WO2019073103A1 - Composition pharmaceutique pour le traitement de maladies cardiovasculaires - Google Patents

Composition pharmaceutique pour le traitement de maladies cardiovasculaires Download PDF

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Publication number
WO2019073103A1
WO2019073103A1 PCT/ES2018/070666 ES2018070666W WO2019073103A1 WO 2019073103 A1 WO2019073103 A1 WO 2019073103A1 ES 2018070666 W ES2018070666 W ES 2018070666W WO 2019073103 A1 WO2019073103 A1 WO 2019073103A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
treatment
patients
berberine
cardiovascular diseases
Prior art date
Application number
PCT/ES2018/070666
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English (en)
Spanish (es)
Inventor
María D. GÓMEZ GARRE
Luca Severino VOLONTÉ
Original Assignee
Fundación Para La Investigación Biomédica Del Hospital Clínico San Carlos
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Application filed by Fundación Para La Investigación Biomédica Del Hospital Clínico San Carlos filed Critical Fundación Para La Investigación Biomédica Del Hospital Clínico San Carlos
Publication of WO2019073103A1 publication Critical patent/WO2019073103A1/fr

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Classifications

    • 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
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • 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
    • A61K31/365—Lactones
    • A61K31/366—Lactones having six-membered rings, e.g. delta-lactones
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Definitions

  • the present invention is encompassed within the field of medicine.
  • the present invention relates to a pharmaceutical composition comprising or consisting of: berberine, statins and, optionally, ubiquinol or coenzyme Q10 (CoQ10), for the treatment of cardiovascular diseases.
  • CVD cardiovascular diseases
  • statins inhibitors of the enzyme HMG-CoA reductase
  • HMG-CoA reductase are the main drugs used as lipid-lowering therapy, not only because they improve the lipid profile, in particular they reduce the plasma concentration of LDL cholesterol (c-LDL), but because its effects Benefits in reducing cardiovascular morbidity and mortality are well documented, both in primary and secondary care.
  • c-LDL LDL cholesterol
  • they have a series of limitations that make it necessary to have other treatments to reduce LDL-C.
  • statins there is no direct proportionality between the increased dose of statins and their efficacy; in fact, doubling the dose of statin only reduces plasma LDL-C levels by about 6%, which means that, in many cases, high doses are necessary to achieve objectives.
  • statins some patients do not tolerate high doses of statins, so about one third of them discontinue treatment. Secondly, approximately 40% of patients on treatment with statins alone do not reach the LDL-c levels targets indicated in the clinical guidelines, so they need other drugs that act through mechanisms other than those of the statins
  • the second-line lipid-lowering drug is ezetimibe, an inhibitor of the intestinal absorption of dietary cholesterol. It can be used in monotherapy but its main use is in combination with a statin, since both drugs together reduce LDL-c levels by 20% more than statin alone. The problem is that it has not clearly demonstrated that it reduces CVD, so its use is very controversial and with a high economic cost.
  • PCSK9 is injectable drugs, which makes their administration in a single presentation with any other medication difficult.
  • CVD cardiovascular risk factor
  • the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of: berberine, statins and, optionally, ubiquinol or CoQ10, for the treatment of cardiovascular diseases.
  • berberine either extract, derivative or analogs
  • a lipid-lowering drug preferably statin
  • ubiquinol or CoQ10 in a single presentation.
  • Berberine is an alkaloid extract found in numerous medicinal plants widely used in traditional Chinese and Indian medicine to treat stomach problems, diarrhea and bacterial and fungal infections and which is easy to obtain.
  • the mechanism of action of berberine is essentially derived from the regulation of AMPK (Adenosine Monophosphate activated Protein Kinase).
  • This protein kinase, activated by AMP, is a fundamental ubiquitic enzyme, which participates in the normalization of energy metabolism and in the regulation of food intake and tissue sensitivity.
  • Berberine by activating AMPK, will act on several levels: 1) stimulating the metabolism of fatty acids in the mitochondria, which will reduce the concentrations of circulating lipids in the blood (triglycerides and c-LDL); 2) recently, it has been shown that berberine decreases the expression of PCSK9 and that it positively affects LDL receptor levels (LDLR), which will help to further decrease LDL-c; 3) favoring the extraction of blood from glucose transporters, which will allow a remarkable decrease in blood sugar levels; 4) increasing the production of GLUT4, a glucose transporter that is only found in muscles and fat cells, which will allow a remarkable improvement in insulin sensitivity.
  • LDLR LDL receptor levels
  • statins already have a generic version.
  • the pharmaceutical composition of the invention would preferably contain atorvastatin, simvastatin, rosuvastatin and / or lovastatin.
  • Statins by inhibiting the enzyme HMG-CoA reductase, block not only the endogenous production of cholesterol in the liver, but also and secondarily, the synthesis of CoQ10, which explains the decrease observed in the levels of this endogenous lipid-soluble antioxidant. in certain people treated with these medications.
  • CoQ10 is an antioxidant whose loss involves the decrease of cellular energy and the increase of free radicals, which, in turn, damage mitochondrial DNA, favoring a vicious circle of increased free radicals-mitochondrial damage, and a high associated oxidative stress with chronic inflammation can, among others, contribute to the pathogenesis of cardiovascular diseases.
  • ubiquinol is preferably used because it is the reduced form of CoQ10, and, in blood plasma, more than 90% of CoQ10 is present in this reduced form. In this way, ubiquinol is ready to enter the process of cellular respiration and energy production, unlike traditional CoQ10 (ubiquinone) that requires an initial enzymatic reduction.
  • berberine, statins and, optionally, ubiquinol in a single presentation would be a highly effective treatment but much cheaper than the current ones for the control of CVD and the associated risk factors.
  • the presentation of berberine with a slow-release formulation allows a better dosage.
  • the fact that complementary mechanisms of action are combined would reduce the dose of statin, which would result in fewer side effects, also reduced by the supplement in CoQ10, so it would be a healthier formulation.
  • the administration would be oral, so the punctures that are always very unpopular among the patients would be avoided.
  • the combination of all the components in a single drug would further favor adherence to the treatment.
  • the first aspect of the present invention refers to a stable pharmaceutical formulation, which serves for oral administration and has the following composition: a) 500-1000 mg of berberine (extract, derivative or analogs), with a slow-release formulation, b) 5-40 mg of a statin and c) 30-90 mg of ubiquinol.
  • the statin is atorvastatin.
  • the statin is simvastatin.
  • the statin is rosuvastatin.
  • the statin is lovastatin.
  • the second aspect of the present invention relates to a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting of: a) berberine and b) at least one statin selected from the group comprising or consisting of: atorvastatin, simvastatin, rosuvastatin and / or lovastatin.
  • the composition of the invention further comprises ubiquinol or coQ10.
  • the dose of statin present in the composition of the invention is between 5 and 80 mg, preferably between 5 and 40 mg.
  • the dose of atorvastatin is 10, 20, 40 or 80 mg
  • the dose of simvastatin is 5, 10, 20, 40 or 80 mg
  • the dose of rosuvastatin is 5, 10, 20 or 40 mg
  • the dose of lovastatin is 10, 20 or 40 mg.
  • the The pharmaceutical composition of the invention comprises or consists of: a) 500-1000 mg of berberine, 5-40 mg of at least one statin selected from the group comprising or consisting of: atorvastatin, simvastatin, rosuvastatin and / or lovastatin, and 30- 90 mg of ubiquinol.
  • the composition of the invention further comprises pharmaceutically acceptable excipients.
  • the third aspect of the present invention refers to the composition of the invention to be used in the treatment of cardiovascular diseases.
  • the present invention relates to a method for the treatment of cardiovascular diseases comprising the administration of a therapeutically acceptable amount of the composition of the invention.
  • the composition of the invention is administered orally.
  • FIG. 1 Schematic view with a possible placement of the chemical compounds in the invention.
  • Example 1 Effect of the combination of statins and berberine in the levels of this role
  • the composition of the invention was administered to 5 patients (Pac) (4 men and 1 woman), with a mean age of 55 years (range IC 40-62 years).
  • the patients took a combination of rosuvastatin (RSV) and 500 mg of berberine (BBR) for 3 months.
  • RSV rosuvastatin
  • BBR berberine
  • the subjects had mean baseline levels of cholesterol (TC) 280 mg / dL (range 201- 340 mg / dL) and, after three months of treatment, they decreased to 180 mg / dL (range IC 120-220 mg / dL). The average reduction observed was 37.5% (range IC 30.8-49.7%).
  • TC cholesterol

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  • Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicinal Preparation (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour le traitement de maladies cardiovasculaires. En particulier, la présente invention concerne une composition pharmaceutique qui comprend de la berbérine, des statines et, éventuellement, de l'ubiquinol ou une coenzyme Q10 (CoQ10), ou est constituée de ceux-ci, pour le traitement de maladies cardiovasculaires.
PCT/ES2018/070666 2017-10-13 2018-10-15 Composition pharmaceutique pour le traitement de maladies cardiovasculaires WO2019073103A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ESP201731206 2017-10-13
ES201731206A ES2645028B2 (es) 2017-10-13 2017-10-13 Preparación farmacéutica única y estable que contiene berberina, en formulación de liberación lenta, una estatina y ubiquinol para el tratamiento de la enfermedad cardiovascular y los factores de riesgo asociados

Publications (1)

Publication Number Publication Date
WO2019073103A1 true WO2019073103A1 (fr) 2019-04-18

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WO (1) WO2019073103A1 (fr)

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052822A1 (fr) * 2000-01-20 2001-07-26 Chopra Raj K Forme reduite de coenzyme q dans des formes posologiques stables a haute biodisponibilite et applications correspondantes
WO2006029577A1 (fr) * 2004-09-17 2006-03-23 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Methodes et compositions de traitement de l'hyperlipidemie

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DK1983989T3 (da) * 2006-02-09 2013-10-14 Ca Nat Research Council Kombinationer af botaniske ekstrakter til fremme af kardiovaskulær sundhed
ITMI20130241A1 (it) * 2013-02-21 2014-08-22 Andrea Rondi Composizione per il trattamento di disordini metabolici
US20170135995A1 (en) * 2015-11-13 2017-05-18 Shenzhen Hightide Biopharmaceutical, Ltd. Pharmaceutical compositions of berberine with epa and dha, and methods thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2001052822A1 (fr) * 2000-01-20 2001-07-26 Chopra Raj K Forme reduite de coenzyme q dans des formes posologiques stables a haute biodisponibilite et applications correspondantes
WO2006029577A1 (fr) * 2004-09-17 2006-03-23 Institute Of Medicinal Biotechnology, Chinese Academy Of Medical Sciences Methodes et compositions de traitement de l'hyperlipidemie

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GIUSEPPE MARAZZI ET AL: "Comparison of Low-Dose Statin Versus Low-Dose Statin + Armolipid Plus in High-Intensity Statin-Intolerant Patients With a Previous Coronary Event and Percutaneous Coronary Intervention (ADHERENCE Trial)", AMERICAN JOURNAL OF CARDIOLOGY., vol. 120, no. 6, 28 June 2017 (2017-06-28), US, pages 893 - 897, XP055556241, ISSN: 0002-9149, DOI: 10.1016/j.amjcard.2017.06.015 *
KONG W J ET AL: "Combination of simvastatin with berberine improves the lipid-lowering efficacy", METABOLISM, CLINICAL AND EXPERIMENTAL, W.B. SAUNDERS CO., PHILADELPHIA, PA, US, vol. 57, no. 8, August 2008 (2008-08-01), pages 1029 - 1037, XP026265410, ISSN: 0026-0495, [retrieved on 20080718], DOI: 10.1016/J.METABOL.2008.01.037 *
LIYI CHI ET AL: "Berberine combined with atorvastatin downregulates LOX-1 expression through the ET-1 receptor in monocyte/macrophages", INTERNATIONAL JOURNAL OF MOLECULAR MEDICINE, vol. 34, no. 1, 22 April 2014 (2014-04-22), GR, pages 283 - 290, XP055556248, ISSN: 1107-3756, DOI: 10.3892/ijmm.2014.1748 *

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ES2645028B2 (es) 2018-06-04
ES2645028A1 (es) 2017-12-01

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