CN101991597B - Applications of oral pharmaceutical composition to preparation of medicament for preventing or treating kidney diseases - Google Patents
Applications of oral pharmaceutical composition to preparation of medicament for preventing or treating kidney diseases Download PDFInfo
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Abstract
The invention belongs to the field of medicines, in particular to the applications of an oral pharmaceutical composition to the preparation of a medicament for preventing or treating kidney diseases including diabetic nephropathy and hypertensive nephropathy. The pharmaceutical composition provided by the invention comprises an active ingredient of rosuvastatin or pharmaceutically acceptable salts thereof and heparin, heparin with low molecular weight or pharmaceutically acceptable salts thereof. Proved by experiments on animal, the pharmaceutical composition provided by the invention has favorable prevention and treatment action on the diabetic nephropathy and the hypertensive nephropathy of mice and has favorable synergy. The pharmaceutical composition can be prepared into solid oral preparations including tablets and capsules according to a conventional preparation technology.
Description
Technical field
The invention belongs to field of medicaments, be specifically related to the purposes of a kind of combination of oral medication in preparation prevention or treatment kidney disease medicine.
Background technology
The Secondary cases nephropathy is meant the kidney damage that systemic disease causes, and wherein the kidney damage that causes of diabetes and hypertension occupies suitable ratio.And diabetic nephropathy and hypertensive nephropathy are bigger to the harm of kidney, should cause abundant attention.
Diabetes (diabetes mellitus; DM) be one group of syndrome that causes by the combined effect of E&H factor; Be because hypoinsulinism or target tissue reduce insulin sensitivity, cause a series of metabolism disorders such as sugar, fat and protein, prolonged illness can cause a plurality of system damages.(diabetic nephropathy DN) has become one of diabetes most common complication to diabetic nephropathy, also is the one of the main reasons that causes diabetics fatality rate and disability rate to raise.Diabetic nephropathy clinical onset rate is high, and is serious to patient health harm, and will get into the agonizing state that the dialysis of dependence kidney is survived very soon, causes very huge financial burden for patient family and society.
Epidemiological study is found in American-European developed country; Clinical observation through to diabetic finds that the patient up to 20%～40% develops into DN, and more serious is that its sickness rate rises rapidly after 10 years in onset diabetes; Reach summit after 20～30 years, be about 40%～50%.In the U.S., diabetes are to cause ESRD (diabetic nephropathy accounts for the kidney merit first place in the cause of disease of declining in whole latter stage, is about 38% for endstage renal disease, ESRD) modal disease; In Japan, diabetic nephropathy is the major reason of dialysis, accounts for 36.6% of dialysis patient; In China; Although diabetic nephropathy only accounts for 10% of secondary glomerulopathy; But the arrival of Along with people's growth in the living standard and aging society; The onset diabetes rate increases fast, and can predict diabetic nephropathy will constantly increase, and diabetic nephropathy causes the ratio meeting that whole latter stage, the kidney merit declined increasingly high.In a single day continuous proteinuria appears in diabetic nephropathy clinically; The carrying out property decline of its renal function with containing; Still lack at present the progress that effective treatment means is prevented diabetic nephropathy; About 25% patient in 6 years, 50% patient in 10 years, 75% patient developed into renal failure in whole latter stage in 15 years, be 10 years from albuminuria occurring to dying from uremia's average course of disease.
Hypertension is common clinical, frequently-occurring disease; And hypertensive nephropathy is one of severe complication of hypertension.Along with the progress of hypertension, kidney damage is almost inevitable.Therefore many hypertensive renal patients do not have the clinical manifestation of kidney damage in early days, fail to attract great attention, in case when clinical manifestation or conventional sense occurring and noting abnormalities, nephropathy has reached suitable degree, and needs medicine evident in efficacy to treat.
Meanwhile, hypertension and diabetes are damaged each other often and are caused increasing the weight of of the state of an illness.Hypertension is quickened the progress and the deterioration of diabetic nephropathy, controls hypertension long-term effectively and can delay the renal function deterioration and help reducing urine protein.Some result of study shows, the diabetic nephropathy patient blood pressure is reduced to＜17.6～18.7/11.3～12.0kPa (130～140/85～90mmHg), to stablizing renal function, avoiding the urine protein increase all to show good effect.The diabetic nephropathy hyperpietic is often comparatively responsive to limit salt and diuretic reaction.Low salt diet (sodium＜3g/d) help controlling of blood pressure, easy to be useful.Diuretic influences insulin secretion and carbohydrate metabolism raises low-density and VLDL, stimulates RAS, and can cause side effect such as cardiovascular complication increase.So should not adopt single diuretic therapy to the diabetic nephropathy hyperpietic.As serum creatinine＞221.0 μ mol/L (2.5mg/dl), thiazide diuretic is invalid, but loop diuretic still can be effective;
Given this, how preventing and treat diabetic nephropathy, diabetes accompanied with hypertension nephropathy and hypertensive nephropathy is the common problem of paying close attention to of numerous medical workers.At present, the treatment for diabetic nephropathy and hypertensive nephropathy does not have very effective medicine clinically, and therefore, the new drug of exploitation this respect is very necessary.
Rosuvastatin is the medicine that is mainly used in treatment hypercholesterolemia and hyperlipemia.U.S. FDA as far back as in August, 2003 according to clinical test results, approval listing.This medicine is mainly used in clinical test results and shows, this medicine can hypercholesterolemia reducing, the sweet sterin of LDL-and triglyceride levels, and the sweet sterin of HDL-that can raise (useful sweet sterin) level.The modal side effect of this medicine comprises myalgia, stomachache, feels sick, constipation and weakness etc.There is the scholar to think before this to take Rosuvastatin for a long time and can makes kidney injury.But show that Rosuvastatin acts on very little causing aspect the kidney damage through secular clinical trial.People such as Jonathan Sorof have disclosed in JACC in diabetes or hypertension etc. and have very easily caused in the disease of kidney damage, take the renal function that Rosuvastatin can improve the patient for a long time.(referring to " taking the renal function that Rosuvastatin can improve the high risk patient of u.s. national cholesterol education program adult treatment group the 3rd guide for a long time ", JACC.2007:392A.Abstract1002-131.).There is not clinical relevant side effect aspect the interaction of medicine between Rosuvastatin and digoxin, fenofibrate, antihypertensive drug, antidiabetic medicine and the Hormone Replacement Therapy.
Heparin class medicine belongs to mucopolysaccharide drug, is one type of material that structural units constitutes by derivants such as hexuronic acid, aminohexose and their sulphation, acetylations, comprises heparin, Low molecular heparin and ultra-low molecular heparin.Heparin is the anticoagulant that the inside and outside all can prolong clotting time.Its blood coagulation resisting function is very complicated, and is all influential to many links of coagulation process.The ratio of the activity/anticoagulant active of low molecular weight heparin is 1.5～4.0, and common heparin is 1, has kept the anti thrombotic action of heparin and has reduced danger of bleeding.Have long half time, the bioavailability advantages of higher just is being widely used in the prevention and the treatment of thrombotic disease, and its effectiveness and safety all are superior to unfractionated heparin, and dose-effect relationship is clear and definite.
The effective report of heparin therapy Masugi nephritis can be traced back to 1940 the earliest.After 15 years, Kleinerman finds that when just beginning to fall ill, just giving heparin therapy has protective effect to rabbit nephritis model.Almost meanwhile, Good and Thomas use heparin therapy Shwartzman reaction, think that heparin can not only prevent intravascular coagulation, and can the inflammation-inhibiting reaction.Nineteen sixty-five, confirmation heparin such as Halpern can obviously alleviate the nephropathy .1970 of anti-basement membrane nephritis model, and Cade etc. carry out subcutaneous injection heparin (200-600mg/d) to 18 routine chronic hyperplastic nephritis patients; Last 12 months; The result shows that during treating, patient's GFR raises; When heparin decrement and drug withdrawal, GFR reduces again; Compare with matched group, treatment group patients serum albumin rises, and urinaryalbumin reduces; The kidney biopsy shows that the glomerule proliferative lesion significantly alleviates.1972, report heparin such as Wardle can stop the deterioration of rapidly progressive glomerulonephritis patient renal function, were of value to the nephritis patient that serious hypertension of merging and renal function go down, even can treat the part kidney transplantation exclusion reaction.The end of the eighties is to the beginning of the nineties; People find that in vitro study heparin can suppress the propagation of mesangial cell; Find that in zoopery heparin alleviates the inductive mesentery damage of snake venom (Habu-venom) through the release that suppresses platelet-derived growth factor (PDGF), and can alleviate the carrying out property glomerular sclerosis of part nephrectomy rat model.But, owing to use inconvenience, and factors such as hemorrhage complication, these early stage results of study do not cause the attention of kidney educational circles.
Statins associating treatment by Low molecule heparin kidney disease reports to some extent that the statins of wherein having reported mainly comprises atorvastatin, simvastatin, fluvastatin, lovastatin etc., and Low molecular heparin all is to adopt drug administration by injection.Hu Qing etc. in " efficacy analysis of Low molecular heparin and lovastatin therapeutic alliance diabetic nephropathy " (West China medical science, 2005 20 (4): the 733rd page) literary composition mention, Low molecular heparin associating lovastatin treatment diabetic nephropathy has been obtained curative effect preferably.Yet Low molecular heparin is used for drug administration by injection in this therapeutic scheme, and it is to inject repeatedly that the heparin ejection preparation is used maximum shortcoming clinically, and subcutaneous injection causes subcutaneous hemorrhage through regular meeting, is difficult to accept for the patient who needs long-term prescription.
Summary of the invention
The present invention provides the purposes of a kind of combination of oral medication in pharmacy, relates to the purposes of this combination of oral medication in preparation treatment diabetic nephropathy and hypertensive renal medicine particularly.
The inventor has carried out conscientious animal experiment study to Rosuvastatin or its officinal salt and heparin, Low molecular heparin or its officinal salt Combined application, has drawn the dose ratio and the usage of suitable said composition.The combination of oral medication that the discovery that use obtains based on these researchs prepares, the inventor has carried out the animal experiment study like embodiment 1-3.The result finds, gives said composition through mode provided by the invention, can reach fabulous glycemic control, can prevent and treat diabetic nephropathy.And has better curative effect aspect prevention and the treatment hypertensive nephropathy.
For this reason, the invention discloses the purposes of a kind of combination of oral medication in the medicine of preparation treatment kidney disease, described kidney disease is diabetic nephropathy or hypertensive nephropathy, and described combination of oral medication contains following active component:
1) Rosuvastatin or its officinal salt and
2) heparin or Low molecular heparin or its officinal salt.
Preferably, the weight ratio of Rosuvastatin or its officinal salt and heparin or its officinal salt is 0.06～16: 1, the tiring in 170IU/mg of wherein said heparin; Further preferably, the weight ratio of Rosuvastatin or its officinal salt and heparin or its officinal salt is 1～8: 1, the tiring in 170IU/mg of wherein said heparin.
Preferably, the weight ratio of Rosuvastatin or its officinal salt and Low molecular heparin or its officinal salt is 0.03～40: 1, the tiring in 104.4IU/mg of wherein said Low molecular heparin; Further preferably, the weight ratio of Rosuvastatin or its officinal salt and Low molecular heparin is 0.1～8: 1, the tiring in 104.4IU/mg of wherein said Low molecular heparin; Again further preferably, the weight ratio of Rosuvastatin or its officinal salt and Low molecular heparin is 0.1～4: 1, and wherein said Low molecular heparin is tired in 104.4IU/mg.
What be worth explanation is; If heparin or Low molecular heparin are tired in other; So according to former to tire down (be that tiring of heparin is 170IU/mg at heparin or Low molecular heparin in the above-mentioned composition; Low molecular heparin is tired and is 104.4IU/mg) the part by weight relation of Rosuvastatin or its officinal salt and heparin or Low molecular heparin or its officinal salt; Can be converted at tire the down Rosuvastatin of (be 125IU/mg such as tiring of heparin, tiring of Low molecular heparin is 80IU/mg) or the part by weight of its officinal salt and heparin or Low molecular heparin or its officinal salt of other of heparin or Low molecular heparin and concern.
When above-mentioned combination of oral medication was used for people's the treatment of diabetic nephropathy, the human dosage of said heparin or Low molecular heparin or its officinal salt was 3～140IU/kgd, and the human dosage of Rosuvastatin or its officinal salt is 0.15～0.42mg/kgd; Preferably, the human dosage of said heparin, Low molecular heparin or its officinal salt is 9～80IU/kgd, and the human dosage of Rosuvastatin or its officinal salt is 0.20～0.33mg/kgd.
In the above-mentioned combination of oral medication, said heparin officinal salt comprises sodium salt, calcium salt, potassium salt, magnesium salt, zinc salt, iron salt, preferably its calcium salt and sodium salt.
The derivant of above-mentioned all heparin that relate to, Low molecular heparin or its officinal salt comprises its sulfating product, desulfurization acidizing product in various degree.
In the above-mentioned combination of oral medication; All heparin that relate to, Low molecular heparin or its officinal salt and Rosuvastatin or its officinal salt; Can process solid orally ingestible through the conventional formulation technology according to their character, comprise ordinary tablet, dispersible tablet, slow releasing tablet or capsule.
Through animal experiment research, the inventor has confirmed the purposes of combination of oral medication in the medicine of preparation treatment rat diabetes nephropathy and hypertensive nephropathy of Rosuvastatin or its officinal salt and heparin, Low molecular heparin or its officinal salt.What be worth explanation is that in the animal experiment research of this part, administering mode all is preferred.Need to prove, adopt the compositions administration of following weight ratio to experimentize, can't change the establishment that this pharmaceutical composition has this conclusion of purposes of preparation treatment rat diabetes nephropathy and hypertensive nephropathy.The compositions of described following weight ratio is: the pharmaceutical composition of the weight ratio of Rosuvastatin or its officinal salt and heparin or its officinal salt 0.06: 1 or 16: 1 (tiring in 170IU/mg of heparin); The pharmaceutical composition of the weight ratio of Rosuvastatin or its officinal salt and Low molecular heparin or its officinal salt 0.03: 1 or 40: 1 (tiring of Low molecular heparin) in 104.4IU/mg.
Particularly, at first the inventor through SD rat disposable celiac injection streptozotocin (STZ) being accomplished the modeling of diabetic nephropathy.Give pharmaceutical composition of the present invention to the successful rat of modeling, successive administration is surveyed microdose urine protein, urine β after 4 months
2Microglobulin, blood specimen detects blood glucose, serum creatinine.The result finds, through long-term gastric infusion Rosuvastatin and Low molecular heparin or its officinal salt, the diabetic nephropathy that can treat rat.To DN rat microdose urine protein (MA) and urine β
2Microglobulin (U-β
2MG) influence the aspect, dosage compound recipe group was in full accord with Rosuvastatin oral combination Low molecular heparin injection groups dosage during Rosuvastatin and Low molecular heparin were oral, they are to DN rat microdose urine protein (MA) and urinate β
2Microglobulin (U-β
2MG) impact effect is suitable; Rosuvastatin is compared with Rosuvastatin oral combination Low molecular heparin injection groups with the oral high dose compound recipe of Low molecular heparin, has significant difference.And pharmaceutical composition provided by the invention all is a solid orally ingestible; The misery that can avoid heparin or Low molecular heparin drug administration by injection to bring shows that further Rosuvastatin and Low molecular heparin Orally administered composition have remarkable advantages at the resultant effect of treatment diabetic nephropathy than oral Rosuvastatin associating Low molecular heparin drug administration by injection.
Secondly, the inventor is through using therapeutic scheme provided by the invention to intervene to Hypertensive Rats (SHR), with microdose urine protein and urine β
2Microglobulin is as the index of weighing renal function, and the result finds that Rosuvastatin and heparin compound recipe can prevent the kidney injury that causes because of hypertension.Secondly, the inventor is through accomplishing the modeling of hypertensive nephropathy to Hypertensive Rats (SHR) administration nitro L-arginine methyl ester, and with glomerular filtration rate, microdose urine protein, urine β
2Three indexs of microglobulin are weighed renal function, and the result finds that Rosuvastatin and Low molecular heparin compound recipe have good therapeutic effect to hypertensive nephropathy.
Another innovative point of the present invention is that this pharmaceutical composition is an oral administration.Traditional heparin or Low molecular heparin drug administration by injection can cause hemorrhage, and especially repetitively administered can increase patient's misery greatly.Yet oral heparin or Low molecular heparin not only can avoid injecting the misery of bringing, and can avoid heparin or Low molecular heparin to inject cause hemorrhage.Particularly heparin or Low molecular heparin and statins Combined application and when selecting optimum dose proportion that the present invention provides, said composition shows beyond thought pharmacodynamic action.
Compare with the medicine of other treatment diabetic nephropathy and hypertensive nephropathy, the pharmaceutical composition among the present invention is having the following advantages or beyond thought effect aspect treatment diabetic nephropathy and the hypertensive nephropathy:
(1) synergism.Compositions of the present invention is passed through animal experiment study; Show when the time with compositions of the present invention; When especially adopting preferred proportioning, compare during with the HMG-COA reductase inhibitor of independent application effective dose or heparin, compositions of the present invention provides beyond thought better effect; Toxicity does not increase simultaneously; Reaching under the situation of identical hypoglycemic effect, two types of drug combinations greatly reduce the using dosage of every kind of medicine, and this has just significantly reduced the untoward reaction of HMG-COA reductase inhibitor and the drug risk of heparin.
(2) make things convenient for administration.Pharmaceutical composition of the present invention can be processed capsule and tablet etc., makes things convenient for the patient to take, and especially for the patient who needs long term administration, the drug administration by injection mode of abandoning tradition of the present invention can greatly alleviate the patient suffering, is applicable to patient's long-term treatment.
The specific embodiment
Below further describe the present invention through specific embodiment, range of application of the present invention is not limited to the following example.Owing to described the present invention according to following preferred embodiment, some is modified and equivalent variations is conspicuous for those of ordinary skill in the art and comprises within the scope of the invention.
1. the pharmacodynamic study of Rosuvastatin or its officinal salt and heparin or Low molecular heparin or its officinal salt pharmaceutical composition
Instance 1 Rosuvastatin and Low molecular heparin compound recipe are to the influence of rat diabetes nephropathy
The foundation of 1 animal model
Select 90 of SD rats for use, male, body weight (250 ± 20) g.After all rat adaptabilities were fed a week, fasting 12h was according to the disposable injection streptozotocin of 65mg/kg intraperitoneal (STZ).STZ faces with preceding that (0.1mol/L PH4.5) is mixed with 2% STZ injection, uses up in the 10min with sodium citrate buffer.Whole rat sub-cage rearings in same Animal House, standard diet.Fed for 2 weeks continuously, survey blood glucose, glucose in urine, 24h microdose urine protein and urine β
2Microglobulin.The choice criteria of diabetic nephropathy (DN) rat need satisfy following three conditions simultaneously: rat blood sugar is higher than 16.7mmol/L, the urine amount increases more than one times and the urinaryalbumin positive.
2 groupings and administration
Become mould DN rat to be divided into model group matched group and administration group (6 groups) at random.The normal control group is selected the SD rat for use, 8 every group.Rosuvastatin is oral to adopt the administration of oral rosuvastain calcium associating tail vein injection low molecular heparin calcium with Low molecular heparin injection groups (his spit of fland oral combination Low molecular heparin injection groups), and all the other each groups are all taked the gastric infusion mode.Concrete grouping and administration are following:
Normal control group: with the purified water of volume;
Model control group: with the sodium carboxymethyl cellulose of volume;
Rosuvastatin group: 0.3mg/ (kg.d) rosuvastain calcium;
Low molecular weight heparin group: 3.0mg/ (kg.d) low molecular heparin calcium;
Oral and the Low molecular heparin injection groups (his spit of fland oral combination Low molecular heparin injection groups) of Rosuvastatin: 0.3mg/ (kg.d) rosuvastain calcium+3.0mg/ (kg.d) low molecular heparin calcium;
Rosuvastatin and Low molecular heparin compound recipe low dose group (the low group of compound recipe): 0.1mg/ (kg.d) rosuvastain calcium+1.0mg/ (kg.d) low molecular heparin calcium;
Dose groups (organizing in the compound recipe): 0.3mg/ (kg.d) rosuvastain calcium+3.0mg/ (kg.d) low molecular heparin calcium in Rosuvastatin and the Low molecular heparin compound recipe;
Rosuvastatin and Low molecular heparin compound recipe high dose group (the high group of compound recipe): 0.9mg/ (kg.d) rosuvastain calcium+9.0mg/ (kg.d) low molecular heparin calcium.
3 experimental techniques and index detect
After the diabetic nephropathy rat model success, continue to feed for 12 weeks, during carry out administration according to above-mentioned dosage regimen, and carry out tight observation.Experiment finishes the previous day, collects 24h urine with metabolic cage, detects microdose urine protein, urine β
2Microglobulin.After the last administration, rat extracting blood steps auspicious automatic clinical chemistry analyzer and detects blood glucose.
3.1 blood glucose target: adopt Advantage electronic induction blood glucose meter and supporting trial-production bar (Roche, Switzerland) to detect.
3.2 microdose urine protein (MA) and urine β
2-microglobulin (U-β
2MG) index: collect rat 24h urine, get the 5ml urine and adopt U.S. nuclear power ACE automatic clinical chemistry analyzer to detect microdose urine protein (MA) and urine β
2-microglobulin (U-β
2MG), method is that granule strengthens dialysis immunoturbidimetry analytic process.Urine β
2-microglobulin test kit is available from U.S. COX company, and the microdose urine protein test kit is available from Britain Randox company.
Blood sugar level is to weigh the index of diabetes, and the state of an illness of the big more expression diabetes of blood sugar concentration is serious more; Microdose urine protein (MA) and urine β
2-microglobulin (U-β
2MG) be the index of weighing glomerule and renal tubules damaged condition, these two numerical value show that more greatly the kidney damaged condition is big more.
4. experimental result
4.1 Rosuvastatin and Low molecular heparin compound recipe are to the influence of DN rat blood sugar
Experimental result shows: compare with model group, only have the high group of Rosuvastatin and Low molecular heparin compound recipe aspect blood sugar lowering, to have significant difference; Difference that there are no significant between other each treatment group.Analyzing possible reason is, thereby the high group of Rosuvastatin and Low molecular heparin compound recipe has been improved the influence to blood glucose that renal function brings.See table 1.
Table 1 Rosuvastatin and Low molecular heparin compound recipe are to the influence of DN rat blood sugar
Annotate:
▲Compare P＜0.05 with model group.
4.2 Rosuvastatin and Low molecular heparin compound recipe are to DN rat microdose urine protein, urine β
2Microglobulin (U-β
2MG) influence
Experimental result shows:
(1) compare with model group, three groups of Rosuvastatin and Low molecular heparin compound recipe are for DN rat microdose urine protein, urine β
2-microglobulin (U-β
2MG) reduction has significant difference.The influence of the high group of group and compound recipe is more remarkable in Rosuvastatin and the Low molecular heparin compound recipe.Three groups of Rosuvastatin and Low molecular heparin compound recipe compare with Rosuvastatin group or Low molecular heparin group respectively, and the high group of group and compound recipe has significant difference in the compound recipe.Explain that Rosuvastatin and Low molecular heparin compound recipe have good effect to prevention and the kidney injury that causes of treatment diabetes, and Rosuvastatin and Low molecular heparin compound recipe are for influence DN rat microdose urine protein and urinating β
2The microglobulin aspect has synergism.See table 2.
(2) oral middle dosage compound recipe of Rosuvastatin and Low molecular heparin and Rosuvastatin oral combination Low molecular heparin injection groups dosage are in full accord, and they are to DN rat microdose urine protein (MA) and urine β
2Microglobulin (U-β
2MG) impact effect is suitable.To DN rat microdose urine protein (MA) and urine β
2Microglobulin (U-β
2MG) influence the aspect, Rosuvastatin is compared with Rosuvastatin oral combination Low molecular heparin injection groups with the oral high dose compound recipe of Low molecular heparin, has significant difference.And pharmaceutical composition provided by the invention all is a solid orally ingestible; The misery that can avoid heparin or Low molecular heparin drug administration by injection to bring shows that further Rosuvastatin and Low molecular heparin Orally administered composition have remarkable advantages at the resultant effect of treatment diabetic nephropathy than oral Rosuvastatin associating Low molecular heparin drug administration by injection.See table 2.
Therefore, the pharmaceutical composition of Rosuvastatin and Low molecular heparin can be used as the use of preparation treatment diabetic nephropathy drugs.
Table 2 Rosuvastatin and Low molecular heparin compound recipe are to DN rat microdose urine protein (MA) and urine β
2Microglobulin (U-β
2MG) influence
Annotate:
▲Compare p＜0.05 with model group;
▲ ▲Compare p＜0.01 with model group;
★Compare p＜0.05 with the Rosuvastatin group;
★ ★Compare p＜0.01 with the Rosuvastatin group;
■Compare p＜0.05 with the Low molecular heparin group;
*Compare p＜0.05 with the Low molecular heparin injection groups with his spit of fland is oral.
The intervention effect of the early stage kidney injury that embodiment 2 Rosuvastatins and heparin compound recipe cause hypertension
1. laboratory animal is divided into groups and administration
48 of the male spontaneous hypertensive rats of SPF level (SHR), 12 ages in week, body weight 280-300g, grinding the Shanghai Experimental Animal Center by Chinese science provides.4 one cages, standard feed is fed, ad lib and drinking-water, 24 ± 2 degrees centigrade constant temperature quiet environment.Simultaneously, other establishes 8 Wistar-Kyoto of the same age (WKY) as the normal control group.Hypertensive Rats (SHR) is divided into model group, administration group at random, 8 every group.Each group is gastric infusion.Concrete grouping and administration are following:
Normal control group: with the purified water of volume;
Model control group: with the sodium carboxymethyl cellulose of volume;
Rosuvastatin group: 0.66mg/ (kg.d) rosuvastain calcium;
Heparin group: 0.165mg/ (kg.d) heparin sodium;
Rosuvastatin and heparin compound recipe low dose group (the low group of compound recipe): 0.22mg/ (kg.d) rosuvastain calcium+0.055mg/ (kg.d) heparin sodium;
Dose groups (organizing in the compound recipe): 0.66mg/ (kg.d) rosuvastain calcium+0.165mg/ (kg.d) heparin sodium in Rosuvastatin and the heparin compound recipe;
Rosuvastatin and heparin compound recipe high dose group (the high group of compound recipe): 2.00mg/ (kg.d) rosuvastain calcium+0.50mg/ (kg.d) heparin sodium.
2. test method and index detect
With all SHR rats and the common raising of WKY rat adaptability 7 days.Every rat marked detects respectively and gathers rat urine detection microdose urine protein (MA) in the blood pressure and the morning.Each is organized rat and is administered to the end of the 9th week from the beginning of the 2nd week according to above-mentioned scheme.When on-test and the 5th week, the 9th week, adopt the arteria caudalis manometry to measure rat blood pressure, survey 3 times at every turn, get its meansigma methods.Treatment of animals is collected rat 24h urine after 8 weeks, gets the 5ml urine and adopts U.S. nuclear power ACE automatic clinical chemistry analyzer to detect microdose urine protein (MA) and urine β
2-microglobulin (U-β
2MG), method is that granule strengthens dialysis immunoturbidimetry analytic process.Urine β
2-microglobulin test kit is available from U.S. COX company, and the microdose urine protein test kit is available from Britain Randox company.
Above gained experimental data is carried out statistical procedures according to method once:
Adopt the SPSS statistical software, (x ± s) expression, many groups data relatively adopts variance analysis to calculating data, relatively adopts the t check in the group with mean ± standard deviation.With p＜0.05 for statistical significance is arranged.
3. result of the test
3.1 Rosuvastatin and heparin compound recipe are to the influence of blood pressure
Experimental result shows, when experiment finishes (the 9th week), compares with model group, heparin group, Rosuvastatin group, and the high group of Rosuvastatin and heparin compound recipe has significant difference to the reduction of SHR blood pressure.With model group relatively, Rosuvastatin group and heparin group are to the reduction of SHR blood pressure there are no significant difference.This explains that to a certain extent Rosuvastatin and heparin compound recipe have synergism for reducing SHR rat blood pressure aspect.
Table 3 Rosuvastatin and heparin compound recipe are to the influence of blood pressure (mmHg)
Annotate
▲Compare p＜0.05 with model group;
★Compare p＜0.05 with the Rosuvastatin group;
■Compare p＜0.05 with heparin group.
3.2 Rosuvastatin and heparin compound recipe are to microdose urine protein and urine β
2The influence of-microglobulin
Experimental result shows, compares with model group, Rosuvastatin group, and Rosuvastatin and heparin compound recipe group are for SHR rat microdose urine protein, urine β
2-microglobulin (U-β
2MG) reduction has utmost point significant difference (p＜0.01); Compare with heparin group, Rosuvastatin and heparin compound recipe are for SHR rat microdose urine protein, urine β
2-microglobulin (U-β
2MG) reduction has significant difference (p＜0.05).Yet the Rosuvastatin group is compared no significant difference with model group, and Rosuvastatin and heparin compound recipe are for reducing SHR microdose urine protein, urine β
2-microglobulin (U-β
2MG) aspect has synergism.Therefore Rosuvastatin with the heparin compound recipe to treat the drug use of the kidney injury that hypertension causes as preparation.(seeing table 4).
Table 4 Rosuvastatin and heparin compound recipe are to microdose urine protein and urine β
2The influence of microglobulin
Annotate
▲Compare p＜0.05 with model group;
▲ ▲Compare p＜0.01 with model group;
★Compare p＜0.05 with the Rosuvastatin group;
★ ★Compare p＜0.01 with the Rosuvastatin group;
■Compare p＜0.05 with heparin group
Embodiment 3 Rosuvastatins and Low molecular heparin compound recipe are to the influence of hypertensive nephropathy
1. the foundation of hypertensive nephropathy animal model
48 of the male spontaneous hypertensive rats of SPF level (SHR), 12 ages in week, body weight 280-300g, grinding the Shanghai Experimental Animal Center by Chinese science provides.All add nitro L-arginine methyl ester (L-NAME) 50mg/L in the drinking water of SHR rat.And on every Mondays, three, renew the water bottle that contains L-NAME of configuration just before dawn.0d, 14d, 28d after the experiment beginning collect rat 24h urine respectively, measure the content of urine protein.Obtain sign of serious hypertensive nephropathy with rat urinaryalbumin urine " ++ " as Hypertensive Rats (SHR), with this as the successful choice criteria of modeling.
2. the hypertensive nephropathy rat divides into groups and administration
40 of preferred hypertensive nephropathy rats are divided into 5 groups at random.Each is organized administering mode and is gastric infusion.Successive administration 14 days.Concrete grouping is following with dosage regimen:
Model control group: with the purified water of volume;
Rosuvastatin group: 0.83mg/ (kg.d) Rosuvastatin sodium;
Low molecular weight heparin group: 0.104mg/ (kg.d) low molecular sodium heparin;
Rosuvastatin and heparin compound recipe low dose group (L group): 0.28mg/ (kg.d) Rosuvastatin sodium+0.035mg/ (kg.d) low molecular sodium heparin;
Dose groups in Rosuvastatin and the heparin compound recipe (M group): 0.83mg/ (kg.d) Rosuvastatin sodium+0.104mg/ (kg.d) low molecular sodium heparin;
Rosuvastatin and heparin compound recipe high dose group (H group): 2.50mg/ (kg.d) Rosuvastatin sodium+0.3125mg/ (kg.d) low molecular sodium heparin.
3. experimental technique and index determining
After having collected last 24h urine sample; With 2% pentobarbital sodium intraperitoneal injection of anesthesia rat 50mg/kg; And the operating-table that is positioned over temperature controllable is to keep the autonomous respiration of rat, and left side groin venous cannulation is in order to injection artificial plasm, inulin and P-aminophippuric acid (PAH).Left side inguinal artery intubate also is connected in order to recording blood pressure (BP), mean arterial pressure (MAP) with a pressure converter.All records pass through the graphic software system handles by computer.Making the otch about a horizontal 1cm with the ventrimeson intersection on the pubic arch, inserting bladder collection urine with a PE pipe that has the edge.During the whole surgery, slowly inject the normal saline that about 1ml artificial plasm, 0.5ml are contained 20mg inulin and P-aminophippuric acid (PAH) from rat vein.Continue intravenous drip with the inulin of concentration dose and the normal saline of P-aminophippuric acid (PAH) with 100 μ l/ (min.kg) again.Through 45 minutes equilibration time, the experiment of kidney clearance rate was made up of the cycle of the collection urine of two lasting 20min.The mid point in each cycle is collected a blood sample (about 150 μ l), and centrifugal blood is collected blood plasma and waited until analysis.
Rat urine after the collection is weighed and is calculated the urine amount and make inulin and the concentration determination of PAH.In the urine with blood plasma in inulin concentration measure with anthrone method.PAH concentration is used colorimetric method for determining.The content of urine protein is chemically examined with the Bradford method, and makes standard curve with bovine serum albumin.These mensuration can calculate the clearance rate of inulin, and (filtration rate that is equivalent to glomerule, GFR), P-aminophippuric acid (PAH) clearance rate (is equivalent to renal plasma flow, RPF).The result in two cycles is obtained the renal function index after average, represent the filtration rate of glomerule, represent renal plasma flow with P-aminophippuric acid (PAH) clearance rate with the clearance rate of inulin.
Above gained experimental data is carried out statistical procedures according to method once:
Adopt the SPSS statistical software, (x ± s) expression, many groups data relatively adopts variance analysis to calculating data, relatively adopts the t check in the group with mean ± standard deviation.With p＜0.05 for statistical significance is arranged.In this experiment, we select mean arterial pressure and two indexs of heart rate as the index of weighing the blood pressure situation, and these two indexs are high more, and the expression blood pressure level is high more.In this simultaneously, we select glomerular filtration rate, two indexs of renal plasma flow as the important indicator of weighing renal function, and the high more renal function that shows of these two numerical value is good more.
4. experimental result
4.1 Rosuvastatin and Low molecular heparin compound recipe are to the influence of hypertensive nephropathy rat blood pressure
Experimental result shows that with model group, the high group of Rosuvastatin and Low molecular heparin compound recipe has significant difference for reducing the mean arterial pressure aspect.Compare with Low molecular heparin group, Rosuvastatin group, three groups of Rosuvastatin and Low molecular heparin compound recipe all do not have significant difference.This explanation, Rosuvastatin and Low molecular heparin compound recipe have certain function aspect horizontal bringing high blood pressure down.
Table 5 Rosuvastatin and Low molecular heparin compound recipe are to the influence of hypertensive nephropathy rat blood pressure and heart rate
Annotate
▲Compare p＜0.05. with model group
4.2 Rosuvastatin and Low molecular heparin compound recipe are to the influence of hypertensive nephropathy rat kidney function.
Experimental result shows:
(1) aspect the glomerular filtration rate influence; The Low molecular heparin group is compared with model group has significant difference (p＜0.05); Three groups of Rosuvastatin and Low molecular heparin compound recipe and model group are compared with the Rosuvastatin group has extremely significant difference (p＜0.01), and group in Rosuvastatin and the Low molecular heparin compound recipe, the high group of compound recipe is compared with the Low molecular heparin group has significant difference (p＜0.05).See table 6.
(2) aspect the renal plasma flow influence, Low molecular heparin group, Rosuvastatin group are compared with model group, do not have significant difference; All have significant difference or extremely significant difference yet three groups of Rosuvastatin and Low molecular heparin compound recipe are compared with model group, Rosuvastatin group, Low molecular heparin group, and Rosuvastatin and Low molecular heparin glomerular filtration rate that hypertension is caused and the influence of renal plasma flow has synergism.See table 6.
Therefore, the pharmaceutical composition of Rosuvastatin and Low molecular heparin can be used as the drug use of preparation treatment hypertensive nephropathy.
Table 6 Rosuvastatin and Low molecular heparin compound recipe are to the influence of hypertensive nephropathy rat kidney function
Annotate
▲Compare p＜0.05 with model group;
▲ ▲Compare p＜0.01 with model group;
★Compare p＜0.05 with the Rosuvastatin group;
★ ★Compare p＜0.01 with the Rosuvastatin group;
■Compare p＜0.05 with the Low molecular heparin group;
■ ■Compare p＜0.01 with the Low molecular heparin group
2. Rosuvastatin or its officinal salt and heparin or Low molecular heparin or its officinal salt preparation of drug combination
Embodiment 4 tablets
Prescription rosuvastain calcium 32g
Heparin sodium 2g
Microcrystalline Cellulose 120g
2% Gonak is an amount of
Low-substituted hydroxypropyl cellulose 8g
Magnesium stearate 2g
Preparation technology: rosuvastain calcium and heparin sodium are crossed 100 mesh sieves; Microcrystalline Cellulose and low-substituted hydroxypropyl cellulose are crossed 80 mesh sieves, take by weighing rosuvastain calcium, heparin sodium and low-substituted hydroxypropyl cellulose, the microcrystalline Cellulose mix homogeneously of recipe quantity, add 2% Gonak and granulate in right amount; 40 ℃ of dryings; 16 mesh sieve granulate, the magnesium stearate mixing of adding recipe quantity in the dried granule, tabletting promptly gets.
Embodiment 5 tablets
Prescription rosuvastain calcium 10g
Heparin sodium 10g
Microcrystalline Cellulose 110g
2% Gonak is an amount of
Low-substituted hydroxypropyl cellulose 7g
Magnesium stearate 2g
Preparation technology is with embodiment 4.
Embodiment 6 tablets
Prescription rosuvastain calcium 32g
Heparin sodium 4g
Microcrystalline Cellulose 130g
2% Gonak is an amount of
Low-substituted hydroxypropyl cellulose 8g
Magnesium stearate 3g
Preparation technology is with embodiment 4.
Embodiment 7 capsules
Prescription Rosuvastatin zinc 1.5g
Heparin sodium 25g
Pregelatinized Starch 60g
Microcrystalline Cellulose 100g
95% alcoholic solution of 6%PVP is an amount of
Magnesium stearate 3g
Preparation technology: Rosuvastatin zinc, heparin sodium, pregelatinized Starch, microcrystalline Cellulose and the magnesium stearate in will writing out a prescription crossed 100 mesh sieves respectively, mixing, and 95% alcoholic solution that adds 6%PVP is granulated in right amount, 40 ℃ of oven dry, 18 mesh sieve granulate, capsule charge gets final product.
Embodiment 8 dispersible tablets
Prescription rosuvastain calcium 20g
Heparin sodium 5g
Crospolyvinylpyrrolidone 7g
5%PVP
K30Ethanol solution is an amount of
Microcrystalline Cellulose 110g
Magnesium stearate 2g
Preparation technology: rosuvastain calcium and heparin sodium are crossed 100 mesh sieves, and crospolyvinylpyrrolidone is crossed 80 mesh sieves, take by weighing rosuvastain calcium, heparin sodium and the crospolyvinylpyrrolidone mix homogeneously of recipe quantity, add 5%PVP
K30Ethanol solution is granulated in right amount, and dry back adds recipe quantity microcrystalline Cellulose, magnesium stearate mixing, and tabletting promptly gets.
Embodiment 9 tablets
Prescription rosuvastain calcium 40g
Low molecular heparin calcium 1g
Microcrystalline Cellulose 120g
2% Gonak is an amount of
Low-substituted hydroxypropyl cellulose 8g
Magnesium stearate 2g
Preparation technology: rosuvastain calcium and low molecular heparin calcium are crossed 100 mesh sieves; Microcrystalline Cellulose and low-substituted hydroxypropyl cellulose are crossed 80 mesh sieves, take by weighing rosuvastain calcium, low molecular heparin calcium and low-substituted hydroxypropyl cellulose, the microcrystalline Cellulose mix homogeneously of recipe quantity, add 2% Gonak and granulate in right amount; 60 ℃ of dryings; 16 mesh sieve granulate, the magnesium stearate mixing of adding recipe quantity in the dried granule, tabletting promptly gets.
Embodiment 10 capsules
Prescription rosuvastain calcium 1g
Low molecular sodium heparin 33g
Pregelatinized Starch 60g
Microcrystalline Cellulose 100g
95% alcoholic solution of 6%PVP is an amount of
Magnesium stearate 3g
Preparation technology: the rosuvastain calcium in will writing out a prescription, low molecular sodium heparin, pregelatinized Starch, microcrystalline Cellulose and magnesium stearate are crossed 100 mesh sieves respectively; Mixing, 95% alcoholic solution that adds 6%PVP is granulated in right amount, 60 ℃ of oven dry; 18 mesh sieve granulate, capsule charge gets final product.
Embodiment 11 capsules
Prescription rosuvastain calcium 10g
Low molecular sodium heparin 10g
Pregelatinized Starch 100g
Microcrystalline Cellulose 100g
95% alcoholic solution of 6%PVP is an amount of
Magnesium stearate 3g
Preparation technology is with embodiment 10.
Embodiment 12 capsules
Prescription rosuvastain calcium 32g
Low molecular sodium heparin 8g
Pregelatinized Starch 60g
Microcrystalline Cellulose 100g
95% alcoholic solution of 6%PVP is an amount of
Magnesium stearate 3g
Preparation technology is with embodiment 10.
Embodiment 13 dispersible tablets
Prescription rosuvastain calcium 2g
Low molecular heparin calcium 20g
Crospolyvinylpyrrolidone 7g
Microcrystalline Cellulose 110g
5%PVP
K30Ethanol solution is an amount of
Magnesium stearate 2g
Preparation technology: rosuvastain calcium and low molecular heparin calcium are crossed 100 mesh sieves, and crospolyvinylpyrrolidone is crossed 80 mesh sieves, take by weighing rosuvastain calcium, low molecular heparin calcium and the crospolyvinylpyrrolidone mix homogeneously of recipe quantity, add 5%PVP
K30Ethanol solution is granulated in right amount, and dry back adds recipe quantity microcrystalline Cellulose, magnesium stearate mixing, and tabletting promptly gets.
Embodiment 14 slow releasing tablet
Prescription rosuvastain calcium 32g
Low molecular sodium heparin 4g
Hydroxypropyl emthylcellulose sodium 40g
Microcrystalline Cellulose 100g
Magnesium stearate 2g
Preparation technology: with rosuvastain calcium, low molecular sodium heparin, hydroxypropyl emthylcellulose sodium, the microcrystalline Cellulose mixing of recipe quantity, granulate according to common process, drying, granulate adds the magnesium stearate mixing, and tabletting promptly gets.
Claims (1)
1. the combination of oral medication purposes in the medicine of preparation prevention or treatment kidney disease, described kidney disease is diabetic nephropathy or hypertensive nephropathy, described pharmaceutical composition is made up of following two kinds of active component:
1) Rosuvastatin or its officinal salt; With
2) heparin or Low molecular heparin, or its officinal salt.
2. purposes as claimed in claim 1 is characterized in that the weight ratio of Rosuvastain spit of fland in the described pharmaceutical composition or its officinal salt and heparin or its officinal salt is 0.06～16:1.
3. purposes as claimed in claim 2 is characterized in that the weight ratio of Rosuvastain spit of fland in the described pharmaceutical composition or its officinal salt and heparin or its officinal salt is 1～8:1.
4. purposes as claimed in claim 1 is characterized in that the weight ratio of Rosuvastain spit of fland in the described pharmaceutical composition or its officinal salt and Low molecular heparin or its officinal salt is 0.03～40:1.
5. purposes as claimed in claim 4 is characterized in that the weight ratio of Rosuvastain spit of fland in the described pharmaceutical composition or its officinal salt and Low molecular heparin or its officinal salt is 0.1～8:1.
6. purposes as claimed in claim 5 is characterized in that the weight ratio of Rosuvastain spit of fland in the described pharmaceutical composition or its officinal salt and Low molecular heparin or its officinal salt is 0.1～4:1.
7. like the arbitrary described purposes of claim 1-6, it is characterized in that the officinal salt of Rosuvastain spit of fland, heparin or Low molecular heparin in the described pharmaceutical composition comprises sodium salt, calcium salt, potassium salt, magnesium salt, zinc salt or iron salt.
8. like the arbitrary described purposes of claim 1-6, it is characterized in that described pharmaceutical composition is a solid orally ingestible.
9. purposes as claimed in claim 8 is characterized in that described pharmaceutical composition is tablet or capsule.
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