WO2016192098A1 - Pharmaceutical composition containing acarbose and use thereof in regulating immunization - Google Patents

Pharmaceutical composition containing acarbose and use thereof in regulating immunization Download PDF

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Publication number
WO2016192098A1
WO2016192098A1 PCT/CN2015/080849 CN2015080849W WO2016192098A1 WO 2016192098 A1 WO2016192098 A1 WO 2016192098A1 CN 2015080849 W CN2015080849 W CN 2015080849W WO 2016192098 A1 WO2016192098 A1 WO 2016192098A1
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pharmaceutical composition
acarbose
disease
treating
drug
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PCT/CN2015/080849
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French (fr)
Chinese (zh)
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陈信华
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台中荣民总医院
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Priority to CN201580063655.6A priority Critical patent/CN107106583B/en
Priority to PCT/CN2015/080849 priority patent/WO2016192098A1/en
Publication of WO2016192098A1 publication Critical patent/WO2016192098A1/en

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    • 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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/702—Oligosaccharides, i.e. having three to five saccharide radicals attached to each other by glycosidic linkages

Definitions

  • the present invention relates to a novel use comprising acarbose, in particular for the use of acarbose for the modulation of immunity or for the treatment of immunoinflammatory conditions.
  • Immune inflammation is characterized by the body's immune response being improperly activated.
  • the immune system does not attack infected foreign objects, but attacks and damages the body's own tissues or transplanted tissues. Tissues attacked by the immune system vary from disease to disease. For example, in multiple sclerosis, the immune response is against nerve tissue, while Crohn's disease is against the digestive tract.
  • Immune inflammatory diseases inflict millions of people, including diseases such as asthma, allergic intraocular inflammation, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatitis, inflammatory Intestinal or gastrointestinal disorders (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritus/inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus erythematosus.
  • diseases such as asthma, allergic intraocular inflammation, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatitis, inflammatory Intestinal or gastrointestinal disorders (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritus/inflammation, psoriasis, rheumatoid arthritis
  • a drug for treating type 2 diabetes acarbose, which is a glucosidase inhibitor drug, and ⁇ -glucosidase on intestinal villi Reversible competitive inhibition to slow down the decomposition of sugars in the small intestine, therefore, delaying the absorption of sugars to avoid the phenomenon of post-prandial hyperglycemia, and achieving a smoother postprandial glycemic control;
  • acarbose which is a glucosidase inhibitor drug
  • ⁇ -glucosidase on intestinal villi Reversible competitive inhibition to slow down the decomposition of sugars in the small intestine
  • the invention provides a pharmaceutical composition for treating an immunoinflammatory condition comprising acarbose.
  • the immune inflammatory condition is: rheumatoid arthritis, cognac, type 1 diabetes, adult sexual history, optic neuromyelitis, Crohn's disease, ulcerative colitis, Asthma, chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arteritis, systemic lupus erythematosus, Atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis, cirrhosis or dryness arthritis.
  • the pharmaceutical composition of the present invention may further comprise a second drug; wherein the second drug is preferably selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, Biomolecules, immunomodulators, small molecule immunomodulators, disease modifying antirheumatic drugs (DMARD), jaundice, anticholinergic compounds, beta receptor synergists, bronchodilators, nonsteroidal immunoaffinity protein-dependent immunosuppressants , a group of vitamin D analogs, psoralen, vitamin A acid and 5-aminosalicylic acid.
  • NSAID non-steroidal anti-inflammatory drug
  • the pharmaceutical composition may be in any dosage form, preferably in the form of a lozenge or capsule.
  • the pharmaceutical composition is formulated for topical administration or systemic administration.
  • Another aspect of the invention is the use of acarbose for the preparation of an immunomodulatory drug.
  • Figure 1A A comparison of the incidence of CIA in the experimental and control groups of CIA mice
  • Figure 1B is a graph showing the comparison of the number of diseased feet in the experimental group and the control group of CIA mice;
  • Figure 1C Photograph of the sole of the foot in the experimental group and the control group of the CIA mouse
  • Figure 1D Comparison of arthritis scores between the experimental group and the control group of CIA mice
  • FIG. 1E Histological (H&E) photograph of the ankle joint in the experimental and control groups of CIA mice;
  • Figure 1F shows a histological comparison of infiltration, synovial hyperplasia, and bone erosion of the ankle joint in the experimental and control groups of CIA mice;
  • Figure 2A shows the content of selective cytokines in the paw tissue of the CIA mouse experimental group and the control group by ELISA;
  • Figure 2B shows the content of selective cytokines in serum in the CIA mouse experimental group and the control group by ELISA
  • Figure 3A Comparison of anti-CII IgG in the experimental and control groups of CIA mice
  • Figure 3B Comparison of CII antigen-stimulated proliferation in CIA mice experimental group and control group
  • Figure 3C shows different cells of lymphocyte supernatant in CIA mice experimental group and control group Hormone content comparison chart
  • Figure 4A Comparison of the efficacy of tofarinib 1 mg/kg/day, 5 mg/kg/day, 25 mg/kg/day dose on CIA mice;
  • Figure 4B Comparison of the efficacy of tofacitinib 1 mg/kg/day, acarbose 500 mg/kg/day, acarbose 500 mg/kg/day and tofacitinib 1 mg/kg/day for CIA mice Figure
  • Figure 4C Comparison of the efficacy of tofacitinib 5 mg/kg/day, acarbose 500 mg/kg/day, acarbose 500 mg/kg/day combined with tofacitinib 5 mg/kg/day for CIA mice Figure
  • Fig. 5A is a photograph showing the skin of an experimental group and a control group which were induced by imiquimod 62.5 mg/kg/day and dried with acarbose 500 mg/kg/day;
  • Fig. 5B is a graph showing the comparison of clinical characterization scores between the experimental group and the control group which were induced by imiquimod 62.5 mg/kg/day and dried with acarbose 500 mg/kg/day;
  • FIG. 6A Control group cream induced skin histology (H&E) photos of dried mice;
  • FIG. 6B imiquimod-induced skin histology (H&E) photographs of dried mice
  • Figure 6C H&E photographs of mice treated with imiquimod-induced dryness and acarbose 50 mg/kg/day;
  • Figure 6D H&E photographs of mice treated with imiquimod induced dry acarbose 50 mg/kg/day.
  • the present invention provides a pharmaceutical composition for treating an immunoinflammatory condition comprising acarbose and an acarbose for use in the preparation of an immunomodulatory drug.
  • treating means administering or prescribing a composition to a patient to treat or prevent an immunoinflammatory condition.
  • patient is meant herein any animal (eg, human).
  • Other animals which can be treated by the methods, compositions and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish and bird.
  • immune inflammatory condition includes many conditions including, but not limited to, autoimmune diseases, proliferative skin diseases, and inflammatory eczema. Immune inflammatory conditions can cause the body's healthy tissues to be destroyed by the inflammatory process, the immune system to lose control, and the unwanted cells to proliferate.
  • Immunoinflammatory conditions such as acne vulgaris; acute dyspnea syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammation, ANCA-related small-vascular vasculitis; ankylosing spondylitis; arthritis Asthma; atherosclerosis; atopic dermatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous pemphigoid Cerebral ischemia; chronic obstructive pulmonary disease; cirrhosis; Cogan's syndrome; contact skin disease; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis; Lupus; eosinophilic fasciitis; erythematous nodules; exfoliative dermatitis; fibromyalgia; glomerular sclerosis; giant cell arteritis; gout; gouty arthritis; Eczema; Henoch-Schonlein purpura;
  • the immunoinflammatory condition comprises rheumatoid arthritis, cognac, type 1 diabetes, adult sexual history, optic neuromyelitis, Crohn's disease, ulcerative colitis, asthma , chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis, cirrhosis or dryness Arthritis or other immunoinflammatory condition associated with dysregulation of the cytokine IL-17.
  • non-skin inflammatory condition includes, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
  • skin inflammatory condition or "inflammatory dermatitis” as used herein includes, for example, psoriasis, acute heat neutrophilic skin disease, eczema (eg, arrhythmia eczema, sweat rash, eczema at the small cystic sac), plasma cell limitation.
  • eczema eg, arrhythmia eczema, sweat rash, eczema at the small cystic sac
  • plasma cell limitation e.g, plasma cell limitation.
  • Penile head inflammation penile head dermatitis, Beth's disease (Behcet's condition), eccentric ring erythema, persistent pigmented erythema, polymorphous erythema, ring granuloma, lustrous moss, lichen planus, hardened atrophic moss Chronic simple moss, small spine moss, money-like dermatitis, gangrenous pyoderma, sarcoma, subcorneal impetigo, urticaria and transitional echinodermitis.
  • "Proliferative skin disease” means a benign or malignant disease characterized by accelerated cell division of the epithelium or epidermis.
  • proliferative skin diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell skin cancer, stratified scales, and epidermal keratinization Excessive symptoms, premalignant keratosis, acne and seborrheic dermatitis.
  • proliferative skin diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell skin cancer, stratified scales, and epidermal keratinization Excessive symptoms, premalignant keratosis, acne and seborrheic dermatitis.
  • a particular disease, condition or condition can be characterized as both proliferative skin disease and inflammatory eczema.
  • An example of this disease is psoriasis.
  • the pharmaceutical composition of the present invention may further comprise a second drug.
  • the second drug is preferably selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, a biomolecule, an immunomodulator, a small molecule immunomodulator, a disease modifying antirheumatic drug (DMARD), and jaundice.
  • NSAID non-steroidal anti-inflammatory drug
  • COX-2 inhibitor a COX-2 inhibitor
  • biomolecule e.g., a COX-2 inhibitor
  • an immunomodulator e.g., a small molecule immunomodulator
  • DMARD disease modifying antirheumatic drug
  • jaundice e.g., anticholinergic compound, ⁇ -receptor synergist, bronchodilator, non-steroid immunoaffinity protein-dependent immunosuppressant, vitamin D analog, psoralen, vitamin A acid and 5-aminosalicylic acid Group.
  • non-steroidal anti-inflammatory drugs includes, but is not limited to, sodium naproxen, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen. , nabumetone, choline magnesium salicylate, sodium salicylate, salicylic acid salicylic acid (sallium), phenoxyprofen, flurbiprofen, ketoprofen, A Sodium chlorfenate, meloxicam, oxaprozin, sulindac and tolmetine.
  • disease-modifying antirheumatic drug includes, but is not limited to, Methotrexate, Azathioprine, Leflunomide, Sulfasalazine, Hydroxychloroquine. ), Tofatinib (Tobactinib).
  • immunomodulator includes, but is not limited to, cyclosporin, imiquimod.
  • antihistamine as used herein means a compound which blocks the action of histamine.
  • Antihistamine types include, but are not limited to, ethanolamine, ethylenediamine, phenothiazine, alkylamine, piperazine, and piperidine.
  • non-steroidal immunoaffinity protein-associated immunosuppressive agent or “NsIDI” as used herein means any non-steroidal agent that reduces the production or secretion of primary inflammatory cytokines, binds to immunoaffinity proteins, or causes a primary inflammatory response. Down regulation. NsIDI includes calcium calcineurin inhibitors such as cyclosporine, heparin (licrolimus), ascomycin, pimecrolimus and other phospholyase activities that inhibit calcineurin Agent (peptide, peptide fragment, chemically modified peptide or peptide mimetic).
  • calcium calcineurin inhibitors such as cyclosporine, heparin (licrolimus), ascomycin, pimecrolimus and other phospholyase activities that inhibit calcineurin Agent (peptide, peptide fragment, chemically modified peptide or peptide mimetic).
  • NsIDI also includes rapamycin (sirolimus) and everolimus, which binds to FK506-binding protein, FKBP-12, and blocks antigen-induced hyperplasia of leukocytes. And cytokine secretion.
  • small molecule immunomodulator as used herein means a non-steroidal, non-NsIDI compound that reduces the production or secretion of primary inflammatory cytokines, leading to downregulation of the primary inflammatory response, or by immunoaffinity protein-non-dependent The way to regulate the immune system.
  • small molecule immunomodulators are p38 MAP kinase inhibitors such as VX 702 (Vertex Pharmaceuticals), SCIO 469 (Scios), doramapimod (Boehringer Ingelheim), RO 30201195 (Roche) and SCIO 323 ( Scios), TACE inhibitors such as DPC 333 (Bristol Myers Squibb), ICE inhibitors such as pranalcasan (Vertex Pharmaceuticals), IMPDH inhibitors such as mycophenolate (Roche) and Meli Merimepodib (Vertex Pharamceuticals).
  • the dosage of the pharmaceutical composition of the present invention can be adjusted to the condition of the patient according to the skilled person, providing a sufficient amount of the active ingredient, or alternatively a low dose, a medium dose or a high dose.
  • the dose effect administered can be judged by a skilled physician using any standard method suitable for the intended indication.
  • the term "low dose” means at least 5% lower than the minimum recommended recommended dose for a particular compound (to treat any human condition in a given path) (eg, at least 10%, 20%, 50%, 80%, 90%) Or even 95%)
  • a low dose of a corticosteroid administered by inhalation is different from a low dose of a corticosteroid administered orally.
  • high dose means a dose that is at least 5% higher than the highest standard recommended for a particular compound (to treat any human condition) (eg, at least 10%, 20%, 50%, 100%, 200%, or even 300). %).
  • Medium dose means that the dose is between a low dose and a high dose.
  • sufficient amount means the amount of the combination of the compounds of the present invention which is required to treat or prevent immune inflammation in a clinically relevant manner.
  • the amount of active compound used to practice the present invention to treat an immune inflammatory disease varies depending on the mode of administration, age, weight, and general health of the patient.
  • Specific routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, topical administration, transdermal and systemic administration (for example, intravenous, intramuscular, inhalation, rectal, collar, vaginal, intraperitoneal, Intra-articular, intraocular or oral administration). Any of the aforementioned routes of administration can be administered in conjunction with conventional drugs for treating immunoinflammatory conditions.
  • the pharmaceutical composition of the present invention may be in any of various forms such as tablets, capsules, pills, powders, granules, suspensions, emulsifiers, solutions, gels (including hydrogels), pastes, ointments, creams, Plaster, infusion, osmotic delivery, suppository, enema, injection, implant, spray or aerosol.
  • Such compositions may be formulated according to conventional pharmaceutical specifications, preferably oral dosage forms such as tablets, capsules, or syrups; or rectal administration, such as suppositories; or other dosage forms, such as sustained release or sustained release dosage forms, and the like. .
  • each compound can be formulated by methods known in the art.
  • the first and second medicaments can be formulated simultaneously or separately.
  • the first and second medicaments are administered simultaneously or nearly simultaneously; if administered simultaneously, they may be formulated together in the same pill, capsule, liquid, and the like.
  • the pharmacokinetic profile of each agent can be appropriately matched.
  • Individual or separately formulated medicaments can be packaged together into a single kit.
  • An unrestricted kit embodiment includes, for example, two pills, one pill and powder, a suppository and a vial solution, and two external creams.
  • the kit can include optional accessories that will help the patient to be administered
  • the unit dose, ingredients include, for example, vials for infusion powders, syringes, custom IV delivery systems, inhalants, and the like.
  • the unit dose kit can include instructions for preparing and administering the composition.
  • the kit can be manufactured as a single dose for one patient, multiple doses for a particular patient (which can be the same dose or the effectiveness of individual compounds as the treatment progresses); or the kit can include multiple patients Multiple doses administered ("big package").
  • the kit can be combined in a carton, blister pack, bottle, tube, and the like.
  • sustained release or “controlled release” means that the therapeutically active ingredient is released from the formulation at a controlled rate such that the ingredient is prolonged ( For example, about 12-24 hours) maintain therapeutically effective blood levels (below the level of toxicity) so that a 12 hour or 24 hour dosage form can be made.
  • the data source was a population-based, matched case-control study using the National Health Insurance Research Database (NHIRD) 1999-2011 from Taiwan.
  • NHIRD National Health Insurance Research Database
  • the NHIRD randomly selected millions of participants in 2000 to form a representative database containing potentially disabling autoimmune diseases, including rheumatoid arthritis (RA).
  • RA rheumatoid arthritis
  • the diagnosis of RA was further verified by the American College of Rheumatology RA Classification Standard (1987).
  • the patient was initially diagnosed with Diabetes Day [International Classification Disease, Ninth Revision, Clinical Revision (ICD9-CM) Code 250.x] after January 1, 2000, and at the same time prescribe any antidiabetic drug for ⁇ 28 days. Listed as DM patients.
  • the DM diagnostic date is used to measure the duration of the DM course as the time to prescribe the initial antidiabetic drug.
  • RA Rheumatoid arthritis
  • Non-rheumatoid arthritis (non-RA) control group
  • acarbose, metformin, thiazolidinedione (TZD), insulin or sulfonylurea/glinide were used for 28 days or more in one year before the date of the indicator.
  • Acarbose users are classified as high-dose users and low-dose users based on the median annual cumulative dose.
  • DM duration Geographical areas, DM duration, and DM terminal organ disease (ICD9-CM code 250.1-9) are listed as potential disruptors. The geographical area was chosen because it was found in the previous study that the RA risk was related. In addition, DM duration and DM terminal organ disease represent the severity of DM. The DM duration is defined as the period from the date of the initial antidiabetic drug to the date of the indicator. Other interfering factors include the Charlson comorbidity index (CCI) rewritten by Deyo et al. (Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.J Clin Epidemiol.
  • CCI Charlson comorbidity index
  • Table 3 Single variable related to the risk of rheumatoid arthritis and newly treated diabetic patients And multivariate adjustment odds ratio 95% confidence interval
  • Example 2 Mouse experiment confirmed acarbose treatment of rheumatoid arthritis
  • mice from each group obtained representative ankle joints on day 38 and fixed, decalcified and embedded in paraffin.
  • Each joint section (5M) was stained with hematoxylin and eosin (H&E) followed by a conventional method (Wooley PH. Collagen-induced arthritis in the mouse. Methods Enzymol. 1988; 162: 361-373.) Observed by a microscope. Synovial hyperplasia, cell infiltration, cartilage destruction, and histopathological changes of bone erosion were blindly graded by pathologists and given 0-3 points according to the following criteria, 0: no change; 1: mild change; 2: moderate Change; 3: Severe change.
  • Each group collected mouse paw tissue on day 38 and frozen in liquid nitrogen, expelling the sample to contain PBS in the protease inhibitor to homogenize the tissue homogenizer. The homogenate was centrifuged for 30 minutes, and the supernatant was collected and diluted to 1 mg/ml tissue protein per ml as a stock solution. The contents of TNF-a, IL-1b, IL-6, IFN-g, IL-17, IL-10 and TGF-b (R&D Systems) were determined in an ELISA kit (Peprotech).
  • mice were bled on day 38 after CII immunization and their serum was analyzed by ELISA titration using anti-CII IgG antibodies. Briefly, each well of an ELISA microplate (Thermo Fisher Scientific, NY, USA) was coated with 10 ⁇ g/200 ml of type II chicken collagen and incubated overnight at 4 °C. To avoid non-specific binding, the antibodies were washed and blocked with 3% bovine serum albumin (BSA) (BD Biosciences) in Tris buffer; the test sera were serially diluted and incubated overnight at 4 °C in a well plate.
  • BSA bovine serum albumin
  • the bound IgG was detected by diluting 1:5000 with HRP-conjugated sheep anti-mouse IgG as a secondary antibody; after washing, the well plate was ABTS (Roche Diagnostic Systems, IN, USA) was used as a matrix reaction, and the reaction was stopped with H 2 SO 4 , and the absorbance was measured at 450 nm with an ELISA reader.
  • CIA has been widely used to cause arthritis that exhibits the pathological features of human RA.
  • acarbose can prevent progression of CIA in the DBA/1 mouse model.
  • water-administered CIA mice control group
  • mice treated with 500 mg/kg/day acarbose had a significant reduction in the incidence of CIA (Fig. 1A) and the number of diseased feet (Fig. 1B), and visual confirmation
  • Fig. 1C erythema and joint stiffness in the hind paw
  • Fig. 1D arthritis score
  • oral treatment with acarbose 100 mg/kg/day had no significant development and severity in CIA. effect.
  • Hormones such as TNF-alpha, IL-6 and IL-17 are significantly reduced.
  • mice were randomly divided into four groups, and a dose of 1 mg/kg/day, a dose of 5 mg/kg/day, a dose of 25 mg/kg/day of tofacitinib, and water were used as a control group, respectively.
  • Two doses were administered daily from 7 to 38 days after the first immunization; the clinical characterization of the severity of mouse paw arthritis was performed using a conventional scoring system.
  • mice were randomized into four groups, each receiving a dose of 1 mg/kg/day of tofacitinib, a dose of 500 mg/kg/day of acarbose, and a dose of 1 mg/kg/day.
  • Tofacitinib combined with a 500 mg/kg/day dose of acarbose and water as a control group, administered twice daily for 7 to 38 days after the first immunization; clinical characterization of the severity of arthritis in the paw of mice With a conventional scoring system.
  • the general acarbose is used to treat the second type diabetes dose, which is better than the dose of 1 mg/kg/day of tofacitinib which is generally used for the treatment of rheumatoid arthritis. Efficacy; and when combined, the effect is better than single administration.
  • acarbose 500 mg/kg/day and tofacitinib 5 mg/kg/day can be used for the treatment of rheumatoid arthritis; and when the two are combined, the effect is more remarkable.
  • Cognac mice were obtained by conventional techniques. Briefly, after removing the hair on the back of the mouse, 62.5 mg of commercially available imiquimod (IMQ) ointment ((Aldara; 3M Pharmaceuticals) was applied daily on the back of the mouse. After a total of 6 days, on the 7th day, the mice were photographed and sacrificed, and the back skin was taken out for section analysis. Acarbose was started one week before the start of the application of imiquimod (IMQ) ointment. Oral feeding until the end of the experiment (Day 6), the dose was 500 mg / kg or 100 mg / kg.
  • IMQ imiquimod
  • the clinical scoring standard is based on the clinical Psoriasis Area and Severity Index (PASI), which is mainly classified into five grades according to its erythema and scaling. 0 means no change, 1 to 4 points, the higher the score, the more serious the erythema and desquamation.
  • PASI clinical Psoriasis Area and Severity Index
  • mice inducing dryness with imiquimod (IMQ) 62.5 mg/kg/day had a remarkable therapeutic effect after administration of acarbose 500 mg/kg/day.
  • acarbose 500mg/kg can significantly slow down the imiquimod (IMQ)-induced mice, resulting in epidermal hypertrophy (acanthosis), thickening of the stratum corneum, and Remaining nuclei and parakeratosis.
  • acarbose can be used for the treatment of rheumatoid arthritis, dryness and other immune inflammatory diseases, and it is confirmed that it can regulate the effect of IL-17, so it can be more widely used with IL- 17 related immune inflammatory conditions.

Abstract

Disclosed is a pharmaceutical composition containing acarbose and the use thereof in preparing medicine for treating immune and inflammatory diseases.

Description

包含阿卡波糖之医药组合物及其用于免疫调节之用途Pharmaceutical composition containing acarbose and its use for immunomodulation 技术领域Technical field
本发明关于一包含阿卡波糖的新用途，特别是阿卡波糖用于调节免疫或治疗免疫发炎病症的新用途。The present invention relates to a novel use comprising acarbose, in particular for the use of acarbose for the modulation of immunity or for the treatment of immunoinflammatory conditions.
背景技术Background technique
免疫发炎之特征为身体的免疫反应被不当地活化。免疫***不对感染外来物加以攻击，而对身体本身的组织或移植组织加以攻击与损害。被免疫***攻击之组织因疾病有所不同。例如，于多发性硬化症，免疫反应系对抗神经组织，而克隆氏症，则对抗消化道。免疫炎症疾病侵扰数百万人，且包括的病症例如有气喘、过敏性眼内炎症、关节炎、异位性皮肤炎、异位性湿疹、糖尿病、溶血性贫血、发炎性皮肤炎、发炎性肠道或胃肠病症(例如，克隆氏症及溃疡性大肠炎)、多发性硬化症、重症肌无力、搔痒症/发炎、牛皮癣、类风湿性关节炎、肝硬化及全身性红斑狼疮。Immune inflammation is characterized by the body's immune response being improperly activated. The immune system does not attack infected foreign objects, but attacks and damages the body's own tissues or transplanted tissues. Tissues attacked by the immune system vary from disease to disease. For example, in multiple sclerosis, the immune response is against nerve tissue, while Crohn's disease is against the digestive tract. Immune inflammatory diseases inflict millions of people, including diseases such as asthma, allergic intraocular inflammation, arthritis, atopic dermatitis, atopic eczema, diabetes, hemolytic anemia, inflammatory dermatitis, inflammatory Intestinal or gastrointestinal disorders (eg, Crohn's disease and ulcerative colitis), multiple sclerosis, myasthenia gravis, pruritus/inflammation, psoriasis, rheumatoid arthritis, cirrhosis, and systemic lupus erythematosus.
目前对免疫发炎疾病已有多种药物开发，但该等药剂之效果不一且常会伴随有不佳的副作用。故，需要有对于免疫炎症疾病治疗更好的治疗药剂及方法。A variety of drugs have been developed for immunoinflammatory diseases, but the effects of these agents are different and often accompanied by poor side effects. Therefore, there is a need for better therapeutic agents and methods for the treatment of immune inflammatory diseases.
发明内容Summary of the invention
鉴于上述问题，本案发明人意外的发现，已知用于治疗第二型糖尿病的药物，阿卡波糖，其系一种葡萄糖苷酶抑制剂类药物，与小肠绒毛上的α-葡萄糖苷酶作可逆性的竞争抑制，以减缓醣类在小肠内的分解，因此，可延迟醣类的吸收，以避免饭后高血糖值的现象，而达到较平稳的饭后血糖控制；经本发明之实验后发现具有调节免疫的功能，而能够用于治疗免疫发炎病症。In view of the above problems, the inventors of the present invention unexpectedly discovered that a drug for treating type 2 diabetes, acarbose, which is a glucosidase inhibitor drug, and α-glucosidase on intestinal villi Reversible competitive inhibition to slow down the decomposition of sugars in the small intestine, therefore, delaying the absorption of sugars to avoid the phenomenon of post-prandial hyperglycemia, and achieving a smoother postprandial glycemic control; After the experiment, it was found to have the function of regulating immunity, and can be used for treating an immunoinflammatory condition.
因此，本发明一方面系提供一种用于治疗免疫发炎病症之医药组合物，其包含阿卡波糖(acarbose)。Accordingly, in one aspect, the invention provides a pharmaceutical composition for treating an immunoinflammatory condition comprising acarbose.
在本发明之一实施例中，该免疫发炎病症为：类风湿性关节炎、干癣、第一型糖尿病、成人性史底耳氏症、视神经脊髓炎、克隆氏症、溃疡性大肠炎、气喘、慢性阻塞性肺病、风湿性多肌痛症、巨细胞动脉炎、全身性红斑狼疮、 异位性皮肤炎、多发性硬化症、重症肌无力、牛皮癣、僵直性脊椎炎、肝硬化或干癣性关节炎。In one embodiment of the present invention, the immune inflammatory condition is: rheumatoid arthritis, cognac, type 1 diabetes, adult sexual history, optic neuromyelitis, Crohn's disease, ulcerative colitis, Asthma, chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arteritis, systemic lupus erythematosus, Atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis, cirrhosis or dryness arthritis.
于本发明之一较佳实施例中，本发明之医药组合物可进一步包含一第二药物；其中该第二药物较佳系选自由非类固醇抗发炎药(NSAID)、COX-2抑制剂、生物分子、免疫调节剂、小分子免疫调节剂、疾病修饰抗风湿药(DMARD)、黄嘌呤、抗胆碱化合物、β受体协同剂、支气管扩张剂、非类固醇免疫亲和蛋白依存免疫抑制剂、维生素D类似物、补骨脂素、维生素A酸及5-胺基水杨酸所构成之群。于一更佳实施例中，该疾病修饰抗风湿药(DMARD)为托法替尼(tobactinib)。In a preferred embodiment of the present invention, the pharmaceutical composition of the present invention may further comprise a second drug; wherein the second drug is preferably selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, Biomolecules, immunomodulators, small molecule immunomodulators, disease modifying antirheumatic drugs (DMARD), jaundice, anticholinergic compounds, beta receptor synergists, bronchodilators, nonsteroidal immunoaffinity protein-dependent immunosuppressants , a group of vitamin D analogs, psoralen, vitamin A acid and 5-aminosalicylic acid. In a more preferred embodiment, the disease modifying antirheumatic drug (DMARD) is tobactinib.
于本发明之实施例中，该医药组合物可为任何剂型，较佳系呈锭剂或胶囊之型式。于另一较佳实施例中，该医药组合物配方为局部投予用药或全身投予用药。In an embodiment of the invention, the pharmaceutical composition may be in any dosage form, preferably in the form of a lozenge or capsule. In another preferred embodiment, the pharmaceutical composition is formulated for topical administration or systemic administration.
本发明之另一方面系一种阿卡波糖供制备免疫调节药物之用途。Another aspect of the invention is the use of acarbose for the preparation of an immunomodulatory drug.
附图说明DRAWINGS
图1A：显示CIA小鼠实验组与对照组中，CIA发生率比较图；Figure 1A: A comparison of the incidence of CIA in the experimental and control groups of CIA mice;
图1B：显示CIA小鼠实验组与对照组中，患病脚掌数量比较图；Figure 1B is a graph showing the comparison of the number of diseased feet in the experimental group and the control group of CIA mice;
图1C：显示CIA小鼠实验组与对照组中，脚掌照片图；Figure 1C: Photograph of the sole of the foot in the experimental group and the control group of the CIA mouse;
图1D：显示CIA小鼠实验组与对照组中，关节炎评分比较图；Figure 1D: Comparison of arthritis scores between the experimental group and the control group of CIA mice;
图1E：显示CIA小鼠实验组与对照组中，踝关节的组织学(H&E)照片；Figure 1E: Histological (H&E) photograph of the ankle joint in the experimental and control groups of CIA mice;
图1F：显示CIA小鼠实验组与对照组中，对发炎细胞的浸润、滑膜增生以及脚踝关节的骨侵蚀之组织学比较图；Figure 1F: shows a histological comparison of infiltration, synovial hyperplasia, and bone erosion of the ankle joint in the experimental and control groups of CIA mice;
图2A：显示CIA小鼠实验组与对照组中，以ELISA测定，脚掌组织中选择性细胞激素的含量；Figure 2A: shows the content of selective cytokines in the paw tissue of the CIA mouse experimental group and the control group by ELISA;
图2B：显示CIA小鼠实验组与对照组中，以ELISA测定，血清中选择性细胞激素的含量；Figure 2B: shows the content of selective cytokines in serum in the CIA mouse experimental group and the control group by ELISA;
图3A：显示CIA小鼠实验组与对照组中，抗CII IgG比较图；Figure 3A: Comparison of anti-CII IgG in the experimental and control groups of CIA mice;
图3B：显示CIA小鼠实验组与对照组中，CII抗原刺激增生比较图；Figure 3B: Comparison of CII antigen-stimulated proliferation in CIA mice experimental group and control group;
图3C：显示CIA小鼠实验组与对照组中，淋巴球细胞上清液的不同细胞 激素含量比较图；Figure 3C: shows different cells of lymphocyte supernatant in CIA mice experimental group and control group Hormone content comparison chart;
图4A:托法替尼1mg/kg/day、5mg/kg/day、25mg/kg/day剂量对CIA小鼠之功效评估比较图；Figure 4A: Comparison of the efficacy of tofarinib 1 mg/kg/day, 5 mg/kg/day, 25 mg/kg/day dose on CIA mice;
图4B：托法替尼1mg/kg/day、阿卡波糖500mg/kg/day、阿卡波糖500mg/kg/day合并托法替尼1mg/kg/day对CIA小鼠之功效评估比较图；Figure 4B: Comparison of the efficacy of tofacitinib 1 mg/kg/day, acarbose 500 mg/kg/day, acarbose 500 mg/kg/day and tofacitinib 1 mg/kg/day for CIA mice Figure
图4C：托法替尼5mg/kg/day、阿卡波糖500mg/kg/day、阿卡波糖500mg/kg/day合并托法替尼5mg/kg/day对CIA小鼠之功效评估比较图；Figure 4C: Comparison of the efficacy of tofacitinib 5 mg/kg/day, acarbose 500 mg/kg/day, acarbose 500 mg/kg/day combined with tofacitinib 5 mg/kg/day for CIA mice Figure
图5A：显示以咪喹莫特62.5mg/kg/day诱发小鼠干癣佐以阿卡波糖500mg/kg/day治疗的实验组与对照组之皮肤照片图；Fig. 5A is a photograph showing the skin of an experimental group and a control group which were induced by imiquimod 62.5 mg/kg/day and dried with acarbose 500 mg/kg/day;
图5B：显示以咪喹莫特62.5mg/kg/day诱发小鼠干癣佐以阿卡波糖500mg/kg/day治疗的实验组与对照组之临床表征评分比较图；Fig. 5B is a graph showing the comparison of clinical characterization scores between the experimental group and the control group which were induced by imiquimod 62.5 mg/kg/day and dried with acarbose 500 mg/kg/day;
图6A：控制组乳膏诱发干癣小鼠皮肤组织学(H&E)照片；Figure 6A: Control group cream induced skin histology (H&E) photos of dried mice;
图6B：咪喹莫特诱发干癣小鼠皮肤组织学(H&E)照片；Figure 6B: imiquimod-induced skin histology (H&E) photographs of dried mice;
图6C：以咪喹莫特诱发干癣佐以阿卡波糖50mg/kg/day治疗小鼠皮肤组织学(H&E)照片；Figure 6C: H&E photographs of mice treated with imiquimod-induced dryness and acarbose 50 mg/kg/day;
图6D：以咪喹莫特诱发干癣阿卡波糖50mg/kg/day治疗小鼠皮肤组织学(H&E)照片。Figure 6D: H&E photographs of mice treated with imiquimod induced dry acarbose 50 mg/kg/day.
具体实施方式detailed description
于下文中，将对本发明所揭示之示例性实施例及范例进行详细的描述，并且附有图式，使得本发明之概念得以经由本发明技术领域人员轻易实行。In the following, the exemplary embodiments and examples disclosed herein are described in detail, and the drawings are attached to the drawings, and the concept of the present invention can be easily implemented by those skilled in the art.
然而，必须注意的是本发明所揭示之内容并不应被限制于发明实施例，且可以不同方式实现。于图式中，部份与本发明不直接相关之内容省略以提高图式之清晰度，标号于文件当中标示。However, it must be noted that the disclosure of the present invention should not be limited to the embodiments of the invention and may be implemented in different ways. In the drawings, parts that are not directly related to the present invention are omitted to improve the clarity of the drawings, and the labels are indicated in the documents.
非限制且非详尽之实施例将结合附图1A至附图6D说明如下。必须了解的是图式仅依据本说明书公开之内容描绘数个实施例，因此，勿因而限制其范围，本发明所揭示之内容将特别详细的藉由这些图式作为说明。Non-limiting and non-exhaustive embodiments will be described below in conjunction with Figures 1A through 6D. It is to be understood that the drawings are merely illustrative of the embodiments of the invention, and therefore, the scope of the invention
整篇说明书当中，所使用之词汇「包含(comprises)」或「包括(includes)」意谓着除了描述的组成、步骤、操作指令及/或元素以外，不排除一或多个其 他组成、步骤、操作指令及/或存在或附加元素。所使用之词汇「大约(about)或约(approximately)」意指具有接近或可允许的误差范围，用于避免本发明所揭示之准确或绝对的数值受未知的第三方非法或非正当使用的。词汇「一」意指该冠词之语法对象为一或一个以上(例如：至少为一)。The word "comprises" or "includes" as used throughout the specification means that one or more of its constituents, steps, operating instructions and/or elements are not excluded. He consists of, steps, instructions, and/or presence or additional elements. The word "about" or "approximately" is used to mean that there is a near or permissible range of error for avoiding the use of the precise or absolute value disclosed herein by an unknown third party. . The term "a" means that the grammatical object of the article is one or more (eg, at least one).
本发明系提供一种用于治疗免疫发炎病症之医药组合物，其包含阿卡波糖(acarbose)，以及一种阿卡波糖供制备免疫调节药物之用途。The present invention provides a pharmaceutical composition for treating an immunoinflammatory condition comprising acarbose and an acarbose for use in the preparation of an immunomodulatory drug.
本文中术语「治疗」意指投予或处方一组成物至一患者以治疗或预防免疫发炎病症。本文中「患者」意指任何动物(例如，人类)。其他可用本发明之方法、组成物及套组治疗之动物包括马、狗、猫、猪、山羊、兔、仓鼠、猴、天竺鼠、大鼠、小鼠、蜥蜴、蛇、绵羊、牛、鱼及鸟。The term "treating" as used herein means administering or prescribing a composition to a patient to treat or prevent an immunoinflammatory condition. By "patient" is meant herein any animal (eg, human). Other animals which can be treated by the methods, compositions and kits of the invention include horses, dogs, cats, pigs, goats, rabbits, hamsters, monkeys, guinea pigs, rats, mice, lizards, snakes, sheep, cattle, fish and bird.
本文中术语「免疫发炎病症」包括许多情况，包括但不限于自体免疫疾病、增生性皮肤病及发炎性湿疹。免疫发炎病症会导致身体的健康组织被发炎过程破坏、使免疫***失去控制及造成不欲之细胞增殖。免疫发炎病症之例如寻常痤疮；急性呼吸困难症候群；艾迪生氏症(Addison’s病症)；过敏性鼻炎；过敏性眼内发炎病症、ANCA-相关性小-血管血管炎；僵直性脊椎炎；关节炎、气喘；动脉硬化症；异位性皮肤炎；自体免疫溶血性贫血；自体免疫肝炎；贝西氏(Behcet’s)病；贝尔氏痲痹(Bell’s palsy)；大水疱性类天疱疮(bul lous pemphigoid)；脑缺血；慢性阻塞性肺病；肝硬化；柯刚氏(Cogan’s)症候群；接触性皮肤病；COPD；克隆氏病；库欣氏(Cushing’s)症候群；皮肤肌炎；糖尿病；圆型红斑狼疮；嗜伊红性肌膜炎；红斑性结节；剥落性皮肤炎；纤维肌痛；肾丝球硬化症；巨细胞动脉炎；痛风；痛风性关节炎；移殖物抗寄主疾病；手部湿疹；过敏性紫斑症(Henoch-Schonlein purpura)；妊娠疱疹性(herpes gestationis)；多毛症；特发性角-巩膜炎；特发性肺纤维化；特发性血小板减少性紫斑；发炎性肠或胃肠疾病、发炎皮肤病；扁平苔藓；狼疮性肾炎；淋巴瘤性气管支气管炎；黄斑部水肿；多发性硬化症；重症肌无力；肌炎；骨性关节炎；胰脏炎；天疮样疹症；寻常天疮；多发性结节性动脉炎；风湿性多肌痛；阴囊搔痒症；搔痒症/发炎；牛皮癣；干癣性关节炎；类风湿性关节炎；再发性的多发性软骨炎；类肉瘤病引起之玫瑰斑；硬皮病引起之玫瑰斑；史维特氏(Sweet’s)症候群造成之玫瑰斑；全身性红斑狼疮造成之玫瑰 斑；荨麻疹引起之玫瑰斑；带疹相关疼痛引起之玫瑰斑；类肉瘤病；硬皮病；局部肾丝球硬化症；败血性休克症候群；肩肌腱炎或滑囊炎；修格连氏(Sjogren’s)症候群；史底耳氏(Still’s)症；中风诱发性脑细胞死亡；史维特氏病；全身性红斑狼疮；全身性硬化症；高安氏(Takayasu’s)动脉炎；颞动脉炎；毒性皮肤坏死；肺结核；第I型糖尿病；溃疡性大肠炎；葡萄膜炎；血管炎；及维格内氏(Wegener’s)囊肿。于本案之较佳实施例中，该免疫发炎病症包含类风湿性关节炎、干癣、第一型糖尿病、成人性史底耳氏症、视神经脊髓炎、克隆氏症、溃疡性大肠炎、气喘、慢性阻塞性肺病、风湿性多肌痛症、巨细胞动脉炎、全身性红斑狼疮、异位性皮肤炎、多发性硬化症、重症肌无力、牛皮癣、僵直性脊椎炎、肝硬化或干癣性关节炎或其他与细胞激素IL-17失调的相关免疫发炎病症。The term "immune inflammatory condition" as used herein includes many conditions including, but not limited to, autoimmune diseases, proliferative skin diseases, and inflammatory eczema. Immune inflammatory conditions can cause the body's healthy tissues to be destroyed by the inflammatory process, the immune system to lose control, and the unwanted cells to proliferate. Immunoinflammatory conditions such as acne vulgaris; acute dyspnea syndrome; Addison's disease; allergic rhinitis; allergic intraocular inflammation, ANCA-related small-vascular vasculitis; ankylosing spondylitis; arthritis Asthma; atherosclerosis; atopic dermatitis; autoimmune hemolytic anemia; autoimmune hepatitis; Behcet's disease; Bell's palsy; bullous pemphigoid Cerebral ischemia; chronic obstructive pulmonary disease; cirrhosis; Cogan's syndrome; contact skin disease; COPD; Crohn's disease; Cushing's syndrome; dermatomyositis; Lupus; eosinophilic fasciitis; erythematous nodules; exfoliative dermatitis; fibromyalgia; glomerular sclerosis; giant cell arteritis; gout; gouty arthritis; Eczema; Henoch-Schonlein purpura; Herpes gestationis; hirsutism; idiopathic horn-scleraitis; idiopathic pulmonary fibrosis; idiopathic platelets Reduced purpura; inflammatory bowel or gastrointestinal disease, inflamed skin disease; lichen planus; lupus nephritis; lymphoma tracheitis; macular edema; multiple sclerosis; myasthenia gravis; myositis; Pancreatitis; acne-like rash; common sore; multiple nodular arteritis; rheumatic polymyalgia; scrotal pruritus; pruritus/inflammation; psoriasis; dry arthritis; rheumatoid joint Inflammation; recurrent multiple chondritis; rose plaque caused by sarcoma-like disease; rose plaque caused by scleroderma; rose plaque caused by Sweet's syndrome; rose caused by systemic lupus erythematosus Spot; rosacea caused by urticaria; rose plaque caused by rash-related pain; sarcoma-like disease; scleroderma; local squamous sclerosis; septic shock syndrome; scapular tendonitis or bursitis; (Sjogren's) syndrome; Still's disease; stroke-induced brain cell death; Schwitt's disease; systemic lupus erythematosus; systemic sclerosis; Takayasu's arteritis; temporal arteritis; Necrosis; tuberculosis; type I diabetes; ulcerative colitis; uveitis; vasculitis; and Wegener's cyst. In a preferred embodiment of the present invention, the immunoinflammatory condition comprises rheumatoid arthritis, cognac, type 1 diabetes, adult sexual history, optic neuromyelitis, Crohn's disease, ulcerative colitis, asthma , chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis, ankylosing spondylitis, cirrhosis or dryness Arthritis or other immunoinflammatory condition associated with dysregulation of the cytokine IL-17.
本文中术语「非皮肤发炎病症」包括，例如类风湿性关节炎、发炎肠病、气喘及慢性阻塞性肺病。The term "non-skin inflammatory condition" as used herein includes, for example, rheumatoid arthritis, inflammatory bowel disease, asthma, and chronic obstructive pulmonary disease.
本文中术语「皮肤发炎病症」或「发炎性皮肤炎」包括，例如牛皮癣、急性热嗜中性皮肤病、湿疹(例如缺脂性湿疹、汗疹、小囊掌跖处湿疹)、浆细胞性局限性阴***炎、阴******炎、贝西氏病(Behcet’s病症)、离心性环形红斑、持久性色素障碍性红斑、多形红斑、环状肉芽肿、光泽苔藓、扁平苔藓、硬化萎缩性苔癣、慢性单纯苔癣、小棘苔藓、钱串状皮肤炎、坏疽性脓皮病、类肉瘤病、角膜下脓疱病、荨麻疹及过渡性棘皮湿疹。「增生性皮肤病」意指良性或恶性病其特征为上皮或表皮之细胞***加速。增生性皮肤病之例子有牛皮癣、异位性皮肤炎、非特异性皮肤炎、初级刺激物接触皮肤炎、过敏性接触皮肤炎、基底及鳞状细胞皮肤癌、层状鳞癣、表皮松懈角化过度症、前恶性角化病、粉刺及脂溢性皮肤炎。熟悉该领域技术者应可了解，某特定疾病、病症或情形可同时定性为增生性皮肤病及发炎湿疹。该疾病之例为牛皮癣。The term "skin inflammatory condition" or "inflammatory dermatitis" as used herein includes, for example, psoriasis, acute heat neutrophilic skin disease, eczema (eg, arrhythmia eczema, sweat rash, eczema at the small cystic sac), plasma cell limitation. Penile head inflammation, penile head dermatitis, Beth's disease (Behcet's condition), eccentric ring erythema, persistent pigmented erythema, polymorphous erythema, ring granuloma, lustrous moss, lichen planus, hardened atrophic moss Chronic simple moss, small spine moss, money-like dermatitis, gangrenous pyoderma, sarcoma, subcorneal impetigo, urticaria and transitional echinodermitis. "Proliferative skin disease" means a benign or malignant disease characterized by accelerated cell division of the epithelium or epidermis. Examples of proliferative skin diseases are psoriasis, atopic dermatitis, non-specific dermatitis, primary irritant contact dermatitis, allergic contact dermatitis, basal and squamous cell skin cancer, stratified scales, and epidermal keratinization Excessive symptoms, premalignant keratosis, acne and seborrheic dermatitis. Those skilled in the art will appreciate that a particular disease, condition or condition can be characterized as both proliferative skin disease and inflammatory eczema. An example of this disease is psoriasis.
本发明之医药组合物可进一步包含一第二药物。其中，该第二药物较佳系选自由非类固醇抗发炎药(NSAID)、COX-2抑制剂、生物分子、免疫调节剂、小分子免疫调节剂、疾病修饰抗风湿药(DMARD)、黄嘌呤、抗胆碱化合物、β受体协同剂、支气管扩张剂、非类固醇免疫亲和蛋白依存免疫抑制剂、维生素D类似物、补骨脂素、维生素A酸及5-胺基水杨酸所构成之群。 The pharmaceutical composition of the present invention may further comprise a second drug. Wherein, the second drug is preferably selected from the group consisting of a non-steroidal anti-inflammatory drug (NSAID), a COX-2 inhibitor, a biomolecule, an immunomodulator, a small molecule immunomodulator, a disease modifying antirheumatic drug (DMARD), and jaundice. , anticholinergic compound, β-receptor synergist, bronchodilator, non-steroid immunoaffinity protein-dependent immunosuppressant, vitamin D analog, psoralen, vitamin A acid and 5-aminosalicylic acid Group.
本文中术语「非类固醇抗发炎药」包含但不限于奈普生钠、双氯芬酸钠、双氯芬酸钾、阿司匹灵、舒林酸、双氟尼酸、吡罗昔康、引朵美辛、布洛芬、萘丁美酮、胆碱三水杨酸镁、水杨酸钠、水杨酸基水杨酸(三柳胆镁，salsalate)、苯氧布洛芬、氟比洛芬、酮洛芬、甲氯芬那酸钠、美洛昔康、奥沙普嗪、舒林酸及托美汀。The term "non-steroidal anti-inflammatory drugs" as used herein includes, but is not limited to, sodium naproxen, diclofenac sodium, diclofenac potassium, aspirin, sulindac, diflunisal, piroxicam, indomethacin, ibuprofen. , nabumetone, choline magnesium salicylate, sodium salicylate, salicylic acid salicylic acid (sallium), phenoxyprofen, flurbiprofen, ketoprofen, A Sodium chlorfenate, meloxicam, oxaprozin, sulindac and tolmetine.
本文中术语「疾病修饰抗风湿药」包含但不限于灭杀除癌(Methotrexate)、硫唑嘌呤(Azathioprine)、来氟米特(Leflunomide)、柳氮磺胺吡啶(Sulfasalazine)、羟氯奎(Hydroxychloroquine)、托法替尼(Tobactinib)。The term "disease-modifying antirheumatic drug" as used herein includes, but is not limited to, Methotrexate, Azathioprine, Leflunomide, Sulfasalazine, Hydroxychloroquine. ), Tofatinib (Tobactinib).
本文中术语「免疫调节剂」包含但不限于环孢灵素(Cyclosporin)、咪喹莫特(imiquimod)。The term "immunomodulator" as used herein includes, but is not limited to, cyclosporin, imiquimod.
本文中术语「抗组织胺」意指一化合物其阻断组织胺之作用。抗组织胺类型包括，但不限定于，乙醇胺、乙二胺、吩噻嗪、烷基胺、哌嗪及哌啶。The term "antihistamine" as used herein means a compound which blocks the action of histamine. Antihistamine types include, but are not limited to, ethanolamine, ethylenediamine, phenothiazine, alkylamine, piperazine, and piperidine.
本文中术语「非类固醇免疫亲和蛋白相关性免疫抑制剂」或「NsIDI」意指任何非类固醇药剂其可减低原发炎细胞激素生产或分泌、结合免疫亲和蛋白或造成原发炎反应之向下调控。NsIDI包括钙调神经磷解酶(calcineurin)抑制剂，例如环孢素、肝磷脂(tacrolimus)、子囊霉素、美莫司(pimecrolimus)及其他可抑制钙调神经磷解酶之磷解酶活性的药剂(肽、肽片段、化学性修饰肽或肽拟似物拟似物)。NsIDI亦包括雷帕霉素(rapamycin)(西罗莫司，sirolimus)及依维莫司(everol imus)，其会结合于FK506-结合蛋白质、FKBP-12，并阻断白血球之抗原诱发性增生以及细胞激素分泌。The term "non-steroidal immunoaffinity protein-associated immunosuppressive agent" or "NsIDI" as used herein means any non-steroidal agent that reduces the production or secretion of primary inflammatory cytokines, binds to immunoaffinity proteins, or causes a primary inflammatory response. Down regulation. NsIDI includes calcium calcineurin inhibitors such as cyclosporine, heparin (licrolimus), ascomycin, pimecrolimus and other phospholyase activities that inhibit calcineurin Agent (peptide, peptide fragment, chemically modified peptide or peptide mimetic). NsIDI also includes rapamycin (sirolimus) and everolimus, which binds to FK506-binding protein, FKBP-12, and blocks antigen-induced hyperplasia of leukocytes. And cytokine secretion.
本文中术语「小分子免疫调节剂」意指非类固醇、非-NsIDI化合物其可减少原发炎细胞激素生产或分泌，导致原发炎反应之向下调控，或者以免疫亲和蛋白-非依存的方式调节免疫***。小分子免疫调节剂之例子有p38 MAP激酶抑制剂，例如VX 702(Vertex Pharmaceuticals)、SCIO 469(Scios)、多拉马皮莫(doramapimod)(Boehringer Ingelheim)、RO 30201195(Roche)及SCIO 323(Scios)，TACE抑制剂例如有DPC 333(Bristol Myers Squibb)、ICE抑制剂例如有普纳卡桑(pranalcasan)(Vertex Pharmaceuticals)，IMPDH抑制剂例如霉酚酸酯(mycophenolate)(Roche)及梅利媒珀地补(merimepodib)(Vertex Pharamceuticals)。 The term "small molecule immunomodulator" as used herein means a non-steroidal, non-NsIDI compound that reduces the production or secretion of primary inflammatory cytokines, leading to downregulation of the primary inflammatory response, or by immunoaffinity protein-non-dependent The way to regulate the immune system. Examples of small molecule immunomodulators are p38 MAP kinase inhibitors such as VX 702 (Vertex Pharmaceuticals), SCIO 469 (Scios), doramapimod (Boehringer Ingelheim), RO 30201195 (Roche) and SCIO 323 ( Scios), TACE inhibitors such as DPC 333 (Bristol Myers Squibb), ICE inhibitors such as pranalcasan (Vertex Pharmaceuticals), IMPDH inhibitors such as mycophenolate (Roche) and Meli Merimepodib (Vertex Pharamceuticals).
本发明之医药组合物之剂量可依照技艺人士针对患者的状况做调整，提供足量的活性成份，或可选用低剂量、中剂量或高剂量。投予的剂量效果可由熟练的医师使用任何适于既定征兆之标准方法判断。The dosage of the pharmaceutical composition of the present invention can be adjusted to the condition of the patient according to the skilled person, providing a sufficient amount of the active ingredient, or alternatively a low dose, a medium dose or a high dose. The dose effect administered can be judged by a skilled physician using any standard method suitable for the intended indication.
本文中术语「低剂量」意指较特定化合物(以既定路径投予以治疗任何人类病症)之最低标准建议剂量低至少5％(例如，至少10％、20％、50％、80％、90％或甚至95％)例如，以吸入投予之皮质类固醇其低剂量与以口服投予之皮质类固醇其低剂量不同。As used herein, the term "low dose" means at least 5% lower than the minimum recommended recommended dose for a particular compound (to treat any human condition in a given path) (eg, at least 10%, 20%, 50%, 80%, 90%) Or even 95%) For example, a low dose of a corticosteroid administered by inhalation is different from a low dose of a corticosteroid administered orally.
本文中术语「高剂量」意指较特定化合物(用以治疗任何人类病症)之最高标准建议剂量高至少5％(例如，至少10％、20％、50％、100％、200％或甚至300％)。「中剂量」意指剂量介于低剂量与高剂量之间。The term "high dose" as used herein means a dose that is at least 5% higher than the highest standard recommended for a particular compound (to treat any human condition) (eg, at least 10%, 20%, 50%, 100%, 200%, or even 300). %). "Medium dose" means that the dose is between a low dose and a high dose.
本文中术语「足量」意指本发明中化合物之组合量其系以临床上相关方式治疗或预防免疫炎症时所须之量。用于实施本发明以治疗由于免疫炎症疾病之活性化合物其足够量依投予方式、年龄、体重及患者的一般健康情形有所不同。The term "sufficient amount" as used herein means the amount of the combination of the compounds of the present invention which is required to treat or prevent immune inflammation in a clinically relevant manner. The amount of active compound used to practice the present invention to treat an immune inflammatory disease varies depending on the mode of administration, age, weight, and general health of the patient.
本发明之医药组合物具体例之投予路径包括，但不限定于局部投予、经皮及全身性投予(例如，静脉内、肌肉内、吸入、直肠内、领、***、腹膜内、关节内、眼或口服投予)。任何前述投予路径可与传统对治疗免疫发炎病症之药物一同投予。Specific routes of administration of the pharmaceutical composition of the present invention include, but are not limited to, topical administration, transdermal and systemic administration (for example, intravenous, intramuscular, inhalation, rectal, collar, vaginal, intraperitoneal, Intra-articular, intraocular or oral administration). Any of the aforementioned routes of administration can be administered in conjunction with conventional drugs for treating immunoinflammatory conditions.
本发明之医药组合物可以为任何种型式，例如锭剂、胶囊、药丸、粉末、颗粒、悬浮剂、乳化剂、溶液、凝胶(包括水凝胶)、糊剂、油膏、乳霜、膏药、浸剂、渗透运送工具、栓剂、灌肠剂、注射剂、植入剂、喷雾或气溶胶。该等组成物可依传统制药规范配制，其中较佳为口服剂型，如锭片、胶囊、或糖浆；或为直肠投予，如栓剂；或为其他种剂型，如持续释放或缓释剂型等。The pharmaceutical composition of the present invention may be in any of various forms such as tablets, capsules, pills, powders, granules, suspensions, emulsifiers, solutions, gels (including hydrogels), pastes, ointments, creams, Plaster, infusion, osmotic delivery, suppository, enema, injection, implant, spray or aerosol. Such compositions may be formulated according to conventional pharmaceutical specifications, preferably oral dosage forms such as tablets, capsules, or syrups; or rectal administration, such as suppositories; or other dosage forms, such as sustained release or sustained release dosage forms, and the like. .
本发明之医药组合物中，如含有第二药物，则各化合物可用该技术领域已知的方法配方。例如，第一及第二药剂可以同时或分别的配方。较佳为，第一及第二药剂同时一起投予或接近同时投予；若同时投予，则可一起配方于同一药丸、胶囊、液剂等。藉由对不同药剂使用不同的配方策略，可以适当配合各药剂的药物动力学曲线。个别或分别配方的药剂可包在一起成为一个套组。无限定的套组实施例，例如包含2个药丸、一个药丸及粉末、栓剂及一药瓶内液剂、2种外用乳霜等形式。该套组可包含选择性的配件，其会帮助对患者投予 单位剂量，成分包括例如用于泡制粉末型之药瓶、注射针筒、客制IV运送***、吸入剂等。此外，该单位剂量套组可包括制备及投予该组成物的说明。该套组可制造为一位患者使用的单一剂量、对特定患者之多次使用剂量(可为相同剂量或者个别化合物随治疗进展其效力不同)；或该套组可包括适用于对多位患者投予之多次剂量(“大包装”)。该套组可组合在纸盒、泡形罩包装、瓶子、管子等。或者，可调配成控制型及/或持续释放，该「持续释放」或「控制性释放」意指治疗上活性成分系从配方中以受控制的速度释出，以使该成分可长时间(例如，约12-24小时)维持治疗上有效的血液水平(低于有毒性之水平)，故可制成12小时或24小时之剂型。In the pharmaceutical compositions of the present invention, if a second drug is included, each compound can be formulated by methods known in the art. For example, the first and second medicaments can be formulated simultaneously or separately. Preferably, the first and second medicaments are administered simultaneously or nearly simultaneously; if administered simultaneously, they may be formulated together in the same pill, capsule, liquid, and the like. By using different formulation strategies for different agents, the pharmacokinetic profile of each agent can be appropriately matched. Individual or separately formulated medicaments can be packaged together into a single kit. An unrestricted kit embodiment includes, for example, two pills, one pill and powder, a suppository and a vial solution, and two external creams. The kit can include optional accessories that will help the patient to be administered The unit dose, ingredients include, for example, vials for infusion powders, syringes, custom IV delivery systems, inhalants, and the like. Additionally, the unit dose kit can include instructions for preparing and administering the composition. The kit can be manufactured as a single dose for one patient, multiple doses for a particular patient (which can be the same dose or the effectiveness of individual compounds as the treatment progresses); or the kit can include multiple patients Multiple doses administered ("big package"). The kit can be combined in a carton, blister pack, bottle, tube, and the like. Alternatively, it may be formulated to be controlled and/or sustained release, and the "sustained release" or "controlled release" means that the therapeutically active ingredient is released from the formulation at a controlled rate such that the ingredient is prolonged ( For example, about 12-24 hours) maintain therapeutically effective blood levels (below the level of toxicity) so that a 12 hour or 24 hour dosage form can be made.
实施例Example
在下文中，将利用范例及图式特别描写本发明所揭示之内容。然而，本发明所揭示之内容不限制于该范例及图式。In the following, the disclosure of the present invention will be specifically described using examples and drawings. However, the disclosure of the present invention is not limited to this example and the drawings.
实施例1-类风湿性关节炎与阿卡波糖关系的统计学调查Example 1 - Statistical investigation of the relationship between rheumatoid arthritis and acarbose
[以族群作为基础案例对照研究][Based on ethnic group as a case-control study]
数据源为使用来自台湾的国民健康保险研究数据库(NHIRD)1999-2011以人群做为基础，匹配的病例对照研究。NHIRD为超过98％的台湾人口全面的加密医疗数据，而为研究目的发布。该NHIRD于2000年随机选取百万参保者，形成具有代表性的数据库，该数据库中包含潜在致残性自身免疫性疾病，包括类风湿性关节炎(RA)。RA的诊断再经由美国风湿病医学会RA分类标准(1987)进行验证。The data source was a population-based, matched case-control study using the National Health Insurance Research Database (NHIRD) 1999-2011 from Taiwan. NHIRD is a comprehensive encrypted medical data for more than 98% of the Taiwanese population, and is released for research purposes. The NHIRD randomly selected millions of participants in 2000 to form a representative database containing potentially disabling autoimmune diseases, including rheumatoid arthritis (RA). The diagnosis of RA was further verified by the American College of Rheumatology RA Classification Standard (1987).
[研究样本][research sample]
糖尿病(DM)案例Diabetes (DM) case
病患初步诊断为糖尿病日[国际分类疾病，第九次修订，临床修改(ICD9-CM)代码250.x]在2000年1月1日之后，并同时处方任何抗糖尿病药物≥28天者被列为DM病患。DM诊断日期用于测量DM病程时间的系定义为初始抗糖尿病药物处方的时间。The patient was initially diagnosed with Diabetes Day [International Classification Disease, Ninth Revision, Clinical Revision (ICD9-CM) Code 250.x] after January 1, 2000, and at the same time prescribe any antidiabetic drug for ≥ 28 days. Listed as DM patients. The DM diagnostic date is used to measure the duration of the DM course as the time to prescribe the initial antidiabetic drug.
类风湿性关节炎(RA)案例Rheumatoid arthritis (RA) case
确定在2001至2010年间有24,429位具有重大伤病证(RA诊断时年龄≥16)新诊断为RA的病患，为了最大限度地减少反因果关系的可能性，排除了在开始 抗糖尿病治疗一年内患有RA的患者。在这些RA患者中，确定了723位病患为第一次诊断(指标日期)为RA之日前具有至少一年的糖尿病史。It was determined that between 2001 and 2010, there were 24,429 patients with a major injury certificate (age ≥16 at the time of RA diagnosis) who were newly diagnosed with RA. In order to minimize the possibility of anti-causal relationship, the exclusion was made at the beginning. Anti-diabetic treatment for patients with RA within one year. Among these RA patients, 723 patients were identified as having a history of diabetes for at least one year prior to the date of the first diagnosis (index date) of RA.
非类风湿性关节炎(non-RA)控制组Non-rheumatoid arthritis (non-RA) control group
使用KHID20000，匹配RA案例的RA诊断年龄(16-25、26-35、36-45、46-55、56-65或>65岁)、性别以及指标日年份(指标年份)，并在1999-2011年份中随机选取7,230位之DM患者，其患有DM病史超过一年且从未诊断出RA作为非RA控制组。选用第一次门诊时间作为控制组的指标日期。Use KHID20000 to match the RA diagnosis age (16-25, 26-35, 36-45, 46-55, 56-65, or >65 years), gender, and indicator date year (indicator year) for the RA case, and in 1999- A total of 7,230 DM patients were randomly selected in the 2011 year who had a history of DM for more than one year and had never been diagnosed with RA as a non-RA control group. The first outpatient time was chosen as the indicator date for the control group.
[使用抗糖尿病药物][Use anti-diabetes drugs]
基于NHIRD的处方纪录，在指针日之前，一年内有28天或以上使用阿卡波糖、二甲双胍、噻唑烷二酮(TZD)、胰岛素或磺酰脲/格列奈者，分别分类为阿卡波糖使用者、二甲双胍使用者、TZD使用者、胰岛素使用者或磺酰脲/格列奈使用者。根据中位年度累积剂量再将阿卡波糖使用者分类为高剂量使用者以及低剂量使用者。Based on the NHIRD prescription record, acarbose, metformin, thiazolidinedione (TZD), insulin or sulfonylurea/glinide were used for 28 days or more in one year before the date of the indicator. Wave sugar users, metformin users, TZD users, insulin users or sulfonylurea/glinide users. Acarbose users are classified as high-dose users and low-dose users based on the median annual cumulative dose.
[潜在的干扰因素][potential interference factors]
地理区域、DM持续时间以及DM终末段器官疾病(ICD9-CM代码250.1-9)列为潜在干扰因素。选择地理区域是因为在以前的研究中发现其语RA风险相关。另外，DM持续时间以及DM终末段器官疾病则代表DM的严重度。DM持续时间定义为初始抗糖尿病药之日至指标日期的期间。其他的干扰因素包含Deyo等人改写之察尔森共病症指标(Charlson comorbidity index,CCI)(Deyo RA,Cherkin DC,Ciol MA.Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.J Clin Epidemiol.1992；45(6):613-619)、如已往研究中定义的牙周炎(Chen HH,Huang N,Chen YM,et al.Association between a history of periodontitis and the risk of rheumatoid arthritis:a nationwide,population-based,case-control study.Ann Rheum Dis.2013；72(7):1206-1211)，以及在指标日一年前使用史他汀(stain)药物≥28天。Geographical areas, DM duration, and DM terminal organ disease (ICD9-CM code 250.1-9) are listed as potential disruptors. The geographical area was chosen because it was found in the previous study that the RA risk was related. In addition, DM duration and DM terminal organ disease represent the severity of DM. The DM duration is defined as the period from the date of the initial antidiabetic drug to the date of the indicator. Other interfering factors include the Charlson comorbidity index (CCI) rewritten by Deyo et al. (Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrative databases.J Clin Epidemiol. 1992; 45(6): 613-619), periodontitis as defined in previous studies (Chen HH, Huang N, Chen YM, et al. Association between a history of periodontitis and the risk of rheumatoid arthritis: a nationwide, population-based, case-control study. Ann Rheum Dis. 2013; 72(7): 1206-1211), and the use of a statin drug for ≥ 28 days a year before the index day.
[结果][result]
由以上的统计结果，共有723位RA病患(年龄≥16岁)作为RA案例，以及7,230位匹配的分RA病患作为非-RA控制组(参下表1)。女性与男性的比例为 2.5：1，案例之平均年龄(±SD)为61.7(±10.8)岁，控制组则为61.8(±10.5)岁。下表2则比较了RA案例与非-RA控制组的临床特点。使用二甲双胍、噻唑烷二酮(TZD)、胰岛素及磺酰脲/格列奈的案例的比例高于控制组的比例。From the above statistical results, a total of 723 RA patients (age ≥ 16 years) were included as RA cases, and 7,230 matched RA patients were treated as non-RA control groups (see Table 1 below). The ratio of women to men is At 2.5:1, the average age of the case (±SD) was 61.7 (±10.8) years, and that of the control group was 61.8 (±10.5) years. Table 2 below compares the clinical features of the RA case with the non-RA control group. The proportion of cases using metformin, thiazolidinedione (TZD), insulin and sulfonylurea/glinide was higher than that of the control group.
在下表3中，调整了潜在的干扰因素后，每年投予超过16,950mg的阿卡波糖使用者相较于非使用者，其RA风险较低(OR,0.60；95％CI,0.41–0.89)；胰岛素的使用则为RA风险的另一个保护因子(OR,0.62；95％CI,0.45–0.87)；RA发展的显著风险因子包含使用二甲双胍(OR,1.26；95％CI,1.06–1.49)、较长的DM持续时间(每增加一年，OR,1.22；95％CI,1.18–1.27)、DM终末段器官疾病的发生(OR,2.67；95％CI,2.23–3.19)以及CCI(OR,1.281；95％CI,1.26–1.31)。In Table 3 below, after adjusting for potential interfering factors, a yearly dose of more than 16,950 mg of acarbose users was associated with a lower risk of RA compared to non-users (OR, 0.60; 95% CI, 0.41–0.89) The use of insulin is another protective factor for RA risk (OR, 0.62; 95% CI, 0.45–0.87); a significant risk factor for RA development involves the use of metformin (OR, 1.26; 95% CI, 1.06–1.49) Longer DM duration (every additional year, OR, 1.22; 95% CI, 1.18–1.27), DM terminal organ disease (OR, 2.67; 95% CI, 2.23–3.19) and CCI ( OR, 1.281; 95% CI, 1.26–1.31).
表1-RA案例以及匹配的非-RA控制组的基础特征Table 1 - Basics of RA cases and matching non-RA control groups
Figure PCTCN2015080849-appb-000001
Figure PCTCN2015080849-appb-000001
缩写：RA-类风湿性关节炎；SD-标准偏差，除非另有说明，百分数都包含在括号中的每个数值之后。Abbreviations: RA-rheumatoid arthritis; SD-standard deviation, unless otherwise stated, the percentages are included after each value in parentheses.
表2-RA案例以及非-RA对照组织之临床特征 Table 2 - Clinical features of RA cases and non-RA control tissues
Figure PCTCN2015080849-appb-000002
Figure PCTCN2015080849-appb-000002
*数据为指针日期前一年收集*Data is collected for the year before the date of the pointer
#数据显示表示平均值±标准偏差#Data display means mean ± standard deviation
Figure PCTCN2015080849-appb-000003
病患每年两次接受抗生素治疗或非牙刮治术的牙周治疗，或牙刮治术
Figure PCTCN2015080849-appb-000003
Patients undergoing periodontal treatment with antibiotic or non-surgical treatment twice a year, or dental curettage
缩写：RA-类风湿性关节炎；ICD9-CM,疾病国际分类，第9版，临床修订；除非另有说明，百分数都包含在括号中的每个数值之后。Abbreviations: RA-rheumatoid arthritis; ICD9-CM, International Classification of Diseases, 9th edition, clinical revision; unless otherwise stated, the percentages are included after each value in parentheses.
表3-于类风湿性关节炎风险与新治疗的糖尿病患者变量相关的单变项 与多变项调整胜算比95％信赖区间Table 3 - Single variable related to the risk of rheumatoid arthritis and newly treated diabetic patients And multivariate adjustment odds ratio 95% confidence interval
Figure PCTCN2015080849-appb-000004
Figure PCTCN2015080849-appb-000004
*P＝0.079,#p＝0.047.*P=0.079, #p=0.047.
由以上可以发现，DM病患若每年投予16,950mg以上的阿卡波糖，将可降低罹患RA的风险。From the above, it can be found that if DM patients are given more than 16,950 mg of acarbose per year, the risk of RA will be reduced.
实施例2-小鼠实验确认阿卡波糖治疗类风湿性关节炎Example 2 - Mouse experiment confirmed acarbose treatment of rheumatoid arthritis
[胶原蛋白诱发小鼠关节炎并以阿卡波糖治疗][Collagen induced arthritis in mice and treated with acarbose]
依据习知方法(Inglis JJ,Simelyte E,McCann FE,Criado G,Williams  RO.Protocol for the induction of arthritis in C57BL/6mice.Nat Protoc.2008；3(4):612-618)对DBA/1(6至8周)小鼠进行胶原蛋白诱发关节炎(collagen-induced arthritis CIA)。将阿卡波糖(DXM，Sigma-Aldrich公司)溶解并以水稀释；小鼠随机分成三组，分别给予500mg/kg/day剂量的阿卡波糖、100mg/kg/day剂量的阿卡波糖，以及水作为对照组，在第一次免疫后的7至38天每天投予两次；小鼠脚掌关节炎严重程度的临床表征以习知的评分***(Zhou R,Tang W,Ren YX,et al.(5R)-5-hydroxytriptolide attenuated collagen-induced arthritis in DBA/1 mice via suppressing interferon-gamma production and its related signaling.J Pharm Exp Ther.2006；318(1):35-44)，以双盲方式进行评价。According to conventional methods (Inglis JJ, Simelyte E, McCann FE, Criado G, Williams RO.Protocol for the induction of arthritis in C57BL/6mice.Nat Protoc. 2008;3(4):612-618) Collagen-induced arthritis in DBA/1 (6-8 weeks) mice CIA). Acarbose (DXM, Sigma-Aldrich) was dissolved and diluted with water; mice were randomly divided into three groups, each given a dose of 500 mg/kg/day of acarbose and a dose of 100 mg/kg/day of Akapo. Sugar, as well as water as a control group, were administered twice daily for 7 to 38 days after the first immunization; the clinical characterization of the severity of mouse foot arthritis was performed using a conventional scoring system (Zhou R, Tang W, Ren YX). , et al. (5R)-5-hydroxytriptolide attenuated collagen-induced arthritis in DBA/1 mice via suppressing interferon-gamma production and its related signaling. J Pharm Exp Ther. 2006; 318(1): 35-44), Evaluation in a double-blind manner.
[组织病理学分析][histopathological analysis]
从每组中各一共三只小鼠在第38天取得代表性的踝关节，于石蜡中进行固定、脱钙及包埋。各关节切片(5M)后以苏木紫及伊红染色(H&E)，接着跟据习知的方法(Wooley PH.Collagen-induced arthritis in the mouse.Methods Enzymol.1988；162:361-373.)以显微镜观察。滑膜增生、细胞浸润、软骨破坏以及骨侵蚀的组织病理变化，由病理学家进行盲目分级，并根据以下标准给予0-3分，0：没有变化；1：轻度变化；2：中度变化；3：重度变化。A total of three mice from each group obtained representative ankle joints on day 38 and fixed, decalcified and embedded in paraffin. Each joint section (5M) was stained with hematoxylin and eosin (H&E) followed by a conventional method (Wooley PH. Collagen-induced arthritis in the mouse. Methods Enzymol. 1988; 162: 361-373.) Observed by a microscope. Synovial hyperplasia, cell infiltration, cartilage destruction, and histopathological changes of bone erosion were blindly graded by pathologists and given 0-3 points according to the following criteria, 0: no change; 1: mild change; 2: moderate Change; 3: Severe change.
[测定细胞激素含量][Measurement of cytokine content]
各组在第38天收集小鼠脚掌组织，并在液态氮中冷冻，揭着样品以含有蛋白酶抑制剂中的PBS，以组织整塑器均质化。将均浆离心30分钟，收集上清液并稀释至每毫升1mg/ml组织蛋白做为原液。TNF-a、IL-1b、IL-6、IFN-g、IL-17、IL-10及TGF-b(R&D Systems)的含量以ELISA套组(Peprotech)测定。Each group collected mouse paw tissue on day 38 and frozen in liquid nitrogen, expelling the sample to contain PBS in the protease inhibitor to homogenize the tissue homogenizer. The homogenate was centrifuged for 30 minutes, and the supernatant was collected and diluted to 1 mg/ml tissue protein per ml as a stock solution. The contents of TNF-a, IL-1b, IL-6, IFN-g, IL-17, IL-10 and TGF-b (R&D Systems) were determined in an ELISA kit (Peprotech).
[抗胶原第II型IgG抗体产生的分析][Analysis of anti-collagen type II IgG antibody production]
小鼠在第CII免疫接种后的第38天抽血，其血清利用抗CII IgG抗体以ELISA滴定分析。简言之，将ELISA微孔盘(Thermo Fisher Scientific,NY,USA)的各孔涂覆10μg/200ml之第II型鸡胶原并于4℃下培育过夜。为避免非特异性的结合，将抗体清洗并以3％牛血清蛋白(BSA)(BD Biosciences)的Tris缓冲液阻断；受测血清进行系列稀释，并加入孔盘中4℃下培育过夜。经过5至7次的清洗后，结合的IgG透过与HRP-共轭的绵羊抗小鼠IgG以1:5000稀释做为二 抗来侦测；清洗后，孔盘以ABTS(Roche Diagnostic Systems,IN,USA)做为基质反应，并以H2SO4停止反应，以ELISA读数器在450nm处量测吸光值。Mice were bled on day 38 after CII immunization and their serum was analyzed by ELISA titration using anti-CII IgG antibodies. Briefly, each well of an ELISA microplate (Thermo Fisher Scientific, NY, USA) was coated with 10 μg/200 ml of type II chicken collagen and incubated overnight at 4 °C. To avoid non-specific binding, the antibodies were washed and blocked with 3% bovine serum albumin (BSA) (BD Biosciences) in Tris buffer; the test sera were serially diluted and incubated overnight at 4 °C in a well plate. After 5 to 7 washes, the bound IgG was detected by diluting 1:5000 with HRP-conjugated sheep anti-mouse IgG as a secondary antibody; after washing, the well plate was ABTS (Roche Diagnostic Systems, IN, USA) was used as a matrix reaction, and the reaction was stopped with H 2 SO 4 , and the absorbance was measured at 450 nm with an ELISA reader.
[细胞增生][cell hyperplasia]
免疫后第38天，取CIA小鼠的腹股沟***，以40μg/ml全变性基CII培养3天。在终止培养的18个小时前，将1μCi之[3H]]胸苷脉冲至各培养盘中，透过Matrix 96直接电离贝他计数器(Packard Instrument,Meridian,CT)，以每分钟计次(counts per minute,cpm)测定细胞增生。On the 38th day after immunization, the inguinal lymph nodes of CIA mice were taken and cultured for 3 days at 40 μg/ml of fully denatured CII. 1 μCi of [ 3 H] thymidine was pulsed into each plate 18 hours before the termination of culture, and counted per minute by Matrix 96 direct ionization beta counter (Packard Instrument, Meridian, CT). Counts per minute, cpm) Cell proliferation was measured.
[结果][result]
CIA已广泛地应用于引起展现出人类RA病理特征的关节炎。首先调查是否阿卡波糖可阻止CIA于DBA/1小鼠模型中的进展。如图1所示，给予水的CIA小鼠(对照组)在第24天有严重的CIA。然而，相较于对照组，以500mg/kg/day阿卡波糖治疗的小鼠则在CIA发生率(图1A)及患病脚掌数量(图1B)有显著地减少，且目视确认下有较不严重的肿胀、红斑以及后脚掌的关节僵硬(图1C)和关节炎评分(图1D)；以阿卡波糖100mg/kg/day口服治疗则在CIA的发展及严重程度没有显著的效果。CIA has been widely used to cause arthritis that exhibits the pathological features of human RA. First investigate whether acarbose can prevent progression of CIA in the DBA/1 mouse model. As shown in Figure 1, water-administered CIA mice (control group) had severe CIA on day 24. However, compared with the control group, mice treated with 500 mg/kg/day acarbose had a significant reduction in the incidence of CIA (Fig. 1A) and the number of diseased feet (Fig. 1B), and visual confirmation There were less severe swelling, erythema and joint stiffness in the hind paw (Fig. 1C) and arthritis score (Fig. 1D); oral treatment with acarbose 100 mg/kg/day had no significant development and severity in CIA. effect.
为了进一步评估关节炎，小鼠踝关节的组织学(H&E)研究在实验结束时进行。与观察到的减缓的脚掌肿胀及临床评分一致，投予500mg/kg/day阿卡波糖的小鼠在以下有显著的降低：发炎细胞的浸润、滑膜增生以及脚踝关节的骨侵蚀(图1E-F)。接着以ELISA测定脚掌组织及血清中选择性细胞激素的含量，如图2A及图2B所示，阿卡波糖治疗的小鼠与对照CIA小鼠相比，其脚掌组织以及血清中的发炎细胞激素如TNF-alpha、IL-6及IL-17明显地减少。这些结果显示，以口服阿卡波糖可有效地预防CIA的发展以及抑制关节的局部炎症。To further assess arthritis, histological (H&E) studies of the ankle joints of the mice were performed at the end of the experiment. Consistent with the observed slowed paw swelling and clinical score, mice given 500 mg/kg/day acarbose had a significant reduction in infiltration of inflamed cells, synovial hyperplasia, and bone erosion of the ankle joint (figure 1E-F). Next, the content of selective cytokines in the paw tissue and serum was measured by ELISA. As shown in FIG. 2A and FIG. 2B, the acarbose-treated mice had ampules in the soles of the feet and serum in comparison with the control CIA mice. Hormones such as TNF-alpha, IL-6 and IL-17 are significantly reduced. These results show that oral acarbose can effectively prevent the development of CIA and inhibit local inflammation of joints.
在CIA模型中，抗体以及T细胞反应在以第II型胶原免疫后的疾病病因有所相关。因此，进一步量测血清中的C-II特异性抗体以及***中的CII特异性T淋巴球扩展。如图3A所示，使用500mg/kg/day阿卡波糖治疗导致抗CII IgG产生的显著下降，再者，与对照组CIA小鼠获得的细胞相比，由阿卡波糖治疗的小鼠中取得的***细胞显示CII抗原刺激增生的显著降低(图3B)，且胶原刺激的***细胞之IL-17以及IFN-产生降低。相反地，L-10则在阿卡波糖治疗的CIA小鼠中有增加的表现量(图3C)。这些数据显示无论是体液或细胞的 免疫反应均会受到阿卡波糖治疗的抑制。In the CIA model, antibody and T cell responses are associated with the etiology of the disease after immunization with type II collagen. Therefore, C-II specific antibodies in serum and CII-specific T lymphocyte expansion in lymph nodes were further measured. As shown in Figure 3A, treatment with 500 mg/kg/day acarbose resulted in a significant decrease in anti-CII IgG production, again, mice treated with acarbose compared to cells obtained from control CIA mice. Lymph node cells obtained in the test showed a significant decrease in CII antigen-stimulated proliferation (Fig. 3B), and IL-17 and IFN-production were decreased in collagen-stimulated lymph node cells. In contrast, L-10 showed an increased amount of expression in acarbose-treated CIA mice (Fig. 3C). These data show whether it is body fluid or cellular The immune response is inhibited by acarbose treatment.
实施例3-阿卡波糖与托法替尼个别及合并投予之CIA小鼠实验比较Example 3 - Comparison of Acarbose and Tofacitini in Individual and Combined CIA Mice
[不同剂量托法替尼对CIA小鼠之功效评估][Evaluation of the efficacy of different doses of tofartinib in CIA mice]
使用如实施例2之CIA小鼠，小鼠随机分成四组，分别给予1mg/kg/day剂量、5mg/kg/day剂量、25mg/kg/day剂量的托法替尼以及水作为对照组，在第一次免疫后的7至38天每天投予两次；小鼠脚掌关节炎严重程度的临床表征以习知的评分***。Using the CIA mice as in Example 2, the mice were randomly divided into four groups, and a dose of 1 mg/kg/day, a dose of 5 mg/kg/day, a dose of 25 mg/kg/day of tofacitinib, and water were used as a control group, respectively. Two doses were administered daily from 7 to 38 days after the first immunization; the clinical characterization of the severity of mouse paw arthritis was performed using a conventional scoring system.
[结果][result]
如图4A所示，使用习知治疗类风湿性关节炎之托法替尼，剂量越高，其对CIA小鼠临床的表征治疗效果越好。As shown in Figure 4A, the use of conventional tofapine in the treatment of rheumatoid arthritis, the higher the dose, the better the clinical characterization of CIA mice.
[阿卡波糖500mg/kg/day合并托法替尼1mg/kg/day对CIA小鼠之功效评估][Akapoose 500mg/kg/day combined with tofartinib 1mg/kg/day evaluation of the efficacy of CIA mice]
使用如实施例2之CIA小鼠，小鼠随机分成四组，分别给予1mg/kg/day剂量的托法替尼、500mg/kg/day剂量的阿卡波糖、1mg/kg/day剂量的托法替尼合并500mg/kg/day剂量的阿卡波糖，以及水作为对照组，在第一次免疫后的7至38天每天投予两次；小鼠脚掌关节炎严重程度的临床表征以习知的评分***。Using CIA mice as in Example 2, mice were randomized into four groups, each receiving a dose of 1 mg/kg/day of tofacitinib, a dose of 500 mg/kg/day of acarbose, and a dose of 1 mg/kg/day. Tofacitinib combined with a 500 mg/kg/day dose of acarbose and water as a control group, administered twice daily for 7 to 38 days after the first immunization; clinical characterization of the severity of arthritis in the paw of mice With a conventional scoring system.
[结果][result]
如图4B所示，以一般阿卡波糖用于治疗第二型糖尿病剂量，相较于一般用于治疗类风湿性关节炎之托法替尼1mg/kg/day的剂量，有更佳的功效；且两者合并使用后，效果也较单一投予为佳。As shown in Fig. 4B, the general acarbose is used to treat the second type diabetes dose, which is better than the dose of 1 mg/kg/day of tofacitinib which is generally used for the treatment of rheumatoid arthritis. Efficacy; and when combined, the effect is better than single administration.
[阿卡波糖500mg/kg/day合并托法替尼5mg/kg/day对CIA小鼠之功效评估][Akapoose 500mg/kg/day combined with tofacitinib 5mg/kg/day evaluation of the efficacy of CIA mice]
[结果][result]
如图4C所示，阿卡波糖500mg/kg/day与托法替尼5mg/kg/day均能用于治疗类风湿性关节炎；且两者合并使用后，效果更为显著。As shown in Fig. 4C, acarbose 500 mg/kg/day and tofacitinib 5 mg/kg/day can be used for the treatment of rheumatoid arthritis; and when the two are combined, the effect is more remarkable.
实施例4-阿卡波糖投予以咪喹莫特诱发干癣之小鼠实验Example 4 - Acarbose administration of imiquimod-induced dryness in mice
[诱发干癣小鼠及投药方式][Inducing dry mice and administration methods]
利用习知技术获得干癣小鼠，简单描述，将小鼠背部的毛发剔除后，每天在小鼠背部连续每天涂抹62.5mg市售的咪喹莫特(IMQ)软膏((Aldara；3M Pharmaceuticals)共涂抹6天，第7天，将小鼠拍照并牺牲后，取出背部皮肤，进行切片分析。阿卡波糖是在开始涂抹咪喹莫特(IMQ)软膏前一个礼拜开始每 天口服喂食直到实验结束(第6天)，剂量分别为500mg/kg或100mg/kg。临床评分标准是参考clinical Psoriasis Area and Severity Index(PASI)，主要是根据其红斑(erythema)、脱屑(scaling)分成5个等级评分。0代表没有变化，1至4分中，分数越高代表红斑及脱屑现象越严重。Cognac mice were obtained by conventional techniques. Briefly, after removing the hair on the back of the mouse, 62.5 mg of commercially available imiquimod (IMQ) ointment ((Aldara; 3M Pharmaceuticals) was applied daily on the back of the mouse. After a total of 6 days, on the 7th day, the mice were photographed and sacrificed, and the back skin was taken out for section analysis. Acarbose was started one week before the start of the application of imiquimod (IMQ) ointment. Oral feeding until the end of the experiment (Day 6), the dose was 500 mg / kg or 100 mg / kg. The clinical scoring standard is based on the clinical Psoriasis Area and Severity Index (PASI), which is mainly classified into five grades according to its erythema and scaling. 0 means no change, 1 to 4 points, the higher the score, the more serious the erythema and desquamation.
[结果][result]
由图5A及图5B中可见，以咪喹莫特(IMQ)62.5mg/kg/day诱发干癣之小鼠在投予阿卡波糖500mg/kg/day后，治疗效果显著。As can be seen from Fig. 5A and Fig. 5B, the mice inducing dryness with imiquimod (IMQ) 62.5 mg/kg/day had a remarkable therapeutic effect after administration of acarbose 500 mg/kg/day.
[组织病理学分析][histopathological analysis]
从每组中各一只小鼠在第7天取得之背部皮肤组织，于石蜡中进行固定、脱钙及包埋。切片(5M)后以苏木紫及伊红染色(H&E)以显微镜观察。如图6所示。根据切片的结果，可以发现阿卡波糖500mg/kg可显著减缓咪喹莫特(IMQ)诱导之小鼠，而造成之表皮肥厚(棘细胞増殖(acanthosis))、角质层增厚，并有残存的细胞核，及有角化不良(parakeratosis)现象。The skin tissue of the back obtained from the day 7 of each mouse in each group was fixed, decalcified and embedded in paraffin. After sectioning (5 M), it was observed with a hematoxylin and eosin stain (H&E) under a microscope. As shown in Figure 6. According to the results of the sectioning, it can be found that acarbose 500mg/kg can significantly slow down the imiquimod (IMQ)-induced mice, resulting in epidermal hypertrophy (acanthosis), thickening of the stratum corneum, and Remaining nuclei and parakeratosis.
综合上开实验可知，阿卡波糖确可用于治疗类风湿性关节炎、干癣等免疫发炎病症，且证实其可调结IL-17的功效，因此，可更广泛的用于与IL-17相关的免疫发炎病症。 Comprehensively, it can be seen that acarbose can be used for the treatment of rheumatoid arthritis, dryness and other immune inflammatory diseases, and it is confirmed that it can regulate the effect of IL-17, so it can be more widely used with IL- 17 related immune inflammatory conditions.

Claims (9)

  1. 一种用于治疗免疫发炎病症之医药组合物，其特征在于：其包含阿卡波糖。A pharmaceutical composition for treating an immunoinflammatory condition, characterized in that it comprises acarbose.
  2. 根据权利要求1所述的用于治疗免疫发炎病症之医药组合物，其特征在于：其中该免疫发炎病症为：类风湿性关节炎、干癣、第一型糖尿病、成人性史底耳氏症、视神经脊髓炎、克隆氏症、溃疡性大肠炎、气喘、慢性阻塞性肺病、风湿性多肌痛症、巨细胞动脉炎、全身性红斑狼疮、异位性皮肤炎、多发性硬化症、重症肌无力、牛皮癣、僵直性脊椎炎、肝硬化或干癣性关节炎。The pharmaceutical composition for treating an immunoinflammatory condition according to claim 1, wherein the immunoinflammatory condition is: rheumatoid arthritis, cognac, type 1 diabetes, adult sexual history , optic neuromyelitis, Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, severe Muscle weakness, psoriasis, ankylosing spondylitis, cirrhosis or dryness arthritis.
  3. 根据权利要求1所述的用于治疗免疫发炎病症之医药组合物，其特征在于：其进一步包含一第二药物。A pharmaceutical composition for treating an immunoinflammatory condition according to claim 1, further comprising a second drug.
  4. 根据权利要求3所述的用于治疗免疫发炎病症之医药组合物，其特征在于：其中该第二药物选自由非类固醇抗发炎药、COX-2抑制剂、生物分子、免疫调节剂、小分子免疫调节剂、疾病修饰抗风湿药、黄嘌呤、抗胆碱化合物、β受体协同剂、支气管扩张剂、非类固醇免疫亲和蛋白依存免疫抑制剂、维生素D类似物、补骨脂素、维生素A酸及5-胺基水杨酸所构成之群。The pharmaceutical composition for treating an immunoinflammatory condition according to claim 3, wherein the second drug is selected from the group consisting of a non-steroidal anti-inflammatory drug, a COX-2 inhibitor, a biomolecule, an immunomodulator, and a small molecule. Immunomodulators, disease-modifying antirheumatic drugs, jaundice, anticholinergic compounds, beta-receptor synergists, bronchodilators, non-steroidal immunoaffinity protein-dependent immunosuppressants, vitamin D analogues, psoralen, vitamins A group of A acid and 5-aminosalicylic acid.
  5. 根据权利要求4所述的用于治疗免疫发炎病症之医药组合物，其特征在于：其中该疾病修饰抗风湿药为托法替尼。The pharmaceutical composition for treating an immunoinflammatory condition according to claim 4, wherein the disease-modifying antirheumatic drug is tofacitinib.
  6. 根据权利要求1至5中任一项所述的用于治疗免疫发炎病症之医药组合物，其特征在于：系呈锭剂或胶囊之型式。The pharmaceutical composition for treating an immunoinflammatory condition according to any one of claims 1 to 5, which is in the form of a tablet or a capsule.
  7. 根据权利要求6所述的用于治疗免疫发炎病症之医药组合物，其特征在于：该医药组合物配方为局部投予用药或全身投予用药。The pharmaceutical composition for treating an immunoinflammatory condition according to claim 6, wherein the pharmaceutical composition is formulated for topical administration or systemic administration.
  8. 一种阿卡波糖，其特征在于：所述阿卡波糖供制备免疫调节药物之用途。An acarbose characterized by the use of the acarbose for the preparation of an immunomodulatory drug.
  9. 根据权利要求8所述的阿卡波糖，其特征在于：其中该免疫调节药物系用于：类风湿性关节炎、干癣、第一型糖尿病、成人性史底耳氏症、视神经脊髓炎、克隆氏症、溃疡性大肠炎、气喘、慢性阻塞性肺病、风湿性多肌痛症、巨细胞动脉炎、全身性红斑狼疮、异位性皮肤炎、多发性硬化症、重症肌无力、牛皮癣、僵直性脊椎炎、肝硬化或干癣性关节炎。 The acarbose according to claim 8, wherein the immunomodulatory drug is used for: rheumatoid arthritis, cognac, type 1 diabetes, adult sexual history, optic neuromyelitis , Crohn's disease, ulcerative colitis, asthma, chronic obstructive pulmonary disease, rheumatic polymyalgia, giant cell arteritis, systemic lupus erythematosus, atopic dermatitis, multiple sclerosis, myasthenia gravis, psoriasis , ankylosing spondylitis, cirrhosis or dryness arthritis.
PCT/CN2015/080849 2015-06-05 2015-06-05 Pharmaceutical composition containing acarbose and use thereof in regulating immunization WO2016192098A1 (en)

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CN1823795A (en) * 2005-12-30 2006-08-30 刘展欣 Medicinal composition for treating diabetes and its preparation method

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