CN101002940B - Medicine composition for treating polycystic renal disease and its uses - Google Patents
Medicine composition for treating polycystic renal disease and its uses Download PDFInfo
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- CN101002940B CN101002940B CN2006100233986A CN200610023398A CN101002940B CN 101002940 B CN101002940 B CN 101002940B CN 2006100233986 A CN2006100233986 A CN 2006100233986A CN 200610023398 A CN200610023398 A CN 200610023398A CN 101002940 B CN101002940 B CN 101002940B
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Abstract
The present invention relates to a composite medicine for treating polycystic kidney disease. The composite medicine for treating polycystic kidney disease contains the epoxidase 2(COX-2) specific depressant and the thiazolidbione-type medicine. The optimal combination provided by the invention is as follows: the epoxidase 2(COX-2) specific depressant is selected from celecoxib, and the thiazolidbione-type medicine selected from rosiglitazone. The therapeutic alliance of the rosiglitazone and the celecoxib is also confirmed by in vivo experiment to improve polycystic kidney disease Han; the curative effect of SPRD rats course and histological lesions is better than a single drug used. With low toxicity, obvious effect better than using a single drug, the composite medicine provided by the present invention is an expecting therapeutic drug of polycystic kidney disease.
Description
Technical field
The present invention relates to drug world, specifically, relate to a kind of pharmaceutical preparation that is used to treat the pharmaceutical composition and the application thereof of MCKD and contains it.
Background technology
(autosomal dominant polycystickidney disease ADPKD) is modal heritability nephropathy to the autosomal dominant MCKD, and sickness rate is about 1/400～1/1000 in the world wide.Its main pathological characters is that bilateral kidney cortex and medullary substance have a plurality of fluidity cysts to form and carrying out property is grown up, and the 26S Proteasome Structure and Function of final failure kidney causes renal failure.ADPKD also is a kind of systemic disease, except that involving kidney, causes also that liver, pancreatic capsule are swollen, organ disease (Extrarenalmanifestations of ADPKD, Perrone RD, Kidney Int.1997 such as valvulopathy and cerebral aneurysm; 51 (6): 2022-36).China has 1,500,000 ADPKD patients approximately at present, wherein 50% after 60 years old, gets into end stage renal failure, accounts for the end stage renal failure cause of disease 5～10%.This shows that ADPKD is the hereditary of one type of serious harm health.
Cause that two Disease-causing gene PKD1 of ADPKD and PKD2 lay respectively on the 16th and the 4th chromosome, are cloned at 1994 and 1996 in succession.Discover that 85% patient is because the PKD1 gene mutation, 10～15% patient is because the PKD2 gene mutation causes, does not find among the part patient that possibly there is other Disease-causing gene (like PKD3) in two genoids sudden change prompting, but no-fix still at present.The pathogenesis of ADPKD is comparatively complicated; Its molecule pathogenesis and pathophysiological change can be summarized as follows: ADPKD patient causes pair of alleles (PKD1 or PKD2) heterozygous mutant to occur the period of embryo through direct heredity or spontaneous mutation; The birth back is individual under environmental factors effects such as toxin, infection; Kidney part segment body cell generation homozygous mutation (two-hit); Make its many capsules of encoding proteins albumen-1 and many capsules albumen-2 dysfunction; Cause that cell cycle regulating and endocellular metabolism are unusual, cause cyst that (The molecular basis of focal cystformation in human autosomal dominant polycystic kidney disease type I. takes place; Qian F, Watnick TJ, Onuchic LF, Germino GG.; Cell.1996; 87 (6): 979-87).The ADPKD pathophysiological change has following characteristics: (1) epithelial cell abnormality proliferation and apoptosis: MCKD is as a kind tumor disease; Cyst epithelium cell proliferation and apoptotic index all obviously increase; Multiple growth factor receptors up-regulated; The receptors bind of mitogeneic factor that contains in the capsule liquid and the dislocation of renal tubules chamber face forms autocrine, paracrine ring, stimulates cyst to continue to increase; (2) liquid secretion with gather unusual: there is a kind of Cl in cyst lining epithelial cells chamber face
-Secretion transhipment son is called cystic fibrosis and strides the film regulon (cystic fibrosis transmembrane regulator, CFTR), under cyclic adenosine monophosphate (cAMP) stimulated, CFTR secreted Cl
-Increase, through charge effect, Na
+Closely connect the entering blister cavities through iuntercellular.Under the osmotic pressure effect, water gets into blister cavities from epithelial cell, causes liquid in the blister cavities accumulated, and carrying out property of cyst is grown up; (3) extracellular matrix is reinvented and interstitial fibrosis: immunohistochemical study finds that fibrin, I, IV collagen type and laminin increase in the cyst of kidney tissue; The heparin sulfate glucosides lacks; Cause that extracellular matrix reinvents; The renal tubular basement membrane compliance reduces, and is beneficial to carrying out property of cyst and grows up, and the disease later stage is often with tangible interstitial fibrosis; (4) cell polarity changes companion's poorly differentiated: cell polarity changes makes Na
+-K
+-ATP enzyme dystopy is in tubule lumen face; Constantly to blister cavities endocrine liquid; Multiple differentiation and maturation index is lost (Recent advances in understanding thepathogenesis of polycystic kidney disease:therapeuticimplications.; Cowley BD Jr., Drugs 2004; 64:1285-1294).
Because ADPKD harm is big, pathogenesis is complicated, make its early treatment quite difficult, still there are not effective intervening measure and medicine clinically so far.In case it develops into end stage renal failure, can only depend on kidney replacement therapy (dialysis, renal transplantation).Therefore, how delaying the MCKD progress through early stage pharmaceutical intervention is a difficult problem that needs to be resolved hurrily (Therapies toslow polycystic kidney disease, Torres VE., Nephron Exp Nephrol.2004; 98 (1): e1-7).
Cycloxygenase (COX) claim PGH2 synzyme, prostaglandin synthase again, is the crucial rate-limiting enzyme in the synthetic initial step of prostaglandin (PGs).Kidney especially renal medulla is one of synthetic most active tissue of PGs.The synthetic main position of medullary substance PGs is MCD epithelial cell and interstitial cell, mainly participates in water-electrolyte metabolism.Prostaglandin and receptors bind are through regulating cAMP and Ca in the cell
2+The biological effect that the level performance is different.The COX product like PGE1, PGE2 and PGI2, can promote the feritin of whole animal, ex vivo perfusion kidney and the glomerule that exsomatizes to discharge.PGs also participates in mesangial cell propagation, extracellular matrix is synthetic and the secretion of other vaso-active substances.According to the difference of 26S Proteasome Structure and Function, COX can be divided into two kinds of isozymes, is called structural type COX-1 and induction type COX-2 respectively.The former distributes extensively, and the latter is local distribution only, inflammatory stimulus like, short tumor agent and the effect of various kinds of cell somatomedin under, expressing sharply increases 10-80 and does not doubly wait.Think that at present the signal of above-mentioned stimulation starts through tyrosine kinase receptor and two approach of Reserpine receptor, signal transmission paths such as activated protein kinase A, APC Protein kinase C, JAK-STAT cause that the generation of cell proliferation and extracellular matrix increases then.Other has the author to think that COX-2 activates the EP3 receptor through increasing the generation of PGE2 in glomerulonephritis, raises pathogenic α and integrates plain the expression, thereby induce inflammation and interstitial fibrosis.Multinomial research shows that specific C OX-2 inhibitor can suppress mesangial cell propagation and extracellular matrix synthesizes, and matter inflammation and fibrosis between improvement confirm also that in experiment in vitro it can suppress tumor cell proliferations such as colon cancer, pulmonary carcinoma simultaneously, promote apoptosis.
In U.S. Patent application US2004024042, its inventor infers that the COX-2 specific inhibitor has therapeutical effect to MCKD.
Because the COX-2 specific inhibitor that gone on the market of report has cardiac toxicity in recent years, the safety of clinical extensive use COX-2 specific inhibitor there is bigger dispute.The concrete using dosage of the undeclared use of this patent COX-2 specific inhibitor treatment and prevention MCKD.
Therefore be necessary the dose therapeutically effective of further research and exploration COX-2 specific inhibitor and assess its safety, thereby seek the medicine of more effective, safer treatment MCKD.
Summary of the invention
The inventor has selected the smaller celecoxib (celecoxib of toxic and side effects in COX-2 (epoxidase 2) inhibitor; Trade name: celecoxib); Carried out the research of treatment MCKD; Find through cell experiment: the COX-2 specific inhibitor can suppress cyst lining epithelial cells propagation and promote apoptosis, and it suppresses effect and is dose dependent; And through zoopery, small dose group celecoxib (10mg/kgd) can improve ADPKD animal model Han:SPRD rat course of disease progress, renal function protecting in the demonstration.Its mechanism is that mainly celecoxib suppresses epoxidase 2 high expresseds, reduces PGE2 and discharges, and the expression of downward modulation inflammatory mediator has alleviated inflammation and interstitial fibrosis.This research is can effectively treat MCKD through experiment in vivo and vitro confirmation epoxidase inhibitor 2 with middle low dose first both at home and abroad.
Because the safety issue that specificity epoxidase inhibitor 2 exists is necessary further to study and seek the medicine that other treated and prevented MCKD more safely and effectively.
Researcher of the present invention is surprised to find that through animal experiment and clinical research: the thiazolidinediones medicine; Comprise troglitazone (troglitazone), rosiglitazone (rosiglitazone), pioglitazone (pioglitazone), ciglitazone (ciglitazone) and englitazone (englitazone) etc.; But dose dependent ground suppresses cyst lining epithelial cells propagation and promotes apoptosis; Experiment shows that it can improve the course of disease and the Histological change of ADPKD animal Han:SPRD rat in the body, can be used as the medicine of prevention and treatment MCKD fully.Purposes about thiazolidine dione compounds prevention and treatment MCKD is new, does not at home and abroad appear in the newspapers as yet in the document.
More surprisingly; Inventor of the present invention is main research platform with former ADPKD patient's cyst lining epithelial cells of being commissioned to train foster and MCKD Han:SPRD rat; The cyst lining epithelial cells and the Han:SPRD rat that confirm 3-5 generation can finely must be reflected ADPKD patient's pathophysiology characteristic, can be used as the reliable platform of estimating curative effect of medication; And find through in vitro tests with this platform: epoxidase 2 specific inhibitors and thiazolidinediones medicine have beyond thought synergism; But they are united use dose dependent ground and suppress cyst lining epithelial cells propagation, have the promotion effect of apoptosis.The present invention has compared the curative effect of different medicine compatibility method therapeutic alliances simultaneously; Discovery is united the effect of using epoxidase 2 specific inhibitors and thiazolidinediones medicine and is higher than single proliferation inhibition rate and apoptosis rate effect sum with two medicines; The low dosage drug combination is superior to heavy dose of single a kind of medicine of using, for experiment and clinical practice in the body provide reference.The present invention further confirms epoxidase 2 specific inhibitors and thiazolidinediones medicine low dosage combination use in the experiment in vivo, can significantly improve the MCKD course of disease and histologic lesion, has the good curing synergism.
Therefore, based on above-mentioned discovery, the invention provides the pharmaceutical composition of a kind of prevention and treatment MCKD, it comprises: thiazolidinediones medicine a) epoxidase 2 specific inhibitors, and b).
In the pharmaceutical composition of the present invention; The cyclooxygenase 2 specific inhibitor includes, but are not limited to: celecoxib (celecoxib), rofecoxib, para are examined former times, valdecoxib, Ai Tuokao former times, meloxicam (meloxicam), nimesulide, radicicol (radicicol) and their pharmaceutically useful salt.Preferred celecoxib, meloxicam, radicicol and their pharmaceutically useful salt.Preferred especially celecoxib.
In pharmaceutical composition of the present invention, the thiazolidinediones medicine is selected from rosiglitazone (rosiglitazone), troglitazone (troglitazone), pioglitazone (pioglitazone), ciglitazone (ciglitazone), englitazone (englitazone) and their pharmaceutically useful salt.Preferred rosiglitazone, troglitazone, pioglitazone and their pharmaceutically useful salt.Preferred especially rosiglitazone, pioglitazone and their pharmaceutically useful salt.
Pharmaceutically useful salt of the present invention comprises the salt that epoxidase 2 specific inhibitors and thiazolidinediones medicine and mineral acid or organic acid form, the salt that for example forms with hydrochloric acid, bromine hydracid, 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.
In a preferred embodiment of the present invention, the salt of preferred especially epoxidase 2 specific inhibitors and thiazolidinediones medicine is maleate, fumarate, citrate, citrate, succinate, tartrate, pantothenate or the malate of celecoxib and rosiglitazone.
In pharmaceutical composition of the present invention, the mol ratio that the cyclooxygenase 2 specificity suppresses with the thiazolidinediones medicine is 1: 0.1-40 is preferably 1: 0.25-20, more preferably 1: 0.5-10 further is preferably 1: 1-5 is preferably 1: 1-2.5 especially.
In pharmaceutical composition of the present invention; Special preferred examples is the pharmaceutical composition that celecoxib and pioglitazone or its pharmaceutically useful salt are combined to form; Wherein the mol ratio of celecoxib and pioglitazone is 1: 0.125-40 is preferably 1: 0.25-20, more preferably 1: 0.5-10; Further be preferably 1: 1-5 is preferably 1: 1-2.5 especially.
In pharmaceutical composition of the present invention; Another special preferred pharmaceutical composition is the pharmaceutical composition that celecoxib and rosiglitazone or its pharmaceutically useful salt are combined to form; Wherein the mol ratio of celecoxib and rosiglitazone is 1: (weight ratio is 1 to 0.125-40: 0.155-49.6); Be preferably 1: (weight ratio is 1 to 0.25-20: 0.31-24.8); More preferably 1: (weight ratio is 1: 0.62-12.4), further be preferably 1: (weight ratio is 1: 1.24-6.2), be preferably 1 especially: (weight ratio is 1 to 1-2.5 to 1-5 to 0.5-10: 1.24-3.1).
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 epoxidase 2 specific inhibitors and above-mentioned thiazolidinediones medicine or its pharmaceutically useful salt as active component and one or more pharmaceutically suitable carrier.Wherein to suppress the mol ratio with thiazolidinediones medicine or its salt be 1 to the cyclooxygenase 2 specificity: 0.1-40 is preferably 1: 0.25-20, more preferably 1: 0.5-10 further is preferably 1: 1-5 is preferably 1: 1-2.5 especially.
In pharmaceutical preparation of the present invention; A special preferred examples is to contain the pharmaceutical preparation of the pharmaceutically useful salt of celecoxib and pioglitazone or its as active component; Wherein the mol ratio of celecoxib and pioglitazone is 1: 0.125-40 is preferably 1: 0.25-20, more preferably 1: 0.5-10; Further be preferably 1: 1-5 is preferably 1: 1-2.5 especially.
In pharmaceutical preparation of the present invention; Another special preferred examples is the pharmaceutical composition that celecoxib and rosiglitazone or its pharmaceutically useful salt are combined to form; Wherein the mol ratio of celecoxib and rosiglitazone is 1: (weight ratio is 1 to 0.125-40: 0.155-49.6); Be preferably 1: (weight ratio is 1 to 0.25-20: 0.31-24.8); More preferably 1: (weight ratio is 1: 0.62-12.4), further be preferably 1: (weight ratio is 1: 1.24-6.2), be preferably 1 especially: (weight ratio is 1 to 1-2.5 to 1-5 to 0.5-10: 1.24-3.1).
Pharmaceutical preparation Orally-administrable of the present invention or parenteral.Parenteral comprises vein, intramuscular, abdominal cavity, 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 or soft capsule or syrup or elixir.
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, strong agent, coloring agent and the antiseptic of hiding, 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 diluent 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 through 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 inert solid diluent; Or 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 is provided 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 the 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 with 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 through 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 the for example above-mentioned sweeting agent of sweeting agent and agreeable to the taste oral formulations is provided with strong ignorant agent.These drug combination preparations can for example butylated hydroxyanisol or alpha-tocopherol be preserved through adding antioxidant.
Dispersion powder of the present invention and granule prepare aqueous suspension through adding entry when being suitable for using.It provides and dispersant, suspending agent and the blended active component of one or more antiseptic.The suitable dispersant and the instance of suspensoid be preceding text mention those.Can also there be the for example sweet ignorant agent of other excipient, correctives and coloring agent.These compositionss can through 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; Like 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 said partial ester and alkylene oxide, for example Tween-81.Said emulsion can also comprise sweeting agent, correctives, antiseptic and antioxidant.
Syrup of the present invention and elixir can be with for example glycerol, propylene glycol, Sorbitol or sucrose preparations of 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.Can oil solution 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 instil fast through the part and be incorporated in patient's blood flow.Perhaps, possibly advantageously use said solution or microemulsion with 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 solvent or the suspension medium done commonly used.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 through 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 through 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.
When pharmaceutical preparation of the present invention during to the human body administration, daily dose is usually by prescriber's decision, and dosage generally becomes with age, body weight, sex and the reaction of individual patient and the order of severity of patient's symptom.Usually, adult's dosage is 0.1-70mg active component/kg body weight every day, is preferably 0.2-10mg active component/kg body weight every day.
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 the medicine that pharmaceutical composition of the present invention is used to prepare prevention and treatment MCKD more on the one hand.
The present invention also provides a kind of method of screening control MCKD active drug, and it may further comprise the steps:
(1) provides a kind of with former ADPKD patient's cyst lining epithelial cells of being commissioned to train foster and said MCKD Han:SPRD rat;
(2) medicine that will be to be screened with contact with former ADPKD patient's cyst lining epithelial cells of being commissioned to train foster, or/and this MCKD Han:SPRD rat is used medicine to be screened;
(3) observe below any phenomenon: epoxidase 2 high expresseds are suppressed, PGE2 discharge reduce, the expression of inflammatory mediator is reduced, inflammation and interstitial fibrosis are alleviated, cyst lining epithelial cells propagation is suppressed or apoptosis;
(4), judge that then this medicine that is screened is the active drug to the control MCKD if listed arbitrary phenomenon takes place in (3) step.
Another purpose of the present invention provides a kind of control mammal, the method for particularly human MCKD, and it comprises uniting to said mammal uses a kind of epoxidase 2 specific inhibitors and a kind of thiazolidinediones medicine.
" uniting use " of the present invention comprise described epoxidase 2 specific inhibitors and thiazolidinediones medicine be taken up in order of priority individually or be applied to mammal simultaneously, perhaps with described epoxidase 2 specific inhibitors with the thiazolidinediones drug regimen forms pharmaceutical composition or pharmaceutical preparation is applied to mammal together.
In the present invention, uniting epoxidase 2 specific inhibitors of use and the mol ratio of thiazolidinediones medicine is 1: 0.1-40, and, be preferably 1: 0.25-20, more preferably 1: 0.5-10 further is preferably 1: 1-5 is preferably 1: 1-2.5 especially.
Among the present invention, the cyclooxygenase 2 specific inhibitor of uniting use includes, but are not limited to: celecoxib, rofecoxib, para are examined former times, valdecoxib, Ai Tuokao former times, meloxicam, nimesulide, radicicol and its pharmaceutically useful salt.Preferred celecoxib, meloxicam and radicicol.Preferred especially celecoxib.
In the present invention, the thiazolidinediones medicine of uniting use comprises, but is not limited to: rosiglitazone, troglitazone, pioglitazone, ciglitazone, englitazone and their pharmaceutically useful salt.Preferred rosiglitazone, troglitazone, pioglitazone and their pharmaceutically useful salt.Preferred especially rosiglitazone, pioglitazone and their pharmaceutically useful salt.
Pharmaceutically useful salt described in the present invention comprises the salt that epoxidase 2 specific inhibitors and thiazolidinediones medicine and mineral acid or organic acid form, the salt that for example forms with hydrochloric acid, bromine hydracid, 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.The salt of preferred especially epoxidase 2 specific inhibitors and thiazolidinediones medicine is maleate, fumarate, citrate, citrate, succinate, tartrate, pantothenate or the malate of celecoxib and rosiglitazone.
Uniting the celecoxib of use and the mol ratio of pioglitazone among the present invention is 1: 0.125-40 is preferably 1: 0.25-20, more preferably 1: 0.5-10 further is preferably 1: 1-5 is preferably 1: 1-2.5 especially.
Description of drawings
Fig. 1 cultivating people's cyst lining epithelial cells of former generation and evaluation
A, inverted phase contrast microscope be observation cultivating people's cyst lining epithelial cells of former generation down
B, the down visible adhesion spot of transmission electron microscope
C, the down visible microvillus of transmission electron microscope
D, the anti-cell keratin positive
E, alkaline phosphatase staining are the grey black positive reaction
F, the Vimentin monoclonal antibody positive
Fig. 2 BrdU method detects the proliferation inhibition rate average increment of cyst lining epithelial cells with the celecoxib Combination application of 25uM rosiglitazone and variable concentrations the time
Fig. 3 BrdU method detects the proliferation inhibition rate average increment of cyst lining epithelial cells with the rosiglitazone Combination application of 10uM celecoxib and variable concentrations the time
Fig. 4 BrdU method detects cyst lining epithelial cells and uses rosiglitazone 50uM single, and celecoxib 10uM share rosiglitazone 50uM and celecoxib 10uM48 hour proliferation inhibition rate
Fig. 5 BrdU method detect cyst lining epithelial cells single with rosiglitazone 25uM, celecoxib 20uM, share the proliferation inhibition rate of rosiglitazone 25uM and celecoxib 20uM48 hour
Fig. 6 BrdU method detect cyst lining epithelial cells single with Roger's row 50uM, celecoxib 20uM, share the proliferation inhibition rate of rosiglitazone 50uM and celecoxib 20uM48 hour
Fig. 7 flow cytometer detect cyst lining epithelial cells single with rosiglitazone 50uM, 100uM, celecoxib 20uM, 50uM share rosiglitazone 50uM and 48 hours apoptosis rate of celecoxib 20uM
Fig. 8 transmission electron microscope observing cyst lining epithelial cells is share rosiglitazone 50uM and 48 hours ultrastructure of celecoxib 20uM
A, chromatin margination B, a large amount of apoptotic body form
Respectively organize the serum urea nitrogen level in Fig. 9 zoopery relatively
Respectively organize kidney weight/weight ratio in Figure 10 zoopery
Following embodiment only is used for further explaining the present invention, rather than limitation of the scope of the invention.
Embodiment
Embodiment 1 finite concentration rosiglitazone and celecoxib Combined application suppress the experimentation of cyst lining epithelial cells propagation
One, experimental technique
1. former generation cultivating people's cyst lining epithelial cells, SABC and Electronic Speculum evaluation.
The polycystic kidney tissue of the nephrectomy is taken from the BIAO and BEN source.The shallow table of clip, transparent vesicle, the overburden removing fibrous membrane, the vesicle wall is cut into chip.Behind 0.1% collagenase digesting 1h, cell inoculation is in the culture bottle that encapsulates through Mus tail collagen, and culture fluid is the D-Valine improvement MEM that contains 20% hyclone.When the approaching fusion of cell, had digestive transfer culture.Inverted phase contrast microscope is observed.SABC and cellular enzymes chemistry carry out cell and identify electron microscopic observation adhesion spot and microvillus.With former foster next step cell experiment that carries out of being commissioned to train of 3-5 generation.
2.BrdU method detects celecoxib Combination application with rosiglitazone 25uM and variable concentrations to the cyst lining epithelial cells inhibited proliferation.
Application of B rdU method is measured cell proliferation.The passage trophophase ADPKD cyst lining epithelial cells of taking the logarithm is inoculated in 96 orifice plates (1 * 10
4/ hole), with the DMEM+F12 culture fluid that contains 10% hyclone hatch 24h (37 ℃, 5%CO2) after, change serum-free DMEM+F12 culture fluid synchronization 24h.Abandon supernatant, add rosiglitazone 25uM with contain the variable concentrations celecoxib (10,20,50,100,200, serum-free DMEM+F12 culture fluid 400uM) acts on 24,48 respectively, 72h, establishing not dosing group simultaneously is matched group.Establish 6 multiple holes for every group.BrdU detects and is undertaken by the Roche description, is summarized as follows: add 10ul BrdU marking fluid in every hole, hatched 6 hours for 37 ℃; Added 200ul pre-cooling fixative in every hole fixing 30 minutes, and added the 100ul ribonuclease in every hole and hatched 30 minutes for 37 ℃, add 100ulanti-BrdU-POD in every hole and hatched 30 minutes for 37 ℃; (washing 3 times with the 0.01mol/L PBS buffer that contains 250ul 10% hyclone between each step); Add 100ul peroxidase substrate liquid+substrate reinforcing agent in every hole, incubated at room colour developing in 20 minutes, ELIASA is measured absorbance; Measure wavelength 405nm, reference wavelength 490nm.Through trypan blue dyeing, living cells reaches and is illustrated in this experimental concentration more than 95%, and medicine does not produce significant cytotoxicity.Cell proliferation inhibition rate computing formula: (matched group absorbance-dosing group absorbance)/matched group absorbance * 100%, the increment of calculating cell proliferation inhibition rate.
3.BrdU method detects rosiglitazone Combination application with celecoxib 10uM and variable concentrations to the cyst lining epithelial cells inhibited proliferation.
Method is the same, and (10,20,50,100,200, serum-free DMEM+F12 culture fluid 400uM) acts on 24,48 respectively, 72h with containing the variable concentrations rosiglitazone to add celecoxib 10uM.Establish 6 multiple holes for every group, calculate the increment of cell proliferation inhibition rate.
Two, experimental result
1. former generation cultivating people's cyst lining epithelial cells and evaluation.
In former generation,, cultivating people's cyst lining epithelial cells anti-cell keratin, Vimentin monoclonal antibody be positive, and the anti-VIII factor, cell node albumen, actin, fibroblast differential protein monoclonal antibody are negative.Alkaline phosphatase staining is the grey black positive reaction, and visible adhesion spot and microvillus under the Electronic Speculum prove its epithelial cell source and do not have fibroblast and pollute, and see Fig. 1.The cyst lining epithelial cells growth rate can reflect ADPKD patient's pathophysiology characteristic well obviously faster than normal renal cells, can be used as the reliable platform of estimating curative effect of medication.
2.BrdU method detects and to show: with rosiglitazone 25uM (11.84mg/L) but with the celecoxib Combination application dose dependent ground increase of variable concentrations to cyst lining epithelial cells inhibition of proliferation effect (see figure 2); With compare without the rosiglitazone group, have significant difference (P＜0.05); But when celecoxib 100-400uM (38.14-152.55mg/L), particularly when 200uM was above, the toxicity of pair cell obviously increased.
3.BrdU method detects and to show: with celecoxib 10uM (3.81mg/L) but with the rosiglitazone Combination application dose dependent ground increase of variable concentrations to cyst lining epithelial cells inhibition of proliferation effect (see figure 3); With without the celecoxib group relatively, have significant difference (P＜0.05); But when rosiglitazone 400uM (189.38mg/L) was above, the toxicity of pair cell increased.
Embodiment 2 rosiglitazones, celecoxib compare with the curative effect of the compositions therapeutic alliance of variable concentrations compatibility.
One, experimental technique
1.BrdU method detects the compositions of rosiglitazone and celecoxib variable concentrations compatibility to the cyst lining epithelial cells inhibited proliferation.
Method is the same, and dosing is used or the compatible combination use by following scheme is single, acts on cyst lining epithelial cells respectively 48 hours.Establish 6 multiple holes, calculate cell proliferation inhibition rate for every group.
Single with group: rosiglitazone 25uM (11.84mg/L), rosiglitazone 50uM (23.67mg/L), rosiglitazone 100uM (47.35mg/L); Celecoxib 10uM (3.81mg/L), celecoxib 20uM (7.62mg/L), celecoxib 50uM (19.05mg/L).
The compatible combination group:
Rosiglitazone 25uM/ celecoxib 10uM (mol ratio 5: 2, weight ratio 3.1: 1), rosiglitazone 25uM/ celecoxib 20uM (mol ratio 5: 4, weight ratio 1.6: 1), rosiglitazone 25uM/ celecoxib 50uM (mol ratio 1: 2, weight ratio 1: 1.6); Rosiglitazone 50uM/ celecoxib 10uM (mol ratio 5: 1, weight ratio 6.2: 1), rosiglitazone 50uM/ celecoxib 20uM (mol ratio 5: 2, weight ratio 3.1: 1), rosiglitazone 50uM/ celecoxib 50UM (mol ratio 1: 1, weight ratio 1.2: 1); Rosiglitazone 100uM/ celecoxib 10uM (mol ratio 10: 1, weight ratio 12.4: 1), rosiglitazone 100uM/ celecoxib 20uM (mol ratio 5: 1, weight ratio 6.2: 1), rosiglitazone 100uM/ celecoxib 50uM (mol ratio 2: 1, weight ratio 2.5: 1).
With flow cytometer and transmission electron microscope detect best compatibility concentration place an order with and share the influence of thiazolidinediones medicine and COX-2 specific inhibitor to the cyst lining epithelial cells apoptosis
The former foster ADPKD cyst lining epithelial cells of being commissioned to train of the trophophase of taking the logarithm is inoculated in 6 orifice plates (5 * 10
5/ hole), gets best compatibility concentration rosiglitazone list and share and act on cell with, rosiglitazone+celecoxib, establish 3 multiple holes for every group with, celecoxib list; Behind the drug effect 48h, trypsinization, pre-cooling PBS washes 2 times; Binding buffer liquid re-suspended cell; Add the colour developing of AnnexinV/FITC and propidium iodide lucifuge, flow cytometer detects, MCYCLE software analysis apoptotic index.Handle cell with method, after digestion centrifugation, 4 ℃ 2.5% glutaraldehyde is 1h fixedly, then with natrium cacodylicum buffer flushing 3 times; 1% starves fixedly 1h of acid, PBS flushing 3 times, conventional embedding; The section of LKB ultramicrotome, lead dyes, observation of cell ultrastructure under the transmission electron microscope.
Two, experimental result
1.BrdU method detects the different compatibility concentration combination with celecoxib of rosiglitazone and acts on the cyst lining epithelial cells proliferation inhibition rate, the part combination uses result and list to put in order as follows with the result:
(1) list is used rosiglitazone 50uM, and celecoxib 10uM share rosiglitazone 50uM/ celecoxib 10uM (mol ratio 5: 1; Weight ratio 6.2: 1); Their proliferation inhibition rate is respectively 24.96% ± 6.25%, and 12.80% ± 2.79%, 46.88% ± 3.55%; Two kinds of drug regimen medication proliferation inhibition rates are higher than single proliferation inhibition rate sum that reaches with two medicines, and the result proves: two kinds of drug regimen medications have the obvious role in synergism (see figure 4).
(2) list is used rosiglitazone 25uM, and celecoxib 20uM share rosiglitazone 25uM/ celecoxib 20uM (mol ratio 5: 4; Weight ratio 1.6: 1); Their proliferation inhibition rate is respectively 11.32% ± 4.74%, and 25.80% ± 5.97%, 46.07% ± 4.62%; The drug combination proliferation inhibition rate also is higher than single proliferation inhibition rate sum that reaches with two medicines, and two kinds of drug regimen medications have the obvious role in synergism (see figure 5).
(3) single rosiglitazone 50uM that uses; Celecoxib 20uM share rosiglitazone 50uM/ celecoxib 20uM (mol ratio 5: 2, weight ratio 3.1: 1); Their proliferation inhibition rate is respectively 24.96% ± 6.25%; 25.80% ± 5.97% and 60.50% ± 3.27%, the drug combination proliferation inhibition rate also is higher than single proliferation inhibition rate sum that reaches with two medicines, and two kinds of drug regimen medications have the obvious role in synergism (see figure 6).
2. flow cytometer has detected the cyst lining epithelial cells list and has used rosiglitazone 50uM, rosiglitazone 100uM, celecoxib 20uM, celecoxib 50uM; When share rosiglitazone 50uM/ celecoxib 20uM (mol ratio 5: 2, weight ratio 3.1: 1), their apoptosis rate is respectively 12.3% ± 2.5%, 18.5% ± 3.8%, 10.9% ± 1.7%, 17.9% ± 2.6%, 30.5% ± 3.9% (see figure 7).In addition, transmission electron microscope finds that the combination group apoptotic cell obviously increases chromatin margination, apoptotic body showed increased (see figure 8).
Above-mentioned result of the test clearly illustrates that: the variable concentrations compositions of thiazolidinediones medicine rosiglitazone and COX-2 specific inhibitor celecoxib and this two kinds of medicine lists are with comparing; Can obviously increase the cyst lining epithelial cells proliferation inhibition rate; And can promote the cyst lining epithelial cells apoptosis more significantly, have significant synergism.
Embodiment 3 other thiazolidinediones medicines and COX-2 specific inhibitor compare with the curative effect of the compositions therapeutic alliance of variable concentrations compatibility.
Method according to embodiment 2; Measured thiazolidinediones medicine troglitazone and pioglitazone and COX-2 specific inhibitor meloxicam and radicicol, they separately with respectively with the compositions of variable concentrations compatibility to the proliferation inhibition rate of cyst lining epithelial cells with to the apoptosis rate of cyst lining epithelial cells.The result show thiazolidinediones medicine and COX-2 specific inhibitor with the compositions of variable concentrations compatibility and this two kinds of medicine lists with relatively; Also can obviously increase the cyst lining epithelial cells proliferation inhibition rate; And can promote the cyst lining epithelial cells apoptosis significantly, have significant synergism.
The curative effect of embodiment 4. rosiglitazones, celecoxib therapeutic alliance MCKD animal model Han:SPRD rat relatively
One, experimental technique
1. zoopery scheme
Male Han:SPRD heterozygote (Cy/+) rat random packet: do not intervene matched group, TZDs treatment group (rosiglitazone 10mg/kgd), Cox-2 inhibitor for treating group (celecoxib 10mg/kgd) and therapeutic alliance group (rosiglitazone 4mg/kgd+ celecoxib 3mg/kgd), 10 every group.In 11 weeks of gastric infusion to the after the 3rd week ablactation, the treatment group gives pharmaceutical purity article (being suspended in 1%CMC-Na) and irritates stomach, and matched group gives 1%CMC-Na filling stomach, surveying record body weight weekly.
2. parameter and biochemical indicator monitoring
Rat is weighed during the 11st week, gets blood 2ml behind the socket of the eye, leaves and takes serum and makes Liver and kidney merit, blood glucose, blood fat and other correlation analysis, leaves and takes whole blood simultaneously and does routine analysis of blood.Metabolic cage is collected urine (prohibit water after 8 hours, go into metabolic cage, fasting water, 12 hours urines of urine collector collection) and is done osmotic pressure of urine and urine protein quantitation analysis.Soften-II Mus tail volume markings blood pressure measuring blood pressure is measured under the rest state, surveys for every and averages for 3 times.
3. histologic analysis
After male heterozygote rat was put to death, kidney, liver were weighed and are drawn materials and fixedly make histologic analysis.The offside kidney is after the perfusion of 4% paraformaldehyde; Leaving and taking part nephridial tissue (comprising cortex, medullary substance and pars papillaris) fixes with 10% neutral formalin; FFPE; Process 3um slice row HE, PAS and Masson dyeing, IDA-2000 pathology picture and text analytical system quantizes the histological indices of cyst property disease: matter cell infiltration degree between cyst index (cyst index), renal fibrosis scoring (fibrosis score) reach.The cyst index: analyze the meansigma methods of the area percentage of the shared dot matrix of the little tube chamber of cyst in image through the picture and text process software amplifying 20 visuals field of 100 times of following picked at random, according to foreign literature report area surpass the glomerule average area (9,000um
2) the tubule chamber counted the cyst scope.Index is judged in the fibrosis scoring: amplifying the meansigma methods of 20 visuals field of 100 times of following picked at random through the area percentage of the picture and text process software analysis Masson dyeing painted shared dot matrix of kidney region fibrosis in image.Between matter cell infiltration deliberated index: 0 does not soak into; 1 is focal slight; 2 focal moderates; 3 fill the air slightly; 4 fill the air middle severe.
4. statistical analysis
All data are represented with
; Use SPSS 11.0 and add up, relatively adopt t check or variance analysis between group.
Two, experimental result
After treating for 8 weeks; Each treatment group is compared body weight in the clinical indices, liver function zero difference with matched group; And SAP, 24h urine protein descend, serum urea nitrogen (P＜0.05); Osmotic pressure of urine rising (P＜0.01); Histological indices middle kidney weight/body weight (P＜0.05); Cyst index, fibrosis index (P＜0.01), a matter cell infiltration degree (P＜0.05) are all obviously improved (seeing table 1), and low dosage therapeutic alliance group has obvious significant difference (P＜0.05) with more heavy dose of single medicine treatment group comparison osmotic pressure of urine, serum urea nitrogen (see figure 9), kidney weight/body weight (see figure 10), cyst index, fibrosis index, and SAP, 24h urine protein quantitation, a matter cell infiltration degree then do not reach significant difference (P＜0.05).
The above results shows: thiazolidinediones medicine rosiglitazone and the combination of COX-2 specific inhibitor celecoxib are used, and are superior to single curative effect with any medicine for the curative effect of improving the MCKD course of disease and histology progress.
Table 1: each organizes male Han:SPRD heterozygote (cy/+) rat parameter and histological indices
Compare with matched group
*P＜0.05
*P＜0.01 is compared with single medicament group
▲P＜0.05
The curative effect of embodiment 5. other thiazolidinediones medicines and COX-2 specific inhibitor therapeutic alliance MCKD animal model Han:SPRD rat relatively
According to the same procedure of embodiment 4, measured thiazolidinediones medicine troglitazone and pioglitazone respectively with the curative effect of the combination treatment MCKD animal model Han:SPRD rat of COX-2 specific inhibitor meloxicam and radicicol combination.The result shows: the compositions of thiazolidinediones medicine and COX-2 specific inhibitor and this two kinds of medicine lists are with comparing; The compositions of thiazolidinediones medicine troglitazone and pioglitazone and COX-2 specific inhibitor meloxicam and radicicol is superior to single curative effect with any medicine for the curative effect of improving the MCKD course of disease and histology progress.
Embodiment 6
Make the compound tablet of pioglitazone and celecoxib by following prescription: (used content is weight percentage)
Pioglitazone 11.2%
Celecoxib 9%
Microcrystalline Cellulose 75.8%
PVP-k30 2％
Magnesium stearate 2%
With pioglitazone, celecoxib, microcrystalline Cellulose, PVP-k30 mixing, with ethanol system soft material, to granulate through 12 mesh sieves, granulate after the aeration-drying below 70 ℃ adds mixing tabletting after the magnesium stearate, promptly gets.Wherein the weight ratio of celecoxib and pioglitazone is 1: 1.24.
Embodiment 7
Make the compound tablet of rosiglitazone and celecoxib by following prescription: (used content is weight percentage)
Rosiglitazone maleate 14%
Celecoxib 4.5%
Microcrystalline Cellulose 77.5%
PVP-k30 2％
Magnesium stearate 2%
With rosiglitazone maleate, celecoxib, microcrystalline Cellulose, PVP-k30 mixing, with ethanol system soft material, to granulate through 12 mesh sieves, granulate after the aeration-drying below 70 ℃ adds mixing tabletting after the magnesium stearate, promptly gets.Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 3.1.
Embodiment 8
According to the same procedure of embodiment 7, made the compound tablet of rosiglitazone and celecoxib by following prescription: (used content is weight percentage)
Celecoxib 8%
Calcium bicarbonate 3%
PVP-k30 4％
Magnesium stearate 6%
Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 1.24.
Embodiment 9
According to the same procedure of embodiment 7, made the compound tablet of rosiglitazone and celecoxib by following prescription: (used content is weight percentage)
Rosiglitazone maleate 2.1%
Celecoxib 13%
Calcium carbonate 21.9%
Calcium bicarbonate 3%
PVP-k30 4％
Magnesium stearate 6%
Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 0.155.
According to the same procedure of embodiment 7, made the compound tablet of rosiglitazone and celecoxib by following prescription: (used content is weight percentage)
Rosiglitazone maleate 24.8%
Celecoxib 2%
Microcrystalline Cellulose 43.2%
Calcium bicarbonate 3%
PVP-k30 4％
Magnesium stearate 3%.
Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 12.4.
Embodiment 11
Make rosiglitazone celecoxib compound tablet by following prescription: (used content is weight percentage)
Rosiglitazone maleate 15.5%
Celecoxib 2.5%
Microcrystalline Cellulose 45%
Calcium bicarbonate 30%
PVP-k30 3％
Magnesium stearate 4%
Method for preparing is with embodiment 7, and wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 6.2.
Embodiment 12
Make the agent of rosiglitazone celecoxib compound capsule by following prescription: (used content is weight percentage)
Rosiglitazone maleate 4%
Celecoxib 6.5%
Calcium carbonate 45%
Starch 44.5%
Calcium carbonate and starch are mixed, sieve, even with the dispersive rosiglitazone maleate of an amount of ethanol, celecoxib powder mixes again, cross 120 mesh sieves, in 60-70 ℃ of oven dry 2 hours, the medicated powder of mixing is filled into capsulae vacuus promptly gets.Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 0.62.
Embodiment 13
Make the agent of pioglitazone celecoxib compound capsule by following prescription: (used content is weight percentage)
Pioglitazone 2%
Celecoxib 6.5%
Calcium carbonate 45.5%
Starch 46%
Calcium carbonate and starch are mixed, sieve, even with the dispersive rosiglitazone maleate of an amount of ethanol, celecoxib powder mixes again, cross 120 mesh sieves, in 60-70 ℃ of oven dry 2 hours, the medicated powder of mixing is filled into capsulae vacuus promptly gets.Wherein the weight ratio of celecoxib and pioglitazone is 1: 0.31.
Embodiment 14
Made rosiglitazone and celecoxib is sent out compound oral liquid by following prescription: (used content is weight percentage)
Rosiglitazone maleate 14%
Celecoxib 6%
D, L MALIC ACID is an amount of
Methyl parahydroxybenzoate 0.5%
Propyl p-hydroxybenzoate 0.5%
Sucrose 69%
Edible essence is an amount of
Distilled water adds to 1000ml
Sucrose is dissolved in an amount of distilled water, makes its dissolving, rosiglitazone maleate, celecoxib, methyl parahydroxybenzoate, propyl p-hydroxybenzoate, monostearate sucrose ester are mixed with 10% alcoholic solution; Add in the above-mentioned dosing, the limit edged stirs, and adds D again; The distilled water solution of L MALIC ACID is regulated pH value and is about 5, and adding distil water is to 1000ml; Mixing, sampling and measuring content, pH value, qualified back canning and sterilizing gets final product.Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 2.3.
Embodiment 15
Make the dropping pill formulation of pioglitazone and celecoxib compositions by following prescription: (used content is weight percentage)
Pioglitazone 35%
Celecoxib 5%
Macrogol 600 60%
Macrogol 600 placed in the water-bath heat, make it fusion, add pioglitazone, celecoxib, mix homogeneously, 90 ℃ of insulations are subsequent use, preheating drop pill device, and the pre-cooling of coolant fluid paraffin body is to 10-15 ℃, drips speed with 50-70 and drips and make.In liquid coolant, collect drop pill, the filtering liquid coolant is absorbed paraffin with filter paper, dries, and promptly gets.Wherein the weight ratio of celecoxib and rosiglitazone maleate is 1: 7.
Embodiment 16: injection vials
Is that 100 gram active component and the 5 gram sodium hydrogen phosphates of forming at 1: 3 are dissolved in the distilled water of 5L with celecoxib and pioglitazone with weight ratio; The solution that obtains is adjusted to pH value 6.5 with 2N hydrochloric acid, and aseptic filtration changes in the injection vials; Lyophilizing under aseptic condition is in sealed under aseptic conditions.Each injection vials contains 20 milligrams active component.
Embodiment 17: injection ampoule
Is that the 100 gram active component of forming at 1: 3.1 are dissolved in the 10L distilled water with celecoxib and rosiglitazone maleate with weight ratio, the solution aseptic filtration of formation, and pour in the ampoule, lyophilizing under aseptic condition is in sealed under aseptic conditions.Each ampoule contains 10 milligrams active component.
Embodiment 18: suppository
Is that the 30 gram active component of forming at 1: 2 and 100 restrain the mixture melt that soybean phospholipids and 1400 restrain cocoa butters with celecoxib and rosiglitazone maleate with weight ratio, pours in the mould cooling into.Each suppository contains 20 milligrams active component.
Embodiment 19: ointment
Is that 500 milligram compositions active component 1: 4 forming with the vaseline of 99.5 grams under aseptic condition mix with rosiglitazone maleate with weight ratio with celecoxib.
Embodiment 20: coated tablet
Method according to embodiment 7 prepares the pharmaceutical composition that contains celecoxib and rosiglitazone maleate, and tabletting, follows with conventional method with sucrose, potato starch, Talcum, Tragacanth and dyestuff coating.
Claims (10)
- Epoxidase 2 specific inhibitors a) with thiazolidinediones medicine b) application in the medicine of preparation treatment mammal MCKD, wherein saidly a) be selected from celecoxib, rofecoxib, para and examine former times, valdecoxib, Ai Tuokao former times, meloxicam, nimesulide and radicicol; Said b) is selected from the salt that rosiglitazone, troglitazone, pioglitazone, ciglitazone, englitazone and they and hydrochloric acid, bromine hydracid, 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; Wherein a) and b) mol ratio be 1: 0.1-40.
- 2. the application of claim 1, wherein said epoxidase 2 specific inhibitors a) are selected from celecoxib, meloxicam and radicicol; Described thiazolidinediones medicine b) is selected from rosiglitazone, troglitazone, pioglitazone and their pharmaceutically useful salt.
- 3. the application of claim 2, wherein said epoxidase 2 specific inhibitors are celecoxibs a), described thiazolidinediones medicine b) be rosiglitazone or pioglitazone or its pharmaceutically useful salt.
- 4. the application of claim 1, wherein said a) and b) mol ratio be 1: 0.25-20.
- 5. the application of claim 4, wherein said a) and b) mol ratio be 1: 0.5-10.
- 6. the application of claim 5, wherein said a) and b) mol ratio be 1: 1-5.
- 7. each application of claim 1-6, wherein said medicine is oral formulations form, ejection preparation form or local administration preparation form.
- 8. the application of claim 7, wherein said oral formulations form comprise tablet, lozenge, aqueous solution or oil suspension, dispersion powder or granule, emulsion, hard or soft capsule, syrup or elixir.
- 9. the application of claim 7, wherein said ejection preparation form are the aqueous solution of aseptic injection or the oil-in-water microemulsion of aseptic injection.
- 10. the application of claim 7, the dosage form of wherein said topical are suppository, cream, unguentum, gel, solution or suspension.
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