WO2019070109A1 - Triconjugués pour le traitement du diabète sucré - Google Patents

Triconjugués pour le traitement du diabète sucré Download PDF

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Publication number
WO2019070109A1
WO2019070109A1 PCT/MX2017/000116 MX2017000116W WO2019070109A1 WO 2019070109 A1 WO2019070109 A1 WO 2019070109A1 MX 2017000116 W MX2017000116 W MX 2017000116W WO 2019070109 A1 WO2019070109 A1 WO 2019070109A1
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Prior art keywords
metformin
rpm
tablet
diabetes
blood glucose
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PCT/MX2017/000116
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English (en)
Spanish (es)
Inventor
Arturo Rodríguez Jacob
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Infinite Clinical Research International, S.A. De C.V.
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Priority to PCT/MX2017/000116 priority Critical patent/WO2019070109A1/fr
Publication of WO2019070109A1 publication Critical patent/WO2019070109A1/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
    • A61K31/13—Amines
    • A61K31/155—Amidines (), e.g. guanidine (H2N—C(=NH)—NH2), isourea (N=C(OH)—NH2), isothiourea (—N=C(SH)—NH2)
    • 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
    • A61K31/357—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having two or more oxygen atoms in the same ring, e.g. crown ethers, guanadrel
    • 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
    • A61K31/64—Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • 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
    • A61K31/66—Phosphorus compounds
    • A61K31/683—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols
    • A61K31/685—Diesters of a phosphorus acid with two hydroxy compounds, e.g. phosphatidylinositols one of the hydroxy compounds having nitrogen atoms, e.g. phosphatidylserine, lecithin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods

Definitions

  • the present invention is related to e! pharmaceutical sector and more specifically with the pharmaceutical sector manufacturing products for the control of blood glucose concentration.
  • Diabetes Mellitus is defined as a group of metabolic diseases characterized by disorders in the metabolism of carbohydrates, lipids and proteins, which occurs due to an insufficiency in the secretion and / or action of insulin and currently this pathology constitutes a public health problem, especially 3a Diabetes Mellitus Type 2 (T2DM) (1).
  • Imarina a mixed extract of pohyphenolic flavonoids isolated from the milk thistle (Silybum marianum), represents a new option as an alternative treatment for Diabetes Meiliius, since different beneficial properties have been identified in e! organism, for example, the positive regeneration of pancreatic tissue as well as its functionality.
  • the extract of siiimarina constitutes approximately between 70-80% of the plant and 20-30% is made up of chemical compounds not yet identified.
  • Siiimarin is composed of three main molecules called fiavonolignans: siiidianin, silicrisin and silybin; the latter being the most abundant (50-60%) and the most active, which is why the beneficial effect is attributed to it (3). So much so that in preclinical studies it has been demonstrated that silybin neutralizes free radicals, thus protecting the liver cells against oxidative damage. It also inhibits the adhesion of toxins, as well as the production of leukotrienes that are involved in the inflammatory response (4).
  • flavonoids have low miscibility with oils or other lipids, which affects their passage through the epididymal membrane of the enterocytes of the small intestine.
  • itosomes these are molecular complexes of water-miscible flavonoids linked to a lipid compound, mainly phosphatidylcholine (PC) derived from soybeans.
  • siiibine and phosphatidylcholine 1: 2 (Siliphos®) on the market, this compound has a higher absorption, a lower therapeutic dose and a better stability profile, increasing the bioavailability and absorption of the compound (8).
  • the most common standard treatment is the biguanides, which are characterized by the reduction of glucose produced by the liver and in turn benefits insulin resistance to regulate both the entry of glucose to the cells to be metabolized and the use of lipids by the tissues, without affecting the secretion of insulin by the pancreas.
  • This mechanism prevents weight gain and hypoglycemia, in addition to improving the yipidic profile.
  • the following side effects have been reported: diarrhea, nausea, vomiting, Flatulence, asthenia, indigestion, abdominal discomfort and headache (7).
  • the contraindications of these medications are: chronic acidosis, kidney disease or dysfunction and congestive heart failure.
  • Metformin is Currently the most common treatment is Metformin. However, depending on the characteristics of the patient to be treated, the doses are modified, which can be distributed in several doses between meals. day to avoid gastrointestinal discomfort; currently there are long-acting tablets. This medication is not recommended in patients with renal insufficiency (8).
  • Metformin does not affect the secretion of the pancreas, however, it is not active in the absence of insulin. It has been described as acting mainly by reducing gluconeogenesis and hepatic glycogenolysis, however it also reduces the absorption of glucose by the gastrointestinal tract while increasing the sensitivity to insulin by increasing glucose utilization by Peripheral tissues (7) by increasing the IP3 kinase activity of the insulin receptor (9)
  • the average diabetic patient diagnosed with Diabetes Meilitus Type 2 has a rate of gluconeogenesis three times higher than normal, and apparently Metformin reduces this situation by more than one third (8). Metformin is not metabolized, but is excreted in the urine with an average elimination time of 6.2 hours (10).
  • Metformin reduces the levels of sa hormone luteinizanie, as well as its acute release induced by agonists of the gonadotropin-releasing hormone (GnRH) (11), probably by decreasing the activity of cytochrome P450C ovarian and adrenai (12).
  • Metformin also improves the I profile of dyslipidemia, characteristic of most diabetic patients, reducing triglyceride values, as well as VLDL and LDL and, at times, has increased the HDL concentration (13),
  • Sulfonylureas help to promote the second phase of insulin secretion by pancreatic ⁇ cells, that is, the release of pre-formed insulin.
  • pancreatic beta cells with insulin-secreting capacity
  • T1D pancreatic beta cells
  • the SUs exert their action through high affinity receptors located in the pancreatic beta cells, the coupling of the SU to these receptors blocks the opening of the ATP-sensitive potassium channels, preventing the potassium from leaving the cell, propitiating the depolarization of the cell membrane.
  • ED drugs There are two groups of ED drugs, the first-generation drugs ( ⁇ olbutamide, acetohexamide, toiazamide and ciorpropamide); and those of second generation (Glibenclamide, glimepiride, gl ⁇ picida, giiquidona, gliclacida).
  • the adverse effects of SUs are; hypoglycemia > cardiovascular events, agranulocytosis, thrombocytopenia, bemolytic and aplastic anemia, rash, pruritus, headache, nausea, diarrhea, vomiting and hepatic porphyria.
  • SUs are contraindicated in patients with hepatic or renal impairment.
  • Glibenclamide is found, although currently as monotherapy is little used.
  • Glibenclamide The bioavailability of Glibenclamide is approximately 70%, for the pharmaceutical form of tablets. It is rapidly absorbed after oral administration. Maximum serum concentrations are reached after 2 to 4 hours. The absorption of Glibenclamide is not significantly altered by food intake.
  • the serum half-life of Glibenclamide is approximately 2 hours after intravenous administration, and 2 to 5 hours after oral administration; however, it has been suggested that in patients with DM, the half-life may be longer approximately 8 to 10 hours. There is no accumulation.
  • Glyburide is mefaboh 'za completely on E! Liver, The main metabolite is 4-trans-hydroxyigi-benclamide; another is the S-cis-bidroxiglibenciamide.
  • the metabolites of Glibenclamide may have some hypoglycaemic effect (16). The excretion of the metabolites takes place in the urine and bile - approximately 50% per each way - and is complete after 45 a
  • Glibenclamide crosses the placenta in minimal amounts. It is believed that Glibenclamide, like other sulfonylureas, is excreted in breast milk. Approximately in 30% of patients there is an insufficient response to any of the aforementioned treatments after 3 months of starting treatment; This is known as primary therapeutic failure. Subjects suffering from DM with hyperglycemia based! most of them present this failure, this is associated to the lack of compliance in the diet and / or the limited insulin reserve caused by a severe modification in the secretion of insulin by the pancreatic ⁇ cells.
  • patients with DM undergoing oral pharmacological treatment for 6 months and with good metabolic control may stop responding to treatment, this is known as secondary therapeutic failure.
  • a therapeutic option in the face of primary or secondary failure is combined therapy (oral drugs or insulin), whose objective is to take advantage of the synergy or complementarity between the mechanisms of action of the drugs.
  • pancreatic ⁇ cells may be highly vulnerable to damage when exposed to oxidative stress (20) as it plays an important role in cell deterioration ⁇ observed frequently in Type 2 Diabetes Meilitus,
  • antioxidants have been proposed for the protection of the pancreas against oxidative stress in Diabetes Meilitus (21).
  • antioxidants have a reducing effect of oxidative stress improving the state of the kidney and pancreas in models of rats with Diabetes Meilitus, being that the protection of the pancreas against oxidative stress can contribute positively to a hypoglycemic effect ( 22; 23),
  • Metformin in conjunction with Gilbenclamide is indicated for non-insulin dependent diabetes (Diabetes Meilitus Type 2), not ketoacidosis, is used when dietary measures and mono-therapy with suifonylureas in patients are not sufficient to achieve a good control of the levels glycemic As well as patients who are under dietary regimen and with failure to mono-therapy with hypoglycemic agents.
  • antioxidants contribute to the decreased concentration of fructosamine.
  • antioxidants such as vitamins C and E reduce HbA1c levels by inhibiting protein glycation (27).
  • the blood glucose concentration was also significantly reduced. Therefore, based on these results, it can be suggested that the combination of hypoglycemic drugs with some antioxidant can reduce the formation and / or the detrimental effects of advanced glycation end products (AGEs), which may delay the development and the progression of complications caused by diabetes (29).
  • AGEs advanced glycation end products
  • the main objective of the present invention is to achieve a synergistic effect between two hypoglycemiants and an antioxidant.
  • Silybin one of the most active components of the whole that makes up the symimarm, has shown beneficial effects for the patient.
  • human being in the treatment of chronic-degenerative diseases (30).
  • being a flavonoid extract it is characterized by its low absorption and bioavailability in the organism.
  • phosphatidylcholine Siiipbos®
  • the complex silibina more fosfatidilcolina ⁇ Siiiphos®) has a fast absorption and greater bioavailability in comparison with the extracts of silymarin and silymarin studied individually.
  • the Cmax is 298 ng / mL and the Tmax is 1.4-1.6 hours, after dose administration equivalent to 360 mg of silybin (6),
  • Metformin and Giibenclamide it was found that the former presents an alkaline pKa value and therefore it would be incompatible with silybin since it does not interact positively with oxidizing agents or strong bases. According to the above, it is suggested that Metformin go through a granulation stage prior to the manufacture of the drug. Likewise, it is suggested to modify the release of Metformin for about 4 hours more after the half-life time of silybin which is less than 4 hours.
  • the Giibenclamide has not been found to present incompatibility with the antioxidant, however, it is suggested a sustained release of! This drug, due to the short life time of silybin.
  • siibin plus phosphotidylcholine complex (Siiiphos ⁇ ) be the active principle of prolonged release, because the hybrid bonds of silybin with the phosphatidylcholine molecules could affect the bioavailability of the product and that silibin has a T max x in plasma for 2 hours, whereas Metformin has a Tma * of 3 hours and this is affected by food intake.
  • the triconjugate formed for the complex of silybin plus phosphatidylcholine (Siiiphos®) plus Glibenclamide and Metformin should be lightly granulated to offset the absorption after 3 hours and is not a competitive substrate for the silibine and phosphatidylcholine complex (Siliphos®),
  • Tablets This pharmaceutical form is chosen for its easy administration and dosage, as well as easily manipulating the absorption and dissolution requirements of active ingredients with well-known technologies.
  • the formulation is:
  • the formula achieves the dissolution of the three active principles in less than one hour.
  • the final formula is suitable for the three active ingredients, the complex of Silybin + Phosphatidylcholine (Siliphos®), Metformin and Glibenclamide), since it maintains chemical stability in short periods involving the manufacture and immediate analysis of! product (tablet).
  • the amounts in mg per tablet are described below
  • Metformin The maximum recommended daily dose of Metformin is 2,550 mg in adults and 2,000 mg in young patients over 18 years of age. Metformin should be administered in divided doses with meals. Using up to 5 Metformin tablets of 500 mg or up to 3 Metformin tablets of 850 mg.
  • siiibin + phosphatidylcholine complex is marketed under the brand name Siliphos® and doses of siiibine greater than 360 mg three times daily for three weeks without toxic effects have been administered in humans.
  • LD50 lethal dose 50
  • mice of 1,000 mg / kg mice of 1,000 mg / kg
  • rabbits of 300 mg / kg mice of 900 mg / kg.
  • the duration of treatment depends on the underlying condition in which it has been indicated. It may be administered indefinitely, since it has no cumulative or toxic effect.
  • the administration of 2.5 mg before breakfast or the main meal is recommended. If the blood glucose results are satisfactory, the same dose should be maintained. In case the dose needs to be increased, it will be increased from 2.5 mg in 2.5 mg in intervals of one to two weeks with constant monitoring of blood glucose, the maximum increase of single daily dose should not be greater than 10 mg. In patients who use fractionated doses, in cases requiring more than 10 mg / dsa, the increase should be divided before lunch or dinner at a rate of 2.5 mg each time, with strict monitoring.
  • the maximum daily dose is 15 to 20 mg, ietformiria / Glibencyamide / SHibin Complex + Phosphatidylcocine
  • the dose of this combination (considering Mephorphine between 230 and 250 mg, Glibenclamide between 15 and 20 mg, and the complex SHibina + FosfatidilcoMna between 180 and 220mg) will be of 1 tablet a! day during the main meal, without spending 2 g of metformin a day, then this daily dose may be decreased at the discretion of the doctor.
  • This combination offers all three drugs in a single pharmaceutical form.
  • the initial dose of this combination will be 1 tablet per day and adjusted according to the patient's metabolic control at the discretion of the attending physician, without exceeding 4 tablets per day.
  • One of the embodiments of the present invention is a tablet with the following composition
  • the manufacturing process of this tablet consists of the following series of steps; a) Metformin is sieved with a number 12 mesh and fed to the high-cut mixer with Polyvinylpyrrolidone PVP K29 / 32 where they are mixed for 3 minutes at 114 rpm, b) The result is slowly fed to a mixer-granulator and added the ethanol by rotating the mixer at 114 rpm and a crusher speed of 1800 rpm. c) The product thus obtained is transferred to the tray dryer, reaching a temperature of 50-80 ° C ; for 3 hours, removing the trays every hour to favor e! dried with a relative humidity of 1.5%. In this step, the ethanol evaporates.
  • the mixture is tabletted making a tablet with average weight of 750 ⁇ 3% mg, individual weight of 750 ⁇ 5%, with a hardness of 9 to 11 kP, friability lower than 1% and disintegration no greater than 15 minutes.
  • the tablet is coated with a coating polymer, such as Aquarius Prime BT419769 Purple dissolved in water, obtaining a tablet with an average weight of 850 ⁇ 3% mg, individual weight of 850 ⁇ 5%.
  • Example 1 Clinical study to evaluate the safety between the drug in Research GHbersclamlda / ietformina / Silibina plus Phosphatidylcholine fSiiiphos® ⁇ and the reference medicine Giibeoclamida / ietforrrsir ⁇ a.
  • Oral administration of the formulations did not produce significant clinical changes in vital signs [systolic blood pressure, diastolic blood pressure, heart rate, respiratory rate and temperature) and were reported as adverse events, one subject with tachycardia, one with fever and another with low-grade fever, the rest was within the normal range. The subjects did not present any allergic reaction to the medication.
  • the same protocol was applied as in the previous example.
  • the concentration of IVIetformin and Glibenclamide in plasma was quantified using high performance liquid chromatography collected by mass spectrometry.
  • Silybin plus Phosphatidylcholine (Siiiphos®) was evaluated as an adjunct to the hypoglycemic agents Metformin and Glibenzamide in the treatment of DM2.
  • the trial presents a phase III, double blind, controlled, multicenter, clinical study design with two study groups (investigational drug Glibencide / Metformin / Silybin plus Phosphatidylcholine (Siiiphos®) and reference drug Glibenzyamide / Metformin ).
  • the treatments are administered for a period of 180 days and a sample is taken to evaluate the levels of glycosylated hemoglobin at 30, 60, 90, 120, 150 and 180 days of treatment, as well as the blood glucose levels.
  • Siiibinin ameliorates hyperglycaemia, hyperlipidemia and prevent oxidative stress in streptozotozin induced diabetes in Sprague Dawley rats. Dilpesh Jain, Rahui Somani, R i tu Gilhorta. india: International Journal of Pharmaceutical Research & Allied Sciences, 2016, Vo ⁇ . 5, pp. 136-144. 2277-3657.
  • UK Prospective Diabetes Study Group Glycemic control with diet, sulfonylurea, metorinum, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49). Turner, RC and Culi, CA, s.l. : JAMA, 1999, Vol. 281.
  • UK Prospec ⁇ ve Diabetes Study 18 Overview of 6 years 1 therapy of type II diabetes: a progressive disease.
  • UK Prospective Diabetes Study Group, sl Diabetes, 1995, Vol. 44.
  • UK Prospective Diabetes Study (UKPDS) Group Glycemic control continue to be deter- mined ater suffonylureas are added to metformin among patiens with type 2 diabetes. Cook, MN, Girman, CJ and Stein, PP, s.l. : Diabetes Care, 2005, Vol. 28.
  • Vitamin E reduction oi protein glycosylation in diabetes new prospect for prevention of diabetic disorders? Cerielio, A, Giugliano, D and Quatrarro, A. 12, 1991, Diabetes Care, Vol. 7, pp. 68-72.
  • UK Prospective Diabetes Study (UKPDS) Group Glycems control continue to be stopped after suifonylureas are added to metformin between patien ⁇ s with ⁇ ype 2 diabetes.

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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)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

L'invention concerne un triconjugué pour le traitement du diabète sucré qui consiste en une composition pharmaceutique pour réguler la concentration en glucose dans le sang. Le triconjugué comprend une combinaison de metformine et de glibenclamide et le complexe silybine+phosphatidylcholine. L'invention concerne également le procédé d'obtention de comprimés avec la composition pharmaceutique mentionnée.
PCT/MX2017/000116 2017-10-03 2017-10-03 Triconjugués pour le traitement du diabète sucré WO2019070109A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/MX2017/000116 WO2019070109A1 (fr) 2017-10-03 2017-10-03 Triconjugués pour le traitement du diabète sucré

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/MX2017/000116 WO2019070109A1 (fr) 2017-10-03 2017-10-03 Triconjugués pour le traitement du diabète sucré

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764508A (en) * 1985-07-17 1988-08-16 Inverni Della Beffa S.P.A. Complexes of flavanolignans with phospholipids, preparation thereof and associated pharmaceutical compositions
EP0974356A1 (fr) * 1998-07-15 2000-01-26 Lipha Comprimés contenant une combinaison de glibenclamide et de metformine
CA2980231A1 (fr) * 2015-03-23 2016-09-29 Tasly Pharmaceutical Group Co., Ltd. Composition pharmaceutique contenant de la silybine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4764508A (en) * 1985-07-17 1988-08-16 Inverni Della Beffa S.P.A. Complexes of flavanolignans with phospholipids, preparation thereof and associated pharmaceutical compositions
EP0974356A1 (fr) * 1998-07-15 2000-01-26 Lipha Comprimés contenant une combinaison de glibenclamide et de metformine
CA2980231A1 (fr) * 2015-03-23 2016-09-29 Tasly Pharmaceutical Group Co., Ltd. Composition pharmaceutique contenant de la silybine

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