CN1857297A - Medicine composition for treating microcirculation dysfunction and its preparing method - Google Patents
Medicine composition for treating microcirculation dysfunction and its preparing method Download PDFInfo
- Publication number
- CN1857297A CN1857297A CN 200610081305 CN200610081305A CN1857297A CN 1857297 A CN1857297 A CN 1857297A CN 200610081305 CN200610081305 CN 200610081305 CN 200610081305 A CN200610081305 A CN 200610081305A CN 1857297 A CN1857297 A CN 1857297A
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- CN
- China
- Prior art keywords
- radix puerariae
- puerariae flavone
- calcium dobesilate
- compositions
- flavone
- 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.)
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Abstract
The present invention relates to medicine composition for treating microcirculation dysfunction and its preparation, and features that the medicine composition contains calcium phenolsulfonate in 10-1000 weight portions and pueraria flavonoid in 10-1000 weight portions as active medicine components.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition that is used for the treatment of the multiple disease that causes by blood capillary circulatory disturbance and preparation method thereof.Said composition contains calcium dobesilate and Radix Puerariae flavone as active constituents of medicine, be mainly used in the multiple disease that treatment is caused by blood capillary circulatory disturbance, especially, be mainly used in the retinopathy that diabetes cause, the heart that microcirculation disturbance causes, brain, kidney disease are as the treatment of syndromes such as atherosclerosis of renal glomerulus and varicosis.
Background technology
Diabetes are one group of common metabolism endocrinopathys, and there is diabetics 1.25 hundred million in the whole world, and the diabetics of China has reached 4,000 ten thousand.World Health Organization (WHO) classifies diabetes one of as three big difficult disease, because blood sugar concentration is higher in the diabetics body, excessive glucose carries out metabolism through pentose shunt, is generated sorbitol by aldose reductase catalysis, and sorbitol can cause blood capillary cell and endotheliocyte impaired; Patient's capillary endothelium can generate too much blood coagulation factor VIII in addition, prostacyclin produces and reduces, all can impel platelet to stick and assemble, promote microthrombusis, blood glucose increases in addition stimulates IV type colloid albumen and the synthetic increase of Fibronectin, the anionic sites in number decreased number that the heparitin sulfate GL-PP constitutes, capillary permeability increases.This a series of reason makes diabetics often follow more complication, as diabetic nephropathy, diabetic ophthalmopathy, diabetic neuropathy, diabetic foot, the diabetes heart, brain macroangiopathy etc.
Simultaneously, other some diseases is also direct or indirect causes blood capillary circulatory disturbance, and then each organ of health is produced harm, has brought great misery to the patient.
Calcium dobesilate lowers the high-permeability of blood capillary and reduces resistance by regulating the physiological function of wall of micrangium, reduces the blood plasma viscosity, reduces hematoblastic high aggregation, thus the thrombosis of preventing; By raising erythrocyte pliability, thereby the drain that increases lymph indirectly reduces edema.Calcium dobesilate can also be by suppressing the high penetration effect that vaso-active substance (histamine, 5-hydroxy tryptamine, Kallidin I, hyaluronidase, prostaglandin) causes, thereby improve the biosynthesis of basement membrane collagen.Therefore can be used for the multiple disease that blood capillary circulatory disturbance (blood capillary circulatory disturbance) causes.
Chinese medicine is improving blood flow state, is improving immunity, demonstrating huge advantage on the anti-ageing multipath of waiting for a long time, many-side, too many levels, and its toxic and side effects is little, and stable curative effect.
Radix Puerariae flavone is the total flavones that extracts from the Chinese medicine Radix Puerariae, has blood sugar lowering, effects such as expansion peripheral blood vessel, particularly coronary artery dilator blood vessel, the high state of aggregation of change and microcirculation, anticoagulant.A kind of as in the Radix Puerariae flavone of puerarin, be an antioxidant, bibliographical information is abroad arranged, puerarin can effectively remove the radical pair islet cells injury (Puerarin protects rat pancreatic islets from damage byhydrogen peroxide.European Journal of Pharmacology[Eur J Pharmacol] 2006 Jan 4; Vol.529 (1-3), PP.1-7).
Because the microcirculation disturbance disease that treatment microcirculation disturbance disease, particularly diabetes cause is an extremely complicated process, single drug is difficult to obtain satisfactory therapeutic effects.Therefore, the inventor finds by a large amount of experiments from the bonded angle of Chinese and western medicine: with calcium dobesilate combination Radix Puerariae flavone, treatment microcirculation disturbance disease can have synergism, has reached mutual supplement with each other's advantages, improves the effect of curative effect.
Summary of the invention
Calcium dobesilate is widely used blood capillary circulation improving agent in the world, is written into European Pharmacopoeia in 1997, is written into British Pharmacopoeia in 1998.To the multiple disease that blood capillary circulatory disturbance (blood capillary circulatory disturbance) causes, determined curative effect,
Radix Puerariae flavone, especially puerarin has anticoagulant, blood viscosity lowering, the effect of microcirculation improvement has obvious inhibitory action to human albumin and the proteic nonenzymatic glycosylation of rat lens.
The present invention treats microcirculation dysfunction with calcium dobesilate and Radix Puerariae flavone applied in any combination, and particularly retinopathy that is caused by diabetes etc. has good synergism, and is better than independent result of use.Based on above-mentioned discovery, the invention provides a kind of pharmaceutical composition that is used for the treatment of the multiple disease that causes by blood capillary circulatory disturbance and preparation method thereof.Said composition contains calcium dobesilate and Radix Puerariae flavone as active constituents of medicine, can be used for treating the multiple disease that causes by blood capillary circulatory disturbance, especially, be mainly used in the retinopathy that diabetes cause, the heart that microcirculation disturbance causes, brain, kidney disease are as the treatment of syndromes such as atherosclerosis of renal glomerulus and varicosis.
Radix Puerariae flavone of the present invention is to extract the extract that contains flavones ingredient that obtains from the Chinese medicine Radix Puerariae, this extract is because the extraction process difference, contained flavones ingredient is also different, this extract can be a Radix Puerariae total flavones, also can be wherein a kind of Radix Puerariae flavone or the mixture of several Radix Puerariae flavones wherein.Preferred Radix Puerariae flavone is puerarin (8-β-D-glucopyanosyl-4 ', 7-dihydroxy isoflavone).
Radix Puerariae flavone has for many years as medicinal application, can buy from the market, the pharmacopeia or the national drug standards have been listed in, its preparation method has multiple, in patent documentation or other documents, a large amount of reports is arranged, belong to prior art, as: Radix Puerariae flavone by pulverize, squeeze, grind, sieve, method such as percolation, extraction, water are carried, alcohol extraction, ester are carried, chromatography is processed Radix Puerariae and is obtained, the gained Radix Puerariae flavone can be the material of extractum form, can be that dry extract also can be a fluid extract, make different concentration according to the different needs decision of preparation.
The present invention also provides the preparation method of Radix Puerariae flavone, specifically sees embodiment.
According to the present invention, described Radix Puerariae flavone is the product that meets pharmaceutical standards, as long as meet pharmaceutical standards, and can be as medicinal application, no matter the Radix Puerariae flavone how to prepare all belongs to protection scope of the present invention.
Compositions of the present invention, wherein the weight proportion of calcium dobesilate and Radix Puerariae flavone is the calcium dobesilate of 10-1000 weight portion and the Radix Puerariae flavone of 10-1000 weight portion.
The weight proportion of preferred calcium dobesilate and Radix Puerariae flavone is the calcium dobesilate of 100-500 weight portion and the Radix Puerariae flavone of 100-500 weight portion.
Most preferred calcium dobesilate and and the weight proportion of Radix Puerariae flavone be the calcium dobesilate of 250 weight portions and the Radix Puerariae flavone of 250 weight portions.
More than form being by weight as proportioning, can be unit with kg as large-scale production, or is unit with t (ton); Preparation can be unit with g also on a small scale.Weight can increase or reduce, but the constant rate of the weight proportion between each composition.
The ratio of above weight proportion obtains through science screening, for especial patient, and as serious symptom or light disease, fat or modest patient, the proportioning of the amount of can corresponding adjustment forming increases or reduces being no more than 100%, and drug effect is constant.
Compositions of the present invention, exist with pharmaceutical dosage forms, the pharmaceutical dosage forms of unit dose preferably, can make any pharmaceutically useful dosage form when making pharmaceutical preparation, these dosage forms are selected from: tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, pill, powder, unguentum, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, cream, spray, patch.Oral formulations form preferably, the best is tablet preferably, capsule, granule.
Pharmaceutical preparation of the present invention can add some medicine acceptable carriers as required, can adopt the galenic pharmacy routine techniques to prepare this pharmaceutical preparation, as pharmaceutically active substance is mixed with the medicine acceptable carrier.The acceptable carrier of described medicine is selected from: mannitol, sorbitol, sorbic acid or potassium salt, sodium pyrosulfite, sodium sulfite, sodium thiosulfate, cysteine hydrochloride, TGA, methionine, vitamin A, vitamin C, vitamin E, vitamin D, azone, the EDTA disodium, EDTA calcium sodium, the alkali-metal carbonate of monovalence, acetate, phosphate or its aqueous solution, hydrochloric acid, acetic acid, sulphuric acid, phosphoric acid, aminoacid, sodium chloride, potassium chloride, sodium lactate, xylitol, maltose, glucose, fructose, dextran, glycine, starch, sucrose, lactose, mannitol, silicon derivative, cellulose and derivant thereof, alginate, gelatin, polyvinylpyrrolidone, glycerol, propylene glycol, ethanol, soil temperature 60-80, span-80, Cera Flava, lanoline, liquid paraffin, hexadecanol, gallate ester, agar, triethanolamine, basic amino acid, carbamide, allantoin, calcium carbonate, calcium bicarbonate, surfactant, Polyethylene Glycol, cyclodextrin, beta-schardinger dextrin-, the phospholipid material, Kaolin, Pulvis Talci, calcium stearate, magnesium stearate etc.
Pharmaceutical preparation of the present invention is determined usage and dosage according to patient's situation in use.
Pharmaceutical preparation of the present invention, when making medicament, the medicament of unit dose can contain pharmaceutically active substance 0.1-1000mg of the present invention, and all the other are pharmaceutically acceptable carrier.Pharmaceutically acceptable carrier can be the 0.1-99.9% of total formulation weight amount by weight.
The most preferred prescription of the present invention is listed in the embodiment of the invention.
Compositions of the present invention is mainly used in the multiple disease that treatment is caused by blood capillary circulatory disturbance, be used in particular for the retinopathy that diabetes cause, the heart that microcirculation disturbance causes, brain, kidney disease are as the treatment of syndromes such as atherosclerosis of renal glomerulus and varicosis.
Following data declaration beneficial effect of the present invention by experiment:
Test example 1: calcium dobesilate and Radix Puerariae flavone compositions are to the hemodynamic influence of rat
Get rat, behind the fasting 12h, quick tail vein injection streptozotocin 50mgkG
-1, measure blood glucose value behind the 72h.Select blood sugar level 13mmolL
-1Above person divides five groups at random by body weight, model group, normal group, Radix Puerariae flavone treatment group (A group), calcium dobesilate treatment group (B group), gained calcium dobesilate and Radix Puerariae flavone combination treatment group (A+B group) among the embodiment 6, every group 8, gastric infusion, dosage 100mgkG
-1, qd, continuous 30d, animal grouping and experimental technique are the same, pluck rat eye and get blood 4ml, (the external anticoagulant of heparin) measures following index: (1) whole blood viscosity (η b), (2) plasma viscosity (η b), (3) packed cell volume (HCT), (4) erythrocyte sedimentation rate (ESR), result of the test is as shown in table 1.
Table 1 Radix Puerariae extract to the hemodynamic influence of STZ rat (x ± s, n=8)
| Group | Height is cut viscosity (γ) (mPa.s) | Hang down and cut viscosity (γ) (mPa.s) | Plasma viscosity (mPa.s) | Packed cell volume % |
| Model group normal group A group B group A+B group | 12.36±0.68 10.13 ±0.57 11.21±0.58 11.08±0.68 10.53±0.52 | 4.73 ±0.45 3.69 ±0.24 4.26±0.30 4.11±0.29 3.78±0.35 | 1.98 ±0.15 1.32 ±0.07 1.60±0.07 1.57±0.15 1.39±0.08 | 45.67±1.43 41.23±0.87 42.59±0.68 42.67±0.79 41.58±0.83 |
Conclusion: by above result of the test as can be known, compare calcium dobesilate and Radix Puerariae flavone combination treatment group with independent medication and model group, can obviously reduce rat whole blood height and cut viscosity, low viscosity and plasma viscosity, the packed cell volume cut.Because height is cut blood viscosity and is mainly reflected erythrocyte deformability, low cut blood viscosity and mainly reflect erythrocytic ability of aggregation, show that calcium dobesilate and Radix Puerariae flavone have blood viscosity lowering, improve the collaborative pharmacological action of local blood circulation, therefore can be used for treating microcirculation dysfunction, the retinopathy that causes as diabetes etc.
Test example 2: calcium dobesilate and puerarin combination treatment diabetic renal papillary necrosis observation of curative effect
Type ii diabetes patient 60 examples meet WHO diabetes diagnosis and typing standard, and clinical diagnosis is a diabetic renal papillary necrosis, except due to the other reasons optical fundus change.Be divided into 4 groups at random, be respectively puerarin treatment group (A group), calcium dobesilate treatment group (B group), calcium dobesilate and puerarin combination treatment group (A+B group).
When four groups of patients gave conventional hypoglycemic drug treatment, the treatment group A gave puerarin 500mg, every day 2 times; The treatment group B give calcium dobesilate 500mg, every day 2 times; Treatment group A+B gives puerarin and each 250mg of calcium dobesilate, every day 2 times, the equal oral administration of above medicine; Matched group gives Methycobal 500 μ g, every day 1 time, and intramuscular injection, 3 weeks were 1 course of treatment, 2 courses of treatment of logotype.
4 groups of patients all measure retinal centre arteriovenous blood flow parameter with color Doppler before and after treatment, shrinkage peak blood flow rate (PSV), acceleration (A), blood flow maximal rate diastasis (EDV) and central vein of retina back-flow velocity (CRV) result of Zinn's artery are as shown in the table before and after the treatment.
Retinal centre arteriovenous hemorheology Herba Wedeliae Wallichii number compares (cm/s) before and after table 2 treatment
| Group | PSV | EDV | A | CRV | |
| To clear group | After treating before the treatment | 9.75±2.38 10.13±1.83 | 3.11±0.95 3.39±1.28 | 90.35±22.16 92.16±20.86 | 8.32±1.84 7.95±1.59 |
| The A group | After treating before the treatment | 9.68±2.86 11.68±2.14 | 3.01±1.43 3.89±1.19 | 88.48±25.67 100.57±19.86 | 8.54 ±2.39 7.37±1.97 |
| The B group | After treating before the treatment | 9.58±1.99 11.58±2.45 | 3.17±1.31 3.91±1.56 | 89.27±21.83 105.4±15.43 | 8.47±2.11 7.25±1.86 |
| The A+B group | After treating before the treatment | 9.73±2.51 12.28±2.22 | 3.09±1.22 4.23±1.39 | 88.93±23.41 113.21±15.77 | 8.41±2.29 6.71±2.16 |
As seen from the experiment, shrinkage peak blood flow rate (PSV), acceleration (A), blood flow maximal rate diastasis (EDV) of Zinn's artery all increase before and after each treatment group treatment, and central vein of retina back-flow velocity (CRV) slows down.Compare with the independent medication of calcium dobesilate and puerarin, compound recipe administration group is more remarkable to the change of retinal centre arteriovenous hemorheology Herba Wedeliae Wallichii number, it is good disclosing the compound recipe administration more individually dosed to retinal microcirculation improvement effect, illustrate that two kinds of medicines have well collaborative microcirculation improvement effect, can use the compound recipe of two medicines to come microcirculation disturbance diseases such as treatment of diabetic retinopathy change.
The specific embodiment
The present invention will be further described below by the specific embodiment, but and do not mean that qualification to protection domain of the present invention.
Embodiment 1
Supplementary material is crossed 100 mesh sieves respectively, get calcium dobesilate 5g, Radix Puerariae flavone 500g adds microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, add 15%PVP and make soft material in right amount, granulate with the 16-24 mesh sieve, wet granular is in 50-80 ℃ of drying, 16-24 mesh sieve granulate, add the magnesium stearate mixing, measure in the granule drug content qualified after, tabletting is made 2000.
Wherein, the extracting method of Radix Puerariae flavone is as follows: get Radix Puerariae 10kg, add 6 times of water gagings and decoct three times, 1.0 hours for the first time, second and third time was 0.5 hour, filtered respectively, merging filtrate, being condensed into relative density is the clear paste of 1.08～1.14 (55 ℃), clear paste is stirred the ethanol that adds 2.8 times down, stir evenly, be heated to 60 ℃, leave standstill 24h, filter, decompression recycling ethanol is condensed into the thick paste shape, the 1.25kg that gets dry extract of vacuum drying below 85 ℃, dried cream porphyrize is standby.By determined by ultraviolet spectrophotometry, the shared percentage ratio of Radix Puerariae flavone is about 40% in the dried cream, and the amount of Radix Puerariae flavone is about 500g in the dried cream.
Embodiment 2
Supplementary material is crossed 100 mesh sieves respectively, get calcium dobesilate 500g, Radix Puerariae flavone 5g adds microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, add 15%PVP and make soft material in right amount, granulate with the 16-24 mesh sieve, wet granular is in 50-80 ℃ of aeration-drying, 16-24 mesh sieve granulate, add the magnesium stearate mixing, measure in the granule drug content qualified after, last capsule racking machine is sealed, and makes 1000.
Wherein, the extracting method of Radix Puerariae flavone is as described in the embodiment 1.
Embodiment 3
Supplementary material is crossed 100 mesh sieves respectively, get calcium dobesilate 100g, puerarin 500g adds microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, add 15%PVP and make soft material in right amount, granulate with the 16-24 mesh sieve, wet granular is in 50-80 ℃ of aeration-drying, 16-24 mesh sieve granulate, add the magnesium stearate mixing, measure in the granule drug content qualified after, tabletting is made 2000.
Embodiment 4
Supplementary material is crossed 100 mesh sieves respectively, get calcium dobesilate 500g, puerarin 100g adds microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, adds 15%PVP and makes soft material 16-24 mesh sieve granulation in right amount, wet granular is in 50-80 ℃ of aeration-drying, 16-24 mesh sieve granulate adds the magnesium stearate mixing, measure in the granule drug content qualified after, last capsule racking machine is sealed, and makes 1000.
Embodiment 5
Supplementary material is crossed 100 mesh sieves respectively, get calcium dobesilate 250g, puerarin 250g adds microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, add 15%PVP and make soft material in right amount, granulate with the 16-24 mesh sieve, wet granular is in 50-80 ℃ of aeration-drying, 16-24 mesh sieve granulate, add the magnesium stearate mixing, measure in the granule drug content qualified after, tabletting is made 2000.
Embodiment 6
Supplementary material is crossed 100 mesh sieves respectively, get calcium dobesilate 250g, Radix Puerariae flavone 250g adds microcrystalline Cellulose, carboxymethyl starch sodium mix homogeneously, add 15%PVP and make soft material in right amount, granulate with the 16-24 mesh sieve, wet granular is in 50-80 ℃ of aeration-drying, 16-24 mesh sieve granulate, add the magnesium stearate mixing, measure in the granule drug content qualified after, last capsule racking machine is sealed, and makes 1000.
Wherein, the extracting method of Radix Puerariae flavone is as described in the embodiment 1.
Claims (10)
1, a kind of pharmaceutical composition that is used for the treatment of the multiple disease that causes by blood capillary circulatory disturbance, it is characterized in that: contain calcium dobesilate and Radix Puerariae flavone as active constituents of medicine, wherein the weight proportion of calcium dobesilate and Radix Puerariae flavone is: the Radix Puerariae flavone of the calcium dobesilate of 10-1000 weight portion and 10-1000 weight portion.
2, compositions according to claim 1 is characterized in that: wherein the weight proportion of calcium dobesilate and Radix Puerariae flavone is: the Radix Puerariae flavone of the calcium dobesilate of 100-500 weight portion and 100-500 weight portion.
3, compositions according to claim 1 is characterized in that: wherein calcium dobesilate and and the weight proportion of Radix Puerariae flavone be: the Radix Puerariae flavone of the calcium dobesilate of 250 weight portions and 250 weight portions.
4, according to any one compositions of claim 1-3, it is characterized in that: wherein Radix Puerariae flavone can be to extract the Radix Puerariae total flavones that obtains from Radix Puerariae, also can be the mixture of a kind of Radix Puerariae flavone or several Radix Puerariae flavones.
5, according to any one compositions of claim 1-3, it is characterized in that: wherein Radix Puerariae flavone is a puerarin.
6, according to any one compositions of claim 1-3, it is characterized in that: be selected from following pharmaceutical dosage form, tablet, sugar coated tablet, film coated tablet, enteric coated tablet, capsule, hard capsule, soft capsule, oral liquid, suck agent, granule, pill, powder, unguentum, sublimed preparation, suspensoid, solution, injection, suppository, ointment, plaster, cream, spray, patch.
7, according to the compositions of claim 6, it is characterized in that: be tablet or capsule.
8, compositions according to claim 1 is characterized in that: also can contain pharmaceutic adjuvant as required, as microcrystalline Cellulose, carboxymethyl starch sodium, starch, dextrin, PVP, magnesium stearate etc.
9, the application of the compositions of claim 1 in the medicine of the disease that the preparation treatment is caused by blood capillary circulatory disturbance.
10, the application of claim 9 is characterized in that: the disease that is caused by blood capillary circulatory disturbance is the retinopathy that diabetes cause, the heart that microcirculation disturbance causes, brain, kidney disease.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110141611A (en) * | 2019-04-01 | 2019-08-20 | 海南林恒制药股份有限公司 | A kind of Calcium Dobesilate solid pharmaceutical preparation and its application |
| 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 |
| CN116019824A (en) * | 2023-03-29 | 2023-04-28 | 吉林华康药业股份有限公司 | Traditional Chinese medicine composition for preventing and treating microcirculation disturbance |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1704048A (en) * | 2004-05-25 | 2005-12-07 | 孙明杰 | Compound calcium phenolsulfonic acid |
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2006
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110141611A (en) * | 2019-04-01 | 2019-08-20 | 海南林恒制药股份有限公司 | A kind of Calcium Dobesilate solid pharmaceutical preparation and its application |
| 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 |
| CN116019824A (en) * | 2023-03-29 | 2023-04-28 | 吉林华康药业股份有限公司 | Traditional Chinese medicine composition for preventing and treating microcirculation disturbance |
| CN116019824B (en) * | 2023-03-29 | 2023-05-30 | 吉林华康药业股份有限公司 | Traditional Chinese medicine composition for preventing and treating microcirculation disturbance |
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