CN1704048A - Compound calcium phenolsulfonic acid - Google Patents
Compound calcium phenolsulfonic acid Download PDFInfo
- Publication number
- CN1704048A CN1704048A CN 200410027309 CN200410027309A CN1704048A CN 1704048 A CN1704048 A CN 1704048A CN 200410027309 CN200410027309 CN 200410027309 CN 200410027309 A CN200410027309 A CN 200410027309A CN 1704048 A CN1704048 A CN 1704048A
- Authority
- CN
- China
- Prior art keywords
- salt
- calcium dobesilate
- metformin
- group
- aforementioned
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention relates to a medicinal composition which comprises calcium dobesilate and hypoglycemic agents (such as Metformin, Glibenclamide, Nateglinide, Rosiglitazone), the medicament can be applied for the reduction of diabetic complication, and the dosage forms include oral preparation, injection and externally used preparation. The compound preparation contains therapeutic active dosage of various reactive constituents, preferably, the weight ratio range of the medicinal salts of calcium dobesilate and the medicinal salts of the hypoglycemic agents is 1:20-20:1, preferably 1:1-1:5, each unit dosage of the preparation contains 5-10000mg of calcium dobesilate..
Description
The present invention is a kind of calcium dobesilate and hypoglycemic medicine of containing, the pharmaceutical composition of metformin associating for example, and in the application of the combination medicine of prevention and treatment diabetes, diabetic complication.
Along with growth in the living standard, diabetes prevalence sharply rises in recent years, having become influences one of healthy principal disease of compatriots, and diabetes can be divided into insulin-dependent (1 type) and non-insulin-depending type (2 type), and wherein 2 type patients account for more than 80% of diabetes cases.For the treatment of type 1 diabetes, mainly adopt insulin preparation and succedaneum, and, developed the hypoglycemic medicine of a lot of types at present for the treatment of type 2 diabetes mellitus.If diabetes do not have and can in time diagnose and treat, can cause multiple chronic complicating diseases.According to statistics, concurrent blood vessel and neuropathy more than 50% are arranged in the diabetics, about 30% concurrent proliferative retinopathy, wherein about 1% patient may cause losing blind.In view of the significant damage of diabetic complication, not only bring health harm to the patient, also increased medical expense (Gao Fan, 1994, Xing Qiuling, 2003, Chen Xingbao, 2003) to society, exploitation is used to prevent and the medicine for the treatment of this class disease seems highly significant.
Diabetic complication comprises diabetes complicated peripheral nerve obstacle, ocular disease, sexual dysfunction, nephropathy, diabetic complication.And because diseases such as the fatigue and weakness that causes of diabetes, insomnia, pained, cardiopalmus uncomfortable in chest, dizzy, edema, thirsty polydipsia, numb hand and foot, pain.Studies show that one of them important pathogenic factor of diabetic complication is because the tip microvascular lesions so protect tip blood capillary, microcirculation improvement will effectively reduce the sickness rate of diabetic complication, is alleviated the symptom of complication.Clinically, had the precedent of a lot of uses to prove, given the tip vasodilation agent when diabetics is taken hypoglycemic medicine, effectively control of diabetes patient's complication occurs or relief of symptoms.As adopt pentoxifylline and hypoglycemic medicine to share.And treat diabetic complication by regulating sanguimotor mode, be approved for the nephropathy that the treatment type 1 diabetes causes as captopril, lisinopril.
Calcium dobesilate (Calcium dobesilate, 2,5 one dihydroxy benzenes sulfonic acid calcium monohydrates) is a kind of novel vascular protective agent, and its main effect is to work by following three aspects: act on wall of micrangium, by reducing its permeability, build up one's resistance to disease; Act on lymph circulation, reflux, reduce edema by improving lymph fluid; Act on the blood flow aspect by reducing the blood plasma viscosity, correct albumins/globulins ratio, reduce hematoblastic high aggregation, thus the thrombosis of preventing, and improve erythrocytic pliability.Calcium dobesilate also can suppress the high penetration effect that vaso-active substance (histamine, 5-hydroxy tryptamine, Kallidin I, hyaluronidase, prostaglandin) causes blood capillary, reduces the tunica intima damage, improves the biosynthesis of basement membrane collagen.Calcium dobesilate can be used for preventing and treating the multiple disease that is caused by blood capillary circulatory disturbance clinically, comprising: 1], the retinopathy that causes of diabetes; 2], the heart that causes of microcirculation disturbance, brain, kidney disease are as myocardial infarction, angina pectoris, thrombus sequela, atherosclerosis of renal glomerulus etc.; 3], blood viscosity lowering; 4], prevention microthrombusis; 5], numb limbs and tense tendons, ice-cold, the pain of trick, diseases such as skin pruritus; 6], varicosis syndrome etc.
Hypoglycemic medicine exploitation at present and that use always clinically has a variety of, wherein more common and representational have following a few class medicine, as tolbutamide, chlorpropamide, the tolazamide of sulfonylurea, and glimepiride, glibenclamide, glipizide, gliclazide, gliquidone, Ge Lieben piperazine etc.; Non-sulfonylurea as repaglinide, Nateglinide; Also have pancreas hyperglycemia sample peptide-1, the troglitazone of thiazolidinediones, rosiglitazone, ciglitazone, pioglitazone; The metformin of biguanides, phenformin, buformin, and the β of other types
3-adrenoceptor agonists, glucagon receptor antagonist, fatty acid metabolism disturb, as relying on not department, and euglycemic agent, adenosine a1 receptor agonists, insulin degradation inhibitor such as chloroquine and hydroxychloroquine, ACE inhibitor and alpha-blocking agent are as captopril, lisinopril.Other medicines that are used for the treatment of diabetes also have inositol and derivant thereof, vanadate, TNF-alpha-2 antagonists etc., reduce medicine, the alpha-glucosidase inhibitor of carbohydrate absorption, as acarbose, voglibose and miglitol, amylin (pramlintide), aldose reductase inhibitor, as tolrestat, epalrestat, insulin analog and preparation thereof such as Semilente Insulin, protamine zine insulin, and the nitric oxide synthase inhibitors aminoguanidine, insulin-like growth factor-i etc.
The present invention finds that calcium dobesilate and blood sugar lowering are special and unites the hyperglycemia symptom that causes diabetics and the remarkable improvement of its complication.More specifically, calcium dobesilate and first in pairs the administering drug combinations of guanidine obtained synergy.Use the administering drug combinations of the officinal salt of calcium dobesilate and metformin, also observe identical beneficial effect.
Therefore, the present invention relates to contain the active component calcium dobesilate, randomly with its a kind of pharmaceutical acceptable salt and metformin or its randomly with its a kind of pharmaceutical acceptable salt as active component, with the pharmaceutical composition of one or more pharmaceutically acceptable excipient associatings.
Further, the present invention finds that calcium dobesilate and other blood sugar lowering unite use, also can cause the remarkable improvement of hyperglycemia symptom He its complication of diabetics.These hypoglycemic medicines comprise insulin, glimepiride, glibenclamide, glipizide, gliclazide, gliquidone, Ge Lieben piperazine, repaglinide, Nateglinide, pancreas hyperglycemia sample peptide-1, troglitazone, rosiglitazone, ciglitazone, pioglitazone, phenformin, buformin, acarbose, voglibose, miglitol, amylin, tolrestat, epalrestat etc., the administering drug combinations of calcium dobesilate and these hypoglycemic medicines is obtained synergy, and reducing for the improvement of diabetes and diabetic complication symptom and sickness rate has beneficial effect.
Clinical use proves that this pharmaceutical composition more particularly is suitable for reducing diabetic complication.
Use known method, the calcium ion of calcium dobesilate can be replaced to other forms of slaines such as sodium salt, potassium salt, barium salt, and these salt various hydrates or the crystallization that can form.
React the officinal salt that obtains metformin with known method by metformin and corresponding acid.It comprises hydrochlorate, acetate, nitrate, nitrite, dithionate, phosphate, benzoate, citrate, fumarate, embonate, tomatotone salt, oxyacetate, aspartate, mesylate, maleate, to chlorobenzene aminoisobutyric hydrochlorate, formates, lactate, succinate, sulfate, tartrate, cyclohexane-carboxylic acid salt, caproate, caprylate, palmate, octadecanoate, the octadecane hydrochlorate, benzene sulfonate, trimethoxybenzoic acid salt, tosilate, adamantanecarboxylic acid salt, glutamate, Glu, pyrrolidone carboxylic acid salt, naphthalene sulfonate, 1-glucose phosphate salt, palmaoate, glycoxylate.In these salt, special preferred salt hydrochlorate, fumarate, embonate and tomatotone salt.
The present composition contains the various words compositions for the treatment of effective dose.Therefore, the ratio of consumption separately of calcium dobesilate and metformin correspondingly changes.Preferably, the weight ratio scope of calcium dobesilate and metformin or its officinal salt is 20: 1-1: 20, preferred 1: 1-1: 5.
The administration of present composition preferred oral, also injectable administration.
When oral administration, the dosage form of the present composition can be gelatine capsule, plant capsule, hard capsule, soft capsule, granule, dispersible tablet, effervescent tablet, coated tablet, medicine bag, coated tablet, lozenge, suppository, powder, oral liquid, drinks the slow release formulation of bottle or solution, microgranule or above-mentioned various dosage forms, disperse dosage form and enteric dosage form.
The present composition can also be that solution, suspension, powder pin and freeze-dried powder form are penetrated in the injection that is used for injecting, be packaged in phial or bottle.
Active substance and all kinds excipient or carrier such as filler, disintegrate (or broken) agent, binding agent, dyestuff, correctives or the like are mixed, then mixture is shaped, be prepared into oral administered dosage form thus.
Dyestuff can be medicinal any dyestuff.
Correctives comprises the agent of various screen flavor, fat material (comprising lecithin, surfactant), hydrophilic medicament embedding medium material (as the agent of polyacrylic resin class medicinal coating film, modified starch series carbohydrate, cyclodextrin glucose oligomer or the like) and ion exchange resin, protein, zeolite, tannic acid, citric acid, the various organic acid of tartaric acid and other pharmaceutic adjuvant, and cocoa powder, Herba Menthae, Borneolum Syntheticum, sweeting agent and cedductor powder.
What binding agent can adopt is polyvinylpyrrolidone, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, ethyl cellulose, methylcellulose, carboxymethyl cellulose, alginic acid, carbomer, dextrin, starch, sodium alginate, polymethacrylates, maltodextrin, liquid glucose, aluminium silicate marquis and guar gum.
Disintegrating agent can be alginic acid, carboxymethyl cellulose, colloidal silica, cross-linking sodium carboxymethyl cellulose, crospovidone, guar gum, aluminium-magnesium silicate, methylcellulose, microcrystalline Cellulose, cellulose powder, pregelatinised starch, sodium alginate or sodium starch glycolate.
Filler can be cellulose, lactose, calcium hydrogen phosphate and microcrystalline Cellulose.
Use conventional method, under the situation that one or more lubricants exist, the granule compacting can be obtained tablet.Suitable lubricant is calcium stearate, glycerol monostearate, rice-pudding paulownia acyl tristerin, hydrogenant Oleum Ricini, hydrogenant vegetable oil, light mineral oil, magnesium stearate, Polyethylene Glycol, sodium benzoate, sodium lauryl sulphate, Fumaric acid octadecyl sodium, stearic acid, Pulvis Talci and zinc stearate.
Can use solution or suspension such as the hydroxypropyl emthylcellulose or the ethyl cellulose of polymer then, these tablets are carried out coating.
As use wet-granulation process, and be starting material with the mixture of active component and one or more excipient such as binding agent, disintegrator (or disintegrating agent) and filler, the used granule of preparation tabletting.
In order to obtain hard capsule, randomly under the situation of lubricant such as magnesium stearate, stearic acid, Pulvis Talci or zinc stearate existence, the mixture of active component and suitable filler (for example lactose) is packed in the empty capsule, and capsule can be gelatine capsule, plant capsule.
Active component is dissolved in the suitable solvent (as Polyethylene Glycol), then packs soft capsule into and make Perle.
Use conventional method, active component is mixed with buffer, stabilizing agent, antiseptic, solubilizing agent, tonicity agent and suspending agent, obtain ejection preparation.According to known technology,, be packaged into the form of intravenous injection, intramuscular injection then subsequently with the sterilization of these blending constituents.
Buffer can use the buffer based on organic phosphate.Suspending agent can adopt methylcellulose, hydroxyethyl-cellulose, arabic gum and sodium carboxymethyl cellulose.Solubilizing agent can be polyoxyethylene, Tween 80, relation by marriage amide or the solidified Oleum Ricini of Macrogol.Stabilizing agent can be inferior coloured glaze acid sodium and sodium pyrosulfite etc.Antiseptic can be to an oxybenzene sodium formate, ascorbic acid, cresol and chlorocresol etc.
In order to prepare oral administration solution or suspension, active component is dissolved in the appropriate carrier with dispersant, wetting agent, suspending agent (as polyvinylpyrrolidone), antiseptic (as methyl parahydroxybenzoate or propyl p-hydroxybenzoate), correctives or dyestuff.
In order to prepare microcapsule, any other additive types associating of active component and suitable diluents, suitable stabilizing agent, the material that promotes the active component slow release or formation SMIS uses suitable polymer (for example resin) with the core coating then.Then, the microcapsule that obtains is randomly made prestige optimal dose unit.
According to the present invention, term " medication combined " or refer to pharmaceutical composition defined above, wherein two kinds of active component are the solvents in the same compositions, perhaps refer to contain the medicine box of two independent composition components, contain metformin in first compositions, or the active component of arbitrary forms such as its precursor or metabolite, or its officinal salt contains calcium dobesilate as unique active component in second compositions, or the active component of arbitrary forms such as its precursor or metabolite, or its officinal salt or one water or many hydrates are as unique active component., carry out separately when being kit form when medication combined,, carry out simultaneously for therapeutic alliance although constitute the administration of two kinds of compositionss of medicine box.
According to the present invention with the pharmaceutical composition of the description of front or definition, wherein metformin can also adopt other alternate medicines, comprise insulin as these hypoglycemic medicines, glimepiride, glibenclamide, glipizide, gliclazide, gliquidone, the Ge Lieben piperazine, repaglinide, Nateglinide, pancreas hyperglycemia sample peptide-1, troglitazone, rosiglitazone, ciglitazone, pioglitazone, phenformin, buformin, acarbose, voglibose, miglitol, amylin, tolrestat, hypoglycemic medicines such as epalrestat, first composition employing in this compositions contains above-mentioned one or both hypoglycemic medicines wherein, or the active component of arbitrary forms such as its precursor or metabolite, or its officinal salt is as unique active component, and second component is for containing calcium dobesilate, or the active component of arbitrary forms such as its precursor or metabolite, or its officinal salt or one water or many hydrates are as unique active component.Wherein two kinds of active component are the solvents in the same compositions, perhaps refer to contain the medicine box of two independent composition components, when being kit form, carry out separately although constitute the administration of two kinds of compositionss of medicine box when medication combined, but, carry out simultaneously for therapeutic alliance.
According to a preferred embodiment of the invention, calcium dobesilate and metformin or its officinal salt part by weight are 1: 20-20: 1, preferred 1: 1-1: 5.
When calcium dobesilate and metformin or its officinal salt mix the back in same unit dose the time, unit dose preferably contains the calcium dobesilate of 5-10000mg.Wherein the unit dose of oral formulations preferably contains the 50-500mg calcium dobesilate, and the unit dose of ejection preparation preferably contains the 2-10000mg calcium dobesilate.The dosage of preparation depends on mode of administration, treatment indication and patient's age and body constitution body weight naturally.
The application of pharmaceutical composition of benzene invention and the purposes advantage of asking for protection are described with reference to following embodiment.
Example one, model induced by alloxan mouse blood sugar raise and test
Experimental technique: get 30 of mices, tail vein injection alloxan 65mg/kg, form the mice hyperglycemia model according to a conventional method, be divided into 3 groups according to the mouse blood sugar value, wherein 2 groups give metformin 50mg/kg and metformin 50mg/kg+ calcium dobesilate 25mg/kg by 0.1ml/10g body weight per os respectively, and the blank group gives isopyknic distilled water, continuous 7 days, fasting is 2 hours before the last administration, and after the administration 1 hour, 2 hours, 3 hours, 5 hours, with determination of glucose oxidase blood glucose.
The result: compare with the blank group, metformin 50mg/kg+ calcium dobesilate 25mg/kg 3 hours (reduction 211.3mg/dl) and 5 hours (reducing 189.4mg/dl) after the hyperglycemia (reducing 138.2mg/dl) that significantly reduced model induced by alloxan after the hyperglycemia trend that the reduction model induced by alloxan was arranged after the administration in 1 hour (reducing 100.0mg/dl), the administration in 2 hours, administration extremely significantly reduces the hyperglycemia of model induced by alloxan.Metformin 3 hours (reducing 111.2mg/dl) after 1 hour (reduction 154.3mg/dl) and 2 hours (reducing 170.2mg/dl) extremely significantly reduce the hyperglycemia of model induced by alloxan, administration after the administration significantly reduces the hyperglycemia of model induced by alloxan and after (reducing 72.6mg/dl) the hyperglycemia trend that reduces model induced by alloxan was only arranged in 5 hours.
The mouse blood sugar that example two, glucose bring out raises and tests
Experimental technique: get 72 of mices, be divided into 6 groups at random, wherein 4 groups give metformin 50mg/kg+ calcium dobesilate 25mg/kg and metformin 50mg/kg by 0.1ml/10g body weight per os respectively, and normal group and matched group give isopyknic distilled water, continuous 7 days.Except that normal group, all the other respectively organize lumbar injection glucose 2g/kg, and normal group is injected isopyknic normal saline, injection back 30,60,90,120 minutes, and the mouse orbit rear vein beard is got blood, and separation of serum is with determination of glucose oxidase blood glucose.
The result: compare with normal group, behind the control group mice lumbar injection glucose 30,60,90,120 minutes, blood glucose extremely significantly raise.Compare with matched group, metformin 50mg/kg+ calcium dobesilate 25mg/kg group and metformin group behind the lumbar injection glucose 30,60,90,120 minutes extremely significantly reduce the hyperglycemia that glucose brings out; Metformin 50mg/kg+ calcium dobesilate 25mg/kg (90 minutes, reduce 28.5mg/dl) is better than metformin 50mg/kg (90 minutes, reduce 20.5mg/dl).
The rat blood sugar of example three, model induced by alloxan raises and tests
Experimental technique: take out 10 of rats at random and be normal group, all the other 40 rat fasting are after 14-16 hour, lumbar injection pentobarbital 30mg/kg, anesthesia back vena femoralis injection alloxan 48mg/kg, cause hyperglycemia model according to a conventional method, get wherein 30 according to blood glucose value and be divided into 3 groups, every group 10, wherein 2 groups give metformin 50mg/kg+ calcium dobesilate 25mg/kg and metformin 50mg/kg by 1ml/100g body weight per os respectively, another group is model group, model group and normal group give isopyknic distilled water, and continuous 18 days, respectively at after the administration the 6th, 12 days with glucose oxidase method survey fasting glucose.In the time of the 18th day, femoral artery is got blood, and measures blood glucose in the serum, insulin level, cholesterol level, content of triglyceride, mda content, superoxide dismutase activity.
The result: compare with normal group, the control rats fasting glucose extremely significantly raises.Compare with matched group, metformin 50mg/kg+ calcium dobesilate 25mg/kg group (6 days, reduced by 134 respectively in 12 days and 18 days, 221.2,236.4mg/dl) and metformin group (6 days, reduced by 111,189.4 respectively in 12 days and 18 days, and 180.9mg/dl) after administration, played the hyperglycemia that extremely significantly reduces model induced by alloxan on the 6th day.
Compare with normal group, the control rats serum insulin levels significantly reduces.Compare with matched group, the metformin group has the trend that low insulin level is gone up, and metformin 50mg/kg+ calcium dobesilate 25mg/kg group obviously makes low serum insulin levels rise (3.17 μ IU/ml go up).
Compare with normal group, control rats serum triglycerides and cholesterol level extremely significantly raise.Compare with matched group, metformin 50mg/kg+ calcium dobesilate 25mg/kg group obviously reduces serum triglycerides and cholesterol level, and (serum triglycerides and cholesterol level reduce by 18.7 respectively, 29.2mg/dl), and the metformin group is to the there was no significant difference that influences of serum cholesterol and content of triglyceride.
Compare with normal group, control rats serum mda content significantly raises, and the hepatic tissue mda content has rising trend simultaneously.Compare with matched group, metformin 50mg/kg+ calcium dobesilate 25mg/kg group significantly reduces serum mda content (reducing 5.06nmol/ml), and the metformin group only has the trend that reduces serum and hepatic tissue mda content.
Compare with normal group, control rats serum and hepatic tissue superoxide dismutase activity significantly reduce.Metformin 50mg/kg+ calcium dobesilate 25mg/kg group can make low serum superoxide dismutases vigor go up (rise 38.1IU/ml), and the metformin group is to the there was no significant difference that influences of serum and hepatic tissue superoxide dismutase activity.
Compare with normal group, the body weight of control rats obviously alleviates, and compares with matched group, and the body weight change influence to rat of metformin 50mg/kg+ calcium dobesilate 25mg/kg group and metformin group is little.
The influence that example four, the mouse blood sugar that streptozotocin is brought out raise
Experimental technique: mice is by every group of 10 random packet, getting wherein one group is normal group, and all the other mouse tail vein injection streptozotocin 160mg/kg press the literature method modeling, divide into groups again according to blood glucose value, each mice is pressed 0.1ml/10g body weight per os by the administration of following (table 1) packet mode, and normal group and model group give isopyknic distilled water, continuous 18 days, in the time of the 18th day, pluck eyeball and get blood, separation of serum, and measure blood glucose in the serum.
Table 1, test packet mode
| Group | Administration content and dosage | |
| Tail vein injection streptozotocin 160mg/kg | Administration content and dosage (filling stomach) | |
| Normal group | Do not have | Do not have |
| Matched group | Have | Do not have |
| Test A group | Have | Metformin 50mg/kg |
| Test B group | Have | Metformin 50mg/kg+ calcium dobesilate 25mg/kg group |
| Test C group | Have | Glibenclamide 2mg/kg+ calcium dobesilate 25mg/kg group |
| Test D group | Have | Pioglitazone 5mg/kg+ calcium dobesilate 25mg/kg group |
The result: compare with normal group, control group mice blood glucose extremely significantly rises (mean raise than normal group 305.2mg/dl).Compare with matched group, each test group all can significantly reduce the hyperglycemia that streptozotocin brings out, the blood glucose that test A, B, C, D group descend is respectively counted meansigma methods and is: test A group reduces 111.6mg/dl, test B group reduces 135.8mg/dl, test C group reduces 197.4mg/dl, and test D group reduces 158.7mg/dl.
Example five, the preliminary test of oral administration acute toxicity
Experimental technique: get 10 of normal mouses, male and female half and half, metformin and calcium dobesilate once gavage by 800mg/kg by after 2: 1 mixed, observe the reaction of animal, put to death each internal organs of perusal after 7 days.
Experimental result: none death of animal, health condition is good, fur gloss, furious bright, mobility is good.Put to death mice after 7 days, the perusal main organs is all no abnormal.
Example six, general pharmacology are learned test
Observed metformin (50mg/kg) associating calcium dobesilate (25mg/kg) group to the influence of normal mouse general signs and spontaneous activity, to the influence of the length of one's sleep of mice pentobarbital sodium, to normal rats breathing motion, blood pressure, heart rate and Electrocardiographic influence.Result of study shows: drug regimen does not all have obvious influence to mice autonomic movement, the mice pentobarbital sodium length of one's sleep and rats breathing motion, blood pressure, heart rate, electrocardiogram.
Claims (11)
1, pharmaceutical composition contains the calcium dobesilate as active component, randomly with its a kind of pharmaceutical acceptable salt and optional a kind of hypoglycemic medicine, with one or more pharmaceutically acceptable excipient.
2, pharmaceutical composition according to claim 1, the salt that it is characterized in that calcium dobesilate are sulfuric monohydrate or many hydrates.
3, pharmaceutical composition according to claim 1, it is characterized by optional a kind of hypoglycemic medicine can be metformin or its a kind of pharmaceutical acceptable salt.
4, according to claim 1,2 described pharmaceutical compositions, it is characterized in that the calcium ion of calcium dobesilate can be substituted by other metal ions such as sodium salt, barium salt, potassium salt, become the hydrate of other salt forms.
5, according to claim 1,3 described pharmaceutical compositions, the salt that it is characterized in that metformin is hydrochlorate, fumarate, embonate, tomatotone salt.
6, according to the described pharmaceutical composition of aforementioned each claim, it is characterized in that the salt that calcium dobesilate or its can be medicinal, the weight ratio of salt that can be medicinal with metformin or its is 1: 20～20: 1, preferred 1: 1～1: 5.
7, according to the described application of aforementioned each claim, it is characterized in that medication combined is the unit dosage form that contains calcium dobesilate and metformin or its a kind of pharmaceutical acceptable salt, and its unit dose contains the drug regimen of the calcium dobesilate of 5～10000mg.
8, according to the described application of aforementioned each claim, it is characterized in that medication combined is the drug regimen that contains above-mentioned two kinds of compositions, it also can be the two kinds of drug packages medicine box together that independently separates, when medication combined when being kit form, although it is independent constituting the administration of two kinds of compositionss of medicine box,, therapeutic alliance gives simultaneously for remaining.
9, according to the described compositions of aforementioned each claim, be suitable for oral administration, drug administration by injection.
10, utilize randomly according in the described pharmaceutical composition of aforementioned each claim with wherein a kind of calcium dobesilate of pharmaceutical acceptable salt and the associating of any hypoglycemic medicine, the medication combined application that is used for preventing and treat diabetes, reaches diabetic complication in preparation.
11, according to the described pharmaceutical composition of aforementioned each claim, be used to prevent and treat diabetes, reach the complication that diabetes cause, comprise: diabetes complicated peripheral nerve obstacle, ocular disease, sexual dysfunction, nephropathy, diabetic complication, and because diseases such as the fatigue and weakness that causes of diabetes, insomnia, pained, cardiopalmus uncomfortable in chest, dizzy, edema, thirsty polydipsia, numb hand and foot, pain.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410027309 CN1704048A (en) | 2004-05-25 | 2004-05-25 | Compound calcium phenolsulfonic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 200410027309 CN1704048A (en) | 2004-05-25 | 2004-05-25 | Compound calcium phenolsulfonic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1704048A true CN1704048A (en) | 2005-12-07 |
Family
ID=35575759
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 200410027309 Pending CN1704048A (en) | 2004-05-25 | 2004-05-25 | Compound calcium phenolsulfonic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN1704048A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100417389C (en) * | 2006-05-16 | 2008-09-10 | 北京国丹药物技术开发有限公司 | Medicine composition for treating microcirculation dysfunction and its preparing method |
| CN101637464B (en) * | 2008-08-02 | 2011-07-27 | 鲁南制药集团股份有限公司 | Drug composite containing calcium 2,5-dihydroxysulfonate and ADP receptor antagonist |
| CN110167542A (en) * | 2016-11-09 | 2019-08-23 | 诺沃梅迪科斯有限公司 | Nitrite, pharmaceutical composition and the application method of 1,1- melbine |
| CN115581681A (en) * | 2022-06-10 | 2023-01-10 | 海南林恒制药股份有限公司 | Novel calcium dobesilate capsule and preparation method thereof |
-
2004
- 2004-05-25 CN CN 200410027309 patent/CN1704048A/en active Pending
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN100417389C (en) * | 2006-05-16 | 2008-09-10 | 北京国丹药物技术开发有限公司 | Medicine composition for treating microcirculation dysfunction and its preparing method |
| CN101637464B (en) * | 2008-08-02 | 2011-07-27 | 鲁南制药集团股份有限公司 | Drug composite containing calcium 2,5-dihydroxysulfonate and ADP receptor antagonist |
| CN110167542A (en) * | 2016-11-09 | 2019-08-23 | 诺沃梅迪科斯有限公司 | Nitrite, pharmaceutical composition and the application method of 1,1- melbine |
| CN115581681A (en) * | 2022-06-10 | 2023-01-10 | 海南林恒制药股份有限公司 | Novel calcium dobesilate capsule and preparation method thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| JP5660094B2 (en) | Concomitant medication | |
| JP6676108B2 (en) | Lixisenatide and metformin for the treatment of type 2 diabetes | |
| RU2684398C2 (en) | Insulin glargine/lixisenatide fixed ratio formulation | |
| CZ20002828A3 (en) | Pharmaceutical preparation consisting of a combination of metformin and fibrate as well as use thereof for preparing medicaments intended for reducing hyperglycemia | |
| CN104136014A (en) | Subcutaneous therapeutic use of DPP-4 inhibitor | |
| CN101014360A (en) | Antidiabetic oral insulin-biguanide combination | |
| EP2324853A1 (en) | Lixisenatide as add-on to metformin in the treatment of diabetes type 2 | |
| EP2903602B1 (en) | Combination drug comprising gemigliptin and metformin, and method for the preparation thereof | |
| US20080249168A1 (en) | Pharmaceutical composition for gout | |
| CZ344498A3 (en) | Pharmaceutical composition and method of treating large blood losses and for inhibiting or treating haemorrhagic shock | |
| TW200838503A (en) | Pharmaceutical composition | |
| US9161910B2 (en) | Method and pharmaceutical compositions for trans-buccal mucosa treatment of postprandial hyperglycaemia in type II diabetes | |
| KR100709528B1 (en) | Drug composition for blood sugar control | |
| CN1729988A (en) | Composite medicine of creatine phosphate sodium and magnesium salt | |
| CN1704048A (en) | Compound calcium phenolsulfonic acid | |
| CN103417971A (en) | Dipeptidyl peptidase inhibitor and vitamin-B pharmaceutical composition and application thereof | |
| WO2012093973A2 (en) | Stable acarbose formulations | |
| JP5117230B2 (en) | Combination medicine for type 2 diabetes treatment | |
| KR20050044594A (en) | Use of alkanoyl l-carnitine for the treatment of erectile dysfunction | |
| KR100657785B1 (en) | A medical agent containing glimepiride, metformin and ginkgo biloba extract | |
| KR101296479B1 (en) | Use of l-carnitine and glucose for the treatment of cardiovascular diseases | |
| KR100709531B1 (en) | Drug composition for prevention or inhibition of advance of diabetic complication | |
| KR102490653B1 (en) | Pharmaceutical composition comprising dapagliflozin and glimepiride | |
| CN111195247B (en) | Alpha-glucosidase inhibitor and application thereof in hypoglycemic drugs | |
| WO2021057661A1 (en) | Pharmaceutical composition for lowering blood sugar |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C57 | Notification of unclear or unknown address | ||
| DD01 | Delivery of document by public notice |
Addressee: Gu Qin Document name: Deemed as a notice of withdrawal |
|
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |