KR20020062556A - A pharmaceutical composition for the treatment of diabetes mellitus - Google Patents

Abstract

PURPOSE: Provided is a therapeutic composition for diabetes by using medicinal herbs, vitamin B1 and B6 and minerals, thereby decreasing blood sugar level and increasing insulin secretion to prevent and treat diabetes. CONSTITUTION: The composition comprises 400-800 par by weight of ginseng, 1900-3400 part by weight of Coptis chinensis Franch, 50-400 part by weight of glossy privet fruit, 170-1700 part by weight of a willow cortex, 50-600 part by weight of Radix et rhizoma RHEI, 500-800 part by weight of Anemarrhena Rhizome , 400-600 part by weight of red sage root, 400-700 part by weight of Figwort root , 500-800 part by weight of Wolfberry root-bark, 400-600 part by weight of red-colored boil, 300-500 part by weight of Balloonflower root, 900-1300 part by weight of Milkvetch root, 600-800 part by weight of Kudzuvine root, 600-800 part by weight of Atractylodes rhizome, 250-450 part by weight of Mulberry root-bark, vitamin B1, B6 and minerals including zinc, manganese, chrome, germanium and the like.

Description

A composition for treating diabetes {A PHARMACEUTICAL COMPOSITION FOR THE TREATMENT OF DIABETES MELLITUS}

The present invention relates to a composition for treating diabetes using a herbal medicine. More specifically, the present invention comprises 15 kinds of herbal ingredients namely ginseng, rhubarb, fermented sperm, willow bark, rhubarb, jimo, sweet ginseng, hyeonsam, phalanges, hojang, gilkyung, rhubarb, brown root, creation, baekbaekpi and herbal medicines, vitamin B₁ It relates to a composition for treating diabetes containing, B ₆ and the inorganic zinc, manganese, chromium, germanium.

The composition of the present invention is a composition having a diabetes prevention and treatment effect that lowers blood sugar of diabetic patients, restores simultaneously damaged beta cells that prevent pancreatic beta cell destruction, and increases insulin secretion. The present invention relates to a herbal composition that exhibits excellent therapeutic effects on (type 1 diabetes mellitus) and insulin-independent diabetes mellitus (type 2 diabetes mellitus) and at the same time stabilizes the state of expression of the drug among individuals, thereby providing a uniform treatment effect.

Diabetes and its complications, along with cancer and renal circulatory disease, are among the world's leading mortalities, and mortality continues to increase, and diabetics are at high risk for complications such as eye disease, kidney disease, and heart disease. There is also a report.

The symptoms of diabetes vary, but the three major symptoms are Daum, Polyuria, and Dasik.

In other words, because of high blood sugar in blood pressure, urine causes glucose and a large amount of water to be excreted by osmotic pressure, which causes urine to be frequent. Therefore, dehydration causes severe thirst to drink a lot of water. You will eat, but you will usually lose a lot of weight.

Diabetes is largely classified into insulin dependent diabetes mellitus (type 1) and insulin independent diabetes mellitus (type 2). Insulin-dependent type 1 is a severe insulin deficiency that causes symptoms to appear suddenly and is often found as a serious condition, such as diabetic ketoacidosis. In Gumi, it is estimated that about 5 ~ 10% of all diabetics, but about 1 ~ 2% in Korea. It is called pediatric diabetes because it usually occurs in young people in their teens and 20s. As a cause, it is associated with HLA antigens (HLA, DR, DQ), which are genetic factors, and as an environmental factor, viral infections or other toxic substances are converted into immunogens by surface antigens of beta cells, which are pancreatic insulin secreting cells. Mechanisms have been shown to be involved in the development of diabetes mellitus, and islet cells, autoantibodies to insulin, and the like are produced. Recently, efforts have been made to delay or prevent the invention of diabetes by detecting such autoantibodies before the onset of type 1 diabetes. Type 2 diabetes occurs mainly in the 40s and occupies most of the diabetic patients in Korea. Unlike type 1, it is also called adult-type diabetes and the cause of the disease is not clear yet, but it is known to be caused by genetic factors and environmental factors. Genetic factors show a variety of familial concentrations, resulting in nearly 90-100% disease matching between identical twins, 58% of children when their parents are all diabetic, and 27% of parents when one of their parents is diabetic. It is known that diabetes occurs in 0.9% when both parents are healthy. Environmental factors include high calorie intake, lack of exercise, obesity, stress and drug abuse, which are rapidly increasing with the recent economic growth.

The etiology of type 2 diabetes has been observed in both pancreatic beta cells and in insulin secretion and in target cells (insulin resistance). It is not clear what changes are of primary importance.

Oral hypoglycemic agents for the treatment of diabetes include sulfonylureas, biguanides, and acarbose. Among these, sulfonylureases are the second generation of products that have a short action time and have a strong hypoglycemic effect. Mainly used for non-fatty adult diabetics, biguanide-based drugs and acarbose are used for diabetics with obesity over normal weight.

One of the biggest differences between biguanide and acarbose in sulfonylurea preparations is the low incidence of hypoglycemia.

In addition, insulin, which is used in the form of an injection, has an excellent hypoglycemic effect, but it is inconvenient to use, and low blood sugar causes complications. Especially in the elderly, such hypoglycemia occurs well, so appropriate care should be taken.

In addition to the drug therapy, there are 158 folk remedies in Korea, and there are 153 folk remedies, and about 73% of adult diabetics have used more than one folk remedy.

The study on the treatment of diabetes drugs is focused on the field of prevention and treatment. In the case of insulin-dependent type, studies for preventing pancreatitis and treating diabetes are mainly conducted on disease model animals such as NOD mice. Therapeutic strategies focus on suppressing and regulating immune responses to prevent beta cell destruction. Insulin-dependent diabetes, an autoimmune disease, is due to an abnormal boost in immune function. Various immunotherapies have been tried to prevent beta cell destruction of the pancreas. Neonatal thymectomy can eliminate T cells to inhibit diabetes onset in NOD mice. In addition, it has been found that treatment of antibodies to T cells removes T cells or macrophages to inhibit diabetes. It has been reported that the production and action of free radicals such as NO secreted by immune cells can be suppressed by the use of antioxidants, which can suppress diabetes, nicotinamide, vitamin E and furobucol. (probucol), MDL29311, U78518F and other antioxidants have been reported.

Therapies using immunosuppressants are being studied. However, the treatment of diabetes with glucocorticoid or cyclophosphamide has not shown any significant effect. Recently, the treatment of diabetes with cyclosporin A, rapamycin, and FK506 is possible. But the results are not yet clear. Treatment with immunosuppressive agents causes secondary infections, nephrotoxicity, and liver toxicity due to excessive immunosuppression, and there are still many problems in use as an antidiabetic agent. In addition, treatment with long-term administration may cause cancer. Recently, studies on the prevention and treatment of diabetes mellitus by immunomodulators other than immunosuppressants have been conducted, and it has been reported that the cytokine treatment of IL-4 and IL-10 inhibits diabetes in NOD mice. Experimental results have shown that immunomodulators such as OK-432, LZ-8, BCG and CFA can cure diabetes, but the mechanism is unknown. In addition, diabetes can be treated with immunosuppressive agents, but it has side effects such as excessive immunosuppression, kidney toxicity, and liver toxicity.

Insulin-independent forms have led to efforts to develop therapeutics that can reduce side effects and treat insulin-dependent and non-dependent diabetes at the same time. Herbal medicines used in Oriental medicine have traditionally been known to have various therapeutic effects with low toxicity. To date, the effects of diabetes treatment by single or combination prescriptions using dozens of herbal medicines have been reported, and there are reports that insulin-dependent and non-dependent diabetes can be treated simultaneously.

Therefore, the present inventors have conducted extensive research to develop a composition capable of simultaneously treating insulin-dependent and non-dependent diabetes mellitus by combining herbal medicines with low side effects. In order to treat insulin-dependent diabetes, it is necessary to prevent the destruction of beta cells and to promote insulin secretion of beta cells, which has been demonstrated using STZ mice and NOD mice. Since it is necessary to suppress the rapid blood sugar rise and remove the insulin resistance of the peripheral tissue, which proved using KK-Ay mice, found the superiority of the composition of the present invention, such as the hypoglycemic effect and the stability of individual treatment effects And to complete the invention. Accordingly, an object of the present invention is to provide a novel herbal composition for treating insulin-dependent or non-dependent diabetes.

Hereinafter, the configuration of the present invention will be described in detail.

1 is a graph showing the results of a glucose tolerance test of a normal ICR mouse. The mice were fasted for 24 hours and then the samples were intraperitoneally administered at a concentration of 267 mg / kg. After 90 minutes, glucose was orally administered at a concentration of 1 g / 1 kg, and the change in blood glucose was measured by time period.

Figure 2 is a graph showing the diabetes treatment effect of the present invention composition for KK-Ay mice. A 267 mg / kg sample was intraperitoneally administered daily and blood glucose changes were measured.

3 is a graph showing the weight change of the KK-Ay mouse used in FIG.

4 and 5 are graphs showing the diabetes treatment effect of the composition of the present invention on streptozotocin-induced diabetic mice. Blood glucose levels were measured weekly to compare the effectiveness of the treatment with diabetes.

Figure 6 is a graph showing the effect of diabetes treatment in NOD mice by the present invention diabetes treatment. Samples were intraperitoneally administered at a concentration of 267 mg / kg from 11 weeks to 20 weeks of age.

7A to 7D are photographs taken by pathological examination of pancreatitis by extracting and separating the pancreas of the NOD mouse used in FIG. 6.

The present invention relates to a composition for treating diabetes. More specifically, 15 kinds of plant herbal medicines of ginseng, rhubarb, italy bark, willow bark, rhubarb, jimo, dansam, hyeonsam, phalanx, hojang, gilkyung, rhubarb, brown root, creation, baekbaekpi, vitamin B ₁ , B ₆ and minerals The present invention relates to a composition for treating diabetes consisting of phosphorus zinc, manganese, chromium and germanium,

Ginseng 400 ~ 800 parts by weight, Rhubarb 1900 ~ 3400 parts by weight, 50 ~ 400 parts by weight of yeast, 170 ~ 1700 parts by weight of willow bark, rhubarb 50 ~ 600 parts by weight, 500 ~ 800 parts by weight of balsam, 400 ~ 600 parts by weight of salvia , 400-700 parts by weight of ginseng, 500-800 parts by weight of phalanges, 400-600 parts by weight, length 300-500 parts by weight, 900-1300 parts by weight, yellow root 600-800 parts by weight, 600-800 parts by weight, 250 to 450 parts by weight of baekryepi, vitamin B ₁ 0.5 to 4.0%, B ₆ 0.5 to 5.0% and inorganic zinc 0.2 to 1.0%, manganese 0.2% to 1.0%, chromium 0.001 to 0.005%, germanium 0.5 It is a composition for treating diabetes composed of ˜4.0%.

In addition, the present invention in addition to 500 to 800 parts by weight of ear cow, 250 to 550 parts by weight of cornus oil, 300 to 600 parts by weight of the deficiency, 300 to 600 parts by weight of McMoon-dong, containing 19 kinds of plant herbal medicines for treating diabetes The composition can be prepared, and furthermore, in addition to these 19 kinds of herbal ingredients, 100-200 parts by weight, 100-200 parts by weight of sheep ginseng, and 300-600 parts by weight of baekchul are added, and agents for treating diabetes containing 22 plant herbs The composition may also be prepared.

1) Ginseng (Shinseng Radix) is a herbal medicine belonging to the Araliaceae family. It is a herbal medicine used in tonics and tonics as an herbal breakdown, general weakness, loss of food, indigestion, vomiting and diarrhea. Inhibits blood sugar and is known to be closely associated with carbohydrate metabolism in animals.

2) Coptis Rhizoma is a herbal medicine belonging to the Ranunculaceae, and its main ingredients are berberine, palmatine, yateorrhizine, cooptisine and borenine. It is used as a high-density gastrointestinal pill, and the main ingredient is berberine, which has an antibacterial effect of inhibiting the growth of intestinal bacteria.

3) Ligustri Fructus Semen is dried fruit of Ligustrum Japonicum Thunberg belonging to Oleaceae. It contains glycoside and syringin and is used as a tonic medicine in oriental medicine. .

4) Salix spp. Cortex is a bark of a plant belonging to the Saliaceae family, and its salicylic acid glycosides contain salicycin and poplin as its main components. Although it has been used, the branches, bark, leaves, etc. are used in antipyretic analgesic and athlete's foot athletes in the herbal medicine, but the willow bark is mainly used in the present invention.

5) Rhei Coreani Rhizoma is a herbal medicine belonging to Polygonaceae. Its main ingredient contains chrysophanic acid, Emodin glycoside, resin, etc. It is used as a king, rhubarb, golden gate rhubarb and bell rhubarb.

6) Anemarrhena Rhizoma is a medicinal herb belonging to the family Liliaceae, and its main ingredient contains saponins, asonin, Sarasapogenin, markogenin, and flavonoids, chimonin. It is used as an antipyretic and diuretic medicine in oriental medicine.

7) Salviae Radix is a herbal medicine belonging to Ladiatae. It contains tanshinone as its main ingredient, and it is a tonic, dysmenorrhea and gynecological medicine in Chinese medicine. Known.

8) Scrophulariae Radix is a herb that belongs to Scrophulariaceae. The main ingredient is known as P-methoxycinamic acid, which is used as an anti-inflammatory, antipyretic and analgesic medicine in oriental medicine.

9) Lycii Cortex Radicis is the root bark of Lycium Chinense Miller, a member of the Solanaceae family.

10) Reynoutriae Radix is dried root of Reynoutria elliptica Migo belonging to Plygonaceae, contains anthraquinone glycosides of Polygonins, and in oriental medicine, relief, diuresis, pain medication, etc. Used as a medicine, it is mixed with licorice to dissolve in civilian medicine.

11) Platycodi Radix is peeled or dried root of the bellflower belonging to the genus Campanulaceae. Kikkyo-saponin, Platycodin, Innlin, phytosterol It contains saponin (Phytosterol) and is widely used as an expectorant in Chinese medicine.

12) Astragali Radix is a herb that belongs to legumes (Leguminosae). It is a plant known to have weakening, tonicity, cold, and diuretic, which is used for weakness and species, and is known to have vasodilation and blood pressure lowering effects. Also used as.

13) Puerariae Radix is made from the roots of Pueraria thunb. Belonging to the legumes (Leguminosae) by removing the cork bark, and then using Daidzin, Puerarian and Starch. Etc., which are widely used as antiperspirant and antipyretic medicine in herbal medicine.

14) Atractylis Rhizoma is a dried root of Atractylis Iyrata Siebold et Zuccarini belonging to the compositae, and contains essential oils such as Atractylone, which is a fragrant dry placebo and diuretic. It is used as a medicine.

15) Morus alba Radix Cortex is the root bark of the mulberry tree belonging to the Moraceae family, and its extract contains pectin, amyrine, etc. It is known.

Other supplementary herbs such as ear cow (Euonymus alatus), Corni Fructus, Cassiae semen, Ophiopogonis Tuber, Panax notoginsen, sheep ginseng, and baekrye It is a plant herb widely known in Korea.

The diabetic therapeutic composition of the present invention may be used in place of sulfur white (phellodendri Cortex), and may be used in place of purified berberine hydrochloric acid. In addition, purified oleanolic acid can be used instead of the journey, and willow bark can also be used as purified or synthesized salicylic acid or acetylsalicylic acid and salts thereof. .

In addition, in addition to the above-mentioned herbal medicine (Rosa rogosa Radix) or the bark (Araliae Cortex) can be added, vitamins B _2, B ₁₂ and vitamins in addition to vitamins B ₁ , B ₆ which is a type of water-soluble vitamins It may further contain C, and may contain calcium (Ca) or potassium (K) in addition to zinc (Zn), manganese (Mn), chromium (Cr), germanium (Ge) as an inorganic agent.

The pharmaceutical composition for treating diabetes mellitus of the present invention may be formulated into tablets or capsules by conventional methods, including pharmaceutically acceptable excipients, and the dosage is 5 to 3000 mg / kg body weight / day, preferably 10 Can be administered at -1000 mg / kg body weight / day. The method of administration is 3-4 times a day. Take 2-4 capsules once a 30 minutes before meals. Dosage adjustment is necessary depending on the patient's condition or blood glucose level. The maintenance amount is preferably 4-6 capsules per day. .

Hereinafter, the preparation example of the present invention and the experimental data for treating diabetes are attached.

(Example 1)

Capsule (for 1,000 capsule production)

Raw material Capsule preparation example Example 1 Example 2 Example 3 Herbal medicine Ginseng 500 g 450 g 700 g goldthread 2,430 g 1,950 g 3,300 g Journeyman 360g 70 g 350 g Willow blooming 1,100 g 200 g 1,000g rhubarb 200 g 60 g 450 g Jimo 660 g 550 g 750 g Salvia 500 g 440 g 550 g figwort 500 g 420 g 650 g Phalanges 660 g 530 g 750 g Hojiang 500 g 400 g 500 g Street view 400 g 360g 450 g Astragalus 1,020 g 950 g 1,200 g Rooting 660 g 660 g 700 g Creation 660 g 640 g 750 g White skin 360g 300 g 400 g Three 110 g Sheep ginseng 120 g Ear woo 750 g 550 g Cornus 520 g 300 g Whiteness 300 g A defector 550 g 320 g Macmundong 560 g 330 g Medicinal Herb Extract Subtotal 381.795g 385.5 g 421.0 g Supplementary Ingredients Hydrochloric acid 3.0 g 3.0 g 3.0 g Pyridoxine hydrochloride 4.0g 4.0g 4.0g Zinc sulfate 3.2 g 3.2 g 3.2 g Manganese sulfate 4.0g 4.0g 4.0g Chromium chloride 5.0mg 5.0mg 5.0mg Germanium (Ge-132) 4.0g 4.0g 4.0g Supplementary Ingredient Subtotal 18.205 g 18.205 g 18.205 g Capsule base 0 capsule 70mg 70mg 70mg Weight of capsule 470 mg 473.7mg 509.2mg

(Example 2)

Tablets (1,000 tablets)

Raw material Tablet formulation example Example 1 Example 2 Example 3 Herbal medicine Ginseng 500 g 450 g 700 g goldthread 2,430 g 1,950 g 3,300 g Journeyman 360g 70 g 350 g Willow blooming 1,100 g 200 g 1,000g rhubarb 200 g 60 g 450 g Jimo 660 g 550 g 750 g Salvia 500 g 440 g 550 g figwort 500 g 420 g 650 g Phalanges 660 g 530 g 750 g Hojiang 500 g 400 g 500 g Street view 400 g 360g 450 g Astragalus 1,020 g 950 g 1,200 g Rooting 660 g 660 g 700 g Creation 660 g 640 g 750 g White skin 360g 300 g 400 g Three 110 g Sheep ginseng 120 g Ear woo 750 g 550 g Cornus 520 g 300 g Whiteness 300 g A defector 550 g 320 g Macmundong 560 g 330 g Medicinal Herb Extract Subtotal 381.795g 385.5 g 421.0 g Supplementary Ingredients Hydrochloric acid 3.0 g 3.0 g 3.0 g Pyridoxine hydrochloride 4.0g 4.0g 4.0g Zinc sulfate 3.2 g 3.2 g 3.2 g Manganese sulfate 4.0g 4.0g 4.0g Chromium chloride 5.0mg 5.0mg 5.0mg Germanium (Ge-132) 4.0g 4.0g 4.0g Supplementary Ingredient Subtotal 18.205 g 18.205 g 18.205 g Excipient Microcrystalline cellulose 50 g 50 g 50 g Lactose 22 g 22 g 22 g Silicon dioxide 5.5g 5.5g 5.5g PVP K30 8.0g 8.0g 8.0g Lubricant Magnesium stearate 16.0 g 16.0 g 16.0 g Coating HPMC 2910 10.0 g 10.0 g 10.0 g PEG 6000 8.0g 8.0g 8.0g Titanium dioxide 0.5g 0.5g 0.5g ethanol 0.16ml 0.16ml 0.16ml Methylene chloride 0.27ml 0.27ml 0.27ml coloring agent Yellow No. 4 / Red No. 40 Quantity Quantity Quantity Weight of tablet 520.4 mg 524.1 mg 559.6mg

(Preprocessing of major herbal medicines and manufacturing process according to preparation)

1. Manufacturing Process of Ginseng Extract

1) Method 1

① Grind the ginseng into powder and put it in 8% of 75% -ethanol and extract it under reflux for 2 hours.

② Wash the extract twice with chloroform (1: 1 for the extract).

③ Extract n-butanol (1: 1) from the aqueous layer three times.

④) Separate the n-butanol layer and dry under reduced pressure below 80 ℃.

⑤ Make the dried powder.

2) Method 2

① Grind the ginseng into powder and put it in 5% of 35% -ethanol and extract it under reflux for 2 hours.

② Add 5% of 35% ethanol to the sample and extract it under reflux for 2 hours.

③ Collect the extract and filter it.

④ Dry under 80 ℃ under reduced pressure to make powder.

3) Method 3

① Grind the ginseng into powder and put it in 8 times of water and extract by heating for about 3 hours.

② Filter the extract after leaving for one day.

③ Dry the filtrate under reduced pressure to obtain a powder.

2. Manufacturing process of rhubarb extract

1) Method 1

① Grind the yellow lotus powder to make powder. Extract it with 8 times the ethanol: 0.1N-hydrochloric acid (100: 1) solution using succinlet extractor until the yellow color disappears.

② Evaporate the extracted ethanol-hydrochloric acid solution to obtain the Berberine hydrochloride powder.

2) Method 2

① Grind the rhubarb into powder, add it to 8-fold ethanol: 0.1N hydrochloric acid (100: 1) solution, and add reflux condenser for 5 hours and extract it under reflux.

② Cool the extract, filter it, and add the residue to 6 times the amount of ethanol: 0.1N hydrochloric acid (100: 1) solution and extract it under reflux for 5 hours using a reflux condenser.

③ Cool down again, filter, and add 4 times the amount of ethanol: 0.1N hydrochloric acid (100: 1) solution to the residue and extract it under reflux for 5 hours with reflux cooler.

④ After cooling, the resultant is filtered and the combined filtrate is evaporated to dryness to obtain berberine hydrochloride powder.

3) Method 3

① Grind the yellow lotus powder to make powder and extract it under reflux for 12 hours at 60 ℃ with 8 times of ethanol: water (2: 1) solution.

② Filter the extract and add 4 times the amount of ethanol: water (2: 1) solution to the residue and extract it under reflux for 12 hours at 60 ℃.

③ Filter the extract, combine the filtrates and distill the ethanol under reduced pressure.

④ Add 2 times the amount of acetone to the aqueous layer, adjust the pH to 2-3 with concentrated hydrochloric acid, and leave it for 1 day at 0-5 ℃, then filter.

⑤ Dry the filtrate at 80 ℃.

3. Manufacturing Process of Journey Extract

1) Method 1

① Dry the fruit part of medicinal herbs well, extract 95% -ethanol for 4 hours by adding 4-5 times the amount of herbal medicine and keep the extract solution.

② Add 5 times n-butanol to the sample and extract for 12 hours.

③ Collect this extract and fractionate and purify it using a chromatography column.

In this case, the column is filled with silica and the eluent is benzene ether (4: 1) solution.

2) Method 2

① Dry the fruit section of the herb well and extract twice with 4 times the amount of methanol.

② Combine extracts and fractionate with polar solvent to separate and purify.

4. Extraction manufacturing process of willow bark

① After crushing the bark of willow, add 5 times ethanol, stir at room temperature for 3 hours, extract and filter.

② After distilling the filtrate under reduced pressure to completely remove ethanol, add 0.5 times distilled water to the residue, and adjust it to pH8-9 using 0.1N-NaOH. At this time, the substance which melts is filtered off.

③ Cool the filtrate, adjust the pH to 2.0 with 1N-HCl, stir for 10 minutes, filter the resulting white powder, and vacuum-dry at 80 ℃ to obtain salicylic acid of white crystals.

In the present invention, salicylic acid or acetylsalicylic acid and salts thereof purified and separated from dry extract or extract extract of willow bark extract may be used.

5. Processing of Rhubarb

1) Method 1. (Pulverization method)

Dry the root stem well to remove impurities, then put it into a grinder and grind it finely to make powder.

2) Method 2. (Extraction method)

① Grind rhubarb into powder, add 8 times water, and heat for 4 hours to extract.

② Separate the extract and concentrate and spray dry the solution.

6. Extraction process of other herbal medicine

① Grind all remaining herbs to powder, add 8 times water, and heat for 4 hours to extract.

② Separate the extract and concentrate and spray dry the solution.

7. Drying and Granulation Process

① Combine the extracts according to the above steps 1-6 and dry at 60 ℃ or less and dry them to 9% or less.

② The dried product is stirred in a mixer by spraying 88% -ethanol.

③ Combine the ingredients such as vitamins and mix homogeneously.

8. Formulation

After granulation using a granulator and dried at 60 ° C to 9% or less moisture, according to the manufacturing process prescribed in the Korean Pharmacopoeia to prepare tablets, capsules and the like prescribed formulation.

(Stability test made of capsule)

1.Product Name: DHS123 Capsule

2.Period of test: January 22, 2001-August 8, 2001

3. Place of test and tester

1) Location: Gyeonggi-do

ОО Pharmaceutical Industry Co., Ltd. Quality Control Department

2) Test facility: HPLC (WATERS)

AA (SHIMADZU)

Chemical Balance (METTLER)

Disintegration Tester (Fine Machine)

3) Investigator: YoonОО and 3 others

4. Test sample

1) Date of manufacture

LOT NO. DHS123C1 (2001.1.16)

LOT NO. DHS123C2 (2001.1.20)

LOT NO. DHS123C3 (2001.1.22)

2) Specimen: Capsule (Capsule according to Preparation Example 1)

5. Storage condition

1) 40 ℃, 75% RH, 6 months

2) room temperature

6.Test Items and Test Methods

1) Test Items

① Property, ② Identification test, ③ Disintegration test, ④ Content test, ⑤ Weight deviation test

2) Test method

Samples stored in the preservation state of 5 shall be taken after 2 months, 4 months, and 6 months, and tested according to the above 1) Test items according to the standards of DHS123 capsules and the test method (KEPCO, Korea Standards).

7. Test Result: Tables 1 to 4 below.

Under the preservation conditions, DHS123 capsule did not show any significant change in all properties, identification, disintegration test, weight deviation, and content test. Thus, it can be seen that the DHS123 capsule of this product is a product having stability under the set storage conditions and use period. have.

Table 1. Stability test result of DHS123 capsule (40 ℃, 75% RH / room temperature)]

LOT NO. Test Items At the start 2 months 4 months 6 months Room temperature 6 months DHS123C1 Constellation Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Test fitness - - fitness fitness Disintegrate fitness - - fitness fitness Weight deviation fitness - - fitness fitness content(%) 103.21 101.58 96.70 99.12 99.40 115.32 116.52 127.36 117.86 124.28 DHS123C2 Constellation Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Test fitness - - fitness fitness Disintegrate fitness - - fitness fitness Weight deviation fitness - - fitness fitness content(%) 101.61 103.76 101.38 100.42 97.46 142.52 139.57 147.88 144.83 143.10 DHS123C3 Constellation Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Test fitness - - fitness fitness Disintegrate fitness - - fitness fitness Weight deviation fitness - - fitness fitness content(%) 103.16 99.56 97.58 100.19 97.09 147.59 141.61 148.33 148.18 138.72

Table 2. DHS123 capsule lot test results (DHS123C1)]

Test date item At the start 2 months acceleration 4 months acceleration Accelerated 6 months Room temperature 6 months Constellation Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Confirm goldthread fitness fitness fitness fitness fitness Ginseng fitness fitness fitness fitness fitness Journeyman fitness fitness fitness fitness fitness Willow blooming fitness fitness fitness fitness fitness rhubarb fitness fitness fitness fitness fitness Jimo fitness fitness fitness fitness fitness Salvia fitness fitness fitness fitness fitness figwort fitness fitness fitness fitness fitness Phalanges fitness fitness fitness fitness fitness Hojiang fitness fitness fitness fitness fitness Street view fitness fitness fitness fitness fitness Astragalus fitness fitness fitness fitness fitness Rooting fitness fitness fitness fitness fitness Creation fitness fitness fitness fitness fitness White skin fitness fitness fitness fitness fitness Hydrochloric acid fitness fitness fitness fitness fitness Pyridoxine hydrochloride fitness fitness fitness fitness fitness zinc fitness fitness fitness fitness fitness manganese fitness fitness fitness fitness fitness chrome fitness fitness fitness fitness fitness Disintegration Test 12 minutes 28 seconds - - 12 minutes 35 seconds 12 minutes 32 seconds Weight deviation fitness - - fitness fitness content Berberine (%) 103.21 101.58 96.70 99.12 99.40 Ginsenoside Rb1 (%) 115.32 116.52 127.36 117.86 124.28 Hydrochloric acid amine (mg / capsule) 3.34 3.49 3.16 2.97 3.71 Pyridoxine hydrochloride (mg / capsule) 4.35 4.41 4.27 4.79 3.95 Manganese (mg / capsule) 1.45 1.49 1.48 1.49 1.49 Zinc (mg / capsule) 1.31 1.28 1.30 1.32 1.30

Table 3. DHS123 capsule lot test results (DHS123C2)]

Test date item At the start 2 months acceleration 4 months acceleration Accelerated 6 months Room temperature 6 months Constellation Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Confirm goldthread fitness fitness fitness fitness fitness Ginseng fitness fitness fitness fitness fitness Journeyman fitness fitness fitness fitness fitness Willow blooming fitness fitness fitness fitness fitness rhubarb fitness fitness fitness fitness fitness Jimo fitness fitness fitness fitness fitness Salvia fitness fitness fitness fitness fitness figwort fitness fitness fitness fitness fitness Phalanges fitness fitness fitness fitness fitness Hojiang fitness fitness fitness fitness fitness Street view fitness fitness fitness fitness fitness Astragalus fitness fitness fitness fitness fitness Rooting fitness fitness fitness fitness fitness Creation fitness fitness fitness fitness fitness White skin fitness fitness fitness fitness fitness Hydrochloric acid fitness fitness fitness fitness fitness Pyridoxine hydrochloride fitness fitness fitness fitness fitness zinc fitness fitness fitness fitness fitness manganese fitness fitness fitness fitness fitness chrome fitness fitness fitness fitness fitness Disintegration Test 12 minutes 28 seconds - - 12 minutes 35 seconds 12 minutes 32 seconds Weight deviation fitness - - fitness fitness content Berberine (%) 101.61 103.76 101.38 100.42 97.46 Ginsenoside Rb1 (%) 142.52 139.57 147.88 144.83 143.10 Hydrochloric acid amine (mg / capsule) 3.36 3.42 3.43 3.34 2.99 Pyridoxine hydrochloride (mg / capsule) 4.43 4.23 4.31 4.04 4.48 Manganese (mg / capsule) 1.46 1.52 1.51 1.48 1.48 Zinc (mg / capsule) 1.38 1.32 1.31 1.33 1.34

Table 4. DHS123 capsule lot test results (DHS123C3)]

Test date item At the start 2 months acceleration 4 months acceleration Accelerated 6 months Room temperature 6 months Constellation Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Unusual smell tan granules Confirm goldthread fitness fitness fitness fitness fitness Ginseng fitness fitness fitness fitness fitness Journeyman fitness fitness fitness fitness fitness Willow blooming fitness fitness fitness fitness fitness rhubarb fitness fitness fitness fitness fitness Jimo fitness fitness fitness fitness fitness Salvia fitness fitness fitness fitness fitness figwort fitness fitness fitness fitness fitness Phalanges fitness fitness fitness fitness fitness Hojiang fitness fitness fitness fitness fitness Street view fitness fitness fitness fitness fitness Astragalus fitness fitness fitness fitness fitness Rooting fitness fitness fitness fitness fitness Creation fitness fitness fitness fitness fitness White skin fitness fitness fitness fitness fitness Hydrochloric acid fitness fitness fitness fitness fitness Pyridoxine hydrochloride fitness fitness fitness fitness fitness zinc fitness fitness fitness fitness fitness manganese fitness fitness fitness fitness fitness chrome fitness fitness fitness fitness fitness Disintegration Test 12 minutes 28 seconds - - 12 minutes 35 seconds 12 minutes 32 seconds Weight deviation fitness - - fitness fitness content Berberine (%) 103.16 99.56 97.58 100.19 97.09 Ginsenoside Rb1 (%) 147.59 141.61 148.33 148.18 138.72 Hydrochloric acid amine (mg / capsule) 3.50 3.09 3.11 4.02 3.24 Pyridoxine hydrochloride (mg / capsule) 4.13 4.80 4.11 4.07 4.72 Manganese (mg / capsule) 1.49 1.45 1.51 1.50 1.48 Zinc (mg / capsule) 1.35 1.35 1.30 1.32 1.34

Diabetes Efficacy Test

The therapeutic effect of the composition of the present invention on diabetes was first conducted by animal experiments using a diabetic model mouse, and then proved by testing the therapeutic effect on human harm.

Animal experiments were conducted with an Oral Glucose Tolerance Test (OGTT) on ICR mice to investigate the hypoglycemic effect of the composition, and KK-Ay to identify the therapeutic effect against type 2 (insulin-independent) diabetes. The effect on the mice was measured and tested using streptozotocin-induced diabetic and NOD mice to characterize the effects on type 1 (insulin dependent) diabetes.

The therapeutic effect on the human body was measured by hypoglycemic effect and improvement of insulin secretion in 118 and 24 cases.

Experimental Example 1 OGTT Test in ICR Mouse

1) Experiment Outline

To determine the hypoglycemic effect of the sample, a hypoglycemic drop between the sample and the control group was performed by using an Oral Glucose Tolerance Test using 5-6 week old ICR mice in SPF (Specific Pathogens Free). The effect was compared and confirmed.

2) Experiment Method

A total of 40 animals were selected and classified into 4 groups of 10 animals, the first control group administered 0.85% saline, and the second control group prescribed according to the embodiment of Patent Application No. 2000-30134 , Dansam, Jigolpi, Hyunsam, Hojang, Astragalus, Creation, Hwangbaekpi contains ten herbal extracts, and the third control group is a capsule of patent application No. 2001-3624, prescribed according to the embodiment (ginseng, rye lotus, itinerary, jimo , Ginseng, Phalanx, Rhubarb, Hyunsam, Hojang, Kilkyung, Astragalus, Brown root, Creation, Sangbaekpi, 14 kinds of herbal extracts), the test group was dissolved in 0.85% saline solution of the sample (capsule of the present invention) and treated ultrasonically It was prepared by suspension and administered.

The dose was calculated based on the adult body weight 60Kg to calculate the dose 13.4mg / Kg, the mouse dose was determined to determine the 10-fold 134mg / Kg.

The sample was dissolved in 0.85% NaCl solution, sonicated to give a suspension, and 0.1 mice were administered orally daily by dividing 10 mice per group.

3) How to measure

Samples were administered to ICR mice fasted for 24 hours, and 2 g / Kg of D-(+)-glucose was administered 0.1 ml per 10 g body weight after 1 hour.

Blood glucose measurement was performed every 0, 10, 30, 60, 120 minutes by taking blood from the eye using a blood glucose meter manufactured by Johnson & Johnson.

4) Experiment result

The results of this experiment are shown in [Table 5] and [Figure 1]. In Table 5, the blood glucose was measured 30 minutes after the administration of the sample, and the average value and the standard deviation were recorded.

Table 5. Mean Glucose and Standard Deviation in OGTT Mice]

division Control group 1 Control 2 Control group 3 Test group Average blood sugar (mg / dl) 345.1 255.8 245.3 228.9 Standard Deviation 35.8 51.7 43.6 32.1

As shown in FIG. 1 and Table 5, in the control mice that did not receive the sample, blood glucose increased to 300 mg / dl or more after 30 minutes of glucose administration. In contrast, the treated control group 2, the control group 3 and the test group had a drop in blood glucose of about 100 mg / dl compared to the untreated group, and especially the test group according to the present invention had an excellent blood sugar drop compared to the control group 2 and the control group 3. It can be seen.

In addition, through the Table 5, the composition of the present invention, as well as the degree of blood sugar drop, as well as the deviation range between test subjects is relatively small, it can be confirmed that the drug expression state is stabilized, so that the equality of treatment effect is excellent.

Experimental Example 2 Blood Glucose Lowering Effect in KK-Ay Mice

1) Experiment Outline

KK mice are type 2 diabetic animal models derived from wild mice with apparent obesity, insulin resistance and blood glucose levels of 300-400 mg / dl. KK-Ay mice are animal models in which the Ay gene, an obesity gene, is introduced into KK mice. In this experiment, to determine the therapeutic effect of the composition of the present invention for type 2 (insulin-independent) diabetes, an Oral Glucose Tolerance Test was conducted using KK-Ay mice to compare and confirm the hypoglycemic effect. It was.

2) Experiment Method

Thirty four-week-old KK-Ay mice were divided into three groups (1st control group, 2nd control group, and test group), each of 10 rats, and 0.85% saline was administered daily at a dose of 10mL / kg to the 1st control group. The prescription according to the capsule example of the application No. 2001-3624 was administered to the test group intraperitoneally every day at a dose of 267 mg / 10 mL / kg of the composition of the present invention. For 8 weeks after the administration of the sample, blood was collected from the orbital vein for each week to measure blood glucose, and the side effects of the composition of the present invention were observed by measuring the weight of KK-Ay mice during the administration of the sample.

After the drug administration, KK-Ay mice were fasted for 24 hours, and the prescription according to the capsule formulation of Patent Application No. 2001-3624 to 0.85% saline for the first control mouse and the second control mouse was tested. The group was intraperitoneally administered the capsule composition of the present invention at a dose of 267 mg / kg. After 90 minutes glucose was administered orally to all mice at a concentration of 1 g / kg. After 30, 45, 60, 90 and 120 minutes, blood was collected from the orbital vein of the mouse to measure blood glucose, and the measurement results were expressed as an increase from the blood glucose level before glucose administration.

3) Experiment result

Blood glucose change test results for KK-Ay mice are shown in [FIG. 2] and [FIG. 3]. As can be seen in FIG. 2, the blood sugar level of the first control mice started to increase after 6 weeks, and the average blood sugar level was higher than 400 mg / dl, whereas the mice of the second control group and the test group had a blood sugar of 250 mg / dl. In the first control group, the blood glucose level increased more than 200 mg / dl after 30 minutes, and then gradually decreased. In the second control group and the test group, the blood glucose level increased about 100 mg / dl at the same time. It showed a sharp decline. In particular, it can be seen from the graph that the test group administered with the composition of the present invention had an excellent effect on lowering blood glucose as compared to the second control group.

As a result of observing the side effects of the sample by measuring the body weight of KK-Ay mice during the eight weeks of administration of the sample, the test group mice did not show weight loss due to drug administration. However, as shown in FIG. 3, the mice of the second control group and the test group had less weight than the first control group, which indicates that the KK-Ay mice are obese type diabetic model animals and have a tendency to decrease in weight gain during diabetes treatment. It seems that this study was attributed to diabetes treatment.

Experimental Example 3 Experiments on Streptozotocin-Induced Diabetic Mice

1) Experiment Outline

Streptozotocin (STZ) is an N-nitroso derivative of D-glucosamine that was originally developed as an antibiotic. Streptozotocin is known to reduce intracellular NAD, which destroys beta cells and causes diabetes. In this experiment, the mice were repeatedly administered with 60 mg / kg of streptozotocin for 5 days to artificially induce type 1 diabetes, and then the samples were administered to compare and observe the changes in blood glucose to type 1 (insulin-dependent) diabetes. The therapeutic effect of the composition of the present invention was elucidated.

2) Experiment Method

The experimental animals were supplied from the Korean Experimental Animal Center and managed in the clean room under the conditions of temperature 22 ± ℃, humidity 55 ± 5%, and illumination 12L / 12D. The test animals were divided into 6 groups, the first control group was a control group not administered streptozotocin, the second control group was intraperitoneally administered 60 mg / Kg 3-5 times, and the third control group was treated with streptozotocin. The placebo was administered 0.85% Saline solution, and the fourth control group was prepared according to the embodiment of Patent Application No. 2000-30134, ginseng, rhubarb, jimo, sweet ginseng, phalanges, hyeonsam, hojang, astragalus, creation, yellow white plant herbal medicine Administered as a test drug, the fifth control group ginseng, rhubarb, sperm, gimo, sweet ginseng, phalanges, rhubarb, hyeonsam, hojang, gilkyung, rhubarb, brown root, creation, baekbaekpi according to the capsule formulation of Patent Application No. 2001-3624 14 herbal drugs and vitamin B ₁, B ₆ and zinc, manganese, chromium, germanium were prepared together and administered as a test drug, and the test group was administered 26.7 mg of salicylic acid according to the capsule of the present invention to a sample administered to the fifth control group. Medicated and administered together .

The drug was administered daily from the day of the administration to the 23rd day and the changes in body weight, urine glucose and blood glucose were measured every 4 days.

3) Experiment result

The blood glucose measurement results for each subject of this experiment are shown in [Table 6]. [Table 6] measured the blood glucose measurement of the mouse was measured only to the highest blood concentration 500mg / dl in the measurement technology, Figure 4 is a diagram comparing the average blood glucose measurement for each group on the 16th day, Figure 5 is each The graph shows the change in blood glucose mean by group.

As can be seen from Figure 4 and Figure 5, when the blood glucose value of 300mg / dl or more is determined to be a diabetic mouse, in control 2, 10 out of 11 animals finished, 10 out of 18 animals in control 3 diabetes Was determined. On the other hand, the control group 4, 5 and the test group treated with a significant inhibition of the onset, especially in control group 4 showed an onset of diabetes in 8 out of 18, control 5 in 18 of the control group, while treated with a sample In one control group, only 2 out of 18 animals developed.

In particular, when comparing the standard deviation between the test group treated with the sample and the individuals of the control group 4 and the control group 5, the test group was significantly lower than the control group, indicating that the treatment effect of the sample was relatively stable compared to the control group. .

From the above experiment, it can be seen that the STZ mice of the test group administered with the sample were completely suppressed from the onset of diabetes.

Table 6. Individual Glucose Measurements in STZ Mice]

Experimental Example 4 Effect Experiments on NOD Mice

1) Experiment Outline

NOD mouse (nonobese diabetic mouse) is an animal model of type 1 diabetes mellitus, which occurs naturally between three and six months of age, very similar to human diabetes. In this experiment, in order to verify the therapeutic effect of the composition of the present invention on insulin-dependent (type 1) diabetes, the composition of the present invention was administered to NOD mice as a sample and the change in blood glucose was observed.

2) Experiment Method

Twenty NOD mice from 11 to 20 weeks were selected and 10 were divided into control group (naturally occurring group), 10 were divided into sample group (test group), and the samples were intraperitoneally administered at a concentration of 134 mg / Kg. The change in blood glucose was measured every week.

3) Experiment result

[Table 7] and [Table 8] are the blood glucose measurements of the control group and the test group of NOD mice, respectively. As a result of measurement technology, only the highest blood concentration was measured up to 500 mg / dl. [Table 9] shows the average blood glucose levels of the two groups. The change is shown.

As can be seen in the above table, blood glucose levels increased from 14 weeks of age in the control NOD mice to over 400 mg / dl of hyperglycemia in 20 weeks of age, whereas 20 mg / dl of mice in the sample was administered until 20 weeks of age. Normal blood sugar levels were maintained.

FIG. 6 is a graph showing the change in blood glucose of the control group and the test group.

Table 7. Blood Glucose Measurements-Control of NOD Mice]

Week One 2 3 4 5 6 7 8 9 10 9 195 169 204 188 200 165 146 201 175 167 10 242 165 231 145 209 163 215 197 169 224 11 207 157 233 159 231 174 201 368 166 214 12 213 170 310 171 212 183 239 469 200 240 13 220 166 347 169 230 221 242 480 213 248 14 244 166 345 170 249 233 244 494 220 382 15 390 179 360 188 235 269 360 500 230 384 16 471 184 441 199 213 270 397 500 301 456 17 493 189 458 220 225 367 402 500 495 490 18 500 211 500 226 239 480 436 500 495 500 19 500 176 500 212 237 495 433 500 500 500

Table 8. Blood Glucose Measurements in NOD Mice—Test Group]

Week One 2 3 4 5 6 7 8 9 10 9 179 169 198 143 178 158 275 150 164 190 19 248 171 154 139 199 212 165 169 175 196 11 154 204 199 145 430 179 188 194 148 198 12 192 158 190 165 332 182 221 198 150 200 13 181 193 149 178 350 162 195 185 147 210 14 228 145 154 221 309 175 205 177 168 230 15 209 174 156 199 301 177 169 168 179 215 16 232 177 202 178 354 198 199 198 161 191 17 233 151 198 232 400 185 186 180 198 192 18 215 370 156 219 394 174 264 188 256 179 19 202 389 167 225 462 204 259 201 270 169

Table 9. Average Blood Glucose Measurements in NOD Mice]

Control Test group Blood sugar (mg / dl) 405.3 ± 138.2 254.8 ± 97.4

Experimental Example 5 Experiment for Destruction and Recovery of Beta Cells

In insulin-dependent diabetes, pancreatitis is caused by lymphocyte infilltration of the immune cells and thereby destruction of beta cells, macrophages and T cells invade, and these immune cells destroy beta cells. In this experiment, the pancreatic Langerhans islet was isolated and observed using NOD mice to verify the beta cell restoration effect of the composition of the present invention.

In the above (Experimental Example 4), the NOD mouse group was divided into two groups, and the control group without treatment of the sample and the test group to which the composition of the present invention was administered. At 20 weeks, the pancreas of the mice to which the sample was administered and the mice to which the sample was not administered was isolated and fixed with formalin to make a tissue specimen. Staining was performed using hematoxylene / eosin and the degree of infiltration of immune cells was measured.

In the test group treated with the composition of the present invention, as shown in FIGS. 7A and 7B, it was confirmed that there was no or weak pancreatitis caused by immune cell infiltration, but the control group was not treated with the sample. As can be seen in Figs. 7c and 7d, severe infiltration is observed.

As a result, it can be seen that the sample of the present invention is effective in suppressing immune cell infiltration and restoring beta cells.

(Clinical Example 1) Therapeutic Effect on 118 Patients with Type 2 (Insulin-Independent) Diabetes

Experiment Outline

In order to verify the therapeutic effect of the test drug on non-insulin dependent diabetes mellitus (NIDD) patients, the Oral Glucose Tolerance Test and Insulin Release Test were performed on 118 NIDD patients.

2. Experiment period: January 2001 to September 2001

3. Laboratory: Changchun City, Jilin Province, China, China

4. Subjects: 118 patients who were treated continuously for more than 60 days among the patients who were not receiving insulin therapy during the above experiments.

5. Test drug: DHS for capsules according to the present invention (manufactured and supplied by Uo Pharmaceutical Co., Ltd.)

Experiment method

1. Subject Selection

1) selection criteria; If any of the following items are met according to the 1998 WHO criteria

① As a result of measuring venous blood glucose, fasting blood sugar is 7.8mmol / l (140mg / dl) or more,

Those who have a blood sugar level of 11.1 mmol / l (200 mg / dl) or more

② Result of oral glucose load test even if fasting blood sugar is below 7.8mmol / l (140mg / dl)

A person with a blood sugar level of 11.1 mmol / l (200 mg / dl) or more

③ When blood glucose after 1 hour and blood glucose after 1 hour of OGTT is 11.1 mmol / l (200 mg / dl) or more, and fasting blood sugar is 7.8 mmol / l (140 mg / dl), respectively.

2) exclusion criteria; Person who meets the above selection criteria

① Even if the blood sugar before the test drug is applied, the fasting blood sugar is 7.8mmol / l (140mg / dl) or less through exercise or diet or 11.1mmol / l (140mg / dl) after 2 hours

② A person who violates the test regulations and causes an effect on the calculation of results.

③ A person diagnosed as a type 1 (insulin-dependent) patient

④ Those who have been diagnosed as having diabetic ketosis or asysis in 1 month

⑤ Persons with serious complications, mental illness

⑥ Interruption of treatment, those with abnormal data

⑦ 15 years old or younger or pregnant or mother

2. Observation Method

1) general observation

General physical examinations, such as blood glucose for individual subjects, and heart, kidney, liver, and blood lipids for some subjects should be measured and recorded.

2) Drug efficacy measurement

① Measure blood glucose 2 hours after fasting and meal (measured every 10-15 days after start of medication)

② Oral Glucose Tolerance Test

③ Insulin Release Rest Test

④ Measurement of blood amino-fructose

① of the above is mandatory and other items are measured whenever necessary. This is then compared with the pretest test measurements 60 days after dosing.

3. Dosing method

The test drug is 800 mg (2 capsules) three times a day orally with a drink such as water 30 minutes before meals.

4. Criteria

According to the Chinese Research Ministry's `` Clinical Research and Guiding Principles for Diabetes '',

1) Present

Fasting blood sugar is 7.2 mmol / l (130 mg / dl) or less, and blood glucose is 8.3 mmol / l (150 mg / dl) or less 2 hours after meals

; When blood sugar and urine sugar decrease by more than 30% compared to before treatment

2) Effective

Fasting blood glucose levels of 8.3 mmol / l (150 mg / dl) or less and blood glucose of 2 hours after meals of 10 mmol / l (180 mg / dl) or less

When blood glucose and urine glucose levels are reduced by more than 10% compared to pretreatment

3) Invalid

There is no improvement of symptoms after treatment, and the decrease in blood sugar and urine glucose does not meet the above criteria.

result

1. Lowering blood sugar

Among 118 non-insulin dependent diabetic patients, 84 cases (71.2%) had significant effects, 31 cases (26.3%) had effective effects, and 3 cases (2.48%) had invalid effects.

The blood glucose changes before and after taking 118 subjects are shown in Tables 10 and 11.

2. Blood sugar drop percentage

Among 118 subjects, blood sugar drop was more than 30% in 97 cases (82.2%), 10% or more in 18 cases (15.2%), and blood glucose did not drop or increased after treatment in 3 cases. Fasting blood glucose was found to be more than 7.2 mmol / l (130 mg / dl) in 15 patients.

3. Average time for lowering blood sugar

The mean time to lower blood glucose in 118 cases was 26.7 days.

4. Side effects

No unusual side effects were observed, and some patients showed abdominal distension and diarrhea during the trial period. However, the timing of the administration was improved after meals or after meals.

Table 10. Blood glucose before treatment (mmol / l)] Table 11. Blood Glucose Level After Treatment (mmol / l)] Blood sugar level south female system Hypoglycemia south female system 7.2-8.0 3 3 6 invalidity One 2 3 8.1-9.0 5 7 12 <1.0 One One 9.1-10.0 4 3 7 1.1-2.0 One One 2 10.1-11.0 5 3 8 2.1-3.0 One 2 3 11.1-12.0 6 5 11 3.1-4.0 5 7 12 12.1-13.0 4 4 8 4.1-5.0 6 8 14 13.1-14.0 3 7 10 5.1-6.0 7 5 12 14.1-15.0 5 2 7 6.1-7.0 9 6 15 15.1-16.0 4 5 9 7.1-8.0 7 6 13 16.1-17.0 2 6 8 8.1-9.0 6 7 13 17.1-18.0 3 5 8 9.1-10.0 4 5 9 18.1-19.0 4 3 7 10.1-11.0 One 2 3 19.1-20.0 2 2 4 11.1-12.0 2 2 20.1-21.0 3 2 5 12.1-13.0 4 One 5 21.1-22.0 2 2 13.1-14.0 One One 2 22.1-23.0 One One 14.1-15.0 One One 23.1-24.0 One One 2 15.1-16.0 One One 24.1-25.0 One One 16.1-17.0 One One 25.1-26.0 One One 17.1-18.0 2 One 3 26.1-30.0 One One > 18.1 One 2 3 system 58 60 118 system 60 58 118

Through the above test, it was confirmed that the test drug shows superior blood glucose lowering effect than oral hypoglycemic agent or known herbal extract drug in insulin-independent diabetes patients and is safe for toxicity and side effects.

(Clinical example 2) 24 experiments on hypoglycemia and improvement of insulin secretion ability

summary

In order to confirm the therapeutic effect of the composition of the present invention on insulin-independent diabetes, 24 patients with non-insulin-dependent diabetes mellitus (NIDDM) were selected to administer the samples, and the change in blood glucose before and after treatment, confirmation of insulin secretion before and after treatment, and blood Lipids were measured.

As a result, the hypoglycemic effect of NIDDM patients was remarkable and there was a significant increase in blood insulin concentration within 1 hour after meal. No unusual side effects were observed during the test period.

Subject

1. Selection

① As a result of measuring venous blood glucose, fasting blood sugar is more than 7.8mmol / l (140mg / dl) or postprandial blood sugar is more than 11.1mmol / l (200mg / dl)

② Persons who have a blood sugar level of 11.1 mmol / l (200 mg / dl) or more as a result of the oral glucose load test even if the fasting blood sugar level is 7.8 mmol / l or less (140 mg / dl)

③ When blood glucose after 1 hour and blood glucose after 1 hour of OGTT is 11.1 mmol / l (200 mg / dl) or more, and fasting blood sugar is 7.8 mmol / l (140 mg / dl), respectively.

※ Those who meet the following selection criteria were excluded from this experiment.

① Even if the blood glucose level before the test drug is applied, the fasting blood sugar level is 7.8 mmol / l (140 mg / dl) or less than 11.1 mmol / l (140 mg / dl) after 2 hours through exercise therapy or diet.

② A person who violates the test regulations and causes an effect on the calculation of results.

③ A person diagnosed as a type 1 (insulin-dependent) patient

④ Those who have been diagnosed as having diabetic ketosis or asysis in 1 month

⑤ Persons with serious complications, mental illness

⑥ Interruption of treatment, those with abnormal data

⑦ 15 years old or younger or pregnant or mother

2. Subject Statistics

Table 12. Target patient statistics]

gender Average age History Complications south female High blood pressure angina pectoris Time Etc 13 11 56.3 years 3-14 years 6 2 One 4

Experiment method

1. Test drug

1) Name of the sample: DHS capsule (manufactured by ОО Pharmaceutical Industry Co., Ltd.)

2) Sample composition: 15 kinds of herbal extracts such as rhubarb, vitamin B1, B6, minerals, etc. in 1 capsule 400mg prepared according to the present invention

2. Dosing

Take 4-6 capsules of the test drug three times a day 30 minutes before meals and adjust the enemy according to the symptoms.

3. Measuring method

1) Dosing period: 60 days after dosing.

2) Measurement time: Glucose was measured every week during the treatment period, and fasting blood glucose and fasting blood glucose levels were measured before and after 60 days of initiation and 1 hour and 2 hours after meals.

3) Measuring device: The blood glucose level was a one-touch type blood glucose meter manufactured by Johnson & Johnson of the United States, and the blood insulin level was measured using the FJ-2008 type linear immunoassay set manufactured by Shanghai Changchang

4) Dosing method: Subjects are divided into two groups, 12 for each of the test group and the control group. The test group is orally administered with the test drug sample and the control group is BBM (commercially available product).

5) Method: Measure symptom, blood pressure and weight every week before and after treatment, and measure glucose level, urine glucose level, insulin, cholesterol (TC) and triglyceride (TG) after fasting and 2 hours after meal by enzyme method. Measure

6) Statistical treatment: All test results shall be expressed as x ± S, and the difference between the two groups shall be expressed as x ² .

result

1. Judgment criteria:

1) sheep arc; Fasting blood sugar is 7.2 mmol / l or less and blood sugar is 8.3 mmol / l or less 2 hours after meals

; Blood sugar and urine glucose are reduced by more than 30% compared to before treatment

2) effective; Fasting blood glucose is less than 8.3 mmol / l and fasting blood sugar is less than 10 mmol / l (180 mg / dl) at 2 hours after meals.

When blood sugar and urine glucose are reduced by more than 10% compared to pretreatment

2. Therapeutic effect

In both the test and control group, the sugar dropped significantly. Of the 12 cases in the test group, 7 cases were good and 4 cases were effective. The control group was 4 cases good and 4 cases effective. The total effective rate was 91.67% / 66.67%, which was higher than that in the test group.

The time required to lower blood sugar was also 26.93 days for the control group, compared with 14.11 days for the test group.

Table 13. Comparison of Auditorium Effect (x ± S)]

group Number of cases Fasting blood sugar necessary period Effectiveness (mmol / L) (day) Test group Before treatment 12 13.11 ± 2.71 14.11 ± 2.50 91.67% After treatment 12 7.26 ± 1.42 Control Before treatment 12 12.98 ± 2.80 26.93 ± 12.24 66.67% After treatment 12 8.62 ± .57

3. Changes in Insulin in Blood

Twelve cases of the test group were measured for blood insulin levels before and after treatment, fasting at 1 hour and 2 hours after eating. Serum insulin levels on fasting and 2 hours post-prandial showed no significant changes before and after treatment (p> 0.05). The results are shown in [Table 14].

4. Changes in Lipids

TC and TG before and after treatment were measured. The TC and TG contents were significantly lower in the observation group and the results are shown in [Table 14].

Table 14. Comparison of Blood Insulin and Blood Concentration Before and After Treatment]

Case Blood Insulin (mmol / L) Blood Lipids (mmol / L) spandrel 1 hour after meal 2 hours after eating TC TG Before treatment 12 10.05 ± 3.98 41.55 ± 7.22 75.66 ± 14.95 6.88 ± 0.69 2.81 ± 0.66 After treatment 12 10.78 ± 3.90 87.29 ± 13.90 97.88 ± 12.15 5.12 ± 0.50 1.19 ± 0.31

5. Symptom improvement and side effects

The whole group was free of polyuria and polyhydramnios, and physical fitness improved significantly.

Six cases of hypertension and one case of visual complication were recovered and one case of angina improved. In 4 other complications such as skin, 3 cases were confirmed to have disappeared.

There were no specific toxicity, no side effects, and no changes in liver or kidney function during the trial.

The needs of patients in diabetes not only control blood sugar but also want to restore normal function and constitution. According to this experiment, it is judged that the sample can sufficiently solve this problem.

(Clinical Example 3) Dosage Case of Type 1 (Insulin-dependent) Diabetic Patients

Case 1

1) Patient Overview

A 58-year-old housewife, she was diagnosed with diabetes when she visited Samda in 1992 and a rapid weight loss from 68 kg to 61 kg in two months. He was hospitalized and received 20 units of insulin per day after discharge. Fasting blood glucose levels were maintained between 180 and 200 mg / dl during insulin administration.

2) Dosing

2001. 5. Obtained the consent of the patient and his / her caregiver, and the samples were supplied and instructed to take 2 capsules 3 times a day 30 minutes before meals.

After taking 3 weeks, blood glucose improved to 138mg / dl, reducing insulin dose to 15 units, and after 1 week, blood glucose was found to be 140mg / dl again, reducing 5 units again. The supply was stopped.

After fasting blood glucose level of 140-180mg / dl, the dose was reduced by 1 capsule every time. As of October 2001, 1 capsule per day and 3 capsules per day maintain normal blood sugar. Improvements were made.

Case 2

1) Patient Overview

A woman, a former middle school teacher born in 1937. She was diagnosed with type 1 diabetes during her physical examination when she retired more than 10 years ago. Since then, she has received regular insulin administration (3 times a day, 10 units each time) and hospital treatment. The average fasting blood glucose of the sample was maintained at 210 to 230 mg / dl.

There were no hospital records and no complications due to triglycerides, weight loss, or diabetes mellitus.

2) Dosing

2001. 2. Obtain the consent of the patient and his / her guardian, supply a sample, take 2 capsules once a day, 30 minutes before meals, and if the fasting blood glucose level is 180 mg / dl or less as a result of blood glucose measurement, Instructed to decrease by 5 units.

Five weeks after taking blood sugar, the blood sugar level was improved and maintained at 132-167mg / dl, and the insulin dose was decreased by 5 units. 2001. 5. Currently, the insulin supply was stopped and the sample was taken 6 capsules per day. The symptoms of thickening were also improved.

Case 3

1) Patient Overview

A 46-year-old male office worker in Changchun, Jilin Province, China, who lost weight from 81Kg to 71Kg with Samda phenomena from July-August 2000, visited and diagnosed as type 1 (insulin-dependent) diabetes. It was measured up to 280 mg / dl, and afterwards, he was hospitalized for 1 week and received insulin for 20 units twice a day through insulin loading test, but blood glucose level was not improved to 220-270 mg / dl. After administration, side effects such as edema and lowering of blood pressure occurred.

2) Dosing

2001. 1. The patient and the guardian's consent were obtained and samples were fed and 2 capsules were taken 3 times a day 30 minutes before meals.

In the first 8 weeks, blood glucose level did not change, but blood glucose began to drop from the ninth week and dropped to 180 mg / dl at the 11th week afterwards. With the disappearance of Samda phenomenon, body weight increased to 76kg.

Case 4

1) Patient Overview

Chinese, a resident of Changchun, Jilin Province, China, born in 1929, retired official, suffering from diabetes from around the age of 50 years. The patient was judged to be receiving 45 units of insulin per day at the time of dosing.

Fasting blood glucose levels before the onset of therapy ranged from 280 to 330 mg / dl. The body weight decreased from 75 kg to 52 kg at the onset of the initial onset.

2) Dosing

2001. 2. Patients and guardians obtained the consent and the sample was supplied. Take 2 capsules with insulin 3 times a day for 30 minutes before meals. The dose was instructed to decrease every 5 units.

As a result, blood glucose improved to less than 160mg / dl 6 weeks after the dose, and the insulin dose was decreased by 5 units. Significant improvement in infection was also observed.

Case 5

1) Patient Overview

Chinese, Residing in Heilongjiang Province, China, self-employed women born in 1959, developed after giving birth in 1985, oral oral hypoglycemic drugs afterwards. Received 10 units each time,

Fasting blood glucose was 210-240mg / dl before the start of the administration. Since 1998, surgery was necessary due to rapid left eye loss and cataract, but postponed due to blood glucose. In addition, he showed severe severity.

2) Dosing

Since February 2001, he has been instructed to take 2 capsules 3 times a day with insulin and to reduce insulin dose every 5 units when fasting blood glucose is below 180mg / dl.

After 3 weeks, the blood glucose level improved from 138 to 178 mg / dl to decrease insulin dose. As a result, the blood glucose level was maintained at 140 mg / dl in 7 weeks.

2001. 5. It was observed that the insulin supply was discontinued and only 4 capsules of the sample were taken per day.

According to the present invention, 15 kinds of herbal medicines of ginseng, rhubarb, sperm, willow bark, rhubarb, jimo, dansam, hyeonsam, phalanx, hojang, gilyeong, rhubarb, brown root, creation, baekbaekpi and vitamin B₁, B ₆ and minerals As a novel diabetic composition containing zinc, manganese, chromium, germanium as a bar, it was confirmed that the drug is very useful for the treatment of insulin-dependent and non-dependent diabetes patients through examples, animal experiments and clinical examples. .

Claims (4)

Ginseng 400 ~ 800 parts by weight, Rhubarb 1900 ~ 3400 parts by weight, 50 ~ 400 parts by weight of yeast, 170 ~ 1700 parts by weight of willow bark, rhubarb 50 ~ 600 parts by weight, 500 ~ 800 parts by weight of balsam, 400 ~ 600 parts by weight of salvia , 400-700 parts by weight of Hyunsam, 500-800 parts by weight of phalanges, 400-600 parts by weight, length 300-500 parts by weight, 900-1300 parts by weight of astragalus, 600-800 parts by weight of brown root, 600-800 parts by weight, A pharmaceutical composition for treating diabetes, comprising 250 to 450 parts by weight of lettuce and skin and an allowable effective amount of vitamins B₁, B _{6 and} an allowable effective amount of zinc, manganese, chromium, and germanium as minerals. The pharmaceutical composition for treating diabetes of claim 1, comprising salicylic acid or a salt thereof instead of willow bark. Paragraph 1 ginseng, rhubarb, itinerary, willow bark, rhubarb, jimo, dansam, hyeonsam, phalanges, hojang, gilkyung, hwanggi, brown root, creation, baekbaekpi, 15 kinds of herbal medicine, 500 ~ 800 parts by weight, Cornus 250 ~ A pharmaceutical composition for treating diabetes comprising 550 parts by weight, 300-600 parts by weight of deficiency, and 300-600 parts by weight of Macmundong, and an allowable effective amount of vitamins B ₁ and B ₆ and allowable effective amounts of zinc, manganese, chromium and germanium. . Claim 1, ginseng, rhubarb, itinerary, willow bark, rhubarb, jimo, dansam, Hyunsam, phalanges, hojang, Gilgyeong, Hwanggi, brown root, creation, Sangbaekpi, 15 kinds of herbal medicine, 500 ~ 800 parts by weight, Cornus 250 ~ 550 parts by weight, 300-600 parts by weight, 300-600 parts by weight of Macmundong, 100-200 parts by weight of samchil 100-200 parts by weight, 100-200 parts by weight of ginseng, and 300-600 parts by weight of baekchul, and allowable effective amounts of vitamins B₁ and B ₆ And a pharmaceutical composition for treating diabetes, comprising an allowable effective amount of zinc, manganese, chromium, and germanium, which are minerals.