EP2714022A1 - Combinaison pour le traitement du diabète sucré - Google Patents

Combinaison pour le traitement du diabète sucré

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Publication number
EP2714022A1
EP2714022A1 EP12738248.9A EP12738248A EP2714022A1 EP 2714022 A1 EP2714022 A1 EP 2714022A1 EP 12738248 A EP12738248 A EP 12738248A EP 2714022 A1 EP2714022 A1 EP 2714022A1
Authority
EP
European Patent Office
Prior art keywords
clause
combination
metformin
ascorbic acid
combination according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP12738248.9A
Other languages
German (de)
English (en)
Inventor
Sergey Petrovich KRECHETOV
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Leshkov Sergey Yurievich
Vikhrieva Nina Sergeevna
Original Assignee
Leshkov Sergey Yurievich
Vikhrieva Nina Sergeevna
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Leshkov Sergey Yurievich, Vikhrieva Nina Sergeevna filed Critical Leshkov Sergey Yurievich
Publication of EP2714022A1 publication Critical patent/EP2714022A1/fr
Withdrawn legal-status Critical Current

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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
    • A61K31/045—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
    • A61K31/12—Ketones
    • 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
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • 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 
    • A61K31/353—3,4-Dihydrobenzopyrans, e.g. chroman, catechin
    • 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
    • A61K31/37—Coumarins, e.g. psoralen
    • 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
    • A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
    • A61K36/18—Magnoliophyta (angiosperms)
    • A61K36/185—Magnoliopsida (dicotyledons)
    • A61K36/74—Rubiaceae (Madder family)
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to the pharmaceutical industry and particularly medicines for the treatment of diabetes mellitus.
  • Diabetes mellitus remains to be a significant problem for national public health services in virtually all countries of the world. Over the past 30 to 40 years, a significant surge in prevalence and incidence of diabetes mellitus has been evident worldwide, especially so in industrially developed countries where from 6 to 10 percent of the population suffer from diabetes mellitus and where its prevalence has a clear uptrend, primarily in age groups over 40.
  • diabetes treatment plan the main goals of a diabetes treatment plan are diminution of symptoms of diabetes, improvement of life quality and prevention of both acute (hyperosmolar coma and ketoacidosis) and chronic complications, e.g. diabetic neuropathy, diabetic nephropathy and early atherosclerosis (Diabetes Control and Complications Trial Research Group; N. Engl. J. Med., 329, 977-986 (1993)).
  • Chronic hyperglycemia is not just the main manifestation of diabetes constituting the basis for diagnosing the disease, but also a most important factor for the development of virtually all complications: micro- and macroangiopathies, neurophaty, nephropaty and others.
  • diabetes mellitus treatment is to achieve compensation of carbohydrate metabolism for a prolonged period of time, i.e. to ensure such indicators of glucose content in blood plasma that would be substantially the same as observed in a healthy person during the day.
  • the treatment of diabetes mellitus commences with prescribing a diet and dosed exercise, but in order to achieve target carbohydrate metabolism indicators, significant effort on the part of the patient are required, while as a rule, diabetes mellitus patients possess that in only an insignificant degree. That is why the main role in diabetes mellitus treatment plays drug therapy.
  • Antihyperglycemic drug therapy does not just reduce glycemia indicators and thus removes clinical manifestations of the disease causes by hyperglycemia. It also breaks the "vicious circle" formed by increasing insulin deficiency due to exhaustion of insulin-secreting cells and growing hyperglycemia given the increasing insulin deficiency.
  • the positive action of antihyperglycemic drugs under insulin deficiency described herein relates to a greater degree to type 2 diabetes and initial stages of type 1 diabetes. At the present time, the following groups of antihyperglycemic oral medications are used for the treatment of type 2 diabetes:
  • pancreas boosting insulin production by the pancreas (sulfonylurea derivatives glibenclamide, glipizide, gliclazide, gliquidone and glimepiride);
  • stimulating postprandial insulin secretion glinides, incretin mimetics, DPP-4 inhibitors, amylin and glucagon-like peptide 1 analogues
  • A-glucosidase inhibitors reduce the absorption of glucose in the intestine and are usually effective at the early stages of the disease. Their side effects are associated with manifestations of meteorism and diarrhea. In most patients, the need to cease the drug administration arises within 3 years from the commencement thereof.
  • Sulfonylurea derivatives stimulate the secretion of insulin by b-cells of the pancreas.
  • the most commonly used sulfonylureas presently are gliclazide, glibenclamide, glipizide and gliquidone.
  • Treatment with sulfonylureas is contraindicated in case of type 1 diabetes mellitus or secondary (pancreatic) diabetes mellitus, pregnancy and lactation, surgery, severe infections, injuries, allergy to sulfonylurea drugs or similar medications in the anamnesis, or the presence risk of severe hypoglycemia.
  • Glinides are characterized with rapid onset and short duration of action, which enables, on the one hand, to effectively control postprandial hyperglycemia, and on the other hand, to not increase the risk of hypoglycemia.
  • Preparations specifically intended to affect postprandial glucose levels are incretin mimetics, DPP-4 inhibitors, amylin analogues and glucagon-like peptide 1 analogues. These drugs compensate the existing deficiency in the secretion of hormones of the pancreas and gastrointestinal tract, affecting insulin and glucagons secretion, sense of satiety and stomach emptying. They are characterized with highly rapid onset and short antihyperglycemic effect, therefore the use thereof is not accompanied with any adverse developments causes by their influence on glucose metabolism. Rapid and short action makes the aforesaid medications useful only as postprandial antihyperglycemic drugs.
  • the group of tableted antihyperglycemic biguanides is currently represented for the main part by metformin. Biguanides do not enhance insulin secretion. Their antihyperglycemic action manifests itself only where there is enough insulin in blood. Biguanides boost its action on peripheral tissues, reducing insulin resistance. Biguanides increase glucose uptake by muscles and adipose tissue. They reduce hepatic glucose production, glucose absorption in the intestine, increase glucose utilization and reduce appetite. It is contraindicated to prescribe biguanides with renal dysfunction, hypoxic conditions of any etiology (heart failure, lung diseases, anaemia, infectious diseases), acute complications of diabetes mellitus, alcohol abuse, lactacidemia in the anamnesis.
  • antihyperglycemic sulfanilamide preparations and biguanides may cause side effects in the form of gastrointestinal disorders, skin allergies, and hypoglycemic states due to the closeness of therapeutic and toxic doses of these drugs.
  • Thiazolidinediones affect the glycemic control by reducing insulin resistance in peripheral tissues, especially adipose tissue, and also reduce hepatic glucose production. Preparations of this group do not cause hypoglycemia but may contribute to weight gain. These drugs are contraindicated for patients with symptoms of heart failure and manifestations of preproliferative and proliferative stages of diabetic retinopathy.
  • antihyperglycemic monotherapy prove ineffective, the desired effect may be achieved sometime by combining antihyperglycemic preparations.
  • the following combinations of oral antihyperglycemic preparations are possible: sulfonylurea preparations and thiazolidinediones, metformin and meglitinides, metformin and thiazolidinediones, sulfonylurea preparations and a-glucosidase inhibitors. If glycemic control is not achieved by a combination of oral antihyperglycemic preparations, combination therapy with insulin and biguanides, or monotherapy with insulin will be prescribed.
  • the oral antihyperglycemic preparation of combined action - Glibomet consists of 2.5 mg of glibenclamide and 400 mg of metformin.
  • Glibenclamide contained in the drug stimulates insulin secretion by b-cells of the pancreas, while metformin lowers insulin resistance mainly in the liver, which is accompanied by inhibition of gluconeogenesis, decreasing the rate of glucose formation in the liver and admission thereof into the circulatory system.
  • the use of combination drugs enhances the antihyperglycemic effect, but keeps intact the threat of lactacidosis that accompanies the use of metformin.
  • Glitazone may be represented by pioglitazone, rosiglitazone or troglitazone (RU 2280447, 15.09.2000).
  • the combination medication may take the form of a combined preparation or a pharmaceutical composition.
  • Such pharmaceutical composition may comprise, as a third antidiabetic agent, metformin in a pharmaceutical carrier.
  • metformin in a pharmaceutical carrier.
  • the combined use of nateglinide with another antidiabetic agent ensures synergistic therapeutic effect for type 2 diabetes and a prolonged duration of the drug action, which results in the putting off of insulin use to a later date.
  • the downside of the combinations is the use of glitazone and metformin, both of which may contribute to the development of lactacidosis.
  • a medication for the treatment of diabetes mellitus comprising a combination of exenatide and dalargin in effective amounts (RU 2413528 18.01.2007).
  • This combination is a combined drug and ensures effective treatment of diabetes mellitus by means of potentiation of hypoglycemic and hypocholesterolemic action of exenatide.
  • the downside of the combinations is the preferred use of the injection form of administration.
  • a medication for the treatment of insulin-independent type 2 diabetes mellitus, which comprises a combination of metformin and glibenclamide in effective amounts, and a method of treating insulin independent diabetes or hyperglycemia with glibenclamide that forms part of a combination medication for oral administration with an area of powder particle surface of from 1.7 to 2.2 m 2 /g (RU > 2286788 12.07.1999).
  • the invention ensures bioavailability of glibenclamide in the composition of metformin- comprising medications comparable to the bioavailability of glibenclamide monoforms.
  • metformin in the proposed preparation results in the need to take into account the increased likelihood of lactacidosis.
  • antihyperglycemic drugs for oral administration currently used solve the problem of reducing blood sugar by different mechanisms, hence they are effective only under certain conditions. Vague manifestation of symptoms of the principal disease and concurrent conditions that cause contraindications in some patient subgroups result in undesirable side effects.
  • One of the most significant contraindications is a predisposition to lactacidosis.
  • the task of increasing the discharge of reduced cofactors might be solved by means of the use, in the composition of antidiabetic drugs, of such components that ensure an enhanced consumption of reduced cofactors in intracellular processes.
  • ascorbic acid and derivatives thereof improves bioavailability of natural phenolic compounds.
  • the effect of the application of that composition consists in the reduction of glucose level in blood, glycated hemoglobin, cholesterol and triglycerides.
  • a method of treating diabetes or diabetes induced disorders in a patient is known by means of injection of a composition comprising coffee beans (US 2009017597).
  • the effect of the application of that composition in treating diabetes or diabetes induced disorders in patients is defined as stabilization of blood sugar, glycated hemoglobin AIC, triglyceride and low-density lipoprotein levels, or as blood sugar level normalization.
  • the target purpose is achieving direct therapeutic effect on diabetes on account of antioxidant action of the given composition.
  • compositions comprising antidiabetic agents, in particular metformin, and methods of diabetes treatment that include prescribing of antidiabetic preparations to a patient (Balabolkin M.I., Diabetology, Moscow, Meditsina, 2000; Ametov A.S. Type 2 Diabetes Mellitus: Basics of Pathogenesis and Therapy. Moscow, 2003)
  • the purpose of this invention is the development of a combination drug for treating diabetes that would reduce the incidence of side effects of antihyperglycemic preparation application due to the accelerated utilization of glycolysis products, and also reduce generation of lactic acid, and creating an opportunity to use such medication in all-round diabetes therapy.
  • the technical effect of the invention consists in the reduction of the risk of lactacidosis development in using known antihyperglycemic agents.
  • the essence of the invention consists in the use of combinations of known antihyperglycemic substances along with natural phenolic compounds capable of uncoupling oxidative phosphorylation, and, additionally, with ascorbic acid improving bioavailability of natural phenolic compounds by maintaining them in an active phenolic state.
  • the authors have suggested a combination for treating diabetes, including at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds capable of uncoupling oxidative phosphorylation.
  • the combination comprises a natural phenolic compound or a mixture of such compounds in an amount of at least 2 %.
  • the antidiabetic agent in a combination is selected from a group comprising biguanides, thiazolidinediones or compositions thereof.
  • the natural phenolic compound capable of uncoupling oxidative phosphorylation to be used in a combination is selected from the group consisting of chlorogenic acid or Epigallocatechin-3-gallate or Epicatechin-3-gallate or ellagic acid or quercetin or dihydroquercetin or fisetin or curcumin or resveratrol or capsaicin or caffeic acid phenethyl ester.
  • Such compounds are known to be present in the composition of green coffee bean extracts, green tea, pomegranate, catechu acacia, curcuma, Japanese knotweed, hot pepper, propolis and a number of other products of vegetable or animal origin.
  • the said natural phenolic compounds may be isolated from products containing them by known methods, or obtained synthetically, or used in the form of concentrated extracts. According to the research conducted by the authors, an effective amount of natural phenolic compounds (one-time dose) is from 10 to 200 mg.
  • the mixture of natural phenolic compounds in the combination consists of a vegetable extract.
  • the combination comprises metformin as an antidiabetic agent and coffee bean extract as a vegetable extract.
  • the combination comprises metformin as an antidiabetic agent and green coffee bean extract as a vegetable extract.
  • the combination additionally comprises ascorbic acid or pharmaceutically acceptable derivatives thereof in an amount of at least 25 % of the amount of green coffee bean extract.
  • compositions for the treatment of diabetes and complications thereof constituting a composition medication including a combination of at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds, and a pharmaceutically acceptable carrier.
  • the preferable embodiment is a composition comprising metformin, green coffee bean extract and ascorbic acid in therapeutically effective amounts as an antidiabetic agent.
  • mass amounts of metformin, green coffee bean extract and ascorbic acid preferably relate to each other in proportion of from 100:20: 10 to 100:40:30.
  • the composition may be executed in the form of a powder, granules, tablets, pellets, capsules, candies, suspensions, emulsions or solubilisate, and comprise auxiliary substances, in particular, fillers (silicon dioxide, microcrystal cellulose, croscarmellose sodium etc.), binders (polyvinylpyrrolidone, vinylpyrrolidone and vinylacetate copolymer etc.), lubricants (magnesium stearate etc.), emulsifiers (oxyethylated castor wax, lecitin etc.), solubilizers (polysorbates, poloxamers, etc.), prolongators (behenic acid glycerides, hydroxypropylmethylcellulose etc.), and correctives (fructose, lactose, sorbite etc.).
  • fillers silicon dioxide, microcrystal cellulose, croscarmellose sodium etc.
  • binders polyvinylpyrrolidone, vinylpyrrol
  • Antidiabetic agents in the composition are used in doses recommended for their individual administration.
  • the frequency of administration of the claimed composition coincides with the frequency of administration of antidiabetic agents - components thereof.
  • the period of administration should is be as long as any lactacidosis symptoms persist, but two weeks in the least. It is preferable that the patient should continue taking the claimed composition after the restoration of pH values and lactate blood content, because it will lower the risk of the recurrence of lactacidosis.
  • the authors have also proposed a pharmaceutical set effective for treating diabetes, including a combination of at least one antidiabetic agent and one natural phenolic compound or a mixture of such compounds.
  • Such set constitutes an individually manufactured preparation composed of antidiabetic agents, and another individually manufactured preparation comprising natural phenolic compounds or a mixture thereof.
  • Such preparations may comprise ascorbic acid or pharmaceutically acceptable derivatives thereof.
  • the said preparation composed of antidiabetic agents may contain, for example, metformin hydrochloride and auxiliary substances (hydroxypropylmethylcellulose, microcrystal cellulose, povidone, magnesium stearate) and be in the tablet form.
  • the preparation comprising natural phenolic compounds may contain, for example, green coffee bean extract (50-55 % polyphenols), ascorbic acid and microcrystal cellulose as an auxiliary substance. Such composition may be placed in a hard gelatin capsule.
  • Tablets and capsules may be packaged in blisters or flasks with appropriate marking and put in a common box with an equal number of tablets and capsules in it.
  • one, two and three tablets and capsules may be prescribed for a single dose.
  • a method of combined diabetes therapy includes prescribing to a patient a combination consisting of at least one antidiabetic agent and a natural phenolic compound or a mixture of such compounds.
  • the claimed pharmaceutical composition may be used as a combination.
  • the pharmaceutical composition is used in treating diabetes mellitus on occurrence of lactacidosis symptoms in the patient or at the beginning of diabetes mellitus treatment in case there is information on the patient having predisposition to acidosis in the anamnesis.
  • the composition is prescribed in an amount corresponding to the therapeutically effective dose of the particular antidiabetic antihyperglycemic agent it comprises, with the division of the daily dose into 2 or 3 one-time doses. It corresponds to the intake of 2-3 capsules or tablets comprising the claimed composition, 2 or 3 times daily at or after meals.
  • the patient takes the composition till the symptoms of acidosis are eliminated but no less than two weeks in the least.
  • the claimed combination may be used in the form of a pharmaceutical set.
  • the pharmaceutical set according to the present invention is used where there are indications with regard to the patient for the use of the claimed combination in the form of a pharmaceutical composition.
  • the amount of combination medication in the form of a pharmaceutical set is determined by the therapeutically effective dose of the particular antidiabetic antihyperglycemic agent it comprises.
  • the combination is prescribed in 1 or 2 sets per intake, 2-3 times daily, at or after meals.
  • the administration of the pharmaceutical set is continued till the elimination of acidosis symptoms in the patient, but no less than for two weeks. That said, the preferred option is to continue the administration of the claimed set in the subsequent treatment of diabetes mellitus. In that period, depending on the clinical laboratory examination results, individual components of an appropriate type may be added to one-time doses of the set for the purpose of enhancing the antihyperglycemic effect or antiacidosis effect.
  • the claimant also intends to protect the application of natural phenolic compounds capable of uncoupling oxidative phosphorylation, or a mixture of such compounds, in treating diabetes with the use of antihyperglycemic preparations as an agent suppressing the development of lactacidosis.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule.
  • the capsule comprises a mixture of 250 mg of metformin hydrochloride, 125 mg of green coffee bean extract (50-55 % polyphenols) and 25 mg of microcrystal cellulose.
  • the combination is prescribed in one-time doses of 2 or 3 capsules.
  • Example 2 The combination is prescribed in one-time doses of 2 or 3 capsules.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule.
  • the capsule comprises a mixture of 250 mg of metformin hydrochloride, 60 mg of green coffee bean extract (50-55 % polyphenols), 36.5 mg of ascorbic acid and 3.5 mg of silicon dioxide.
  • the combination is prescribed to be taken 2-3 capsules at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical composition encapsulated in a hard gelatin capsule.
  • the capsule comprises a mixture of 250 mg of metformin hydrochloride, 1 mg of rosiglitazone maleate, 50 mg of chlorogenic acid, 74 mg of ascorbic acid and 25 mg of microcrystal cellulose.
  • the combination is prescribed to be taken 2-3 capsules at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical composition in a tablet form.
  • the tablet comprises 250 mg of metformin hydrochloride, 60 mg of chlorogenic acid, and auxiliary substances (microcrystal cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethyleneglycol, titanium dioxide).
  • auxiliary substances microcrystal cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethyleneglycol, titanium dioxide.
  • the tablet is manufactured by a method comprising the production of granules by means of wet granulation of a mixture of metformin and chlorogenic acid with the addition of a binder, the subsequent mixing of granules with a solubilizer and a lubricant, tableting the mixture and coating the resultant tablets with hydrophilic polymer film.
  • the combination is prescribed to be taken 2-3 tablets at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical composition in a tablet form.
  • the tablet comprises 250 mg of metformin hydrochloride, 1.25 mg of glibenclamide, 30 mg of chlorogenic acid, 40 mg of ascorbic acid and auxiliary substances (microcrystal cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethyleneglycol, titanium dioxide).
  • auxiliary substances microcrystal cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethyleneglycol, titanium dioxide.
  • the tablet is manufactured by a method comprising the production of granules by means of wet granulation of a mixture of metformin, glibenclamide, chlorogenic and ascorbic acids with the addition of a binder, the subsequent mixing of granules with a solubilizer and a lubricant, tableting the mixture and coating the resultant tablets with hydrophilic polymer film.
  • the combination is prescribed to be taken 2-3 tablets at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical set consisting of separately manufactured tablets, which comprises an antidiabetic antihyperglycemic agent and a tablet containing a natural phenolic compound.
  • the tablet containing antihyperglycemic substances includes 500 mg of metformin hydrochloride, 15 mg of pioglitazone hydrochloride and auxiliary substances (microcrystal cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethyleneglycol, titanium dioxide, talc)
  • auxiliary substances microcrystal cellulose, croscarmellose sodium, polyvinylpyrrolidone, magnesium stearate, hydroxypropylmethylcellulose, polyethyleneglycol, titanium dioxide, talc
  • the tablet is manufactured by a method comprising the production of granules by means of wet granulation of a mixture of metformin and pioglitazone with the addition of a binder, the subsequent mixing of granules with a solubilizer and a lubricant, tableting the mixture and coating the resultant tablets with hydrophilic polymer film.
  • the tablet containing a polyphenolic compound includes 100 mg of chlorogenic acid and auxiliary substances (hydroxypropylmethylcellulose, microcrystal cellulose, povidone, magnesium stearate).
  • the tablet is manufactured by a method comprising the production of granules by means of wet granulation of a mixture of chlorogenic acid and a binder, the subsequent mixing of granules with a solubilizer and a lubricant, and tableting the mixture.
  • Tablets containing antihyperglycemic agents, on the one hand, and tablets containing a natural phenolic compound, on the other hand, are packaged in blisters or flasks with different marking and placed in a common box with an equal number of tablets of each type in the box.
  • the combination is prescribed to be taken one or two tablets of each type at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical set consisting of separately manufactured tablets containing an antidiabetic antihyperglycemic agent, and capsules containing a mixture of a natural phenolic compound with ascorbic acid.
  • the tablet comprises 500 mg of metformin hydrochloride and auxiliary substances (hydroxypropylmethylcellulose, microcrystal cellulose, povidone, magnesium stearate).
  • the tablet is manufactured by a method comprising the production of granules by means of wet granulation of a mixture of metformin with the addition of a binder, the subsequent mixing of granules with a solubilizer and a lubricant, and tableting the mixture.
  • the capsule comprises a mixture of lOO mg of green coffee bean extract (50-55 % polyphenols), 75 mg of ascorbic acid and 25 mg of microcrystal cellulose.
  • Tablets and capsules are packaged in blisters or flasks with a respective marking and placed in a common box with an equal number of tablets and capsules in the box.
  • the combination is prescribed to be taken one (1 tablet and 1 capsule) or two (2 tablets and 2 capsules) sets at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical set consisting of separately manufactured tablets containing an antidiabetic antihyperglycemic agent, and tablets containing a mixture of a natural phenolic compound with ascorbic acid.
  • the tablet containing an antihyperglycemic agent comprises 500 mg of metformin hydrochloride, 5 mg of glibenclamide and auxiliary substances (croscarmellose sodium, magnesium stearate, starch, microcrystal cellulose, povidone, lactose monohydrate).
  • auxiliary substances croscarmellose sodium, magnesium stearate, starch, microcrystal cellulose, povidone, lactose monohydrate.
  • the tablet is manufactured by a method comprising the production of granules by means of wet granulation of a mixture of metformin and glibenclamide with the addition of a binder, the subsequent mixing of granules with a solubilizer and a lubricant, and tableting the mixture.
  • the tablet for a prolonged release of active substances comprising 200 mg of green coffee bean extract, 50 mg of ascorbic acid and auxiliary substances (compritol 888 ATO, kollidon VA64, kollidon 17PF, magnesium stearate).
  • the tablet is manufactured by the direct compression method of tablet masses in the form of granulates obtained by disintegration of direct-compression cakes of a mixture of active substances, and auxiliary components.
  • Tablets containing antihyperglycemic agents, on the one hand, and tablets containing a mixture of a natural phenolic compound and ascorbic acid, on the other hand, are packaged in blisters or flasks with different marking and placed in a common box with an equal number of tablets of each type in the box.
  • the combination is prescribed to be taken one or two tablets of each type at a time.
  • a combination for treating diabetes according to the present invention represented by a pharmaceutical set consisting of separately manufactured tablets containing an antidiabetic antihyperglycemic agent, and soft gelatin capsules containing a suspension of a mixture of a natural phenolic compound with ascorbic acid.
  • a soft gelatin capsule comprising a suspension of a mixture of 75 mg of green coffee bean extract (50-55 % polyphenols) and 50 mg of ascorbic acid in 150 mg of polysorbate 80 (Tween 80).
  • Suspension for the filling of capsules is produced in the form of homogeneous pasty body gradually admixing a premixed preparation of green coffee bean extract with ascorbic acid to polysorbate 80 under constant stirring in a vacuum reactor.
  • Tablets and capsules are packaged in blisters or flasks with a respective marking and placed in a common box with an equal number of tablets and capsules in the box.
  • the suppression of intracellular pH decrease induced in the MDCK continuous line cells (dog's liver cells) by means of natural phenolic compounds capable of uncoupling oxidative phosphorylation in mitochondria was performed by means of adding metformin and rosiglitazone to cell culture medium.
  • a MDCK cell culture was grown in DMEM medium with the addition of a 10% calf serum at 37°C and 5% of C02 (pH 7.4). After the formation of an uninterrupted monolayer the cells were transferred to a suspension with the use of a Trypsin-EDTA solution. When cells were completely separated in order to halt any further action of EDTA-Trypsin, fetal calf serum and DMEM medium were introduced into the culture flask in equal proportions (1 :1). The cells were washed twice with the DMEM medium.
  • cell suspensions were prepared in culture flasks with a concentration of 1 ⁇ 10 6 cells/mL in Krebs- Henseleit medium containing 10 MM of d-glucose, with the addition of one of the following antihyperglycemic substances: metformin hydrochloride (5 MM) or rosiglitazone maleate (25 ⁇ ), and one natural phenolic compound (50 ⁇ ).
  • metformin hydrochloride 5 MM
  • rosiglitazone maleate 25 ⁇
  • one natural phenolic compound 50 ⁇
  • the suspension was incubated for 60 minutes at 37°C under stirring every 10 minutes by means of shaking the test-tubes. On completion of the incubation, the cells were precipitated by centrifuging, and re-suspended in Krebs-Henseleit medium containing 10 MM of d-glucose and 5 ⁇ of pH-susceptible dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester (BCECF-AM). The resultant suspension was incubated 25 minutes at 37°C to induce the dye absorption by the cells. Then the suspension was washed three times in Krebs- Henseleit medium where HEPES was replaced with bicarbonate.
  • Krebs-Henseleit medium pH-susceptible dye 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein acetoxymethyl ester
  • the resultant cells were suspended in the same buffer with a concentration of 1 ⁇ 10 6 cells/mL and introduced into a microcuvette for fluorescence measurements, thermostated at 37°C. Fluorescence measurements were conducted on a Perkin Elmer LS-5 spectrofluorometer with fluorescence registered at 530 nm and excitation at two wavelengths: 490 nm (fluorescence susceptible to pH) and 440 nm (isobestic point).
  • the ratio of fluorescence at 490 nm to fluorescence at 440 nm was used to calculate the intracellular pH based on calibration correlation obtained with the use of a cell suspension 1 ⁇ 10 6 cells/mL in Krebs-Henseleit medium with different pH values (from 6.5 to 7.5) containing H+/K+ ionophore nigericin (10 ⁇ g/mL).
  • tablette 1 demonstrate the ability of natural phenolic compounds, capable of uncoupling oxidative phosphorylation, to prevent the reduction of intracellular pH induced in the MDCK continuous line cells by the addition to a cell culture medium of antihyperglycemic agents from the groups of biguanides (metformin) and thiazolidinediones (rosiglitazone).
  • Sprague Dawley rats aged 8 months with a body mass of 250-280 g were used. Animals were held under the light/darkness cycle of 12 hours each, with a free access to water and feedstuff for rodents. Twelve hours prior to the start of an experiment, the animals were denied access to food but continued to enjoy free access to water. Metformin was injected directly into the tail vein in a dose of 250 mg/kg in the form of a 2.5 % solution in physiological solution four times with intervals of 1 hour. Half an hour before the first injection of metformin, the laboratory animals orally received a solution or suspension of natural phenolic compounds in water or in an aqueous solution of ascorbic acid.
  • the dose of natural phenolic compounds amounted to 5 mg/kg, and that of ascorbic acid - 2.5 mg/kg.
  • Control groups were represented by intact animals; animals that received only metformin; and animals that received metformin and an ascorbic acid solution without natural phenolic compounds.
  • the supernatant (0.4 mL) was collected into new microcentrifuge tubes, acid was neutralized by the addition of a 25 ⁇ , of 5 M potassium carbonate solution, and residue separated by centrifuging for 5 minutes at 10,000g and 4°C. The collected supernatant was immediately used to determine the lactate content according to the fluorometric methodology with the use of a standard set of reagents adapted to the use in microcuvettes on Perkin Elmer LS-5 spectrofluorometer.
  • tablette 2 demonstrate the ability of natural phenolic compounds capable of uncoupling oxidative phosphorylation in mitochondria to suppress lactic acid accumulation and lactacidosis development, in particular, one induced by the administration of large doses of antihyperglycemic agent metformin.
  • the administration of the aforementioned phenolic compounds along with ascorbic acid contributes to the enhancement of the recorded antiacidosis effect, which confirms benefit of the combined use of these substances according to the invention.
  • Patient V. 47 y/o, diagnosed with type 2 diabetes for the first time.
  • antihyperglycemic therapy was prescribed in the form of metformin monopreparation, starting with 500 mg daily.
  • metformin was increased to 500 mg twice daily.
  • the clinical laboratory examination conducted a week later detected weak lactacidosis symptoms in the patient (see table 3), which manifested themselves by blood lactate content slightly exceeding the upper range, and blood pH declining lower than the lower range.
  • the tendency to develop acidosis was related to a hepatic insufficiency, in turn related to hepatitis in the medical history.
  • the patient was switched to two combinations daily consisting of a tablet of antihyperglycemic agent and a capsule comprising a mixture of a natural phenolic compound with ascorbic acid according to example 7 for a period of two weeks.
  • the clinical laboratory examination conducted in due time established lactate content and blood pH normalization. Normal values of the said indicators remained stable after the addition, to the two daily combinations according to example 7, of an additional 500 mg tablet of metformin monpreparation (to the total of 500 mg x 3 daily) for the period of four weeks, with a subsequent transition to the administration of metformin monopreparation in the dosage of 500 mg x 3 daily for the period of the following four weeks.
  • Intracellular pH in cells under incubation in a culture medium without antihyperglycemic substances and substances capable of uncoupling oxidative phosphorylation in mitochondria was equal to 7.43 1 0.06.
  • the recorded decline of intracellular pH on the addition to the incubation medium of just antihyperglycemic agents corresponds to ⁇ 0.05 according to Student's /-test.
  • Lactate content in blood serum of intact animals is 1.64 ⁇ 0.19 mM.
  • the recorded increase of lactate content caused by metformin administration corresponds to P ⁇ 0.05 according to Student's i-test.

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Abstract

L'invention concerne une combinaison pour le traitement du diabète sucré qui peut être réalisée sous la forme d'une composition pharmaceutique ou d'un ensemble pharmaceutique. La combinaison comprend des agents anti-hyperglycémiques et des composés phénoliques naturels aptes à découpler une phosphorylation oxydante. Ladite composition donne la possibilité de réduire l'incidence d'effets secondaires résultant de l'utilisation de préparations anti-hyperglycémiques, en particulier le risque d'acidose lactique.
EP12738248.9A 2011-06-02 2012-04-05 Combinaison pour le traitement du diabète sucré Withdrawn EP2714022A1 (fr)

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EA201301308A1 (ru) 2014-03-31

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