KR20050100784A - Pharmaceutical compositions for the treatment or prevention of diabetes mellitus - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for the prevention or treatment of diabetes mellitus and its complications, including oltipraz, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient, the composition of the present invention Not only can effectively cure, but also to suppress the proliferation and differentiation of fat cells at the same time lowering blood sugar can treat diabetes and its complications without the side effects of obesity.

Description

Pharmaceutical compositions for the treatment or prevention of diabetes mellitus}

The present invention relates to oltipraz: 5- (2-pyrazinyl) -4-methyl-1,2-dithiol-3-thione], pharmaceutically acceptable salts thereof, or solvates or hydrates thereof. It relates to a pharmaceutical composition for the prevention or treatment of diabetes mellitus and thereby complications as an active ingredient.

Several substituents of dithiolthion, a sulfur-containing compound naturally present in vegetables belonging to the cruciferous family, are known to have a protective effect on the liver. Of these, oltipraz is a drug used for the treatment of schistosomiasis in the early 1980s. Has the following structural formula:

The drug induces and increases the expression of enzymes involved in the translation of electrophilic substances in addition to the enzymes involved in increasing cellular thiol content and maintenance of glutathione (GSH) pools in various tissues in vivo. Enzymes whose activity is increased by oltipraz include NAD (P) H: quinone reductase, microsomal epoxide hydrolase, glutathione S-transferase (GST), and UDP-GT. Among these, GST is composed of carbon tetrachloride or acetaminophen. It is an enzyme that protects against hepatotoxicity by the same toxic substances.

Oltipraz has been reported to increase the level of GSH in most tissues, thereby removing free radicals produced by radiation or xenobiotics, or contribute to maintaining homeostasis of cells as a bioadaptive response to radiation damage. There is a bar. Oltipraz, which has this effect, has been shown to have a weak protective effect in a large clinical trial on liver cancer suppression conducted in China, and it is well known to moderately suppress liver toxicity caused by toxic substances.

However, there is a problem that side effects appear when high doses of oltipraz to the human body. In the early 1980s, 1284 patients were administered a total dose of 1.25-7.5 g for 1 to 5 days in a wide range of clinical trials on the effectiveness of Oltipraz's schistosomiasis treatment. At this time, more than 90% of patients showed high antiparasitic effect, but more than 10% of patients showed high side effects. The side effects were nausea, abdominal pain, vomiting, diarrhea and other side effects on the digestive system, such as headaches, dizziness. Side effects such as paraesthesia and purple or black spots, such as fingertip pain, have worsened after exposure to sunlight.

In addition, animal experiments in which rats and dogs were administered at a high dose of 60 mg / kg / day for 1 year or longer showed dose-dependent toxicity, such as an increase in liver weight. Although the cause of this side effect is not clearly identified, inhibition of CYP3A4 in the cytochrome P450 enzyme system is considered to be one of the causes.

Such side effects may be weakened or lost after a few days of administering Oltipraz, but may reduce the compliance of the drug. Therefore, in order to maximize the utilization of Oltipraz, it is necessary to set an appropriate drug dose that can reversible but reduce the occurrence of potential side effects.

Diabetes mellitus is a disease of high insulin and metabolic abnormalities persist due to lack of insulin action, chronically is a disease with high risk of vascular complications. Diabetes can be roughly divided into type 1 diabetes and type 2 diabetes, and type 2 diabetes is a disease in which both insulin resistance and insulin secretion disorder are related. More than 85% of diabetics are adult type 2 diabetes, Due to aging and changing lifestyles, the number of type 2 diabetes patients is steadily increasing. As described above, type 2 diabetes, which corresponds to the majority of diabetic patients, develops hyperinsulinemia due to glucose intolerance and insulin resistance in the early stage of onset, and as the disease progresses, hyperglycemia and hypoinsulinemia It is a disease with the same characteristics. The insulin resistance refers to a state in which the reactivity of the cell or tissue to insulin at a given insulin concentration is reduced than normal.

Therefore, it is very important to select an appropriate drug that is effective according to the stage of diabetes, and also to develop a drug that can simultaneously act on several different targets rather than a drug that acts on a single target because the etiology of diabetes is so complicated. Is required. Existing therapies have abnormalities of fat metabolism when correcting the metabolic abnormalities, and have a fundamental limitation that drug resistance does not occur continuously due to drug resistance when the therapeutic drug is repeatedly used. Development is required.

Recently, the utilization rate of glitazone-based drug, which is a PPARγ agonist, is increasing, and the treatment rate of diabetes is increasing by using this type of drug. Proxisome proliferator activated receptors (PPARs) bind to Retinoid X Receptors (RXRs) to form transcriptional heterodimers, and to PPX (Peroxisome proliferator response elements) in the promoter of target genes involved in carbohydrates and lipid metabolism. It plays a role in enhancing the gene expression necessary for the metabolism of the party. There are three types of PPARs: PPARα, PPARβ / δ, and PPARγ. Among them, PPARα is mainly distributed in the liver, and is involved in fatty acid degradation, and PPARγ is mainly expressed in adipocytes and promotes adipogenesis and glucose uptake. For this reason, PPARγ agonist is currently used as a treatment for type 2 diabetes, and therefore, thiazolidinedione-based drugs having PPARγ agonist activity are forming the mainstream on the market.

However, clinical studies have shown that glitazone-based drugs, which are PPARγ agonists, do not have high antidiabetic effects alone. In addition, the drug lowers blood sugar and decreases insulin resistance, but also has side effects of accumulating fat by participating in gene expression associated with adipocyte differentiation.

 Therefore, there is a need for a drug that not only normalizes the metabolic abnormalities but also corrects the metabolism of lipid metabolism and glucose metabolism at the same time and further normalizes protein metabolism, and also develops an ideal therapeutic agent that does not produce drug resistance even when the drug is repeatedly used. Required. Recently, in order to solve the problem of adipocyte proliferation and differentiation which is a side effect of many antidiabetic drugs, researches on the development of PPARα / γ dual agonists, PPARγ antagonists or partial agonists have been actively conducted.

Beta-cells in the pancreas and cell-specific glucokinases in the liver act as glucose sensors to promote insulin secretion in the pancreas when activated. Thus, glucokinase may be a new pharmacological point that plays a major role in insulin secretion in pancreatic cells. In the DNA binding site of the gene promoter expressing glucokinase, there are specific DNA binding sites to which transcription factors such as HNF and C / EBP can bind. Therefore, the regulation of glucokinase gene expression by the transcription factor activity may be a new drug action point. The activation of glucokinase can be explained by the enhancement of enzyme activity and the enhancement of enzyme expression, but there are no drugs developed by setting the glucokinase drug action point in the latter.

The inventors found a phenomenon in which oltipraz activates several isoenzymes of C / EBP through previous studies, and based on these findings, C / EBP activation has invented the phenomenon of treating cirrhosis and regenerating liver tissue. (Korean Patent Application No. 2000-18134 and Korean Patent No. 0377789). During extended research, alltifras simultaneously activated key transcription factors HNF1, HNF4, cAMP responsive element binding protein (CREB) and PPAR, which are related to diabetic disease, in addition to C / EBP. Surprisingly, we observed a phenomenon that promotes the expression of key genes involved in improving diabetic disease affected by these transcription factors. The present inventors have come up with the invention of the ideal diabetes therapeutics from the promotion of the expression of the major genes related to glucose metabolism is associated with the promotion of glucose absorption in the major organs of the human body, and the hypoglycemic effect in the diabetic state, has been carried out with intensive studies As a result, the inventors have found that Oltipraz exerts an excellent effect on the prevention or treatment of diabetes mellitus and its complications, and have completed the present invention.

Accordingly, it is an object of the present invention to provide a pharmaceutical composition for the prevention or treatment of diabetes mellitus and its complications, including oltipraz, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient.

Another object of the present invention is to provide a pharmaceutical composition for treating or preventing diabetes mellitus and thereby complications, characterized in that it further comprises another diabetes therapeutic agent, including insulin, in addition to oltipraz.

In order to achieve the above object, the present invention provides a pharmaceutical composition for the prevention or treatment of diabetes mellitus and its complications, including ortiphrase, pharmaceutically acceptable salts thereof, or solvates or hydrates thereof as an active ingredient. .

In the present invention, the complications include, but are not limited to, diseases caused by elevated blood levels of triglycerides, cholesterol, high density lipids or low density lipids.

In the composition of the present invention, as an active ingredient, a pharmaceutically acceptable salt of oltipraz may be used. Examples of such salts include acid addition salts and quaternary ammonium salts. Pharmaceutically acceptable acid addition salts include, for example, inorganic acid salts such as hydrochloride salts, hydrobromide salts, iodide salts, sulfates, and phosphates, oxalate salts, maleic acid salts, fumaric acid salts, lactic acid salts, malic acid salts, and succinate salts. And organic acid salts such as tartaric acid salts, ancinhic acid salts and methanesulfonic acid salts. As the quaternary ammonium salts, for example, lower alkylhalogenides such as methyl iodide, methyl bromide, ethyl iodide, ethyl bromide and the like; Lower alkylsulfonates such as methylmethanesulfonate and ethylmethanesulfonate; And quaternary ammonium salts such as lower alkylarylsulfonate such as methyl-p-toluenesulfonate.

Since oltipraz or a pharmaceutically acceptable salt thereof may exist as a solvate or hydrate, solvates or hydrates thereof may be used as an active ingredient of the therapeutic agent of the present invention.

In another aspect, the present invention provides a pharmaceutical composition for the prevention or treatment of diabetes mellitus and thereby complications, including another glycemic control agent as an active ingredient in addition to the oltipraz.

Blood glucose regulators that can be additionally used with oltipraz are biguanide-based drugs such as metformin and phenformin, rosiglitazone and thiogolidinedione such as pioglitazone. The drug includes sulfonylurea drugs such as tolbutamide, glyburide, and glipizide. The oltipraz and blood glucose control agent is preferably contained in a weight ratio of 1-25: 1-25, more preferably 1-10: 1-10.

The present invention also provides a pharmaceutical composition wherein the pharmaceutical composition is formulated as an oral preparation and an injection. The preparation for oral administration is preferably selected from capsules, tablets, suspensions, syrups or powders.

Hereinafter, the present invention will be described in more detail.

In the present invention, the invention was based on the discovery that Oltipraz is effective for treating glucose metabolism disease as an insulin sensitivity enhancer. Indeed, according to the experimental example, oltipraz significantly reduced blood glucose in ob / ob mice at 30 mg / kg dose and increased glucose uptake of adipocytes. In addition, Oltipraz activated transcription factors (HNF, C / EBP), which may be a new pharmacological action point for the treatment of glucose metabolic diseases, and activation of this specific transcription factor is the basic principle of the therapeutic action of diabetes and metabolic disorders. .

According to the present invention, oltipraz has a therapeutic effect on the present time through insulin and other pharmacological pathways. Among several transcription factors activated by oltipraz, PPARγ increases the expression of C / EBPβ and increases the expression of GLUT4, a glucose uptake pathway in muscle and adipocytes, C / EBPβ independent. Lipoate, an insulin sensitivity enhancer, synergistically increases C / EBPβ activation during the process of improving insulin responsiveness in the target organ phase of drug action. Therefore, activation of C / EBPβ enhances insulin sensitivity. Thus, C / EBβ activation of oltipraz is interpreted to contribute to the improvement of glucose metabolism by enhancing insulin sensitivity.

HNF binding sites and PPAR response elements (PPREs) are DNA binding sites that regulate the expression of glucokinase genes. HNF1, HNF4 and PPAR activation, which are transcription factors that regulate HNF binding sites and PPRE, may increase glucokinase expression. Can be. Thus, Oltipraz is expected to activate HNF and PPAR to increase the expression of glucokinase, thereby enhancing glucose sensitivity and promoting insulin secretion.

Pancreas, liver, muscle, and adipose tissues are organs affected by glucose metabolism in the pathologic process of chronic disease. Insulin resistance decreases the concentration of insulin receptors and phosphorylation activity of the receptors on insulin stimulation, decreases the concentration or phosphorylation of insulin receptor substrate protein family members IRS-1,2, cell transport of glucose transporter, PI3-kinase activity And other decreases in intracellular glucose metabolism related enzyme activity. Therefore, Oltipraz, which has the effect of enhancing the activity of major transcription factors in the various organs listed above, can overcome insulin resistance and improve and treat the pathology of the present generation.

Oltipraz, a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof, which is an active ingredient of the composition of the present invention may be administered to the patient itself, but generally one or two or more of these active ingredients Pharmaceutical compositions comprising a can be prepared or administered, or mixed with other useful glycemic control agents may be formulated in a complex form to administer. In practice, it is preferable to formulate and administer in a unit dosage form suitable for oral administration according to a conventional method in the pharmaceutical field. Oral dosage forms suitable for this purpose include hard and soft capsules, tablets, powders, suspensions, syrups and the like. Such oral preparations include, in addition to the two pharmacologically active ingredients, one or more pharmaceutically inert conventional carriers such as excipients such as starch, lactose, carboxymethylcellulose, kaolin, water, gelatin, alcohols, glucose, arabian Additional additive components may be included such as rubber, binders such as tragacanta rubber, disintegrants such as starch, dextrin, sodium alginate, and lubricants such as talc, stearic acid, magnesium stearate, liquid paraffin, and the like. In the present invention, a dissolution aid for dissolution may also be added.

The daily dose of the drug according to the present invention depends on various factors such as the degree of diabetes progression, onset time, age, health condition, complications, etc. of the subject to be administered, but generally based on the adult weight ratio mentioned above 5 to 200 mg, preferably 25 to 50 mg, may be administered in divided doses once or twice a day. However, patients with severe diabetes or complications may be administered by increasing the drug of the present invention to a large amount out of the above range in order to improve treatment efficiency. Most preferably, 1-2 unit doses containing 25-50 mg of oltipraz are orally administered once or twice daily.

Since the composition according to the present invention has an excellent hypoglycemic effect and protection effect of pancreatic tissue of oltipraz, the pancreatic inflammation inhibition effect caused by various causes is optimally in harmony with the anti-diabetic effect, improving the symptoms of diabetes, progression Not only does it provide a therapeutic effect on organ damage caused by inhibition and complications, but it has little toxicity and side effects caused by drugs, so it is a drug that can be used safely for long-term use as well as for therapeutic purposes.

The present invention is described in more detail by the following experimental examples and examples of hard and soft capsules, tablets, powders, etc., but the present invention is not limited to these examples.

Experimental Example

Experimental Example 1 <hypoglycemic effect of oltipraz in ob / ob mice>

The hypoglycemic effect of oltipraz was evaluated using ob / ob mice, a typical animal model of obesity and diabetes. Ob / ob mice were fed with normal feed, oral administration of 30 mg / kg body weight (suspended in 40% PEG400) once every two days, orally, three times in total, followed by first 5 days of body weight. The results are shown in Table 1 below. As shown in Table 1, no significant weight change was observed.

In addition, the blood glucose level of ob / ob mice was statistically significantly decreased after the administration of Oltipraz 30 mg / kg compared to the pre-administration of drugs, and the effect of reducing blood glucose was superior to that of pioglitazone and was similar to that of rosiglitazone. 2).

Serum triglycerides and total cholesterol content are used as representative indicators of liver function. Observation of liver function indicators maintained normal values in animals fed ortiprose, but increased total cholesterol content in animals administered rosiglitazone (see Table 2).

Table 1 shows the measurement of body weight and liver weight change by oltipraz and non-drug in ob / ob animal model, and Table 2 shows glucose, triglycerides and total cholesterol in blood by oltipraz and non-drug in ob / ob animal model. Content measurement, shows the efficacy of diabetes treatment by Oltipraz.

Test group Initial weight (g) Final weight (g) Weight change (g) Liver weight (g) Liver weight / weight Control 42.9 ± 1.5 43.5 ± 1.3 +0.6 3.01 ± 0.3 0.069 ± 0.006 Pioglitazone (10 mg / kg) 42.3 ± 3.1 43.8 ± 2.6 +1.5 3.41 ± 0.4 0.078 ± 0.007 Rosiglitazone (10 mg / kg) 42.5 ± 4.4 42.4 ± 4.0 0 3.41 ± 0.3 0.080 ± 0.003 Oltipraz (30 mg / kg) 41.5 ± 0.49 43.0 ± 2.9 +0.4 2.46 ± 0.4 0.057 ± 0.009 Results show mean ± standard deviation (number of objects = 5) While feeding ob / ob mice as normal feed, 30 mg / kg of Oltipraz (suspended in 40% polyethylene glycol 400) was orally administered once every two days, for a total of three times, and pioglitazone 롸 rosiglitazone was 10 mg as a control drug. / kg was administered orally once daily for 5 days. Body weights were measured on the start of the experiment and on the fifth day after the start of the experiment.

Test group Blood sugar (mg / dl) Triglycerides (mg / dl) Total cholesterol (mg / dl) Control 231.1 ± 29.5 (100%) 64.8 ± 4.3 (100%) 159.1 ± 8.0 (100%) Pioglitazone (10 mg / kg) 195.9 ± 19.1 (84.4%) 56.1 ± 2.9 ^* (86.5%) 171.1 ± 8.3 ^* (107%) Rosiglitazone (10 mg / kg) 132.9 ± 19.1 ^** (57.1%) 50.1 ± 3.8 ^** (77.3%) 184.8 ± 9.4 ^** (115%) Oltipraz (30 mg / kg) 147.2 ± 37.0 ^* (63.6%) 66.5 ± 13.5 (102%) 149.5 ± 15.4 (93.9%) ^* p <0.05, ^** p <0.01, ^*** p <0.001 vs. The numerical value of the control data represents the mean ± standard deviation (number of objects = 5) () represents% of the control. While ob / ob mice were bred with normal feed, 30 mg / kg of Oltipraz (suspended in 40% PEG400) was orally administered once every two days, for a total of three times. As a control drug, pioglitazone and rosiglitazone were orally administered 10 mg / kg once daily for 5 days. After the eye was collected at 1 hour after the last 5 days of drug administration, blood glucose was measured using whole blood using a blood glucose meter (Accuit, Roche). Was measured. Some of the blood was separated from the serum and the blood glucose analyzer was used to measure triglycerides and total cholesterol.

As can be seen in Table 1 and Table 2, there was almost no change in body weight and liver weight compared to the comparative drug when administering Oltipraz, and also significantly reduced blood sugar levels to show excellent diabetes treatment efficacy, serum triglycerides and Total cholesterol content also remained normal.

Experimental Example 2 <Influence of Oltipraz on Blood Insulin Content>

Ob / ob mice were fed normal diet with oral administration 30 mg / kg (suspended in 40% PEG400) once every 2 days, 3 times orally, and then observed changes in insulin content in animal serum. The results are shown in Table 3 below.

As shown in Table 3, hypoinsulinemia did not occur, which is a symptom of the disadvantage of pioglitazone or rosiglitazone, the currently used glucose metabolic disease treatment agent.

Control Pioglitazone (10 mg / kg) Rosiglitazone (10 mg / kg) Oltipraz (30 mg / kg) Insulin (μU / ml) 3.2 ± 0.3 1.6 ± 0.2 ^** 0.8 ± 0.2 ^*** 2.8 ± 0.4 ^** p <0.01, ^*** p <0.001 vs. The numerical values of the control data represent the mean and standard deviation (number of objects = 5). While ob / ob mice were bred to normal feed, 30 mg / kg of Oltipraz (suspended in 40% PEG400) was orally administered once every two days, for a total of three times. As a control drug, pioglitazone and rosiglitazone were orally administered 10 mg / kg once daily for 5 days. Insulin content in serum separated by ocular blood collection at 1 hour after drug administration was measured using the ELISA kit for insulin measurement.

Experimental Example 3 <Increase of Intracellular Sugar Transport Efficacy by Oltipraz

Muscle and adipose tissue, responsible for about 90% of the body's blood glucose homeostasis, absorb blood sugar into cells through a glucose transporter called GLUT4. Therefore, smooth glucose transport from the cytoplasm to the cell membrane by the expression and activity of GLUT4 and insulin stimulation is an essential condition for glycemic control. In this experiment, we evaluated the change of intracellular glucose uptake by oltifras using fat cells obtained by culturing 3T3-L1 preadipocytes, which are pro-adipocyte lines, in the cell culture medium in the presence of various hormones for about 10 days.

3T3-L1 adipocytes differentiated from adipocytes were incubated in Krebs-Ringer Hepes Buffer at 37 ° C and treated with 30 μM of Oltipraz. To evaluate glucose absorption capacity, 0.5 μCi of 2- [ ³ H] deoxyglucose (2-DOG) was added after 1 hour of Oltipraz treatment, and the reaction was stopped after 15 minutes to 2 hours. Radioactivity of the absorbed 2-DOG was measured by a liquid scintillation counter, and the results are shown in FIG. 2.

As can be seen in Figure 2, oltipraz in adipocytes increased the sugar transport effect (2- [ ³ H] deoxyglucose uptake) from the initial time significantly increased the influx of sugar into the cells for 1-2 hours.

Experimental Example 4 <Activation of Glucokinase Gene Expression Control Transcription Factors of Oltipraz>

Activation of glucokinase is a drug action point for treating glucose metabolic disorders. Transcriptional regulatory sites that regulate the expression of the glucokinase gene include HNF binding sites and PPRE. Therefore, the activation of HNF1, HNF4, and PPAR, transcription factors that regulate HNF binding site and PPRE activation, may have a therapeutic effect on diabetes through increased expression of glucokinase. In this experimental example, in order to observe the activation of HNF by oltipraz as a phenomenon in which HNF1 in the cytoplasm moves into the nucleus, the cytoplasm and nuclear fractions were separated, and the amount of HNF in these fractions was analyzed by immunochemical method and gel shift analysis. Quantification [Fig. 3]. In addition, the role of PI3-kinase activity, a signal transduction enzyme that affects the growth, movement, survival, etc. of cells as a signal of these transcription factor shifts was observed [FIG. 4]. PI3-kinase is a key signaling enzyme in the expression of several target genes, including glucokinase, against insulin stimulation in the liver and pancreatic beta cells. Binding stimulation of membrane receptor ligands, such as insulin, results in a series of reactions such as tyrosine kinase activation, PI3-kinase activation, and PIP3 (phosphatidylinositol-3,4-phosphate) as an intracellular second messenger. This leads to cell membrane movement of the sugar transporter.

After treatment with 30 μM of oltipraz in H4IIE cells, only nuclear fractions of cells were separated from each hour from 1 hour to 24 hours, and the amount of HNF was observed by immunochemical method. In addition, using HNF response element DNA probe labeled [ ³² P] -ATP using the same cell nuclear fraction, HNF-DNA binding ability and components of HNF-DNA conjugate were analyzed by gel shift analysis and supershift analysis using HNF antibody. It observed and the result is shown in FIG.

As shown in Figure 3, when quantified by the immunochemical method, it was observed that the amount of HNF in the nuclear fraction increased from 3 hours to 12 hours. In addition, the binding capacity of HNF-DNA increased in HNF-DNA binding capacity 12 hours after treatment.

In addition, in order to identify cellular signaling systems that regulate HNF1, HNF4α nuclear translocation and DNA binding increase by Oltipraz treatment, LY294002 (Ly) 10 μM, wortmannin (Wor) 100 nM, Alternatively, 30 μM of rapamycin (Rap) was treated and 30 μM of Oltipraz. At 6 hours, the time when HNF intracellular migration was observed, the nuclear fraction was separated and the amount of HNF in the nucleus was observed by immunochemical method, and the results are shown in FIG. 4. As shown in FIG. 4, activation of HNF1 and HNF4α by oltipraz was partially inhibited.

EXAMPLE

Example 1

Oltipraz 25mg

Lactose 50mg

Starch 10mg

Magnesium stearate proper amount

The tablets were prepared by mixing the above components and tableting according to a conventional method for producing tablets.

Example 2

Oltipraz 100mg

Lactose 50mg

Starch 10mg

Magnesium stearate proper amount

The tablets were prepared by mixing the above components and tableting according to a conventional method for producing tablets.

Example 3

Oltipraz 250mg

Lactose 50mg

Starch 10mg

Magnesium stearate proper amount

The above components were mixed and compressed into tablets according to a conventional method for preparing starch.

Example 4

Oltipraz 25mg

Lactose 30mg

Starch 28mg

Talc 2mg

Magnesium stearate proper amount

The above ingredients were mixed and filled into gelatin light capsules according to the method for preparing capsules in the usual manner to prepare capsules.

Example 5

Oltipraz 100mg

Lactose 30mg

Starch 28mg

Talc 2mg

Magnesium stearate proper amount

The above ingredients were mixed and filled into gelatin light capsules according to a conventional method for preparing capsules to prepare capsules.

Example 6

Oltipraz 250mg

10 g of isomerized sugar

30 mg of sugar

Sodium CMC 100mg

Lemon flavor

Add 100 ml of purified water to make 100 ml

Suspending agent was prepared according to the conventional method for preparing a suspending agent, and filled into a 100 ml brown bottle and sterilized to prepare a suspending agent.

Example 7

Oltipraz 500mg

20 g of isomerized sugar

20 g of sugar

Sodium Alginate 100mg

Orange flavor

Add 100 ml of purified water to make 100 ml

Suspending agent was prepared according to the conventional method for preparing a suspending agent, and filled into a 100 ml brown bottle and sterilized to prepare a suspending agent.

Example 8

Oltipraz 250mg

Lactose 30mg

Starch 20mg

Magnesium stearate proper amount

The above ingredients were mixed closely and filled and sealed in a polyethylin coated cloth to prepare a powder.

Example 9

Content in 1 tablet of soft capsule

Oltipraz 100mg

Polyethylene Glycol 400 400mg

Concentrated glycerin 55mg

Purified water 35mg

After mixing polyethylene glycol and concentrated glycerin, purified water was added, and the mixture was kept at about 60 ° C., followed by Oltipraz, followed by uniform mixing with a stirrer at about 1,500 rpm. Bubbles were removed using a vacuum pump to obtain the contents of the soft capsule. Soft capsule coating is generally prescribed soft gelling agent of gelatin, plasticizer, gelatin 132mg per 1 capsule, concentrated glycerin 52mg, dissolbitol solution 70% 6mg and the amount of ethyl vanillin as a flavor, using carnauba wax as a coating agent It prepared by the usual preparation method.

As described above, the composition according to the present invention has the effect of normalizing the hyperglycemia of the pathological state, and has a unique pharmacological mechanism at the molecular level, thereby preventing the proliferation and differentiation of fat cells as well as diabetic obesity It can also be used for the prevention or treatment of diabetes diseases and their complications, which have the effect of treating diabetes without side effects. In particular, Oltiphrase has a unique pharmacological action unlike other diabetes treatments can be a therapeutic agent with little side effects.

1 shows the chemical structural formula of Oltipraz,

Figure 2 is a graph showing the glucose uptake capacity of oltipraz in adipocytes,

Figure 3 shows the nuclear nucleus migration and activation of hepatocyte nuclear factor (HNF) 1 and HNF4α by oltipraz,

Figure 4 shows the role of PI3-Kinase (phosphatidylinositol 3-kinase) as a higher signal of HNF activation.

Claims (6)

Oltipraz [5- (2-pyrazinyl) -4-methyl-1,2-dithiol-3-thione], a pharmaceutically acceptable salt thereof, or a solvate or hydrate thereof as an active ingredient Pharmaceutical compositions for the prevention or treatment of diabetes mellitus and the complications thereby. The pharmaceutical composition of claim 1, wherein the complication comprises a disease due to an increase in blood levels of triglyceride, cholesterol, high density lipid or low density lipid. The pharmaceutical composition according to claim 1, further comprising a blood glucose control agent as an active ingredient together with the oltipraz. The pharmaceutical composition according to claim 3, wherein the oltipraz and the glycemic regulator are contained in a 1-25: 1 to 1-25 weight ratio. A pharmaceutical composition according to claim 1 which is formulated as a preparation or injection for oral administration. The pharmaceutical composition according to claim 5, wherein the formulation for oral administration is a formulation selected from capsules, tablets, suspensions, syrups or powders.