WO2017211182A1 - 一种预防或治疗炎性疾病的药物组合物 - Google Patents
一种预防或治疗炎性疾病的药物组合物 Download PDFInfo
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- WO2017211182A1 WO2017211182A1 PCT/CN2017/085619 CN2017085619W WO2017211182A1 WO 2017211182 A1 WO2017211182 A1 WO 2017211182A1 CN 2017085619 W CN2017085619 W CN 2017085619W WO 2017211182 A1 WO2017211182 A1 WO 2017211182A1
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- WIPO (PCT)
- Prior art keywords
- hydroxychloroquine
- ilamodide
- composition
- group
- salt
- Prior art date
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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
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/47—Quinolines; Isoquinolines
- A61K31/4706—4-Aminoquinolines; 8-Aminoquinolines, e.g. chloroquine, primaquine
-
- 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
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/35—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom
- A61K31/352—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having six-membered rings with one oxygen as the only ring hetero atom condensed with carbocyclic rings, e.g. methantheline
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- 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
Definitions
- the invention belongs to the field of medicine, and in particular relates to a combination pharmaceutical composition of hydroxychloroquine and ilamodide.
- Inflammation contributes to the pathogenesis of, for example, the following inflammatory diseases or diseases associated with inflammation: (1) autoimmune diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE); (2) inflammatory components Degenerative diseases such as osteoarthritis (OA); et al. Certain inflammatory diseases can be treated using hydroxychloroquine or ilamodide as an anti-inflammatory agent.
- autoimmune diseases including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE); (2) inflammatory components Degenerative diseases such as osteoarthritis (OA); et al.
- OA osteoarthritis
- Certain inflammatory diseases can be treated using hydroxychloroquine or ilamodide as an anti-inflammatory agent.
- Hydroxychloroquine chemically known as 2-[[4-[(7-chloro-4-quinolinyl)amino]pentyl]ethylamino]-ethanol, is an antimalarial drug of the same chloroquine, due to its inhibition of antigen presentation, It inhibits synovial hyperplasia and has been used in the treatment of rheumatic diseases such as systemic lupus erythematosus, rheumatoid arthritis and Sjogren's syndrome.
- the clinical application is in the form of sulfate. However, its clinical application has many adverse reactions, which limits its further widespread use.
- the main adverse reactions of hydroxychloroquine include: (1) central nervous system response: excitement, nervousness, mood changes, nightmares, mental illness, headache, dizziness, dizziness, tinnitus, nystagmus, neurological deafness, convulsions, ataxia. (2) Neuromuscular reaction: extraocular muscle paralysis, skeletal muscle weakness, deep tendon reflex disappeared or decreased. (3) eye reaction: adjustment disorder, with symptoms of blurred vision; transient edema, punctate to linear opacity, decreased corneal sensitivity; macular edema, atrophy, abnormal pigmentation; visual field defect:; (4) skin Reaction: whitening of hair, hair loss, itching, skin and mucous membrane pigmentation, rash.
- Hematological reactions such as aplastic anemia, neutropenia, leukopenia, thrombocytopenia, and glucose-6-phosphate dehydrogenase (G-6-PD) deficiency in individuals with hemolysis.
- G-6-PD glucose-6-phosphate dehydrogenase
- Gastrointestinal reactions loss of appetite, nausea, vomiting, diarrhea, and abdominal cramps.
- Others weight loss, burnout, deterioration or acceleration of porphyria and non-photosensitive psoriasis.
- Iramod chemical name: N-[3-(formamido)-4-oxo-6-phenoxy-4H-1-benzopyran-7-yl]-methanesulfonamide, can inhibit The expression of various cytokines and rheumatoid factors has multiple effects, which can significantly improve the symptoms and signs of patients with rheumatoid arthritis, effectively prevent bone destruction, reduce the disability rate and teratogenic rate of patients, and improve the quality of life of patients; In addition, ilamod has a significant therapeutic effect on diseases such as lupus erythematosus.
- ALT alanine aminotransferase
- AST glutamic acid Aminotransferase
- ⁇ -GTP increased in 86 cases (15.72%, 547 cases
- ALP increased in 119 cases (14.91%)
- NAG increased in 72 cases (9.02%)
- ⁇ 2 microglobulin increased in 59 cases (7.39%)
- total bile acid increased in 22 cases (5.71%, 385 cases)
- abdominal pain in 44 cases 5.51%
- rash in 41 cases 5.14%.
- the present invention first provides a combination pharmaceutical composition for preventing or treating an inflammatory disease or a disease associated with inflammation.
- compositions of the present invention are suitable for treating different patient populations and different stages of the disease process by administering to the individual an effective amount of hydroxychloroquine and ilamodide, including risk periods, early and established inflammatory properties.
- Diseases including autoimmune diseases, degenerative inflammatory diseases, metabolic inflammatory diseases, and other inflammatory diseases and diseases associated with inflammation.
- the treatment is initiated when the individual has established a disease to prevent disease progression, treat symptoms and symptoms, or reverse signs and symptoms.
- Administration of the pharmaceutical compositions of the invention may last for a longer period of time, such as over a period of months or years, and in some embodiments, the treatment lasts for a lifetime.
- composition of the present invention comprises hydroxychloroquine and ilammod, and the molar ratio of hydroxychloroquine to ilamod is Preferred More preferably, it is 2.8:1, 8.4:1 or 16.7:1.
- the hydroxychloroquine of the present invention also includes pharmaceutically acceptable salts thereof.
- composition of the present invention comprises hydroxychloroquine sulfate and ilamodide, wherein the weight ratio of hydroxychloroquine sulfate and ilamodide is selected from 1:1 to 20:1, further preferably 5:2, 15 : 2, 15:1.
- the invention provides a unit dosage form of a formulation of the invention.
- the composition of the present invention comprises hydroxychloroquine sulfate 150 mg and ilamodide 20 mg, or hydroxychloroquine 100 mg and ilamore 20 mg, hydroxychloroquine 150 mg and ilamodide 10 mg, hydroxychloroquine sulfate 100 mg.
- Elamomod 10mg is a formulation of the invention.
- the invention relates to the use of hydroxychloroquine and a salt thereof for the manufacture of a medicament for alleviating the toxic side effects of ilamodide, in particular, said side effects being elevated alanine aminotransferase in the blood.
- the present invention provides the use of hydroxychloroquine and a salt thereof for the manufacture of a medicament for use in combination with elalimide.
- pharmaceutically acceptable salt means that the compounds of the invention are considered safe (and effective) for oral and topical use in mammals (eg, administrations such as FDA and EMEA) and have The desired biologically active salt.
- Pharmaceutically acceptable salts include the salts of acidic or basic groups present in the compounds of the invention.
- salts include, but are not limited to, sulfates, hydrogen sulfates, phosphates, hydrochlorides, as are known in the art. Hydrobromide, hydroiodide, nitrate, acid phosphate, isonicotinic acid, acetate, lactate, salicylate, citrate, tartrate, pantothenate, hydrogen tartrate , ascorbate, succinate, maleate, gentisate, fumarate, gluconate, gluconate, saccharate, formate, benzoate, glutamine Acid salt, methanesulfonate, ethanesulfonate, besylate, p-toluenesulfonate, pamoate (ie 1,1'-methylene-bis-(2-hydroxy-3-naphthate) )), aluminum salt, calcium salt, lithium salt, magnesium salt, potassium salt, sodium salt, zinc salt and the like.
- a preferred salt is a sulfate, hydrogen s
- the pharmaceutical composition of the present invention may further comprise a pharmaceutically acceptable excipient.
- Excipients are generally pharmacologically inactive materials formulated with a pharmaceutical active pharmaceutical ingredient ("API").
- API active pharmaceutical ingredient
- excipients are often used to inflate the active ingredient-containing formulation (and thus often referred to as “extenders”, “fillers” or “diluents”) to allow for convenience and accuracy.
- Dispense the drug substance It can also serve different therapeutic enhancing purposes, such as promoting drug absorption or dissolution, or other pharmacodynamic considerations.
- compositions of the present invention may be formulated into pharmaceutical compositions by combining with a pharmaceutically acceptable carrier or diluent, and may be formulated as a solid, semi-solid, liquid or gaseous form.
- a pharmaceutically acceptable carrier or diluent such as tablets, capsules, powders, granules, ointments, solutions, suppositories, injections, inhalants, gels, microspheres and aerosols.
- administration of the compound can be accomplished in a variety of ways, including orally, buccally, rectally, parenterally, intraperitoneally, intradermally, transdermally, intratracheally, intra-articularly, and the like.
- the active agent can be systemic after administration, or can be localized by the use of regional, intramural administration or use of an implant that retains the active dose at the site of implantation.
- the formulation is an oral formulation.
- the combination therapies used in the present invention may allow the dosage of each monotherapy to be lower than currently used in standard procedures while achieving significant efficacy, including efficacy over conventional administration of either monotherapy.
- the dosage level can vary with the particular compound, the severity of the condition, and the sensitivity of the subject to side effects. Some specific compounds are more effective than others.
- the preferred dosage of a given compound can be readily determined by one of ordinary skill in the art by a variety of means. A preferred means is to measure the physiological potency of a given compound.
- the use of combination therapies may allow the dosage of each monotherapy to be lower than currently used in standard procedures while achieving significant efficacy, including greater efficacy than would be achieved with conventional monotherapy.
- the preferred route of administration and corresponding dosage form and amount, as well as the dosage regimen are within the skill of the clinician.
- the combination therapy will be delivered two to three times a day.
- administration can be used twice daily.
- such generalization does not take into account specific types such as inflammatory diseases, the particular therapeutic agent involved, and its pharmacodynamic profile, as well as important variables such as the particular individual involved.
- For approved products on the market much of this information has been provided through the results of clinical studies conducted to obtain such approval. In other cases, such information may be obtained in a straightforward manner based on the teaching content and guidelines contained in this specification, based on the knowledge and skill of the skilled person.
- the results obtained may also correspond to the approved products from the same assay.
- the data of the assessment is relevant.
- unit dose or "unit dosage form” refers to a physically discrete unit suitable as a single dose for use in a human subject, each unit containing a predetermined amount of the drug calculated to produce the desired effect, together with a pharmaceutically acceptable dilution. Agent, carrier or vehicle.
- the specifications of the unit dosage form of the invention depend on the particular combination employed and the effect to be achieved and the pharmacodynamic properties associated with the host.
- Example 1 Effect of hydroxychloroquine sulfate and ilamodide in the treatment of arthritis in mice
- Dose group design normal control group, model control group (normal saline), hydroxychloroquine sulfate (15 mg/kg) group, ilamodide (1 mg/kg) group, ilamodide (2 mg/kg) group, hydroxysulfate Chloroquine/Iramod was administered in combination with 2.8:1 group (5 mg/kg hydroxychloroquine sulfate + 2 mg/kg ilamodide), hydroxychloroquine sulfate/ilalimote 8.4:1 group (15 mg/kg sulphuric acid) Hydroxychloroquine + 2 mg/kg ilamodide, hydroxychloroquine sulfate / ilamodide combined with 16.7:1 group (15 mg/kg hydroxychloroquine +1 mg/kg ilamod), the ratio is Ratio calculation.
- a collagen-type mouse arthritis animal model Using a mouse as a test animal, 80 SPF-class DBA/1 mice, male, 7-8 weeks old, weighing 18-22 g, were randomly divided into 8 groups. On the 0th day, except for the normal group, the mouse CIA model was established: chicken cartilage type II collagen (cII) was dissolved in a solution of 4 mg/ml with 0.1 mol/l acetic acid, and placed in a refrigerator at 4 ° C for 24 h. Type II collagen was fully emulsified in the same volume as complete Freund's adjuvant (CFA) containing 4 mg/ml Myeobaeterium tuberculosis strain H37Rv.
- CFA complete Freund's adjuvant
- each emulsifier was injected into the tail skin for sensitization. After 21 days, it was fully emulsified with 4 mg/ml of type II collagen (cII) and incomplete Freund's adjuvant (IFA) in the same volume, and then re-immunized at the tail with the same dose of emulsifier.
- cII type II collagen
- IFA incomplete Freund's adjuvant
- Subcutaneous injection from the 30th day of modeling Each dose group was taken twice a day for 10 consecutive days, and the body weight and joint score were measured every 3 days from the 21st to the 70th day after modeling. The diameter of the hind foot was used to observe the effect of the drug on collagen-induced arthritis in mice. On day 70, mice were sacrificed by dislocation.
- the arthritis evaluation indicators are as follows:
- the diameters and the thickness of the ankles of the left and right ankles of the mice were measured by vernier calipers before and after the modeling and from the 21st to the 70th day after the modeling, and the results were recorded.
- test results were expressed by mathematical mean plus or minus standard deviation (mean ⁇ SD), and t test was performed between each drug-administered group and the control group by SPSS11.0 software, where * indicates p ⁇ 0.05, ** indicates p ⁇ 0.01.
- Example 2 Effect of hydroxychloroquine sulfate and ilamodide on improving liver function
- Lewis rats were divided into 4 treatment groups, 10 in each group: control group, hydroxychloroquine sulfate (15 mg/kg) group, ilamodide (2 mg/kg) group, hydroxychloroquine sulfate / ilamodide co-administration group (15 mg/kg hydroxychloroquine + 2 mg/kg ilamodide, the ratio is calculated as a molar ratio of 25:1).
- the treatment group was administered once a day for feeding.
- Alanine aminotransferase (ALT: ⁇ mol.s -1 /L) was measured at 1, 4, 8 and 12 weeks after the start of each rat.
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- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Epidemiology (AREA)
- Immunology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
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- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
Description
组别 | 关节评分 |
正常对照组 | 0.00±0.00** |
模型对照组(生理盐水) | 15.1±1.8 |
硫酸羟氯喹(15mg/kg)组 | 14.3±1.1** |
艾拉莫德(1mg/kg)组 | 10.5±1.1** |
艾拉莫德(2mg/kg)组 | 5.1±1.5** |
硫酸羟氯喹/艾拉莫德联合给药2.8:1组 | 4.2±1.2** |
硫酸羟氯喹/艾拉莫德联合给药8.4:1组 | 3.5±1.0** |
硫酸羟氯喹/艾拉莫德联合给药16.7:1组 | 7.1±1.2** |
Claims (11)
- 一种药物组合物,包括羟氯喹和艾拉莫德。
- 权利要求2所述的组合物,其特征在于所述羟氯喹和艾拉莫德的摩尔比为2.8:1、8.4:1或16.7:1。
- 权利要求1所述的组合物,其特征在于所述羟氯喹为药学上可接受的盐的形式,优选为硫酸盐
- 权利要求1所述的组合物,进一步包括药学上可以接受的赋形剂。
- 权利要求6所述的的组合物,其单位剂量含有硫酸羟氯喹150mg及艾拉莫德10mg。
- 羟氯喹及其盐在制备减轻艾拉莫德毒性副作用的药物中的用途。
- 权利要求7中所述的用途,其特征在于所述的盐为硫酸盐。
- 权利要求7所述的的用途,其特征在于所述的副作用为血液谷丙转氨酶升高。
- 羟氯喹及其盐在制备与艾拉莫德联合用药的药物中的用途。
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CN201610390779.1 | 2016-06-06 | ||
CN201610390779.1A CN107456454A (zh) | 2016-06-06 | 2016-06-06 | 一种预防或治疗炎性疾病的药物组合物 |
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Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115089584A (zh) * | 2022-06-14 | 2022-09-23 | 广州惠善医疗技术有限公司 | 手性羟氯喹或其药学上可接受的盐在制备防诊治免疫疾病药物中的应用 |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102076845A (zh) * | 2008-04-28 | 2011-05-25 | 特克赛尔公司 | 用于治疗关节炎病的组合物 |
CN103599109A (zh) * | 2013-11-26 | 2014-02-26 | 桂林医学院 | 强的松和羟氯喹在制备复方抗炎药物中的应用 |
CN103826624A (zh) * | 2011-08-30 | 2014-05-28 | 富山化学工业株式会社 | 类风湿性关节炎等自身免疫疾病的处置的改善方法 |
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EP2539470B1 (en) * | 2010-02-24 | 2017-02-22 | The Board of Trustees of The Leland Stanford Junior University | Methods for autoimmune disease diagnosis, prognosis, and treatment |
CA2941429A1 (en) * | 2014-05-27 | 2015-12-03 | Almirall, S.A. | Medical use |
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- 2016-06-06 CN CN201610390779.1A patent/CN107456454A/zh active Pending
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102076845A (zh) * | 2008-04-28 | 2011-05-25 | 特克赛尔公司 | 用于治疗关节炎病的组合物 |
CN103826624A (zh) * | 2011-08-30 | 2014-05-28 | 富山化学工业株式会社 | 类风湿性关节炎等自身免疫疾病的处置的改善方法 |
CN103599109A (zh) * | 2013-11-26 | 2014-02-26 | 桂林医学院 | 强的松和羟氯喹在制备复方抗炎药物中的应用 |
Cited By (1)
Publication number | Priority date | Publication date | Assignee | Title |
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CN115089584A (zh) * | 2022-06-14 | 2022-09-23 | 广州惠善医疗技术有限公司 | 手性羟氯喹或其药学上可接受的盐在制备防诊治免疫疾病药物中的应用 |
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