TWI308870B - Pharmaceutical composition for the prevention or delay of the progression to overt diabetes - Google Patents

Description

A7 B7 1308870 V. INSTRUCTIONS (1) Glucose metabolism P·?·(Im) is defined as a sugar concentration above the normal range, but not yet high enough to meet the diagnostic criteria for type 2 diabetes. The incidence of IGM varies from country to country' but usually occurs 2-3 times more often than symptomatic diabetes. IGM strings are considered to be pre-diabetes patients, but until recently, data from several epidemiological studies have refutes that IGM patients do not have a risk of developing diabetes and the risk of cardiovascular disease and death. These data suggest that IGM patients, especially IGT patients, do not always develop diabetes, but whether they are diabetics or non-diabetics, there is a high risk of cardiovascular disease and death. Among the IGM patients, 'about 58% have glucose tolerance disorder (igt), another 29% have fasting glucose disorder (IFG) and 13% have these two abnormalities (IFG/IGT). IGT is characterized by hyperprandemia after meals, and IFG is defined by the American Diabetes Association (ADA) (see table below) based on fasting blood glucose values. Normal glucose tolerance (NGT), classification of IGM and type 2 diabetes by

The ADA was defined in 1997 and the classification is as follows: NGT IGM Type 2 Diabetes IFG FPG Concentration <6.1 mmol/L (<11 mg/100 ml) 6.1-7 mmol/L (110-126) Mg/100 ml) >7 mmol/L (> 126 mg/1 ml) and/or or IGT 2 hours postprandial glucose concentration (75 g OGTT*) <7.8 mmol / liter (<140 mg/100 ml) 7.8-11.1 millimoles/liter (140-220 mg/100 ml) >11.1 millimoles/liter (>200 mg/100 ml) This paper size is applicable to China National Standard (CNS) A4 Specification (210 X 297 Gongchu) 1308870 V. Invention Description (: The second-class standard is the implementation condition of the recommended job (〇GTT). m-type test t%75^ ^ Oral administration

Si: Glucose and soluble in water glucose load, and in 2 hours

Class and ^ analysis of postprandial blood glucose. Other conditions that can be used to confirm the 1GT non-test include: ^ (4) grams and secrets A, grape vines, 2) use non-fasted glucose samples as points and 3) 1 hour after glucose load Instead of 2 hours, analysis = Dessert. Under all of these conditions, the blood glucose class defined above is associated with an increased risk of v, but standardization 〇gtt is preferred to minimize differences in test results. It is known that IGM patients, especially those in the IFG subgroup, are worsening into diabetes (4), which is clearly higher than those with normal blood sugar, and their risk of cardiovascular disease is also high, especially in people with diabetes. Interestingly, IGM patients, especially those with subtypes of IGT, have high rates of morbidity and mortality from cancer and cardiovascular disease, even those without diabetes. Therefore, patients with IGM, especially those with subtype IFG, are clearly at high risk of developing cardiovascular disease, especially after patients have symptomatic diabetes. On the other hand, it is associated with a high risk of cancer and cardiovascular disease and a high mortality rate in non-diabetic and diabetic patients. The increased risk associated with IGT is independent of all other known cardiovascular risk factors (including age, gender, hypertension, low Hdl, and high LDL cholesterol concentrations) [Lancet 1999; 354: 617-621]. In the absence of abnormal FPG characteristics of glucocorticoid disease, one of the mechanisms associated with ICAM (especially IGT) and microangiogenic and macrovascular complications is postprandial blood glucose. Individual postprandial hyperglycemia, even in non-diabetic patients, is also applicable to the Chinese National Standard (CNS) A4 specification (210X297 mm) on the paper scale 1308870 A7

The display reduces the amount of natural free radical scavenger (TRAP) present in the serum. It has been shown that under experimental conditions, the decrease in the concentration of TRAP is associated with increased free radical formation and increased oxidative stress. These free radicals are involved in microvascular and macrovascular disease associated with atherosclerosis, morbidity and mortality of cardiovascular disease, and cancer [Ceriello, A, Diabetic Medicine 15: 188-193, 1998]. The reduction in natural antioxidants such as TRAP during postprandial hyperglycemia can explain why cardiovascular disease is present in patients with IGM (especially igt) but no diabetes. IGT is an independent risk factor among non-diabetic patients and diabetics. It is a new target for the prevention and treatment of cardiovascular disease, death and cancer. IGM is associated with the following underlying diseases or conditions: u worsens into symptomatic type 2 diabetes (Category Code 25〇.2 = ICD_9 Code 250.2 in the International Classification of Diseases) [Diabetes Research and Clinical Practice 1998; 40 • S1-S2] ' 2) Increased microvascular complications of diabetes, especially diabetic retinopathy and other eye complications. (ICD-9 code 250. 5), nephropathy (ICD-9 code 250.4), neuropathy ( ICD-9 code 250_6)[Diabetes

Care 2000 ; 23 : 1113-1118] and peripheral vascular lesions and gangrene (1 (:]:) _ 9 code 250.7); 3) increased incidence of cardiovascular disease (ICD_9 codes 410-414) 'especially myocardial infarction ( ICD-9 code 410), coronary heart disease or atherosclerosis (ICD-9 code 414) and other acute and subacute coronary ischemia (ICD-9 code 411); 4) severe cerebrovascular disease such as Stroke (ICD-9 codes 430-438) [Circulation 1998 ; 98 : 2513-2519] ; 5) Increased cardiovascular deaths (1〇〇-9(:〇(163 390-459) [Lancet 1999; 354 : 617-621 ] and sudden death (ICD_9 code

This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) A7 B7 1308870 V. Invention description (4) 798.1) ; 6) High incidence and mortality of malignant tumors (ICD-9 codes 140-208 ) [Am J Epidemiol. 1990 ; 131 : 254-262, Diabetologia 1999 ; 42 : 1050-1054]. Other metabolic disorders associated with IGM include dyslipidemia (ICD-9 code 272), hyperuricemia (iCD-9 code 790.6), and hypertension (ICD-9 codes 401-404) and angina pectoris (ICD-9 code 413· 9) [Αηη Int Med 1998 ; 128 : 524-533]. The wide range of diseases and conditions associated with IGMs (especially IGTs) clearly represent a major area of medical needs. Many of these diseases and conditions are associated with both IGM and diabetes, but it has only recently been identified that non-diabetic individuals with IGM (especially IGT) should also be targeted for prevention and treatment. Therefore, in patients with ZGm (especially 疋IGT and / or IFG), early insulin secretion recovery and / or postprandial hyperglycemia should help prevent or delay the progression to symptomatic diabetes 'and preventive symptoms The occurrence of diabetes prevents or reduces microvascular complications associated with sugar and urinary diseases. In addition, in patients with IGM, especially in patients with IGT and/or IFG, early recovery of insulin secretion and/or reduction in postprandial hyperglycemia should also prevent or reduce the incidence and mortality of severe cardiovascular disease. Prevent cancer or reduce cancer mortality.

Therefore, at the stage between normal blood sugar and type 2 diabetes, especially during the stage of hyperglycemia, it becomes a major stage of interest' and there is a strong need for a suppression or delay in its progression to type 2 diabetes and various types of IGM (especially It is a method of cardiovascular and microvascular conditions or diseases and cancer associated with iFG and/or IGT. It has now unexpectedly been found that hypoglycemic agents such as insulin secretion enhancers can be used to prevent or delay the progression to symptomatic diabetes, reducing the standard of the paper to the Chinese National Standard (CNS) A4 specification (210 X 297 mm). 1308870 V. Description of the invention (5 microvascular complications, reduction of Qing · · > incidence of blood disease and cardiovascular disease incidence and death of Fu You, lower the rate of cancer, and IGT ~ or 1 (four) The blood glucose lowering agent contains, for example, a bet 4 / i lysin as a secretion promoter or an insulin sensitivity additive (insulin resistance remover) 哎〒歌 ^ 为其 for its medically permitted salt 姨 素, in Each case is appropriate, can be = prime secretion promoting material has promoted insulin (4)

The active ingredient of the nature. ^ A, an insulin secretion promoter (also known as a secretagogue and a nucleophile) is, for example, a short-acting or long-acting hypoglycemic agent. Short-acting hypoglycemic agents such as ^, J, such as the acetoacetic acid, and gliquidone (gliquidone) ° corresponding to the phenylalanine acid derivative, for example, natgHnide, N_ (trans _ 4_isopropylcyclohexylidene)_d_phenylalanine) (Ref. EP 196222 and EP 526171): H ^)=0 (I); Η-Ο and 莱帕格利:!:德[repaglinide,(S -2 -ethoxy- 4- {2-[[3-methyl-1-[2-(1-hexahydro-p-pyridyl)phenyl]butyl]amino]_2-ketoethyl ) citric acid]; it is in its free form in each case, or a pharmaceutically acceptable salt if appropriate. Similarly, the term 'nagiginide.' contains the Chinese National Standard (CNS) A4 specification (2l〇X297 mm). The A7 B7 1308870 A. The invention (6) modifier , such as the European Patent No. 0 526 171 B1 or the U.S. Patent No. 5, 488, 5, the disclosure of each of which is incorporated herein by reference in its entirety in its entirety in its entirety in its entirety in Among them, the reference value is the subject of the above-mentioned U.S. Patent Application No. 8-10 (for Η-type crystal modification) and the Β-type crystal modification in European Patent No. 196222 , 1, the subject of which is particularly Identification, manufacture and characterization of Β-type crystal modifications. In the present invention, it is preferred to use a Β- or Η-type, and it is more preferable to use a Η-type. Long-acting hypoglycemic agents are, for example, bimodal derivatives or indeed parotid derivatives. Suitable double veins are, for example, metformin, or a pharmaceutically acceptable salt thereof, if appropriate, especially a hydrochloride salt. Examples of sulfonylurea derivatives (SU) (especially those that promote insulin secretion from the pancreas-cell via the SU receptor in the cell membrane) include, but are not limited to, tolbutamide ), chlorpropamide, tolazamide, (acetohexamide), 4-chloro-N-[(1 - p piroxicam)-based phenyl hydrazine (glycopyramide) ), glibenclamide (glyburide), vermiculite yellow p-urea (gliclazide), 1-butyl-3-m-aniline urea, carbutamide, glibonuride, P ratio glipizide, gliquidone, glisoxepid, sulfonate? Glybuthiazole, glibuzole, glyhexamide, glymidine, glypinamide, phenbutamide And tolyl toluene (tolylcyclamide), or in each case, if appropriate, may be a pharmaceutically acceptable salt-9- This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308870 A7 _________ Β7 V. Description of invention (7) Insulin secretion promoters also include representatives of the new generation of su such as (28)_2-benzyl-3-(cis-hexahydro-2-isoxylcarbonyl)-calcium propionate dihydrate (kad_ 1229) and glimepiride (Hoe 490), which are free or pharmaceutically acceptable salt forms. Likewise, insulin secretion promoters include DPP-IV inhibitors, GLP1 & G L P1 agonists. DPP] V is a serine protease and a cleavage that catalyzes the N' terminal Xaa_pr〇 or XaaAla dipeptide residue (including glucagon-like protein _ 1). The corresponding inhibitor of DPP-IV will increase (the circulating concentration of jLpq will increase the insulin concentration. A representative example of DPP IV inhibitor. It is recorded in wq98/19998 and WO 00/34241. Preferably, it is 1 2 - [(5-cyanopyridine-2-yl)amino]ethylamino}ethenyl-2(S)-cyano-pyrrolidine dihydrochloride (refer to Example 3 of w〇98/19998) and (S) 1 - [(3 -Hydroxy-1 1 -adamantyl)amino]-ethinyl-2-cyano-pyrrolidine (refer to the example of w〇〇/34241) GLP-1 and GLP- 1 agonist promotes insulin secretion. The preferred insulin secretion promoter is repaglinide and diterpene, which is best based on nateglinide. Insulin sensitivity enhancer can be repaired. Impaired insulin receptor function to reduce the resistance of 姨 ' ' and thus increase the sensitivity of 姨 。. Suitable insulin sensitivity-increasing agents such as appropriate hypoglycemic far-oxazolidine (Glita) Zong, glitaz〇ne). The appropriate glitazone is, for example, (s) _ ((3,4-dihydro-2-(phenyl-methyl)-2 Η-1-benzopyran) _ 6 - base) A _ p-pyrazolidine _ 2,4 _dione (A-10- This paper scale applies to China National Standard (CNS) Α4 specifications (2l〇X297 public) A7 B7 1308870 V. Invention description (8) Glitazian ,englitazone), 5-{[4-(3-(5-methyl-2-phenyl-4_, succinyl)-1-ketopropyl)-phenyl]-indolyl oxazolidine 唆2,4_二嗣 (Daglitazone, darglitazone), 5-{[4-((1-methyl-cyclohexyl)methoxy)-phenyl]-methylpyrazolidine-2, 4-dione (Sigritazi, cigHtaz〇ne), 5-{[4-(2-(1-indenyl)ethoxy)phenyl]-methyl}-pyrazolidine_2, 4_dione (DRF2189), 5-{4-[2-(5-methyl_2_phenyl_4_ocoxazolyl^ethyl)]-benzylthiazolidine-2,4-dione (BM_ 13 1246), 5_(2_naphthalenesulfonyl)oxazolidine-2,4-dione (Αγ_31637), 贰{4_[(2,4·diketothiazolyl)indolyl]phenyl} Decane (ΥΜ268), 5-{4_[2_(5-methyl-2-phenyl-4-isoxazolyl)_2-hydroxyethoxy]indolyl}_thiazolidine_2,4_2^ ( AD-5075), 5-[4-(1-phenylcyclopropanecarbonylamino)-benzyl]-thiazolidine-2,4-dione (DN-108), 5-{[4-(2- (2,3-dihydroindole-i-yl)ethoxy)phenyl]methyl}- Pyrazolyl-2,4-dione, 5-{[3-(4-chlorophenyl)]-2-propynyl]-5-benzenesulfonyl} pyrazinidine-2,4-dione , 5_{[3_(4_气phenyl)]-2-propynyl]-5-(4-fluorophenyl-sulfonyl}pyrazolidine_2,4_dione, 5 - {[ 4 - (2-(methyl-2-pyridyl-amino)ethoxy)phenyl]-indolyl carbazole _2,4-one-one (Rosiglita, rosiglitazone), 5- {[4-(2. (5-ethyl-2-pyridinyl)ethenyl)phenyl]-indenyl}oxazolidine-2, ketone (Pioglitazone) 5-{[4_((3,4_Dihydro·6_hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl)methoxy)phenyl]_ Methyl}thiazolidine-2,4-dione (Troglia tazon, tr〇glitaz〇ne), 5_[6_(2fluoro)qin-2-ylmethyl] sitbit _2,4 _Diketone (MCC5 5 5), 5-{[2-(2-mercapto)-benzoxazole-5-yl]-methyl}thiazolidinyl 2,4-dione (T-174) and 5-(2,4-diisopropylpyrazolidine-5(yl)methyl)_2-methoxy_N-(4-tri-l-methylmethyl)-ylamine (KRp297p is preferably Piog -11 - This paper is applicable to China National Standard (CNS) A4 specification (2 lying 297 public) 1308870 A7 B7 V. Invention description (9 ) piuta Utazone, Rosigli Tazon (r〇sigHtaz) troglitazone. ', 结构 The structure of the active agent named after the scientific name or trade name can be taken from the current version of the standard summary "The Merck Index", or a database such as an international patent (example = IMS World Publication). The corresponding content is hereby incorporated by reference. Anyone who is skilled in the art can, according to this reference; II β, these references can fully identify the active agent'. Similarly, the standard test 槿 叛 叛 叛 叛 叛 ( (in vitro and in vivo) test medical indications and nature. Poetry proves that hypoglycemic agents such as islet tone 丨 丄 丄 枫 枫 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常 常Multicenter, replacement/dination for IGM patients. A randomized, double-blind, parallel group study to evaluate nateglinide 30 mg, 6 mg or 12 before each main meal during the 8th session of the Aw SP). The effect of sputum on the incidence of hypoglycemia and the effect on postprandial glucose concentration. Patients selected according to the 2-hour plasma glucose value after the 75-gram oral glucose tolerance test (〇GTT), and patients who generally met the following additional criteria were included in the study: -0 GTT 2 hours after blood glucose at 7.8 disks 1丨1 $ $ ·δ/, 11·1 millimoles/liter (the first OGTT was performed during the year before the study, and the second 0GTT was performed within two weeks prior to participation in the study); -FPG<; 7 millimoles / liter; _____ -12- This paper scale HSBC standard (CNS) A4^ (21GX297 mm) ~---- 1308870 A7 ________ B7 V, invention description (10) - _ patient Body mass index (BMI) was 20-32 kg/m2; - patients maintained their previous diet throughout the study period; - males, infertile women and fertile women using medically permitted birth control laws were included; Do not use other anti-diabetic agents during the trial. Take a corresponding dose of nateglinide in a large glass of water, taking 2 times, 3 times or 4 times per serving, depending on the number of main meals (breakfast, Chinese food, snacks, dinner). The first dose is given at the first main meal (standard meal, ie 55% carbohydrate, 25% fat and 2% protein). At the 2nd, 4th and 8th week of the visit, and the patient was fasted for at least 7 hours. All blood samples for laboratory evaluation were taken between 7 am and 丨〇. HbAic was measured before the start of treatment (basal value) and after 8 weeks of treatment (fasting glucose and fructosamine). Blood samples were taken at 10, 2, 30, 12, and 180 minutes after administration of the drug (time 0) and the glucose and insulin concentrations were measured. At the 0th and 8th week of the visit, the patient received a standard meal challenge of approximately 5 〇仟 Leica and measurements of insulin and glucose. From the analysis of all the data obtained from the study, it was found that the glucose concentration, HBAlc and glucosamine concentrations in the 2 hours after the meal were surprisingly significantly reduced, and the early secretion of the hormone was restored' and the nategiinide was prevented or delayed. Deteriorated into symptomatic type 2 diabetes. Through longer treatment and recovery, symptoms and diseases associated with IGM can be prevented or reduced. This study in patients with IGM (especially IFG and IGT) is different from the study in patients with diabetes because the patient has normal FP.G and is a non-diabetic or pre-diabetic patient. -13- This paper scale applies to China National Standard (CNS) A4 specification (210 X 29? public love) 1308870 A7 ________B7 V. Invention description (11), ·? Surprisingly, a combination of hypoglycemic agents and hypoglycemic agents can be used in igm patients (especially #疋IFG and/or IGT patients) to prevent or delay exacerbation into symptomatic type 1 type 2 diabetes; and prevent, reduce or Delay in the occurrence of a condition in a private group consisting of: increased microscopic complications, increased cardiovascular disease incidence, severe cerebrovascular disease, increased cardiovascular mortality, sudden death, malignancy Higher incidence and mortality and other metabolic disorders associated with IGM. Further, a combination of a hypoglycemic agent and a hypoglycemic agent can be used in an IGM patient (especially in an IFG and/or IGT patient) to prevent, reduce or delay the occurrence of a condition selected from the group consisting of, for example: I retinopathy, other eye complications of diabetes, nephropathy, neuropathy, peripheral vascular disease, gangrene, myocardial infarction, coronary heart disease, atherosclerosis, other acute and subacute forms of coronary ischemia, Stroke, dyslipidemia, diuricemia, southern blood pressure, angina pectoris, microvascular disease resulting in amputation, cancer, cancer death, obesity, uric acidemia, tamsin resistance, and arterial obstructive disease. According to the present invention, a hypoglycemic agent can be used in patients with IGM (especially IFG and/or IGT patients) to prevent or delay the progression to symptomatic diabetes, reduce the microvascular complications of diabetes, and reduce the incidence of vascular diseases. And mortality, especially cardiovascular disease morbidity and mortality, and increased cancer-related increased mortality in IGT patients. Accordingly, the present invention relates to a method for use in an IGM patient, particularly and/or an IGT patient, which is used to prevent or delay the progression to symptomatic Type 2 diabetes, and to prevent, reduce or delay selected from: The composition of the paper size of the paper ss home _ _ _ A4 specifications (2lGX 297 public 1 1308870

The situation in the group occurs: increased microvascular complications, increased incidence of cardiovascular disease, severe cerebrovascular disease, increased cardiovascular mortality and sudden death, higher incidence of malignancy and mortality, and other Related metabolic disorders. More particularly, the present invention relates to a method for use in an IGM patient, particularly an IFG and/or IGT patient, which method is used to prevent, reduce or delay the occurrence of a condition selected from the group consisting of, for example, the retina Lesions, other ocular complications of diabetes, nephropathy, neuropathy, peripheral vascular disease, gangrene, myocardial infarction, coronary heart disease, atherosclerosis, other acute and subacute forms of coronary ischemia, stroke, Dyslipidemia, hyperuricemia, hypertension, angina pectoris, microvascular disease of the limbs, cancer, cancer death, obesity, uric acidemia, insulin resistance, and arterial obstructive disease. Therefore, the present invention relates to a method for use in patients with IGM, particularly in ipg and IGT, which is used to prevent or delay the onset of diabetes, especially type 2 (ICD-25. 2); Complications such as retinopathy (ICD_9 c〇de 25〇5), neuropathy (icd_9 code 250.6), nephropathy (ICD_9 c〇de 25〇·4), and peripheral vascular lesions and gangrene (ICD-9 code 250.7). Further, the present invention relates to a method for use in an IGM patient, particularly a patient with IFG and IGT, which is used to prevent or reduce the condition of severe cardiovascular disease (ICD_9 c〇des 41〇_414), such as myocardial infarction (ICD-9 code 410), as well as arterial obstructive disease, atherosclerosis and other acute and subacute forms of coronary ischemia (ICD_9(3) heart 411-414); prevention, reduction or delay of severe cerebrovascular disease Occurred as -15- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

Binding

A7 B7 13 1308870 V. INSTRUCTIONS (Wind (ICD-9 codes 430-438), reduced cardiovascular mortality (ICD-9 codes 390-459) and sudden death (ICD-9 code 798.1); prevention of cancer Occurrence (ICD-9 codes 140-208) and reduction of cancer death. This method is also concerned with preventing or reducing other metabolic disorders associated with IGM in IGM patients, especially in 11? (1) patients. Includes hyperglycemia (including postprandial hyperglycemia), dyslipidemia (ICD-9 code 272), hyperuricemia (ICD_9 code 790.6), and hypertension (ICD-9 codes 401-404) and angina pectoris (icd_ 9 code) 413.9) ° The classification codes described above and below are incorporated herein by reference in accordance with the International Classification of Diseases, and the corresponding definitions of the diseases therein, and constitute a part of the present invention. The role of insulin secretion can quickly reverse and reduce postprandial blood glucose concentration, which is conducive to the prevention or treatment of IGM. The method comprises administering an effective amount of a hypoglycemic agent such as an insulin secretion promoter or a pharmaceutically acceptable salt thereof. Patient. Need this party The patient is a warm-blooded animal, including humans. The invention also relates to a method for use in patients with IGM (especially IFG and/or IGT) and related diseases and conditions (such as postprandial hyperglycemia), which is used for prevention Or delay the progression to symptomatic diabetes (especially type 2), prevent, reduce or delay the onset of microvascular complications, prevent or reduce gangrene or microvascular disease leading to amputation, prevent or reduce the incidence of severe cardiovascular disease and Cardiovascular disease mortality, cancer prevention, and cancer death reduction 0 The present invention also relates to treatment and IGM [especially IFG and/or IGT (including separate 16-paper standards applicable to Chinese national standards (CNS> A4 specifications (21〇χ 297) Public pet) 1308870 A7

1308870 A7 B7 V. INSTRUCTIONS (15) Uses in the manufacture of pharmaceuticals' This medicine is used to prevent or delay the progression to symptomatic diabetes, especially type 2, to prevent or reduce microvascular complications, to prevent or reduce serious Cardiovascular disease incidence and cardiovascular disease mortality rate 'prevent cancer and reduce cancer deaths. The present invention also relates to a drug that is used in a patient for IGM (especially IFG and/or IGT) and related diseases and conditions (such as postprandial hyperglycemia) in the manufacture of a drug for the administration of a drug for the administration of IGM (especially IFG and/or IGT) and related diseases and conditions (such as individual postprandial hyperglycemia). For the purpose of preventing or delaying the progression to symptomatic diabetes, especially type 2, preventing or reducing microvascular complications, preventing or reducing the incidence of serious cardiovascular diseases and cardiovascular mortality, prevention Cancer and reduce cancer deaths. The invention also relates to a pharmaceutical composition for use in patients with IGM (especially IFG and/or IGT) for preventing or delaying the progression to symptomatic Type 2 diabetes, and for preventing, reducing or delaying the following The occurrence of the disease in the ethnic group, the increased microvascular complications, the increased incidence of cardiovascular disease, severe cerebrovascular disease, increased cardiovascular mortality and sudden death, the incidence of death and the death of the tumor Rate and other associated metabolic disorders; the composition comprises a hypoglycemic agent or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The invention relates to a type of diabetes for preventing the deterioration of symptoms into symptoms, especially type 2, preventing or reducing microvascular complications, preventing or reducing serious cardiovascular disease incidence and cardiovascular mortality, preventing cancer and A pharmaceutical composition for reducing cancer mortality comprising an insulin secretion promoter or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The present invention relates to a drug combination for IGM (especially IFG and/or iwt) and related diseases -18-A7 B7 1308870. V. INSTRUCTIONS (16) Diseases and conditions (such as individual postprandial hyperglycemia) 'Therapeutic compound is used to: prevent or delay the progression to symptomatic diabetes," 疋 2 i prevent or reduce micro-gray tube complications, prevent or reduce the incidence of severe u blood disease and cardiovascular death Rate, prevention of cancer and reduction of cancer death. Corresponding activity I·Production or its pharmaceutically acceptable salt may also be used in the form of a hydrate or a solvent for crystallization. Furthermore, the present invention also relates to a conjugate, Such as a group pharmaceutical composition comprising at least one tamsin secretion and two insulin sensitizers respectively; or comprising at least two insulin secretion promoters; or comprising at least two insulin sensitizers; which are used in patients with IGM In particular, in patients with IFG and/or IGT, ribs or delays worsen into symptomatic type 2 diabetes and prevent, reduce or delay the occurrence of a condition selected from the group consisting of increased microvessels and Symptoms, increased incidence of cardiovascular disease, severe cerebrovascular disease, increased cardiovascular mortality, and higher incidence and mortality of malignant tumors and other metabolic disorders associated with IGM. Another benefit of the article is to reduce the dose of the individual drug being combined 'for example, not only is the required dose less often and the frequency of administration is less', thus reducing the incidence of side effects. The use of the composition is based on the expectation of the patient to be treated. Depending on the requirements, a combination of therapeutically effective amounts of the active agents can be administered simultaneously, sequentially (in any order) or separately, or in a fixed combination, according to the compositions of the present invention. Scale phase Zhongguanjia (CNS) domain (four) - Gong Gong) 1308870 A7 B7 V. Description of the invention (17 term "therapeutic effective amount" means that the drug or composition can stimulate the desired biological or pharmaceutical response' Achieving the specific therapeutic effect of the present invention in warm-blooded animals (including humans). When administering a fixed or free combination of a single hypoglycemic agent or a second hypoglycemic agent, it can be administered " Effective amount " In the composition according to the invention, the term "joint effective amount" may also include at least one ineffective hydrazine of the combined agent, as long as the (fixed or free) composition is administered to achieve the desired The sum of the effects of the present invention may be carried out simultaneously, sequentially (in any order) or separately, or in a fixed combination. The preferred composition of the composition of the present invention is It has been identified as a preferred hypoglycemic agent, and is selected from the group consisting of nateglinide, repaglinide, metf〇rmin, and Piogli "(一), Rosigli Tazon ((10) 丨 细 e e) and Trogley Tazon (_*_), 1 - ( 2 - [ (5 - cyanopyridine-2-yl)) Amino]ethylamino} Ethyl-2-(S)-cyano L and (s)1_[(3_yl-based fluorene-based) Amino]ethinyl-2-cyano- The pyrrolidine may be a pharmaceutically acceptable salt as appropriate in each case. A variant of the invention is in the case of a group of strokes, in which case the components which can be combined according to the invention can be administered separately, or different fixing compositions can be used at the same time or at different points (ie different The group of quantities can therefore be dosed (for example) at the same time or in a timed manner, ie any component in the set can be at different points in time (equal intervals are equal or ^ is equal to the brother.): The better choice is to make the effect of the combined disease on the treated disease or condition greater than that of the lungs and the components. -20- The paper scale applies to the Chinese National Standard (CNS) Α4 specification (210X297) Dong) 1308870

The invention is also directed to commercial packages comprising the compositions of the invention, as well as instructions for how to use them simultaneously, separately or sequentially. The compound of the second death can also be a pharmaceutically acceptable salt. If such a combination = (for example) at least one test center, an acid addition salt can be formed. If the corresponding acid addition salt is also formed, it can be formed with a test center. And what is the base? Compounds such as C00H) can also form salts. 1. The medically acceptable nate of nateglinide = a salt formed by the test, which is called a cationic salt, such as an alkali metal and an alkaline earth metal salt and an ammonium salt. The medicinal diners according to the invention are suitable for the preparation of 'and blood animals' via the intestines (for example, the mouth or the rectum), including humans, and the two have external effects, "mammals (warm alone or with - or multiple medicines) Top: Xu: or the parenteral user) After the combination, the carrier is given to Xu (especially, it is suitable for the novel medicine system Nanxun &#., (80%), and the tongue is about 1〇 % to about 1% (better for bloating, " to contain from about 2% to about 6% of the active ingredient is more than: type = or parenteral administration of the pharmaceutical preparation of the invention, such as a military position : self-tablets, capsules or suppositories, as well as ampoules, etc.. Prepared in a manner known per se, such as mixing, granulating, sugaring, dissolving or cold drying, etc. Medicament; agent: obtained by combining active ingredient with a solid carrier, granulating the mixture as needed, and mixing the mixture Adding a suitable amount of excipients to a lozenge or a sugar core. When the dosage of the hypoglycemic agent is used according to the present invention, for example, it may be a marketed drug -21 1308870

V. Description of the invention (19) User of the agent. For example, the dose of the component μ 7 is . .5 milli;; 丄: For the Tegley tea bond, 'activity ^ .. ., ν no mg or 2 mg; for diterpene double bismuth tablets % : = component dose of 5 〇〇 mg g. The same : = Do not: The dose of the combined agent can also be used. Familiar with this technique = fixed dose. Special effects when the special hypoglycemic agent is used alone or in combination: When the blood animal is a human of about 7 kilograms of body weight, Nataige (I) is administered to the animal of the warm-blooded animal. Preferably, the agent is preferably from about 5 to 1200 mg/hr, and is preferably from 25 to 800 m/v. Φ/m ^^. The preferred dose contains 30 mg, 60 mg or 120 mg of Natgli benzene. The number of times the main meal is served... before the meal. Administration method, depending on D., - twice a day (BID) or - three times four times (QID). The example of the invention is described in the following example (4), but the scope of the invention is not limited. ^ ^ ^ i—Example 1: Nayong is a part of the article: De (1) is compared to the Ministry [6:_ ingots, each key contains 12. Although the composition of milligrams of Natiger is (1): ^.960 kg 30.564 kg 4.336 kg 2.592 kg 3.974 kg 1.382 kg 1.231 kg Natig Lizard (I)

Lactose, NF microcrystalline cellulose, NF polyvinylpyrrolidone, USP croscarmellose sodium, NF colloidal cerium oxide, NF magnesium stearate, NF -22- This paper scale applies to Chinese national standards ( CNS) A4 size (210X 297 mm) 1308870 A7 B7 1-944 kg plus sufficient amount V. Invention description: Insulating yellow pigment pure water, USP* 氺•• Remove microcrystalline cellulose, poly in the process The vinylpyrrolidone, the partially croscarmellose sodium, the Natrichinide (I) and the lactose are mixed in a high shear mixer and subsequently granulated using pure water. The wet granules are dried in a fluid bed dryer and passed through a screen. The colloidal cerium oxide and the remaining croscarmellose sodium are mixed, passed through a sieve and blended with the dried granules in a mash blender. The magnesium stearate was passed through a sieve, blended with the blend obtained from the V blender, and then all of the mixture was compressed into a tablet. The opaque yellow pigment was suspended in pure water, and the tablet was coated with the suspension of the coating. Natigli m m 药 药 丨 丨 丨 丨 内部 内部 内部 内部 : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : : 内部 内部 内部 内部 内部Vitamin Sodium granules external: Magnesium stearate opaque yellow pigment Example 3: Naphrinol granules Internal: 120 mg 283 mg 142 mg 24 mg 24 mg 7 mg 20 mg ΐ )·) Pharmacy formula 2 -23- This paper The scale applies to the Chinese National Standard (CNS) Α 4 regulations 1308870 A7 B7 V. Description of invention (21) Natig Lizard (I) 120 mg lactose monohydrate 283 mg microcrystalline cellulose 142 mg polyethylene P ratio σ Ketone 24 mg croscarmellose sodium 24 mg granules External: croscarmellose sodium 12.8 mg magnesium stearate 11.4 mg opaque yellow pigment 18.0 mg colloidal cerium oxide 12.8 mg Example 4: Natiger 108,000 spindles of rituximab, containing 120 mg of Natagliinide per ingot, prepared according to the following method: Composition: Natalglid 12.60 kg of lactose, NF 30.564 kg of microcrystalline cellulose, NF 15.336 kg Vinylpyrrolidone , USP 2.592 kg of croscarmellose sodium, NF 3.974 kg of colloidal cerium oxide, NF 1.382 kg of magnesium stearate, NF 1.231 kg of ingot: opaque yellow pigment 1.944 kg of pure water, USP# plus enough *: Removal of the preparation method in the process: Microcrystalline cellulose, polyvinylpyrrolidone, a part of cross-linked carboxy fluorenyl-24- This paper scale is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1308870 V. DESCRIPTION OF THE INVENTION (22 Cellulose sodium, Natiglige and α-granule machine, granulation, granules, two systems. The colloidal dioxide oxidation dream and the remaining cross-linking several mesh screens and dry and sloppy Cellulose sodium blending 'blending through the Xingganzhi granules in a V-type blender' and from the V-type blender media λ 曰夂螨逋 师 师 师 〜 〜 从 从 从 从 从 从 从 从 从 从 从 从The opaque yellow multi-key coating suspension is coated with water, and the material is added to the second granulator after drying with the base cellulose steel:: _ knife and merge 'every batch 3 times granulator / dryer processing. Compound 120 mg 283 mg 142 m 24 mg 36.8 mg 11.4 mg 18.0 mg 12.8 mg Natigli-navide lactose monohydrate microcrystalline cellulose polyethylene P Polo bite 酉 cross-linked carboxymethyl cellulose sodium magnesium stearate opaque yellow colloid Ceria-25-

Claims (1)

1308870 】--medicine composition for preventing or delaying the progression of symptomatic type 2 diabetes in patients with glucose metabolism disorder (fine) (especially fasting glucose disorder (IFG) and/or glucose tolerance disorder (IGT)) , where prevention: reduction or delay - from the following components: increased microvascular complications, increased cardiovascular disease incidence, severe cerebrovascular disease, increased cardiovascular mortality and sudden death, malignancy Higher incidence and mortality of tumors and other metabolic disorders associated with Cong; the composition comprises between 30 mg and 6 mg of nateglinide or a pharmaceutically acceptable salt thereof and a medicament The carrier allowed on it. 2. A pharmaceutical composition as claimed in claim 1 for use in patients with IGM and related diseases and conditions (such as postprandial hyperglycemia) to prevent or delay the progression to symptomatic diabetes, especially the second Type, prevent or reduce microvascular complications, prevent or reduce the incidence of cardiovascular disease, reduce cardiovascular mortality, prevent cancer and reduce cancer death. 3. A pharmaceutical composition as claimed in claim 1 or 2 for use in the treatment or prevention of conditions and diseases associated with IGT or IFG, respectively. 4. A pharmaceutical composition according to claim 1 or 2, which is used in patients with IGM, especially IFG and/or IGT, to prevent, reduce or delay the occurrence of a condition selected from the group consisting of, for example, the following: : Retinopathy, other eye complications of diabetes, nephropathy, neuropathy, peripheral vascular disease, gangrene, myocardial infarction, coronary heart disease, atherosclerosis, other acute and subacute forms of winter coronary ischemia, stroke In the case of lipid abnormalities, hyperuricemia, hypertension, angina pectoris, and the size of the amputated paper, the Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1308870 as B8 C8 I-------D8 Sixth, the scope of patent application for microvascular disease, cancer, cancer death, obesity, uric acidemia, insulin resistance and arterial obstructive diseases. 5. A pharmaceutical composition according to claim 1 or 2 for use in the treatment of diseases and conditions associated with postprandial hyperglycemia and/or IFG, including obesity, increased age, diabetes during pregnancy, Dyslipidemia, hypertension, uric acidemia, insulin resistance, arterial obstructive disease, atherosclerosis, retinopathy, nephropathy, angina pectoris, myocardial infarction, and stroke +. 6 · The pharmaceutical composition according to claim 1 or 2, wherein the postprandial glucose falls within an abnormal range (2 hours after OGTT or temporary glucose test, plasma glucose value is 7.8 to uj millim/liter) Individuals take prevention. 7 _ The pharmaceutical composition of claim 1, which comprises 6 mg of Natalglid or a pharmaceutically acceptable salt thereof. •2· The paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 mm)