MXPA01004255A - Method of treating metabolic disorders, especially diabetes, or a disease or condition associated with diabetes - Google Patents

Abstract

The invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, which comprises nateglinide (I) or repaglinide and at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazones), sulfonyl urea derivatives and metformin for simultaneous, separate or sequential use in the prevention, delay of progression or treatment of diseases, especially metabolic disorders and in particular type 2 diabetes and diseases and conditions associated with diabetes;to a composition, respectively, which comprises nateglinide and a pharmaceutically acceptable carrier and to a process of making such composition;the use of such combination or composition for the preparation of a medicament for the prevention, delay of progression or treatment of metabolic disorders;a method of prevention, delay of progression or treatment of diseases in warm-blooded animals;the uses of such combination or composition for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight;and to a method of improving the bodily appearance of a warm-blooded animal.

Description

METHOD FOR THE TREATMENT OF METABOLIC DISORDERS, ESPECIALLY DIABETES, OR OF A DISEASE OR CONDITION ASSOCIATED WITH DIABETES The invention relates to a combination, such as a combined preparation or a pharmaceutical composition, respectively, comprising nateglinide or repaglinide, and at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazoles), derivatives of sulfonylurea, and metformin, for simultaneous, separate, or sequential use, in the prevention, delay of progress, or treatment of diseases, especially metabolic disorders, and in particular type 2 diabetes, and associated diseases and conditions. Wfn diabetes; to the use of this combination for the preparation of a medication for the prevention, delay of progress, or treatment of metabolic disorders; to the use of this combination for the cosmetic treatment of a mammal in order to effect a cosmetically beneficial loss of body weight; to a method for the prevention, delay of progress, or treatment of diseases in warm-blooded animals; to a method for improving the body appearance of a warm-blooded animal; to a pharmaceutical composition comprising nateglinide as the sole active agent in the composition and a pharmaceutically acceptable carrier, and to a process for making this pharmaceutical composition.

The objectives generally accepted in the treatment of diabetes are to provide relief of symptoms, improvement of quality of life, and prevention of both acute (hyperosmolar and ketoacidosis) and chronic complications (for example, diabetic neuropathy, diabetic nephropathy, and atherosclerosis). premature clerosis). Type 2 diabetes is characterized by both increased peripheral resistance to insulin and abnormal insulin secretion. At least two insulin secretion abnormalities are recognized: in the first phase, insulin is delayed and inadequate when facing high circulating levels of glucose, and in the second phase the secretion of insulin is lost. It is known that several metabolic, hormonal, and pharmacological entities stimulate the secretion of insulin, including glucose, amino acids, and gastrointestinal peptides. The Control of Diabetes and Complications Trial (DCCT) conducted in subjects with IDDM Type I, has estabed that the reduction of blood glucose is associated with decreases in the estabment and progress of diabetic microvascular complications (Diabetes Control and Compli- -cations Trial Research Group; N. Engl. J. Med. 1993, 329, 977-986). Therefore, a therapeutic approach is in the optimization and potentially normalization of glycemic control in subjects with type 2 diabetes. Currently available oral agents fail to meet this therapeutic challenge in some subgroups of patients, and some Side effects sometimes result and are complicated by other problems. The present invention relates to a combination, such as a combined preparation or pharmaceutical composition, respectively, comprising nateglinide of the formula (I): or repaglinide, and at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazones), sulfonylurea derivatives, and metformin, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate, or sequential use, particularly in the prevention, delay of progression, or treatment of diseases, especially metabolic disorders, and in particular diabetes mellitus type 2, and diseases and conditions associated with diabetes mellitus. This combination of preference is a combined preparation or a pharmaceutical composition. The term "a combined preparation or pharmaceutical composition, respectively, comprising nateglinide or paglinide, and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally # at least one pharmaceutically acceptable carrier, for simultaneous, separate, or sequential use ", especially means a" set of parts "in the sense that the components nateglinide or repaglinide and at least one other Anti-diabetic compounds selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, can be dosed independently or by using different fixed combinations with distinguished amounts of the components, i.e., in a simultaneous manner or in different points of time The parts of the set of parts can be managed then, for example, in a simultaneous or chronologically staggered manner, that is, at different points of time and with equal or different time intervals for any part of the set of parts. Preferably, the time intervals are selected in such a way that the effect on the disease or condition treated in the combined use of the parts is greater than the effect that would be obtained by using only any of the components. Preferably, there is at least one beneficial effect, for example a mutual potentiation of the effect of nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylureas, and metformin, in particular a synergism, by example an effect other than additive, additional convenient effects, fewer side effects, a combined therapeutic effect in an ineffective dosage of one or each of the components nateglinide or repaglinide, and at least one other antidiabetic compound selected from the group consisting of in glitazones, sulfonylurea derivatives, and metformin, and especially a strong synergism between nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin. In particular, the present invention relates to a method for the treatment of metabolic disorders, more especially diabetes, and in particular diabetes mellitus type 2, or of a disease or condition associated with diabetes, which comprises administering to a warm-blooded animal in need thereof, a therapeutically effective amount of a combined preparation comprising nateglinide and an antidiabetic thiazolidinedione derivative, wherein each of the active ingredients is present in free form or in the form of a pharmaceutically acceptable salt. The term "a combined preparation or pharmaceutical composition, respectively, comprising nateglinide and an antidiabetic thiazolidinedione derivative, wherein each of the active ingredients is present in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier, as a combined preparation for simultaneous, separate, or sequential use "especially means a" set of parts "in the sense that the nateglinide and the thiazolidinedione antidiabetic derivative components can be dosed independently, or by the use of different fixed combinations with distinguished quantities of the components at different points of time. Preferably, there is at least one beneficial effect, for example a mutual potentiation of the effect of nateglinide and the thiazolidinedione antidiabetic derivative, in particular a synergism, for example an effect rather than an additive, additional convenient effects, fewer side effects, a combined therapeutic effect in a non-effective dosage of one or each of the components nateglinide and the thiazolidinedione derivative antidiabetic, especially a strong synergism between nateglinide and the derivative of thiazolidinedione antidiabetic. "Diseases and conditions associated with diabetes mellitus", as defined in this application, include, but are not limited to, hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration , cataracts, diabetic nephropathy, glomerulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, and ulcerative colitis. In addition, "diseases and conditions associated with diabetes mellitus" include, but are not limited to: coronary heart disease, hypertension, angina pectoris, myocardial infarction, embolism, skin and connective tissue disorders, foot ulcers, metabolic acidosis, arthritis, osteoporosis, and in particular impaired glucose tolerance conditions. The term "prevention" means the prophylactic administration of the combination, such as a combined preparation or a pharmaceutical composition, to healthy patients, to prevent the presentation of the diseases and conditions mentioned herein. Moreover, the term "prevention" means the prophylactic administration of this combination to patients who are in a previous stage of the disease, especially diabetes, to be treated. The term "progress delay", used herein, means the administration of the combination, such as a combination preparation or a pharmaceutical composition, to patients who are in a previous stage of the disease, especially diabetes, to be treated. , where patients are diagnosed with a preform of the corresponding disease. The term "method of treatment" used herein, includes a method of prevention of a disease, ie, the prophylactic administration of the combination, such as a combined preparation or a pharmaceutical composition, to healthy patients, for prevent the presentation of the diseases and conditions mentioned herein. In the present description, the meaning of the terms "active agent", "active compound", or in some cases "compound", is to be understood as equivalent. Unless otherwise reported, in the present disclosure, radicals and organic compounds designated as "lower" contain no more than 7, preferably no more than 4, carbon atoms. Lower alkylene is preferably methylene, ethylene, or propylene. It can be unsubstituted or substituted, for example by hydroxyl. A sulfonylurea derivative is, for example, glisoxe-pida, glyburide, acetohexamide, chloropropamide, glibornuride, tolbutamide, tolazamide, glipizide, carbutamide, gliquidone, glihexamide, fenbutamide, or tolcylamlamide.; and preferably gly-mepiride or gliclazide. Halogen preferably represents fluorine, chlorine, or bromine. Lower alkyl is, if not otherwise reported, preferably ethyl, or more preferably methyl. Lower alkoxy is preferably methoxy or ethoxy-lo.

Cycloalkyl is, for example, cycloalkyl of 3 to 8 carbon atoms, preferably cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl. Aryl is, for example, phenyl or naphthyl, each of which may be substituted, for example, by lower alkyl or halogen, or trifluoromethyl. Nateglinide (Patents Numbers EP 196222, EP 526171, US 5,463,116, and US 5,488,150), 2-ethoxy-4- [N-] acid. { 1- (2-piperidino-phenyl) -3-methyl-l-butyl} -aminocarbonylmethyl] benzoic (repaglinide, U.S. Patent Number US 5,216,167 - also known as (S) -2-ethoxy-4- { 2- [[3-methyl-l- [2- (1 -piperidinyl) phenyl] butyl] -amino] -2-oxoethylbenzoic acid); 5-. { [4- (2- (5-ethyl-2-pyridyl) ethoxy) phenyl] -methyl} iazolidin-2,4-dione (pioglitazone, European Patent Number EP 0,193,256 Al), 5. { [4- (2-methyl-2-pyridinyl-amino) -ethoxy) phenyl] methyl} -thiazolidin-2, -dione (rosiglitazone, European Patent Number EP 0,306,228 Al), 5-. { [4- ((3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl) methoxy) -phenyl] -methyl} -thiazolidin-2,4-dione (troglitazone, European Patent Number EP 0, 139, 21), (S) - ((3,4-dihydro-2- (phenyl-methyl) -2H-l-benzopyran-6-) il) methyl-thiazolidin-2, -dione (englitazone, European Patent Number EP 0,207,605 Bl), 5- (2,4-dioxothiazolidin-5-ylmethyl) -2-methoxy-N- (4-trifluoromethylbenzyl) benzamide (KRP297, Japanese Patent Number JP 10087641-A), 5- [6- (2-fluoro-benzyloxy) naphthalen-2-ylmethyl] thiazolidin-2,4-dione (MCC555, European Patent Number EP 0,604,983 Bl), 5- { [4- (3- (5-Methyl-2-phenyl-4-oxazolyl) -1-oxopropyl) -phenyl] -methyl] -thiazolidin-2,4-dione (darglitazone, European Patent Number EP 0,332,332 ), 5- (2-naphthylsulfonyl) -thiazolidin-2, -dione (AY-31637, U.S. Patent Number US 4,997,948), and 5- { [4- (1-methyl-cyclohexyl) methoxy) -phenyl} methyl } -thiazolidin-2,4-dione (ciglitazone, U.S. Patent No. US 4,287,200), are disclosed in a generic and specific manner in the documents cited in parentheses next to each substance, in each case in particular The compound claims the final products of the working examples, the subject matter of the final products, the pharmaceutical preparations, and the claim is incorporated in the present application by reference to these publications. In the same way, the stereoisomers are included, as well as the corresponding crystal modifications, for example solvates and polymorphs, which are disclosed therein. The term "nateglinide" as used herein, comprises crystal modifications (polymorphs), such as those disclosed in Patent Numbers EP 0526171 Bl or US 5,488,510, respectively, the subject matter of which is incorporated by reference in this application, especially the subject matter of claims 8 to 10, as well as the references corresponding to the modification of the type B crystal. Preferably, in the present invention, type B or H is used, more preferably type H. Any or more of the combinations of these compounds and other similar compounds or fragments, are hereinafter referred to as "antidiabetic drugs", in the description of the compositions and methods for the treatment of the disease. In addition, MCC555 can be formulated as disclosed on page 49, lines 30 to 45, of European Patent Number EP 0,604,983 Bl; in glitazone, as disclosed on page 6, line 52, page 7, line 6, or in a manner analogous to examples 27 to 28 on page 24 of European Patent Number EP 0,207,605 Bl; and darglitazone and 5-. { 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -ethoxy)] benzyl} -thiazolidin-2,4-dione (BM-13.1246) can be formed as disclosed on page 8, line 42 to line 54 of European Patent Number EP 332,332 Bl. AY-31637 may be administered as disclosed in column 4, lines 32 through 51, of the United States Patent Number US 4, 997,948, and rosiglitazone as disclosed on page 9, lines 32 to 40 of European Patent Number EP 0,306,228 Al, the latter preferably as its maleate salt. In a manner corresponding to the needs of the individual patient, and under the condition that it is the doctor who intends to administer the combinations, for example the pharmaceutical compositions, in separate tablets, it is possible to administer the antidiabetics as they are distributed, for example rosiglitazone in the way it is distributed under the brand name AVANDIAMR. Troglitazone can be administered in the form as it is distributed under the brands ReZulin ™, PRELAY ™, ROMOZIN ™ (in the United Kingdom), or NOSCAL ™ (in Japan). Pioglitazone can be administered as disclosed in Example 2 of European Patent Number EP 0,193,256, Al, preferably in the form of the monohydrochloride salt, or in the form as it is distributed under the trademark ACTOS ™. Ciglitazone, for example, can be formulated as disclosed in Example 13 of U.S. Patent No. US 4,287,200. If the drug metformin is administered in a separate pharmaceutical composition, it can be administered in the form as it is distributed, for example under the brand DIABETOSAN ™. If the drug metformin is administered in a separate pharmaceutical composition in the form of its hydrochloride salt, the metformin hydrochloride salt can be administered in the form as it is distributed, for example, under the trademarks DIABETASE 500"*, DIABETASE 850MR, or GLUCOPHAGE SMR Glyburide can be taken in the form as it is distributed under the brand name AZUGLUCONMR or EUGLUCONMR Tolbutamide can be administered in the form as it is distributed under the brand ORABET, glimepiride as it is distributed under the brand AMARYLMR, gliclazide as it is distributed under DIAMICRONMR, glibornuride as it is distributed under the brand name GLUBORIDMR, and gliquidone as it is distributed under the GLU-RENORMMR brand.Compounds to be combined may be present as pharmaceutically acceptable.If these compounds have, for example, at least one center basic, they can form acid addition salts.The corresponding acid addition salts can also be formed that have, If desired, a basic center additionally present. Compounds having an acidic group (for example COOH) can also form salts with bases. For example, the compounds to be combined may be present as a sodium salt, such as a maleate or hydrochloride. The compounds to be combined may also be present in the form of solvates. The recommended dose for rosiglitazone taken as a single drug is 4 milligrams or 8 milligrams administered either as a single dose, or in divided doses twice a day. The best responses with rosiglitazone in the treatment of diabetes are observed with 4 milligrams twice a day. The recommended dose for pioglitazone taken as a single drug is 15 milligrams, 30 milligrams, or 45 milli-grams, taken once a day. The nature of diabetes and related diseases or conditions is multifactorial. Under certain circumstances, drugs with different mechanisms of action can be combined. However, only considering any combination of drugs that have a different mode of action, but that act in the similar field, does not necessarily lead to combinations with suitable effects. Most surprising is the experimental discovery that the combined administration of nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, in particular rosiglitazone, troglitazone, and pioglitazone, sulfonylurea derivatives, and metformin, results not only in a beneficial, especially synergistic, therapeutic effect, but also in additional benefits resulting from combined treatment, and surprising additional beneficial effects compared to a monotherapy that applies only one of the pharmaceutically active compounds used in the combinations disclosed in the present . In particular, the most surprising is the experimental discovery that the combined administration of nateglinide or a pharmaceutically acceptable salt thereof and an antidiabetic thiazolidinedione derivative, results in not only a beneficial therapeutic effect, especially synergistic, but also resulting additional benefits of the combined treatment, such as a surprising prolongation of efficacy, a wider variety of therapeutic treatment, and surprising beneficial effects on the diseases and conditions associated with diabetes, for example less weight gain.

By the established test models, and especially those test models described herein, it can be demonstrated that the combination of nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, in particular rosiglitazone, troglitazone, and picoglitazone, sulfo-nilurea derivatives, and the biguanide metformin, or in each case a pharmaceutically acceptable salt thereof, results in a more effective prevention, or preferably the treatment of diseases, especially metabolic disorders, and in particular of diabetes mellitus type 2, and diseases and conditions associated with diabetes mellitus. In particular, by the established test models, and especially those test models described herein, it can be demonstrated that the combination of nateglinide and an antidiabetic thiazolidinedione derivative, or in each case a pharmaceutically acceptable salt thereof, gives as more effective prevention, or preferably the treatment of diseases, especially of metabolic disorders, more especially diabetes, and in particular diabetes mellitus type 2, and diseases and conditions associated with diabetes. If taken simultaneously, this results not only in an additional enhanced, especially synergistic, therapeutic benefit, but also in additional benefits resulting from simultaneous treatment, such as a surprising prolongation of efficacy, a wider variety of therapeutic treatment, and effects. surprising benefits, for example less weight gain, in diseases and conditions associated with diabetes mellitus, for a number of combinations as described herein. Moreover, for a human patient, especially for elderly people, it is more convenient and easier to remember to take two tablets at the same time, for example before a meal, than a staggered time, that is, according to a treatment program more complicated. More preferably, both active ingredients are administered as a fixed combination, i.e., as a single tablet, in all cases described herein. Taking a single tablet is even easier to manage than taking two tablets at the same time. In addition, packaging can be done with less effort. The person skilled in the relevant art is absolutely qualified to select a relevant animal test model to test the therapeutic indications indicated hereinafter and subsequently herein, and the beneficial effects. The pharmacological activity, for example, can be demonstrated by essentially following an in vivo test procedure in mice or in a clinical study as described hereinafter.

In vivo test in mice for blood glucose control.

ICR-CDI mice (males, 5 weeks of age, body weight: approximately 20 grams) abstain from feeding for 18 hours, and then used as test subjects. The combination according to the present invention, and the active ingredients alone, are suspended in a 0.5% CMC-0.14 M sodium chloride buffer solution (pH 7.4), or suspended at 0.5 percent by weight. The solution or suspension thus obtained is orally administered in fixed volume amounts to the test subjects. After a previously determined time, the percentage decrease in blood glucose against the control group is determined.

Clinical studies of randomized, double-blind, parallel groups in subjects with type 2 diabetes inadequately controlled with diet monotherapy and diet only These studies prove in particular the synergism of the claimed combinations, such as the combined preparations or the pharmaceutical compositions, respectively . The beneficial effects on the diseases and conditions associated with diabetes mellitus, as defined in this application, can be determined directly through the results of these studies, or through changes in the design of the study, which are known to a person skilled in the art. this field .

Studies are particularly suitable for evaluating the effects of monotherapy with nateglinide, repaglinide, glitazone, a sulphonylurea derivative, or metformin, and a combination of nateglinide or repaglinide with one or more compounds selected from the group consisting of glitazones, sulfonylurea derivatives, or metformin, on glycemic control. The studies are especially suitable for evaluating the effects of monotherapy with metformin or the corresponding hydrochloride, or a combination of nateglinide and metformin or the corresponding hydrochloride salt on the glycemic control. Subjects with a diagnosis of type 2 diabetes who have not reached almost normoglycemia, (HbA? C < 6.8 percent) with diet only, are the ones selected for this test. The effects on glycemic control achieved with monteglinide monotherapy, monotherapy with a glitazone, monotherapy with metformin, and combination therapies given below, are determined in these studies after 16 or 24 weeks, with control or grade in placebo , continuing all subjects with the same diet as in the period before treatment. Glycemic control measures are surrogate endpoints validated for the treatment of diabetes. HbAlc is the only reliable measure to evaluate glycemic control (D. Goldstein et al, Tests of Glycemia in Diabetes, Diabetes Care 1995, 18 (6), 896-909) and is the variable of the primary response in these studies. . Because glycosylation of hemoglobin is determined by the concentration of glucose at the time each red blood cell is made, HbA? C provides an estimate of the average blood glucose for the previous three months. Before starting the double-blind treatment for 16 or 24 weeks, the subjects are given, for 4 or 8 weeks, placebos that agree with nateglinide before breakfast, lunch, and lunch, and (1) a placebo that agrees with glitazone troglitazone administered later, for example, only with breakfast (study 1 - period I), (2) a placebo that agrees with gliozone pio-glitazone, in a 5 milligram tablet administered subsequently before of breakfast, lunch, and food. (study 2 - period I). Subjects are then separated into four treatment groups for the 16-week or 24-week double-blind studies (period II), as illustrated below. Approximately 150 to 170 subjects are randomized for each treatment group. The total duration of the study, including the period of introduction for each subject, is 24 to 28 weeks. The statistical analysis can be carried out by methods known in the art.

Study 1: Combination of 120 milligrams of nateglinide and troglitazone In a particular modality of this study, before starting the double-blind treatment for 24 weeks, the subjects are administered, during 4 weeks, placebos that agree with nateglinide before the breakfast, lunch, and lunch, and a placebo that agrees with the antidiabetic thiazolidinedione, administered later with breakfast only (period I). Subjects are then separated into four treatment groups for the 24-week double-blind study (period II) as illustrated below for the case in which troglitazone is selected as the thiazolidinedione antidiabetic. Approximately 170 subjects are randomized for each treatment group. The total duration of the study, including the period of introduction for each subject, is 28 weeks. * administered before breakfast, lunch, and lunch. ** daily dosage. Nateglinide tablets contain 120 milligrams, or matching placebo. Troglitazone tablets are commercially available, and are used to prepare the 600 milligram tablets that match the corresponding placebo capsules. Study 2: Combination of 120 milligrams of nateglinide and pioglitazone * administered before breakfast, lunch and dinner. Nateglinide tablets contain 120 milligrams, or the matching placebo. Pioglitazone tablets are commercially available, and are used to prepare the 5 milligram tablets that match the corresponding placebo capsules.

Study 3: Combination of 60 milligrams of nateglinide and 250 milligrams of metformin, administered as a single pharmaceutical composition In this study, in period I, subjects are administered, during 4 weeks, placebos that agree before breakfast, lunch, and food, before starting the 24 weeks treatment. The subjects are then separated into 4 treatment groups for the 24-week study (period II) as illustrated below. The total duration of the study, including the period of introduction for each subject, is 28 weeks. Both drugs are combined in a fixed pharmaceutical composition administered before each main food, comprising, as the pharmaceutically active components: Study 4: Combination of 60 or 120 milligrams of nateglinide before meals, and 1000 milligrams of metformin as a daily dose. Subjects with HbAlc values of 6.8 to 11 percent receive metformin for at least three months, and at least 1500 milligrams / day for the last 4 weeks before the 0 start period. After period 0, extending to more than four weeks , in which period 1000 milligrams / day of metformin plus nateglinide placebo are given to subjects, subjects are randomized with nateglinide placebo, 60 milligrams of nateglinide, or 120 milligrams of nateglinide before main foods for 24 weeks, while they continue to receive 1000 milligrams of metformin daily. * administered before the main foods; ** immediately after breakfast and lunch. For example, the following procedure can be followed for the purpose of taking blood samples: The subject is advised not to take the morning dose of the study medication or to skip breakfast on the day of a scheduled study visit. The morning dose is administered by the personnel of the site after the collection of all the fasting laboratory samples, and of carrying out all the study procedures. Visits are scheduled to take place at 2-week intervals during period I, and at intervals of 4 to 8 weeks during period II. Subjects have fasted for at least 7 hours at the time of each visit. All blood samples for lab evaluations are taken between 7:00 AM and 10:00 AM. All tests are conducted in accordance with GLP principles (Good Laboratory Practice) following the procedures known in this field. HbAlc is measured by High Performance Liquid Chromatography (HPLC), using the ion exchange method in a Bio-Rad Diamat analyzer. A backup affinity method is used if hemoglobin variants or peaks of hemoglobin degradation are observed. Other parameters that must be determined are fasting plasma glucose (FPG), fasting lipids (total HDL (high density lipoprotein) - and LDL (low density lipoprotein) - cholesterol, and triglycerides) and body weight . Fasting plasma glucose will be measured using the hexokinase method, and LDL-cholesterol will be calculated using the Friedewald formula if the triglycerides are < 400 milligrams / deciliter (4.5 millimoles / liter). Laboratory tests determine hematocrit and hemoglobin, platelet count, erythrocyte count, total and differential counting (of leukocytes (basophils, eosinophils, lymphocytes, monocytes, segmented neutrophils, and total neutrophils), albumin, alkaline phosphatase. , ala-nina-aminotrasferasa (serum glutamic pyruvic transaminase), aspartate-aminotransferase (serum glutamic oxaloacetic transaminase), urea-nitrogen or blood urea, bicarbonate, calcium, chloride, total creatine-phosphokinase (CPK), creatine-phosphokinase muscle-brain fraction isoenzyme (if the CPK is elevated), direct bilirubin, creatinine, β-glutamyltransferase, lactate dehydrogenase, potassium, sodium, total bilirubin, total protein, and uric acid in blood, and bilirubin, glucose, ketones, pH, protein, and specific gravity in the urine of the subjects. In addition, body weight, blood pressure (systolic and diastolic, after 3 minutes of sitting), and radial pulse (after 3 minutes of sitting) during the visit are determined. The results clearly show that the combinations according to the present invention can be used for the prevention, the delay of progress, and preferably the treatment of metabolic disorders, and in particular diabetes, especially diabetes mellitus type 2, and diseases and conditions associated with diabetes. The combinations of the present invention can also be used for the prevention, and preferably the treatment of other diseases. The combined administration of nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, results in a beneficial therapeutic effect, especially synergistic, especially on type 2 diabetes, and also benefits additional, such as a reduction in diabetes-related mortality, a surprising prolongation of drug efficacy (such as delay in the eventual need for insulin), a wider variety of therapeutic treatment, maintenance of the target blood glucose level in patients with type 2 diabetes, provision of good initial blood glucose control in patients with type 2 diabetes, only modest changes in fasting plasma glucose level, and also surprising beneficial effects comprising, for example, less or no gain in body weight, a decrease in side effects gastrointestinal, or a better safety profile, combining with a monotherapy applying only one of the pharmaceutically active compounds used in the combinations disclosed herein. In particular, the additional surprising beneficial effects can also be observed during the treatment of metabolic disorders different from type 2 diabetes, and during the treatment of diseases and conditions associated with type 2 diabetes. Other benefits are that lower doses can be used. of the individual drugs to be combined according to the present invention, in order to reduce the dosage, for example, that the dosages not only need to be frequently smaller, but that they are also applied less frequently, or they can be used in order to decrease the incidence of side effects (eg, anemia, edema, headache). Furthermore, in a number of combinations as disclosed herein, the side effects observed with one of the components are not accumulated in a surprising manner in the application of the combination. The beneficial therapeutic effect, the additional benefits, and especially the beneficial or surprising effects, are observed in particular with nateglinide. Very good results have been obtained with the combination of nateglinide and metformin or metformin hydrochloride. The beneficial therapeutic effects, the additional benefits, and also the surprising beneficial effects, are observed especially in human subjects suffering from a more severe form of type 2 diabetes, that is, human subjects having a high HbAαc value (glycosylated hemoglobin) ) in the baseline greater than 8 percent, and more particularly in human subjects who have an HbA? c value in the baseline greater than 9.5 percent, before treatment with the combinations described herein. If nateglinide is administered to these human patients, preferably these human patients obtain a dose of between 90 and 200 milligrams, more preferably between 100 and 150 milligrams, for example 120 milligrams of nateglinide per food as part of the combination that They are given. In a preferred embodiment of the invention, a dose of between 45 and 85 milligrams, more preferably 60 milligrams of nateglinide per food as part of the combination is administered to human subjects having an HbAic value at the baseline of between 6.8 percent and 8 percent, particularly between 6.8 percent and 7 percent. This provides the option of increasing the amount of nate-glinide subsequently, the option of which is desirable especially in a situation in which the HbAlc value in the baseline exceeds 7% values after the start of treatment of the human subject during a period of time or constantly, or if the responsible physician determines that the treatment program needs to be changed to higher amounts of nateglinide for other reasons. A preferred combination component in this embodiment is metformin. In addition, the beneficial therapeutic effects, the additional benefits, and also the surprising beneficial effects are observed, especially in human subjects who have a body mass index (BMI) of 20 to 35 kilograms / square meter, in particular a BMI of 27 to 35 kilograms / square meter, and even better in human subjects with a BMI of 30 to 35 kilograms / square meter. Human subjects who have a BMI greater than 30 kilograms / square meter are defined as clinically obese. Additionally, the beneficial therapeutic effects, the additional benefits, and also the surprising beneficial effects are observed, especially in patients poorly controlled by monotherapy with one of the components of the combinations disclosed herein. Additional benefits are that lower doses of the individual drugs to be combined according to the present invention can be used to reduce dosing, for example, that the dosages need not only be smaller, but they are also applied less frequently, or can be used in order to decrease the incidence of side effects (eg anemia, adema, headache). This is in accordance with the wishes and requirements of the patients to be treated. In a preferred embodiment of the invention, the combination is a combined preparation comprising nateglinide and a glitazone for simultaneous, separate, or sequential use in the prevention or treatment of diseases. In particular, the present invention relates to a combined preparation comprising nateglinide and a glitazone, wherein the active ingredients are present in each case in free form or in the form of a pharmaceutically acceptable salt, and optionally at least one pharmaceutically acceptable carrier , as a combined preparation for simultaneous, separate, or sequential use, in the prevention or treatment of diseases, especially metabolic disorders, more especially diabetes, and in particular diabetes mellitus type 2, and diseases and conditions associated with diabetes. In a preferred embodiment of the invention, the combination comprising nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulphonylurea derivatives, further comprises insulin, or the combination and comprises at least two compounds antidiabetics selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, or a pharmaceutically acceptable salt thereof. Also preferred is a combination wherein this antidiabetic compound is metformin or metformin hydrochloride., or is selected from the group of glitazone, especially rosiglitazone or troglitazone, or in particular pioglitazone. The preferred antidiabetic thiazolidinedione derivatives (glitazones) are those represented by the formula (II): wherein A represents: naphthyl, benzoxazolyl, dihydrobenzopyranyl; phenyl or phenylethynyl, both radicals unsubstituted or substituted by halogen; Ri represents halogen or a radical -XR4, wherein: X can be oxygen, methylene, carbonyl, or -NH-, R4 is: (i) naphthyl; (ii) phenyl, unsubstituted or substituted by 2,4-dioxo-5-thiazolidinyl; or (iii) lower alkyl or lower hydroxyalkyl, in each case unsubstituted or substituted by: a) indole or 2,3-dihydroindole, b) pyridyl, lower alkylpyridyl, N-lower alkyl-N-pyridylamino, or halophenyl, c) dihydrobenzopyranyl , which is unsubstituted or substituted by hydroxyl and lower alkyl, d) oxazolyl which is substituted by lower alkyl and phenyl, e) cycloalkyl, which is unsubstituted or substituted by lower alkyl, of) arylcycloalkylcarbonyl; R 2 represents hydrogen or trifluoromethylphenylalkyl-carbamoyl, and R 3 represents hydrogen or arylsulfonyl. In a highly preferred embodiment of the invention, A represents naphthyl, preferably 2-naphthyl; Ri is preferably placed in the 6-position of the naphthyl radical, and is -XR4 wherein X is oxygen; R 4 is lower alkyl, more preferably methyl, which is substituted by halophenyl, more preferably 2-fluorophenyl. R and R3 are both hydrogen. In another preferred embodiment of the invention, A represents dihydrobenzopyranyl, preferably 3, -dihydro-2H-l-benzopyran-2-yl; Rx is preferably placed at the 2-position of the benzopyranyl radical, and is preferably -XR4, wherein X is lower alkylene, preferably methylene; and R 4 is preferably unsubstituted phenyl. R2 and R3 are both hydrogen. In another preferred embodiment of the invention, A represents phenylethynyl; Ri is preferably placed in the 4-position of the phenyl radical, and is preferably halogen, more preferably chlorine; R2 is preferably hydrogen, and R3 is arylsulfonyl, wherein aryl is preferably phenyl which is unsubstituted or substituted by halogen, preferably fluorine, lower alkyl, preferably methyl or lower alkoxy, preferably methoxy; or naphthyl. More preferably, R3 is phenylsulfonyl which is unsubstituted. In a further preferred embodiment, the glitazone is represented by the formula (bundle), wherein Ri is XR, X is oxygen, and R4 is lower alkyl, substituted by indole or 2,3-dihydroindole, more preferably 2- (indol-1-yl) ethoxy, or 2- (2,3-dihydroindole) -yl) ethoxy R2 and R3 are hydrogen. In another preferred embodiment of the invention, the gli-tazone is represented by the formula (bundle), wherein Ri is XR4, X is oxygen, and R4 is lower hydroxyalkyl, preferably 2-hydroxyethyl, substituted by oxazolyl, preferably -oxazolyl, which is substituted by phenyl and lower alkyl, preferably methyl. R2 and R3 are both hydrogen. In a highly preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR, X is oxygen, and R is lower alkyl, preferably methyl or ethyl, and more preferably methyl; R 2 is trifluoromethylphenyl-lower alkylcarbamoyl, preferably trifluoromethylbenzylcarbamoyl; and R3 is hydrogen. In another preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR4, X is -NH-, and R4 is arylcycloalkylcarbonyl. Preferably, R 4 is phenylcycloalkylcarbonyl, in which radical, the phenyl residue and the carbonyl residue are linked to the same carbon atom of the cycloalkyl ring. More preferably, R 4 is 1-phenyl-1-cyclopropanecarbonyl. R2 and R3 are both hydrogen. In a highly preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR4, X is oxygen, and R4 is lower alkyl, preferably methyl or ethyl, and more preferably methyl, substituted by pyridyl or lower alkylpyridyl. More preferably, lower alkyl is substituted by lower alkyl-2-pyridyl, and more preferably by ethyl-2-pyridyl. R2 and R3 are hydrogen. In a highly preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR, X is oxygen, and R4 is lower alkyl, preferably methyl, which is substituted by dihydrobenzopyranyl, preferably 3, 4-dihydro-2H-l-benzopyran-2-yl, which is unsubstituted, or preferably substituted by lower alkyl, preferably methyl or ethyl, and hydroxyl. More preferably, X is oxygen, R 4 is methyl which is substituted by 3,4-dihydro-6-hydroxy-2,5,7,8-tetramethyl-2H-1-benzopyran-2-yl. R2 and R3 are hydrogen. In another preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR4, X is preferably oxygen, and R4 is lower alkyl substituted by cycloalkyl, preferably cycloalkyl of 5 to 7 carbon atoms. carbon, more preferably cyclohexyl, which is unsubstituted or substituted by lower alkyl, preferably ethyl or methyl, and more preferably methyl. R2 and R3 are hydrogen. In a highly preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR4, X is oxygen, and R4 is lower alkyl, preferably ethyl, which is substituted by N-lower alkyl-N pyridylamino, preferably N-methyl-N-pyridylamino, and more preferably N-methyl-N-2-pyridylamino. R2 and R3 are hydrogen. In another preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR4, X is oxygen or carbonyl, and R4 is lower alkyl, preferably ethyl, which is substituted by oxazolyl substituted by lower alkyl , preferably methyl, and unsubstituted phenyl. R2 and R3 are hydrogen. In another preferred embodiment of the invention, the glitazone is represented by the formula (lia), wherein Ri is XR4, X is lower alkylene, preferably methylene, R4 is substituted phenyl, preferably in the 4 position, by 2.4 -dioxo-5-thiazolidinyl. R2 and R3 are hydrogen. In a further preferred embodiment of the invention, the glitazone is 5- (2-naphthylsulfonyl) thiazolidin-2,4-dione. In a highly preferred embodiment of the invention, A represents benzoxazolyl, preferably 5-benzoxazolyl; Ri is preferably placed at the 2-position of the benzoxazolyl radical, and is -XR4, wherein X is lower alkylene, preferably methylene, and R4 is naphthyl, preferably 2-naphthyl. R2 and R3 are both hydrogen. A highly preferred glitazone according to all aspects of the present invention is selected from the group consisting of rosiglitazone, MCC555, troglitazone, and especially pioglitazone, and their pharmaceutically acceptable salts. In the case of pioglitazone, the invention relates in particular to the monohydrochloride salt. In a further preferred embodiment of the invention, a glitazone according to all aspects of the present invention is selected from the group consisting of T-174, KRP297, and its pharmaceutically acceptable salts. Another preferred glitazone according to all the aspects of the present invention is selected from the group consisting of englitazone, darglitazone, ciglitazone, AY-31637, 5-. { [4- (2- (1-indolyl) ethoxy) phenyl] methyl} -thiazolidin-2,4-dione (DRF2189), 5-. { [4- (2 - (2,3-dihydroindol-1-yl) ethoxy) phenyl] methyl} -thiazolidin-2,4-dione, BM-13.1246, bis. { 4- [(2,4-dioxo-5-thiazolidinyl) methyl] phenyl} methane (YM268), 5-. { 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-hydroxyethoxy] benzyl} -thiazolidin-2,4-dione (AD-5075), 5- [3- (4-chlorophenyl]) 2-propynyl] -5-phenylsulfonyl) -thiazolidin-2,4-dione, 5- [3- (4 chlorophenyl) -2-propynyl] -5- (4-flu-orophenylsulphonyl) thiazolidin-2,4-dione, 5- [4- (1-phenyl-1-cyclopropanecarbonylamino) -benzyl] -thiazolidin-2, 4-dione (DN-108), and its pharmaceutically acceptable salts. In a highly preferred embodiment of the invention, nateglinide is administered in combination with metformin, metformin hydrochloride, or a mixture thereof. Nateglinide and metformin, metformin hydrochloride, or a mixture thereof, can be administered at different points of time, for example nateglinide before breakfast, lunch, and meal, and metformin, metformin hydrochloride, or a mixture of the same, after breakfast, lunch and dinner, or in a simultaneous manner. Preferably, nateglinide and metformin, metformin hydrochloride, or a mixture thereof, are administered in a simultaneous manner. Most preferably, nateglinide and metformin, metformin hydrochloride, or a mixture thereof, are administered three times daily, before breakfast, lunch and dinner. It is also highly preferred to administer nateglinide and metformin, metformin hydrochloride, or a mixture thereof, together in a fixed combination. It is an object of this invention to provide a pharmaceutical composition comprising an amount, which is jointly therapeutically effective against metabolic disorders, in particular diabetes mellitus type 2, or a disease or condition associated with diabetes mellitus, of (i) nate-glinide or repaglinide, or in each case a pharmaceutically acceptable salt thereof, and (ii) at least one other antidiabetic compound selected from the group consisting of sulfonylurea-derived glitazones, and metformin, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vehicle. In this composition, components (i) and (ii) can be administered together, one after the other, or separately, in a combined unit dosage form, or in two separate unit dosage forms. Preferably, the unit dosage form is a fixed combination. Preferably, a pharmaceutical composition of the present invention comprising nateglinide, comprises modification of the type B or H crystal of nateglinide, more preferably type H. In particular, the present invention relates to a pharmaceutical composition comprising amounts in the form of Therapeutically effective pool of nateglinide or a pharmaceutically acceptable salt thereof, a glitazone or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable vehicle. In addition, the invention relates to a combined preparation or pharmaceutical composition, respectively, comprising nateglinide and a glitazone, wherein the combined preparation or pharmaceutical composition, respectively, comprises at least one additional pharmaceutically active compound, for example selected from of the group consisting of a sulfonylurea derivative, a pharmaceutically acceptable salt thereof, metformin, and insulin; or wherein the combined preparation or pharmaceutical composition, respectively, comprises at least one additional glitazone, or a pharmaceutically acceptable salt thereof. A further aspect of the present invention is the use of a pharmaceutical composition comprising nateglinide or repaglinide, and at least one other antidiabetic compound selected from the group consisting of glytazones, sulfonylurea derivatives, and metformin, in each case in the form free or in the form of a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the prevention, delay of progress, or treatment of metabolic disorders, in particular of type 2 diabetes mellitus, or a disease or associated condition with diabetes mellitus. In particular, this additional aspect of the present invention relates to the use of a pharmaceutical composition comprising nateglinide and a glitazone, in each case in free form or in the form of a pharmaceutically acceptable salt thereof, for the preparation of a pharmaceutical preparation for the prevention or treatment of diseases, especially metabolic disorders, more especially diabetes, and in particular diabetes mellitus type 2, and diseases and conditions associated with diabetes. Furthermore, the invention relates to a pharmaceutical composition comprising nateglinide or repaglinide, and at least one other antidiabetic compound selected from the group consisting of glitazones, sulphonylurea derivatives, and metformin, in each case in free form or in the form of a pharmaceutically acceptable salt thereof, for the prevention, delay of progress, or treatment of hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glo-merulosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, coronary heart disease, hypertension, angina pectoris, myocardial infarction, embolism, skin and connective tissue disorders, foot ulcers, metabolic acidosis , ar-tritis, osteoporosis, and in particular tolerant conditions impaired glucose, and especially type 2 diabetes. Additional aspects of the present invention are oral dosage forms and pharmaceutical formulations (compositions) for administration to mammals suffering from, or at risk of, diseases that have the characteristics of type 2 diabetes. It will be understood that any statistically significant attenuation in the symptoms of type 2 diabetes disease according to the treatment of the present invention is within the scope of the invention. Each oral formulation (composition) according to the present invention may further comprise inert constituents, including pharmaceutically acceptable carriers, diluents, fillers, solubilizing or emulsifying agents, and salts, as are well known in the art. For example, tablets used for combination therapy can be formed according to conventional procedures, using solid carriers well known in the art. The capsules employed for the combination therapies of the present invention can be made from any pharmaceutically acceptable material, such as gelatin or cellulose derivatives. The term "combination therapy", as used herein, means that a combination comprising nateglinide or repaglinide, and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, and is used for the treatment, delay of progress, or prevention of one of the diseases, especially meta-bolic disorders, mentioned herein. Examples of solid vehicles include bentonite, silica, and other commonly used vehicles. Additional non-limiting examples of carriers and diluents that can be used in the combination therapy formulations of the present invention include serum and any physiologically regulated saline solution, such as phosphate buffered saline (PBS) and water. It will be appreciated that the unit content of the active ingredient or ingredients contained in a single dose of each dosage form need not constitute an effective amount, because the effective amount needed can be achieved by the administration of a plurality of units. of dosage. The preferred route of administration of the dosage forms of the present invention is orally or enterally. Preferred oral or enteral pharmaceutical dosage forms or formulations may comprise, for example, between about 1 milligram and about 1000 milligrams of nateglinide, for example. In an alternative preferred embodiment of the present invention, the pharmaceutical formulations or dosage forms for the combination therapies of the present invention may also be administered to mammals suffering from diseases having the characteristics of type 2 diabetes in the form of aerosol. It is expected that lower amounts of antidiabetic drugs, or disease suppressor fragments or analogues thereof, will be required, using aerosol administration for the treatment or prevention of type 2 diabetes, as has been found in the treatment of other conditions. of allergic diseases. The amounts of antidiabetic drugs or analogs thereof that can be administered in an aerosol dosage form would be between 0.1 milligrams and 10 milligrams per kilogram of body weight of a mammal per day, and can be administered in one dosage form, or in multiple dosage forms. The exact amount that must be administered will vary depending on the state and severity of a patient's illness, and the physical condition of the patient. Aerosol pharmaceutical formulations for use in combination therapies of the present invention may include, as optional ingredients, pharmaceutically acceptable carriers, diluents, solubilizing or emulsifying agents and salts of the type that are well known in the art. Examples of these substances include normal saline solutions, such as physiologically regulated salt solutions, and water. The route of administration of the antidiabetic drugs or of the disease suppressor fragments or analogs thereof according to this alternative embodiment of the present invention is an aerosol or inhaled form. The antidiabetic drugs and related compounds of the present invention can be administered as a dry powder or in an aqueous solution. Preferred aerosol pharmaceutical formulations may comprise, for example, a physiologically acceptable regulated saline solution containing between about 1 milligram and about 1000 milligrams of antidiabetic drugs, disease suppressor fragments, or analogs thereof. The dry aerosol in the form of finely divided solid particles of antidiabetic drugs, of disease suppressor fragments, or analogs thereof, which do not dissolve or suspend in a liquid, is also useful in the practice of the present invention. invention. The antidiabetic drugs may be in the form of dusts to be sprinkled, and comprise finely divided particles having an average particle size of between about 1 and 5 microns, preferably between 2 and 3 microns. The finely divided particles can be prepared by spraying and sieving using techniques well known in the art. The particles can be administered by inhaling a predetermined amount of the finely divided material, which may be in the form of a powder. Specific non-limiting examples of the carriers and / or diluents that are useful in the aerosol pharmaceutical formulations used for the combination therapies of the present invention include water and physiologically acceptable regulated saline solutions, such as phosphate buffered saline solutions with a pH of 7.0 to 8.0. The pharmaceutical formulations of the present invention can be administered in the form of an aerosol spray using, for example, a nebulizer, such as those described in U.S. Patent Nos. 4,624,251 issued November 25, 1986.; 3,703,173 issued November 21, 1972; 3,561,444 issued on February 9, 1971, and 4,635,627 issued on January 13, 1971. The aerosol material is inhaled by the subject being treated. When practicing the present invention, other aerosol delivery systems, such as the pressurized metered dose inhaler (MDI), and the dry powder inhaler disclosed in Newman, S.P. in Aerosols and the Lung, Clarke, SW and Davia, D. editors, pages 197-224, Buterworths, London, England, 1984. The aerosol delivery system of the type disclosed herein is available in numerous. commercial sources, including Fisons Corporation (Bedford, Mass.), Schering Corp. (Kenil O'rth, NJ) and American Pharmoseal Co., (Valencia, California). In practical use, antidiabetic drugs or combinations thereof, can be combined as the active ingredients in intimate admixture with a pharmaceutical carrier according to conventional pharmaceutical composition techniques. The vehicle can take a wide variety of forms, depending on the form of preparation desired for administration, for example oral or parenteral (including intravenous). In the preparation of the compositions for the oral dosage form, any of the usual pharmaceutical media, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents and the like in the case of oral liquid preparations, such as, for example, suspensions, elixirs, and solutions; or vehicles such as starches, sugars, microcrystalline cellulose, diluents, granulating agents, lubricants, binders, disintegrating agents, and the like, in the case of oral solid preparations, such as, for example, powders, capsules, and tablets, being preferred solid oral preparations on liquid preparations. Because of their ease of administration, tablets and capsules represent the most convenient oral dosage unit form, in which case, solid pharmaceutical carriers are obviously employed. If desired, the tablets can be coated by conventional aqueous or non-aqueous techniques. In addition to the common dosage forms stipulated above, antidiabetic drugs or combinations thereof may also be administered by controlled release elements and / or controlled delivery devices, such as those described in US Pat. North America Numbers 3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200, and 4,008,719, the disclosures of which are incorporated herein by reference. The pharmaceutical compositions of the present invention used for combination therapy suitable for oral administration, may be presented as separate units, such as capsules, lozenge, or tablets, each containing a predetermined amount of the active ingredient, such as a powder or granules , or as a solution or suspension in an aqueous liquid, in a non-aqueous liquid, an oil-in-water emulsion, or a water-in-oil liquid emulsion. These compositions can be prepared by any of the pharmacy methods, but all methods include the step of bringing the active ingredient into association with the vehicle which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately mixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compressing the active ingredient in a free-flowing form in a suitable machine., such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface activity agent or dispersant. The molded tablets can be made by molding in a suitable machine, a mixture of the powdered compound moistened with an inert liquid diluent. The combination of the compounds of the present invention is useful in the treatment of diabetes. For these purposes, the combinations of the present invention can be administered orally, parenterally (including subcutaneous injections, intravenous, intramuscular, intrasternal injection, or infusion techniques), by inhalation spray, or rectally, in unit dosage formulations that contain carriers, adjuvants, and conventional non-toxic pharmaceutically acceptable vehicles. These may be administered in a fixed or separate combination dosage form. Accordingly, in accordance with the combination therapies of the present invention, there is further provided a method for the treatment, and a pharmaceutical composition for the treatment of obesity and diabetes. The treatment involves administering to a patient in need of such treatment, a pharmaceutical composition comprising a pharmaceutical carrier and a therapeutically effective amount of each combination of the combination of the present invention. These pharmaceutical compositions may be in the form of orally administrable suspensions or tablets.; nasal sprays; sterile injectable preparations, for example as sterile injectable aqueous or oleaginous suspensions, or suppositories. In accordance with the methods of the present invention, the individual components of the combination can be administered separately at different times during the course of therapy, or in a concurrent manner in divided or individual combination forms. For example, in a combination of two components of, for example, nateglinide or repaglinide and / or a glitazone as defined herein, or metformin, treatment with nateglinide or repaglinide may begin before, subsequent to, or concurrently with, the start of treatment with glitazone and / or metformin. In addition, the term "administer" also encompasses the use of prodrugs of any of the antidiabetic drugs that are converted in vivo to the selective antidiabetic drug. Accordingly, it should be understood that the present invention encompasses all simultaneous or alternate treatment regimens, and the term "administer" should be interpreted accordingly. When any of the active ingredients is administered in combination therapy orally as a suspension, these compositions are prepared according to techniques well known in the art of pharmaceutical formulation, and may contain microcrystalline cellulose to impart volume, alginic acid, or sodium abatement as a suspending agent, methylcellulose as a viscosity enhancer, and sweetening / flavoring agents known in the art. In addition, these compositions may contain calcium diphosphate, starch, magnesium stearate, and lactose and / or other excipients, binders, extenders, disintegrants, diluents, and lubricants known in the art. When administered by aerosol spray or inhalation, these compositions are prepared according to techniques well known in the field of pharmaceutical formulation, and can be prepared as solutions in serum, using benzyl alcohol or other suitable preservatives, absorption promoters. to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. The compounds used in the combination can also be administered in an intravenous form (both bolus and infusion), intraperitoneai, subcutaneous, topical or nonocclusive, or intramuscular, all using forms well known to those of ordinary skill in the art. pharmaceutical When administered by injection, injectable solutions or suspensions may be formed according to the known art, using suitable parenterally acceptable non-toxic solvents or diluents, such as mannitol, 1,3-butanediol, water, Ringer's solution, or isotonic sodium chloride solution, or suitable dispersing or wetting and suspending agents, such as sterile, soft, fixed oils, including synthetic mono- or diglycerides, and fatty acids, including oleic acid. When administered rectally in the form of suppositories, these compositions can be prepared by mixing the drug with a suitable non-irritating excipient, such as cocoa butter, synthetic glyceride esters or polyethylene glycols, which are solid at ordinary temperatures, but that they become liquid and / or dissolve in the rectal cavity to release the drug. The active ingredients of the combination of the present invention can be administered as a pharmaceutical composition, for example, with an inert diluent, or with an edible assimilable carrier, or they can be enclosed in hard or soft-cover capsules, or can be compress into tablets, or they can be incorporated directly with the diet food. For oral therapeutic administration, which includes sublingual administration, these active compounds can be incorporated with excipients, and can be used in the form of tablets., pills, capsules, ampoules, sachets, elixirs, suspensions, syrups, and the like. These compositions and preparations must contain at least 0.1 percent of the active ingredients. The percentage of active ingredients in these compositions, of course, can vary, and can conveniently be between about 2 percent and about 60 percent of the unit's weight. The amount of active ingredients in these tera-pharmaceutically useful compositions is such that an effective dosage is obtained. The active compounds can also be administered intranasally, such as, for example, liquid drops or sprays. The effective dosage of each of the active ingredients employed in combination therapy may vary depending on the particular compound employed, the mode of administration, the condition being treated, and the severity of the condition being treated. Accordingly, the dosage regimen using the compounds of the present invention is selected according to a variety of factors, including type, species, age, weight, sex, and medical condition of the patient.; of the severity of the condition to be treated; of the route of administration; of the renal and hepatic function of the patient; and of the particular compound employed. A physician, clinician, or veterinarian of ordinary experience can easily determine and prescribe the effective amount of the drug required to prevent, counteract, or stop the "progress of the condition." The optimal precision to achieve drug concentration within the range that produces efficacy without toxicity requires a regimen based on the kinetics of drug availability to target sites This involves a consideration of the distribution, equilibrium, and elimination of a drug The amount of nateglinide or repaglinide in the compositions of the invention will, of course, vary, for example depending on the intended route of administration, and to what extent other components are present, as described hereinabove, however, in general, nateglinide or repaglinide will be present in an amount within the 0.05 scale especially from about 0.1 to about 35 percent by weight, based on the total weight of the composition. The nateglinide or repaglinide will suitably be present in the compositions of the invention in an amount of about 0.5 to about 90 weight percent, based on the total weight of the composition. In the case of the compositions according to the invention, which comprise an additional component of metformin, it will generally be present in an amount from about 1 to about 90 weight percent, more commonly from about 5 to 10 weight percent. to about 70 weight percent, based on the total weight of the composition. In the case of the compositions according to the invention, which comprise an additional component of thiazolidinone derivative, this will generally be present in an amount of about 2 to about 50 weight percent, based on the total weight of the thiazolidinone derivative. the composition. Tablets, pills, capsules, and the like, may also contain a binder, such as gum tragacanth, acacia, corn starch, or gelatin; excipients, such as calcium diphosphate; a disintegrating agent, such as corn starch, potato starch, alginic acid; a lubricant, such as magnesium stearate; and a sweetening agent, such as sucrose, lactose, or saccharin. When a unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a fatty oil. There may be other different materials present as coatings or to modify the physical form of the dosage unit. For example, the tablets can be coated with shellac, sugar, or both. A syrup or elixir may contain, in addition to the active ingredient, sucrose as a sweetening agent, methyl- and propylparabens as preservatives, a dye and a flavoring, such as cherry or naran-ja flavoring. These active compounds can also be administered parenterally for the combination therapies of the present invention. Solutions or suspensions of these active compounds in water may be prepared suitably mixed with a surfactant such as hydroxypropylcellulose. Dispersions in glycerol, liquid polyethylene glycols, and mixtures thereof in oils can also be prepared. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms. Especially, the present invention relates to a pharmaceutical composition for combination therapy, which comprises nateglinide and metformin in a pharmaceutical carrier, which is preferably in the form of a tablet, a capsule, a suspension, or a liquid. This pharmaceutical composition more preferably contains from about 100 milligrams to about 130 milligrams of nateglinide, and from about 320 milligrams to about 1500 milligrams, more preferably from 330 milligrams to 350 milligrams of metformin per dosage unit. The pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions, and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions. In all cases, the form must be sterile, and must be fluid to the extent that it exists in an easily injectable manner. It must be stable under the conditions of manufacture and storage, and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or a dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol), suitable mixtures thereof, and vegetable oils. When the combinations of antidiabetic drugs described in this invention are formulated, the ratio of the ingredients in the compositions of the invention will, of course, vary considerably, depending on the particular type of composition concerned, for example if it is a tablet, trocus, liquid, such as an emulsion or microemulsion, or suspension, and so on. The relative proportions will also vary depending on the particular ingredients employed and the desired physical characteristics of the composition of the product. The determination of workable proportions in any particular case, will generally be within the ability of the expert in the field. All the indicated proportions and relative weight range described below, according to the foregoing, should be understood as indicative of the preferred or individually inventive teachings only, and not to limit the invention in its broadest aspect. It will be understood that, in the discussion of the methods that follow, references to the compounds of the formula I also include the pharmaceutically acceptable salts. A further aspect of the present invention is a method for the treatment of a warm-blooded animal, especially a human being, having metabolic disorders, in particular diabetes mellitus type 2, or a disease or condition associated with diabetes mellitus, which comprises administering to the animal a combination of nateglinide or repaglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulphonylurea derivatives, and metformin, in an amount which is jointly therapeutically effective against metabolic disorders, wherein both compounds may also be present in the form of their pharmaceutically acceptable salts. Preferably, this method of treatment is carried out with nateglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, contained in the same unit dosage form. The combination of preference is administered in a simultaneous manner. In particular, the present invention relates to a method for the treatment of diabetes or a disease or condition associated with diabetes, which comprises administering to a warm-blooded animal in need thereof, in a joint manner, therapeutically effective amounts of nateglinide in free or pharmaceutically acceptable salt form, and a glitazone, in free or pharmaceutically acceptable salt form, simultaneously or in sequence in any order, separately, or in a fixed combination. Preferably, nateglinide and glitazone are provided in this method as a combined preparation. In a preferred embodiment, this method further comprises administering a therapeutically effective amount of at least one additional pharmaceutically active compound selected from the group consisting of sulfonylurea derivatives, a pharmaceutically acceptable salt thereof, metformin, and insulin; or at least one additional glitazone, or a pharmaceutically acceptable salt thereof. Preferably, in this method, the glitazone is a compound of the formula (II), wherein A represents naphthyl, benzoxazolyl, dihydrobenzopyranyl, indole, phenyl (optionally substituted by halogen), or phenylethynyl (optionally substituted by halogen); Ri represents halogen or a radical -XR4, wherein X can be oxygen, lower alkylene, carbonyl, or -NH-, and R4 is naphthyl; phenyl, unsubstituted or substituted by 2,4-dioxo-5-thiazolidinyl; or lower alkyl or lower hydroxyalkyl, unsubstituted or substituted by a) indole or 2,3-dihydroindole, b) pyridyl, lower alkylpyridyl, N-lower alkyl-N-pyridylamino, or halophenyl, c) dihydrobenzopyranyl, which is unsubstituted or substituted by hydroxyl and lower alkyl, d) oxazolyl, which is substituted by lower alkyl and phenyl, e) cycloalkyl, which is unsubstituted or substituted by lower alkyl, of) arylcycloalkylcarbonyl; R 2 represents hydrogen or trifluoromethylphenyl-lower alkylcarbamoyl; and R3 represents hydrogen or arylsulfonyl. In a most preferred first mode of this method, glitazone is selected from the group consisting of englitazone, darglitazone, ciglitazone, DRF2189, BM-13.1246, AY-31637, YM268, AD-5075, DN-108, 5 -. { [4- (2- (2,3-dihydroindol-1-yl) ethoxy) phenyl] methyl} -thiazolidin-2, -dione, 5- [3- (4-chlorophenyl]) -2-propynyl] -5-phenylsulfohyl) thiazolidin-2,4-dione, and 5- [3- (4-chlorophenyl) -2 -propynyl] -5- (4-fluorophenylsulfonyl) thiazolidin-2,4-dione, or a pharmaceutically acceptable salt thereof. In a second more preferred embodiment of this method, the glitazone is selected from the group consisting of rosiglitazone, piogli-tazone, troglitazone, and MCC555, or a pharmaceutically acceptable salt thereof. In a second, more preferred embodiment of this method, the glitazone is selected from the group consisting of T-174 and KRP297, or a pharmaceutically acceptable salt thereof. Especially, the present invention relates to a method for the treatment of diabetes or a disease or condition associated with diabetes, which comprises administering to a warm-blooded animal in need thereof, in a joint manner, a therapeutically effective amount of nateglinide in free form or pharmaceutically acceptable salt, and a glitazone, in free or pharmaceutically acceptable salt form, simultaneously or in sequence in any order separately or in a fixed combination, which method further comprises the administration of a therapeutically effective amount of at least one additional pharmaceutically active compound selected from the group consisting of sulfonylurea derivatives, a pharmaceutically acceptable salt thereof, metformin, and insulin; or at least one additional glitazone or a pharmaceutically acceptable salt thereof. This particular embodiment of the invention relates especially to a method for the treatment of patients with type 2 diabetes, by using an effective amount of a combination of at least one short-acting hypoglycemic agent, with at least one other hypoglycemic agent. of longer action, in an amount sufficient to treat post-prandial hyperglycemia. Preferably, the short-acting hypoglycemic agent is nateglinide. Also preferably, the long acting hypoglycemic agent is metformin. In an alternative preferred embodiment, the long acting hypoglycemic agent is a glitazone, more preferably 5- (2-naphthylsulfonyl) -thiazolidin-2,4-dione; rosiglitazone, pioglitazone, troglitazone, MCC555; T-174; KRP297; Englitazone, Darglitazone, Ciglite-zone, AY-31637, 5-. { [4- (2- (1-indolyl) ethoxy) phenyl] methyl} -thiazolidin-2,4-dione (DRF2189), 5-. { [4- (2- (2,3-dihydroindol-1-yl) ethoxy) phenyl] methyl} -thiazolidin-2,4-dione, BM-13.1246, bis. { 4- [(2,4-dioxo-5-thiazolidinyl) methyl] phenylj-methane (YM268), 5-. { 4- [2- (5-methyl-2-phenyl-4-oxazolyl) -2-hydroxyethoxy] benzyl} -thiazolidin-2,4-dione (AD-5075), 5- [3- (4-chlorophenyl]) -2-propinyl] -5- phenylsulfonyl) -thiazolidin-2,4-dione, 5- [3- ( 4-chlorophenyl]) -2-propynyl] -5- (4-fluorophenylsulfonyl) thiazolidin-2,4-dione; or 5- [4- (1-phenyl-1-cyclopropanecarbonylamino) -benzyl] -thiazolidin-2,4-dione (DN-108); or a pharmaceutically acceptable salt thereof. In the present embodiment, the short-acting hypoglycemic and the long-acting hypoglycemic agent are contained in the same dosage unit. The invention also relates to a combination as disclosed herein, for use in the prevention, delay of progress, or treatment of diseases, to the use of this combination for the preparation of a medicament for the prevention, delay of progress , or treatment of metabolic disorders, and the use of this combination for the cosmetic treatment of a mammal, in order to effect a cosmetically beneficial loss of body weight. The ratio of the daily doses of nateglinide or repaglinide or a pharmaceutically acceptable salt thereof, to the glitazone, to the sulfonylurea derivative, or to metformin, or in each case a pharmaceutically acceptable salt thereof, may vary within wide limits , especially depending on the nature of the compounds selected. In order to obtain a synergistic effect of the components, preferably the proportion of the nateglinide or a pharmaceutically acceptable salt thereof to the glitazone is between 12,000: 1 and 1: 2,800, more preferably between 500: 1 and 1: 100, for example between 1.5: 1, and between 400: 1 and 2: 1 in the case of rosiglitazone; and between 50: 1 and 1: 3 in the case of pioglitazone. The ratio of nateglinide to rosiglitazone is preferably between 50: 1 and 20: 1, for example 22.5: 1 or 45: 1. The ratio of nateglinide to pioglitazone is preferably between 30: 1 and 3: 1, for example 24: 1, 12: 1, or 8: 1. In a preferred embodiment of the invention, the ratio of the daily doses of nateglinide to metformin is between 1: 3.5 and 1:40, preferably between 1: 4 and 1: 7.1, and most preferably between 1: 4.1 and 1: 4.5 , for example 1: 4.2. In a further preferred embodiment of the invention, the ratio of the daily doses of nateglinide to metformin is between 1: 2 and 1: 3. In a preferred embodiment of the invention, the ratio of the daily doses of nateglinide to metformin hydrochloride is between 1: 1.25 and 1: 9, more preferably between 1: 2.5 and 1: 5, for example 1: 4.2. In a further preferred embodiment of the invention, the ratio of the daily doses of nateglinide to metformin hydrochloride is between 4: 1 and 1: 1, more preferably between 2.5: 1 and 1.5: 1, for example 2: 1. In another preferred embodiment of the invention, the ratio of the daily doses of nateglinide to metformin hydrochloride is between 25: 1 and 4.5: 1, more preferably between 20: 1 and 8: 1, in particular 18: 1. , 16: 1, 14: 1, 10: 1, and especially 12: 1. A therapeutically effective amount of each of the components of the combination of the present invention can be administered in a simultaneous or sequential manner, and in any order. The corresponding active ingredient or a pharmaceutically acceptable salt thereof, may also be used in the form of a hydrate, or may include other solvents used for crystallization. In particular, a therapeutically effective amount of each of the components of the combination of the present invention can be administered in a simultaneous or sequential manner and in any order, and the components can be administered separately or as a fixed combination. . For example, the method of treatment of the invention may comprise between (i) the administration of the nateglinide in free or pharmaceutically acceptable salt form, and (ii) the administration of the glitazone in free or pharmaceutically acceptable salt form, simultaneously or sequentially in any order, in joint therapeutically effective amounts, preferably in synergistically effective amounts, for example in daily dosages corresponding to the proportions described herein. If not indicated otherwise, the pharmaceutical compositions according to the invention can be prepared in a manner known per se, and are suitable for enteral administration, such as orally or rectally, and parenterally, to mammals (warm-blooded animals), including the man, comprising a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. Unless otherwise indicated, novel pharmaceutical preparations contain, for example, from about 10 percent to about 100 percent, preferably 80 percent, preferably from about 20 percent to about 60 percent. percent of the active ingredient. Pharmaceutical preparations for combination therapy that can be used for enteral or parenteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, capsules, or suppositories, and in addition ampoules. If not stated otherwise, they are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar coating, dissolving, or lyophilizing processes. Accordingly, pharmaceutical preparations for oral use can be obtained by combining the active ingredient with solid carriers, if it is desired to granulate a obtained mixture, and process the mixture or the granules, if desired or necessary, after the addition. of suitable excipients, to give tablets or cores of tablets coated with sugar. The dosage regimen of any of the individual components of the combination disclosed herein can be adjusted to provide the optimal therapeutic response. The exact amount of the pharmaceutically active compounds mentioned below, the specific dose level, and the frequency of the dosage for any particular patient, may vary depending on factors known to the person skilled in the art, including the species of blood animal. hot, body weight, sex, diet and age, the nature and severity of the condition to be treated, the mode of administration, and the particular combination used. In particular, the dosage range of the combination of nateglinide and an antidiabetic thiazolidinedione derivative of the formula (II) which is to be employed, depends on factors known to the person skilled in the art, including the species of warm-blooded animal. , body weight and age, the nature and severity of the condition to be treated, the mode of administration, and the particular substance used. Unless otherwise reported herein, the nateglinide and the glitazone of the formula (II) are preferably divided and administered 1 to 4 times a day, preferably the combination is taken together with , or preferably before, each food. The nateglinide is preferably administered to the warm-blooded animal at a dosage in the range of about 5 to 1200, more preferably 10 to 1000, and most preferably 25 to 800 milligrams / day especially when the warm-blooded animal is a human body of approximately 70 kilograms of body weight. In a preferred embodiment of the invention, 60 milligrams or 120 milligrams of nateglinide (I) are applied 3 times a day. Repaglinide is administered in a dosage of preferably 0.01 to 8 milligrams per feed, more preferably about 0.2 to 5 milligrams per feed, and most preferably 0.5 milligrams to 4 milligrams per feed. If the warm-blooded animal is a human being, the dosage of MCC555 is preferably on a scale of about 0.1 to 2,000, more preferably about 0.25 to 500, and most preferably 0.5 to 100 milligrams / day per adult patient . The dosage of englitazone or darglitazone is preferably in the range of approximately 0.05 to 50, more preferably from about 0.05 to 5 milligrams / kilogram of the patient's body weight per day, if the warm-blooded animal is a human being. The dosage of AY-31637 is on the scale of about 0.5 to 200, more preferably about 2.5 to 100 milligrams / kilogram of body weight of the patient per day, if the warm-blooded animal is a human being. The dosage of ciglitazone is on the scale of about 0.25 to 200, more preferably about 0.5 to 50 milligrams / kilogram of body weight of the patient per day, if the warm-blooded animal is a human being. The dosage of DN-108 is on the scale of about 0.25 to 200, more preferably about 5 to 100 milligrams / kilogram of the body weight of the warm-blooded animal. If the thiazolidinedione antidiabetic is T-174, KRP297, AD-5075, 5- [3- (4-chlorophenyl]) -2-propynyl] -5-phenylsulfonyl) -thiazolidin-2, -dione, or 5- [3- (4-chlorophenyl] -2-propynyl] -5- (4-fluorophenylsulfonyl) -thiazolidin-2,4-dione, the dosage of this preferential compound is in the range from about 0.1 to 2.500, more preferably from about 0.5 to 2,000, and most preferably from 1 to 1,000 milligrams / day. If the thiazolidinedione antidiabetic is rosiglitazone, the dosage of this compound, in the case of the warm-blooded animal being a human being of approximately 70 kilograms of body weight, is preferably on the scale of about 0.1 to 500, more usually of about 0.5 to 100, and most preferably from 1 to 20, for example 1, 2, 4 or 8 milligrams / day, per adult patient. If the warm-blooded animal is a human being of approximately 70 kilograms of body weight, the dosage of pioglitazone preferably is in the range of about 0.1 to 1,000, more usually about 1 to 500, and most preferably 10 to 150, for example 15, 30, 45, or 90 milligrams / day per adult patient. In a preferred embodiment, the active ingredient is metformin, the warm-blooded animal is a human being of approximately 70 kilograms of body weight, and the dosage of the compound is preferably in the range of from about 750 to 2,000, and more preferably from 1,000. at 1,500 milligrams / day per adult patient. In a preferred embodiment of the invention, 180 milligrams of nateglinide and 750 milligrams of metformin are given as a daily dose to a human patient of approximately 70 kilograms of body weight. In a further preferred embodiment of the invention, the active ingredient metformin should be applied in the form of metformin hydrochloride in a dosage between 1,500 and 3,000, especially 1,500, 1,700, or 2,550 milligrams / day, to a warm-blooded animal of approximately 70 kilograms of body weight. In another preferred embodiment, the active ingredient metformin will be applied in the form of metformin hydrochloride, in a dosage between 700 and 1,250, especially between 750 and 1,100, for example 1,000 milligrams / day, to a warm-blooded animal of approximately 70 kilograms of body weight. If the sulfonylurea derivative glyburide is selected as the active ingredient, and the warm-blooded animal is a human being of approximately 70 kilograms of body weight, the dosage of this compound is preferably in the range of about 0.5 to 20, more preferably from 1.75 to 15, for example 3.5, 7.0, or 10.5 milligrams / day. If the sulfonylurea derivative tolbutamide is selected as the active ingredient, and the warm-blooded animal is a human being of approximately 70 kilograms of body weight, the dosage of this compound is preferably in the range of about 100 to 3,500, more preferably 250 to 3,000, for example 500, 1,000, 1,500, 2,000, 2,500 milligrams / day. If the sulfonylurea derivative glimepiride is selected as the active ingredient, and the warm-blooded animal is a human being of approximately 70 kilograms body weight, the dosage of this compound preferably being on the scale of about 0.25 to 12, more preferably 0.5 to 10, and most preferably between 1 and 3 milligrams / day. If the sulfonylurea derivative gliclazide is selected as the active ingredient, and the warm-blooded animal is a human of approximately 70 kilograms of body weight, the dosage of this compound is preferably on the scale * of about 5 to 500, more preferably from 15 to 300, and most preferably between 40 and 120 milligrams / day. If the sulfonylurea derivative glubornuride is selected as the active ingredient, and the warm-blooded animal is a human being of approximately 70 kilograms body weight, the dosage of this compound is preferably in the range of about 5 to 250, more preferably from 12.5 to 75, and most preferably between 12.5 and 50 milligrams / day. If the sulfonylurea derivative gliquidone is selected as the active ingredient, and the warm-blooded animal is a human being of approximately 70 kilograms of body weight, the dosage of this compound is preferably in the range of about 5 to 500, more preferably from 30 to 120, and most preferably between 30 and 45 milligrams / day. The preparation of metformin (dimethyldiguanide) and its hydrochloride salt is state of the art, and was first disclosed by Emil A. Werner and James Bell, J. Chem. Soc. 121, 1992, 1790-1794. The preparation of DRF2189 and 5-. { [4- (2- (2, 3-dihydroindol-1-yl) -ethoxy) phenyl] methyl} -thiazolidin-2,4-dione is described in B.B. Lohray et al., J. Med. Chem. 1998, 41, 1619-1630; Examples 2d and 3g on pages 1627 and 1628. The preparation of 5- [3- (4-chlorophenyl] -2-propynyl] -5-phenylsulfo-nyl) -thiazolidin-2,4-dione and the other compounds in where A is phenylethynyl mentioned herein, can be carried out according to the methods described in J. Robel et al., J. Med. Chem. 1998, 41, 1084-1091. A further object of the invention is to provide a pharmaceutical composition that is effective for the treatment or prevention of metabolic disorders, more particularly diabetes, and in particular diabetes mellitus type 2, or a disease or condition associated with diabetes. Another object of the invention is to provide a composition, in particular a pharmaceutical composition, for example of nateglinide, which is easily manufactured. The compositions disclosed hereinafter, preferably comprise nateglinide as the sole active agent, in particular pharmacologically active agent. Under these aspects and as disclosed hereinafter, the present invention relates to a composition, in particular to a pharmaceutical composition, containing nateglinide in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier, wherein the composition can be granulated in the presence of water without the need for a subsequent spray step prior to tabletting; and to a composition, in particular to a pharmaceutical composition, comprising nateglinide in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier, wherein, after administration, about 90 weight percent of nateglinide is released within a period of 10 minutes. The present invention also relates to a process for making a composition, in particular a pharmaceutical composition, which contains nateglinide in free or pharmaceutically acceptable salt form, and a pharmaceutically acceptable carrier, wherein the process includes granulating the drug substance. and one or more pharmaceutically acceptable carriers in the presence of water, without a subsequent spray step. The present invention also relates to a method for the treatment or prophylaxis of diabetes or of a disease or condition associated with diabetes, by administering to a warm-blooded animal in need thereof, a pharmaceutical composition containing a therapeutically effective amount of Nateglinide in free or pharmaceutically acceptable salt form, wherein the composition can be granulated in the presence of water without the need for a subsequent spray step prior to tabletting. As the active agent, in particular the drug substance, for the composition, in particular the pharmaceutical composition, the nateglinide is described in European Patent Nos. EP-196222 and EP 526171, the total content of each of which is hereby expressly incorporated herein by reference. reference. The active drug substance can be present as its pharmaceutically acceptable salts as defined hereinabove, such as acid addition salts, for example as a sodium salt or as a maleate. Each oral composition according to the present invention may further comprise inert constituents, including pharmaceutically acceptable carriers. As used herein, the term "pharmaceutically acceptable carrier" refers to the ingredients of the composition, in particular the pharmaceutical composition, excluding the active drug substance. Examples of pharmaceutically acceptable carriers include binders, disintegrants, diluents, fillers, brighteners, anti-adherents, lubricants, solubilizing or emulsifying agents, and salts. For example, tablets can be formulated according to conventional procedures, using solid carriers well known in the art. You can use auxiliaries for tablet formation, commonly used in the composition of tablets, and reference is made to the extensive literature on the subject, see in particular "Lexicon der Hilfstoffe" by Fiedler, fourth edition, ECV Aulendorf 1996, which is incorporated herein by reference. Disintegrants that can be used include CMC-Ca, CMC-Na, cross-linked polyvinylpyrrolidone (Crospovidone, Polyplasdone from Kollidon XL), alginic acid, sodium alginate, and guar gum. Preferred disintegrants include crosslinked polyvinylpyrrolidone (Crospovidone), croscarmellose sodium (Ac-Di-Sol). Other disintegrants include hydroxypropyl ether-cellulose with a low degree of substitution, wherein a very small portion of hydroxyl groups possessed by a pyranose ring of the cellulose is etherified with propylene oxide. These hydroxypropylcelluloses contain from 5.0 to about 16.0 weight percent of a hydroxypropyl in the quantitative determination of a dry hydroxypropyl cellulose with a low degree of substitution (see Japanese Pharmacopoeia, 13th edition, D-885 to D-888).; Pharmacopoeia, United States 23rd edition, pages 2253-2254; each of which is expressly incorporated herein by reference). Examples of these cellulose hydroxypropyl ethers include L-HPC manufactured by Shin-Etsu Chemical Co., Ltd. (LH-11, LH-20, LH-21, LH-22, LH-30, LH-31, LH-32 and Similar) . The presence of hydroxypropyl cellulose in the pharmaceutical composition is optional. Therefore, in a preferred embodiment, the composition, in particular the pharmaceutical composition, does not contain the hydroxypropyl ether-celluloses described above. Particularly preferred disintegrants are croscarmellose sodium and crosslinked polyvinyl pyrrolidone. The amount of disintegrant employed may be from about 2 to about 20, or up to about 30 weight percent, although the higher level could cause blistering of the tablet during storage. A particularly preferred scale is from 2 to 15 weight percent, and still more preferred is from 2 to 10 weight percent; also 4 to 10 weight percent is a preferred scale of the disintegrant.

Binders for the composition, in particular the pharmaceutical composition, include starches, for example potato starch, wheat starch, corn starch, gums, such as tragacanth gum, acacia gum, or gelatin, microcrystalline cellulose, example products known under the trademarks Avicel Filtrak, Heweten or Pharmacel, hydroxypropylcellulose, hydroxyethylcellulose (HEC), and hydroxypropylmethylcellulose (HPMC), for example hydroxypropylcellulose having a hydroxypropyl content of 5 to 16 weight percent, and a molecular weight of 80,000 to 1,150,000, more particularly of 140,000 to 850,000, or a polyvinylpyrrolidone, such as Povidone. Polyvinylpyrrolidone is particularly preferred. The amount of binder employed may be from about 0.1 to about 5 weight percent. A particularly preferred scale is from 1 to 5 weight percent, and still more preferred is from 2 to 4 weight percent. The brighteners that can be used include silica, magnesium trisilicate, powdered cellulose, starch, talc, and tribasic calcium phosphate. Particularly preferred are colloidal silica (e.g., Aerosil). The amount of anti-adherent employed may be up to about 5 percent by weight, or from 0 to about 5 percent by weight. A particularly preferred scale is 0.5 to 2 percent by weight, and still more preferred is 0.5 to 1 percent by weight. The fillers or diluents that can be used include confectionery sugar, compressible sugar, dextrates, dextrin, dextrose, lactose, mannitol, microcrystalline cellulose, in particular with a density of about 0.45 grams / cubic centimeter, for example Avicel, cellulose powder, sorbitol, sucrose, and talcum. Particularly preferred microcrystalline lactose and cellulose, individually or in a mixture of 10-90 to 90-10, 25-75 to 75-25 especially, for example 67 to 33 weight percent, respectively. Lubricants for the composition, in particular pharmaceutical composition, include stearic acids and their salts, such as stearate Mg, Al, or Ca, polyethylene 4.000 to 8.000, for example 6.000, and talc. Magnesium stearate is particularly preferred. The amount of lubricant employed can be from about 0.75 to about 3 weight percent. A particularly preferred scale is from about 1.5 to about 3 weight percent, and still more preferred is from about 1.8 to about 2.5 weight percent. Accordingly, a particularly preferred embodiment for this embodiment of the invention includes a galenic formula for nateglinide or repaglinide in the form of a tablet comprising in the core monohydrate of lactose, microcrystalline cellulose, povidone, croscarmellose-sodium, and in the coating, magnesium stearate, opadry white, croscarmellose-sodium, and colloidal silicon dioxide. The total amount of pharmaceutically acceptable vehicles in the composition, in particular in the pharmaceutical composition, can be from about 30 to about 75 weight percent. A particularly preferred scale is from 50 to 70 weight percent, and still more preferred is from about 53 to about 67 weight percent. One or more of these additives may be selected, and may be used by the skilled person, considering the particular properties desired of the solid oral dosage form by routine experimentation and without undue burden. Within the ranges of preferred ingredients above, the absolute amounts of each additive, and the amounts in relation to other additives, depend on the desired properties of the solid oral dosage form, and may also be chosen by the expert by experimentation. routine without an undue burden. Where an accelerated release is desired, for example from about 60 percent to 95 percent, for example 75 percent, for example 85 percent, for example about 90 percent by weight of release within a period of 30 minutes, for example 20 minutes, for example 10 minutes, more particularly 5 minutes, for example, in water or in artificial stomach juices (for example 0.1 N HCl), for example in the form of tablets, one can use a disintegrant, such as cross-linked polyvinylpyrrolidone, for example the products known under the registered trademarks Polyplasdo-ne®XL or Kollidon®CL. In particular, the disintegrant has a molecular weight greater than 1,000,000, more particularly having a particle size distribution of less than 400 microns or less than 74 microns, or reactive additives (effervescent mixtures) that effect rapid disintegration of the tablet in the presence of water, for example so-called effervescent tablets containing an acid in solid form, usually citric acid, which acts in water on a base containing chemically combined carbon dioxide, for example sodium hydrogen carbonate or sodium carbonate, and that releases carbon dioxide. Accordingly, the present invention relates to a composition, in particular to a pharmaceutical composition, comprising (a) nateglinide in free or pharmaceutically acceptable salt form and (b) a pharmaceutically acceptable carrier, wherein, after administration, About 90 weight percent of nateglinide is released within a period of 10 minutes. Preferably, this composition comprises a disintegrant having, in particular, a molecular weight greater than 1,000,000. In addition, the disintegrant preferably has a particle size distribution of less than 400 microns, or more preferably less than 74 microns. In a highly preferred embodiment of this aspect of the invention, the disintegrant is a crosslinked polyvinylpyrrolidone. In a solid oral dosage form, wherein the active agent is nateglinide or a pharmaceutically acceptable salt thereof, the preferred additives are microcrystalline cellulose, hydroxypropylcellulose, carboxymethylcellulose (CMC), or CMC-Na, Mg stearate, Ca , or Al, polyvinyl pyrrolidone, anhydrous colloidal silica, lactose, and any combination thereof. The amounts of additive used will depend in part on how much active agent is to be used. Stearate, for example magnesium stearate, is preferably used in amounts of 1.0 to 5.0 percent by weight, for example 1.5 to 3.0 percent by weight. The silica preferably is used in an amount of 0.5 to 10 percent, especially 1 to 5 percent by weight. The composition, in particular the pharmaceutical composition, of the present invention, suitable for oral administration, may be presented as separate units, such as capsules, lozenges, or tablets, each containing a predetermined amount of the active ingredient, such as a powder or granules These compositions may be prepared by any of the pharmacy methods, but all methods include the step of bringing the active ingredient into association with the vehicle, which constitutes one or more necessary ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers, or both, and then, if necessary, shaping the product into the desired presentation. For example, a tablet can be prepared by compression or molding, optionally with one or more accessory ingredients. Compressed tablets can be prepared by compression in a suitable machine, of the active ingredient in free flowing form, such as powder or granules, optionally mixed with a binder, lubricant, inert diluent, surface active agent, or dispersant. Molded tablets can be made by molding in a suitable machine, of a mixture of the powdered compound moistened with an inert liquid diluent. Desirably, each tablet contains from about 2.5 milligrams to about 500 milligrams of the active ingredient, preferably from about 60 milligrams to about 200 milligrams, and more preferably from about 120 milligrams to about 180 milligrams of the active ingredient. When a dosage unit form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a fatty oil. The capsules employed in the present invention can be made from any pharmaceutically acceptable material, such as gelatin or cellulose derivatives. There may be other different materials present as coatings or to modify the physical form of the dosage unit. For example, the tablets can be coated with shellac, sugar and both. The composition, in particular the pharmaceutical composition can be used for enteral administration, such as orally or rectally, to mammals (warm-blooded animals), including man, which comprises a therapeutically effective amount of the pharmacologically active compound, alone or in combination with one or more pharmaceutically acceptable carriers, especially suitable for enteral or parenteral application. The composition, in particular the pharmaceutical composition, contains, for example, from about 10 to about 100 weight percent, preferably 80 weight percent, preferably from about 20 to about 60 weight percent of the active ingredient. The most preferable commercial levels are from 18 to 29 percent of active ingredients. The compositions according to the invention for enteral administration are, for example, those in unit dosage forms, such as sugar-coated tablets, tablets, capsules, or suppositories.

These are prepared in a manner known per se, for example by means of conventional mixing, granulating, sugar coating, dissolving, or lyophilizing processes. Accordingly, the pharmaceutical composition can be obtained by combining the active ingredient with solid carriers, if desired a mixture obtained is granulated, and the mixture or granules are processed, if desired or necessary, after the addition of excipients suitable, to give tablets or cores of tablets coated with sugar. The granulation step can be carried out by means of a high-shear wet granulator, of the type conventional in the art. An upper or lower pulse granulator can be used, an example of a preferred embodiment being a Collette Gral granulator. A person skilled in the art can easily determine the optimum granulation time. A preferred granulation time is from about 1 to about 4 minutes, and more preferably is about 2 minutes. After granulation, the granules can be dried by conventional steps, including, for example, a drying step performed by a fluid bed dryer. Then the dried granules can be passed to a wire mesh apparatus to break up any fraction of granules having an undesirable size. Examples of preferred malia devices include Frewitt MG 400 and Frewitt MG 624.

After granulation, the granules can be further mixed with additional ingredients of the composition, or even with additional amounts of previously granulated ingredients. Diffusion mixers of different geometries of mixing vessels can be used for the mixing step. Typical mixers used for mixing include, for example, a V-blender, or a tray mixer, such as a Stocklin mixer. In a preferred embodiment of the invention, the composition, in particular the pharmaceutical composition, is produced by a process comprising granulating, the presence of water to form granules, drying the granules, and optionally sieving the granules, for example through of a wire mesh. All ingredients of the composition can be added before or during granulation. Alternatively, all or a portion of one or more of the ingredients may be added after the granulation step is completed. For example, all or a portion of a nonstick (e.g., silica), all or a portion of lubricant (e.g., magnesium stearate), and / or all or a portion of a disintegrant (e.g., croscarmellose or any salt) of it), can be added after granulation. In a preferred aspect of the invention, all ingredients, except magnesium stearate and colloidal silica, are charged to the granulator, and then added later.

In one aspect of the invention, the process of producing the composition, in particular the pharmaceutical composition, can be performed without the need for a spray step. As used herein, the terms "spraying" and "spraying" refer to any process involving the grinding or crushing of particles to reduce the size of the particles. In a preferred aspect of the invention, the composition, in particular the pharmaceutical composition, can be produced without spraying the granules between the granulation step and the drying and / or compression step used to form the granules in a tablet. The composition, in particular the pharmaceutical composition, described herein, can further be granulated without the need for spraying before or after the granululation step. As used herein, the term "can be granulated without the need for spraying", defines a property of the composition, as opposed to a requirement that the composition actually occur without a spraying step. Therefore, the term "can be ...", when used to describe a composition, does not specifically impose any limitation of the process or the product by the process on the composition. The composition can also be successfully formed, by compression, for example in tablets that are easy to administer to the patient. It has been observed that, after granulation, a granular composition having an acceptable granule size was obtained, even when water was added during granulation. More specifically, the composition, in particular the pharmaceutical composition, can be granulated (and can be successfully tabletted after granulation) in the presence of about 25 to about 80 weight percent of water, without the need for the aforementioned spraying. Preferably, the granulation can be carried out with the addition of about 25 to about 40 weight percent water. More preferably, the granulation can be carried out with the addition of about 22 to about 37 weight percent water, and still more preferably 27 weight percent water, when producing tablets containing 120 milligrams, 90 milligrams, 60 milligrams, and 30 milligrams of nateglinide. When 180 mg tablets of nateglinide are produced, preferably from about 33 to about 40, and more preferably from 33 to about 37 weight percent of water is added to the granulation. Because the granules can be screened, after a drying step, without the loss of substantial amounts of material, a spray step can be successfully avoided. A further aspect of the present invention is a composition, in particular a pharmaceutical composition, for nateglinide in the form of a pharmaceutically acceptable composition, such as a tablet, comprising pharmaceutically acceptable binders, excipients, and the like, as well as an acceptable coating. This composition further preferably comprises lubricants, more preferably stearic acid, or Mg, Al or Ca stearate, antiadhesives, or colorants. It can be demonstrated, by established test models, and especially the test models described herein, that nateglinide or its pharmaceutically acceptable salt results in a prevention, delay of progress, or preferably more effective treatment of diseases, especially metabolic disorders, more especially diabetes, and in particular diabetes mellitus type 2, and diseases and conditions associated with diabetes. The person skilled in the pertinent art can absolutely select a relevant animal test model to test the therapeutic indications hereinafter and subsequently indicated herein, and the beneficial effects. For example, the pharmacological activity can be demonstrated by essentially following an in vivo test procedure in mice, or in a clinical study as described above. In addition, the invention relates to a preparation or a composition, in particular to a pharmaceutical composition, respectively, comprising nateglinide or a pharmaceutically acceptable salt thereof. A further aspect of the present invention is a composition, in particular a pharmaceutical composition, for nateglinide in the form of a pharmaceutically acceptable composition, such as a tablet comprising pharmaceutically acceptable binders, excipients, and the like, as well as an acceptable coating. Preferably, the composition comprises the modification of type B or H crystal of nateglinide, more preferably in type H. The active ingredient, or a pharmaceutically acceptable salt thereof, may also be used in the form of a hydrate, or may include other solvents used for crystallization. The dosage scale of nateglinide depends on factors known to the person skilled in the art., including the species of the warm-blooded animal, body weight and age, the nature and severity of the condition to be treated, and the mode of administration to be used. Unless otherwise reported herein, nateglinide is preferably divided and administered 1 to 4 times per day. The nateglinide is preferably administered to the warm-blooded animal at a dosage in the range of about 5 to 1,200, more preferably 10 to 1,000, and most preferably 25 to 800 milligrams / day, especially when the warm-blooded animal be a human being of approximately 70 kilograms of body weight. A further aspect of the present invention is a pharmaceutical composition for nateglinide in the form of a tablet comprising in the core, lactose monohydrate, microcrystalline cellulose, polyvinylpyrrolidone, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate, and optionally a coating, such as yellow opadry. Additionally, the invention relates to a pharmaceutical composition comprising (a) nateglinide in free or pharmaceutically acceptable salt form, and (b) a pharmaceutically acceptable carrier, wherein the composition can be granulated in the presence of water without the need for a subsequent spraying step before tabletting, for the prevention, delay of progress, or treatment of hyperglycemia, hyperinsulinemia, hyperlipidemia, insulin resistance, impaired glucose metabolism, obesity, diabetic retinopathy, macular degeneration, cataracts, diabetic nephropathy, glomerosclerosis, diabetic neuropathy, erectile dysfunction, premenstrual syndrome, vascular restenosis, ulcerative colitis, coronary heart disease, hypertension, angina pectoris, myocardial infarction, embolism, skin and connective tissue disorders, Foot ulcers, metabolic acidosis, arthritis, osteoporosis, and in particular conditions s of impaired tolerance to glucose, and especially type 2 diabetes. Additional aspects of the present invention are a pharmaceutical composition comprising (a) nateglinide in free or pharmaceutically acceptable salt form, and (b) a pharmaceutically acceptable carrier, wherein the composition can be granulated in the presence of water without the need for a subsequent spray step prior to tabletting (i) for use in the prevention, delay of progress, or treatment of metabolic disorders, and (ii) the use of this composition for the preparation of a medicament for the prevention, delay of progress, or treatment of metabolic disorders. Furthermore, the invention relates to a method for improving the body appearance of a mammal, including the male, especially a man suffering from a metabolic disorder, in particular type 2 diabetes, which comprises orally administering to this mammal : (i) a combination, for example as a combined preparation or as a composition, as described herein, or (ii) a composition comprising (a) nateglinide in free or pharmaceutically acceptable salt form, and (b) a pharmaceutically acceptable carrier, wherein the composition can be granulated in the presence of water without the need for a subsequent spray step prior to the formation of ta-tablets, in an effective dosage to influence, for example increase or decrease, the metabolism of glucose, or to influence body weight by other mechanisms, and repeat this dosage until a cosmetically beneficial loss of the p that body. These combinations and compositions described herein, independently of one another, can also be used to prevent, for cosmetic reasons, a further increase in body weight in humans experiencing this increase. Moreover, the invention relates to the combinations and compositions described herein to improve the body appearance of a mammal, especially a human being, and to the use of these combinations and compositions in order to improve the physical appearance of a mammal, especially a human being. Overweight is one of the risk factors for developing a metabolic disorder, in particular type 2 diabetes, and at the same time, often the result of this metabolic disorder, especially type 2 diabetes. In addition, it is known that a number of antidiabetic drugs cause weight gain. Therefore, humans who suffer from metabolic disorders, especially type 2 diabetes, often face overweight. Accordingly, the cosmetically beneficial loss of body weight can be effected especially in humans suffering from a metabolic disorder, such as type 2 diabetes. The combinations, for example a combined preparation or a composition, and the compositions described in the present, independently of each other, they can also be used to replace or supplement an antidiabetic drug taken pr, a human being suffering from type 2 diabetes, in order to prevent, for cosmetic reasons, an additional increase in weight bodily. In particular, the present invention relates to a method for improving the body appearance of a mammal, which comprises orally administering to this mammal nateglinide in free or pharmaceutically acceptable salt form, and a glitazone in free or pharmaceutically acceptable salt form, in an effective dosage for influencing glucose metabolism, and repeating this dosage until a cosmetically beneficial loss of body weight has been presented, wherein the active ingredients are administered in a simultaneous or sequential manner in any order, separately , or in a fixed combination. Also in particular, the present invention relates to a method for improving the body appearance of a mammal, which comprises orally administering to this mammal a composition comprising (a) nateglinide in free or pharmaceutically acceptable salt form, and ( b) a pharmaceutically acceptable carrier, wherein the composition can be granulated in the presence of water without the need for a subsequent spray step prior to the formation of tablets. Moreover, the present invention relates to a method for improving the body appearance of a mammal, which comprises orally administering to this mammal a composition comprising (a) nateglinide in free or pharmaceutically acceptable salt form, and (b) a a pharmaceutically acceptable carrier, wherein, after administration, approximately 90 percent by weight of nateglinide is released within a period of 10 minutes. The following examples illustrate the invention described above; however, they are not intended to limit the scope of the invention in any way.

Example 1: Nateglinide Tablets 108,000 tablets are prepared, each containing 120 milligrams of nateglinide, as follows: Composition: nateglinide 12,960 kg. lactose, NF 30,564 kg. microcrystalline cellulose, NF 15,336 kg. povidone, USP 2. 592 kg. croscarmellose sodium, NF 3. 974 kg. colloidal silicon dioxide, NF 1. 382 kg. magnesium stearate, NF 1. 231 kg. coating: yellow opadry 1. 944 kg. purified water, USP * C. S. *: it is removed during the process.

Preparation process - variant (a): Microcrystalline cellulose, povidone, parts of croscarmellose sodium, nateglinide, and lactose, are mixed in a high shear mixer, and then granulated using purified water. Alternatively, microcrystalline cellulose, povidone, a portion of croscarmellose sodium, nateglinide, and lactose, are granulated in a Collette Gral granulator, with the addition of purified water. The wet granules are dried in a fluid bed dryer, and passed through a screen. The colloidal silicon dioxide and the rest of the croscarmellose-sodium are mixed, passed through a sieve, and mixed with the dried granules in a V-blender. The magnesium stearate is passed through a sieve, mixed with the mixture from the V-mixer, and then the whole mixture is compressed into tablets. The yellow opadry is suspended in purified water, and the tablets are coated with the coating suspension.

Example 2: Galenic Formulation of Nateglinide No. 1. intragranular: nateglinide 120 mg. lactose monohydrate 283 mg. microcrystalline cellulose 142 mg. povidone 24 mg. croscarmellose-sodium 24 mg. extragranular: magnesium stearate / mg. white opadry 20 ma.

Example 3: Galenic Formulation of Nateglinide No. 2 intragranular: nateglinide 120 mg. lactose monohydrate 283 mg. microcrystalline cellulose 142 mg. povidone 24 mg. croscarmellose-sodium 24 mg. extragranular: croscarmellose-sodium 12.8 mg. magnesium stearate 11.4 mg. yellow opadry 18.0 mg. colloidal silicon dioxide 12.8 mg.

The following Examples illustrate the manufacture of monotherapy compositions, wherein nateglinide is the sole active agent, and a subsequent spray step is not performed after granulation; however, they are not intended to limit the scope of the invention in any way.

Example 4: Nateglinxda Tablets 108,000 tablets are prepared, each containing 120 milligrams of nateglinide, as follows: Composition: nateglinide 12,960 kg. lactose, NF 30,564 kg. microcrystalline cellulose, NF 15,336 kg. povidone, USP 2.592 kg. croscarmellose sodium, NF 3,974 kg. colloidal silicon dioxide, NF 1,382 kg. magnesium stearate, NF 1,231 kg. coating: yellow opadry 1.944 kg. purified water, USP * C.S. *: it is removed during the process. Preparation process: The microcrystalline cellulose, the povidone, a portion of the croscarmellose-sodium, the nateglinide, and the lactose, are granulated in a Collette Gral granulator with the addition of purified water. The wet granules are dried in a fluid bed dryer, and passed through a screen. The colloidal silicon dioxide, and the rest of the croscarmellose-sodium, are mixed, passed through a sieve, and mixed with the dry granules in a V-blender. The magnesium stearate is passed through a screen, mixed with the mixture from the V-mixer, and then the whole mixture is compressed into tablets. The yellow opadry is suspended in purified water, and the tablets are coated with the coating suspension. Variants of this process include adding the silica coloi-dal and the remaining croscarmellose-sodium to the second charge of the granulator after drying, and then screened together; and as many as three granulator / dryer loads per batch are combined. • Example 5: Pharmaceutical composition of Nateglinide (60 mg) nateglinide 60 mg. Lactose monohydrate 141.5 mg. microcrystalline cellulose 71 mg. povidone 12 mg. croscarmellose-sodium 18.4 mg. magnesium stearate "5.7 mg colloidal silicon dioxide 6.4 mg pink opadry 9 mg Example 6: Pharmaceutical composition of Nateglinide (120 mg) nateglinide 120 mg lactose monohydrate 283 mg microcrystalline cellulose 142 mg povidone 24 mg croscarmellose -sodium 36.8 mg magnesium stearate 11.4 mg yellow opadry 18.0 mg colloidal silicon dioxide 12.8 mg.

Example 7 Pharmaceutical composition of Nateglinide (180 mg) nateglinide 180 mg. lactose monohydrate 214 mg. microcrystalline cellulose 107 mg. povidone 23 mg. croscarmellose-sodium 58.5 mg. magnesium stearate 15.2 mg. red opadry 18.0 mg. colloidal silicon dioxide 12.3 mg. Example 8: Composition, in particular pharmaceutical composition, of Nateglinide 5,112 kilograms of microcrystalline cellulose, 0.864 kilograms of polyvinylpyrrolidone, 0.864 kilograms of croscarmellose sodium, 4,320 kilograms of nateglinide, and 10,118 kilograms of lactose, are granulated in a Collette Gral granulator , while 5/7 liters of purified water are added. The resulting granules are dried in a Glatt CGP30 fluid bed dryer. The particle size distribution of a sample was determined by sieve, as shown in Table 1. TABLE 1 Accordingly, as can be seen in Table 1, the composition can be granulated in the presence of water, to provide, without a spray step, a granular composition containing less than about 1 weight percent granules having a size of 710 microns (# 25) or more, less than about 5 weight percent of granules having a size of 500 microns (# 35) or more, less than about 12 weight percent of granules having a size of 355 microns or more, less than about 20 weight percent of granules having a size of 250 microns or more, less than about 25 weight percent of granules having a size of 180 microns or more, less than about 40 weight percent of granules having a size of 125 microns or more, less than about 70 weight percent of granules having a size of 90 microns or more and / or less than about 99. hundred in p that of granules that have a size of 45 microns or more. More preferably, the composition can be granulated in the presence of water, to provide, without a spray step, a granular composition containing less than about 1 weight percent granules having a size of 710. microns (# 25) or more, less than about 5 weight percent granules having a size of 500 microns (# 35) or more, less than about 2 weight percent granules having a size of 355 microns or more, less than about 20 weight percent granules having a size of 250 microns or more, less than about 25 weight percent granules having a size of 180 microns or more, less than about 25 weight percent of granules having a size of 125 microns or more, less than about 40 to 50 weight percent of granules having a size of 90 to 95 microns or more, and / or less than about 90 percent by weight of gra nulls that have a size of 45 microns or more. Other embodiments of the invention will be apparent to those skilled in the art, from a consideration of the specification and practice of the invention disclosed herein. It is intended that the specification and examples be considered as examples only, with a true scope and spirit of the invention being indicated by the following claims.

Claims (41)

1. CLAIMS A combination comprising nateglinide (I ' and at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazones), sulfonylurea derivatives, and metformin, wherein the active ingredients are present in each case in free form or the form of a pharmaceutically salt acceptable, and optionally at least one pharmaceutically acceptable carrier; for simultaneous, separate, or sequential use.
2. 2. The combination according to claim 1, which is a combined preparation or a pharmaceutical composition.
3. 3. The combination according to claim 2, which is a combined preparation comprising nateglinide and a glitazone, for simultaneous, separate, or sequential use, in the prevention or treatment of diseases.
4. 4. The combination according to claim 1 or 2, characterized in that the other antidiabetic compound is metformin or metformin hydrochloride.
5. 5. The combination according to claim 1 or 3, characterized in that the other antidiabetic compound is selected from the group of glitazones.
6. 6. The combination according to claim 5, wherein the glitazone is selected from rosiglitazone and troglitazone.
7. The combination according to claim 5, wherein the glitazone is pioglitazone.
8. 8. The combination according to any of claims 1 to 7, characterized in that the combination further comprises insulin, or in that the combination comprises at least two antidiabetic compounds selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, or a pharmaceutically acceptable salt thereof.
9. 9. The combination according to any of claims 1 to 8, characterized in that the nateglinide is present in the modification of type B crystal, or type H.
10. 10. A method for improving the body appearance of a mammal, which comprises administering orally to this mammal a combination according to any of claims 1 to 9, in an effective dosage for influencing glucose metabolism, and repeating this dosage until a cosmetically beneficial loss of body weight has occurred.
11. 11. A method for __ the treatment of a warm-blooded animal having metabolic disorders, which comprises administering to the animal a combination of nateglinide and at least one other antidiabetic compound selected from the group consisting of glitazone, sulfonylurea derivatives, and metformin, in an amount that is overall therapeutically effective against metabolic disorders, wherein the compounds may also be present in the form of their pharmaceutically acceptable salts.
12. 12. A pharmaceutical composition comprising an amount, which is collectively therapeutically effective against metabolic disorders, of a combination according to any of claims 1 to 9, and at least one pharmaceutically acceptable carrier.
13. 13. A pharmaceutical composition comprising nateglinide and metformin in a pharmaceutical carrier.
14. The combination according to any of claims 1 to 9, for use in the prevention, delay of progress, or treatment of diseases.
15. 15. The use of a combination according to any of claims 1 to 9, for the preparation of a medicament for the prevention, delay of progress, or treatment of metabolic disorders.
16. 16. The use of a combination according to any of claims 1 to 9, for the cosmetic treatment of a mammal, for the purpose of effecting a cosmetically beneficial loss of body weight.
17. 17. A composition comprising: (a) nateglinide in free or pharmaceutically acceptable salt form, and (b) a pharmaceutically acceptable carrier, wherein the composition can be granulated in the presence of water without the need for a step of Subsequent spraying before tablet formation.
18. 18. The composition of claim 17, which comprises nateglinide as the only pharmacologically active agent.
19. 19. The composition of claim 17 or 18, wherein the composition is in the form of a tablet.
20. The composition of claim 17 or 18, wherein the composition is a granular composition.
21. The composition of claim 17 or 18, wherein the composition is contained in a gelatin capsule.
22. 22. The composition of any one of claims 17 to 21, wherein the composition may be granulated in the presence of about 25 to about 80 weight percent water.
23. 23. The composition of any of claims 17 to 21, wherein the composition can be granulated in the presence of water, without the need for subsequent spraying to form a granular composition having less than about 20 percent by weight. weight of granules that have a size of 250 microns or more.
24. 24. A composition comprising: (a) nateglinide in free or pharmaceutically acceptable salt form, and (b) a pharmaceutically acceptable carrier, wherein about 60 to 95 weight percent of nateglinide is released within a period of thirty minutes
25. 25. The composition of claim 24, which comprises nateglinide as the sole pharmacologically active agent.
26. 26. The composition of claim 24 or 25, which comprises a disintegrant.
27. The composition of claim 26, wherein the disintegrant has a molecular weight greater than 1,000,000.
28. The composition of claim 26 or 27, wherein the disintegrant has a particle size distribution of less than 400 microns or less than 74 microns.
29. 29. The composition of any of claims 26 to 28, wherein the disintegrant is a cross-linked polyvinylpyrrolidone.
30. 30. The composition of any of claims 17 to 29, which comprises colloidal silicon dioxide.
31. 31. A composition in the form of a tablet, which comprises lactose monohydrate, microcrystalline cellulose, povidone, croscarmellose sodium, colloidal silicon dioxide, and magnesium stearate.
32. The composition of any of claims 17 to 31, characterized in that nateglinide is present in the modification of type B or type H crystal.
33. 33. A process for making a pharmaceutical composition, comprising: (a) nateglinide in free form or pharmaceutically acceptable salt, and (b) a pharmaceutically acceptable carrier, wherein the process comprises granulating component (a) and one or more pharmaceutically acceptable carriers in the presence of water, without a subsequent spray step.
34. 34. The process of claim 33, which further comprises compressing the composition into a tablet, or placing the composition in a gelatin capsule.
35. 35. The process of claim 33, wherein the composition is granulated in the presence of about 25 to about 80 weight percent water.
36. 36. The process of any of claims 33 to 35, wherein, after granulation, the composition contains less than about 20 weight percent granules having a size of 250 microns or more.
37. 37. A method for the treatment, delay of progress, or prophylaxis of metabolic disorders, more especially diabetes, or a disease or condition associated with diabetes, which comprises administering to a warm-blooded animal in need, a pharmaceutical composition comprising an amount Therapeutically effective of nateglinide in free or pharmaceutically acceptable salt form, wherein the pharmaceutical composition is a composition according to any of claims 17 to 32.
38. 38. A method for improving the body appearance of a mammal, which comprises orally administering to this mammal, a composition according to any of claims 17 to 32.
39. 39. The composition according to any of claims 17 to 32, for use in the prevention, delay of progress, or treatment of metabolic disorders.
40. 40. The use of a composition according to any of claims 17 to 32, for the preparation of a medicament for the prevention, delay of progress, or treatment of metabolic disorders.
41. 41. A commercial package comprising, as an active ingredient, nateglinide and at least one other antidiabetic compound selected from the group consisting of glitazones, sulfonylurea derivatives, and metformin, together with instructions for simultaneous, separate, or sequential use. the same, in the prevention, delay of progress, or treatment of metabolic disorders, or in a method to improve the corporal appearance of a mammal. SUMMARY The invention relates to a combination, such as a combined preparation or a pharmaceutical composition, respectively, comprising nateglinide (I): or repaglinide, and at least one other antidiabetic compound selected from the group consisting of thiazolidinedione derivatives (glitazones), sulfonylurea derivatives, and metformin, for simultaneous, separate, or sequential use, in prevention, progress delay, or treatment of diseases, especially metabolic disorders, and in particular type 2 diabetes, and diseases and conditions associated with diabetes; to a composition, respectively, comprising nateglinide and a pharmaceutically acceptable carrier, and to a process for making this composition; to the use of this combination or composition for the preparation of a medicament for the prevention, delay of progress, or treatment of metabolic disorders; to a method for the prevention, delay of progress, or treatment of diseases in warm-blooded animals; al * «-» use of this combination or composition for the cosmetic treatment of a mammal for the purpose of effecting a cosmetically beneficial loss of body weight; and to a method for improving the body appearance of a warm-blooded animal.