafter, 100 ⁇ l test sample (the foregoing plasma) and standard of appropriate dilution were added to each well to stand at room temperature for 2 hours, and the aforementioned washing step was repeated.
  • Detection Antibody mixture solution 100 ⁇ l was added to each well to stand at room temperature for 2 hours, and the aforementioned washing step was repeated again. Thereafter, 100 ⁇ l of Streptavidin-HRP mixture solution was added to each well for reaction at room temperature away from light for 20 minutes. After repeating the aforementioned washing step, 100 ⁇ l of Substrate Solution (TMB) was added to each well for reaction at room temperature away from light for 20 minutes. Finally, 50 ⁇ l of Stop Solution (1N HCl) was added to each well to stop the color reaction, and the absorbance of OD 450 nm was measured.
  • TMB Substrate Solution
  • the experimental results were expressed by mean ⁇ standard error (referred to as S.E.), and t-test statistics was used to distinguish the differences between the groups. ** represents that p value of less than 0.01 and indicates that there exists a statistically significant difference between the two groups.
  • the experimental results are shown in FIG. 1 .
  • the extract of A. tsao - ko HE-06 could inhibit the secretion of TNF- ⁇ in LPS-induced acute inflammatory mice, and the inhibition level was up to 34%, indicating that the extract of A. tsao - ko HE-06 could effectively in vivo inhibit TNF- ⁇ secretion induced by inflammation.
  • Example 4 The Extract of A. tsao - Ko HE-06 can Slow Down the Progress of Experimental Autoimmune Encephalomyelitis (EAE) and Improve the Clinical Symptoms of EAE
  • mice Female C57BL/6 mice, aged about 8 weeks, were purchased from National Laboratory Animal Center (Tainan). After acclimation and quarantine, the mice were approximately 10-12 weeks of age at the time of performing the EAE experiments.
  • the experimental animals were bred in the environment: 12 hours light and 12 hours dark, room temperature of 23 ⁇ 2° C., and relative humidity of 40-70%.
  • animals were free to obtain adequate food and drinking water, but after the onset of EAE, the soaked soft feed and agar gel jelly were especially given in the bottom of the feeding cage, so that the onset animals were easier to feed and drink.
  • the animals were observed and recorded by the veterinarian and the experimental staff of ITRI to ensure health of these experimental animals.
  • mice were administered subcutaneously with 200 ⁇ l emulsion including 200 ⁇ g MOG35-55 peptide and 400 ⁇ g Mycobacterium tuberculosis H37Ra, followed by intraperitoneal injection of 500 ng pertussis toxin for induction of EAE.
  • EAE clinical symptoms were recorded daily according to the recognized Ataxia score (grading of nervous system disorder) and EAE score as the scoring criteria (description of Ataxia score and EAE score are as follows).
  • Ataxia score grade of nervous system disorder
  • EAE score as the scoring criteria
  • mice During the period, the condition of the mice was observed daily and their clinical symptoms were recorded according to the EAE score, and the group only administered with solvent was considered as the control group. Thereafter, animals were sacrificed on the 15 th day, and blood or related organs were collected for subsequent analysis.
  • Ataxia score The criteria of Ataxia score are as follows: 0+ represents that the rear foot of the animal is splayed while moving, swing left and right, and gait imbalance; 0++ represents that when grasping the rear neck of the animal to observe whether its tail can be raised by itself and to test the tensile strength of its tail by fingers, the tail appears unable to be raised by itself as well as reduced tension.
  • EAE score The criteria of EAE score are as follows: Score 0 represents no EAE symptoms; Score 0.5 represents temporal weak tail, sometimes raised; Score 1 represents limp tail, unable to lift normally; Score 2 represents paralyzed tail or slightly hind limb weakness; Score 3 represents moderate to severe hind limb paralysis or mild forelimb weakness; Score 4 represents complete hind limb paralysis or moderate to severe forelimb weakness; Score 5 represents limb paralysis accompanied by incontinence or presenting a dying state; Score 6 represents death.
  • mice after induction of EAE, the mice have been to show the clinical symptoms of hind limb paralysis and severe forelimb weakness (such as Score 4 described above) on 14 th day after onset, but administering the extract of A. tsao - ko HE-06 could significantly slow down the progress of EAE, indicating that the extract of A. tsao - ko HE-06 could effectively improve the clinical symptoms in EAE animal model.
  • the extract of A. tsao - ko , HE-06 was further extracted with a distillation step by steam for 24 hours to remove the portion of essential oil. Then, a step of heating and refluxing with a specific solvent was performed for 8 hours to remove the dregs and reduce the toxic portion.
  • the resulting extract was designated as 2015-0803-2.
  • the extract 2015-0909-2 with the better toxicity-attenuating effect was considered as the active fractional interval (I) of HE-06.
  • Example 6 The Active Fractional Interval (I) of HE-06 can Improve the Clinical Symptoms of EAE
  • the active fractional interval (I) of HE-06 was replaced with the active fractional interval (I) of HE-06 and the administered active fractional interval (I) of HE-06 with the concentration of 0 mg/ml (as the control group or vehicle), 30 mg/ml, and 100 mg/ml
  • the experimental animals, the established of mouse autoimmune EAE model, and the scoring criteria are the same as described above, and will not repeat them here.
  • the experimental results were shown in FIG. 3A-3E . In which the group administered with solvent of the equal volume was considered as the control group, and the group administered with 5 mg/ml methylprednisolone (a steroid medication, can be used for anti-inflammation) was considered as the positive control group.
  • mice after induction of EAE, the mice have been appeared the clinical symptoms of hind limb paralysis and severe forelimb weakness (such as Score 4 described above) on 14 th day after onset, but administration of the active fractional interval (I) of HE-06 with the concentration of 30 mg/ml and 100 mg/ml could significantly slow down the progress of EAE.
  • * represents p value of less than 0.05
  • ** represents p value of less than 0.01
  • *** represents p value of less than 0.001.
  • LLB Luxol fast blue stain
  • myelin is a tubular sheath that is wrapped outside the axons of the neuronal cell, the integrity of the myelin under normal or pathological conditions can be observed by performing the myelin staining.
  • the active fractional interval (I) of HE-06 could significantly improve the symptom of demyelination of cervical vertebrae in EAE animal model.
  • the condition of the spinal cord was checked with the guidelines of Histopathological Lesion Severity Scores in the literature published by Shackelford et al.
  • the histopathological grade and the degree of myelination damage of the spinal cord including cervical vertebrae, thoracic vertebrae and lumbar vertebrae were evaluated by a pathologic veterinarian.
  • the grade of histopathology is divided into five grades: Grade 1 represents the smallest damage (overall damage area ⁇ 1%); Grade 2 represents minor damage (approximately 1-25% of total damage area); Grade 3 represents moderate Grade 4 represents moderate to severe injury (approximately 51-75% of total damage area); Grade 5 represents severe injury (approximately 76-100% of total damage area).
  • FIGS. 3D and 3E The observed and scored results were shown as FIGS. 3D and 3E .
  • the mice After induction of EAE, the mice have been to show the clinical symptoms of demyelination of spinal cord and axonal swelling on 14 th day after onset, but administering the active fractional interval (I) of HE-06 with the concentration of 30 mg/ml and 100 mg/ml could significantly reduce the degree of damage of the spinal cord in EAE animal model.
  • * represents p value of less than 0.05
  • ** represents p value of less than 0.01.
  • Example 8 The Active Fractional Interval (II) of HE-06 can Inhibit IL-17 and TNF- ⁇ Secretion
  • the active fractional interval (II) of HE-06 could inhibit the secretion of TNF- ⁇ in LPS-induced acute inflammatory mice, and the inhibition level was about 16%, indicating that the active fractional interval (II) of HE-06 could in vivo inhibit TNF- ⁇ secretion induced by inflammation.
  • Example 9 The Active Fractional Interval (II) of HE-06 can Improve the Clinical Symptoms of EAE
  • the active fractional interval (II) of HE-06 was replaced with the active fractional interval (II) of HE-06 and the administered active fractional interval (II) of HE-06 with the concentration of 0 mg/ml (as the control group or vehicle), 30 mg/ml, 100 mg/ml and 300 mg/ml, the experimental animals, the established mouse autoimmune EAE model, and the scoring criteria are the same as described above, and will not repeat them here.
  • the experimental results were shown in FIG. 4B , and the group to be administered with equal volume of solvent was considered as the control group.
  • Example 10 The Active Fractional Interval (II) of HE-06 can Alleviate the Symptom of Imiquimod (IMQ)-Induced Psoriasis-Like Dermatitis
  • mice The 8 weeks BALB/c male mice were purchased from BioLASCO Taiwan Co., Ltd. After acclimation and quarantine, the batch of mice were approximately 9-10 weeks of age at the time of performing the experiment of IMQ-induced psoriasis-like dermatitis.
  • the experimental animals were bred in the environment: 12 hours light and 12 hours dark, room temperature of 23 ⁇ 2° C., and relative humidity of 40-70%. During feeding, animals were free to obtain adequate food and drinking water. In addition, during the quarantine and testing period, the animals were observed and recorded by the veterinarian and the experimental staff of ITRI to ensure health of these experimental animals.
  • mice were weighed and grouped so that the average body weight of each group was not significantly different. Then, the hair on the back of each mouse was shaved, and the shaving area was about 4*2 cm 2 . Since day 0, 3.125 mg imiquimod (IMQ) was administered by smearing to the skin of shaved area of each mouse daily for consecutive 6 days. At the same time, the active fractional interval (II) of HE-06 or solvent was also administered by performing tube feeding (10 ml/kg) or skin smearing (about 30 ⁇ 50 mg/mouse) for 6 days, and these mice were sacrificed on the 6 th day with excess CO 2 .
  • IMQ 3.125 mg imiquimod
  • II active fractional interval
  • Scale 0-4 is defined as follows: Scale 0 represents no obvious symptoms, Scale 1 represents mild symptoms, Scale 2 represents moderate symptoms, Scale 3 represents moderate to severe symptoms, and Scale 4 represents severe symptoms.
  • mice As shown in FIG. 4C , after induction of psoriasis-like dermatitis by IMQ, the mice have been appeared the clinical symptoms of psoriasis-like dermatitis on 2 nd day after induction, such as erythematous skin, uneven thickness, and wrinkled dander, but administration of the active fractional interval (II) of HE-06 could alleviate the clinical symptoms of IMQ-induced psoriasis-like dermatitis.
  • II active fractional interval
  • Example 11 Isolation and Preparation of the Active Ingredient Compound, Vanillin or Tsaokoin (TK), of HE-06
  • the extract of A. tsao - ko , HE-06 was first extracted with a distillation step by steam for 24 hours to remove the portion of essential oil. Then, a step of heating and refluxing with a low polarity solvent was performed for 8 hours. Thereafter, the extract was eluted by gradient elution with n-Hexane, EtOAc and MeOH, and the step of Silica Gel Column Chromatography was further performed. Each fraction was analyzed and separated by TLC and the active fraction was checked by performing the activity test. Further, two compounds were isolated from the active fraction and determined to be vanillin and tsaokoin after analysis. Then, the fraction containing either vanillin or tsaokoin component was combined respectively to obtain the active ingredient compound vanillin and tsaokoin of HE-06.
  • Example 12 The Active Ingredient Compound Tsaokoin (TK) can Inhibit IL-17 and TNF- ⁇ Secretion
  • IC 50 is the concentration of TK causing 50% IL-17 secretion inhibition.
  • TNF- ⁇ secretion was shown in FIG. 5B .
  • the active ingredient compound tsaokoin (TK) of HE-06 could significantly inhibit the secretion of TNF- ⁇ in LPS-induced acute inflammatory mice, indicating that TK could in vivo inhibit TNF- ⁇ secretion induced by inflammation.
  • TK represents p value of less than 0.001.
  • Example 13 The Active Ingredient Compound Tsaokoin (TK) can Improve the Clinical Symptoms of EAE
  • TK active ingredient compound tsaokoin
  • the administered tsaokoin with the concentration of 0 mg/ml (as the control group or vehicle), 30 mg/ml, and 100 mg/ml
  • the experimental animals, the established mouse autoimmune EAE model, and the scoring criteria are the same as described above, and will not repeat them here.
  • the experimental results were shown in FIG. 5C , and the group to be administered with equal volume of solvent was considered as the control group.
  • mice after induction of EAE, the mice have been appeared the clinical symptoms of hind limb paralysis and severe forelimb weakness as above described Score 4 on 14 th day after onset, but administration of tsaokoin with the concentration of 30 mg/ml and 100 mg/ml could slow down the progress of EAE, and present a dose-dependent effect, indicating that tsaokoin can effectively improve the clinical symptoms in EAE animal model.
  • * represents p value of less than 0.05
  • ** represents p value of less than 0.01
  • *** represents p value of less than 0.001.
  • Example 14 The Active Ingredient Compound Tsaokoin (TK) can Alleviate the Symptom of Imiquimod (IMQ)-Induced Psoriasis-Like Dermatitis
  • mice As shown in FIG. 5D , after induction of psoriasis-like dermatitis by IMQ, the mice have been appeared the clinical symptoms of psoriasis-like dermatitis on 2 nd day after induction, such as erythematous skin, uneven thickness, and wrinkled dander, but administration of tsaokoin could significantly alleviate the clinical symptoms of IMQ-induced psoriasis-like dermatitis.
  • * represents p value of less than 0.05
  • ** represents p value of less than 0.01.

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