CN102580060B - Medicine composition for curing diabetes mellitus and complications of diabetes mellitus - Google Patents
Medicine composition for curing diabetes mellitus and complications of diabetes mellitus Download PDFInfo
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Abstract
The invention belongs to the field of pharmaceuticals, and specifically relates to a medicine composition for curing diabetes mellitus and complications of diabetes mellitus, in particular to a medicine composition containing insulin analogue and low molecular heparin or medicinal salts of insulin analogue and low molecular heparin. Compared with single dose, the medicine composition has remarkable superiority on improving blood sugar, urine sugar and glycated serum protein level of a glucose kinase (GK) rat, has good synergistic effect and has good synergistic effect on improvement of C-reactive protein (CRP) level and inhibition of complement C3 activation so that the medicine composition for curing diabetes mellitus and complications of diabetes mellitus can be used for preventing and/or curing diabetes mellitus and complications of diabetes mellitus.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to a kind of pharmaceutical composition for the treatment of diabetes and complication thereof, particularly contain the pharmaceutical composition of insulin analog and Low molecular heparin or their officinal salt.
Background technology
Diabetes (diabetes mellitus, DM) be one group of syndrome caused by the combined effect of E&H factor, its basic pathology feature be insulin secretion definitely or relative deficiency, or peripheral tissues is to insulin insensitivity, cause based on carbohydrate metabolism disturbance, comprise a kind of systemic disease of fat, protein metabolism disorder.The multinomial Study of evidence based medicine such as clinical trial (DCCT), the perspective diabetes study of Britain (UKPDS) of blood glucose control and complication has made people reach common understanding to the meaning strengthening glycemic control, blood glucose fluctuation not only can prevent or delay the generation of chronic complicating diseases of diabetes, improve the quality of life of patient, and greatly can reduce the relevant medical expense of diabetes.But the blood glucose fluctuation rate of diabetics is lower in reality.According to a statistics display, China connects subject diabetics has 2/3 not reach therapeutic goal.Along with the prolongation of the type 2 diabetes mellitus course of disease, a lot of patient relies on merely orally-taken blood sugar reducing cannot reach the target of intensive treatment, and now insulinize just becomes the important method of blood glucose fluctuation.
But find in clinical treatment, also there are the following problems for injection of insulin itself: the blood glucose during (1) can only reduce injection, change of blood sugar curve controlled blood glucose can not be pressed completely; (2) easily hypoglycemia is produced; (3) Vapor recovery unit of insulin is poor, and absorption difference reaches 52%; (4) effectively complication can not be controlled.
" inflammation " is that this theory is thought in recent years about the brand-new idea of pathogenesis of diabetes mellitus, and type ii diabetes may be cytokine mediated inflammatory reaction, and inflammation plays instrumentality in the pathogenesis of type ii diabetes.Between inflammatory reaction and type ii diabetes complication, there is close contacting.Be mainly manifested in:
(1) inflammation and diabetictrunk angiopathy relation:
The pathologic basis of diabetictrunk angiopathy is atherosclerosis.The perspective diabetes study of Britain confirms, glycemic control well obviously can not reduce the incidence rate of diabetictrunk angiopathy, illustrates in the generation, evolution of diabetictrunk angiopathy, also has other factors to play an important role in addition to elevated plasma glucose concentration.Think now, atherosclerosis is the arterial wall diseases associated with inflammation coming from endothelial system exception.The atherosclerotic a series of pathological process of the inflammation factor wide participations such as solube intercellular adhesion molecule-1, CRP, Interleukin-1β, interleukin-6, comprise and cause endothelial injury and dysfunction, expression of adhesion molecule increases, the release of chemotactic factor, leukocyte and migration, oxidized low-density lipoprotein is by macrophage picked-up, macrophage activation, foam wanshing, the mononuclear cell of activation discharges a series of cytokine, smooth muscle cell migration and propagation, finally forms atheromatous plaque.If inflammatory reaction sustainable development, the macrophage of activation produces some metalloproteases and other proteases, and the fibrous cap weakness of atherosclerotic arteries is broken, and slough is released into blood, forms embolus, causes acute myocardial infarction etc.
(2) relation of inflammation and diabetic microvascular complication:
Result of study displays numerous in recent years, strict glycemic control, to regulate in kidney and systemic hemodynamic only has certain retarding action to part of diabetes mellitus nephrotic, part of diabetes mellitus nephrotic still slowly advances to end stage renal failure, infers that other factors play an important role in addition in the generation, evolution of diabetic nephropathy.Existing result of study confirms, inflammation may be the key factor of diabetic nephropathy sustainable development.Inflammation can by initiated oxidation stress, make LDL oxidation be oxidized low-density lipoprotein, increase mononuclear cell sticking and infiltrating vascular endothelial cell, damage glomerular endothelial cells.
Existing research confirms, inflammation mechanism take part in generation, the evolution of diabetic renal papillary necrosis.Vincent etc. are at " Inhibition of caspase-1/Interleu-kin 1 β signaling prevents degeneration of retinal capillaries indiabetes and galactosemia " (Diabetes, 56 volume 1 phases in 2007) literary composition is to after diabetic renal papillary necrosis injected in mice il-1 beta antagonists, found by long-term observation, it can suppress the microvascular degeneration of diabetic renal papillary necrosis Mouse Retina.Demircan etc. " Determination of vitreous interleukin-21 (IL21) and tumournecrosis factor (TNF) levels in proliferative diabetic retinopathy " (Eye, 20 volume 12 phases in 2006) one literary composition by test find, suffer from Interleukin-1β in the patients serum of diabetic proliferative retinopathy and TNF-alpha levels raises than Normal group, both promptings may play an important role in the generation of diabetic proliferative retinopathy, development.
Non-alcoholic fatty liver disease is normal to accompany with type ii diabetes obese patient, the pathological development of non-alcoholic fatty liver disease has 4 stages of simple fatty liver, fat hepatitis, fatty liver fibrosis and fatty cirrhosis, and inflammation plays an important role in whole process.CA ID etc. are at " Local and systemic insulin resistance resulting from hepaticactivation of IKK-2 β and NF2kappaB " (NatMed, 11 volume 2 phases in 2005) to disclose its mechanism may be that the accumulation of intrahepatic fat increases to a literary composition, the expression of inflammatory factor gene strengthens, also proinflammatory inflammation factor may be discharged by abdominal adipose tissue, arrive liver by portal vein, cause inflammation in liver.
Summary of the invention
In order to significantly improve the blood sugar level of diabetics, reduce diabetic complication as much as possible, especially the incidence rate of atherosclerosis, diabetic renal papillary necrosis, non-alcoholic fatty liver disease and the progress of diabetic complication and deterioration, the invention provides a kind of pharmaceutical composition, it is containing, for example lower active component:
(1) insulin analog; With
(2) Low molecular heparin or its officinal salt,
Described insulin analog is insulin aspart, insulin lispro or insulin Glargine, and described Low molecular heparin can be selected from Enoxaparin, edegliparin., DALT, parnaparin or Clivarin.
Preferably, in aforementioned pharmaceutical compositions, insulin analog is insulin Glargine.
Preferably, in aforementioned pharmaceutical compositions, the officinal salt of Low molecular heparin is sodium salt or calcium salt.The officinal salt of described Low molecular heparin can be selected from low molecular heparin calcium, low molecular sodium heparin, Enoxaparin Sodium, nadroparin calcium, dalteparin sodium, Parnaparin Sodium or Clivarin sodium.
The present invention creatively introduces Low molecular heparin or their officinal salt on the basis of conventional hypoglycemic medicine insulin analog, result achieves good synergism improving in blood glucose, level of sugar, and suppression Complement C_3 activate, improve hs-CRP (CRP) horizontal in there is marked improvement, and then inflammation-inhibiting reaction generation and deterioration aspect achieve unforeseeable therapeutic effect.
The present invention carries out preferably, preferably, containing, for example lower active component in pharmaceutical composition to the active component in aforementioned pharmaceutical compositions:
(1) insulin Glargine; With
(2) low molecular heparin calcium or low molecular sodium heparin.
The present invention have studied the impact of pharmaceutical composition of the present invention on GK rat blood sugar level, level of sugar, glycated serum protein level by embodiment 11, found that the pharmaceutical composition of Low molecular heparin and insulin Glargine may be used for treating diabetes, and Be very effective.Especially to be the low molecular heparin calcium of 0.25 ~ 50000: 1 or the pharmaceutical composition of low molecular sodium heparin and insulin Glargine achieve beyond thought synergism improving in blood glucose, level of sugar, glycated serum protein to weight ratio.Therefore in pharmaceutical composition of the present invention, the weight ratio of low molecular heparin calcium or low molecular sodium heparin and insulin Glargine is preferably 0.25 ~ 50000: 1, can more preferably 10 ~ 8000: 1.
Meanwhile, the invention provides a kind of method for the treatment of diabetes, i.e. administration pharmaceutical composition of the present invention, preferably in compositions containing 2.5mg ~ 500mg low molecular heparin calcium or low molecular sodium heparin and 0.01mg ~ 10mg insulin Glargine; More preferably, in compositions containing 20mg ~ 40mg low molecular heparin calcium or low molecular sodium heparin and 0.05mg ~ 2mg insulin Glargine.For a person skilled in the art, dosage rate is determined after can considering according to the combined factors such as condition, age.
As immune core component, the physiological action of complement is mainly attacked external cause of disease and removes immune complex.Under pathological state, the complement of excessive activation forms membrane attack complex, normal cell dissolved destruction can be made, or produce the contraction of the various intermediate product induction smooth muscle such as C3a and C5a, histamine release of mast cell, the increase of vascular permeability and chemotactic attract to have the granulocyte of corresponding receptor and mononuclear phagocyte to the areas of inflammation migration of complement activation and gathering, participate in exacerbate inflammation reaction and tissue injury.Therefore, suppress complement activation, inflammatory reaction and tissue injury can be weakened.
The close ties such as between atherosclerosis, diabetic renal papillary necrosis, non-alcoholic fatty liver disease in view of inflammatory reaction and type ii diabetes complication, the present invention especially have studied the antiphlogistic effects of insulin Glargine and Low molecular heparin, to making progress in reduction diabetic complication incidence rate.Although Low molecular heparin itself has certain anti-inflammatory activity, anti-inflammatory activity mainly concentrates on the effect of Low molecular heparin to inflammatory cell, inflammatory factor and adhesion factor.A kind of mechanism is not also had to can be good at explaining the anti-inflammatory activity mechanism of action of Low molecular heparin at present.The present invention simultaneously pharmaceutically acceptable sodium salt of administration Low molecular heparin or Low molecular heparin or calcium salt on the basis of insulin Glargine, found that the administration simultaneously of insulin Glargine associating Low molecular heparin significantly can suppress the activation of Complement C_3, thus suppress generation or the deterioration of diabetics inflammatory reaction, this be carry out treatment diabetes while carry out improving diabetic complication and provide a brand-new approach.
Show (see embodiment 12 by clinical experiment, from the level of the Complement C_3 before and after treatment, with individually dosed Low molecular heparin, individually dosed insulin Glargine is compared, the pharmaceutical composition that the present invention contains Low molecular heparin and sweet smart islets of langerhans improve Complement C_3 horizontal in there is significant difference (p < 0.05), and achieve synergism, this shows that pharmaceutical composition of the present invention is in suppression complement activation further, weaken inflammatory reaction and tissue injury aspect and achieve unexpected collaborative therapeutic effect effect, therefore pharmaceutical composition of the present invention can as the drug use treating and/or preventing diabetic complication, especially the treating and/or preventing of type ii diabetes complication.
Therefore the invention provides a kind of novelty teabag of pharmaceutical composition of the present invention, namely pharmaceutical composition of the present invention suppresses the application in the medicine of Complement C_3 activation in preparation treatment.The present invention carries out preferably to the content of the active component in pharmaceutical composition, preferably in pharmaceutical composition containing 2.5mg ~ 500mg low molecular heparin calcium or low molecular sodium heparin and 0.01mg ~ 10mg insulin Glargine.Further preferably, in compositions containing 20mg ~ 40mg low molecular heparin calcium or low molecular sodium heparin and 0.05mg ~ 2mg insulin Glargine.Wherein dosage rate is determined after can considering according to the various factors such as the state of an illness, age to one skilled in the art.
Serum CA125 is marker of inflammation, and when febrile disease, various inflammatory conditions and wound, serum CRP level can obviously increase.For a long time, clinically often judge that patient is with or without obvious infective inflammation with the 95% reference value upper limit of health population CRP.But the development and application result of study of high sensitivity CRP (Hs-CRP) detection method shows, originally think that the generation of height but with following cardiovascular diseases of normal serum CRP level is closely related.A large amount of research data shows, atheromatous thrombosis, except being athero process, be also a chronic inflammation processes, and CRP is mediation and the mark of atheromatous thrombotic disease.CRP, to angina pectoris, acute coronary syndrome and After percutaneous transluminal patient, has the effect of prediction myocardial ischemia risk of relapse and death risk.By clinical research (see embodiment 12), the present invention confirms that pharmaceutical composition of the present invention significantly reduces Diabetes Mellitus CRP, and have synergism, this imply that and will significantly weaken the diabetics complication reaction relevant to inflammation.This further illustrates, and pharmaceutical composition of the present invention may be used for treating and/or preventing such as diabetic complication atherosclerosis, diabetic renal papillary necrosis, non-alcoholic fatty liver disease etc.
Meanwhile, present invention also offers a kind of method treating and/or preventing diabetic complication especially atherosclerosis, diabetic renal papillary necrosis, non-alcoholic fatty liver disease, namely treated with compositions of the present invention, preferably in pharmaceutical composition containing 2.5mg ~ 500mg low molecular heparin calcium or low molecular sodium heparin and 0.01mg ~ 10mg insulin Glargine.Further preferably, containing 20mg ~ 40mg low molecular heparin calcium or low molecular sodium heparin and 0.05mg ~ 2mg insulin Glargine in compositions, wherein dosage rate concerning and those skilled in the art can consider according to the various factors such as the state of an illness, age after determine.
What deserves to be explained is, in the pharmaceutical composition that the present invention relates to Low molecular heparin tire in 100IU/mg, tiring in 26IU/mg of insulin.But the present invention is not only confined to Low molecular heparin, insulin is above-mentioned tires.If change tiring of Low molecular heparin and/or insulin, under technology enlightenment of the present invention, obtain corresponding part by weight relation and corresponding medicament contg is apparent.Such as, Low molecular heparin tire in 100IU/mg, insulin tire in 26IU/mg, in pharmaceutical composition of the present invention, the weight ratio of Low molecular heparin and insulin Glargine is 30: 1, containing 30mg Low molecular heparin and 1mg insulin Glargine in pharmaceutical composition, at this moment the potency ratio of Low molecular heparin and insulin Glargine is 3000: 26.When ensure the potency ratio of Low molecular heparin and insulin Glargine be 3000: 26 constant, if Low molecular heparin tire in 80IU/mg, insulin tire in 26IU/mg, in pharmaceutical composition of the present invention, the weight ratio of Low molecular heparin and insulin Glargine is 37.5: 1, containing 37.5mg Low molecular heparin and 1mg insulin Glargine in pharmaceutical composition.
In order to express the present invention better, the invention provides the injection containing pharmaceutical composition of the present invention, also containing zinc chloride, metacresol, glycerol, and pH value is 3.0 ~ 7.0.The preparation of injection can be prepared by conventional formulation technologies completely.
In a word, pharmaceutical composition of the present invention compared with prior art has following outstanding advantage:
(1) compared with individually dosed, pharmaceutical composition of the present invention improve GK rat blood sugar, glucose in urine and glycated serum protein horizontal in there is significant advantage, and there is good synergism.
(2) compared with individually dosed, pharmaceutical composition of the present invention is improving serum CRP level, is suppressing to have good synergism in Complement C_3 activation, pharmaceutical composition of the present invention in suppression complement activation, weaken in inflammatory reaction and tissue injury and achieve unexpected technique effect, may be used for preventing and/or treating diabetes and complication thereof.
Detailed description of the invention
Further describe the present invention below by way of detailed description of the invention, but the present invention is not limited only to following examples.
Embodiment 1 injection
Prescription:
Low molecular sodium heparin 50g
Insulin Glargine 0.001g
Zinc chloride 10g
Metacresol 8g
Glycerol 10g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the low molecular sodium heparin of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 7.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 2 injection
Prescription:
Low molecular sodium heparin 0.25g
Insulin Glargine 1g
Zinc chloride 1g
Metacresol 0.8g
Glycerol 1g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the low molecular sodium heparin of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 3.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 3 injection
Prescription:
Low molecular sodium heparin 10g
Insulin Glargine 1g
Zinc chloride 1g
Metacresol 2g
Glycerol 4g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the low molecular sodium heparin of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 5.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 4 injection
Prescription:
Low molecular sodium heparin 80g
Insulin Glargine 0.01g
Zinc chloride 15g
Metacresol 10g
Glycerol 10g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the low molecular sodium heparin of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 3.5, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 5 injection
Prescription:
Low molecular sodium heparin 30g
Insulin Glargine 1g
Zinc chloride 5g
Metacresol 8g
Glycerol 10g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the low molecular sodium heparin of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 5.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 6 injection
Prescription:
Low molecular heparin calcium 50g
Insulin aspart 0.001g
Zinc chloride 10g
Metacresol 9g
Glycerol 8.6g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the low molecular heparin calcium of recipe quantity, insulin aspart, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 7.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 7 injection
Prescription:
Enoxaparin Sodium 0.25g
Insulin Glargine 1g
Zinc chloride 1g
Metacresol 0.8g
Glycerol 1g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the Enoxaparin Sodium of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 3.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 8 injection
Prescription:
Nadroparin calcium 10g
Insulin Glargine 1g
Zinc chloride 1.2g
Metacresol 2g
Glycerol 4.5g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the nadroparin calcium of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 5.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 9 injection
Prescription:
Parnaparin Sodium 80g
Insulin Glargine 0.01g
Zinc chloride 15g
Metacresol 8.8g
Glycerol 10g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the Parnaparin Sodium of recipe quantity, insulin Glargine, adds appropriate water for injection, then add glycerol, metacresol, zinc chloride fully dissolve, and adjust ph to 3.5, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
Embodiment 10 injection
Prescription:
Dalteparin sodium 30g
Insulin lispro 1g
Zinc chloride 10g
Metacresol 8g
1,2-PD 5g
Sodium chloride 9g
Water for injection adds to 1000g
Preparation technology: get the dalteparin sodium of recipe quantity, insulin lispro, adds appropriate water for injection, then adds 1,2-propylene glycol, metacresol, zinc chloride fully dissolve, and adjust ph to 5.0, add sodium chloride, filter, embedding, 100 degrees Celsius of sterilizing 30min and get final product.
The experimental study that embodiment 11 pharmaceutical composition of the present invention affects diabetic GK rats blood glucose, glucose in urine and glycated serum protein
1, materials and methods
1.1 material
(1) laboratory animal and feedstuff:
Normal Wistar rats 10, SPF level male GK rat in 12 week age 148, is purchased from Shanghai Si Laike animal center.High lipid food is provided by the feed corporation,Ltd that pulls together of Beijing Australia of section; Normal feedstuff is provided by Military Medical Science Institute's animal center.
(2) reagent and instrument
Tes-Tape, microplate reader (Thermo company of the U.S. provides), the full blood glucose meter of German Luo Kang and supporting reagent paper.
1.2 method
After all rat adaptabilities feed 1 week, GK rat fasting blood-glucose >=11.1mmol/L is entered group, reject residue GK rat 18.To enter to organize GK rat 130 to be divided into model group (10) at random, to test one group (40), to test two groups (40), to test three groups (40), and then each group will be fed and be handled as follows:
Model group (10): continue normal nursing 1 week, wait to be administered;
Test one group (40): high glucose and high fat feedstuff of feeding is (by 10.0% Adeps Sus domestica, 20.0% sucrose, 10.0% yolk powder, 0.5% sodium cholate and 59.5% conventional feed composition) 1 week, after 35 GK rat blood sugar levels reach 25.0 ~ 30.0mmol/L, select 30 to be divided into Low molecular heparin A group (10), insulin Glargine A group (10) and compound recipe A group (10) at random, wait to be administered, pick out residue GK rat;
Test two groups (40): continue adaptability and feed 1 week, select blood sugar level 11.1 ~ 15.0mmol/LGK rat 30, be divided into Low molecular heparin B group (10), insulin Glargine B group (10) and Compound B group (10) at random, etc. to be administered, reject undesirable GK rat 10 simultaneously;
Test three groups (40): high sugar feed of feeding is (by 10.0% sucrose, 10.0% yolk powder, 0.5% sodium cholate and 79.5% conventional feed composition) 1 week, after whole GK rat blood sugar level reaches 15.1 ~ 24.9mmol/L, 30 rats are selected to be divided into Low molecular heparin C group (10), insulin Glargine C group (10) and compound recipe C group (10) at random, etc. to be administered, reject residue GK rat 10 simultaneously.
Concrete dosage regimen is as follows:
1.2.1 Normal group: normal saline;
1.2.2 model control group: normal saline;
1.2.3 Low molecular heparin A group: lumbar injection Low molecular heparin injection (4mg/kg Low molecular heparin, preparation technology is with embodiment 3)
1.2.4 insulin Glargine A group: lumbar injection insulin glargine injecta (0.4mg/kg insulin Glargine, preparation technology is with embodiment 3);
1.2.5 compound recipe A group: lumbar injection is as the injection (4mg/kg Low molecular heparin+0.4mg/kg insulin Glargine) of embodiment 3;
1.2.6 Low molecular heparin B group: lumbar injection Low molecular heparin injection (80mg/kg Low molecular heparin, preparation technology is with embodiment 4);
1.2.7 insulin Glargine B group: lumbar injection insulin glargine injecta (0.01mg/kg insulin Glargine, preparation technology is with embodiment 4);
1.2.8 Compound B group: lumbar injection is as the injection (80mg/kg Low molecular heparin+0.01mg/kg insulin Glargine) of embodiment 4;
1.2.9 Low molecular heparin C group: lumbar injection Low molecular heparin injection (6mg/kg Low molecular heparin, preparation technology is with embodiment 5);
1.2.10 insulin Glargine C group: lumbar injection insulin glargine injecta (0.2mg/kg insulin Glargine, preparation technology is with embodiment 5);
1.2.11 compound recipe C group: lumbar injection is as the injection (6mg/kg Low molecular heparin+0.2mg/kg insulin Glargine) of embodiment 5.
All rats are administered once every day, freely drink water, and all GK rats all give high lipid food, Wistar rat normal diet.Wherein Low molecular heparin is tired in 100U/mg, and insulin Glargine is tired in 26U/mg.
2, sample preparation and Indexs measure
In medication treatments period, weekly orbital vein blood sampling, the change of monitoring fasting blood sugar.Medication treats the 28th day, fasting 12h, after last administration 1h, abdominal aortic blood, injects a clean tube and leaves standstill, separation of serum, detect FBG immediately, all the other blood serum samples are sub-packed in 1.5ml cryopreservation tube, and-20 DEG C of Refrigerator stores are waited for associated biochemical, put and exempt from index determining.Extract as early as possible after collection of specimens, extract and undertaken by pertinent literature, should test as early as possible after extraction.If can not test at once, specimen can be put in-20 DEG C of preservations, but should multigelation be avoided.
Testing index and method as follows:
The mensuration of 2.1 fasting glucose (FBG), adopts glucose oxidase method;
2.2 glycated serum proteins (GSP) assay, adopts fructosamine method;
The mensuration of 2.3 glucoses in urine, adopts Tes-Tape;
2.4 statistical procedures
Above obtained experimental data is carried out statistical procedures in accordance with the following methods: adopt SPSS15.0 statistical software, calculate data with mean ± standard deviation (
) represent, many groups data compares employing variance analysis, compares and adopt t inspection in group.With p < 0.05 for there being statistical significance.
3, experimental result
The blood glucose of 3.1 pharmaceutical compositions of the present invention on diabetes rat, the impact of glucose in urine
As shown in Table 1:
(1) compared with model group, pharmaceutical composition of the present invention all has significantly or pole significant difference the impact of blood glucose in diabetic rats, glucose in urine.This shows that pharmaceutical composition of the present invention has good effect improving in diabetes glucose, level of sugar.
(2) compared with Low molecular heparin A group, insulin Glargine A group, compound recipe A group has significant difference improving in diabetes glucose, level of sugar, and achieve good synergism, this shows pharmaceutical composition of the present invention respectively compared with individually dosed Low molecular heparin, individually dosed insulin Glargine, in treatment diabetes, have the outstanding advantage significantly reducing blood glucose and glucose in urine.
(3) compared with Low molecular heparin B group, insulin Glargine B group, Compound B group has significant difference improving in diabetes glucose, level of sugar, and achieve good synergism, this shows pharmaceutical composition of the present invention respectively compared with individually dosed Low molecular heparin, individually dosed insulin Glargine, in treatment diabetes, have the outstanding advantage significantly reducing blood glucose and glucose in urine.
(4) compared with Low molecular heparin C group, insulin Glargine C group, compound recipe C group has significant difference improving in diabetes glucose, level of sugar, and achieve good synergism, this shows pharmaceutical composition of the present invention respectively compared with individually dosed Low molecular heparin, individually dosed insulin Glargine, in treatment diabetes, have the outstanding advantage significantly reducing blood glucose and glucose in urine.
As can be seen here, the pharmaceutical composition that the present invention contains Low molecular heparin and insulin Glargine has beyond thought technique effect improving in blood glucose in diabetic rats, level of sugar, and achieves the collaborative effect improving blood glucose, level of sugar.
What deserves to be explained is, the present invention also investigated weight ratio be 50000: 1 and 0.25: 1 Low molecular heparin and insulin Glargine compound medicine on the impact of GK rat blood sugar and glucose in urine, result of the test show weight ratio be 50000: 1 Low molecular heparin and insulin Glargine compound medicine improving in blood glucose in diabetic rats, level of sugar, blood sugar level meansigma methods is reduced to 13.2mmol/L from 28.5mmol/L, and level of sugar meansigma methods is reduced to 1.10mmol/L from 3.02mmol/L; Weight ratio be 0.25: 1 Low molecular heparin and insulin Glargine compound medicine improving in blood glucose in diabetic rats, level of sugar, blood sugar level meansigma methods is reduced to 14.2mmol/L from 27.5mmol/L, and level of sugar meansigma methods is reduced to 1.25mmol/L from 3.12mmol/L.This shows further, and weight ratio is the Low molecular heparin of 50000: 1 and 0.25: 1 and insulin Glargine compound medicine improves GK rat blood sugar and level of sugar aspect has good effect.
Experimental result shows, for different blood sugar levels, gives the dosage different from pharmaceutical composition of the present invention, and the pharmaceutical composition that the present invention contains Low molecular heparin and insulin Glargine may be used to treat diabetes, and Be very effective.Especially weight ratio is that the Low molecular heparin of 0.25 ~ 50000: 1 and the pharmaceutical composition of insulin Glargine achieve beyond thought technique effect in reduction blood glucose, glucose in urine.
Table 1 pharmaceutical composition of the present invention is on the impact of blood glucose in diabetic rats (mmol/L), glucose in urine (mmol/L)
Note:
▲compare with model group, P < 0.05;
▲ ▲compare with model group, P < 0.01;
△compare with Low molecular heparin A group, P < 0.05;
△ △compare with Low molecular heparin A group, P < 0.01;
#compare with insulin Glargine A group, P < 0.05;
★ ★compare with Low molecular heparin B group, P < 0.01;
☆compare with insulin Glargine B group, P < 0.05;
aMP.AMp.Amp &compare with Low molecular heparin C group, P < 0.01;
compare with insulin Glargine C group, P < 0.05.
3.2 pharmaceutical compositions of the present invention are on the impact of diabetes rat glycated serum protein (GSP)
Glycated serum protein is the material of a kind of macromolecule ketoamine similar fructosamine formed in protein in blood plasma and glucose nonenzymatic glycosylation process, and its concentration becomes positive correlation with blood sugar level, and relatively keeps stable, makes a variation in the daytime little.Its mensuration is not by the impact of feed, motion, body condition, instant blood glucose.Half-life due to plasma protein is 17 ~ 20 days, therefore GSP can reflect that diabetics detects the average blood glucose levels in first 1 ~ 3 week.The height of glycated serum protein level directly affects generation and the development of diabetic various chronic complicating diseases in future.When glycated serum protein is in higher level, illustrate that patient also exists Persistent hyperglycemia, the complication such as diabetic nephropathy, arteriosclerosis, acute myocardial infarction, cerebrovas-cularaccident, cataract may be occurred.Therefore, the clinical blood glucose situation understanding patient's nearly stage usually through glycated serum protein index, the generation of assessment chronic complicating diseases of diabetes and development.
As shown in Table 2:
(1) compared with model group, the impact of pharmaceutical composition of the present invention on diabetes rat glycated serum protein level all has significantly or pole significant difference.This show pharmaceutical composition of the present invention improve glycated serum protein horizontal in there is good effect.
(2) compared with Low molecular heparin A group, insulin Glargine A group, compound recipe A group has significant difference improving in diabetes saccharifying serum protein levels, and achieve good synergism, this shows pharmaceutical composition of the present invention respectively compared with individually dosed Low molecular heparin, individually dosed insulin Glargine, in treatment diabetes, have the outstanding advantage significantly reducing glycated serum protein.
(3) compared with Low molecular heparin B group, insulin Glargine B group, Compound B group has significant difference improving in diabetes saccharifying serum protein levels, and achieve good synergism, this shows pharmaceutical composition of the present invention respectively compared with individually dosed Low molecular heparin, individually dosed insulin Glargine, in treatment diabetes, have the outstanding advantage significantly reducing glycated serum protein.
(4) compared with Low molecular heparin C group, insulin Glargine C group, compound recipe C group has significant difference improving in diabetes saccharifying serum protein levels, and achieve good synergism, this shows pharmaceutical composition of the present invention respectively compared with individually dosed Low molecular heparin, individually dosed insulin Glargine, in treatment diabetes, have the outstanding advantage significantly reducing glycated serum protein.
What deserves to be explained is, the present invention also investigated weight ratio be 50000: 1 and 0.25: 1 Low molecular heparin and insulin Glargine compound medicine on the impact of GK rat glycated serum protein, result of the test show weight ratio be 50000: 1 Low molecular heparin and insulin Glargine compound medicine improve diabetes rat glycated serum protein horizontal in, glycated serum protein level average is reduced to 2.665mmol/L from 4.755mmol/L; Weight ratio be 0.25: 1 Low molecular heparin and insulin Glargine compound medicine improving in blood glucose in diabetic rats, level of sugar, blood sugar level meansigma methods is reduced to 2.786mmol/L from 4.682mmol/L.
Experimental result shows, the pharmaceutical composition of Low molecular heparin and insulin Glargine may be used for treating diabetes, and Be very effective.Especially weight ratio is that the Low molecular heparin of 0.25 ~ 50000: 1 and the pharmaceutical composition of insulin Glargine achieve beyond thought technique effect in reduction glycated serum protein.
As can be seen here, the pharmaceutical composition that the present invention contains Low molecular heparin and insulin Glargine improve diabetes rat glycated serum protein horizontal in there is beyond thought technique effect, and achieve the collaborative effect improving glycated serum protein level.
Table 2 pharmaceutical composition of the present invention is on the impact of diabetes rat glycated serum protein (GSP)
Note:
▲compare with model group, P < 0.05;
▲ ▲compare with model group, P < 0.01;
△compare with Low molecular heparin A group, P < 0.05;
△ △compare with Low molecular heparin A group, P < 0.01;
#compare with insulin Glargine A group, P < 0.05;
★ ★compare with Low molecular heparin B group, P < 0.01;
☆compare with insulin Glargine B group, P < 0.05;
aMP.AMp.Amp &compare with Low molecular heparin C group, P < 0.01;
compare with insulin Glargine C group, P < 0.05.
Embodiment 12 pharmaceutical composition of the present invention is on the research of the impact of diabetes clinical volunteers Complement C_3, hs-CRP level
1, the selection of experimental subject and grouping
In LINYI PEOPLE'S HOSPITAL outpatient service and ward according to the diabetes diagnostic criterion meeting WHO in 1999 and specify, select the routine diabetes clinical volunteers of observation 60 (in August, 2007 to 2008 year December), male 23 example, women 37 example, age 36-72 year, 56 years old mean age.Select outpatient service same period health to look into volunteer 20 example as a control group, wherein male 18 example, women 14 example, age 35-68 year, average 40 years old.60 routine diabetes clinical volunteers are divided into 3 groups at random, often organize 20 people:
Low molecular heparin group: subcutaneous injecting of low molecular heparin sodium 30mg/d;
Insulin Glargine group: subcutaneous injection insulin Glargine 1mg/d;
Compound recipe group: subcutaneous injecting of low molecular heparin sodium 30mg/d+ insulin Glargine 1mg/d;
Wherein Low molecular heparin is tired in 100U/mg, and insulin Glargine is tired in 26U/mg.
After treating 4 weeks, all objects all adopt median cubital vein blood 4ml on an empty stomach, get serum refrigerator freezing, to be measured.
2, observation index and assay method
The mensuration of 2.1 serum complement C3s adopts (C3) ELISA kit.
Operating procedure is as follows:
(1) dilution of standard substance and application of sample: at enzyme mark bag by the accurate sample wells 10 of bidding on plate hole, add standard substance 100 μ l respectively in first, second hole, then add standard dilutions 50 μ l in first, second hole, mixing; Then from the first hole, the second hole, respectively get 100 μ l be added to the 3rd hole and the 4th hole respectively, then add standard dilutions 50 μ l respectively in the 3rd, the 4th hole, mixing; Then in the 3rd hole and the 4th hole, first respectively get 50 μ l to discard, respectively get 50 μ l and be added to respectively in the 5th, the 6th hole, then in the 5th, the 6th hole, add standard dilutions 50ul respectively, mixing; From the 5th, the 6th hole, respectively get after mixing that 50 μ l are added to the 7th respectively, in octal, again the 7th, add standard dilutions 50 μ l respectively in octal, after mixing from the 7th, get 50 μ l respectively octal and be added in the 9th, the tenth hole, add standard dilutions 50 μ l respectively in the 90 hole again, from the 90 hole, respectively get 50 μ l after mixing and discard.(after dilution, each hole application of sample amount is all 50 μ l, and concentration is respectively 120 μ g/ml, 80 μ g/ml, 40 μ g/ml, 20 μ g/ml, 10 μ g/ml).
(2) application of sample: establish blank well (blank control wells does not add sample and enzyme marking reagent, and respectively step operation is identical for all the other), testing sample hole respectively.In enzyme mark bag is by testing sample hole on plate, first adds sample diluting liquid 40 μ l, and then adds testing sample 10 μ l (the final dilution factor of sample is 5 times).Sample is added on bottom ELISA Plate hole by application of sample, does not touch hole wall as far as possible, rocks mixing gently.
(3) incubation: use the rearmounted 37 DEG C of incubations of shrouding film shrouding 30 minutes.
(4) dosing: by for subsequent use after 20 times of concentrated cleaning solution distilled water 20 times dilution
(5) wash: carefully take shrouding film off, discard liquid, dry, cleaning mixture is filled it up with in every hole, leaves standstill and discards after 30 seconds, so repeats 5 times, pats dry.
(6) enzyme-added: every hole adds enzyme marking reagent 50 μ l, except blank well.
(7) incubation: operation is with 3.
(8) wash: operation is with 5.
(9) develop the color: every hole first adds developer A50 μ l, then adds developer B50 μ l, and shake mixing gently, 37 DEG C of lucifuges develop the color 15 minutes.
(10) stop: every hole adds stop buffer 50 μ l, cessation reaction (now blue standing turns yellow).
(11) measure: the absorbance (OD value) sequentially measuring each hole with blank air-conditioning zero, 450nm wavelength.Mensuration should be carried out within 15 minutes after adding stop buffer.
(12) calculate, with the concentration of reference material for abscissa, OD value is vertical coordinate, and standard curve drawn by graph paper, and OD value per sample finds corresponding concentration by standard curve; Be multiplied by extension rate again; Or the linear regression equation of standard curve is calculated by the concentration of reference material and OD value, the OD value of sample is substituted into equation, calculates sample concentration, then be multiplied by extension rate, be the actual concentrations of sample.
2.2 hs-CRP, adopt immune rate nephelometry.
Hs-CRP (CRP) in serum forms complex as antigen and corresponding antibodies, and the speed of the immune complex formed is different in each unit interval, when antibody excess, along with the prolongation in response time, the total amount of antigen antibody complex increases gradually, the fastest in response time sometime, antigen antibody complex formation volume is maximum, scattered light intensity is maximum, i.e. so-called speed peak, peak value is directly proportional to the amount of CRP, according to the standard curve that standard concentration and scattered light speed peak are made, the amount of the CRP in serum can be calculated, this experiment measures with 7020 automatic clinical chemistry analyzers and calculates serum CA125 content.
3. experimental result
3.1 pharmaceutical compositions of the present invention are on the impact (experimental result is in table 3) of diabetics level of complement
(1) before the treatment, Low molecular heparin group, insulin Glargine group and compound recipe group three the group horizontal there was no significant difference of Complement C_3 (p > 0.05);
(2) compared with Complement C_3 level before treatment, after Low molecular heparin group, insulin Glargine group patient treatment, Complement C_3 level declines to some extent, but there was no significant difference;
(3) compared with Complement C_3 level before treatment, after compound recipe group patient treatment, Complement C_3 level declines to some extent, and has significant difference;
(4) after treatment, compared with Low molecular heparin group, insulin Glargine group, compound recipe group improve Complement C_3 horizontal in all there is significant difference (p < 0.05), and achieve synergism.
Complement activation products is the common effector molecule of specific immunity and nonspecific immunity, plays a significant role, also can cause tissue injury under particular case in body infection, immunomodulating, immune surveillance.The covalent bond energy Immunosuppression complex of complement component C3 and immune complex be combined with each other and forms large grid and be easy to deposit in the tissue, histogenic immunity complex activating complement and bring out a series of pathology damage, also can destroy the space structure of immune complex and make it dissolve.Studies have reported that, diabetes merge microangiopathies patient more simple diabetics Complement C_3 level and significantly raise.The mechanism of level of complement change is considered relevant with insulin resistant, Anomalous lipid metablism.The rising of C3 may be a kind of self regulation reaction of body to dyslipidemia.The pathological process of diabetes microvascular damage is the acceleration apoptosis of microthrombusis, Leukostasis and vascular cell, the cascade reaction after complement activation can with and aggravate above-mentioned pathological process.On the one hand, microthrombus and Leukostasis can cause ischemical reperfusion injury, and by complement classical pathway activation complement, the endotheliocyte of apoptosis also can start complement alternative route; On the other hand, there is after complement activation coagulant, proinflammatory and apoptosis-promoting effect, thus form vicious cycle, accelerate the development of microangiopathies.
Therefore, suppress complement activation, inflammatory reaction and tissue injury can be weakened.This experimental result shows, from the level of the Complement C_3 before and after treatment, compared with Low molecular heparin group, insulin Glargine group, compound recipe group improve Complement C_3 horizontal in there is significant difference (p < 0.05), and achieve synergism.That is simultaneously administration pharmaceutical composition of the present invention in suppression complement activation, weaken in inflammatory reaction and tissue injury and achieve unexpected technique effect.
Table 3 pharmaceutical composition of the present invention is to Diabetes Mellitus Complement C_3 testing result
Note:
△compare with Low molecular heparin group, P < 0.05;
#compare with insulin Glargine group, P < 0.05.
3.2 pharmaceutical compositions of the present invention are on the impact (experimental result is in table 4) of Diabetes Mellitus CRP
(1) before the treatment, Low molecular heparin group, insulin Glargine group and compound recipe group three group serum CRP level there was no significant difference (p > 0.05);
(2) compared with serum CRP level before treatment, after insulin Glargine group patient treatment, serum CRP level declines to some extent, but there was no significant difference;
(3) compared with serum CRP level before treatment, after Low molecular heparin group, compound recipe group patient treatment, serum CRP level declines to some extent, and has significant difference;
(4) after treatment, compared with Low molecular heparin group, insulin Glargine group, compound recipe group all has significant difference (p < 0.05) improving in serum CRP level, and achieves synergism.
Table 4 pharmaceutical composition of the present invention is on the impact of Diabetes Mellitus CRP
Note:
▲compare with before treatment, P < 0.05;
▲ ▲compare with before treatment, P < 0.01;
△compare with Low molecular heparin group, P < 0.05;
#compare with insulin Glargine group, P < 0.05.
Claims (7)
1. the pharmaceutical composition being active component with insulin Glargine and low molecular heparin calcium or low molecular sodium heparin is preparing the application in hypoglycemic medicine.
2. the application of pharmaceutical composition as claimed in claim 1, is characterized in that the weight ratio of described low molecular heparin calcium or low molecular sodium heparin and insulin Glargine is 0.25 ~ 50000:1.
3. the application of pharmaceutical composition as claimed in claim 2, is characterized in that in described compositions containing 2.5mg ~ 500mg low molecular heparin calcium or low molecular sodium heparin and 0.01mg ~ 10mg insulin Glargine.
4. the application of pharmaceutical composition as claimed in claim 2, is characterized in that the weight ratio of low molecular heparin calcium or low molecular sodium heparin and insulin Glargine is 10 ~ 8000:1.
5. the application of pharmaceutical composition as claimed in claim 4, is characterized in that in compositions containing 20mg ~ 40mg low molecular heparin calcium or low molecular sodium heparin and 0.05mg ~ 2mg insulin Glargine.
6. the application of the pharmaceutical composition as described in claim 3 or 5, is characterized in that it is injection, and also containing zinc chloride, metacresol, glycerol, and pH value is 3.0 ~ 7.0.
7. the application of pharmaceutical composition as claimed in claim 1, is characterized in that described pharmaceutical composition can suppress Complement C_3 to activate.
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