WO2015178683A1 - Composition pharmaceutique comprenant un inhibiteur de la glycoprotéine p et un médicament substrat de la glycoprotéine - Google Patents

Composition pharmaceutique comprenant un inhibiteur de la glycoprotéine p et un médicament substrat de la glycoprotéine Download PDF

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Publication number
WO2015178683A1
WO2015178683A1 PCT/KR2015/005053 KR2015005053W WO2015178683A1 WO 2015178683 A1 WO2015178683 A1 WO 2015178683A1 KR 2015005053 W KR2015005053 W KR 2015005053W WO 2015178683 A1 WO2015178683 A1 WO 2015178683A1
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Prior art keywords
glycoprotein
drug
dabigatran
pharmaceutical composition
substrate
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Ceased
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PCT/KR2015/005053
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English (en)
Korean (ko)
Inventor
장영길
이재헌
이재구
최경진
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Hanmi Fine Chemicals Co Ltd
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Hanmi Fine Chemicals Co Ltd
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Publication of WO2015178683A1 publication Critical patent/WO2015178683A1/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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • 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
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
    • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole

Definitions

  • compositions comprising inhibitors of P-glycoproteins and substrate drugs of P-glycoproteins
  • the present invention relates to pharmaceutical compositions comprising inhibitors of P-glycoproteins and substrate drugs of P-glycoproteins.
  • Dabigatran etexilate Product name Pradaxa, Pradaxa
  • Pradaxa is a thrombin inhibitor that is effective in preventing postoperative deep vein thrombosis, stroke, and atrial fibrillation and stroke, especially atriai fibrillation.
  • AF is the first oral anticoagulant drug released worldwide in about 60 years after warfarin. Compared with warfarin, this drug has little drug interaction, a relatively wide range of treatment, and does not require anti-ungogenic activity monitoring.
  • dabigatran is a relatively safe drug with relatively low gastrointestinal bleeding or intracranial hemorrhage compared to warfarin (Souffi OTffi MR e: Eng: J. of Med). ⁇ 3; DOI: DOI: 10.1056 / NEJMpl302834).
  • the dabigat duct etexilate is a prodrug with very low solubility and is a substrate of P-glycoprotein, which inhibits its absorption by p-glycoprotein in the intestinal tract and thus oral bioavailability. Only about%. As demonstrated by this low oral bioavailability, only a portion of dabigatran etexilate is absorbed from the digestive tract and the remainder remains in the GI tract and is eventually excreted in feces. Two-thirds are converted to active dabigatran by gut esterase (Jay Desai et al., Trombo Haemost. 10 (2), 205-12 (2013); see FIG. 1).
  • dabigatran etexilate When oral intake of tran etexilate, dabigatran etexilate, a substrate of P-glycoprotein, is absorbed from the digestive tract and transported through the gut wall into the blood vessels, where some dabigatran etexilate is released from the MONO—After being converted to prodrugs, blood vessels are transformed into blood vessels, dabigatran. Dabigatran etexilate is excreted back into the lumen by the P-glycoprotein at the barrier, consequently the substrate of the p-glycoprotein. Therefore, limited absorption of dabigatran occurs and thus lowers bioavailability.
  • dabigatran an anticoagulant active agent
  • the lumen of the gastrointestinal tract rather than in blood vessels, hemorrhage in the lesion. Therefore, it is necessary to reduce the exposure of dabigatran in the gastrointestinal tract, since the amount of dabigatran remaining in the gastrointestinal tract is a major factor in the degree of bleeding.
  • an object of the present invention is to provide a pharmaceutical composition that enhances the pharmacological effect of the substrate drug of P-glycoprotein, including dabigatran, enjoys side effects, and can effectively administer the drug in a small amount.
  • the present invention provides an inhibitor of P-glycoprotein and
  • a pharmaceutical composition comprising a substrate drug of P-glycoprotein.
  • the pharmaceutical compositions of the present invention can reduce the side effects of drugs caused by P-glycoprotein and activity, and further provide equivalent pharmacological effects using smaller amounts of drugs.
  • the combination of P-glycoprotein substrate drug dabigatran etexilate and P-glycoprotein inhibitor tetrazole derivatives can significantly increase the bioavailability of dabigatran etexilay S.
  • Reduction of the amount of use of the same level of bioavailability can significantly reduce the residual amount of dabigatran in the gastrointestinal tract.
  • this reduces the amount of drug exposure in the gastrointestinal tract, thereby reducing the risk of bleeding, a fatal drawback for patients taking conventional dabigatran etexilate.
  • Figure 1 is a schematic diagram showing the path of absorption of dabigatran etexilate by P-glycoprotein in the gastrointestinal tract.
  • the present invention provides a pharmaceutical composition comprising an inhibitor of P-glycoprotein and a substrate drug of P-glycoprotein.
  • inhibitors of the P-glycoprotein used in the composition of the present invention include tetrazole derivatives of the general formula (1) or pharmaceutically acceptable salts thereof:
  • Tetrazole derivatives of Formula 1 are known as effective P-glycoprotein inhibitors (see US Pat. No. 7,625,926) and can be readily prepared according to known methods. Can be. Pharmaceutically acceptable salts of the tetrazole derivatives include all salt forms prepared using organic or inorganic acids.
  • a substance known as a third generation p-glycoprotein inhibitor such as LY 335979, XR 9576, OC 144-093, quercetin, Rutin, etc. J. Pharm. Pharmaceut. Sci., 12 (1): 46-78, 2009) or combinations thereof.
  • P-glycoprotein is a substance that causes multi-drug resistance (MDR) of cancer cells and is a transporter (excretion transporter) involved in the excretion of many drugs. They are distributed in the human body such as kidney, liver and brain barrier. Especially, P-glycoprotein in small intestine epithelium is reversed from digestive tract absorption. do.
  • MDR multi-drug resistance
  • p-glycoprotein inhibitors such as verapamil or cyclosporine
  • side effects such as hypotension or immunosuppression are present in clinical trials. Cancer Res., 41, 1967-1972, 1981. Therefore, such pharmacologically substances can not be used with the substrate drug of the P-glycoprotein of the present invention, such as dabigatran etexilate.
  • substrate drug of the P-glycoprotein of the present invention such as dabigatran etexilate.
  • Substrate drugs of P-glycoproteins used in the compositions of the present invention include dabigatran, Apixaban, Rivaroxaban, naproxen, celecoxib, Meloxicam ), Clarithromycine, clopidogrel, aspirin, duloxetine, silodosine, pharmaceutically acceptable precursors thereof, pharmaceuticals thereof It can be selected from the group consisting of acceptable salts, and combinations thereof.
  • the substrate drug of the p ⁇ glycoprotein is Dabigatran etexilate of Formula 2 or a pharmaceutically acceptable salt thereof:
  • Preferred examples of the pharmaceutically acceptable salt of dabigatran etexilate include, but are not limited to, dabigatran etexilate mesylate.
  • the substrate drug of the P-glycoprotein may be used in an amount of 0.1 to 10 equivalents, preferably 0.5 to 5 equivalents, based on the P-glycoprotein inhibitor.
  • the pharmaceutical compositions of the present invention may further comprise pharmaceutically acceptable additives such as carriers, excipients and the like.
  • the pharmaceutical compositions of the present invention may be formulated in a variety of oral dosage forms. The inventors have found a way to reduce exposure of dabigatran to the gastrointestinal tract.
  • dabigatran etexilate is a P-glycoprotein substrate
  • administration of dabigatran etexilate or a pharmaceutically acceptable salt thereof with a P-glycoprotein inhibitor results in the gastrointestinal tract of dabigatran.
  • the inventors of the present invention have determined that they will be able to enjoy the exposure at.
  • the pharmaceutical compositions of the present invention may exhibit an improved effect of reducing the dosage of P-glycoprotein matrix drugs, or reducing drug exposure in the gastrointestinal tract, and reducing gastrointestinal related side effects such as ulcers.
  • the rats were administered dabigatran etexilate mesylate with or without P-glycoprotein inhibitor and examined the dabigatran concentration in the gastrointestinal tract, P- It was confirmed that the concentration of dabigatran in the gastrointestinal tract was lower than in the case of using the glycoprotein inhibitor. From these results, it can be inferred that co-administration of P-glycoprotein inhibitors and P-glycoprotein substrate drugs can reduce bleeding in vulnerable lesions.
  • the present invention provides a method for lowering gastrointestinal bleeding, which is not a substrate drug of P-glycoprotein in a subject, comprising administering an inhibitor of P-glycoprotein and a substrate drug of P-glycoprotein to a subject in need thereof. To provide.
  • the present invention provides a method for lowering ulcers caused by substrate drugs of P-glycoprotein in a subject, comprising administering P-glycoproteins and inhibitors and substrate drugs of P-glycoprotein to a subject in need thereof.
  • Preparation Example 1 N- (2- (2- (4- (2- (6, gdimethoxy-3,4-dihydroisoquinolin-2 (1H) -yl) ethyl) phenyl) -2H-tetrazol Preparation of -5-yl) -4,5-dimethoxyphenyl) -4-oxo-4H-chromen-2-carboxamide (tetrazole derivative of formula 1) 2- (2- (4- (2- (6,7-dimethoxy— 3,4-dihydroisoquinolin-2 (1H) -yl) ethyl) phenyl) -2H-tetrazol-5-yl) 0.85 g of -4,5-dimethoxybenzeneamine and 0.
  • Preparation Example 3 Preparation of dabigatran etexilate mesylate (DAEM) 20 g of dabigatran etexilate (4chembiogenix) was added to 112 mL of acetone and then dissolved by stirring at about 40-50 ° C. The dissolved reaction solution was slowly cooled to about 30-36 ° C. On the other hand, a solution of 3.5 g of mesylic acid (MSA) dissolved in 10 mL of acetone was slowly added to the reaction solution for 15 to 40 minutes while maintaining 30 to 36 ° C. The reaction liquid 26-3
  • MSA mesylic acid
  • Example 2 Concentration and pharmacokinetic characterization of P-glycoprotein substrate drugs in the small and large intestine according to the combination of p—glycoprotein inhibitors and P-glycoprotein substrate drugs
  • the concentrations of p-glycoprotein substrate drugs in the small and large intestine following the combination of P-glycoprotein inhibitors and P-glycoprotein substrate drugs were analyzed.
  • DAEM dabigatran etexilate mesylate
  • DAEM dabigatran etexilate mesylate
  • the control group administered with dabigatran etexilate mesylate alone had a high concentration with dabigatran in the small and large intestine
  • the experimental group co-administered with dabigatran etexylate mesylate and tetrazole derivatives. Showed a relatively low dabigatran concentration.
  • the results show that co-administration of P-glycoprotein inhibitors and P-glycoprotein substrate drugs can lower gastrointestinal side effects caused by P-glycoprotein substrate drugs.

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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)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

La présente invention concerne une composition pharmaceutique comprenant un inhibiteur de la glycoprotéine P et un médicament substrat de la glycoprotéine P. La composition pharmaceutique selon la présente invention réduit les effets secondaires du médicament provoqués par l'activité de la glycoprotéine P, et peut en outre fournir un effet pharmacologique équivalent en utilisant une plus petite quantité de médicament. En particulier, l'utilisation de dabigatran étexilate, un médicament substrat de la glycoprotéine P, avec un dérivé de tétrazole, un inhibiteur de la glycoprotéine P, peut augmenter de manière significative la biodisponibilité du dabigatran étexilate, et par conséquent la quantité résiduelle de dabigatran étexilate dans le tractus gastro-intestinal peut être nettement réduite du fait que le médicament a le même niveau de biodisponibilité en dépit d'une quantité réduite de celui-ci. De plus, étant donné les raisons détaillées ci-dessus, la dose du médicament dans le tractus gastro-intestinal est réduite, la composition pharmaceutique de la présente invention peut ainsi réduire le risque d'hémorragie, un effet indésirable fatal pour les patients prenant un dabigatran étexilate classique.
PCT/KR2015/005053 2014-05-23 2015-05-20 Composition pharmaceutique comprenant un inhibiteur de la glycoprotéine p et un médicament substrat de la glycoprotéine Ceased WO2015178683A1 (fr)

Applications Claiming Priority (2)

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KR10-2014-0062229 2014-05-23
KR20140062229 2014-05-23

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WO2015178683A1 true WO2015178683A1 (fr) 2015-11-26

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KR101750428B1 (ko) 2015-09-24 2017-06-23 엘지디스플레이 주식회사 터치 스크린 일체형 표시장치
CN107970225B (zh) * 2017-12-22 2022-06-03 植恩生物技术股份有限公司 一种达比加群酯固体脂质纳米粒及其制备方法

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7625926B2 (en) * 2003-10-07 2009-12-01 Hanmi Pharm. Co., Ltd P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7625926B2 (en) * 2003-10-07 2009-12-01 Hanmi Pharm. Co., Ltd P-glycoprotein inhibitor, method for preparing the same and pharmaceutical composition comprising the same

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
FROMM, M. F. ET AL.: "Inhibition of P-glycoprotein-mediated drug transport a unifying mechanism to explain the interaction between digoxin and quinidine", CIRCULATION, vol. 99, 1999, pages 552 - 557 *
KIM, R. B.: "Drugs as P-glycoprotein substrates, inhibitors, and inducers", DRUG METABOLISM REVIEWS, vol. 34, no. 1&2, 2002, pages 47 - 54 *
THOMAS, H. ET AL.: "Overcoming multidrug resistance in cancer: an update on the clinical strategy of inhibiting p-glycoprotein", CANCER CONTROL, vol. 10, no. 2, 2003, pages 159 - 165 *
WESSLER, J. D. ET AL.: "The P-glycoprotein transport system and cardiovascular drugs", JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY, vol. 61, no. 25, 2013, pages 2495 - 2502, XP028571029 *

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