CN101590007A - A kind of metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions and preparation thereof - Google Patents
A kind of metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions and preparation thereof Download PDFInfo
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Abstract
The invention provides a kind of metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions and preparation thereof; The weight ratio of two kinds of contained principal agents be 8000: 1～375: 1 preferred 2500: 1～625: 1.Except that principal agent, also can further contain the common drug adjuvant, as binding agent, filler, disintegrating agent, lubricant, correctives, wetting agent, fluidizer, resultant composition can be made tablet, granule, soft or hard capsule and sustained-release preparation according to a conventional method, preferred enteric coated tablet, enteric coated granule and enteric soft or hard capsule.Advantages such as compositions provided by the invention has the complementation of principal agent mechanism of action, many target spots, and patient's compliance is good.This hypoglycemic oral preparation compositions can be used for the first-line treatment of type 2 diabetes mellitus; Or can under failing the condition of single effective blood sugar control, metformin hydrochloride or sulfonylureas medicine be used for second line treatment; Be particularly useful for the treatment of the diabetic of LADA (adult sends out Autoimmune Diabetes evening), hyperinsulinemia.
Description
Technical field
The invention belongs to medical technical field, relate to a kind of hypoglycemic oral preparation compositions and preparation thereof.
Background technology
Diabetes are a kind of commonly encountered diseases and frequently-occurring disease, International Diabetes Federation's recent statistics data show, and 20 years in the past, global diabetics number increased severely to 2.3 hundred million people from 3,000 ten thousand people.The expert estimates that in 20 years, global diabetics total number of persons will be increased to 3.5 hundred million people.At present, the annual whole world has about 3,000,000 people to die from diabetes, and mortality rate can be increased to 25% in following 10 years.If the untimely treatment of diabetes or control badly can cause multiple complications, as 1. diabetic nephropathy: renal function injury, make kidney can not keep the protein useful, can not drain refuse, and cause edema human body, (lower limb, face is obvious) develop into uremia easily; 2. diabetic oculopathy: the optical fundus retinal vascular disease causes retinal hemorrhage, and visual deterioration causes cataract, glaucoma, and weight person is blind; 3. diabetic cardiovascular diseases: hypertension easily takes place, coronary heart disease, the coronary atherosclerosis distortion, narrow and stop up, cause angina pectoris, myocardial infarction, even die suddenly; 4. diabetic neuropathy and diabetic foot.So at present diabetes have become one of the most serious healthy disaster that the whole world faces; People make every effort to the generation that all ways come control of diabetes and the generation of development and control complication.
Diabetes are one group, and to increase with blood sugar level be the metabolic disease group of feature, and patient's blood glucose under empty stomach is higher than the normal person, and the back blood glucose peak value of having meal is higher than the normal person, and the blood sugar increasing persistent period is than normal person significant prolongation.Epidemic research shows, hyperglycemia state not only reduces the function of beta Cell of islet and the sensitivity of insulin, produce insulin resistant, and it is closely related with the chronic complicating diseases of diabetes, and in fasting glucose and two indexs of post-prandial glycemia, the level of postprandial blood sugar increase is a key factor relevant with vascular complication.Therefore, how when keeping reducing fasting glucose, better post-prandial glycemia being lowered, make the blood glucose profile held stationary, is vital steps to the treatment diabetes.
Voglibose is a kind of a-D glucosidase inhibitor; Its blood sugar reducing function mechanism is that competition suppresses the maltase on the little goldbeater's skin, and isomaltase, glycosides carbohydrase etc. make disaccharidase decompose to monosaccharide and reduce, a little less than the a-diastatic action to pancreas, therefore can delay digesting and assimilating of starch and sucrose after oral, thus blood sugar lowering, especially postprandial hyperglycemia.
The mechanism of this kind uniqueness makes voglibose on the basis of blood sugar lowering, also has following special advantages: 1. not only can slow down the post-prandial glycemia peak by the absorption that suppresses carbohydrate, and do not cause hypoglycemia, be that the what is called peak that disappears goes paddy, alleviate blood glucose fluctuation, further reduce the danger of suffering from cardiovascular disease; 2. do not stimulate insulin secretion, thereby can not cause hypertension, the coronary heart disease that hyperinsulinemia further causes diabetics because of improving blood insulin concentration; 3. reduce the post-prandial glycemia of diabetics safely and effectively, fasting glucose is also had in various degree reduction effect, can reduce the glycolated hemoglobin level simultaneously; 4. the voglibose low dose can be improved postprandial hyperglycemia, and gastrointestinal side effect is also corresponding simultaneously alleviates.
Metformin hydrochloride has gone on the market for many years, and clinical data is sure in a large number for curative effect.Pharmacological action is as follows: promote the anerobic glycolysis of sugar in the surrounding tissue, tissues such as increase muscle are to the sugar opposite sex in picked-up, utilization and the inhibition liver of glucose, inhibition or delay glucose absorb at gastrointestinal, promote insulin and insulin binding, increase the elimination effect of insulin to blood glucose, except that improving insulin sensitivity, can also suppress Hyperinsulinism after meal.
At present people to the carrying out of the single preparations of ephedrine of above two hypoglycemic medicines vast amount of clinical.Sun Hongjiang with regard to comparative study the clinical efficacy of the sharp metformin hydrochloride treatment of voglibose type 2 diabetes mellitus, result of study shows: voglibose reduces after the meal 2h blood glucose imitates and is better than metformin hydrochloride, metformin hydrochloride reduces the fasting glucose effect and is better than voglibose, and both obstructed stimulation oversaturation insulin secretions and working, so can alleviate the illeffects of hyperinsulinemia after the meal, reduce insulin resistant, help the syndromic control of metabolism such as cardiovascular complication.(Sun Hongjiang, the curative effect of voglibose and metformin hydrochloride treatment type 2 diabetes mellitus compares Hebei medical science,, Vol16 (12), P1073-1075 in 2000.)
From top result of study because both blood sugar reducing function mechanism is different, although the both has the effect of blood sugar lowering, both fall fasting glucose and after the meal 2h blood glucose emphasize particularly on different fields.When how to make hypoglycemic medicine energy safety, effective blood sugar lowering, make the blood glucose profile held stationary again, and can improve insulin resistant, this is only the key point that people seek the blood sugar lowering medicament.
The compound preparation that the drug regimen that two kinds of blood sugar reducing function mechanism is different becomes has many advantages: can bring into play the characteristics of dissimilar medicines, mechanism of action is had complementary advantages, and improves curative effect, and blood sugar control reduces the generation of complication effectively; The compound preparation of fixed mixing ratio also helps the compliance that improves the patient, and this point is particularly important to long-term chronic disease.
Show through relevant patent and prior art literature search result, there is no the relevant report of metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions.
Summary of the invention
In order to overcome the defective that two kinds of single preparationss of ephedrine of voglibose and metformin hydrochloride are applied to clinical existence, we are according to the mechanism of action of above two kinds of hypoglycemic medicines, consider from many target spots, effect mutual supplement with each other's advantages, through exploring repeatedly, developed one group of hypoglycemic oral preparation compositions, principal agent comprises voglibose and metformin hydrochloride.This compound preparation reaches mechanism of action complementation, many target spots, and can guarantee patient's compliance, convenience by the exquisite scientific combination of two kinds of different hypoglycemic drugs.
The purpose of this invention is to provide one group is hypoglycemic oral preparation compositions of principal agent and preparation method thereof with voglibose and metformin hydrochloride.
Technical scheme of the present invention is: one group is the hypoglycemic oral preparation compositions of principal agent with voglibose and metformin hydrochloride, and said composition comprises voglibose, metformin hydrochloride and one or more pharmaceutically acceptable excipient.The weight ratio scope of metformin hydrochloride and voglibose be 8000: 1～375: 1 preferred 2500: 1～625: 1.Described hypoglycemic oral preparation compositions comprises the metformin hydrochloride of 100mg～2000mg, preferred 150mg～1500mg.Described hypoglycemic oral preparation compositions comprises the voglibose of 0.05mg～0.6mg, preferred 0.1mg～0.4mg.
Described metformin hydrochloride is the salt that is selected from following form: hydrochlorate, acetate, benzoate, citrate, fumarate, embonate, tomatotone salt, glycollate, palmitate, aspartate, methane sulfonates, maleate, Chlorophibrinic Acid salt, formates, lactate, succinate, sulfate, tartrate, cyclohexane-carboxylic acid salt, caproate, caprylate, caprate, palmitate, the octadecane hydrochlorate, benzene sulfonate, trimethoxybenzoic acid salt, tosilate, adamantanecarboxylic acid salt, glyoxylate, glutamate, Glu, pyrrolidone carboxylic acid salt, naphthalene sulfonate, 1-glucose phosphate salt, nitrate, sulphite, dithionate or phosphate; Preferred salt hydrochlorate, fumarate, embonate, tomatotone salt.
Described hypoglycemic oral preparation compositions, also can further contain carrier and/or adjuvant commonly used in the pharmaceuticals industry, for example binding agent, filler, disintegrating agent, lubricant, correctives, wetting agent, fluidizer etc., resultant composition can be made tablet, granule, soft or hard capsule and sustained-release preparation according to a conventional method.Found through experiments, if it is compositions conventional tablet of the present invention is enteric coated, can alleviate compositions principal agent of the present invention stimulates gastrointestinal, and gastrointestinal reaction is few, so the preferred enteric coated tablet of present composition dosage form, enteric coated granule and enteric soft or hard capsule.
Tablet and granule can be by dry method or wet granulation technology preparations, dry according to a conventional method after the granulation, granulate becomes granule, or further tabletting, coating are made tablet, and the suitable hybrid particles that capsule can be made compositions is filled in the soft hard ' Yanming ' capsules for clearing or prepares in the enteric coated capsule and finishes.
Described hypoglycemic oral preparation compositions, it is used for the first-line treatment of type 2 diabetes mellitus, or can be under metformin hydrochloride or sulfonylureas medicine be failed the condition of single effective blood sugar control, be used for second line treatment, be particularly useful for the treatment of the diabetic of LADA (adult sends out Autoimmune Diabetes evening), hyperinsulinemia.
The specific embodiment
Embodiment 1 (specification voglibose 0.1mg: metformin hydrochloride 250mg)
Make enteric coated capsule, with 1000 is example, get acid hydrochloride salt metformin 295.85g (by metformin hydrochloride 250.00g), voglibose 0.10g, microcrystalline Cellulose 180.00g, polyvinylpyrrolidone 25.00g and cross 100 mesh sieves respectively, in blender, fully mix, add 60% an amount of alcoholic solution and make soft material.Soft material is granulated by 20 eye mesh screens on the granulator.With the above-mentioned granule that makes in 50 ℃ of dry 30min.Again by oscillating granulator, with 18 eye mesh screen granulate.Hybrid particles is carried out assay, and definite enteric softgel shell range of capacity is filled.After the passed examination, packing.
Embodiment 2 (specification voglibose 0.2mg: metformin hydrochloride 150mg)
Make enteric coated capsule, with 1000 is example, get acid hydrochloride salt metformin 177.51g (by metformin hydrochloride 150.00g), voglibose 0.20g, starch 109.30g, polyvinylpyrrolidone 13.00g and cross 100 mesh sieves respectively, in blender, fully mix, add 85% an amount of alcoholic solution and make soft material.Soft material is granulated by 20 eye mesh screens on the granulator.With the above-mentioned granule that makes in 50 ℃ of dry 30min.Again by oscillating granulator, with 18 eye mesh screen granulate.Hybrid particles is carried out assay, and definite enteric capsule shell range of capacity is filled.After the passed examination, packing.
Embodiment 3 (specification voglibose 0.1mg: metformin hydrochloride 250mg)
Make enteric coated tablet, with 1000 is example, get acid hydrochloride salt metformin 295.85g (by metformin hydrochloride 250.00g), voglibose 0.10g, pregelatinized Starch 157.00g, polyvinylpyrrolidone 25.00g, carboxymethyl starch sodium 20.00g and cross 100 mesh sieves respectively, put into blender, mix homogeneously adds an amount of 85% alcoholic solution again and makes soft material.Soft material in 50 ℃ of dry 30min, always mixes granule with dried granule and magnesium stearate 2.05g by waving 18 eye mesh screens granulation on the granulation machine, crosses 16 eye mesh screen granulate with oscillating granulator, and granule is carried out assay, and the heavy scope of definite sheet, tabletting.Or the coating pan coating is used, drying with 80% ethanol configuration coating solution in the back.
Embodiment 4 (specification voglibose 0.2mg: metformin hydrochloride 150mg; 0.5g/ bag)
Make granule; with 1000 bags is example; get acid hydrochloride salt metformin 177.51g (by metformin hydrochloride 150.00g), voglibose 0.20g, lactose 200.00g, microcrystalline Cellulose 107.30g, citric acid 15.00g and cross 100 mesh sieves respectively; in blender, fully mix; add 80% an amount of alcoholic solution and make soft material; soft material is by waving 18 eye mesh screens granulation on the granulation machine; again with the granule that makes in 50 ℃ of dry 30min; cross 16 eye mesh screen granulate by oscillating granulator; hybrid particles is carried out assay, determine loading amount.
Embodiment 5 specification voglibose 0.2mg: metformin hydrochloride 250mg)
Make enteric coated capsule, with 1000 is example, get acid hydrochloride salt metformin 295.85g (by metformin hydrochloride 250.00g), voglibose 0.20g, microcrystalline Cellulose 130.00g, polyvinylpyrrolidone 24.00g and cross 100 mesh sieves respectively, in blender, fully mix, add 60% an amount of alcoholic solution and make soft material.Soft material is granulated by 20 eye mesh screens on the granulator.With the above-mentioned granule that makes in 50 ℃ of dry 30min.Again by oscillating granulator, with 18 eye mesh screen granulate.Hybrid particles is carried out assay, and definite enteric softgel shell range of capacity is filled.After the passed examination, packing.
Embodiment 6 (specification voglibose 0.2mg: metformin hydrochloride 250mg; 0.5g/ bag)
Make granule; with 1000 bags is example; get acid hydrochloride salt metformin 295.85g (by metformin hydrochloride 250.00g), voglibose 0.20g, lactose 100.00g, microcrystalline Cellulose 89.00g, citric acid 15.00g and cross 100 mesh sieves respectively; in blender, fully mix; add 80% an amount of alcoholic solution and make soft material; soft material is by waving 18 eye mesh screens granulation on the granulation machine; again with the granule that makes in 50 ℃ of dry 30min; cross 16 eye mesh screen granulate by oscillating granulator; hybrid particles is carried out assay, determine loading amount.
Embodiment 7 (specification voglibose 0.1mg: metformin hydrochloride 500mg; The 1g/ bag)
Make granule; with 1000 bags is example; get acid hydrochloride salt metformin 591.70g (by metformin hydrochloride 500.00g), voglibose 0.10g, lactose 150.00g, microcrystalline Cellulose 243.20g, citric acid 15.00g and cross 100 mesh sieves respectively; in blender, fully mix; add 80% an amount of alcoholic solution and make soft material; soft material is by waving 18 eye mesh screens granulation on the granulation machine; again with the granule that makes in 50 ℃ of dry 30min; cross 16 eye mesh screen granulate by oscillating granulator; hybrid particles is carried out assay, determine loading amount.
Embodiment 8 (specification voglibose 0.2mg: metformin hydrochloride 150mg)
Make enteric coated tablet, with 1000 is example, get acid hydrochloride salt metformin 177.51g (by metformin hydrochloride 150.00g), voglibose 0.20g, pregelatinized Starch 112.30g, polyvinylpyrrolidone 30.00g, carboxymethyl starch sodium 25.00g and cross 100 mesh sieves respectively, put into blender, mix homogeneously adds an amount of 85% alcoholic solution again and makes soft material.Soft material in 50 ℃ of dry 30min, always mixes granule with dried granule and magnesium stearate 5.00g by waving 18 eye mesh screens granulation on the granulation machine, crosses 16 eye mesh screen granulate with oscillating granulator, and granule is carried out assay, and the heavy scope of definite sheet, tabletting.Or the coating pan coating is used, drying with 80% ethanol configuration coating solution in the back.
Creativeness of the present invention, practicality are verified by following experiment:
As the finished product verification sample, do following drug effect and toxicity test with the capsule that provides by the embodiment of the invention 1:
1. pharmacodynamics test:
Select the Wistar rat for use, male and female half and half, body weight 150-200g,
Be divided into 5 groups at random: 1. normal control group (n=32), 2. model ground is according to group (n=32), 3. voglibose group (n=32), 4. metformin hydrochloride group (n=32), 5. compositions group (n=32).
Cause rat type 2 diabetes mellitus experimental model with streptozotocin.
Experimental technique: it is 1/50 of 0.1mg that the each stomach tube of voglibose group pours into the glad capsule of occasion (the anti-drugmaker in Shandong, Shandong provides) dosage, every day 3 times; The each stomach tube of metformin hydrochloride group pours into 1/50 of the flat capsule of three types of diabetes (Changzhou Lanling Pharmaceutical Co., Ltd.'s production) 250mg, every day 3 times; The each stomach tube of compositions group pours into 1/50 amount of finished product verification sample, every day 3 times; Normal control group and model control group pour into 10ml/kg body weight normal saline simultaneously; Continuous 12 all administrations.Reach 2h blood glucose (FBS, P2hBS) after the meal on an empty stomach in detecting respectively in 0,4,8,12 weeks of administration, reach 2h insulin, glycolated hemoglobin after the meal on an empty stomach in detecting respectively in 0,12 weeks of administration.
The results are shown in Table 1 and table 2, experimental result is represented with x ± s, with t check analysis result.
Table 1 is respectively organized the variation (mmol/L) of rat blood sugar level
Annotate: FBG is a fasting glucose, and BG2h is 2h blood glucose after the meal
Table 2 is respectively organized the variation of rat insulin and glycolated hemoglobin level
Can find out by table 1 and table 2, in the 4th, 8 and 12 weeks of laboratory observation, zero difference before each time point blood sugar level zero difference of normal control group, 12 all glycolated hemoglobins and insulin level and the medication; At identical time point, model control group blood glucose, glycolated hemoglobin, the 2h insulin level all is higher than the normal control group after the meal, and the fasting insulin level all is lower than the normal control group, and the normal matched group of model control group has significant difference (P＜0.05).When the course of treatment, the 12nd week finished, compare between compositions group, voglibose group, metformin hydrochloride group and model control group, blood glucose, glycolated hemoglobin level all are lower than model control group, the compositions group has significant difference (P＜0.05) than model control group, and normal matched group unknown significance poor (P＞0.05); And the compositions group reaches on an empty stomach than voglibose group, metformin hydrochloride group that 2h blood glucose is more approaching after the meal, and whole day blood glucose is more steady.
Experimental result shows: use metformin hydrochloride/voigelibo sugar-lowering oral preparation compositions, and effectively control of diabetes patient's blood glucose, glycolated hemoglobin, it is obvious to treat the diabetics curative effect.
2. toxicity test:
Anxious poison: carry out acute toxicity test by " chemicals acute toxicity test technological guidance principle " (in March, 2005 version), experimental result is as follows.
The mice single oral gives the toxic reaction basically identical of compositions metformin hydrochloride/voglibose appearance of three kinds of proportionings, 10～30 minutes part animal activities reduce, close one's eyes after the administration, 1 hour part animal diarrhoea, instability of gait behind the medicine, the number of animals that toxic reaction takes place and the order of severity and dosage are proportionate.Animal dead appears at behind the medicine 4～5 hours the earliest, and all animal deads all occurred in behind the medicine in 18 hours.Dead animal is cutd open inspection, the slight pneumorrhagia of visible part animal, other internal organs are not seen any obvious pathological changes.Behind the medicine 18 hours, all surviving animals were recovered normal activity substantially.Surviving animals is not seen death in 14 days observation period.Getting the part surviving animals on the 14th day cuts open inspection and does not see obvious pathological changes.Median lethal dose(LD 50) (the L of the different proportionings of mice orally give compositions metformin hydrochloride/voglibose (150: 0.2,250: 0.2,250: 0.1,500: 0.1)
D50) be respectively 3405.3,3321.5,3223.8,3047.1mg/kg.
Long poison: carry out long term toxicity test by " chemicals long term toxicity test technological guidance principle " (in March, 2005 version), experimental result is as follows.
Respectively organize general symptom during the administration and there is no unusually, all no abnormal variation of outward appearance sign, behavioral activity, body weight gain; Blood and biochemical every index all within normal range, compare there was no significant difference with matched group; Each treated animal is put to death behind administration 9 months and drug withdrawal 14d and is cutd open inspection, each main organs heart, liver, spleen, lung, kidney, adrenal gland, all no abnormal variation of brain naked eyes, and pathological examination is not also seen significantly pathological change such as atrophy, degeneration, necrosis.Experimental result shows the ratio that adopts metformin hydrochloride provided by the present invention/voigelibo sugar-lowering oral preparation compositions, and its safety of toxicity test data show is good.
Conclusion: metformin hydrochloride provided by the present invention/voigelibo sugar-lowering oral preparation compositions is a kind of efficient, safe compound oral compositions.
Claims (7)
1, a kind of hypoglycemic oral preparation compositions and preparation thereof is characterized in that said composition comprises voglibose, metformin hydrochloride and one or more pharmaceutically acceptable excipient.
2, according to the described hypoglycemic oral preparation compositions of claim 1, it is characterized in that metformin hydrochloride is the salt that is selected from following form: hydrochlorate, acetate, benzoate, citrate, fumarate, embonate, tomatotone salt, glycollate, palmitate, aspartate, methane sulfonates, maleate, Chlorophibrinic Acid salt, formates, lactate, succinate, sulfate, tartrate, cyclohexane-carboxylic acid salt, caproate, caprylate, caprate, palmitate, the octadecane hydrochlorate, benzene sulfonate, trimethoxybenzoic acid salt, tosilate, adamantanecarboxylic acid salt, glyoxylate, glutamate, Glu, pyrrolidone carboxylic acid salt, naphthalene sulfonate, 1-glucose phosphate salt, nitrate, sulphite, dithionate or phosphate; Preferred salt hydrochlorate, fumarate, embonate, tomatotone salt.
3, according to the described hypoglycemic oral preparation compositions of claim 1, the weight ratio that it is characterized in that metformin hydrochloride and voglibose be 8000: 1～375: 1 preferred 2500: 1～625: 1
4,, it is characterized in that comprising the metformin hydrochloride of 100mg～2000mg, preferred 150mg～1500mg according to the described hypoglycemic oral preparation compositions of claim 1.
5,, it is characterized in that comprising the voglibose of 0.05mg～0.6mg, preferred 0.1mg～0.4mg according to the described hypoglycemic oral preparation compositions of claim 1.
6, according to the described hypoglycemic oral preparation compositions of claim 1～5, also can further contain medicinal binding agent, filler, disintegrating agent, lubricant, correctives, wetting agent, fluidizer, resultant composition can be made tablet, granule, soft or hard capsule and sustained-release preparation according to a conventional method, preferred enteric coated tablet, the sharp enteric soft or hard of enteric coated granule capsule.
7, as each described hypoglycemic oral preparation compositions of claim 1～6, it can be used for the first-line treatment of type 2 diabetes mellitus, or can be under metformin hydrochloride or sulfonylureas medicine be failed the condition of single effective blood sugar control, be used for second line treatment, be particularly useful for the treatment of the diabetic of LADA (adult sends out Autoimmune Diabetes evening), hyperinsulinemia.
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| US9480663B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
| US9481642B2 (en) | 2011-01-07 | 2016-11-01 | Elcelyx Therapeutics, Inc. | Biguanide compositions and methods of treating metabolic disorders |
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| US10603291B2 (en) | 2012-01-06 | 2020-03-31 | Anji Pharma (Us) Llc | Compositions and methods for treating metabolic disorders |
| US9770422B2 (en) | 2012-01-06 | 2017-09-26 | Elcelyx Therapeutics, Inc. | Compositions and methods for treating metabolic disorders |
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| WO2013115742A1 (en) * | 2012-01-31 | 2013-08-08 | Mahmut Bilgic | Pharmaceutical composition comprising alpha-glucosidase inhibitor |
| WO2013115743A1 (en) * | 2012-01-31 | 2013-08-08 | Mahmut Bilgic | Effervescent tablet formulations comprising the combination of voglibose and metformin |
| JP2016509065A (en) * | 2013-03-06 | 2016-03-24 | シージェイ ヘルスケア コーポレイションＣｊ Ｈｅａｌｔｈｃａｒｅ Ｃｏｒｐｏｒａｔｉｏｎ | Preparations for the prevention or treatment of diabetes |
| CN104027328A (en) * | 2013-03-06 | 2014-09-10 | Cj第一制糖株式会社 | Formulation for prevention or treatment of diabetes |
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