CN103721261A - Pharmaceutical composition containing SGLT2 (sodium-glucose type 2 transporter) inhibitors and group B vitamins as well as application thereof - Google Patents
Pharmaceutical composition containing SGLT2 (sodium-glucose type 2 transporter) inhibitors and group B vitamins as well as application thereof Download PDFInfo
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Abstract
The invention relates to a pharmaceutical composition containing SGLT2 (sodium-glucose type 2 transporter) inhibitors and group B vitamins. The pharmaceutical composition consists of SGLT2 inhibitors in therapeutically effective amount and one of medicinal precursors, active metabolites or salts thereof, one or more in group B vitamins in therapeutically effective amount, and pharmaceutically acceptable carriers, wherein the SGLT2 inhibitors mainly comprise dapagliflozin, remogliflozin and sergliflozin and have the content of 2.5-500mg, and the content of the group B vitamins is 0.01-50mg. The invention also relates to application of the composition in preparation of medicines for treating diabetes. The medicine prepared by the pharmaceutical composition provided by the invention has the beneficial effect of obviously preventing or delaying complication of diabetic angiopathies on the basis of effectively reducing blood sugar. In addition, the pharmaceutical composition can be conveniently taken by a patient, and the compliance is improved.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that contains sodium-glucose 2 type transporters (sodium glucose co-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 follows because of hypoinsulinism and/or effect the defect sugar, fat and the protein metabolism disorder that cause.According to Epidemiological study, China's diabetes prevalence is up to 9.7%, estimate that national maturity-onset diabetes patient sum reaches 9,240 ten thousand people [Yang W, et al.Prevalence of diabetes among men and women in China.N Engl J Med.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 the method solving from the different angles of clinical medicine, preventive medicine.
With course advancement, often there is vascular complication in diabetes, comprise macroangiopathy and microangiopathies, cause the chronic progressive external infringement of the organs such as the heart, brain, kidney, eye, 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. 10 years Retrospective Analysis of national Inpatients with Diabetic Mellitus chronic complicating diseases and Related Risk Factors 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 is blood glucose is reached or approach normal level, corrects metabolism disorder, eliminates diabetic symptom, prevents or delays complication, reduces 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 for diabetics provides a kind of brand-new blood sugar lowering approach: during blood-glucose process kidney, can be absorbed by glomerular filtration and renal tubules again, and absorption process is to carry out again, by SGLT, along sodium gradient, transport glucose in the brush border membrane of renal cells.Have at present three kinds of SGLT hypotypes that physicochemical property is different 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.Inhibition SGLT will partly suppress glucose and absorb to blood from Glomerular filtrate again, thereby generation hypoglycemic activity, and cause glycosuria [Idris I, et al.Sodium-glucose co-transporter-2inhibitions:an emerging new class of oral antidiabetic drug.Diabetes ObesMetab, 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 is the 1st SGLT2 inhibitor granted and that go on the market in Europe only, its treating diabetes effect has obtained tentative confirmation [the Bailey CJ of clinical research, et a1.Effect of dapagliflozin in patients with type2diabetes who have inadequate glycaemic control with metformin:a randomised, double-blind, placebo-controlled trial.Lancet, 2010, 375:2223-2233].It is reported, SGLT2 inhibitor has the body weight of reduction, seldom causes that hypoglycemia, therapeutical effect do not rely on the advantages such as existence of insulin.But, also there is the deficiency of " congenital " in SGLT2 inhibitor: compares with traditional hypoglycemic medicine, SGLT2 inhibitor is not having the evidence of evidence-based medicine EBM aspect prevention or delaying complications of diabetes, whether it causes long-term glycosuria state kidney to be had a negative impact (as urinary system infection, renal function injury or nephropathy increase the weight of), 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., to body metabolism, erythrocyte, form, keep nervous system and function of immune system to there is important function.Vitamin B group belongs to water soluble vitamins, through human body intestinal canal, absorbs, and by urine, is excreted, and retention time is of short duration in vivo, seldom accumulate, so must be often 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, serious anemia and heart damage etc.Wherein, folic acid, vitamin B
6, vitamin B
12while supplementing deficiency, affect the biochemical metabolism of homocysteine (Homocysteine, Hcy) in human body, and think that at present Hcy is a kind of cardiovascular risk factor, especially easily blood vessel endothelium is produced to infringement.
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 focuses on correcting pathoglycemia state and the metabolism disorder of diabetes mostly in the market, and ignored to cause diabetic complication (for example diabetic angiopathy) compound risk factor in early days, synchronously intervene.As aforementioned, one of important goal for the treatment of diabetes is prevention or delays various complication, thus reduction case fatality rate, so need to process damage factor various and that deposit or clinical disease.Therefore; the clinical value, the reinforcement that how further to improve SGLT2 inhibitor are caused the danger of vascular complication to the protection of diabetic vascular tissue or reduction by diabetes;, from clinical medicine or the angle of preventive medicine, be no matter all a problem that is worth further investigation and needs to solve.
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 aspect 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 pharmaceutical composition, comprises
(1) a kind of 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 have amount collaborative, that prevent or treat the pharmacological action of effect.
Described SGLT2 inhibitor is selected from a kind of of Da Gelie clean (dapagliflozin), Rui Gelie clean (remogliflozin), She Gelie clean (sergliflozin), Kan Gelie clean (canagliflozin), A Gelie clean (atigliflozin).
Research 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 the derivant of pyridoxol, 2-methyl-3-hydroxy-4-formyl-5-hydroxymethylpyridine., pyridoxamine, pyridoxin phosphate, pyridoxal 5-phosphate, phosphopyridoxamine and above-mentioned substance and metabolism and/or generate the material of this compounds in vivo.
Described vitamin B
12comprise the derivant of cobalamine, mecobalamin element, 5 '-deoxyadenosyl cobalamin, hydroxocobalamine, cyanocobalamin and above-mentioned substance and metabolism and/or generate the material of this compounds in vivo.
Described folacin compound comprises the active metabolite of folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt, folic acid or folic acid officinal salt and 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 is the pharmaceutical composition as active ingredient by the component of following content preferably: 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 is found, when vitamin B group and SGLT2 inhibitor share, can work in coordination with the hypoglycemic activity that strengthens the latter, and can work in coordination with prevention or the mitigation of strengthening diabetes to cause vascular lesion.Therefore the pharmaceutical composition that, the invention provides acceptable carrier on the vitamin B group of the SGLT2 inhibitor that contains pharmaceutical dosage, 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 a kind of 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 chambers 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, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, oral liquid, membrane or patch.Particularly point out, one or more pharmaceutical compositions that contain SGLT2 inhibitor and vitamin B group are made to tablet or capsule.
In this pharmaceutical composition, also contain pharmaceutics acceptable carrier, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described in while making tablet, pharmaceutically suitable carrier comprises excipient and the accessory drugs that contributes to reactive compound to be mixed with pharmaceutical formulation, compositions as one or more materials of microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc., belongs to this area general knowledge.
Compound in pharmaceutical composition provided by the invention can be granted diseased individuals in identical preparation simultaneously, also in succession grants discriminably individuality.If in succession grant, the delay that second active component granted should not cause active component to combine the loss of the beneficial effect bringing.If grant diseased individuals simultaneously, the compound in compositions can mix and be present in same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively with same dosage form, pharmaceutical composition can exist with " Combined drug box " form on flexible ground." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms and operation instructions, in the present invention one or more compositions " medicine box " of a kind of and vitamin B group in preferred SGLT2 inhibitor.
The purposes of the pharmaceutical composition of one or more and pharmaceutically suitable carrier of vitamin B group that another object of the present invention is to provide a kind of, the pharmaceutical dosage in the SGLT2 inhibitor that contains pharmaceutical dosage and medicinal precursor, active metabolite or its esters in the medicine for the preparation for the treatment of diabetes.Pharmaceutical composition provided by the invention is because treating diabetes, prevent and treat and delay diabetic vascular complications, thereby becomes antidiabetic medicine preferably.Wherein, SGLT2 inhibitor is selected from a kind of 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: one or more and the pharmaceutical composition of pharmaceutically suitable carrier of vitamin B group that the invention provides a kind of, the pharmaceutical dosage of the SGLT2 inhibitor that contains pharmaceutical dosage.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 that type 2 diabetes mellitus patient's reduce the generation of vascular complication on the basis of significantly improving hyperglycemia.That is to say, SGLT2 inhibitor and vitamin B group drug combination have been obtained synergistic therapeutic effect, are therefore antidiabetic medicines preferably.
Below in conjunction with the specific embodiment, the present invention will be further described, limitation of the invention not, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.
The specific embodiment
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 equivalent incremental method mix homogeneously, standby; Take microcrystalline Cellulose, low-substituted hydroxypropyl cellulose (L-HPC), the carboxymethylstach sodium of recipe quantity, fully mix with crude drug mixed powder, cross 80 mesh sieves, add appropriate 5% polyvidone 95% alcoholic solution to make soft material, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of controlling granule is 2-3%, and dried granule is mixed homogeneously with the magnesium stearate of recipe quantity, intermediate detects, and is pressed into 1000.In preparation process, note lucifuge, the tablet of making needs aluminium-plastic bubble plate packing.In the compound tablet of making, every contains 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 equivalent incremental method mix homogeneously, obtain mixed powder 1; The microcrystalline Cellulose, lactose, the carboxymethylstach sodium that take residue recipe quantity, fully mix by equivalent incremental method only with Rui Gelie, obtains mixed powder 2; Mixed powder 1 and mixed powder 2 and the mountain of the recipe quantity acid glyceride of healing is mixed homogeneously, obtain finally mixed powder intermediate, detect mixed powder intermediate, be pressed into 1000.In preparation process, note lucifuge, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.In the compound tablet of making, every contains 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 is only according to equivalent incremental method mix homogeneously, standby; 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 ℃ of dry about 6h cross 24 mesh sieve granule processed, and the water content of controlling granule is 2-3%, dried granule and recipe quantity micropowder silica gel, the mountain acid glyceride of healing is mixed homogeneously, the granule intermediate obtaining carries out content detection, detect qualified after, pack Capsules into and get final product.In preparation process, note lucifuge, the capsule of making 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 of making
120.1mg.
Embodiment 4. preparation Da Gelie are 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 to 80 mesh sieves, drying for standby.Get that 20g Da Gelie is clean, 122.0g Celluloasun Microcrystallisatum and 18.0g carboxymethylstach sodium, according to equivalent incremental method, evenly mix, with 3% carmellose sodium solution, make soft material, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of 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 equivalent incremental method, evenly mix, with 5% PVPK29/32-95% alcoholic solution, make soft material, 20 mesh sieves are granulated, 50 ℃ of dry about 6h, 20 mesh sieve granulate, the water content of 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, dried granule B and the mountain acid glyceride of healing is mixed homogeneously; Semi-finished product detect respectively, measure after content, are respectively charged in hopper, with double-layer tablet tablet machine, are pressed into 1000.In preparation process, note lucifuge, the tablet of making needs aluminium-plastic bubble plate packing, keeps in Dark Place.Every, 5-MTF of 0.4mg clean containing 20mg Da Gelie, 10mg vitamin B in the compound tablet of making
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 is approximately 60, chooses at random 12 rats as Normal group, and all the other rats are pressed 30mg/kg single intraperitoneal injection STZ solution, normal diet, but in drinking-water, contain 1% methionine, intend causing homocysteine (Hcy) in body to raise.After 2 weeks, after socket of the eye, fasting glucose (FPG) value is measured in blood sampling, 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 model group, clean group of Da Gelie, Da Gelie clean+5-MTHF group, every group 12, every day respectively gavage normal saline, Da Gelie clean (2mg/kg/d), Da Gelie clean+5-MTHF (2+0.08mg/kg/d), separately with normal rat, make blank, give equivalent normal saline gavage, each group is 1 perfusion every day.After successive administration 6 weeks, each is organized the blood sampling of rat eye socket and surveys FPG, endothelin-1 (ET-1) and homocysteine (Hcy), and statistical test method adopts t check.
Result: in Table 1.Model group rat FPG, Hcy level are significantly higher than rats in normal control group, show that model group rat presents hyperglycemia, high Hcy state, modeling success.Give with rat Drug therapy after, Da Gelie is clean, the clean 5-MTHF compositions of Da Gelie group rat FPG significantly reduces (all P<0.01), but the clean 5-MTHF compositions of Da Gelie is better than Da Gelie alone (P<0.05) only to the hypoglycemic activity of rat, prompting 5-MTHF has auxiliary hyperglycemic effect; The clean 5-MTHF compositions of Da Gelie group rat Hcy significantly reduces, but the not reduction of the clean group of Da Gelie is pointed out 5-MTHF to have and significantly fallen Hcy effect.Plasma ET is one of index of reflection diabetic angiopathy, and this experiment discovery, organizes comparison only with model group or Da Gelie, and the clean 5-MTHF compositions of Da Gelie 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: with normal group comparison, * P<0.01; With model group comparison,
#p<0.05,
##p<0.01; Only organize comparison with Da Gelie, Δ P<0.05.
The protective effect of the clean folate composition of embodiment 6. Rui Gelie to diabetes rat blood vessel, kidney
Method: (1) animal model and administration: 60 of male SD rats, body weight 200～230g, adaptability is raised l and after week, is randomly drawed 13 as blank group, all the other give respectively 30mg/kg STZ single intraperitoneal injection, after 14d, FPG level is measured in rat tail vein blood sampling, be greater than 11.1mmoL/L and be defined as diabetes modeling success, be divided at random 3 groups, it is model control group, clean group of Rui Gelie, Rui Gelie is clean+folic acid group, every group 13, latter two groups give respectively the clean 15mg/kg/d of Rui Gelie, the clean 15mg/kg/d+ folic acid of Rui Gelie 0.12mg/kg/d, be 2 administrations every day, blank group, model group gives the normal saline filling of equivalent and feeds, each organizes medication or the processing time is 8 weeks.Except Normal group is fed normal diet, all the other each groups are all fed with high-calorie feed.(2) collection of specimens, index detect: l0% chloral hydrate intraperitoneal injection of anesthesia animal after 8 weeks, and abdominal aortic blood is surveyed blood glucose, is pressed test kit description survey serum superoxide dismutases (SOD), catalase (CAT), Endothelin (ET) level; Metabolic cage method accesses 24h urine, measures 24h urine albumen amount.Each is organized result and adds up in Table 2,3.
Result: give with diabetes rat Drug therapy after 8 weeks, with model group comparison, Rui Gelie is clean, the clean folate composition group of Rui Gelie rat FPG significantly reduces, and the clean folate composition of Rui Gelie that the blood sugar reducing function of rat is slightly better than to Nateglinide is 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 declining appears in folate composition urine protein, and (with model group ratio, P<0.05), 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: with normal group comparison, * P<0.01; With model group comparison,
#p<0.05,
##p<0.01.
With rats in normal control group comparison, the rising of model group rat blood serum ET level, SOD, CAT level reduce, and prompting diabetes model merges early stage vascular endothelial injury; Only organize comparison with Rui Gelie, the clean folic acid group of Rui Gelie shows the effect of falling ET, increased SOD, CAT, and prompting folic acid has further antioxidation and the anti-endothelial injury effect (table 3) that improves rat.
The clean folate composition of table 3 Rui Gelie to the protective effect of rat aorta (
n=13)
Note: with normal group comparison, * P<0.01; With model group comparison,
#p<0.05,
##p<0.01; Only organize comparison with Rui Gelie, Δ P<0.05.
Diabetic angiopathy be take arteriosclerosis as main manifestations, and vascular endothelial injury is the initiating link of diabetic vascular complications, and the generation of diabetic angiopathy simultaneously further promotes again endothelial injury, 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 progress, ET level raises gradually, is the good index of reflection diabetic angiopathy.Oxygen-derived free radicals is the key factor that causes endothelial injury, and in blood, SOD, CAT are the important protease of removing oxygen-derived free radicals.According to the above results, Preliminary conclusion: the clean use in conjunction of folic acid and Rui Gelie not only hypoglycemic activity is strengthened, the effect of the diabetes rat vascular endothelial injury that is also significantly improved.
Embodiment 7. She Gelie are clean/formyl tetrahydrofolic acid/Vit B
12to the blood vessel of diabetes rat and Endothelium Protective effect
Method: Wistar rat (male, body weight 200-250g) high lipid food is fed 12 weeks.Before rat modeling, fasting is 12 hours, lumbar injection STZ(30mg/kg), after 2 weeks, after socket of the eye, adopt fasting blood, surveying blood glucose FPG>=11.1mmoL/L is diabetes modeling success, diabetes rat is divided into 3 groups at random by blood glucose value, be respectively model control group, She Gelie clean group (10mg/kg/d), She Gelie clean/formyl tetrahydrofolic acid/Vit B
12group (10+0.08+0.01mg/kg/d), 13 every group, gastric infusion, every day 1 time, continuous 12 weeks; Separately set up rats in normal control group, with normal diet, feed (model contrast and normal control rat gavage every day distilled water).Each group of diabetes rat all continues to feed with high-calorie feed, experimental session drinking water for animals and feedstuff do not limit, test blood sampling while finishing for 12 weeks, survey blood glucose and press test kit description and measure NO (nitrate reductase method), total nitric oxide synthetase (T-NOS) and total SOD vigor; Put the method for exempting from and measure serum thromboxane (TXB
2), prostaglandin (6-keto-PGF1 α, be called for short PGF1 α) and blood plasma ET.Data represent by mean ± standard deviation, row paired t-test relatively between group.
Result: in Table 4-6.1. She Gelie clean/formyl tetrahydrofolic acid/Vit B
12the impact of compositions on blood glucose: model group blood glucose significantly raises, She Gelie can significantly reduce blood glucose only, and She Gelie is clean/formyl tetrahydrofolic acid/Vit B
12compositions blood sugar reducing function strengthens to some extent, but does not reach significant level.2. She Gelie clean/formyl tetrahydrofolic acid/Vit B
12the impact of compositions on NO, T-NOS, ET and NO/ET: with normal group comparison, model group blood plasma NO reduces, and serum T-NOS vigor significantly declines, and ET content raises, and NO/ET ratio reduces; With model group comparison, She Gelie only organizes only NO, T-NOS and raises to some extent, and She Gelie clean/formyl tetrahydrofolic acid/Vit B
12group NO, T-NOS raise more obvious, and ET reduces, and NO/ET ratio significantly increases simultaneously, prompting formyl tetrahydrofolic acid/Vit B
12strengthen blood vessel endothelium protection.3. She Gelie clean/formyl tetrahydrofolic acid/Vit B
12compositions is to TXB
2, PGF1 α and both ratio impact: with normal group comparison, model group blood plasma TXB
2significantly raise, PGF1 α changes not obvious, TXB
2/ PGF1 α ratio raises; With model group comparison, 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 equally formyl tetrahydrofolic acid/Vit B
12there is the preventive and therapeutic effect strengthening blood vessel embolism.4. She Gelie clean/formyl tetrahydrofolic acid/Vit B
12the impact of compositions on the total SOD vigor of serum: with normal group comparison, the total SOD vigor of model group serum significantly reduces, administration group SOD vigor all has rising in various degree.Wherein, only organizing comparison with She Gelie, She Gelie is clean/formyl tetrahydrofolic acid/Vit B
12group SOD vigor raises more obvious, the collaborative vascular protection effect between prompting medicine.
Table 4 She Gelie is clean/formyl tetrahydrofolic acid/Vit B
12compositions to the effect of rat blood sugar (
n=13)
Note: with normal group comparison, * P<0.01; With model group comparison,
##p<0.01.
Table 5 She Gelie is clean/formyl tetrahydrofolic acid/Vit B
12compositions is to the protective effect of endothelium (n=13)
Note: with normal group comparison, * P<0.05, * * P<0.01; With model group comparison,
#p<0.05,
##p<0.01;
Only organize comparison with She Gelie, Δ P<0.05, Δ Δ P<0.01.
Table 6 She Gelie is clean/formyl tetrahydrofolic acid/Vit B
12compositions is to the protective effect of rat aorta (n=13)
With normal group comparison, * P<0.05, * * P<0.01; With model group comparison,
#p<0.05,
##p<0.01; Only organize comparison with 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 is to maintaining the normal function of endotheliocyte and hemodynamics etc. being played an important role.This result of study prompting, compares with folk prescription, the clean and formyl tetrahydrofolic acid/Vit B of She Gelie
12use in conjunction is more conducive to maintain the homeostasis of NO/ET and thromboxane/prostaglandin, is conducive to assist to regulate microvascular easypro contracting, anticoagulant and thrombosis, therefore has the pharmacological action of control diabetic angiopathy.
Claims (9)
1. a pharmaceutical composition, comprising:
(1) sodium-glucose 2 type transporter (SGLT2) inhibitor of pharmaceutical dosage and medicinal precursor, active metabolite or salt apoplexy due to endogenous wind is a kind of;
(2) one or more of the vitamin B group of pharmaceutical dosage;
(3) acceptable carrier on pharmaceutics.
2. pharmaceutical composition according to claim 1, is characterized in that: described SGLT2 inhibitor is selected from a kind of 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.
3. pharmaceutical composition according to claim 1, is characterized in that: described vitamin B group is selected from vitamin B
6, vitamin B
12, folacin compound one or more, content is 0.1～50mg.
4. pharmaceutical composition according to claim 2, is characterized in that: the clean content of described Da Gelie is 2.5～250mg, and the clean content of Rui Gelie is 25～500mg, and the clean content of She Gelie is 10～500mg.
5. pharmaceutical composition according to claim 3, it is characterized in that: described folacin compound is selected from a kind of of folic acid, 5-methyltetrahydrofolate, formyl tetrahydrofolic acid, folinic acid, calcium levofolinate, folic acid officinal salt etc., content is 0.2～5mg, and preferred content is 0.4～1.6mg.
6. according to the pharmaceutical composition described in any one in claim 1～5, it is characterized in that the pharmacy dosage form of this pharmaceutical composition is oral formulations, comprise tablet, capsule or granule etc.
7. the purposes of the pharmaceutical composition described in any one in the medicine for the preparation for the treatment of diabetes in claim 1～5, is particularly useful for the diabetes with hyperhomocysteinemiainjury.
In claim 1～5 pharmaceutical composition described in any one for the preparation of prevention, treat or delay the purposes in the medicine of diabetic vascular complications.
9. purposes claimed in claim 8, is characterized in that: described diabetic vascular complications comprises atherosclerosis, coronary heart disease, cerebrovascular, lower limb gangrene, nephropathy and retinal microvascular pathological changes.
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Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106727445A (en) * | 2016-12-21 | 2017-05-31 | 河北科技大学 | A kind of Dapagliflozin pelliculae pro cavo oris and preparation method thereof |
| CN110141566A (en) * | 2018-02-11 | 2019-08-20 | 清华大学深圳研究生院 | Application of the SGLT2 inhibitor in regulation 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 |
| CN112438975A (en) * | 2019-09-03 | 2021-03-05 | 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 |
| WO2021245253A1 (en) | 2020-06-05 | 2021-12-09 | Krka, D.D., Novo Mesto | Preparation of highly pure amorphous dapagliflozin |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
-
2014
- 2014-01-07 CN CN201410006739.3A patent/CN103721261B/en active Active
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| 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 |
| CN106727445A (en) * | 2016-12-21 | 2017-05-31 | 河北科技大学 | A kind of Dapagliflozin pelliculae pro cavo oris and preparation method thereof |
| 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 |
| CN110141566A (en) * | 2018-02-11 | 2019-08-20 | 清华大学深圳研究生院 | Application of the SGLT2 inhibitor in regulation inflammation |
| 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 |
| CN112438975A (en) * | 2019-09-03 | 2021-03-05 | 清华大学深圳研究生院 | Application of diabetes treatment medicine in bacteriostasis |
| 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 |
| WO2021245253A1 (en) | 2020-06-05 | 2021-12-09 | Krka, D.D., Novo Mesto | Preparation of highly pure amorphous dapagliflozin |
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| CN103721261B (en) | 2016-01-20 |
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Address after: Three No. 16 biological incubator, No. 518057, Middle District, Nanshan District hi tech Development Zone, Guangdong, Shenzhen Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd. Address before: 518057, No. 16, No. 1, Nanshan District hi tech, Shenzhen, Guangdong Patentee before: SHENZHEN AUSA PHARMED Co.,Ltd. |
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Effective date of registration: 20230510 Address after: 518057 the 1st and 2nd floors of No.2 building, phase III of biological incubator, No.16, Gaoxin Zhongyi Road, central high tech Zone, Nanshan District, Shenzhen City, Guangdong Province Patentee after: SHENZHEN AUSA PHARMACEUTICAL Co.,Ltd. Patentee after: SHENZHEN AUSA PHARMED Co.,Ltd. Address before: Phase III of Biological Incubator, No. 16 Zhongyi Road, High tech Zone, Nanshan District, Shenzhen City, Guangdong Province, 518057 Patentee before: SHENZHEN AUSA PHARMED Co.,Ltd. |