CN101590039A - The composition and use thereof that contains indopamide and statins - Google Patents

Abstract

The present invention relates to contain the pharmaceutical composition of indopamide and selected statins and the purposes in preparation treatment hyperhomocysteinemiainjury or the homocysteine rising thereof.Indopamide and selected statins share and can further reduce the Hcy level, are better than list and use medicine, show that indopamide and selected statins share the level at reduction Hcy, have synergism thereby alleviate in the Hcy damage.Compositions innovation and creation provided by the invention are selections of treatment Hcy, for the treatment of homocysteine provides more effective therapeutic scheme.The invention belongs to pharmaceutical field.

Description

The composition and use thereof that contains indopamide and statins

Technical field

The present invention relates to contain the pharmaceutical composition and the purposes in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising thereof of indopamide and statins.Belong to pharmaceutical field.

Background technology

As far back as people in 1969 hypothesis is just proposed, think homocysteine (Hcy, a kind of sulfur-containing amino acid) may be the risk factor of cardiovascular disease, since then, there is big quantity research to accumulate objective evidence, thinks that Plasma Homocysteine and cardiovascular disease (CVD) and other systemic disease occurrence risk are closely related.

A large amount of dissimilar studies confirm that, Plasma Homocysteine is independent of conventional risk factors such as hypertension, hyperlipidemia, the Hcy 5 μ mol/L that raise, the apoplexy risk increases by 59% (OR, 1.59; 95%CI, 1.30-1.95), the deep venous thrombosis risk increases by 60% (OR, 1.60; 95%CI, 1.15-2.22), ischemic heart desease (comprising coronary heart disease, angina pectoris, arrhythmia, heart infarction, heart failure and sudden death) risk increases by 33% (OR, 1.33; 95%CI, 1.22-1.46); And Hcy reduces by 3 μ mol/L, and the apoplexy risk reduces by 24%, and the deep venous thrombosis risk reduces by 25%, and the ischemic heart desease risk reduces by 16%.Show all closely related [the Wald DS of Hcy and ischemic heart desease, apoplexy, deep venous thrombosis, Law M, Morris JK.Homocysteine and cardiovascular disease:evidence on causality froma meta-analysis.BMJ.2002; 325:1202-1206.].The mechanism of the body injury that high Hcy mass formed by blood stasis causes it is generally acknowledged and response to oxidative stress, the blood coagulation of destruction body and fibrinolytic between balance, cause that vascular smooth muscle cell proliferation and direct cytotoxicity are relevant.

High Hcy except in CVD develops, playing an important role, also and other diseases such as Alzheimer (Alzheimer ' s disease, AD), cognitive dysfunction, dementia (Clarke et al.1998; Morris, 2003), osteoporosis (Verhoef ﹠amp; De Groot, 2005), depression, parkinson disease (PD), schizophrenia, death, the neonate defective, multiple disease such as habitual abortion is closely related.

Since the nineties in 20th century, the high Hcy of a large amount of report prompting blood plasma and brain function go down and the generation of AD relevant.The blood Hcy level that studies show that AD patient in a large number is higher than normally.1998 by people such as Clarke [Clarke R, SmithAD, Jobst KA, et al.Folate, vitamin B12, and serum total homocysteine levels inconfirmed Alzheimer disease.Arch Neurol 1998; 55:1449-1455.] being AD to 164 clinical diagnosises more than 55 years old, the patient has carried out comparative study with 148 similar old peoples of age.The result shows, AD patient's Cambridge cognitive competence is checked (the Cambridge Cognitive Examination, CAMCOG) scoring and simple and easy mental status examination (mini-mental state examination, MMSE) scoring significantly is lower than matched group, and the Plasma Hcy level significantly increases; The maximum characteristics of this research are to have 76 patients to make a definite diagnosis in after death obtaining the histology in the case, the difference of Hcy concentration more remarkable than 164 clinical diagnosis patients between AD patient after making a definite diagnosis and the contrast; There are some researches show the every rising 5mmol/L of Hcy, the danger of suffering from AD just increases by 40%, and thinks and the diagnosis of the Hcy level before 8 years and dementia and AD can be interrelated at least; Postrglion[Postiglione A, Milan G, Ruocco A, Gallotto G, Di Mimmo G.Plasma folate, vitamin B12, and total homocysteine tetrahydrofolatereducase gene in patients with Alzheimer ' s dementia.A case-control study.Gerontolgy 2001; 47:324-349.] etc. the people studies confirm that AD patient not only has higher Plasma Hcy level, its course of disease progress also is directly proportional with Hcy, therefore thinks that the Hcy mass formed by blood stasis not only be the independent hazard factor of AD, more develop with its course of disease and the order of severity relevant.More have research to think, the Hcy level can be used as and is independent of beyond age, sex, education degree, renal function, vitamin B6 level, smoking history and the hypertension and self-existent cognitive competence on the horizon descended and the predictive factors of decline degree.Hcy possible mechanism of action in AD, dementia or cognitive function are impaired: Hcy is to neuronic direct infringement; Strengthen the neurotoxicity of amyloid A β; Influence brain function etc. by the infringement microcirculation.

There is research [OpSuilleabhain PE, Sung V, Hernandez C, et al.Arch Neurol, 2004,61:865.] to show that depression takes place the PD patient of high Hcy and Cognitive function damage is tighter.The research that Susser etc. carry out is schizophrenia group and matched group homocysteine level relatively, and they are divided into normal folate level group and low folate level group, found that two groups there were significant differences in low folate level.Prompting supports that there is homocysteine metabolic imbalance hypothesis [Susser E in schizophrenia thus, Brown AS, Klonowski E, Allen RH, Lindenbaum J:Schizophreniaand impaired homocysteine metabolism:a possible association[J] .Biol Psychiatry1998,44:141].Gonzalez S etc. studies show that, in the old people of no any chronic disease, high Hcy and closely related [the Gonzalez S of its death, Huerta JM, Fernandez S, et al.Homocysteine increase the riskof mortality in elderly individuals.BJN 2007; 1-7].

It is generally acknowledged that the infringement that the Hcy level causes with it is proportionate, do not have a tangible dangerous decomposition point.The external about 8-10 μ of Hcy level mol/L.Hughes et al[J Epidemiol Community Health.2000; 54 (1): 31-4.] find, Chinese male Hcy average out to 15.3 μ mol/L, the women is 12.2 μ mol/L.If with blood plasma tHcy＞14 μ mol/L is criterion, the high tHcy incidence rate of Chinese male is 57%, and the women is 31%.Hao et al[J Nutr 2007; 137:407-13] research also show that the high Hcy incidence rate of Chinese population is higher.Show that high Hcy is extensive China morbidity crowd, cause important social danger.

Mainly using vitamin B group at present, mainly is that folic acid reduces Hcy, and a meta the analysis showed that folic acid is less than 1mg/d (average 0.5mg), and 1-3mg/d (average 1.2mg) is greater than the therapeutic equivalence (BMJ1998 of 3mg/d (average 5.7mg) reduction Hcy; 316:894-898).It is relevant that other there are some researches show that folic acid reduces the level of the curative effect of Hcy and Hcy, better in the horizontal the higher person curative effect of Hcy.Demarcating under the Hcy level, take the effect that 0.8mg folic acid can produce maximum reduction Hcy every day, add vitamin B12 (400 μ g/day) simultaneously and can make Hcy further descend 7%, can not strengthen effect [the Arch Intern Med.2001 that folic acid reduces Hcy and add vitamin B6; 161:695-700.Am J Clin Nutr2005; 82:806-812.].The above results shows uses vitamin or compound vitamin to have certain limit on reduction Hcy curative effect, and escalated dose can not improve the effect that reduces Hcy.

Finish vitamin B group such as multinomial Supplement of folic acid, VB12, VB6 at present and reduced Hcy, observe the clinical research of cardiovascular and cerebrovascular vessel terminal point incident, but it is opposite with expectation, nearly all large-scale clinical research such as VISP, NORVIT, HOPE2, WACFAS etc. all do not observe folic acid at the compound terminal point of cardiovascular and cerebrovascular vessel incident, even the curative effect on all secondary endpoints, only the possible useful result of folic acid on secondary endpoints observed in HOPE2 research, but the author thinks by analysis and may have nothing to do with the folic acid effect.Such the possibility of result occurring the degree deficiency of the factor of three aspects: Hcy reduction, has research to think that Hcy reduction greatly can obtain better apoplexy curative effect; For the body injury that high Hcy has caused, single with folic acid effect and insufficient; Folic acid itself can reduce Hcy, reduces the damage that Hcy causes, and may produce adverse influence to body but take folic acid itself for a long time.The summary that Wright AJA et al (2007) is published on " Britain threpsology magazine " is recently pointed out, give heavy dose of folic acid, the folic acid that has significant proportion enters the body circulation with not metabolism prototype, may bring some worries thus for the safety aspect of prolonged application folic acid, comprise: cover vitamin B12 deficiency, and then cause irreversible nervous function damage; For the old people, folic acid is taken for a long time and may be increased the weight of cognitive impairment, causes dementia symptom to worsen; Take folic acid for a long time and may increase the weight of risk of cancer, influence anticarcinogen effect [Wright AJA simultaneously, Dainty JR, Finglas PM.Folicacid metabolism in human subjects revisited:potential implications for proposedmandatory folic acid fortification in the UK.British Journal of Nutrition (2007), 98,667-675.].Aspirin-folic acid intervention study (Cole et al) has patient's life-time service folic acid 1mg/d of nodus hemorrhoidalis intestinal tumour near-mid term, and not observing it has protective effect in the recurrence of primary terminal point colorectum tumor.Wherein do not observe folic acid group and placebo group no any difference on primary, secondary endpoints when finishing following up a case by regular visits in 3 years; It is about 60% to continue patient that secondary follows up a case by regular visits to, though the result shows primary terminal point zero difference, the folic acid group has degradating trend (not proofread and correct RR, 1.67 in the damage of carrying out property of secondary endpoints; 95%CI, 1.00-2.80; P=.05) [Cole BF, Baron JA, Sandler RS, et al.Folic Acid for the Prevention of Colorectal Adenomas.A Randomized Clinical Trial.JAMA.2007; 297:2351-2359].Same use vitamin B group reduce Hcy to the influence of cognitive function etc. also conclusion differ, may be also relevant with other effects of falling Hcy of vitamin B group itself.

Thereby action pathway and the medicine of further seeking the body injury that can the high Hcy of comprehensive, safe antagonism causes have important medical value and social value.

Indopamide is a kind of antihypertensive drugs commonly used, is a kind of sulphone amide derivative that has indole ring, has diuresis and certain calcium antagonism, and its definite blood pressure lowering mechanism it be unclear that.

Summary of the invention

The objective of the invention is to overcome the deficiency of existing medicine when the high Hcy of treatment, a kind of pharmaceutical composition that contains indopamide and statins is provided, and the purposes of this pharmaceutical composition in the medicine of preparation treatment hyperhomocysteinemiainjury.

For achieving the above object, the present invention is by the following technical solutions:

A kind of pharmaceutical composition for the treatment of hyperhomocysteinemiainjury comprises:

(1) indopamide of pharmaceutical dosage;

(2) statins of pharmaceutical dosage; And

(3) acceptable carrier on the pharmaceutics.

In compositions provided by the invention, the content of indopamide is 0.2mg-5mg, preferred 0.625-2.5mg.

In compositions provided by the invention, described statins is selected from a kind of in atorvastatin (atorvastatin), Pitavastatin (pitavastatin), the Rosuvastatin (rosuvastatin rosuvastatin).Wherein, atorvastatin content is that 5-80mg, Pitavastatin content are that 1-4mg, Rosuvastatin content are 5-80mg.

The component of the preferred following content of pharmaceutical composition provided by the invention is as active component:

Indopamide and atorvastatin, wherein the content of indopamide is 0.625-2.5mg, atorvastatin content is 10-80mg; Or

Indopamide and Rosuvastatin, wherein the content of indopamide is 0.625-2.5mg, Rosuvastatin content is 5-80mg; Or

Indopamide and Pitavastatin, wherein the content of indopamide is 0.625-2.5mg, Pitavastatin content is 1-4mg; Or

According to the present invention, active component in the pharmaceutical composition is the solvent in the compositions, one of them activity is an indopamide, another active component is from statins, the dosage form of this pharmaceutical composition includes but not limited to conventional tablet, bilayer tablet, multilayer tablet, slow releasing tablet, the single chamber controlled release tablet, two chambers controlled release tablet, the pore type controlled release tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, granule, pill, enteric coated capsule, delayed-release tablet, regularly/the position releasing piece, conventional capsule, slow releasing capsule, controlled release capsule, the capsule that contains micropill or small pieces, the pH dependent form capsule that contains micropill or small pieces, oral liquid, membrane or patch, what should particularly point out is that the pharmaceutical composition that will contain indopamide and statins is made tablet or capsule.

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into common oral preparation, comprise conventional tablet, conventional capsule, granule etc., described pharmaceutically suitable carrier includes excipient and the accessory drugs that helps reactive compound is mixed with pharmaceutical formulation when making tablet, compositions as one or more materials of microcrystalline Cellulose, inorganic salts, lactose, sodium chloride, citric acid and sodium sulfite etc. belongs to this area general knowledge.

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into slow releasing preparation, comprise excipient and adjuvant etc.Described excipient and adjuvant have comprised that the adjuvant of slow releasing function is that the solubility/insoluble salt of hydroxypropyl methylcellulose and/or ethyl cellulose and/or polyacrylic resin class and/or polycarboxy ethene and/or alginic acid and/or ethyl cellulose and/or other play the adjuvant of slow releasing function, the hypromellose employing includes the extensive stock of hydroxypropyl methylcellulose (HPMC) such as U.S. many elegant (Methocel) of all size, ethyl cellulose adopts the extensive stock that includes ethyl cellulose (EC), and polyacrylic resin adopts and includes polyacrylic resin II, the acrylic resin of III class or analog such as all size (Eudragit).

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into controlled release preparation, comprise that active medicine has reached the adjuvant of controlled release effect.The above-mentioned adjuvant that plays the controlled release effect is polyoxyethylene and/or hypromellose and/or ethyl cellulose and/or sodium chloride and/or lactose and/or mannitol and/or fructose and/or glucose and/or sucrose or low-substituted hydroxypropyl cellulose and/or cross-linking sodium carboxymethyl cellulose and/or crospolyvinylpyrrolidone and/or cellulose acetate.Above-mentioned adjuvant is pharmaceutical carrier, expanding material, permeation-promoter, solubilizing agent, binding agent, wetting agent, lubricant, coloring agent, porogen, membrane material, antiplastering aid, plasticizer, lucifuge agent, solvent.Pharmaceutical carrier, expanding material can adopt polyoxyethylene, hypromellose, ethyl cellulose, hydroxypropyl cellulose, methylcellulose, Glyceryl Behenate class etc.; Permeation-promoter can adopt sodium chloride, lactose, mannitol etc.; Solubilizing agent can be adopted sodium lauryl sulphate or poloxamer etc.; Binding agent can adopt polyvinylpyrrolidone, hypromellose, chitosan, sodium alginate, methylcellulose, ethyl cellulose, starch slurry, arabic gum, gelatin, sucrose, polyvinyl alcohol etc.; Wetting agent can adopt the ethanol-water solution of dehydrated alcohol, water, various concentration; Lubricant can adopt stearic acid, magnesium stearate, Pulvis Talci, starch, paraffin etc.; Coloring agent can adopt natural pigment such as carmine, amaranth, lemon yellow, bright orchid, indigo, brownish red ferrum oxide and synthetic dyestuff or the like; Porogen can adopt sucrose, mannitol, Polyethylene Glycol, titanium dioxide, Pulvis Talci, silicon dioxide etc.; Membrane material can adopt cellulose acetate, ethyl cellulose, hydroxypropyl emthylcellulose acetic acid succinate, beautiful jade Cellulose Acetate Phthalate, poly-phthalic acid vinyl acetate cellulose, hydroxypropyl cellulose, hydroxyethyl-cellulose etc.; Solvent can adopt acetone, dehydrated alcohol, ethanol, water etc.

Also contain the pharmaceutics acceptable carrier in the said composition, can be made into sublingual lozenge, oral cavity quick disintegrating slice or dispersible tablet etc.; Comprise excipient and adjuvant etc.Described excipient and adjuvant have mannitol, sorbitol, maltose alcohol, low substituted hydroxy-propyl methylcellulose, microcrystalline Cellulose, carboxymethyl starch sodium, cross-linked carboxymethyl cellulose sodium, crospolyvinylpyrrolidone, processing agar, cyclodextrin, glycyrrhizic acid, stevioside, citric acid, Oleum menthae, eucalyptus oil, Oleum Caryophylli, Fructus Citri Limoniae oil, citrus seed oil and some other correctives that wraps up with microcapsule etc.

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into enteric coatel tablets or enteric coated capsule etc.; comprise excipient and adjuvant etc.; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc.; enteric-coating material comprises: Lac; the cellulose acetate phthalate ester; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose, and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into delayed-release tablet or timing (position) releasing piece; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., described coating material that postpones release or regularly (position) release comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen (as PEG1000; PEG4000; various medicaments adjuvant such as PEG6000).

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition; can be made into slow releasing capsule; controlled release capsule; the capsule that contains micropill or small pieces; contain the pH dependent form capsule of micropill or small pieces etc.; comprise excipient and adjuvant; described excipient and adjuvant have starch; microcrystalline Cellulose; inorganic salts; hydroxypropyl emthylcellulose; ethyl cellulose; the polyacrylic resin class; polycarboxy ethene; the solubility of alginic acid/insoluble salt; octadecanol; stearic acid; sodium chloride; cysteine; the compositions of one or more materials of citric acid and sodium sulfite etc., coating material comprises: Lac; the cellulose acetate phthalate ester; ethyl cellulose; hydroxypropyl emthylcellulose; hydroxypropyl cellulose; crylic acid resin (as Eudragit L and S type etc.); the polyvinyl acetate phthalic acid ester; phthalic acid hypromellose ester; succinic acid acetic acid hydroxypropyl methylcellulose; the polyvinyl acetate phthalic acid ester; and plasticizer is (as diethyl phthalate; Polyethylene Glycol; propylene glycol; glycerol triacetate; dimethyl phthalate; dibutyl sebacate; triethyl citrate; tributyl citrate; CitroflexA-2; the acetylated monoglycerides of Oleum Ricini and percentage etc.) with porogen various medicaments adjuvants such as (as PEG6000).

Also contain the pharmaceutics acceptable carrier in this pharmaceutical composition, can be made into dosage forms such as granule, oral liquid, membrane, patch.Described pharmaceutically acceptable carrier includes excipient and the adjuvant that helps reactive compound is mixed with pharmaceutical formulation when making the patch membrane; as polyvinyl alcohol, Triafol T, ethylene-vinyl acetate copolymer, polyvinylpyrrolidone, polyacrylamide, polybutene class pressure sensitive adhesive, crylic acid resin pressure sensitive adhesive, silicone pressure sensitive adhesive etc.; and back lining materials such as polrvinyl chloride, polyethylene, aluminium foil, polypropylene, polyester, the compositions of one or more materials of protecting film such as polyethylene, polystyrene, polypropylene etc.

Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in identical preparation, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss of the beneficial effect that brings.If grant diseased individuals simultaneously, the chemical compound in the compositions can mix and be present in the same pharmaceutical dosage forms, also can independently exist respectively with same dosage form.If independently exist respectively with same dosage form, then pharmaceutical composition can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.Select the compound tablet of a kind of composition in indopamide and the described statins in the present invention for use.

Chemical compound in the pharmaceutical composition provided by the invention can be granted diseased individuals simultaneously in preparation inequality, also grant diseased individuals discriminably in succession.If grant diseased individuals in succession, then the delay of granting of second (or additional) active component should not cause active component to unite the loss that brings beneficial effect.If grant diseased individuals simultaneously, the chemical compound in the compositions independently exists with different dosage forms, and pharmaceutical composition also can flexible existing with " Combined drug box " form." Combined drug box " is a kind of case type container, the drug regimen of built-in one or more dosage forms, and operation instructions.

Another object of the present invention provides the purposes of compositions in the medicine of preparation treatment hyperhomocysteinemiainjury that contains indopamide and statins.

Beneficial effect of the present invention:

The at present clinical medicine that does not still have rising of efficient treatment homocysteine or homocysteine rising uses vitamin B group (folk prescription or compound recipe) unsatisfactory curative effect, even can produce adverse influence; Indopamide and selected statins share and can further reduce Hcy, thereby reduce the Hcy damage, have synergism, can solve the clinical blank of present treatment Hcy.

The present invention will be further described below in conjunction with the specific embodiment, is not limitation of the invention, all any this areas of carrying out according to content of the present invention be equal to replacement, all belong to protection scope of the present invention.

The specific embodiment

Embodiment 1: preparation atorvastatin indopamide sheet (1000)

Prescription is formed:

Atorvastatin 10g

Indopamide 1.25g

Starch 10g

Microcrystalline Cellulose 50g

Carboxymethyl starch sodium (CMSNa) 30g

10% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of

Magnesium stearate is an amount of

Preparation technology:

10g atorvastatin, 1.25g indopamide 5g, 50g lactose, 50g microcrystalline Cellulose, 10g starch are pulverized, cross 120 mesh sieves, according to the equivalent method mix homogeneously that progressively increases, poly-ly make soft material for the ketone alcoholic solution with an amount of 10%, granulation, dry, granulate, with water content is about 3% granule and an amount of magnesium stearate mix homogeneously, makes 1000 according to a conventional method promptly.

Embodiment 2: preparation atorvastatin indopamide sheet (1000)

Prescription is formed:

Atorvastatin 10g

Indopamide 2.5g

Starch 10g

Microcrystalline Cellulose 50g

Carboxymethyl starch sodium (CMSNa) 30g

10% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of

Magnesium stearate is an amount of

Preparation technology is with embodiment 1.

Embodiment 3: preparation Rosuvastatin indopamide sheet (1000)

Prescription is formed:

Rosuvastatin 10g

Indopamide 2.5g

Starch 10g

Microcrystalline Cellulose 50g

Carboxymethyl starch sodium (CMSNa) 30g

10% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of

Magnesium stearate is an amount of

Preparation technology is with embodiment 1.

Embodiment 4: preparation Pitavastatin indopamide sheet (1000)

Prescription is formed:

Pitavastatin 2g

Indopamide 2.5g

Starch 10g

Microcrystalline Cellulose 50g

Carboxymethyl starch sodium (CMSNa) 30g

10% 30 POVIDONE K 30 BP/USP-30 (solvent is a dehydrated alcohol) is an amount of

Magnesium stearate is an amount of

Preparation technology is with embodiment 1.

Embodiment 5: preparation Rosuvastatin indopamide capsule (1000)

Prescription is formed:

Atorvastatin 10.0g

Indopamide 2.5g

Lactose 30.0g

Microcrystalline Cellulose 15.0g

Starch 20.0g

Carboxymethyl starch sodium 5.0g

Magnesium stearate is an amount of

Preparation technology:

According to the prescription proportioning, get lactose, microcrystalline Cellulose, starch, carboxymethylstach sodium and in about 100 ℃, distinguish dry about 2 hours, cross 100 mesh sieves; With crude drug cross behind 100 mesh sieves with above-mentioned adjuvant by equivalent incremental method mix homogeneously, with No. 3 capsule fills.

Embodiment 6: the indopamide Rosuvastatin is to the curative effect of high Hcy rat model

1, method

Get 105 of 250～300g male rats, be divided into 7 groups at random, 15/group.Wherein 1 group gives normal feedstuff, and other groups give the feedstuff of homomethionin, continuous 12 weeks.Each group gives indopamide (0.25mg/kg), indopamide (0.5mg/kg), Rosuvastatin (1mg/kg), Rosuvastatin (2mg/kg), indopamide+Rosuvastatin (0.25mg+1mg/kg) respectively then, and all the other two group model groups and normal group give the equivalent normal saline respectively.

2, result

The result shows, compares with normal group, and methionine feed group Hcy all significantly raises.Indopamide list medicine group, Rosuvastatin list medicine group does not all make significant difference to Hcy; Indopamide+Rosuvastatin group can significantly reduce the Hcy level, is better than list with indopamide group and Rosuvastatin group, shows that the two has significant synergism on reduction Hcy.

It is the independent hazard factor of body that brief summary: Hcy raises, and uses folic acid or Compound B vitamin effect in the treatment of clinical high Hcy unsatisfactory at present, even can produce untoward reaction.The compound medicine of this invention can further reduce Hcy, thereby reduces the Hcy damage, will be better selection, for the treatment of homocysteine provides more effective therapeutic scheme.

Claims (10)

1. treat the pharmaceutical composition that hyperhomocysteinemiainjury or homocysteine raise for one kind, comprising:

(1) indopamide of pharmaceutical dosage;

(2) statins of pharmaceutical dosage; And

(3) acceptable carrier on the pharmaceutics.

2. the described compositions of claim 1 is characterized in that: described statins is selected from a kind of in atorvastatin, Pitavastatin, the Rosuvastatin.

3. the described compositions of claim 2, it is characterized in that: atorvastatin content is that 5-80mg, Pitavastatin content are that 1-4mg, Rosuvastatin content are 5-80mg.

4. the described compositions of claim 1, it is characterized in that: the content of described indopamide is 0.2mg-5mg.

5. the described compositions of claim 4, it is characterized in that: the content of described indopamide is 0.625-2.5mg.

6. the described compositions of claim 2, it is characterized in that: the content of described indopamide is 0.625-2.5mg, Rosuvastatin content is 5-40mg.

7. the described compositions of claim 2, it is characterized in that: the content of described indopamide is 0.625-2.5mg, Pitavastatin content is 1-4mg.

8. the described compositions of claim 2, it is characterized in that: the content of described indopamide is 0.625-2.5mg, atorvastatin content is 10-80mg.

9. each described compositions in the claim 1 to 8 is characterized in that: this pharmaceutical composition can be made into conventional tablet, conventional capsule, granule, slow releasing tablet, sublingual lozenge, oral cavity quick disintegrating slice, dispersible tablet, enteric coatel tablets, enteric coated capsule, delayed-release tablet, regularly/position releasing piece, slow releasing capsule, controlled release capsule, contain micropill or small pieces capsule, contain pH dependent form capsule, granule, oral liquid, membrane, the patch dosage form of micropill or small pieces.

10. the purposes of each described compositions in the medicine of preparation treatment hyperhomocysteinemiainjury or homocysteine rising disease in the claim 1 to 9.