KR20130017859A - Combination of pinitol and drug for treating diabetes mellitus - Google Patents

Abstract

PURPOSE: A combination kit containing pinitol and a drug for preventing or treating diabetes is provided to reduce side effects and to quickly treat diabetes. CONSTITUTION: A combination kit of a component for preventing or treating diabetes contains pinitol as a first ingredient, and a drug of biguanide, meglitinide, or sulfonylurea as a second ingredient. The biguanide is metformin. The meglitinide is repaplinide or nateglinide. The sulfonylurea is carbutamide, acetohexamide, chlorpropamide, tolbutamide, tolazamide, gliclazide, glibenclamide, gliquidone, glyclopyramide, or glimepiride. [Reference numerals] (AA) Insulin; (BB) Control group; (CC) Before injection; (DD) 3 days after injection; (EE) 2 weeks after injection; (FF) 4 weeks after injection; (GG) 8 weeks after injection

Description

Combination of Pinitol and Drug for Treating Diabetes Mellitus}

The present invention relates to a combination of finitol and drugs for the treatment of diabetes.

Insulin resistance and diabetes are closely related and sometimes develop together with little time difference, and sometimes progress to diabetes after some time of insulin resistance. Insulin resistance means that insulin does not function properly. Insulin secretion works well, but the pancreatic beta cells continue to secrete insulin because they do not send signals into the cells that allow glucose in the blood to enter the cells. Generates. Accumulated insulin in the blood does not send glucose-related signals, but it actively signals the fat cell manufacturing process that makes the body obese, making many people with insulin resistance obese. This causes a variety of metabolic syndrome including diabetes. In the insulin resistance phase, the beta cells of the pancreas continue to secrete more insulin than usual under the direction of the brain, but eventually become exhausted and ultimately destroy most of the beta cells, resulting in extremely low insulin production. This is when diabetes develops and the symptoms of diabetes such as fatigue, thirst, hunger, and urination become apparent.

Most medications prescribed for diabetic patients have the ability to inhibit rapid blood sugar rise and stimulate the pancreas to promote insulin secretion. However, in diabetics, the functions of drugs that promote insulin secretion are limited in a situation where many cells of the pancreas are destroyed and fail to function properly. Therefore, the effects of most existing drugs are limited to the ability to suppress rapid blood sugar rise. Conventional diabetes treatment drugs have a relatively low and rapid hypoglycemic function, but various side effects (diarrhea, headache, bloating, nausea, etc.) have been reported. In addition, it has a function of promoting insulin secretion, but in already advanced diabetes, the pancreas does not function normally, so only a very small amount of insulin is secreted.

In this situation, to supplement the limited functions of the existing drugs and to eliminate side effects, a natural substance derived from legumes, pinitol, has emerged as a substitute for insulin's signaling function. Finitol is a substance derived from inositol. Inositol is a substance mainly found in plants, and has a structure of many stereo isomers and optical isomers. The official name of finitol is 3-O-methylation of d-chiro-inositol. It is mainly produced from pine, alfalfa and legumes. Finitol is reported as a substance that induces creatine production in muscle and functions like insulin. In addition, many studies have shown that it is effective for many diseases such as cancer, immune-related, anti-microbial, and heart disease, and has a bactericidal effect against various pathogens. Finitol can help prevent obesity and native diabetes by taking it early in insulin resistance, and even in diabetic patients whose insulin levels are extremely low, even small amounts of insulin in the body can faithfully perform insulin signaling. There is an advantage in that it helps. However, it is pointed out that finitol is a natural product that requires a high cost and takes at least 3-5 months to confirm its effect.

Numerous papers and patent documents are referenced and cited throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to better understand the state of the art to which the present invention pertains and the content of the present invention.

The present inventors have tried to develop a co-formulation that can improve treatment of diabetes more efficiently by co-administering finitol and other drugs. As a result, co-administration of finitol and conventional diabetes treatments can not only reduce the dosage of expensive finitol and therapeutic drugs while synergistic treatment effect, but can also achieve anti-diabetic effect in a short time, and anti-diabetic drugs It was confirmed that the side effects of can be reduced to complete the present invention.

Accordingly, an object of the present invention is to provide a combination kit of components for treating or preventing diabetes, including finitol and a diabetes treatment drug.

The objects and advantages of the present invention will become more apparent from the following detailed description of the invention, claims and drawings.

According to one aspect of the present invention, the present invention provides (i) finitol as a first component component; And (ii) as a second component, a combination kit of components for treating or preventing diabetes comprising at least one drug selected from the group consisting of biguanides, meglitinides, and sulfonylureas.

The combination kit of the present invention has a synergistic effect of the therapeutic or prophylactic efficacy of diabetes by the combination of the first component and the second component, and reduces the side effects of the second component, in particular the diabetes therapeutic drug.

Pinitol

The present invention is the first component D-pinitol (D-pinitol, 3-O-methyl- D-chiro-inositol, Formula 1) can be extracted from pine, alfalfa, legumes, etc. It is known to have a therapeutic effect (WO / 9629063), induces the production of creatine in muscle, has a therapeutic effect on immune disease, heart disease, and is known to have antimicrobial effects.

The dosage of finitol in the combination kit of the present invention is 400-800 mg / 1 day, preferably 450-750 mg / 1 day, more preferably 500-700 mg / 1 day, most preferably 600 mg / day. 1 day.

Biguanide Ingredients

The combination kit of the present invention includes Biguanide (Formula 2) as a second component.

Biguanides do not affect insulin production, unlike other diabetic drugs, sulfonylurea or meglitinide. Its mechanism of diabetic treatment is not clear, but it is known to reduce blood glucose level by reducing Gluconeogenesis in liver. It is also known to promote the uptake of sugars in the blood to lower blood sugar levels and to treat insulin resistance. Biguanide family drugs are therapeutically effective for both type 1 and type 2 diabetes.

In the present invention, biguanide-based drugs include metformin (Metformin, Formula 3), phenformin, Buformin, and proguanil, but metformin in view of side effects and diabetes treatment efficacy. Is most preferred.

Side effects of biguanide-based drugs, including metformin, include diarrhea and dyspepsia. The most important side effects include lactic acidosis (lactic acidosis).

The dosage of biguanide drug in the combination kit of the present invention is 0.0001-1000 mg / day, preferably 0.001-500 mg / day, more preferably 0.01-400 mg / day, most preferably 250 mg / 1 day.

In the present invention, when the biguanide component is co-administered with finitol, blood glucose lowering and cholesterol reduction are equivalent to or better than those when the biguanide drug is administered at a 100% dose while reducing the dosage of the pinitol and biguanide drugs by 50%. Show a synergistic effect.

Meglitinide Ingredients

The combination kit of the present invention includes, as a second component, a meglitinide family of drugs.

Meglitinide binds to the ATP-dependent K ⁺ (KATP) channel of the pancreatic beta cells' membranes, making the potential of the cell membranes positive, thereby opening voltage-gate Ca2 + channels to increase the concentration of Ca2 + in the beta cells It is known to promote the secretion of insulin. Drugs of the meglitinide family in the present invention include repaglinide (Repaplinide, Novonorm ™) and nateglinide (Nateglinide, Fastic ™). Side effects of meglitinide-based drugs include weight gain and hypoglycemia.

The dosage of meglitinide-based drugs in the combination kit of the present invention is 0.0001-1000 mg / 1 day, preferably 0.001-500 mg / 1 day, more preferably 0.01-100 mg / 1 day, most preferably Is 50 mg / 1 day.

In the present invention, when the meglitinide drug is co-administered with finitol, blood glucose lowering is equivalent to or better than that when the meglitinide drug is administered at a 100% dose while reducing the dose of the finitol and meglitinide drug respectively. In addition, it shows a synergistic effect, indicating a cholesterol-lowering effect.

Sulfonylurea Ingredient

The combination kit of the present invention includes, as the second component, a drug of sulfonylurea (Sulfonlyurea, Formula 4) family. Sulfonylurea-based drugs are known to treat type 2 diabetes through the action of promoting insulin secretion in the beta cells of the pancreas.

Sulfonylurea-based drugs have a mechanism of action such as meglitinide, that is, they bind to the ATP-dependent K ⁺ (KATP) channel of the membrane of the beta cells of the pancreas, making the potential of the cell membrane positive and thereby voltage-gate. It is known to promote the secretion of insulin by opening Ca2 + channels and increasing the concentration of Ca2 + in the beta cells. However, the binding sites of sulfonylurea-based drugs and meglitinide-based drugs are known to be different.

Sulfonylurea-based drugs include carbutamide, acetohexamide, chloropropamide, tolbutamide, tolazamide, and glyclazide. , Glibenclamide, glyquidone, glyclopyramide, and glymepiride.

Sulfonylurea-based drugs, unlike metformin-based drugs, have side effects that can cause hypoglycemia by overproduction and secretion of insulin. These hypoglycemic side effects are particularly pronounced when patients take high doses of the drug while fasting or fasting. In addition, an increase in insulin levels may lead to an increase in the utilization rate of blood sugar resulting in weight gain. Other side effects include abnormal vomiting, headaches and hypersensitivity.

The dosage of sulfonylurea based drugs in the combination kit of the present invention is 0.0001-1000 mg / day, preferably 0.001-500 mg / day, more preferably 0.01-250 mg / day, most preferably Is 50 mg / 1 day.

In the present invention, when the sulfonylurea drug is co-administered with finitol, the blood sugar equivalent to or better than that of the sulfonylurea drug is administered at 100% dose while reducing the dose of the pinitol and sulfonylurea drug by 50%. It shows a synergistic effect, with a lowering effect on cholesterol.

The present invention provides a composition comprising (i) finitol as a first component component; And (ii) a combination kit of components for treating or preventing diabetes, comprising at least one drug selected from the group consisting of biguanides, meglitinides, and sulfonylureas as a second component. According to the concomitant kit of the present invention, synergistic therapeutic efficacy can be obtained while greatly reducing the dose of the drug and the expensive pinitol used in the related art for diabetic treatment, and the side effects of the drug can be greatly reduced. In addition, the therapeutic efficacy of diabetes can be obtained more quickly.

Figure 1 shows the analysis of insulin in the blood taken during the first study period.
Figure 2 shows the analysis results of blood glucose in the blood collected during the first study period.
Figure 3 shows the results of analysis of glycated hemoglobin in blood collected during the first study period.
Figure 4 shows the analysis results of fatty acids in blood collected during the first study period. Figure 5 shows the results of the analysis of total cholesterol in the blood collected during the first study period.
Figure 6 shows the results of insulin analysis in blood taken during the second study.
Figure 7 shows the analysis results of blood glucose in the blood collected during the second study period.
Figure 8 shows the analysis results of glycated hemoglobin in blood collected during the second study period.
9 shows the analysis results of fatty acids in blood taken during the second study period. Figure 10 shows the results of the analysis of total cholesterol in the blood collected during the second study period.
FIG. 11 shows the results of analyzing the change in blood glucose levels in blood collected 2 hours after meals during the second study period.
12 shows the results of analyzing the change in fasting blood glucose during the second study period.

Hereinafter, the present invention will be described in more detail with reference to Examples. It is to be understood by those skilled in the art that these embodiments are only for describing the present invention in more detail and that the scope of the present invention is not limited by these embodiments in accordance with the gist of the present invention .

Example

Example 1 Composition and Consumption of Finitol Complex

Finitol complex preparation used in this Example experiment is summarized in Table 1 below. Finitol was purchased from Amicogen, and prescription drugs were purchased from pharmaceutical companies.

Complex type Complex composition Dose Remarks A Finitol 1200mg / 1 day Original research Finitol
Combination F Finitol + Biguanide 600mg + 250mg / 1 day Metformin G Finitol + Meglitinide 600mg + 50mg / 1 day Pepaglinide H Finitol + Biguanide + Sulfonylurea 600mg + 250mg + 50mg / 1 day Metformin
Amarillo

Example 2: Selection and Management of Subjects for Administration

   (1) Target selection range

The experimental study subjects of the present invention selected people belonging to a similar environment. As with many previous studies, the plan was to avoid the use of patients who visited the hospital and to see the effects of the combination of finitol and finitol alone. In other words, the study of selecting subjects with the same occupation contributed to the efficiency of the study due to the regular shift time and the ease of meeting. Subjects who have the same occupation selected in the present invention are taxi drivers, and when they select the subjects, they receive an application from a taxi company and a union in a major metropolitan city and check their simple post-prandial blood sugar (hypoglycemia 2 hours after dinner) and mainly impaired glucose tolerance (Impaired Glucose). Approximately 1,000 male knights (including 50 healthy subjects) under Tolerance (before and after blood sugar 180 mg / dL) were selected. In addition, the initial selection was referred to the existing health checkup tables of the parties.

   (2) Eligibility Conditions

Out of 1,000 primary candidates, secondary health screenings excluded those with the following conditions: (i) abnormal medical examinations, (ii) alcoholism, mental disorders (including interview findings), and (iii) prior to conducting the experiment. Subjects who took the drug within 2 months, (i) Insulin therapist, Insulin treatment for more than 7 days in the last 3 months, (i) Renal disease (serum creatine> 20 mg / dL), (i) Liver disease (AST and ALT are twice normal), (i) Cardiovascular, gastrointestinal, and malignant tumor disorders. Of the 1,000 people who went through the first selection, 350 were selected as the finalists.

   (3) blood measurement index of subject

The subjects of the study were as follows.

(Iii) Blood glucose check: Provide blood glucose checkers and strips to individual subjects, and then check self-checking fasting blood sugar and postprandial blood sugar 2 hours after dinner for 1 week after starting the 1st and 2nd study, and 3 days thereafter. Blood glucose was checked in the same manner at intervals.

(Ii) Blood collection: Blood collection was done before dosing, 3 days after study start dosing, 1 week after, and 1 month every week thereafter. Thereafter, a total of four blood samples were collected at two week intervals, and a total of 13 blood samples were taken for three months. Blood samples were analyzed for insulin, blood sugar, glycated hemoglobin, triglycerides, and cholesterol.

Example 3: Measurement of Blood Index Before Administration of Subjects

The results of measuring blood indices of people selected as study subjects of the present invention are shown in Table 2 below.

Item Finitol Combination Medication Group
(80 primary, 200 secondary: 280 total) Placebo Dosing Group
(20 control group, 50 group: 70 members in total) age 45.3 ± 5.1 46.5 ± 3.4 gender Male Male Body mass index (BMI) 25.30 ± 5.74 26.30 ± 4.71 Blood pressure (deflator) 127.67 ± 15.74 128.65 ± 12.04 Blood pressure (diastolic) 76.67 ± 11.51 76.07 ± 13.32 Glycated hemoglobin (HbAlc,%) 9.45 ± 1.51 7.45 ± 1.51 Triglyceride 297.67 ± 11.72 197.67 ± 12.34 Total cholesterol 245.37 ± 12.02 155.63 ± 13.24 HDL-cholesterol 37.67 ± 14.47 30.67 ± 11.73 LDL-cholesterol 107.63 ± 11.04 101.67 ± 10.74 Hemoglobin (g / dL) 13.45 ± 1.51 13.65 ± 2.53 AST (U / L) 23.04 ± 1.33 24.05 ± 1.42 ALT (U / L) 22.02 ± 1.82 24.07 ± 1.53 Creatinine (mg / dL) 0.91 ± 0.12 0.88 ± 0.15 Blood sugar (after 2 hours after meals) 180 ± 11.34 120 ± 15.37 Insulin ( u U) (2 hours after eating) 12 ± 1.54 30 ± 2.54

Before administering the co-formulations of the present invention to the subjects, five main indicators to be checked in this study were measured in blood. The five main indicators showed higher levels of glycated hemoglobin, triglycerides, cholesterol, and blood glucose than the control group (normal, healthy group) and the control group showed higher results. Subsequently, a total of 350 study subjects (including 50 controls) were administered with the pinitol combination formulation shown in Table 1 above. In the first-dose trial, 10 patients were assigned to each combination and 20 placebo-controlled placebo-dose groups (10 lifestyle control and 10 placebo-controlled). A total of 4 blood samples were taken after commencement of the combination preparation and a life record was presented. Table 3 and Figure 8 show the analysis results during the first dose experiment. The management records for the study period are also shown in Table 4.

Item Finitol Combination Medication Group Placebo Dosing Group (Control) Dosing Formulation and Control A Finitol Complex Placebo Control General control Type of formulation F G H Glycated hemoglobin (HbAlc,%) 7.45 ± 1.51 7.45 ± 1.51 Triglyceride (mg / dL) 197.6 ± 12.34 197.6 ± 12.34 Total Cholesterol (mg / dL) 155.6 ± 13.24 155.6 ± 13.24 HDL-cholesterol 30.67 ± 11.73 30.67 ± 11.73 LDL-cholesterol 101.6 ± 10.74 101.6 ± 10.74 Insulin ( u U) 30 ± 2.54 30 ± 2.54 Blood sugar (mg / dL) 120 ± 15.37 120 ± 15.37

As shown in Table 3 above, when comparing the finitol alone A and the finitol combination preparation, F shows a distinct difference between F and a mixture of finitol and metformin. Next, H was the agent that showed the effect. Based on these results, in the second administration experiment, the analysis was attempted using the above two agents. On the other hand, the criteria for selection of the formulation to be applied in the second administration experiment was applied as the first priority to appear much faster than A, so it was an important criterion along with the effect of lowering blood glucose levels and glycated hemoglobin.

Item Writer :
Record Date (Month 2011-Month 2011) month anger Number neck gold Sat Work Drinking alcohol, alcohol Cigarettes, quantity Meals, time records Kind of meal (morning) Kind of meal (lunch) Kind of meal (evening) Exercise time, exercise time Blood glucose check, numerical record Blood sugar readings Medication or not, time of taking Total sleep time Bedtime-Wake up time Other (e.g. irregular living)

Example 4 Measurement of Blood Index Before Administration of Subjects

The analysis of four types of finitol complex formulations selected through the first administration experiment was performed on 250 subjects in the second administration experiment. The second dose test consisted of two blood glucose checks and intense daily care under more stringent conditions than the first dose. A total of 200 experimental groups were assigned to 50 people for each of the finitol combinations, and the control group consisted of 50 placebo-administered groups.

Table 5 and FIG. 9 show changes in blood glucose, changes in insulin, triglycerides, and cholesterol for each blood collection time. Table 6 and FIG. 10 compare the averages of total fasting and postprandial blood glucose measured regularly during the second administration experiment, divided before and after dosing.

Item Finitol Combination Medication Group Placebo Dosing Group
(Control group) Dosing Formulation and Control A Finitol Complex Formulation (I) Type of formulation F H Glycated hemoglobin (HbAlc,%) 7.45 ± 1.51 7.45 ± 1.51 Triglyceride (mg / dL) 197.6 ± 12.34 197.6 ± 12.34 Total Cholesterol (mg / dL) 155.6 ± 13.24 155.6 ± 13.24 HDL-cholesterol 30.67 ± 11.73 30.67 ± 11.73 LDL-cholesterol 101.6 ± 10.74 101.6 ± 10.74 Insulin ( u U) 30 ± 2.54 30 ± 2.54 Blood sugar (mg / dL) 120 ± 15.37 120 ± 15.37

According to the results shown in Table 5 as in Table 3, the combined formulations F, H selected compared to the finitol alone administration group A showed a hypoglycemic effect. In addition, other major indicators showed a marked change.

Item Finitol Combination Medication Group Placebo Dosing Group
(Control group) Dosing Formulation and Control Blood sugar levels
division A Finitol Complex Formulation (I) Placebo Control Type of formulation F H Before dosing Blood sugar (mg / dL) - 180 ± 11.34 180 ± 11.34 180 ± 11.34 120 ± 15.37 120 ± 15.37 After dosing Fasting Blood Sugar (mg / dL) The highest figure Lowest Change Postprandial Blood Sugar (mg / dL) The highest figure Lowest Change

Having described the specific part of the present invention in detail, it is apparent to those skilled in the art that the specific technology is merely a preferred embodiment, and the scope of the present invention is not limited thereto. Accordingly, the actual scope of the present invention will be defined by the appended claims and their equivalents.

Claims (6)

(i) finitol as a first component component; And (ii) a combination kit of components for the treatment or prevention of diabetes, comprising at least one drug selected from the group consisting of biguanides, meglitinides, and sulfonylureas as a second component.
The combination kit according to claim 1, which has a synergistic effect of the therapeutic or prophylactic efficacy of diabetes by the combination of the first component and the second component.
The combination kit of components for treating or preventing diabetes mellitus according to claim 1, wherein the biguanide is metformin.
[Claim 2] The combination kit of claim 1, wherein the meglitinide is repaglinide or nateglinide.
According to claim 1, wherein the sulfonyl urea is carbutamide (Carbutamide), aceto hexaamide (Acetohexamide), Chloropropamide (Clorpropamide), Tolbutamide, Tolazamide (Tolazamide), Glyclazide (Gliclazide), Glibenclamide (Glibenclamide), Glyquidone (Gliquidone), Glyclopyramide (Glyclopyramide), or a combination kit of components for the treatment or prevention of diabetes, characterized in that Glymepiride (Glimepiride).
2. The combination kit of claim 1, wherein the second component is biguanide.

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