CN101396560B - Medicine composition for treating polycystic kidney disease and use thereof - Google Patents
Medicine composition for treating polycystic kidney disease and use thereof Download PDFInfo
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- CN101396560B CN101396560B CN2007100467540A CN200710046754A CN101396560B CN 101396560 B CN101396560 B CN 101396560B CN 2007100467540 A CN2007100467540 A CN 2007100467540A CN 200710046754 A CN200710046754 A CN 200710046754A CN 101396560 B CN101396560 B CN 101396560B
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Abstract
The invention relates to a pharmaceutical composition for treating polycystic kidney disease. The active ingredients of the pharmaceutical composition comprise effective doses of thiazolidinediones and diuretics. The preferential combination is as follows: the thiazolidinediones are selected from rosiglitazone and the diuretics are selected from amiloride hydrochloride. The animal experiments prove that the efficacy of the composition of the rosiglitazone and the diuretics on the treatment of the polycystic kidney disease is better than the single use of one drug. The effect of the pharmaceutical composition for treating the polycystic kidney disease is better than the single use of one drug, thereby being a drug for treating the polycystic kidney disease and being worth expecting.
Description
Technical field
The present invention relates to drug world, specifically, relate to a kind of pharmaceutical preparation that is used for the treatment of the pharmaceutical composition and the application thereof of multicystic kidney disease and contains it.
Background technology
Multicystic kidney disease is divided into autosomal dominant polycystic kidney disease (autosomaldominant polycystic kidney disease according to mode of inheritance, ADPKD) and the recessive hereditary multicystic kidney disease (autosomal recessive polycystic kidney disease, ARPKD).Wherein ADPKD is one of single gene inheritance disease that the mankind are the most common, harm is maximum, occupies first of heritability nephropathy.ADPKD is 1/400-1/1000 at worldwide sickness rate, and China has more than 150 ten thousand people to suffer from this disease at present approximately, and wherein 50% patient can advance to end-stage renal failure in the time of 60 years old.Its feature shows as bilateral kidney cortex and medullary substance has a plurality of fluidity cysts that differ in size, can involve simultaneously the outer organ of a plurality of kidneys, form [Patricia D.Wilson such as polycystic liver, ductus pancreaticus and cholangiectasis, colonic diverticula, intracranial aneurysm, heart valve disorders, P.D., The new england journal of medicine, 2004.].
Along with the clone in succession of ADPKD Disease-causing gene and the continuous development of gene diagnosis technology, imaging examination means, prenatal diagnosis, the preceding diagnostic techniques of disease progressively is applied to clinical, and more and more patients just can not be diagnosed as ADPKD when disease has any clinical symptoms and iconography evidence in early days even.But still there are not any specific treatment medicine and intervening measure for this disease at present, how to delay the polycystic kidney disease progress by early stage pharmaceutical intervention is a difficult problem that needs to be resolved hurrily, Chinese scholars is devoted to seek the treatment novel targets [Wahl of ADPKD always, P.R., et al., Nephrol Dial Transplant, 2006.21 (3): p.598-604; Torres, V.E.and P.C.Harris, Nat Clin Pract Nephrol, 2006.2 (1): p.40-55; Quiz 55. S., H., ADPKD:Clinical and Experimental Nephrology 2005.9-4.].
Peroxisome Proliferator-activated receptor (peroxisome proliferator-activedreceptors gamma, PPAR-γ) belongs to the nuclear receptor superfamily member, with another nuclear receptor retinoid X receptor (retinoid X receptors, RXR) form heterodimer, combine with the specific reaction element (PPRE) in target gene promoters district, thus the effect of performance important function of gene regulation and control.Recent study show PPAR-γ except with many human diseasess as obesity, insulin resistant, type 2 diabetes mellitus, hypertension, atherosclerosis and inflammation in close relations, also become the novel targets of multicystic kidney disease treatment.[Iglesias, P.and J.J.Diez, Eur J Endocrinol, 2006.154 (5): p.613-21.] research such as external Muto shows that also application PPAR-gamma agonist pioglitazone can prolong [Muto life cycle (usually in period of fetus death) of gene knockout multicystic kidney disease mice (Pkd1-/-), S., et al., Hum Mol Genet, 2002.11 (15): p.1731-42.].
The conventional P PAR-gamma agonist of extensive use comprises troglitazone, rosiglitazone, pioglitazone etc. clinically at present.Troglitazone is promptly stopped using because find serious liver toxicity after previous generation soon.Although rosiglitazone, the pioglitazone activity is better than troglitazone and liver toxicity is little, still there is liver injury in prolonged application, water-sodium retention, weight increase and increase untoward reaction such as heart failure incidence rate [adverse effect magazine, the 137th page of the second phase in 2004; 418 pages of 2002 the 6th phases].
Therefore seek a kind of pharmaceutical composition that contains the thiazolidinediones medicine, early intervention delays the polycystic kidney disease progress, reduces its relevant untoward reaction simultaneously, seems necessary.
Summary of the invention
Researcher of the present invention is found by animal experiment and clinical research: the thiazolidinediones medicine, comprise troglitazone (troglitazone), rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), ciglitazone (ciglitazone) and englitazone (englitazone) etc., unite use with the diuretic amiloride hydrochloride and can treat multicystic kidney disease, and reduced the untoward reaction of thiazolidinediones medicine.
Study us by experiment and find, rosiglitazone and amiloride hydrochloride coupling all can delay kidney of rats function progress, reduce albuminuria, reduce two cyst of kidney sizes and volume; Pharmaceutical intervention 5 months does not see that it influences rat body weight, blood pressure, blood glucose, blood fat, liver function, hematuria electrolyte etc.In the drug combination group, the effect of this group of amiloride+rosiglitazone (0.35mg/kg.d+0.56mg/kg.d) obviously is better than other and closes the medicine group.Concrete experimental result is seen embodiment 1.
In fact, complication such as the weight increase that rosiglitazone causes, edema and its increase renal tubular epithelial sodium channel are open, and water sodium absorbs heavily that to increase the water-sodium retention that causes relevant.Amiloride hydrochloride is a kind of clinical isokalaemic diuretic commonly used, as Na
+/ H
+The exchange blocker, it is open to suppress the epithelium sodium channel, and effect is steady, and side effect is little, and prolonged application is safe.Because the multicystic kidney disease patient usually needs to take medicine for a long time even all the life, so the safety of medicine seems particularly important in this class crowd.By rosiglitazone and amiloride hydrochloride coupling, strengthened therapeutic effect, reduce untoward reaction simultaneously, for early this type of medicinal application being had very important practical sense in the ADPKD clinical treatment.
Therefore, based on above-mentioned discovery, the invention provides a kind of pharmaceutical composition for the treatment of multicystic kidney disease, it comprises: diuresis class medicine A) thiazolidinediones medicine, and B).
In the pharmaceutical composition of the present invention, diuresis class medicine, including, but not limited to: Potassium-sparing diuretic amiloride hydrochloride, triamterene, spironolactone, thiazide diuretic such as hydrochlorothiazide, methyclothiazide, benzthiazide, polythiazide, bemetizide, loop diuretic such as furosemide, azosemide, bumetanide, and their pharmaceutically useful salt, preferred amiloride hydrochloride, triamterene, hydrochlorothiazide, bumetanide and their pharmaceutically useful salt.Preferred especially amiloride hydrochloride and officinal salt thereof.
In pharmaceutical composition of the present invention, the thiazolidinediones medicine is selected from rosiglitazone, troglitazone, pioglitazone, ciglitazone, englitazone and their pharmaceutically useful salt.Preferred rosiglitazone, troglitazone, pioglitazone and their pharmaceutically useful salt.Preferred especially rosiglitazone and pharmaceutically useful salt thereof.
Pharmaceutically useful salt of the present invention comprises the salt that diuresis class medicine and thiazolidinediones medicine and mineral acid or organic acid form, for example the salt that forms with hydrochloric acid, bromine hydracid, iodine hydracid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, the acid of Chinese holly edge, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-methyl benzenesulfonic acid.
In a preferred embodiment of the present invention, the salt of particularly preferred diuresis class medicine and thiazolidinediones medicine is hydrochlorate, maleate, fumarate, Chinese holly edge hydrochlorate, citrate, succinate, tartrate, pantothenate or the malate of amiloride hydrochloride and rosiglitazone.
In pharmaceutical composition of the present invention, the weight ratio of diuresis class medicine and thiazolidinediones medicine is 1: 0.01-40 is preferably 1: 0.01-30, more preferably 1: 0.1-20, more preferably 1: 0.1-10 is preferably 1: 0.1-5 especially.
In pharmaceutical composition of the present invention, a particularly preferred pharmaceutical composition or its officinal salt are the pharmaceutical compositions that rosiglitazone maleate and amiloride hydrochloride are combined to form, wherein the weight ratio of amiloride hydrochloride and rosiglitazone maleate is 1: 0.01-40, be preferably 1: 0.01-30, more preferably 1: 0.1-20, more preferably 1: 0.1-10 is preferably 1: 0.1-5 especially.
Pharmaceutical composition of the present invention can be separately or preferred and pharmaceutically suitable carrier, excipient or mixing diluents, and the administration of pharmacy standard and the mammal of establishing criteria comprise the mankind.
Therefore, another aspect of the present invention provides a kind of pharmaceutical preparation, and it contains above-mentioned diuresis class medicine and above-mentioned thiazolidinediones medicine or its pharmaceutically useful salt as active component and one or more pharmaceutically suitable carrier.The weight ratio of wherein diuresis class medicine and thiazolidinediones medicine or its salt is 1: 0.01-40 is preferably 1: 0.01-30, more preferably 1: 0.1-20, more preferably 1: 0.1-10 is preferably 1: 0.1-5 especially.
In pharmaceutical preparation of the present invention, a particularly preferred example is to contain the pharmaceutical preparation of the pharmaceutically useful salt of rosiglitazone and amiloride hydrochloride or its as active component, wherein the weight ratio of amiloride hydrochloride and rosiglitazone is 1: 0.01-40, be preferably 1: 0.01-30, more preferably 1: 0.1-20, more preferably 1: 0.1-10 is preferably 1: 0.1-5 especially.
Pharmaceutical preparation Orally-administrable of the present invention or parenteral.Parenteral comprises vein, intramuscular, peritoneum, subcutaneous, rectum and local route of administration.
Pharmaceutical preparation of the present invention can be the form that is suitable for orally using, for example tablet, slow releasing tablet, lozenge, aqueous solution or oil suspension, dispersion powder or granule, emulsion, hard capsule or soft capsule, syrup, elixir etc.
The preparation of the present invention that is used to orally use can make according to any known method that this area is used to prepare combination of oral medication, and such compositions can comprise one or more and be selected from following material: sweeting agent, correctives, coloring agent and antiseptic, and to provide pharmacy attractive in appearance and agreeable to the taste preparation.
Tablet contains active component and the nontoxic pharmaceutically acceptable excipient that be suitable for prepare tablet blended with it.These excipient can be: inert filler such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; Granulation agent and disintegrating agent be microcrystalline Cellulose, sodium carboxymethyl cellulose, corn starch or alginic acid for example; Binding agent is starch, gelatin, polyvinylpyrrolidone or Radix Acaciae senegalis for example; With lubricant for example magnesium stearate, stearic acid or Pulvis Talci.
Tablet can be not coating or can be by technology well known in the art with its coating with the taste beastly of masking agents or postpone it in gastrointestinal disintegrate and absorption, and in the longer time, keep lasting effect thus.For example, can use for example for example ethyl cellulose, cellulose acetate-butyrate of hydroxypropyl emthylcellulose or hydroxypropyl cellulose or time delay material of water solublity taste masked material.
Oral formulations of the present invention can also provide with hard gelatin capsule, wherein for example calcium carbonate, calcium phosphate and Kaolin mix active component with the inert solid filler, or provide active component and water-solubility carrier for example Oleum Arachidis hypogaeae semen, liquid paraffin or mixed with olive oil of Polyethylene Glycol or oil medium for example wherein with Perle.
Aqueous suspension of the present invention contains active substance and the excipient or the dispersant that are suitable for prepare aqueous suspension blended with it.Described excipient comprises: suspensoid is sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl emthylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and Radix Acaciae senegalis for example.Described dispersant can be for example condensation product of lecithin or alkylene oxide and fatty acid of natural phospholipid, Myrj 45 for example, or the condensation product of alkylene oxide and the long chain aliphatic rare oxygen base of 17 second spermol for example, perhaps alkylene oxide with derived from fat and and the condensation product of the partial ester of hexitol, for example polyoxy ethane sorbitol monooleate.
Aqueous suspension of the present invention can also contain one or more antiseptic for example ethylparaben or P-hydroxybenzoic acid n-propyl, one or more can coloring agent, one or more correctivess and one or more sweeting agents be sucrose, glucide or aspartame for example.
Oil suspension of the present invention can be by being suspended in active component vegetable oil for example in Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or the Oleum Cocois, and perhaps mineral oil is for example prepared in the liquid paraffin.Oil suspension can contain thickening agent for example Cera Flava, hard paraffin or spermol.Also can add for example above-mentioned sweeting agent of sweeting agent and correctives agreeable to the taste oral formulations is provided.These drug combination preparations can for example butylated hydroxyanisol or alpha-tocopherol be preserved by adding antioxidant.
Dispersion powder of the present invention and granule prepare aqueous suspension by adding entry when being suitable for using.It provides and dispersant, suspending agent and the blended active component of one or more antiseptic.Those that the suitable dispersant and the example of suspensoid are above to be mentioned.Can also there be other excipient for example sweeting agent, correctives and coloring agent.These compositionss can by add antioxidant for example ascorbic acid preserve.
Pharmaceutical composition of the present invention can also be the form of O/w emulsion.Oil phase can be for example olive oil or an Oleum Arachidis hypogaeae semen of vegetable oil, or mineral oil for example liquid paraffin or these oily mixture.Suitable emulsifying agent is a natural phospholipid, as soybean lecithin with derived from the ester or the partial ester of fatty acid and hexitol anhydride, the for example condensation product of dehydrated sorbitol mono-fatty acid ester and described partial ester and alkylene oxide, for example Tween-81.Described emulsion can also comprise sweeting agent, correctives, antiseptic and antioxidant.
Syrup of the present invention and elixir can for example glycerol, propylene glycol, Sorbitol or sucrose be prepared with sweeting agent.Such preparation also can comprise buffer agent, antiseptic, correctives and coloring agent and antioxidant.
Pharmaceutical preparation of the present invention can be the form of aseptic injection aqueous solution.Spendable carrier or solvent comprise water, Ringer's solution and isotonic sodium chlorrde solution.
Aseptic injection preparation of the present invention can also be the oil-in-water microemulsion of aseptic injection, and wherein active component is dissolved in the oil phase.For example, can at first active component be dissolved in the mixture of soybean oil and lecithin.Oil solution can be incorporated in the mixture of water and glycerol then, and be processed to form microemulsion.
Injection solution of the present invention or microemulsion can be incorporated in patient's blood flow by local bolus injection.Perhaps, maybe advantageously use described solution or microemulsion in the mode that can keep the circulation composition of the constant present composition.In order to keep such constant density, can use continuous vein delivery apparatus.
Pharmaceutical preparation of the present invention can be to be used for the sterile injectable water of intramuscular and subcutaneous administration or the form of oil suspension.Can use suitable dispersant mentioned above and suspensoid to prepare this suspension according to methods known in the art.Aseptic injection can also be aseptic injectable solution or the suspension that is dissolved in acceptable nontoxic diluent of parenteral or the solvent.The solution in 1,3 butylene glycol for example.In addition, aseptic expressed oi is commonly used for solvent or suspension medium.The expressed oi that is used for any gentleness of this purpose can use, and comprises synthetic monoglyceride or diglyceride.In addition, fatty acid for example oleic acid also can be used for preparing injection.
Pharmaceutical preparation of the present invention can also be the suppository form that is used for the medicine rectally.It can make by pharmaceutical composition of the present invention is mixed with suitable non-irritating excipient.Such excipient is solid at normal temperatures.But under rectal temperature, be liquid, so it can and discharge active medicine in the rectum fusing.Described non-irritating excipient comprises Oleum Cocois, glycerin gelatine, the mixture of hydrogenated vegetable oil, different molecular weight polyethylene glycol and the fatty acid ester of Polyethylene Glycol.
Use for the part, can adopt cream, unguentum, gel, solution or the suspension etc. that contain pharmaceutical composition of the present invention.Topical application also comprises collutory solution and collutory.
Pharmaceutical composition of the present invention can perhaps can use the well-known per nasal patch of those skilled in the art form percutaneous dosing by using suitable intranasal carrier and delivery apparatus with the intranasal form administration.For with the transdermal delivery system administration, during whole dosage regimen, dosage should be successive rather than intermittence certainly.
Another aspect of the present invention has provided a kind of method of useful in preparing drug formulations, comprises above-mentioned pharmaceutical composition of the present invention in one or more above-mentioned pharmaceutically useful carrier or mixed with excipients.
Of the present invention is that pharmaceutical composition of the present invention is used to prepare the medicine for the treatment of multicystic kidney disease more on the one hand.
The specific embodiment
The following examples only are used for further explaining the present invention, rather than limitation of the scope of the invention.
Embodiment 1:
Observe prolonged application rosiglitazone, amiloride and the two and share kidney protective effect and toxic and side effects ADPKD animal model Han:SPRD rat.
Experiment material and method
(Mayo Clinic MedicalCenter) introduces ADPKD animal model Han:SPRD rat from medical center, U.S. Mayo, now at The 2nd Army Medical College Experimental Animal Center Steady breed nearly 7 years.The inventor with Han:SPRD male 3 age in week heterozygote cy/+ rat serve as to intervene object, set up negative control group, rosiglitazone group (0.56mg/kg.d), 5 groups of amiloride group (0.35mg/kg.d) and drug combinations: amiloride+rosiglitazone (0.35mg/kg.d+0.56mg/kg.d), amiloride+rosiglitazone (0.175mg/kg.d+0.56mg/kg.d), amiloride+rosiglitazone (0.35mg/kg.d+1.12mg/kg.d), amiloride+rosiglitazone (0.35mg/kg.d+0.28mg/kg.d), amiloride+rosiglitazone (0.70mg/kg.d+0.56mg/kg.d).Gastric infusion 5 months, the variation of rat body weight, food-intake, blood pressure after the observation Drug therapy, detect hepatic and renal function, 24h urine protein quantitation, osmotic pressure of urine, the electrolytical variation of hematuria, after rat is put to death, observe conscience kidney volume, weight, renal function progress and drug side effect situation after the comprehensive assessment pharmaceutical intervention.
Experimental result
1, renal function BUN value: rosiglitazone group and two drug combination groups all significantly are lower than negative control group, remarkable significant difference are arranged, P＜0.01.See attached list 1
2,24h urine protein quantitation: rosiglitazone group and two drug combination groups all significantly are lower than negative control group, remarkable significant difference are arranged, P＜0.01.See attached list 2
3, two kidney weights, kidney weight/body weight: rosiglitazone group and two drug combination groups all significantly are lower than negative control group, remarkable significant difference are arranged, P＜0.01.See attached list 3
4, cardiac weight, heart weight/body weight: the rosiglitazone group is significantly higher than negative control group, and remarkable significant difference is arranged, P＜0.01.See attached list 3
5, liver weight, liver weight/body weight: the rosiglitazone group is significantly higher than negative control group, and remarkable significant difference is arranged, P＜0.01.See attached list 3
6, body weight, osmotic pressure of urine, blood pressure, blood glucose, blood fat, liver function ALT, AST, and hematuria sodium, potassium, chlorine, calcium: diversity on the no statistics between each group.The result slightly
7, in the drug combination group, first group every index such as renal function BUN value, 24h urine protein quantitation, kidney weight/body weight, heart weight/body weight, liver weight/body weight all significantly are better than other and close the medicine group, have significant difference, and P＜0.01 sees Table 1,2,3.
Above-mentioned result of the test clearly illustrates that: rosiglitazone and amiloride coupling all can significantly delay kidney of rats function progress, reduce albuminuria, and two cyst of kidney sizes and volume reduce; Pharmaceutical intervention 5 months does not see that it influences rat body weight, blood pressure, blood glucose, blood fat, liver function, hematuria electrolyte etc.; Rat heart, liver volume and weight increase after the rosiglitazone intervention, and the coupling amiloride can improve the influence of rosiglitazone intervention to conscience.
The progress of renal function BUN after table 1 pharmaceutical intervention
| Group | Renal function BUN value (mmol/L) | |||||
| Baseline | After January | After February | After March | After April | After May | |
| Negative control group rosiglitazone group amiloride group amiloride+rosiglitazone (0.35mg/kg.d+0.56mg/kg.d) amiloride+rosiglitazone (0.175mg/kg.d+0.56mg/kg.d) amiloride+rosiglitazone (0.35mg/kg.d+1.12mg/kg.d) amiloride+rosiglitazone (0.35mg/kg.d+0.28mg/kg.d) amiloride+rosiglitazone (0.70mg/kg.d+0.56mg/kg.d) | 5.28± 1.47 5.69± 0.87 5.22± 1.03 5.05± 0.79 5.12± 0.80 5.25± 0.74 5.30± 0.82 5.45± 1.01 | 7.63± 1.96 7.86± 1.25 7.05± 0.59 7.03± 1.72 7.56± 1.81 7.41± 1.49 7.44± 1.78 7.19± 1.96 | 13.27± 1.83 12.75± 1.52 13.36± 0.82 12.87± 3.39 12.90± 2.85 12.84± 3.47 12.80± 2.87 12.91± 1.18 | 15.40± 2.40 13.85± 2.6* 14.71± 2.72 13.24± 2.0* 13.47± 2.7 13.82± 2.0 13.71± 1.9 13.67± 2.9 | ?17.55±?1.49?12.8±?1.4**?16.79±?1.41?13.1±?2.0**?13.52±?1.76?13.49±?2.01?13.80±?1.78?13.90±?2.04 | 18.17 ±1.51 13.1± 1.9** 17.60 ±1.57 13.3± 1.5** 13.78 ±1.77 13.19 ±1.07 13.27 ±1.14 13.55 ±1.19 |
*P＜0.05，**P＜0.01
The variation of 24h urine protein after table 2 pharmaceutical intervention
| Group | Urine protein (mg/24h) | |||||
| Baseline | After January | After February | After March | After April | After May | |
| Negative control group rosiglitazone group amiloride group amiloride+rosiglitazone (0.35mg/kg.d+0.56mg/kg.d) amiloride+rosiglitazone (0.175mg/kg.d+0.56mg/kg.d) amiloride+rosiglitazone (0.35mg/kg.d+1.12mg/kg.d) amiloride+rosiglitazone (0.35mg/kg.d+0.28mg/kg.d) amiloride+rosiglitazone (0.70mg/kg.d+0.56mg/kg.d) | Fail to predict to fail to predict to fail to predict to fail to predict to fail to predict to fail to predict to fail to predict and fail to predict | ?125±31?125±19?127±21?129±20?129±18 127±18 130±26 129±24 | ?156±18?161±21?159±31?164±23?162±28 159±19 154±22 158±30 | ?179±42?159±22?160±17?164±27?167±26 170±22 170±36 169±28 | 183±35154±20*157±24159±16146±17*?150±18?178±17?174±16 | ?181±29?153±18**?160±25?155±20?142±14** 149±27 176±19 158±19 |
*P＜0.05，**P＜0.01
The variation of conscience kidney weight after table 3 pharmaceutical intervention
| Group | Two kidneys heavy (g) | The heart heavy (g) | Liver heavy (g) | Body weight (g) | Kidney weight/body weight (%) | Heart weight/body weight (%) | Liver weight/body weight (%) |
| Negative control group rosiglitazone group amiloride group amiloride+rosiglitazone (0.35mg/kg.d+0.56mg/kg.d) amiloride+rosiglitazone (0.175mg/kg.d+0.56mg/kg.d) amiloride+rosiglitazone (0.35mg/kg.d+1.12mg/kg.d) amiloride+rosiglitazone (0.35mg/kg.d+0.28mg/kg.d) amiloride+rosiglitazone (0.70mg/kg.d+0.56mg/kg.d) | ?8.06±?1.71?6.25±?1.05**?7.89±?0.52?6.13±?1.49**?6.98±?0.91?6.46±?1.12?6.42±?1.55?6.36±?0.68 | 3.44± 0.63 4.22± 0.42** 3.31± 0.52 3.68± 0.49 3.66± 0.50 3.51± 0.35 3.49± 0.49 3.76± 0.37 | 13.4± 2.8 17.6± 2.7* 14.2± 2.0 14.6± 1.9 15.47± 2.3 14.77± 1.8 13.79± 2.4 14.56± 2.7 | ?414±36?406±27?400±20?426±39?431±32?428±34?401±29?427±30 | 1.94 1.53** 1.97 1.44** 1.62 1.51 1.6 1.49 | ?0.83?1.03**?0.82 .86?0.85?0.82?0.87?0.88 | 3.23 4.33** 3.55 3.42 3.59 3.45 3.44 3.41 |
*P＜0.05，**P＜0.01
Embodiment 2: compound recipe (amiloride hydrochloride+rosiglitazone maleate) solution
Prescription: amiloride hydrochloride 2.5g
Rosiglitazone maleate 5g
Sodium lauryl sulphate 0.1g
Distilled water is in right amount to 10000m1
Technology: get above-mentioned amiloride hydrochloride, rosiglitazone maleate and sodium lauryl sulphate, after the adding distil water 1000ml dissolving, adding distil water to 10000ml promptly.
Embodiment 3: compound recipe (amiloride hydrochloride+rosiglitazone maleate) syrup
Prescription: amiloride hydrochloride 1g
Rosiglitazone maleate 2g
Distilled water 1500ml
Simple syrup adds to 10000ml
Technology: get amiloride hydrochloride, rosiglitazone maleate is dissolved in the distilled water, adds simple syrup to full dose, promptly.
Embodiment 4: compound recipe (amiloride hydrochloride+rosiglitazone maleate) injection
Prescription: amiloride hydrochloride (principal agent) 2g
Rosiglitazone maleate (principal agent) 4g
Disodium edetate (chelating agent) 5g
Hydrochloric acid (PH regulator) 50g
Sodium sulfite (antioxidant) 10g
Water for injection adds to 10000ml
Technology: in the preparation container, add recipe quantity 80% water for injection, add amiloride hydrochloride, rosiglitazone maleate dissolving after, gradation slowly adds sodium bicarbonate, be stirred to dissolving fully, add disodium edetate and hydrochloric acid solution that preparation configures, stir, regulate medicinal liquid PH6.0～6.2, water for injection is to full dose, consider device and membrane filter filtration with incipient fusion glass, and embedding under stream of nitrogen gas, at last in 100 ℃ of flowing steam 15min sterilizations.
Embodiment 5: compound recipe (amiloride hydrochloride+rosiglitazone maleate) transfusion
Prescription: amiloride hydrochloride 2g
Rosiglitazone maleate 4g
Sodium sulfite (antioxidant) 10g
Water for injection adds to 100000ml
Technology: get the hot water for injection of about 800ml, press recipe quantity and drop into amiloride hydrochloride, rosiglitazone maleate, stirring makes molten entirely, add antioxidant, and with about 10% hydrochloric acid accent PH to 6.0, it is an amount of to add the injection water, adds 0.15% activated carbon decolorizing again, be filtered to clear and bright, embedding is in the 100ml infusion bottle, and inflated with nitrogen is jumped a queue, roll lid, get final product in 100 ℃ of sterilization 30min.
Embodiment 6: injection use compound (amiloride hydrochloride+rosiglitazone maleate) sterile freeze-drying preparation
Prescription: amiloride hydrochloride 2mg
Rosiglitazone maleate 4mg
Gelatin hydrolysate (filler) 5ml
Mannitol (filler) 10mg
Calcium gluconate (filler) 1mg
Cysteine (stabilizing agent) 0.5mg
Technology: with above-mentioned each composition with the dissolving of an amount of injection water after, aseptic filtration is installed in the ampoule, seals after the lyophilization, leak test promptly.
Embodiment 7: compound recipe (amiloride hydrochloride+rosiglitazone maleate) granule (thousand bags of amounts)
Prescription: amiloride hydrochloride 2.5g
Rosiglitazone maleate 4g
PVP?K30 10g
Cross-linked pvp 10g
Lactose 1500g
Sucrose 500g
Citric acid 20g
Technology: amiloride hydrochloride, rosiglitazone maleate are crossed 80 mesh sieves,, add the PVPK30 slurry and make soft material with lactose, sucrose mixing, after the granulation of 14 mesh sieves, put 70 ℃～80 ℃ dry backs in 12 mesh sieve granulate, behind adding cross-linked pvp and the citric acid mixing, pack gets final product.
Embodiment 8: compound recipe (acid hydrochloride salt amiloride+rosiglitazone maleate) sheet
Prescription: acid hydrochloride salt amiloride 2.5g
Rosiglitazone maleate 4g
Starch 400g
10% starch slurry 24g
Dried starch 23g
Magnesium stearate 3g
Make 1000
Technology: amiloride hydrochloride, rosiglitazone maleate are crossed 80 mesh sieves,, add starch slurry and make soft material, after granulating with 14 mesh sieves, put 70 ℃～80 ℃ dry backs in 12 mesh sieve granulate with the starch mixing, behind adding dried starch and the magnesium stearate mixing, tabletting, promptly.
Embodiment 9: compound recipe (bumetanide+rosiglitazone maleate) sheet
Prescription: bumetanide 5mg
Rosiglitazone maleate 8mg
Citric acid 10mg
Microcrystalline Cellulose 200mg
Lactose 180mg
Starch slurry is an amount of
Magnesium stearate 2mg
Technology: with amiloride hydrochloride, rosiglitazone maleate and lactose, microcrystalline Cellulose mixing, citric acid are dissolved in the starch slurry, and the system soft material is granulated, drying, and granulate adds the magnesium stearate mixing, and tabletting is promptly.
Embodiment 10: compound recipe (acid hydrochloride salt amiloride+rosiglitazone maleate) soft gelatin capsule
Prescription: 1 part of amiloride hydrochloride
2 parts of rosiglitazone maleate
100 parts in gelatin
55～66 parts of glycerol
120 parts in water
Cod-liver oil or refining of edible vegetable oil are an amount of
Technology: get amiloride hydrochloride and rosiglitazone maleate, add cod-liver oil or refining of edible vegetable oil (about 0 ℃, sloughing hard fat), dissolving, and adjustment concentration to the hydrochloric amiloride of every ball is 90%～120% of a labelled amount, contain rosiglitazone maleate and should be more than 90%～120% of labelled amount, stand-by as medicinal liquid; Other gets glycerol and water is heated to 70 ℃～80 ℃, add gelatin, stirring is dissolved, and is incubated 1～2 hour, remove the foam of come-up, filtering, add dropping-pill machine system, is liquid coolant with the liquid paraffin, collect the soft gelatin capsule of condensation, wipe adherent liquid coolant away with gauze, at room temperature blew a cold wind over 4 hours, be put in 25～35 ℃ and dried by the fire 4 hours down, again through twice (each 3～5min) of petroleum ether, remove soft gelatin capsule outer liquid paraffin body, reuse 95% washing with alcohol was once dried about 2 hours at 30～35 ℃ at last, screening, quality inspection, packing, promptly.
Embodiment 11: compound recipe (amiloride hydrochloride+rosiglitazone maleate) bolt
Prescription: amiloride hydrochloride 1.5g
Rosiglitazone maleate 3g
Ethyl hydroxybenzoate 0.5g
50% ethanol 100ml
Polyoxyethylene sorbitan monoleate 50ml
Glycerin gelatine adds 3000g
Make 1000 pieces altogether
Technology: get amiloride hydrochloride, rosiglitazone maleate adds ethanol and boils dissolving, add the ethyl hydroxybenzoate stirring and dissolving, add an amount of glycerol again and stir evenly, slowly add in the gelatin glycerol substrate heat preservation for standby use.Add Polysorbate, after stirring, add in the above-mentioned insulation substrate under slowly stirring, fully stir, be incubated 55 ℃, irritate mould, every piece heavy 4g.
Claims (12)
1. a pharmaceutical composition for the treatment of multicystic kidney disease is characterized in that said composition comprises: a) amiloride or its pharmaceutically useful salt, and b) rosiglitazone or its pharmaceutically useful salt, wherein a) and b) weight be 1: 0.1-5.
2. the pharmaceutical composition of claim 1, wherein said salt are the salt that rosiglitazone and amiloride and mineral acid or organic acid form.
3. the pharmaceutical composition of claim 2, wherein said salt are the salt that rosiglitazone and amiloride and hydrochloric acid, hydrobromic acid, iodine hydracid, sulphuric acid, nitric acid, phosphoric acid, acetic acid, maleic acid, fumaric acid, citric acid, citric acid, oxalic acid, succinic acid, tartaric acid, malic acid, mandelic acid, trifluoroacetic acid, pantothenic acid, methanesulfonic acid and p-methyl benzenesulfonic acid form.
4. the pharmaceutical composition of claim 3, the salt that it is characterized in that wherein said rosiglitazone is the rosiglitazone maleate, the salt of described amiloride is amiloride hydrochloride.
5. pharmaceutical preparation for the treatment of multicystic kidney disease is characterized in that pharmaceutical composition that it contains among the claim 1-4 each is as active component and one or more pharmaceutically useful carriers.
6. the pharmaceutical preparation of claim 5 is characterized in that wherein said pharmaceutical preparation is oral administration form, drug administration by injection form or topical form.
7. the pharmaceutical preparation of claim 6 is characterized in that wherein said oral administration form comprises ordinary tablet, slow releasing tablet, granule, hard or soft capsule, solution, Emulsion.
8. the pharmaceutical preparation of claim 6 is characterized in that the aqueous solution that wherein said drug administration by injection form is an aseptic injection or the oil-in-water microemulsion or the injectable sterile powder of aseptic injection.
9. the pharmaceutical preparation of claim 6 is characterized in that wherein said topical form is patch, suppository, cream, unguentum, gel, solution or suspension.
10. one kind prepares each the method for pharmaceutical preparation of claim 5-9, it is characterized in that the pharmaceutically useful carrier of wherein said active component and one or more is mixed.
11. the application of each pharmaceutical composition in the medicine of preparation treatment multicystic kidney disease among the claim 1-4.
12. the described application of claim 11 is characterized in that described medicine is with oral administration form, drug administration by injection form or topical form administration.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
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| CN2007100467540A CN101396560B (en) | 2007-09-28 | 2007-09-28 | Medicine composition for treating polycystic kidney disease and use thereof |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2007100467540A CN101396560B (en) | 2007-09-28 | 2007-09-28 | Medicine composition for treating polycystic kidney disease and use thereof |
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| CN101396560B true CN101396560B (en) | 2011-11-09 |
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| CN103251954A (en) * | 2013-05-22 | 2013-08-21 | 罗国安 | Diabetes treating compound medicine for reducing side effect of rosiglitazone and preparation method thereof |
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Non-Patent Citations (2)
| Title |
|---|
| YouFei Guan et al.Thiazolidinediones expand body fluid volume through PPARγ stimulation of EnaC2mediated renal salt absorption.《Nature medicine》.2005,第11卷(第8期), * |
| 戴兵.PPAR-γ激动剂治疗常染色体显性多囊肾病的实验研究.《中国优秀博硕士学位论文全文数据库(博士)医药卫生科技辑》.2007,(第4期),第87页第3段,第89页第2段. * |
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