WO2012041898A1 - Combinaison de l'inhibiteur de sglt2 et d'un composé de sucre pour le traitement du diabète - Google Patents

Combinaison de l'inhibiteur de sglt2 et d'un composé de sucre pour le traitement du diabète Download PDF

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WO2012041898A1
WO2012041898A1 PCT/EP2011/066848 EP2011066848W WO2012041898A1 WO 2012041898 A1 WO2012041898 A1 WO 2012041898A1 EP 2011066848 W EP2011066848 W EP 2011066848W WO 2012041898 A1 WO2012041898 A1 WO 2012041898A1
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formula
compound
alkyl
crc
component
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PCT/EP2011/066848
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Mateusz Mach
Piotr Guzenda
Maciej Wieczorek
Monika Lamparska-Przybysz
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Celon Pharma Sp. Z O.O.
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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • 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
    • A61P13/00—Drugs for disorders of the urinary system
    • 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

Definitions

  • the invention relates to the combination of SGLT2 inhibitor compound useful in the treatment of type 2 diabetes and a sugar compound.
  • the combination can be used in the treatment of type 2 diabetes for preventing or treating infections of urinary tract or genital organs.
  • Type 2 diabetes represents most diabetes cases in the world. It is characterized by insulin-independence and destruction of pancreatic beta-cells responsible for insulin secretion. Constant growth of morbidity and its prevalence indicate worldwide epidemy of type 2 diabetes. The necessity of life- long treatment and occurrence of many serious complications such as cardiovascular complications that often lead to limbs amputation and exclusion of patients from job market, in combination with its prevalence cause that type 2 diabetes is a serious economic and social problem. Additional problem which must be combated by diabetic patients are infections. Bacterial, fungal and viral infections occur more often in diabetes patients than in the general population. As a rule, the course of these infections in diabetes patients is more severe and complications are more often.
  • the main disadvantage of insulin is increase of body weight as a result of appearance of high levels of insulin in the blood after injection and its influence on adipocytes. Serious problem during use of insulin injections are cases of hypoglycemia. Disadvantage of this therapy are also injections themselves. Similarly, use of sulphonylurea derivatives leads to increase of body weight and occurrence of hypoglycemia.
  • the use of PPAR agonists from the group of thiazolidinediones compounds causes increase of the risk of cardiologic complications, increase of body weight, bone fragility and retention of body fluids.
  • the use of newest medicaments potentiating the GLP-1 action also causes reactions of gastrointestinal tract and pancreatitis. In the case of GLP-1 analogs there is a risk of immune response and their use requires injections, similarly as insulin.
  • the most recent approach in the therapy of type 2 diabetes is reduction of glucose level in blood by inhibition of renal SGLT2 transporters, thereby toxic action of insulin is blocked, especially on pancreatic beta cells.
  • the kidney are responsible for the whole glucose re-absorption from urine, returning back to the body approximately 180 g of glucose per day.
  • Two types of glucose transporters are present in the kidney, SGLT1 and SGLT2. The latter is located in the convoluted segment of the proximal tubule (S1 cells) and is responsible for 90% of glucose re-absorption.
  • SGLT1 is located in the distal straight segment of the proximal tubule (S2, S3 cells) and is responsible for re- absorption of remaining part of sugars. It has been shown that inhibition of SGLT2 contributes directly to lowering glucose level and occurrence of glycosuria. Inhibition of SGLT2 activity appears to be the strategy safe and effective from the point of view of correct functioning of the body, as confirmed by the fact of the existence in the population of hereditary mutation within the gene encoding SGLT2 protein. This mutation leads to the production of nonfunctional protein and disease called familial renal glycosuria. Despite of persistent isolated glycosuria (10-130 g/day) in the face of normal fasting serum glucose and correct response to the glucose tolerance test, no increase of urinary tract infections rate has been observed in these individuals.
  • SGLT2 inhibitors SGLT2 inhibitors
  • C-arylglycosides Unlike O-arylglycosides, C-arylglycosides are chemically stable and after oral administration there is no hydrolysis of glycosidic bond by beta-glycosidases present in the intestinum.
  • C-Arylglycosidic SGLT2 inhibitors are disclosed inter alia in WO01 /027128, WO04/013118, WO04/080990, EP1852439A1 , WO01 /27128, WO03/099836, WO2005/092877, WO2006/034489, WO2006/064033, WO2006/117359, WO2006/117360, WO2007/025943, WO2007/028814, WO2007/031548, WO2007/093610, WO2007/ 128749, WO2008/049923, WO2008/055870, and WO2008/055940.
  • the search of new SGLT2 inhibitors is also carried out.
  • Several SGLT2 inhibitors are currently at different stages of clinical trials in diabetes treatment.
  • glycosuria i.e. glucose excretion with urine. This effect is dependent on a mechanism of action and thus is specific for the whole class of SGLT2 inhibitors, irrespective of the chemical structure of a given compound.
  • the inventors have found that therapy of diabetes with SGLT2 inhibitors generally may cause increased risk of infections of urinary tract and genital organ as undesired reactions. The increased risk of these undesired reactions is believed to be a class effect associated with glycosuria and serious problem in therapy based on SGLT2 inhibition that should require attention, the more that therapy of type 2 diabetes is a life-long one, and glycosuria will be present during the whole duration of the treatment with SGLT2 inhibitors.
  • dapagliflozin (1 ,5-anhydro-1 -C-[4-chloro-3-[(4-ethoxyphenyl)methyl]phenyl]- (IS)-D-glucitol).
  • dapagliflozin urinary tract infections occurred in 4.2 - 12.5% of patients compared with values of 0,0 - 6,0% in placebo patients (see List, J. F., V. Woo, et al. (2009). "Sodium-Glucose Cotransport Inhibition With Dapagliflozin in Type 2 Diabetes.” Diabetes Care 32(4): 650-657; Wilding, J. P. H., P. Norwood, et al.
  • Antibacterial treatment of urinary-genital infections in diabetic patients is additionally complicated by the possibility of occurrence of diabetic nephropathy and necessity of simultaneous diabetes control.
  • the use of antibiotics, especially nephrotoxic ones, can be dangerous.
  • the necessity of controlling diabetes in urinary-genital infections once present often requires withdrawal of oral medicaments and introduction of insulin therapy.
  • antibiotic treatment can be used in single cases of infections, it will be impossible to treat with antibiotics an infection associated with constant glycosuria, i.e. a chronic one, during the use of SGLT2 inhibitors.
  • said problem is solved by a combination of SGLT2 inhibitor and a sugar compound exhibiting affinity to bacterial lectins.
  • this invention relates to a combination which comprises
  • the combination finds its use as a medicament, in particular for the treatment of type 2 diabetes.
  • the invention relates also to a combination of anti-diabetic SGLT2 inhibitor compound and a sugar compound exhibiting affinity to bacterial lectins for use as a medicament for mammals, in particular for humans.
  • the invention relates also to the use of anti -diabetic SGLT2 inhibitor compound in combination with a sugar compound exhibiting affinity to bacterial lectins for treating diabetes, especially type 2 diabetes, in mammals, especially in humans.
  • the invention relates also to a method for treating type 2 diabetes which comprises administration to a patient in need thereof of an effective amount of SGLT2 inhibitor and a sugar compound exhibiting the affinity to bacterial lectins, in particular oral administration.
  • Lectins also called agglutinins, are receptors binding simple carbohydrates present on the surfaces of microorganisms. These receptors are specific for each simple sugar.
  • All bacteria can possess on their surface several types of lectins specific for various carbohydrates, mainly in bacterial fimbriae. Occurrence of lectins on these structures allow bacteria to adhere to the epithelium of infected tissue by strong binding to sugar residues on the surface of epithelial cells, and then multiply and initiate the infection. This ability of bacteria to adhere to epithelium is very important infection-enabling factor. Sufficiently strong adherence of bacteria to epithelium protects them from being swept away from the body in the normal process of cleansing mucosal surfaces. This enables multiplication of bacterial colonies and infection, among others gastrointestinal tract, urinary tract or genital organs.
  • the combination of the invention can be used in diabetic patients both for the prevention of the appearance of urinary tract and genital organs infections and for alleviation and treatment of already existing infection.
  • the combination of the invention can be used in the treatment of type 2 diabetes in diabetic patients wherein urinary tract infection has not appeared yet.
  • the administration of SGLT2 inhibitor as a component of the combination of the invention can prevent such infection to occur.
  • the combination of the invention can be used in the treatment of type 2 diabetes in diabetic patients wherein said infection has already appeared and is present at the moment of beginning of the treatment.
  • the combination of the invention can cure such infection or assist therapy of such infection.
  • any compound exhibiting SGLT2 inhibition can be used in the combination of the invention.
  • the SGLT2 inhibitor can be a selective SGLT2 inhibitor or a non-selective SGLT2 inhibitor.
  • the compound - SGLT2 inhibitor is a C-arylglycosidic SGLT2 inhibitor or its prodrug.
  • SGLT2 inhibitor can be in particular selected from the group of compounds represented by general Formula (I)
  • X represents -0- or -S-;
  • A represents -0-, -S- or (CH 2 -) n , where n is an integer from 0 to 4;
  • C represents 5- or 6-membered aromatic or heteroaromatic ring comprising heteroatom selected from 0 and S;
  • R 3 and R 4 independently are selected from the group consisting of: hydrogen atom; chlorine or fluorine atom; -OH; -CN; -CrC 4 -alkyl, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -C 2 -C 4 -alkenyl;
  • -0-CrC 4 -alkynyl -C C 4 -alkoxy, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -C C 4 -alkoxy substituted with -CrC 4 - alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom, -0-CrC 4 -alkenyl, or -0-Ci-C 4 -alkynyl;
  • R 4a represents hydrogen atom
  • R 5 and R 6 independently are selected from the group consisting of: hydrogen atom; chlorine or fluorine atom; -OH; -CN; -COOH; -CrC 4 -alkyl, wherein one or more hydrogen atoms can be replaced with -OH or fluorine atom; -CrC 4 -alkyl substituted with -d-C 4 -alkoxy, wherein one or more hydrogen atoms can be replaced with fluorine atom; -CrC 4 -alkyl substituted with -0-C 3 -C6-cycloalkyl; -C 2 -C 4 -alkenyl; -C 2 -C 4 -alkynyl; -C 2 -C 4 -alkynyl substituted with -Ci-C 4 -alkoxy; -C 3 -C 6 -cycloalkyl; -CrC 4 -alkylphenyl, wherein phenyl is unsubstit
  • R 5 and R 6 are attached to neighboring carbon atoms and together form a 5-, 6- or 7-membered aromatic or heterocyclic group comprising heteroatom selected from O and S, wherein heterocyclic group can be saturated, unsaturated or aromatic;
  • alkyl, alkenyl, alkynyl, alkadienyl and alkatrienyl groups can be straight or branched.
  • C-arylglucosidic SGLT2 inhibitor can be especially selected from the group 1 ) do 11 ) presented below.
  • Dapagliflozin is disclosed inter alia in WO03/099836 and WO2008/002824.
  • R 1 represents CI, methyl or cyano
  • R 2 represents H, methyl, methoxy or hydroxy
  • R 3 represents ethyl, cyclopropyl, ethynyl lub ethoxy, or a prodrug of this compound
  • R represents ethyl, iso-propyl, tert-butyl, methoxy or trifluoromethoxy, disclosed in WO2007/140191 and WO2008/013280, or a prodrug of this compound;
  • component a) of the combination according to the invention may be the prodrug of SGLT2 inhibitor.
  • Particular compounds selected from the following group and their mixtures can be mentioned sugar compounds exhibiting the affinity to bacterial lectins:
  • oligosaccharides containing 2 to 10 of sugar units and built from mannose, fructose and/or galactose units can be mentioned as sugar compounds exhibiting the affinity to bacterial lectins.
  • oligosaccharides are mannooligosaccharides, fructooligosaccharides, galactomannooligosaccharides and galactooligo- saccharides.
  • oligosaccharides that include 4-0- -galactopyranosyl-D-gluco- pyranosyl, 2-acetamido-2-deoxy- -D-glucopyranosyl-(1 ⁇ 3)-D-galactopyranosyl, -D-galactopyranosyl-(1 ⁇ 4)-2-acetamido-2-deoxy-D-glucopyranosyl, N-acetyl-a- neuraminyl-(2 ⁇ 3)- -D-galactopyranosyl-(1 ⁇ 3)-2-acetamido-2-deoxy-D- galactopyranosyl or N-glycolyl-a-neuraminyl-(2 ⁇ 3)- -D-galactopyranosyl-(1 ⁇ 4)- D-glucopyranosyl as a oligosaccharide fragment, for example and without such limitation as a terminal oligosaccharide fragment,
  • the combination of the invention includes the SGLT2 inhibitor in the amount of 2,5 to 1000, in particular 2.5 to 100 mg per unit dosage, and the sugar compound in the amount of from 100 mg to 10 g per unit dose, in particular 100 to 400 mg per unit dosage.
  • the examples of advantageous combination are the combinations of 2.5 mg of SGLT2 inhibitor and 100 mg of mannose, 5 mg of SGLT2 inhibitor and 100 mg of mannose, 10 mg SGLT2 inhibitor and 100 mg of mannose, 25 mg of SGLT2 inhibitor and 100 mg of mannose, or 50 mg of SGLT2 inhibitor and 100 mg of mannose.
  • Another examples of advantageous combination are the combinations of 2.5 mg of SGLT2 inhibitor and 400 mg of mannose, 5 mg of SGLT2 inhibitor and 400 mg of mannose, 10 mg of SGLT2 inhibitor and 400 mg of mannose, 25 mg of SGLT2 inhibitor and 400 mg of mannose or 50 mg of SGLT2 inhibitor and 400 mg of mannose, and 100 mg of SGLT2 inhibitor and 400 mg of mannose.
  • the sugar compound is selected from the group consisting of mannose, galactose and their mixtures.
  • Especially advantageous sugar compound is mannose.
  • the SGLT2 inhibitor is dapagliflozin of Formula 1
  • the sugar compound is selected from the group consisting of mannose, galactose and their mixtures.
  • SGLT2 inhibitor is dapagliflozin, and the sugar compound is mannose.
  • the SGLT2 inhibitor is canagliflozin of Formula 2, and the sugar compound is selected from the group consisting of mannose, galactose and their mixtures, especially mannose.
  • the SGLT2 inhibitor and the sugar compound are administered to a patient in distinct pharmaceutical formulations/compositions, preferably in two distinct pharmaceutical formulations/compositions for oral administration.
  • the SGLT2 inhibitor and the sugar compound can be administered orally simultaneously, consecutively (concurrently) one after another in any order, or separately with each other with time intervals.
  • Distinct compositions for oral administration can be, independently for both components, selected from among tablets, coated tablets, capsules, powders and granulates, syrups and suspensions.
  • tablets, powders and granulates are effervescent.
  • SGLT2 inhibitor and the sugar compound for administration simultaneously, consecutively one after another or separately, can be incorporated in distinct pharmaceutical compositions or formulations for oral administration and can be packed in two distinct packagings or in a single common packaging, including both the formulation of SGLT2 inhibitor and the formulation of the sugar compound.
  • said distinct compositions/formulations of the SGLT2 inhibitor and the sugar compound can be tablets and/or capsules placed in separate and specifically marked compartments of a blister containing such tablets and/or capsules.
  • one from the SGLT2 inhibitor and the sugar compound can be in the form of a tablet and the second of them in the form of a capsule, both can be in the form of a tablet or both can be in the form of a capsule.
  • the SGLT2 inhibitor can have the form of a tablet, and the sugar compound the form of a powder, a granulate or a tablet, optionally effervescent, for dissolution in water before ingestion.
  • compositions of SGLT2 inhibitors in a solid form for oral administration including the form of capsules and tablets, are known for example from W010/092123.
  • the SGLT2 inhibitor and the sugar compound are administered to a patient in the same pharmaceutical composition for oral administration common for both components.
  • compositions comprising a combination as defined above, together with pharmaceutically acceptable carriers and/or excipients.
  • compositions for oral administration can be selected from among solid oral formulations.
  • Exemplary solid oral formulations are formulations in the form of distinct units, each containing specified amount of active components a) and b) of the compositions, such as tablets, tablets coated with a non-functional coating, soft and hard capsules, effervescent tablets, quick-dissolving tablets, orodispersible tablets.
  • Other examples of solid oral formulations are powders and granulates, in particular powders and granulates for the preparation of suspensions for oral administration of a liquid. Powders and granulates for the preparation of suspensions can be effervescent.
  • the preferred sugar compound is mannose or galactose.
  • the sugar compound is mannose or galactose and the common composition is capsule or tablet, optionally coated.
  • mannose or galactose apart of its role as a second active ingredient, mannose or galactose can have simultaneously the function of a filler and/or a binder.
  • the sugar compound is mannose
  • SGLT2 inhibitor is dapagliflozin of Formula 1 or canagliflozin of Formula 2 or the compound of Formulae 3, 3a or 3b
  • common composition has the form of a tablet, which tablet can be coated with a coating.
  • the tablet can additionally include any other conventional filler/binder, such as for example starches, pregelatinised starches, cellulose and cellulose derivatives, such as ethylcellulose, hydroxypropylcellulose, hydroxyethylmethylcellulose, microcrystalline cellulose, carboxymethylcellulose; polymers such as polyvinylpyrrolidone, polyethylene glycols, polyvinyl alcohol; gelatine, and their mixtures.
  • Advantageous filler/binder is microcrystalline cellulose.
  • Tablet can contain typical disintegrant, such as for example starch, crosslinked polyvinylpyrrolidone, croscarmelose sodium, sodium starch glycolate, preferably croscarmelose sodium.
  • typical disintegrant such as for example starch, crosslinked polyvinylpyrrolidone, croscarmelose sodium, sodium starch glycolate, preferably croscarmelose sodium.
  • Tablet can contain typical lubricant, such as for example magnesium stearate, stearic acid, polyethylene glycol, talc, sodium stearylfumarate, and typical glidant, such as for example anhydrous colloidal silica.
  • typical lubricant such as for example magnesium stearate, stearic acid, polyethylene glycol, talc, sodium stearylfumarate, and typical glidant, such as for example anhydrous colloidal silica.
  • Tablet for oral administration of the combination according to the invention may generally contain, with respect to the total weight of the tablet, a binder in a total amount of 1 -20% by weight, a disintegrant in a total amount of 0,5-15% by weight, a lubricant in a total amount of 0,2-5% by weight, a glidant in a total amount of 0,2-10% by weight, a filler in a total amount of 0-80% by weight.
  • Typical excipients and methods for the preparation of tablets are taught extensively in the literature in the field of invention, for example in ..Handbook of Pharmaceutical Excipients", 3 Ed., Arthur H. Kibbe ed. , American Pharmaceutical Association, Washington, USA and Pharmaceutical Press, London. A skilled person can select in routine experiments and employ to obtain desired properties of a tablet one or more from among excipients mentioned above.
  • tablets containing combination of the invention and suitable excipients will be manufactured by direct compression of the a mixture of formulation ingredients.
  • dry mixture of formulation ingredients after optional compacting, can be also used as the filling for capsules, especially hard gelatine capsules.
  • a granulate containing the sugar compound, especially mannose or galactose can be obtained, for example by fluid bed granulation, and subsequently the granulate mixed with component a) of the combination and excipients and compressed to form tablets.
  • powders and granulates mixtures of an organic acid and a carbonate can be used as disintegrants.
  • formulations for oral administration can include flavoring and/or coloring substances.
  • the invention will be exemplified in details in the Examples, specific embodiments and drawing presented below, which are not limiting for the scope of the invention.
  • Fig. 1 presents the progress of the infection in dapagliflozin treated rats in comparison with the treatment using dapagliflozin-mannose combination.
  • Example 1 Influence of administration of SGLT2 inhibitor in combination with a sugar compound
  • mice Six days before inoculation, mice were given only 5% aqueous glucose solution to drink. At one day before of the beginning of the experiment (before inoculation), the animals were given first a dose of SGLT2 inhibitor and a sugar compound - mannose or galactose. After aspiration of urine from the bladder, 10 8 of Escherichia coli in 0.05 ml of a physiological saline were introduced directly to the bladder. The animals were administered with daily dosages of SGLT2 inhibitor and a sugar compound once daily by means of stomach probe for 9 consecutive days, before each administration being starved for 6h with unlimited access to 5% glucose. The compounds were administered in the hydroxypropylmethylcellulose solution. The inhibitors were administered in a dose of 1 mg/kg of body weight, and the sugar compound in a dose of 80 mg/kg of body weight.
  • Table 1 and in Fig. 1 show that at day 9 the reduction of the number of CFU in the group receiving dapagliflozin and mannose to the level of 9% with respect to the value in the group receiving dapagliflozin alone was observed. Reduction of the infection progress was also observed in the case of other SGLT2 inhibitors tested. After dissection and analysis of the presence of bacteria in the kidney no ascending kidney infection was found in any animal. The results show that using the combination of the invention allows to achieve inhibition of the progress of the infection induced by direct injection of the bacterial suspension.
  • Example 2 The effect of long-term administration of an SGLT2 inhibitor in combination with a sugar compound
  • the animals in the groups wherein the influence of a sugar compound was analyzed were administered for 6 weeks mannose or galactose p.o. in a dose of 2 mg/kg m.c./day. Every 7 day before administration of the compound blood was collected (starvation for 18 h) from incision of the tail vein for determination of glucose level. Also every 7 day, twenty-four-hour collection of urine was performed for determination of glucose level and seeding. At the end of the experiment kidney and bladder were collected, also for seeding.
  • Example 3 Compositions of an SGLT2 inhibitor in combination with a sugar compound
  • compositions were formulated into tablets by direct compression.
  • suitable weighed amounts of dapagliflozin, mannose and anhydrous colloidal silica were blended together for 2 minutes.
  • microcrystalline cellulose and croscarmelose sodium were consecutively added to the mixer.
  • magnesium stearylfumarate was added and stirring was continued for 5 minutes.
  • the blend was tabletted using oval punches.
  • tablets were coated with a standard coating. Before tabletting tablets were heated to about 30-45 °C, and the whole process of coating was performed at that temperature.
  • Tablets containing another SGLT2 inhibitor and tablets containing galactose in place of mannose can be prepared analogously.
  • the solution for the dose of 2.5 mg of SGLT2 inhibitor + 100 mg of a sugar compound can be prepared from the following ingredients.
  • Glycol methylparaben and propylparaben were added to about 50% of the total amount of propylene glycol and stirred until dissolution.
  • Mannose was added to 95% of the total amount of purified water and stirred until dissolution.
  • sorbitol and active substance dissolved in ethyl alcohol were added and stirred to obtain intimate mixture.
  • propylene glycol, flavor, sodium saccharinate, sodium citrate, and citric acid were added and stirred until dissolution. pH was measured and adjusted to pH 7-7.5, if needed. Water was added to bring to the required volume, and the solution was filtered. Suspension for oral administration
  • advantageous variant of pharmaceutical formulation for higher doses is a powder for the preparation of a suspension, which contains 100 mg of SGLT2 inhibitor, for example dapagliflozin, and 400 mg of mannose per 5 ml of a suspension after reconstitution, and pharmaceutically acceptable excipients suitable for the preparation of a powder for reconstitution.
  • the powder for the preparation of the suspension can comprise in particular dispersing and viscosity-enhancing agent, for example selected from the group of polysaccharides such as guar gum, starch, xanthan gum; natural cellulose derivatives, such as croscarmelose sodium, hypromellose, hydroxyethylocellulose, synthetic polymers, for example polyvinylalcohol, polyvinylpyrrolidone or inorganic substances, such as colloidal silica, aluminium magnesium, or their mixtures.
  • a powder containing xanthan gum and colloidal silica is especially advantageous for the preparation of suspension.
  • SGLT2 inhibitor, mannose, sodium citrate and mannitol were micronized in jet mill to obtain median particle size ⁇ 10 ⁇ . Weighed substances were placed in a mixer and stirred for 20 minutes to obtain homogenous suspension. The mixture was poured into 100 ml bottles, 40 g per each bottle.

Abstract

Selon l'invention, la combinaison d'un composé antidiabétique, l'inhibiteur de SGLT2, et d'un composé de sucre présentant une affinité avec des lectines bactériennes peut être utilisée comme médicament pour le traitement du diabète de type 2 avec prévention ou traitement simultané d'infections des voies urinaires ou des organes génitaux.
PCT/EP2011/066848 2010-09-29 2011-09-28 Combinaison de l'inhibiteur de sglt2 et d'un composé de sucre pour le traitement du diabète WO2012041898A1 (fr)

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EP2535047A1 (fr) * 2011-06-16 2012-12-19 Alpiflor S.R.L. Composition nutritionnelle, complément alimentaire comprenant ladite composition nutritionnelle et kit comprenant ledit complément alimentaire
CN104672227A (zh) * 2013-11-28 2015-06-03 镇江新元素医药科技有限公司 一类新型sglt2抑制剂化合物及其药物组合物
JP2016504285A (ja) * 2012-11-20 2016-02-12 レクシコン ファーマシューティカルズ インコーポレイテッド ナトリウムグルコース共輸送体１の阻害剤
US9340553B2 (en) 2014-05-19 2016-05-17 Pfizer Inc. Substituted-6,8-dioxabicyclo[3.2.1]octane-2,3-diol compounds as targeting agents of ASGPR
US9340521B2 (en) * 2013-03-18 2016-05-17 Green Cross Corporation Method for dual inhibition of SGLT1 and SGLT2 using diphenylmethane derivatives
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WO2017079505A1 (fr) * 2015-11-04 2017-05-11 Research Institute At Nationwide Children's Hospital Rnase7 pour le traitement d'une infection bactérienne
WO2017217792A1 (fr) * 2016-06-17 2017-12-21 주식회사 대웅제약 Procédé de production d'un dérivé de diphénylméthane
JP2019502757A (ja) * 2016-01-04 2019-01-31 ジェイイー アイエル ファーマシューティカル カンパニー リミテッド 融合フェニル環が含まれたｃ−グルコシド誘導体またはその薬学的に許容可能な塩、その製造方法、およびそれを含む薬学的組成物
WO2019241568A1 (fr) * 2018-06-14 2019-12-19 Astrazeneca Uk Limited Procédés pour abaisser la glycémie avec une composition pharmaceutique glifozine, inhibiteur de cotransporteur glucose-sodium de type 2
CN113620938A (zh) * 2020-05-07 2021-11-09 北京康派森医药科技有限公司 一种恩格列净异构体杂质的合成方法
RU2774998C2 (ru) * 2017-06-15 2022-06-27 Даевунг Фармасьютикал Ко., Лтд. Способ получения производного дифенилметана
US11817188B2 (en) 2018-06-14 2023-11-14 Astrazeneca Uk Limited Methods for lowering blood sugar with a metformin pharmaceutical composition

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RU2814846C1 (ru) * 2016-06-17 2024-03-05 Даевунг Фармасьютикал Ко., Лтд. Способ получения производного дифенилметана
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US10889574B2 (en) 2016-06-17 2021-01-12 Daewoong Pharmaceutical Co., Ltd. Method for producing diphenylmethane derivative
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RU2774998C2 (ru) * 2017-06-15 2022-06-27 Даевунг Фармасьютикал Ко., Лтд. Способ получения производного дифенилметана
US11495339B2 (en) 2018-06-14 2022-11-08 Astrazeneca Uk Limited Methods for lowering blood sugar with a gliflozin sodium-glucose cotransport 2 inhibitor pharmaceutical composition
CN112955966A (zh) * 2018-06-14 2021-06-11 阿斯利康(英国)有限公司 用吉列净钠(gliflozin Sodium)-葡萄糖共转运剂2抑制剂医药组合物降低血糖的方法
US11817188B2 (en) 2018-06-14 2023-11-14 Astrazeneca Uk Limited Methods for lowering blood sugar with a metformin pharmaceutical composition
US11817195B2 (en) 2018-06-14 2023-11-14 Astrazeneca Uk Limited Methods for lowering blood sugar with a gliflozin sodium-glucose cotransport 2 inhibitor pharmaceutical composition
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