WO2017076271A1 - Composition combinée à base d'acide obéticholique et de berbérine et ses utilisations - Google Patents

Composition combinée à base d'acide obéticholique et de berbérine et ses utilisations Download PDF

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Publication number
WO2017076271A1
WO2017076271A1 PCT/CN2016/104202 CN2016104202W WO2017076271A1 WO 2017076271 A1 WO2017076271 A1 WO 2017076271A1 CN 2016104202 W CN2016104202 W CN 2016104202W WO 2017076271 A1 WO2017076271 A1 WO 2017076271A1
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Prior art keywords
pharmaceutically acceptable
acceptable salt
berberine
oleic acid
acid
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PCT/CN2016/104202
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English (en)
Chinese (zh)
Inventor
潘海
高妍
杨健
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北京凯因科技股份有限公司
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Publication of WO2017076271A1 publication Critical patent/WO2017076271A1/fr

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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
    • A61K31/4353—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 ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4375—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 ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a six-membered ring having nitrogen as a ring heteroatom, e.g. quinolizines, naphthyridines, berberine, vincamine
    • 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
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/575—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of three or more carbon atoms, e.g. cholane, cholestane, ergosterol, sitosterol

Definitions

  • the present invention belongs to the field of pharmaceutical technology, and in particular, the present invention relates to a combination composition, preparation, preparation method and application thereof comprising oleic acid and berberine.
  • Obeticholic acid also known as 6-ethyl chenodeoxycholic acid (6-ECDCA)
  • OCA is a natural ligand for the farnesyl derivative X receptor (FXR) and is an excitement of FXR.
  • Agent Chinese Patent Application No. 201380043964 discloses a C-type crystal of oleic acid, which is expressly recognized to bring about side effects such as lowering high-density lipoprotein; and Chinese Patent Application No. 201510384385 discloses a chemical synthesis method of oleic acid None of them involved in combination therapy.
  • Berberine its hydrochloride form (Berberine Hydrochloride, BBR for short) is commonly known as berberine, an important alkaloid with significant bacteriostatic effects, including against multiple pathogenic bacteria ( For example, dysentery bacilli, Mycobacterium tuberculosis, pneumococcal bacteria, typhoid bacillus, and diphtheria bacilli have inhibitory effects. Among them, dysentery bacilli have the strongest effect, and are commonly used in clinical treatment of gastrointestinal diseases such as bacterial gastroenteritis and dysentery. Chinese Patent Application Nos.
  • 201110100034, 201110100066, and 201110100157 respectively disclose derivatized compounds of berberine-coupled cholic acid, which utilize the targeting of cholic acid, so that the administration of the uncoupled forms is not revealed, and the gallstones therein are The acid is not oleic acid.
  • a combination of oleic acid and berberine hydrochloride not only increases (or even synergistically increases) the efficacy of both reducing triglycerides, blood sugar and/or transaminase, but also lowers cholesterol, low-density lipoprotein And/or high-density lipoprotein-induced side effects or adverse reactions, as a whole, can also lower cholesterol and / or low-density lipoprotein, and even reduce the use of oleic acid and / or berberine hydrochloride the amount.
  • the preparation of the compound medicine can be as simple as direct mixing of oleic acid and berberine hydrochloride, and the preparation process is simple and low in cost, and the safety evaluation result and quality index of oleic acid and berberine can be partially used. , saving the cost of approval.
  • the technical problem to be solved by the present invention is to provide a new pharmaceutical composition which can be used for lowering blood sugar, blood fat and low density. Lipoprotein and/or transaminase levels, and/or, can be used to treat cirrhosis, fatty liver, hyperlipidemia, hyperglycemia, obesity, and/or liver fibrosis. Further, the present invention also provides a preparation, a preparation method, an application, and the like based on the pharmaceutical composition.
  • the present invention provides a pharmaceutical composition comprising oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof.
  • the pharmaceutical composition of the present invention may not include other active pharmaceutical compounds, that is, the pharmaceutical composition of the present invention may be composed of oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof.
  • composition As used herein, the terms pharmaceutical composition and combination composition are used interchangeably unless otherwise indicated or contradicted.
  • a pharmaceutically acceptable salt refers to a salt suitable for contact with tissues of a human or animal without excessive toxicity, irritation or allergic reaction, and the like.
  • Pharmaceutically acceptable salts are well known in the art.
  • the pharmaceutically acceptable salt of berberine may be an acid addition salt
  • the pharmaceutically acceptable salt of oleic acid may be a base addition salt.
  • Representative acid addition salts include, but are not limited to, acetate, dihexanoate, alginate, citrate, aspartate, benzoate, besylate, hydrogen sulfate, butyric acid Salt, camphorate, camphor sulfonate, glycerol phosphate, hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide, 2-hydroxyethyl Sulfonate, lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate, oxalate, 3-phenylpropionate, propionate, succinate, tartaric acid Salts, phosphates, glutamates, bicarbonates, p-toluenesulfonates and undecanoates.
  • Preferred acids which can be used to form pharmaceutically acceptable salts are hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, oxalic acid, maleic acid, succinic acid and citric acid.
  • the cations in the pharmaceutically acceptable base addition salts include, but are not limited to, alkali metal or alkaline earth metal ions such as lithium, sodium, potassium, calcium, magnesium, and aluminum, and non-toxic quaternary ammonium cations such as ammonium, tetramethylammonium, Tetraethylammonium, methylamine, dimethylamine, trimethylamine, triethylamine, diethylamine, ethylamine, diethylamine, ethanolamine, diethanolamine, piperidine, piperazine, and the like.
  • Preferred base addition salts include sodium and potassium salts.
  • oleic acid or a pharmaceutically acceptable salt thereof is oleic acid, i.e., a form which does not form a salt.
  • berberine or a pharmaceutically acceptable salt thereof is berberine hydrochloride, that is, berberine.
  • the weight ratio of oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof is octoberic acid and berberine hydrochloride.
  • one skilled in the art can calculate other pharmaceutically acceptable salts of octaerythric acid and berberine or other pharmaceutically acceptable thereof by the weight ratio of oleic acid and berberine hydrochloride described above. The weight ratio of salt.
  • the present invention provides a process for the preparation of a pharmaceutical composition according to the first aspect of the present invention, which comprises a mixture of oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof process.
  • a pharmaceutical composition according to the first aspect of the present invention which comprises a mixture of oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof process.
  • the method is simple in operation and low in cost.
  • the preparation method of the second aspect of the present invention may preferably each of the preferred aspects of the first aspect of the present invention, if not specifically indicated or contradicted, for example, oleic acid or a pharmaceutically acceptable salt thereof and berberine or Weight of pharmaceutically acceptable salt Quantity ratio and so on.
  • the present invention provides a pharmaceutical preparation comprising the pharmaceutical composition of the first aspect of the invention and a pharmaceutically acceptable adjuvant.
  • pharmaceutically acceptable adjuvants include pharmaceutically acceptable carriers, excipients, diluents and the like which are compatible with the active ingredient.
  • the preparation of pharmaceutical preparations using pharmaceutically acceptable adjuvants is well known to those of ordinary skill in the art.
  • the pharmaceutical preparation of the present invention combines an active ingredient (obeyolic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof) with a pharmaceutically acceptable adjuvant to prepare various
  • the preparation is preferably a solid preparation and a liquid preparation.
  • the preparation of the present invention may be in a unit dosage form such as a tablet, a pill, a capsule (including a sustained release or a delayed release form), a powder, a suspension, a granule, an elixir, a syrup, an emulsion, a suspension, an injection
  • a unit dosage form such as a tablet, a pill, a capsule (including a sustained release or a delayed release form), a powder, a suspension, a granule, an elixir, a syrup, an emulsion, a suspension, an injection
  • the dosage form and various sustained release dosage forms are suitable for various administration modes, such as oral, parenteral injection, mucosal, intramuscular, intravenous, subcutaneous, intraocular, intradermal or transdermal administration.
  • the pharmaceutical preparation of the third aspect of the invention is an oral pharmaceutical preparation.
  • the amount of the pharmaceutical preparation can be lowered by the active ingredient (for example, oleic acid and berberine hydrochloride, especially oleic acid), thereby reducing side effects or adverse reactions caused by the active ingredient.
  • the active ingredient for example, oleic acid and berberine hydrochloride, especially oleic acid
  • the pharmaceutical preparation of the third aspect of the present invention may preferably each of the preferred aspects of the first aspect of the present invention, if not specifically indicated or contradicted, for example, oleic acid or a pharmaceutically acceptable salt thereof and berberine or The weight ratio of the pharmaceutically acceptable salt, and the like.
  • the present invention provides a combination of oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof for use in the preparation for lowering blood glucose, blood lipids, low density lipoprotein and/or Application in transaminase levels of drugs.
  • the drug in the application of the fourth aspect of the invention may be used to reduce any of these levels.
  • the blood lipid level is cholesterol and/or triglyceride levels; it is also preferred that the transaminase level is alanine aminotransferase and/or aspartate aminotransferase levels. Either of these levels can be caused by a poor diet structure, so it may not constitute a disease.
  • the medicament is for reducing blood glucose, blood lipids, low density lipoprotein and/or transaminase levels which have not reached the disease standard, that is, the medicament in the application of the fourth aspect of the invention can be regarded as Food or health products.
  • the present invention provides a combination of oleic acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for the prevention and/or treatment of liver cirrhosis, fatty liver (preferably It is used in steatohepatitis such as nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), hyperlipidemia, hyperglycemia, obesity and/or liver fibrosis.
  • NAFLD nonalcoholic fatty liver disease
  • NASH nonalcoholic steatohepatitis
  • hyperlipidemia hyperglycemia
  • obesity and/or liver fibrosis a medicament in the application of the fifth aspect of the invention may be for the treatment of any of these diseases. These diseases all go beyond the scope of health standards.
  • the liver fibrosis may be chemical liver fibrosis, that is, caused by ingestion of hepatotoxic substances (for example, alcohol and/or carbon tetrachloride, or hepatotoxic drugs).
  • Hepatic fibrosis can also be caused by non-chemical liver fibrosis (such as high fat, high sugar, high cholesterol diet to the accumulation of fat in the liver, or caused by liver damage caused by metabolic disorders).
  • the present invention provides the use of berberine or a pharmaceutically acceptable salt thereof for the preparation of a medicament for reducing side effects or adverse reactions of oleic acid or a pharmaceutically acceptable salt thereof.
  • the side effect or adverse reaction is to increase cholesterol and/or low density lipoprotein levels; and preferably, side effects or adverse reactions are to lower high density lipoprotein levels.
  • the present inventors have found that administration of oleic acid raises cholesterol levels, increases low-density lipoprotein levels, and/or lowers high-density lipoprotein levels, which are adverse health factors, and administration of berberine can be reduced. Side effects or adverse reactions.
  • the side effect or the adverse reaction is a side effect or an adverse reaction which is lowered by lowering the dose of oleic acid.
  • the medicament may not comprise other active pharmaceutical compounds, ie the active pharmaceutical compound of the medicament in the application of the fourth, fifth and/or sixth aspects of the invention Orbital acid or a pharmaceutically acceptable salt thereof and berberine or a pharmaceutically acceptable salt thereof.
  • the drug in the application of the fourth, fifth and/or sixth aspects of the invention is the pharmaceutical composition of the first aspect of the invention or the pharmaceutical preparation of the third aspect of the invention.
  • the oleic acid or a pharmaceutically acceptable salt thereof is oleic acid, and/or berberine or a pharmaceutically acceptable compound thereof
  • the salt accepted is berberine hydrochloride (ie berberine).
  • oleic acid or a pharmaceutically acceptable salt thereof and berberine or the berberine or the berberine hydrochloride or the like is from 3 to 30:30 to 300, preferably from 4 to 20:50 to 250, more preferably from 5 to 10:90 to 180, for example, 10:100 or 5:90.
  • the excellent effects achieved by the present invention include increased efficacy, reduced side effects or adverse reactions, reduced dosage, simple preparation, and/or reduced cost.
  • Figure 1 is a comparison of the degree of liver fibrosis in each group, where 1 is the control group, 2 is the CCl 4 group, 3 is the BBR group; 4 is the OCA group; 5 is the OCA + BBR high dose group; 6 is the OCA + BBR Low dose group.
  • SD rats were fed a basal diet for one week as an acclimation period, and then randomly divided into 6 groups: (1) normal group (control), fed a low-fat diet; (2) high-fat diet group, with high-fat diet (78.85) % raw grain, 21% lard, 0.15% cholesterol); (3) BBR group, high fat diet (same as above) + berberine (administration, 180mg/kg, qd); (4) OCA group, high fat diet (ibid.) feeding + oleic acid (glycing, 10 mg/kg, qd); (5) high dose OCA + BBR group, high fat diet (ibid.) + high dose of olbecholic acid combined with berberine (irrigation) Stomach, 10mg/kg+180mg/kg, qd); (6) Low dose of OCA+BBR, high-fat diet (ibid.) + high dose of olbecholic acid combined with berberine (glycing, 5mg/kg+90
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • TC serum total cholesterol
  • LDL-c low-density lipoprotein
  • HDL-c triglyceride
  • Glucose blood glucose
  • Acid can reduce the levels of triglycerides, blood sugar and liver function indicators, but oleic acid can not reduce, even increase the level of total cholesterol and low-density lipoprotein, reduce the level of high-density lipoprotein, and berberine can reduce The levels of total cholesterol and low-density lipoprotein, but have little effect on the level of high-density lipoprotein; combined administration of berberine and oleic acid can reduce, in addition to having little effect on the level of high-density lipoprotein, Even further lowering blood glucose, blood lipids, low-density lipoprotein and liver function indicators, especially in the low-dose group, suggests that co-administration may have a synergistic effect on these levels. The same effect, especially the possibility of reducing the side effects or adverse reactions caused by oleic acid in total cholesterol, low density lipoprotein and high density lipoprotein.
  • mice Male C57/B6 mice were randomly divided into normal group (Control), CCL 4 group, BBR group (BBR 100 mg/kg), OCA group (administered OCA 10 mg/kg), OCA after 1 week of adaptive feeding. +BBR high dose group (10mg/kg+100mg/kg), OCA+BBR low dose group (5mg/kg+50mg/kg). Except the normal group, the other groups were intraperitoneally injected with 10% CCl 4 2 ⁇ l/g 3 times a week for 4 weeks. The normal group was intraperitoneally injected with the same amount of olive oil. The corresponding drugs were administered by intragastric administration on the first day of the model, and the normal group and the CCL 4 group were given an equal volume of 1% methylcellulose.
  • liver function indexes such as alanine aminotransferase (ALT) and aspartate aminotransferase (AST); liver was taken, HE pathological examination of liver was performed, and liver fibrosis was detected by collagen staining.
  • ALT alanine aminotransferase
  • AST aspartate aminotransferase
  • the liver function index results of mice with liver fibrosis induced by CCl 4 are shown in Table 2, and the degree of liver fibrosis is shown in Fig. 1.
  • the liver function index of the CCl 4 group was significantly higher than that of the normal group, indicating that the liver injury was induced by CCl 4 induction.
  • the administration of berberine and oleic acid alone can reduce the liver function index of mice with liver injury.
  • Combined administration of berberine and oleic acid can further reduce the liver function index of mice with liver injury, especially in the low-dose group. It is suggested that the combined administration may synergistically increase the efficacy and reduce the dose of oleic acid. Reduce the side effects or adverse reactions caused by it.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
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Abstract

La présente invention concerne une composition pharmaceutique comprenant de l'acide obéticholique ou un sel de qualité pharmaceutique de celui-ci et de la berbérine ou un sel de qualité pharmaceutique de celle-ci. De plus, la présente invention concerne également une préparation associée à la composition pharmaceutique, un procédé de préparation de celle-ci et ses utilisations.
PCT/CN2016/104202 2015-11-04 2016-11-01 Composition combinée à base d'acide obéticholique et de berbérine et ses utilisations WO2017076271A1 (fr)

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CN201510740833.6A CN105168228B (zh) 2015-11-04 2015-11-04 奥贝胆酸和小檗碱的复方组合物及其应用
CN201510740833.6 2015-11-04

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CN105168228B (zh) * 2015-11-04 2016-06-22 北京凯因科技股份有限公司 奥贝胆酸和小檗碱的复方组合物及其应用
WO2017137931A1 (fr) 2016-02-10 2017-08-17 Dr. Reddy’S Laboratories Limited Sel d'amine de l'acide obéticholique
CN111138427B (zh) 2018-12-05 2021-09-17 江西富祥药业股份有限公司 黄连素及其类似物的非诺贝特酸盐、晶型、制备方法及应用
CN114716498B (zh) * 2022-01-20 2024-01-23 成都贝诺科成生物科技有限公司 一种高稳定性的失碳熊去氧胆酸小檗碱盐晶型及其制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN105168228A (zh) * 2015-11-04 2015-12-23 北京凯因科技股份有限公司 奥贝胆酸和小檗碱的复方组合物及其应用
WO2016015634A1 (fr) * 2014-07-29 2016-02-04 Shenzhen Hightide Biopharmaceutical, Ltd. Sels de berbérine, sels ursodésoxycholiques et des combinaisons, des procédés de préparation et d'application correspondants

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US20140187633A1 (en) * 2012-12-31 2014-07-03 Amarin Pharmaceuticals Ireland Limited Methods of treating or preventing nonalcoholic steatohepatitis and/or primary biliary cirrhosis
CN103479635A (zh) * 2013-08-01 2014-01-01 中国人民解放军第三〇二医院 一种用于预防和治疗非酒精性脂肪肝的药物组合物及其用途

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016015634A1 (fr) * 2014-07-29 2016-02-04 Shenzhen Hightide Biopharmaceutical, Ltd. Sels de berbérine, sels ursodésoxycholiques et des combinaisons, des procédés de préparation et d'application correspondants
CN105168228A (zh) * 2015-11-04 2015-12-23 北京凯因科技股份有限公司 奥贝胆酸和小檗碱的复方组合物及其应用

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
THOMPSON, ALEXANDER JAMES ET AL.: "Antifibrotic Therapies: Will We Ever Get There", CURRENT GASTROENTEROLOGY REPORTS, vol. 12, no. 1, 28 January 2010 (2010-01-28), pages 23 - 29, XP001525248, ISSN: 1522-8037 *

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