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WO2021173036A1 - Composition pharmaceutique à base d'un inhibiteur de dipeptidylpeptidase-4 - Google Patents

Composition pharmaceutique à base d'un inhibiteur de dipeptidylpeptidase-4 Download PDF

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Publication number
WO2021173036A1
WO2021173036A1 PCT/RU2021/000042 RU2021000042W WO2021173036A1 WO 2021173036 A1 WO2021173036 A1 WO 2021173036A1 RU 2021000042 W RU2021000042 W RU 2021000042W WO 2021173036 A1 WO2021173036 A1 WO 2021173036A1
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Prior art keywords
acid
pharmaceutical composition
substance
composition according
salt
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Russian (ru)
Inventor
Владимир Михайлович ТРУХАН
Татьяна Витальевна Зиневич
Борис Борисович СЫСУЕВ
Денис Сергеевич КАЗАК
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Obschestvo S Ogranichennoi Otvetstvennostju "neobiotek"
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Obschestvo S Ogranichennoi Otvetstvennostju "neobiotek"
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—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
    • A61K31/439—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 the ring forming part of a bridged ring system, e.g. quinuclidine
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00

Definitions

  • the field to which the invention relates The invention relates to medicine, in particular to pharmacology, and relates to an agent for preventing the development and treatment of type 2 diabetes mellitus.
  • Type 2 diabetes mellitus is a chronic endocrine disease associated with insulin resistance and dysfunction of pancreatic ⁇ -cells, which causes persistent and excessive blood glucose (hyperglycemia), which, in turn, directly or indirectly triggers a cascade disorders of all types of metabolism and metabolism.
  • CD-2 endocrine system disorders, increased lipolysis in adipose tissue, increased glucagon secretion, increased renal glucose reabsorption and, finally, eating disorders are associated. This disease greatly impairs the quality of life of patients, and its development leads to severe complications and consequences - disability and even death (Drucker, DJ, & Nauck, MA (2006).
  • the incretin system glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet, 365 (9548), 1696-1705). Diabetes mellitus is a serious medical and social problem all over the world, and the proportion of people suffering from this disease is constantly growing. Analysts from the International Diabetes Federation (IDF) report that by 2045 the number of patients with diabetes mellitus will rise to 700 million (Karuranga, S., Cho, NH, Ohlrogge, AW, Shaw, JE, da Rocha Fernandes, JD, Huang, Y., & Malanda, B. (2018). IDF Diabetes Atlas: Global estimates of diabetes prevalence for 2017 and projections for 2045. Diabetes Research and Clinical Practice, 138, 271-281).
  • DPP-4 inhibitors that successfully passed clinical trials and appeared on the pharmaceutical market in various countries were sitagliptin (https://www.lsgeotar.ru/sitagliptin.html) and vildagliptin (https://www.lsgeotar.ru/vildagliptin .html). and later they were joined by saxagliptin (https://www.lsgeotar.ru/saxagliptin.html). alogliptin (https://www.lsgeotar.ru/alogliptin.html). linagliptin
  • DPP-4 inhibitors significantly reduce postprandial and fasting hyperglycemia (blood glucose levels), glycated hemoglobin levels in blood plasma, stimulate insulin synthesis, and also have good oral bioavailability and relatively long action and do not affect the change body weight.
  • Known RF patent for invention No. 2443687 "New inhibitors of dipeptidyl peptidase IV, methods for their preparation and pharmaceutical compositions containing them.”
  • Known RF patent 2483716 for an invention concerning a pharmaceutical composition comprising a dipeptidyl peptidase-4 inhibitor, preferably vildagliptin from 1.5 to 20% and metformin from 80 to 98.5%. In this case, the active ingredients make up from 60 to 98% of the composition.
  • Cellulose or its derivatives are used as a binder in an amount of 1 to 20%.
  • Known patent application RF 2006121339 concerning a pharmaceutical composition
  • a pharmaceutical composition comprising a therapeutically effective amount (8) -1 - [(3-hydroxy-1- adamantyl) amino] acetyl-2-cyanopyrrolidine or a pharmaceutically acceptable salt thereof, preferably 25-100 mg, in combination with one or more pharmaceutically acceptable carriers, for the treatment of cardiovascular diseases or damage, renal disease or damage, heart failure or diseases associated with heart failure.
  • Known RF patent 2606840 for the invention of a composition containing a long-acting insulin conjugate and a long-acting insulinotropic peptide conjugate for the prevention or treatment of diabetes, as well as a method for treating diabetes.
  • Known RF invention N “2589258, which describes pharmaceutical compositions based on a peptide agent that inhibits dipeptidyl peptide azu-4.
  • sitagliptin is contraindicated in type 1 diabetes mellitus and diabetic ketoacidosis.
  • the objective of the present invention is to expand the arsenal of existing pharmaceutical compositions by developing and creating pharmaceutical compositions for oral administration based on a new inhibitor of dipeptidyl peptide ase-4, an active hypoglycemic and non-toxic component for preventing the development and treatment of type 2 diabetes mellitus.
  • the development includes pharmaceutical compositions containing excipients and carriers that provide various mechanisms for the release of the active ingredient, namely, immediate, prolonged and modified release of the active active ingredient.
  • Another object of the present invention is to develop the preparation of pharmaceutically acceptable salt forms of the active substance - the basis for compositions and GDF.
  • compositions for oral administration containing the active ingredient, a highly effective inhibitor of DPP-4 exo (28) -3 - [(311) -3-amino-4- (2,4,5-trifluorophenyl) butanoyl] -3-azabicyclo [2.2.1] heptane-2-carbonitrile - substance I in the form of pharmaceutically acceptable salt forms, excipients and carriers providing immediate, prolonged and modified release of the active ingredient for the treatment of patients with type 2 diabetes mellitus.
  • the structure of the active active ingredient is substance I.
  • FIG. 1 shows a typical LC / MS chromatogram of compound I with a mass detector.
  • examples 2-4 In the chromatograms obtained by the LC / MS method using a mass detector, in all cases (hereinafter examples 2-4), one peak of substance I with a purity of 100% was observed. The molecular weight (M) was determined by the mass detector and exactly corresponded to that calculated for substance I.
  • the resulting solution was evaporated, 200 ml of ethanol, 5% Pd on carbon (0.8 g), and Boc 2 0 (6.9 g, 0.0316 mol) were added. It was then hydrogenated at 20 psi on a Parr apparatus. The completeness of the reaction was monitored by the LCMS method. The resulting reaction mixture was used in the next step.
  • Triethylamine 3.45 ml (2.5 g) was added to a solution of acid 4 (5.42 g) in dry THF on cooling to --20 ° ⁇ in an argon atmosphere, then ethyl chloroformate (2.68 g, 0.0247 mol) was added dropwise over 10 min. The reaction mixture was kept under cooling for 40 min. Then ammonia was passed from a balloon for 1 h. The solvent was evaporated, the residue was treated with citric acid solution to pH 4, extracted with ethyl acetate, ethyl acetate extracts were washed with soda solution, dried with sodium sulfate and concentrated. Received 5.29 g of colorless crystalline amide 5. The yield is quantitative.
  • p-TSA p-toluenesulfonic acid
  • Typical chromatogram of substance I (Examples 2-4) obtained by LC / MS analysis with mass detection.
  • Pharmacologically acceptable salt forms of substance I include salts with inorganic acids - hydrochloric acid (hydrochloride), hydrobromic acid, nitric acid, sulfuric acid and phosphoric acid; and organic acids and their derivatives from among sulfo-, alkyloxy-, hydroxy-, oxo-substituted acids: formic acid, acetic acid, fumaric acid, oxalic acid, tartaric acid, maleic acid, citric acid, succinic acid, malic acid, methanesulfonic acid, trifluoromethanesulfonic acid, benzenesulfonic acid and p-toluenesulfonic acid (tosylate), naphthyl sulfonic acid and sulfosalicylic acid, lactic acid, tartaric acid, adipic acid, gluconic acid, glucoheptonic acid, glucuronic acid, terephthalic acid, hippuric acid, 1,2-
  • Salt-free A free base
  • salt form B of substance I in general form where HX is any of the acids described above.
  • Salt-free form A of substance I is obtained by isolating the free base after treatment of the salt forms with basic reagents using any standard chemical and physicochemical methods applied on the basis of basic knowledge of organic chemistry.
  • Example 4
  • any of the pharmacologically acceptable salt forms B of substance I are obtained by a standard procedure either at the final stage of the synthesis (removal of the MH 2 -protecting group), as shown in Examples 1-3, or by any easily practicable and standard method (Example 5), by mixing equimolar amounts any appropriate acid, its solvate or hydrate and an amine-containing substance (in this case, substance I) or salt exchange using well-known physicochemical methods, for example, ion exchange chromatography.
  • Table 1 Comparison of the obtained and published data for commercial pharmaceutical compositions - DPP-4 inhibitors with the results obtained for substance (I) in salt-free and salt forms.
  • type 2 diabetes mellitus there are no restrictions on the types of pharmaceutical compositions.
  • the most preferred route of administration for the treatment of diabetes mellitus is chosen orally.
  • the present invention includes the description of pharmaceutical compositions in the following dosage forms - tablets, granules, granules or pellets in the form of hard gelatin capsules.
  • the pharmaceutical composition for the treatment of diabetes mellitus comprises the active ingredient substance I in the form of a free base and / or in the form of a pharmacologically acceptable salt form from among those listed above, pharmacologically acceptable carriers and additional components, auxiliary substances, binders, lubricants, coating agents, aqueous solvents, solubilizing agents, which provide an acceptable pharmaceutical composition that meets the requirements of the State Pharmacopoeia.
  • the method of administration of the pharmaceutical composition for treating diabetes mellitus according to the present invention is presented in dosage forms for internal use (oral), but is not limited thereto.
  • the preferred intake is oral.
  • the dosage of the composition for treating diabetes mellitus according to the present invention is appropriately determined based on the patient's condition, the severity of the symptoms, the age, the route of administration, and the diagnosis by the physician.
  • Preferred dosages for oral administration are from 1 mg to 50 mg of substance I per day, most preferably 5 mg.
  • the above dose according to the present invention is taken by the patient as a single dose or divided into several doses for a period of 2-4 to 8-12 hours, depending on the severity of the symptoms and the doctor's diagnosis.
  • the drug is made in the form of the following dosage forms - tablets, granules, granules or pellets in the form of hard gelatin capsules, providing immediate (Examples 6-8), modified (examples 9-14) and prolonged (Examples 15-18) action.
  • Oral pharmaceutical composition representing a film-coated tablet containing substance I in salt-free form (free base) at a dosage of 5 mg in a ratio of 5 to 94% of the total weight of the tablet with the following ratio of ingredients per 100 mg, wt% indicated in the table 2.
  • a method of obtaining a medicinal product made on the basis of a pharmaceutical composition containing substance I in salt-free form (free base) as the only active substance in a dosage of 1 and 50 mg (in terms of base) in a ratio of 5 to 94% of the total weight of the tablet in the implementation of which magnesium stearate, substance I in salt-free form (free base), microcrystalline cellulose (type 21 or similar), cellulose 2-hydroxypropyl ether (low-substituted, type LH-21 or similar) and colloidal silicon dioxide (type A 200 or similar), prepare a mixture of substance I in salt-free form (free base), microcrystalline cellulose, cellulose 2-hydroxypropyl ether (low substituted) (25-60%) and colloidal silicon dioxide, magnesium stearate (35-65%), the components are mixed until homogeneous (visual control) for 3-24 minutes at a stirring speed of 7-25 rpm, transferred to a compacting device and the resulting mixture is subjected to dry granulation (compaction) and the resulting granulate is
  • compositions presenting a film-coated tablet containing substance I in the hydrochloride salt form was prepared analogously to the procedure described in Example 6, with the conversion of the hydrochloride salt form loading to the free base so that the same dosage of substance I (5 mg) was provided.
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 2.
  • compositions representing a film-coated tablet containing substance I in the form of a tosylate salt was prepared similarly to the procedure described in Example 6, recalculating the loading of the salt form of tosylate to the free base so that the same dosage of substance I (5 mg) was obtained. ...
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 2.
  • Modified release granules are prepared according to the following procedures (Examples 9-11 and / or 12-14).
  • Oral pharmaceutical composition representing a capsule containing granules containing substance I in salt-free form (free base) at a dosage of 5 mg per 1 capsule (in in terms of base) in a ratio from 5 to 94% of the total mass of the mixture with the following ratio of ingredients per 100 mg, mass% indicated in table 4.
  • the capsule contains enteric-coated granules and a slow-release coating.
  • the pellet ratio ranges from 5:90 to 90: 5.
  • the mixer is charged with substance I in salt-free form (free base), hypromellose (for example, type 2208), lactose monohydrate and corn starch.
  • the mixture of powders is mixed.
  • the mixture of powders is then transferred to a granule production unit by fluidization.
  • Granules are obtained by spraying a wetting mixture in which substance I was previously dissolved in salt-free form (free base) in a fluidized bed.
  • the resulting granulate is calibrated through a 0.25-0.5 mm sieve.
  • the resulting granules are coated with an enteric coating.
  • Hypromellose for example, type 2208
  • polysorbate-80 is added. All actions are carried out at a temperature of 40-55 degrees. Then add the calculated amount of talc and mix thoroughly again for 5-15 minutes. Thereafter, a film coating of a neutral copolymer based on ethyl acrylate and methyl methacrylate (eg EUDRAGIT NM 30 D / NE 30 D), stirred for 5 minutes and filtered through a sieve with a pore size of 0.5 mm.
  • EUDRAGIT NM 30 D / NE 30 D eg EUDRAGIT NM 30 D / NE 30 D
  • the process of coating is carried out in a fluidized bed installation.
  • the granules are heated to 35-37 ° C with periodic stirring in a fluidized bed.
  • Process parameters product temperature 27-37 ° ⁇ .
  • the process of coating is carried out in a fluidized bed installation.
  • the granules are heated to 35-37 ° C with periodic stirring in a fluidized bed.
  • spraying of the film suspension is started.
  • the appearance of the pellets is controlled.
  • Process parameters product temperature 27-37 ° ⁇ After full consumption of the suspension, the process is stopped and the granules are cooled to a temperature not exceeding 33 ° ⁇ . After the end of the process, the containers are closed. A representative selection of granules is carried out for intermediate control, according to the specification. Next, the resulting granules are encapsulated, based on the calculation that the ratio of the pellets ranges from 5:90 to 90: 5. In this case, the dosage of active ingredient I in 1 capsule should be 5 mg.
  • the resulting pharmaceutical composition provides the release profile shown in Table 5.
  • Oral pharmaceutical composition which is granules for internal use containing substance I in the hydrochloride salt form was prepared analogously to the procedure described in Example 9, with recalculating the loading of the hydrochloride salt form on the free base so that the same dosage of substance I (5 mg) was provided.
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 3.
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 5.
  • Modified release hard gelatin capsule granules are prepared according to the following procedure.
  • Oral pharmaceutical composition in the form of granules in the form of hard gelatin capsules for internal applications containing substance I in salt-free form at a dosage of 5 mg per 1 dose in a ratio of 5 to 94% of the total mass of the mixture with the following ratio of ingredients per 100 mg, wt% indicated in table 6.
  • the ratio of granules in 1 dose per dose ranges from 5:90 to 90: 5.
  • a hypromellose-based humidifier solution is prepared.
  • Swelling of the polymer is carried out in a part of water (1/3), after which the remaining part (2/3) is added and homogenization is carried out using a mechanical stirrer. The calculated amount of the substance is added to the resulting solution. The quality of dissolution and swelling of the polymer is assessed after preparation of the solution (visual control).
  • the mixer is loaded with lactose monohydrate and corn starch. The mixture of powders is mixed.
  • Granules are obtained by spraying a wetting mixture in which substance I was previously dissolved in salt-free form (free base) in a fluidized bed.
  • the resulting wet granulate is calibrated through a 0.25-0.5 mm sieve. Fractions of granules above 0.5 mm and below 0.25 mm are considered substandard products.
  • the obtained granules are coated with a film coating made of a graft copolymer of macrogol and polyvinyl alcohol (for example, Kollicoat IR).
  • a film coating made of a graft copolymer of macrogol and polyvinyl alcohol for example, Kollicoat IR.
  • the calculated amount (1.5-9, 8%) of Kollicoat IR is added to the purified water and agitation is carried out for 5 minutes and filtered through a sieve with a pore size of 0.5 mm.
  • the process of coating is carried out in a fluidized bed installation.
  • the granules are heated to 35-37 ° C with periodic stirring in a fluidized bed.
  • aqueous solution of a copolymer of methacrylic acid and ethyl acrylate (1: 1) (eg Vivacoat E) is used.
  • An overhead stirrer is used to prepare the polymer suspension. A measured amount of water is placed in a glass and the stirrer is turned on so that a cone is formed. Then the coating is gradually poured into the formed cone. Then continue stirring for another 45 minutes. After that, the finished solution is filtered through a sieve with a hole size of 0.5 mm.
  • the process of coating is carried out in a fluidized bed installation.
  • the granules are heated to 35-37 ° C with periodic stirring in a fluidized bed.
  • Process parameters product temperature 27-37 ° ⁇ After full consumption of the suspension, the process is stopped and the granules are cooled to a temperature not exceeding 33 ° ⁇ . After the end of the process, the containers are closed. A representative selection of granules is carried out for intermediate control, according to the specification. Next, the resulting granules are dosed, based on the calculation that the ratio of the granules ranges from 5:90 to 90: 5. In this case, the dosage of the active ingredient in 1 dose should be 5 mg.
  • the resulting pharmaceutical composition provides the release profile shown in Table 7.
  • Example 13 Obtaining granules in the form of hard gelatin capsules based on substance I in the form of a hydrochloride salt (preparation - Example 3) with modified release of the active component (substance I).
  • An oral pharmaceutical composition consisting of granules for internal use containing substance I in the form of a hydrochloride salt was prepared similarly to the procedure described in Example 12, recalculating the loading of the hydrochloride salt form on the free base so that the same dosage of substance I (5 mg) was obtained. ...
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 4.
  • Example 14 Obtaining granules based on substance I in the form of tosylate salt (preparation - Example 2) with modified release of the active component (substance I).
  • An oral pharmaceutical composition in the form of granules for internal use containing substance I in the form of a tosylate salt was prepared similarly to the procedure described in Example 12, recalculating the loading of the hydrochloride salt form on the free base so that the same dosage of substance I (5 mg) was obtained. ...
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 4.
  • Example 15 Obtaining pellets of prolonged release of the active component (substance I) based on substance I in salt-free form (free base; preparation - Example 4).
  • Oral pharmaceutical composition representing a capsule containing pellets containing substance I in salt-free form at a dosage of 5 mg per capsule in a ratio of 5 to 94% of the total mass of the mixture.
  • the ratios are shown in Table 8.
  • Table 8 A method of obtaining a pharmaceutical composition based on a pharmaceutical composition containing substance I in salt-free form (free base) as the only active substance in a dosage of 5 mg per 1 capsule in a ratio of 5 to 94% of the total mass of the mixture, during which the substance is sieved I in salt-free form (free base), hypromellose (for example, type 2208) on a sieve with apertures of 0.25-0.5 mm.
  • the capsule contains pellets coated with a pH-independent shell.
  • a hypromellose-based humidifier solution is prepared. Swelling of the polymer is carried out in a part of water (1/3), after which the remaining part (2/3) is added and homogenization is carried out using a mechanical stirrer. The calculated amount of the substance is added to the resulting solution. The quality of dissolution and swelling of the polymer is assessed after preparation of the solution (visual control).
  • the calculated amount of pellets with a fraction size of 0.25-0.5 mm (20-90%) is placed in the installation for obtaining pellets by fluidization, the pellets are heated to a temperature of 40-45 degrees.
  • a mixture of hypromellose with substance I is sprayed in salt-free form (free base).
  • the spray rate is 12-20 g / min.
  • the inlet air flow temperature is 60-65 degrees.
  • the spraying process is continued until the film-former solution is completely consumed. After that, continue drying the pellets for 10-15 minutes, in a stream of warm air. After that, the resulting pellets are unloaded.
  • the resulting pellets are calibrated through a 0.25-0.5 mm sieve. Fractions of granules above 0.5 mm and below 0.25 mm are considered substandard products. A representative selection of pellets is carried out for intermediate control, according to the specification.
  • the resulting pellets are encapsulated, based on the calculation that the active ingredient in 1 capsule should be 5 mg.
  • the resulting pharmaceutical composition provides a sustained release profile shown in Table 9.
  • Example 16 Obtaining granules of prolonged release of the active component (substance I) based on substance I in the hydrochloride salt form (preparation - Example 3).
  • An oral pharmaceutical composition which is granules for internal use, containing substance I in the form of a hydrochloride salt was prepared similarly to the procedure described in Example 15, recalculating the loading of the hydrochloride salt form on the free base so that the same dosage of substance I (5 mg) was obtained. ...
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 5.
  • Example 17 The resulting pharmaceutical composition provides a release profile similar to that shown in Table 5.
  • pellets of prolonged release of the active component (substance I) based on substance I in tosylate salt form (preparation - Example 2).
  • An oral pharmaceutical composition in the form of pellets for internal use containing substance I in the form of a tosylate salt was prepared similarly to the procedure described in Example 15, recalculating the loading of the hydrochloride salt form on the free base so that the same dosage of substance I (5 mg) was obtained. ...
  • the resulting pharmaceutical composition provides a release profile similar to that shown in Table 9.
  • Another object of the invention consisting in the use of the developed compositions and GLF as a hypoglycemic agent for the prevention and treatment of type 2 diabetes mellitus, was achieved by studying the effects and indicators in in vivo experiments on rats.
  • Tests to identify the effects of substance I in the composition of HDF were carried out in in vivo experiments with the determination of the main indicators:
  • Indicators of levels of glycosylated hemoglobin (HbAlc) and glucose, as well as the dynamics of body weight of animals were evaluated in experiments using the composition presented in Example 7.
  • the acute toxicity indicator was evaluated in experiments using substance I in the form of a hydrochloride salt form.
  • the technical result of the invention is a hypoglycemic effect and positive dynamics of body weight in animals on selected rat models - streptozotocin-induced (STZ) diabetes mellitus and a sugar load model.
  • Another result is the low toxicity after oral administration (4th class of toxicity), revealed in experiments on acute toxicity in rats. The results obtained are illustrated by the following examples.
  • Diabetes was induced by a single intraperitoneal injection of 60 mg / kg streptozotocin (dissolved in 0.1 M sodium citrate buffer).
  • the control group (Healthy control) was injected with an equal amount of sodium citrate buffer.
  • Diabetic animals were randomly assigned to three groups using body weight as a criterion.
  • the study preparation the composition described in Example 7, for oral administration was prepared daily at the beginning of the study on 1% starch, in concentrations that provide the dosage of substance I (in terms of the free base) in doses of 5 and 20 mg / kg and was administered in the first half days every day after induction of STZ orally, since this route of administration corresponds to the clinical one. Animals of the diabetic and healthy control groups were injected with 1% starch as a placebo.
  • the assessment of the specific pharmacological activity of substance I in the composition was carried out according to the level of glycosylated hemoglobin (HbAlc).
  • HbAlc glycosylated hemoglobin
  • the planned slaughter of animals was carried out with blood sampling for HbAlc analysis.
  • the level of glycosylated hemoglobin in the groups upon administration of the Composition described in Example 7 at doses of 5 mg / kg and 20 mg / kg was statistically significantly reduced compared to the group of control animals (diabetes group) (Table 10).
  • Table 10 Glycosylated hemoglobin level in the STZ-diabetes model (M ⁇ SD). The blood sugar levels of the animals were measured weekly. Starting from the forty-ninth day, in the experimental groups, the blood sugar level statistically differs from the diabetes group (p ⁇ 0.05). (Table 11) Table 11. Dynamics of blood sugar levels in rats in the STZ-diabetes model (M ⁇ SD).
  • Sugar load was induced by oral administration of 5 g glucose per rat.
  • Glucose was prepared with 10% starch.
  • the control group Healthy control
  • Glucose was measured with an Accu-Chek Active glucometer at time intervals of 0.5, 1, 1.5, 2, 3, and 4 hours after the sugar load.
  • test composition described in Example 7 and the comparison drug vildagliptin for oral administration were prepared at the beginning of the study on 10% starch, in concentrations that provide a dosage of the study drug at a dose of 20 mg / kg.
  • the drugs were administered half an hour before the sugar load in a volume of 1 ml / live.
  • the diabetic and healthy controls were treated with saline as a placebo.
  • the assessment of specific pharmacological activity was carried out according to the level of glucose in the blood. Glucose was determined with an Accu-Chek Active glucometer.
  • the dose of 20 mg / kg is more effective than the dose of 5 mg / kg in terms of blood sugar, body weight, and glycosylated hemoglobin level.
  • the sugar level in the groups upon administration of the Composition described in Example 7 at doses of 5 mg / kg and 20 mg / kg was statistically significantly reduced compared to the control group (diabetes group).
  • the preparation-composition described in Example 7 showed a higher activity than vildagliptin.
  • the toxic effect was additionally investigated in experiments on acute toxicity with a single administration of large doses of substance I to rats in the form of a hydrochloride salt.
  • Example 20 The toxic effect was additionally investigated in experiments on acute toxicity with a single administration of large doses of substance I to rats in the form of a hydrochloride salt.
  • Single-dose toxicity studies are carried out to qualitatively and quantitatively assess toxic reactions that occur after a single dose. (usually orally or intravenously) a large dose of the substance. Research is usually done in rodents. The rat is the preferred species for research.
  • the drug was administered once orally to CD outbred rats at doses of 500, 1000, and 2000 mg / kg.
  • obvious signs of intoxication were observed: a decrease in muscle tone, a decrease in spontaneous motor activity, and the development of general depression. No death was recorded (Table 10), therefore, the calculation of half-lethal doses was impossible, LD 5 o> 2000 mg / kg.
  • the developed pharmaceutical composition containing substance I when administered orally to rats, belongs to the 4th class of toxicity (low toxicity).
  • the objectives of the present invention are solved by the development of pharmaceutical compositions and finished dosage forms for oral administration containing inactive excipients and carriers providing immediate and / or prolonged and / or modified release of the active component of substance I - a highly effective inhibitor of dipeptidyl peptidase-4, low-toxic (class 4 toxicity) and showing an active hypoglycemic effect, to prevent the development and treatment of type 2 diabetes mellitus. Confirmed by examples.

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  • Medicinal Preparation (AREA)

Abstract

L'invention se rapporte au domaine de la médecine et de l'industrie pharmaceutique, et concerne notamment des compositions pour administration orale afin de prévenir le développement et de traiter le diabète sucré de type 2. L'invention concerne essentiellement la création d'une composition pharmaceutique comprenant un composant actif ayant une action anti-hyperglycémique qui consiste en un inhibiteur hautement efficace de dipeptidylpeptidase-4 (DPP4), exo-(28)-3-[(ЗК)-3- amino-4-(2,4,5-trifluorophénl)butanoyl]-3-azabicyclo[2.2.1]heptane-2- carbonitrile, substance I sous forme de sels pharmaceutiquement acceptables, des substances auxiliaires et des excipients assurant une libération rapide, prolongée et modifiée du composant actif afin de traiter des malades souffrant du diabète sucré de type 2. (I) Masse mol. 337. Ces compositions comprennent également des composants inactifs qui, d'un côté, maintienne l'efficacité de la substance active et, de l'autre, permettent de varier le dosage, la libération et la durée de son action dans l'organisme.
PCT/RU2021/000042 2020-02-25 2021-02-03 Composition pharmaceutique à base d'un inhibiteur de dipeptidylpeptidase-4 Ceased WO2021173036A1 (fr)

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RU2019144636 2020-02-25
RU2019144636A RU2727898C1 (ru) 2020-02-25 2020-02-25 Фармацевтическая композиция на основе действующего вещества, ингибитора дипептидилпептидазы-4, для предупреждения развития и лечения сахарного диабета 2 типа

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2286986C2 (ru) * 2000-03-10 2006-11-10 Бристол-Маерс Сквибб Ко. Ингибиторы дипептидилпептидазы iv на основе конденсированных циклопропилпирролидинов и способ их применения
WO2007029086A2 (fr) * 2005-09-05 2007-03-15 Ranbaxy Laboratories Limited Derives de 3-azabicyclo[3.1.0]hexane en tant qu'inhibiteurs de la dipeptidyl peptidase-iv
RU2483716C2 (ru) * 2005-09-29 2013-06-10 Новартис Аг Новый состав
WO2017186934A1 (fr) * 2016-04-29 2017-11-02 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Inhibiteurs de dipeptidyl peptidase-4 pour le traitement topique oculaire de maladies neurodégénératives rétiniennes
RU2712097C1 (ru) * 2018-09-28 2020-01-24 Общество с ограниченной ответственностью "Необиотек" Ингибитор дипептидилпептидазы-4 для лечения сахарного диабета 2-го типа, соединения (варианты)

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2015104602A2 (fr) * 2014-01-08 2015-07-16 Wockhardt Limited Procédé de préparation d'anagliptine et de ses intermédiaires

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2286986C2 (ru) * 2000-03-10 2006-11-10 Бристол-Маерс Сквибб Ко. Ингибиторы дипептидилпептидазы iv на основе конденсированных циклопропилпирролидинов и способ их применения
WO2007029086A2 (fr) * 2005-09-05 2007-03-15 Ranbaxy Laboratories Limited Derives de 3-azabicyclo[3.1.0]hexane en tant qu'inhibiteurs de la dipeptidyl peptidase-iv
RU2483716C2 (ru) * 2005-09-29 2013-06-10 Новартис Аг Новый состав
WO2017186934A1 (fr) * 2016-04-29 2017-11-02 Fundació Hospital Universitari Vall D'hebron - Institut De Recerca Inhibiteurs de dipeptidyl peptidase-4 pour le traitement topique oculaire de maladies neurodégénératives rétiniennes
RU2712097C1 (ru) * 2018-09-28 2020-01-24 Общество с ограниченной ответственностью "Необиотек" Ингибитор дипептидилпептидазы-4 для лечения сахарного диабета 2-го типа, соединения (варианты)

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