CN103721261B - Medical composition and its use containing SGLT2 inhibitor and vitamin B group - Google Patents
Medical composition and its use containing SGLT2 inhibitor and vitamin B group Download PDFInfo
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Abstract
The present invention relates to a kind of pharmaceutical composition containing sodium-glucose 2 type transporter (SGLT2) inhibitor and vitamin B group, be made up of one or more and pharmaceutically acceptable carrier of the vitamin B group of a kind of, the treatment effective dose of the SGLT2 inhibitor for the treatment of effective dose and medicinal precursor, active metabolite or salt apoplexy due to endogenous wind; Wherein, SGLT2 inhibitor mainly comprises that Da Gelie is clean, Rui Gelie is clean, She Gelie is clean, and content is 2.5 ~ 500mg, and the content of vitamin B group is 0.01 ~ 50mg.The invention still further relates to the purposes of said composition in the medicine for the preparation for the treatment of diabetes.The medicine be made up of pharmaceutical composition provided by the invention, on effective hypoglycemic basis, has the beneficial effect preventing or delay diabetic angiopathy complication significantly.In addition, the present invention also can make patient consumes convenient, increases compliance.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition containing sodium-glucose 2 type transporter (sodiumglucoseco-transporter2, SGLT2) inhibitor and vitamin B group, belong to pharmaceutical field.
Background technology
Diabetes are a kind of common endocrine metabolism diseases, are characterized in that chronic hyperglycemia is with the sugar, fat and the protein metabolism disorder that cause because of hypoinsulinism and/or effect defect.According to Epidemiological study, China's diabetes prevalence, up to 9.7%, estimates that national maturity-onset diabetes patient populations reaches 9,240 ten thousand people [YangW, etal.PrevalenceofdiabetesamongmenandwomeninChina.NEnglJM ed.2010; 362:1090-1101].In addition, according to IDF (IDF) statistics, within 2010, global diabetics reaches 2.85 hundred million, and expecting the year two thousand thirty whole world will have nearly 500,000,000 people to suffer from diabetes.Therefore, diabetes have been a serious public health problem, need to explore from the different angles of clinical medicine, preventive medicine the method solved.
Often vascular complication is there is in diabetes with course advancement, comprise macroangiopathy and microangiopathies, cause the chronic progressive external of the organs such as the heart, brain, kidney, eye to damage, the harm of diabetes, mainly from these complication, is also the main cause that medical expense increases.According to diabetes branch of Chinese Medical Association, the prevalence of China's diabetic vascular complications is: hypertension 31.9%, cerebrovascular 12.2%, cardiovascular diseases 15.9%, lower limb vascular disease 5.0%, nephropathy (glomerular microangiopathy change) 33.6%, retinopathy 24.3%, chronic complicating diseases investigation team of diabetes branch of total prevalence rate 73.2%[Chinese Medical Association. national Inpatients with Diabetic Mellitus chronic complicating diseases and Related Risk Factors 10 years Retrospective Analysis thereof. diabetes mellitus in China magazine, 2003; 11:232-237].
According to China's Guidelines for Management of Diabetes Mellitus (2010), the therapeutic goal of diabetes blood glucose is reached or close to normal level, corrects metabolism disorder, eliminates diabetic symptom, prevent or delay complication, reduce case fatality rate.The common drug for the treatment of type 2 diabetes mellitus comprises biguanides, sulphanylureas, thiazolidinediones, meglitinide, alpha-glucosidase inhibitor, dipeptidyl peptidase-4 inhibitors etc., SGLT2 inhibitor is then for diabetics provides a kind of brand-new blood sugar lowering approach: blood-glucose can be absorbed by glomerular filtration and renal tubules through kidney again, and absorption process is carried out in the brush border membrane of renal cells again, transport glucose by SGLT along sodium gradient.Have the SGLT hypotype that three kinds of physicochemical properties are different at present at least, wherein SGLT2 is only expressed in kidney, and SGLT1 is also expressed in the tissues such as intestinal, skeleton and cardiac muscle, and SGLT3 does not have transport function.Under the normal situation of blood sugar concentration, glucose is absorbed by the SGLT of kidney completely again, and the absorbability again of kidney is saturated when concentration of glucose is greater than 10mmol/L, exceeds, and causes glycosuria.SGLT is suppressed to suppress glucose to absorb in blood again from Glomerular filtrate part, thus generation hypoglycemic activity, and cause glycosuria [IdrisI, etal.Sodium-glucoseco-transporter-2inhibitions:anemergin gnewclassoforalantidiabeticdrug.DiabetesObesMetab, 2009,11:79-88].
SGLT2 inhibitor comprises Da Gelie clean (dapagliflozin), Rui Gelie clean (remogliflozin), She Gelie clean (sergliflozin), Kan Gelie clean (canagliflozin), A Gelie clean (atigliflozin) etc., wherein Da Gelie be only the 1st granted and Europe listing SGLT2 inhibitor, its treating diabetes effect has obtained the tentative confirmation [BaileyCJ of clinical research, eta1.Effectofdapagliflozininpatientswithtype2diabeteswho haveinadequateglycaemiccontrolwithmetformin:arandomised, double-blind, placebo-controlledtrial.Lancet, 2010, 375:2223-2233].It is reported, SGLT2 inhibitor has reduction body weight, seldom causes hypoglycemia, therapeutical effect not to rely on the advantages such as the existence of insulin.But, also there is the deficiency of " congenital " in SGLT2 inhibitor: compared with traditional hypoglycemic medicine, SGLT2 inhibitor does not have the evidence of evidence-based medicine EBM in prevention or delaying complications of diabetes, whether it causes long-term glycosuria state to have a negative impact (as urinary system infection, renal function injury or nephropathy increase the weight of) to kidney, still has and waits to investigate.
Vitamin B group comprises vitamin B
1, vitamin B
2, vitamin PP, vitamin B
6, vitamin B
12, folic acid, pantothenic acid and biotin etc., body metabolism, erythrocyte are formed, keep nervous system and function of immune system to have important function.Vitamin B group belongs to water soluble vitamins, through human body intestinal canal absorb, excreted by urine, retention time is of short duration in vivo, seldom accumulates, thus constantly from external picked-up to meet body nutrition and metabolism needs.Vitamin B group lacks can cause many adverse consequencess, comprises myasthenia, confusion, nerve problems, gastricism, wrinkled skin, severe anemia and heart damage etc.Wherein, folic acid, vitamin B
6, vitamin B
12affect the biochemical metabolism of homocysteine (Homocysteine, Hcy) in human body when supplementing not enough, and think that Hcy is a kind of cardiovascular risk factor at present, especially easy generation blood vessel endothelium is damaged.
The vascular lesion of diabetes is results of multifactor long term, not only has this key factor of chronic hyperglycemia, also has the participation of other complicated factor.Antidiabetic medicine is focused on correcting the pathoglycemia state of diabetes and metabolism disorder mostly in the market, and have ignored to the compound risk factor causing diabetic complication (such as diabetic angiopathy) early stage, synchronously intervene.As aforementioned, namely one of important goal for the treatment of diabetes is prevention or delays various complication, thus reduces case fatality rate, so need to process various and the damage factor deposited or clinical disease.Therefore; how improve the clinical value of SGLT2 inhibitor further, strengthen the protection of diabetic vascular tissue or reduce by the danger of diabetes initiation vascular complication; no matter from the angle of clinical medicine or preventive medicine, being all one is worth further investigation and needs the problem that solves.
Summary of the invention
The object of the invention is to overcome the deficiency that SGLT2 inhibitor exists, provide a kind of in prevention or delay to be better than SGLT2 inhibitor in diabetic vascular complications and pharmaceutical composition (compound medicine and preparation) that toxic and side effects does not increase.
For achieving the above object, the present invention is by the following technical solutions:
A kind of pharmaceutical composition, comprises
(1) one in the SGLT2 inhibitor of pharmaceutical dosage and medicinal precursor, active metabolite or its esters;
(2) one or more of the vitamin B group of pharmaceutical dosage;
(3) acceptable carrier on pharmaceutics.
Above-mentioned " pharmaceutical dosage " refers to the amount of pharmacological action with collaborative, prevention or response to treatment.
Described SGLT2 inhibitor is selected from the one of Da Gelie clean (dapagliflozin), Rui Gelie clean (remogliflozin), She Gelie clean (sergliflozin), Kan Gelie clean (canagliflozin), A Gelie clean (atigliflozin).
Study by experiment, the content of SGLT2 inhibitor is respectively: Da Gelie clean (2.5 ~ 250mg), Rui Gelie clean (25 ~ 500mg), She Gelie clean (10 ~ 500mg), the content of the medicinal precursor of above-mentioned substance, active metabolite or salt is equal to corresponding above-mentioned substance content.
Described vitamin B group is selected from vitamin B
6, vitamin B
12with one or more of folacin compound.
Described vitamin B
6comprise pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxin phosphate, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance derivant and can metabolism and/or generate the material of this compounds in vivo.
Described vitamin B
12comprise cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and above-mentioned substance derivant and can metabolism and/or generate the material of this compounds in vivo.
Described folacin compound comprise folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt, folic acid or folic acid officinal salt active metabolite and can metabolism and/or generate the material of folic acid in vivo.
Vitamin B group treatment effective dose is in the present invention respectively: the folacin compound of 0.1mg ~ 5mg, the vitamin B of 5 ~ 50mg
6, the vitamin B of 0.01 ~ 1mg
12; Its better treatment effective dose is respectively: 0.4 ~ 1.6mg folacin compound, 10mg ~ 40mg vitamin B
6, 0.05 ~ 0.5mg vitamin B
12.
The present invention preferably by the component of following content as the pharmaceutical composition of active ingredient: wherein SGLT2 inhibitor is selected from Da Gelie clean (10 ~ 100mg), Rui Gelie clean (50 ~ 250mg), She Gelie clean (25 ~ 250mg), and vitamin B group is selected from folacin compound (0.4 ~ 1.6mg).
Research finds, when vitamin B group and SGLT2 inhibitor share, can work in coordination with the hypoglycemic activity strengthening the latter, and can work in coordination with prevention or the mitigation strengthening diabetes being caused to vascular lesion.Therefore, the pharmaceutical composition that the invention provides acceptable carrier on the SGLT2 inhibitor containing pharmaceutical dosage, the vitamin B group of pharmaceutical dosage and pharmaceutics for the preparation for the treatment of diabetes, prevent and delay the purposes in the medicine of diabetic vascular complications and relevant disease.
The vascular complication that diabetes cause includes but not limited to atherosclerosis, coronary heart disease, cerebrovascular, diabetic nephropathy, diabetic retinopathy, diabetic foot etc.
According to the present invention, active component in pharmaceutical composition is the solvent in compositions, one of them active component comes from the one in SGLT2 inhibitor, another active component is one or more of vitamin B group, the dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, single chamber controlled release tablet, two rooms controlled release tablet, pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, capsule containing micropill or small pieces, pH dependent form capsule containing micropill or small pieces, oral liquid, membrane or patch.It is emphasized that one or more pharmaceutical compositions containing SGLT2 inhibitor and vitamin B group are made tablet or capsule.
Also containing pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., when making tablet, described pharmaceutically suitable carrier comprises the excipient and accessory drugs that contribute to reactive compound being mixed with pharmaceutical formulation, as the compositions of one or more materials of microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc., belong to this area general knowledge.
Compound in pharmaceutical composition provided by the invention can grant diseased individuals in identical preparation simultaneously, also in succession grants individuality discriminably.If in succession grant, then the loss of the beneficial effect that the delay that second active component is granted should not cause active ingredient combination to bring.If grant diseased individuals simultaneously, the compound in compositions can mix and is present in same pharmaceutical dosage forms, also independently can exist with same dosage form.If independently exist with same dosage form, then pharmaceutical composition can alternatively exist with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of one or more dosage forms built-in and operation instructions, one or more compositions " medicine box " of a kind of and vitamin B group in the present invention in preferred SGLT2 inhibitor.
Another object of the present invention is to provide the purposes of pharmaceutical composition in the medicine for the preparation for the treatment of diabetes of one or more and pharmaceutically suitable carrier of the vitamin B group of a kind of, the pharmaceutical dosage in SGLT2 inhibitor containing pharmaceutical dosage and medicinal precursor, active metabolite or its esters.Pharmaceutical composition provided by the invention, because treating diabetes, prevent and treat and delay diabetic vascular complications, thus becomes antidiabetic medicine preferably.Wherein, SGLT2 inhibitor is selected from the one that Da Gelie is clean, Rui Gelie is clean, She Gelie is clean, Kan Gelie is clean, A Gelie is clean, and vitamin B group is selected from vitamin B
6, vitamin B
12with one or more in folacin compound.
Advantage of the present invention: the invention provides one or more of the vitamin B group of a kind of, the pharmaceutical dosage of the SGLT2 inhibitor containing pharmaceutical dosage and the pharmaceutical composition of pharmaceutically suitable carrier.The combined effect of SGLT2 inhibitor and vitamin B group is not the simple addition of each self-applying of each active substance, but causes the generation reducing vascular complication on the basis of significantly improving hyperglycemia of type 2 diabetes mellitus patient.That is, SGLT2 inhibitor and vitamin B group drug combination achieve synergistic therapeutic effect, are therefore antidiabetic medicines preferably.
Below in conjunction with detailed description of the invention, the present invention will be further described, not limitation of the invention, and the equivalent replacement of all any this areas of carrying out according to content of the present invention, all belongs to protection scope of the present invention.
Detailed description of the invention
Embodiment 1. prepares compound recipe Da Gelie clean/5-methyltetrahydrofolate sheet (1000 amounts)
Formula:
Preparation method: get recipe quantity 5-methyltetrahydrofolate, Da Gelie only according to equal increments method mix homogeneously, for subsequent use; Take the microcrystalline Cellulose of recipe quantity, low-substituted hydroxypropyl cellulose (L-HPC), carboxymethylstach sodium, fully mix with crude drug mixed powder, cross 80 mesh sieves, add appropriate 5% polyvidone 95% alcoholic solution and make soft material, 20 mesh sieves are granulated, 50 DEG C of drying about 6h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, is mixed homogeneously by dried granule with the magnesium stearate of recipe quantity, intermediate detects, and is pressed into 1000.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing.In the compound tablet made, every sheet is containing the clean 10mg of Da Gelie, 5-methyltetrahydrofolate 0.8mg.
Clean/YESUAN PIAN (1000 amounts) that embodiment 2. prepares compound recipe Rui Gelie
Formula:
Preparation method: adjuvant is vertical compression adjuvant, drying for standby.Get the folic acid of recipe quantity and microcrystalline Cellulose 30g according to equal increments method mix homogeneously, obtain mixed powder 1; Take microcrystalline Cellulose, lactose, the carboxymethylstach sodium of residue recipe quantity, only fully mix by equal increments method with Rui Gelie, obtain mixed powder 2; Acid glyceride of being healed in mixed powder 1 and mixed powder 2 and the mountain of recipe quantity is mixed homogeneously, and obtains finally mixed powder intermediate, detects mixed powder intermediate, be pressed into 1000.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet made, every sheet is containing the clean 75mg of Rui Gelie, folic acid 0.6mg.
Embodiment 3. prepares compound recipe She Gelie clean/formyl tetrahydrofolic acid/vitamin B
12capsule (1000 amounts)
Formula:
Preparation method: get recipe quantity formyl tetrahydrofolic acid, vitamin B
12, She Gelie only according to equal increments method mix homogeneously, for subsequent use; After mixing homogeneously with microcrystalline Cellulose, carboxymethyl starch sodium again, cross 80 mesh sieves, add 5% polyvidone 95% alcoholic solution appropriate, soft material processed, 50 DEG C of drying about 6h cross 24 mesh sieve granules, and the water content controlling granule is 2-3%, acid glyceride of being healed in dried granule and recipe quantity micropowder silica gel, mountain is mixed homogeneously, the granulate intermediate obtained carries out content detection, detect qualified after, load Capsules and get final product.Note lucifuge in preparation process, the capsule made needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every the clean 50mg of She Gelie, formyl tetrahydrofolic acid 0.6mg, vitamin B in the capsule made
120.1mg.
Embodiment 4. prepares Da Gelie clean/5-methyltetrahydrofolate (5-MTHF)+vitamin B
6double-layer tablet
Formula:
Nateglinide layer:
The preparation method of Da Gelie net layer granule: supplementary material was pulverized 80 mesh sieves, drying for standby.Get that 20g Da Gelie is clean, 122.0g Celluloasun Microcrystallisatum and 18.0g carboxymethylstach sodium, according to equal increments method Homogeneous phase mixing, soft material is made with 3% carmellose sodium solution, 20 mesh sieves are granulated, 50 DEG C of drying about 6h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, must arrive lattice row net layer granule A;
Vitamin layer:
The preparation method of vitamin layer granule: get 0.8g5-MTHF, 10g vitamin B
6, 220.0g microcrystalline Cellulose and 20.0g low-substituted hydroxypropyl cellulose, according to equal increments method Homogeneous phase mixing, soft material is made with 5% PVPK29/32-95% alcoholic solution, 20 mesh sieves are granulated, 50 DEG C of drying about 6h, 20 mesh sieve granulate, the water content controlling granule is 2-3%, obtains vitamin layer granule B;
The preparation method of double-layer tablet: dried granule A is mixed homogeneously with magnesium stearate, acid glyceride of dried granule B and mountain being healed is mixed homogeneously; Semi-finished product detect respectively, after measuring content, are respectively charged in hopper, are pressed into 1000 with double-layer tablet tablet machine.Note lucifuge in preparation process, the tablet made needs aluminium-plastic bubble plate packing, keeps in Dark Place.5-MTF, 10mg vitamin B of every sheet, 0.4mg clean containing 20mg Da Gelie in the compound tablet made
6.
The clean 5-MTHF compositions of embodiment 5. Da Gelie is to the blood sugar lowering of diabetes rat, vascular protection effect
Method: (1) streptozotocin solution: take 600mg streptozotocin (STZ) and be dissolved in before use in 200ml citric acid solution, be made into the solution of 3mg/ml.(2) healthy rat about 60, random selecting 12 rats are as Normal group, and all the other rats press 30mg/kg single intraperitoneal injection STZ solution, normal diet, but containing 1% methionine in drinking-water, intend causing homocysteine in body (Hcy) to raise.After 2 weeks, after socket of the eye, blood sampling measures fasting glucose (FPG) value, and the rat of getting FPG>11.1mmol/L, Hcy>12mmol/L is that diabetes merge high Hcy mass formed by blood stasis rat, for subsequent experimental.(3) diabetes rat is divided at random the clean+5-MTHF group of clean group of model group, Da Gelie, Da Gelie, often organize 12, every day is gavage normal saline, the clean+5-MTHF (2+0.08mg/kg/d) of Da Gelie clean (2mg/kg/d), Da Gelie respectively, separately make blank with normal rat, give normal saline gavage, each group is 1 perfusion every day.Successive administration is after 6 weeks, and FPG, endothelin-1 (ET-1) and homocysteine (Hcy) are surveyed in the blood sampling of each group rat eye socket, and statistical test method adopts t inspection.
Result: in table 1.Model group rats FPG, Hcy level is significantly higher than rats in normal control group, shows that model group rats presents hyperglycemia, high Hcy state, modeling success.Give with rat Drug therapy after, Da Gelie is clean, Da Gelie clean 5-MTHF compositions group rat FPG significantly reduces (equal P<0.01), but the hypoglycemic activity of Da Gelie clean 5-MTHF compositions to rat is better than Da Gelie alone (P<0.05) only, prompting 5-MTHF has auxiliary hyperglycemic effect; Da Gelie clean 5-MTHF compositions group rat Hcy significantly reduces, but Da Gelie organizes not reduction only, points out 5-MTHF to have and significantly falls Hcy effect.Plasma ET is one of index of reflection diabetic angiopathy, and this experiment finds, compare with model group or clean group of Da Gelie, Da Gelie clean 5-MTHF compositions group rat plasma ET-1 has remarkable reduction, and prompting 5-MTHF has protective effect to blood vessel endothelium.
The clean 5-MTHF compositions of table 1 Da Gelie to the effect of rat (
n=12)
Note: compare with normal group, * P<0.01; Compare with model group,
#p<0.05,
##p<0.01; Compare with clean group of Da Gelie, Δ P<0.05.
The clean folate composition of embodiment 6. Rui Gelie is to the protective effect of diabetes rat blood vessel, kidney
Method: (1) animal model and administration: male SD rat 60, body weight 200 ~ 230g, adaptability randomly draws 13 as blank group after raising l week, all the other give 30mg/kgSTZ single intraperitoneal injection respectively, after 14d, rat tail vein blood sampling measures FPG level, be greater than 11.1mmoL/L and be defined as Glycemia Decline success, be divided into 3 groups at random, i.e. model control group, clean group of Rui Gelie, Rui Gelie is clean+folic acid group, often organize 13, latter two groups give the clean 15mg/kg/d of Rui Gelie respectively, Rui Gelie clean 15mg/kg/d+ folic acid 0.12mg/kg/d, be 2 administrations every day, blank group, the normal saline filling that model group gives equivalent is fed, each group of medication or processing time are 8 weeks.Except Normal group feeds normal diet, all the other are respectively organized and all feed with high-calorie feed.(2) collection of specimens, Indexs measure: l0% chloral hydrate intraperitoneal injection of anesthesia animal after 8 weeks, abdominal aortic blood is surveyed blood glucose, is surveyed serum superoxide dismutases (SOD), catalase (CAT), Endothelin (ET) level by test kit description; Metabolic cage method accesses 24h urine, measures 24h urine albumen amount.Each group of result and statistics are in table 2,3.
Result: give with diabetes rat Drug therapy after 8 weeks, compare with model group, Rui Gelie is clean, Rui Gelie clean folate composition group rat FPG significantly reduces, and the clean folate composition of Rui Gelie to be slightly better than Nateglinide to the blood sugar reducing function of rat alone, but there was no significant difference.Model group urine protein significantly raises; Rui Gelie organizes rat urine albumen only without remarkable decline; Rui Gelie is clean/and to decline (with model group ratio, P<0.05) appear in folate composition urine protein, and the clean and folic acid of prompting Rui Gelie share has significant protective effect (table 2) to renal function.
The clean folate composition of table 2 Rui Gelie to the effect of rat blood sugar, 24h urine protein (
n=13)
Note: compare with normal group, * P<0.01; Compare with model group,
#p<0.05,
##p<0.01.
Compare with rats in normal control group, the rising of model group rats Serum ET level, SOD, CAT level reduce, and prompting diabetes model merges early stage vascular endothelial injury; Compare with clean group of Rui Gelie, the clean folic acid group of Rui Gelie shows the effect of falling ET, increased SOD, CAT, and prompting folic acid has the antioxidation and anti-endothelial injury effect (table 3) that improve rat further.
The clean folate composition of table 3 Rui Gelie to the protective effect of rat aorta (
n=13)
Note: compare with normal group, * P<0.01; Compare with model group,
#p<0.05,
##p<0.01; Compare with clean group of Rui Gelie, Δ P<0.05.
Diabetic angiopathy take arteriosclerosis as main manifestations, and vascular endothelial injury is the initiating link of diabetic vascular complications, and the generation of diabetic angiopathy simultaneously promotes endothelial injury again further, but the mechanism of vascular lesion is illustrated not yet completely.In blood, ET is the active substance of vascular endothelial cell secretion, is strong vasoconstrictor, closely related with diabetic vascular complications.According to the literature, with diabetes development, ET level raises gradually, is the good index of reflection diabetic angiopathy.Oxygen-derived free radicals is the key factor causing endothelial injury, and in blood, SOD, CAT are the important protease of scavenging activated oxygen.According to the above results, Preliminary conclusion: folic acid and the clean use in conjunction of Rui Gelie not only hypoglycemic activity are strengthened, the effect of the diabetes rat vascular endothelial injury that is also significantly improved.
Embodiment 7. She Gelie is clean/formyl tetrahydrofolic acid/VitB
12to blood vessel and the Endothelium Protective effect of diabetes rat
Method: Wistar rat (male, body weight 200-250g) high lipid food is fed 12 weeks.Fasting 12 hours before rat modeling, lumbar injection STZ(30mg/kg), fasting blood is adopted after socket of the eye after 2 weeks, surveying blood glucose FPG>=11.1mmoL/L is Glycemia Decline success, diabetes rat is divided into 3 groups at random by blood glucose value, be respectively model control group, clean group of She Gelie (10mg/kg/d), She Gelie clean/formyl tetrahydrofolic acid/VitB
12group (10+0.08+0.01mg/kg/d), often organizes 13, gastric infusion, every day 1 time, continuous 12 weeks; Separately set up rats in normal control group, feed (model comparison and normal control rat gavage every day distilled water) with normal diet.Diabetes rat is respectively organized and is all continued to feed with high-calorie feed, experimental session drinking water for animals and feedstuff do not limit, test at the end of 12 weeks and take a blood sample, survey blood glucose and press test kit description mensuration NO (nitrate reductase method), total nitric oxide synthetase (T-NOS) and total SOD vigor; Put method of exempting from and measure serum thromboxane (TXB
2), prostaglandin (6-keto-PGF1 α, be called for short PGF1 α) and blood plasma ET.Data mean ± standard deviation represents, relatively row paired t-test between group.
Result: in Table 4-6.1. She Gelie clean/formyl tetrahydrofolic acid/VitB
12compositions is on the impact of blood glucose: model group blood glucose significantly raises, and She Gelie significantly can reduce blood glucose only, and She Gelie is clean/formyl tetrahydrofolic acid/VitB
12compositions blood sugar reducing function strengthens to some extent, but does not reach significant level.2. She Gelie clean/formyl tetrahydrofolic acid/VitB
12compositions is on the impact of NO, T-NOS, ET and NO/ET: compare with normal group, and model group blood plasma NO reduces, and serum T-NOS vigor significantly declines, and ET content raises, and NO/ET ratio reduces; Compare with model group, She Gelie only organizes only NO, T-NOS and raises to some extent, and She Gelie clean/formyl tetrahydrofolic acid/VitB
12group NO, T-NOS raise more obvious, and ET reduces, and NO/ET ratio significantly increases simultaneously, prompting formyl tetrahydrofolic acid/VitB
12strengthen blood vessel endothelium protection.3. She Gelie clean/formyl tetrahydrofolic acid/VitB
12compositions is to TXB
2, PGF1 α and both ratio impact: compare with normal group, model group blood plasma TXB
2remarkable rising, PGF1 α changes not obvious, TXB
2/ PGF1 α ratio raises; Comparing with model group, She Gelie is clean/formyl tetrahydrofolic acid/VitB
12group TXB
2have obvious decline, PGF1 α amplitude of variation is little, TXB
2/ PGF1 α ratio obviously declines, and points out formyl tetrahydrofolic acid/VitB equally
12there is the preventive and therapeutic effect strengthened blood vessel embolism.4. She Gelie clean/formyl tetrahydrofolic acid/VitB
12compositions is on the impact of the total SOD vigor of serum: compare with normal group, and the total SOD vigor of model group serum significantly reduces, and administration group SOD vigor all has and rises in various degree.Wherein, comparing with clean group of She Gelie, She Gelie is clean/formyl tetrahydrofolic acid/VitB
12group SOD vigor raises more obvious, the collaborative vascular protection effect between prompting medicine.
Table 4 She Gelie is clean/formyl tetrahydrofolic acid/VitB
12compositions to the effect of rat blood sugar (
n=13)
Note: compare with normal group, * P<0.01; Compare with model group,
##p<0.01.
Table 5 She Gelie is clean/formyl tetrahydrofolic acid/VitB
12compositions is to the protective effect (n=13) of endothelium
Note: compare with normal group, * P<0.05, * * P<0.01; Compare with model group,
#p<0.05,
##p<0.01;
Compare with clean group of She Gelie, Δ P<0.05, Δ Δ P<0.01.
Table 6 She Gelie is clean/formyl tetrahydrofolic acid/VitB
12compositions is to the protective effect (n=13) of rat aorta
Compare with normal group, * P<0.05, * * P<0.01; Compare with model group,
#p<0.05,
##p<0.01; Compare with clean group of She Gelie, Δ P<0.05.
Diabetic angiopathy, especially microangiopathies are the pathologic basis of diabetes multiple complications, wherein vascular endothelial cell damage may be one of major reason, and nitric oxide/endothelin (NO/ET) and thromboxane/prostaglandin are two groups of vaso-active substances, by vascular endothelial cell secretion, two groups of dynamic equilibrium are to maintaining the normal function of endotheliocyte and playing an important role to hemodynamics etc.This result of study is pointed out, compared with folk prescription, and the clean and formyl tetrahydrofolic acid/VitB of She Gelie
12use in conjunction is more conducive to the homeostasis maintaining NO/ET and thromboxane/prostaglandin, is conducive to assisting to regulate microvascular easypro contracting, anticoagulant and thrombosis, therefore has the pharmacological action of control diabetic angiopathy.
Claims (9)
1. a pharmaceutical composition, composition is:
(1) sodium-glucose 2 type transporter inhibitors of pharmaceutical dosage or the one of salt apoplexy due to endogenous wind;
(2) one or more of the vitamin B group of pharmaceutical dosage;
(3) acceptable carrier on pharmaceutics,
Wherein, vitamin B group is selected from vitamin B
6, vitamin B
12, folacin compound one or more, content is 0.1 ~ 50mg, and described sodium-glucose 2 type transporter inhibitors is selected from the one that Da Gelie is clean, Rui Gelie is clean, She Gelie is clean, Kan Gelie is clean, A Gelie is clean, and content is 2.5 ~ 500mg.
2. pharmaceutical composition according to claim 1, is characterized in that: the clean content of the clean content of described Da Gelie to be the clean content of 2.5 ~ 250mg, Rui Gelie be 25 ~ 500mg, She Gelie is 10 ~ 500mg.
3. pharmaceutical composition according to claim 1, is characterized in that: described folacin compound is selected from the one of folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt, and content is 0.2 ~ 5mg.
4. pharmaceutical composition according to claim 3, is characterized in that: described folacin compound content is 0.4 ~ 1.6mg.
5. the pharmaceutical composition according to any one of Claims 1 to 4, is characterized in that the pharmaceutical dosage form of this pharmaceutical composition is oral formulations.
6. the purposes of the pharmaceutical composition according to any one of Claims 1 to 4 in the medicine for the preparation for the treatment of diabetes.
7. purposes according to claim 6, is characterized in that: described diabetes are with hyperhomocysteinemiainjury.
8. the pharmaceutical composition according to any one of Claims 1 to 4 for the preparation of prevention, treat or delay the purposes in the medicine of diabetic vascular complications.
9. purposes according to claim 8, is characterized in that: described diabetic vascular complications is atherosclerosis, coronary heart disease, cerebrovascular, lower limb gangrene, nephropathy and retinal microvascular disease.
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Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106474480A (en) * | 2016-11-15 | 2017-03-08 | 深圳奥萨医疗有限公司 | Medical composition and its use containing glucokinase activator and B family vitamin |
| CN106727445B (en) * | 2016-12-21 | 2019-08-23 | 河北科技大学 | A kind of Dapagliflozin pelliculae pro cavo oris and preparation method thereof |
| CN110141566B (en) * | 2018-02-11 | 2022-04-19 | 清华大学深圳研究生院 | Application of SGLT2inhibitor in regulation and control of inflammation |
| WO2020155098A1 (en) * | 2019-02-01 | 2020-08-06 | 天津药物研究院有限公司 | Pharmaceutical composition for treating diabetes, preparation method therefor, and use thereof |
| CN112438975B (en) * | 2019-09-03 | 2022-03-22 | 清华大学深圳研究生院 | Application of diabetes treatment medicine in bacteriostasis |
| WO2021176096A1 (en) | 2020-03-05 | 2021-09-10 | Krka, D.D., Novo Mesto | Pharmaceutical composition comprising sglt2 inhibitor |
| CN115867538A (en) | 2020-06-05 | 2023-03-28 | 新梅斯托克公司 | Preparation of highly pure amorphous dapagliflozin |
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| WO2006058597A1 (en) * | 2004-12-03 | 2006-06-08 | Merck Patent Gmbh | Tetrahydropyrane derivatives for use as antidiabetics |
| CN103153288A (en) * | 2010-07-09 | 2013-06-12 | 詹姆斯·特林卡·格林 | Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin |
| CN103417971A (en) * | 2013-08-13 | 2013-12-04 | 深圳奥萨医药有限公司 | Dipeptidyl peptidase inhibitor and vitamin-B pharmaceutical composition and application thereof |
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| WO2006058597A1 (en) * | 2004-12-03 | 2006-06-08 | Merck Patent Gmbh | Tetrahydropyrane derivatives for use as antidiabetics |
| CN103153288A (en) * | 2010-07-09 | 2013-06-12 | 詹姆斯·特林卡·格林 | Combination immediate/delayed release delivery system for short half-life pharmaceuticals including remogliflozin |
| CN103417971A (en) * | 2013-08-13 | 2013-12-04 | 深圳奥萨医药有限公司 | Dipeptidyl peptidase inhibitor and vitamin-B pharmaceutical composition and application thereof |
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