CN1688301A

CN1688301A - Dosage forms and related therapies

Info

Publication number: CN1688301A
Application number: CN 03824403
Authority: CN
Inventors: G·J·S·库珀; J·R·贝克; N·R·A·比利
Original assignee: PUROTMIX Ltd
Current assignee: PUROTMIX Ltd; Protemix Corp Ltd
Priority date: 2002-08-20
Filing date: 2003-08-20
Publication date: 2005-10-26

Abstract

This invention relates to novel doses, dosage formulations, and routes of administration of such doses and dose formulations, said dose and dose formulations containing one or more copper chelators, for example, one or more trientine active agents, including trientine analogues, trientine salts, trientine prodrugs, and trientine derivatives, useful in the treatment of diseases, disorders and conditions, including in indications where copper may play a role.

Description

Pharmaceutical dosage form and relevant therapeutic use

Technical field

The present invention relates to treat dosage and dosage form and their application (being called " treatment " here) in the method for the treatment of, reverse or improve mammiferous disease and/or disease of reagent.The mammal for the treatment of with the dosage and the dosage form of the present invention's description comprises suffering from the people that maybe might suffer from the damage of blood capillary and/or trunk, the for example damage of cardiovascular organization, be meant the mammal that comprises the people that suffers from the development that maybe may suffer from undesirable copper level especially, it comprises the development of copper level that can cause or cause including but not limited to the tissue injury of blood vessel injury.Described treatment includes but not limited to treat to improve whole or in part and/or to reverse the damage that is caused by disease, disorder or following symptom, the feature of this state is to be caused or the tissue that mediates and/or the damage of vascular system by copper, and/or is caused or the stem cell response of the normal structure that mediates by copper.The present invention by the active copper chelate matter of administration as, one or more triethyl group tetramines (trientine), the salt of triethyl group tetramine, the prodrug of triethyl group tetramine and the salt of described prodrug, the analog of triethyl group tetramine and the salt of described analog and prodrug, and/or the salt of the metabolite of active triethyl group tetramine and this metabolite and prodrug, include but not limited to N-acetyl triethyl group tetramine and salt and prodrug, especially can be applicable to the heart failure that for example diabetes are relevant or non-diabetic is relevant, the trunk i or I, microvascular disease or damage, and/or the i or I of poison (for example, hypertension) tissue and/or organ (comprises with heart failure, cardiomyopathy, the disease of myocardial infarction and related arteries and organ is the disease of feature).

Background technology

Following narration comprises and is used to understand various information of the present invention.Do not think that any information described here belongs to the prior art or the related content of description of the present invention and claims, do not think that any publication of special incorporated by reference or document can be as the documents of the patentability of estimating description of the present invention and claims yet.

Diabetes are a kind of chronic symptoms, it is characterized in that showing as the high sugar of fasting and can develop into early onset atherosclerosis widely.The M ﹠ M of diabetics is all because of the rising of cardiovascular disease, particularly coronary artery disease.The vascular complication of diabetics can be divided into the blood capillary disease that influences retina, kidney and nerve and mainly influence coronary vasodilator, cerebrovascular and peripheral arterial circulation trunk disease.

The chronic hyperglycemia of diabetes and the long-term damage of various organs, malfunction and depleted relevant, particularly eye, kidney, nerve, heart and blood vessel, the long-term complications of diabetes comprises the retinopathy with blind danger; The nephropathy that can cause renal failure; Can cause the peripheral neuropathy of foot ulcers, amputation and carbonization joint symptom; And the autonomic nerve sexually transmitted disease (STD) that causes gastronintestinal system, urinary system and cardiovascular system symptom becomes and sexual dysfunction.

Think and cause the mechanism of tissue injury to comprise histone and other macromolecular glycosylation and from the excessive generation of the polyhydric alcohol material of glucose because of chronic hyperglycemia.Diabetics has the sickness rate of atherosclerotic cardiovascular, peripheral blood vessel and the cerebrovascular disease of rising.Hypertension, lipoprotein metabolism is unusual, and periodontal also in diabetic population, find.

Hyperglycemia has been induced many changes of vascular tissue, promotes atherosclerotic acceleration probably.At present, except the non-enzymatic glycosylation of albumen and lipid, also have other two main mechanism, it has comprised great majority observed pathological change, i.e. activation of oxidative stress and Protein kinase C (PKC) in the diabetic animal and the mankind.Independent between these mechanism, for example, the formation of hyperglycemia inductive oxidative stress promotion AGEs and PKC activation, and 1 type and type 2 diabetes mellitus all are the risk factors of independently inducing coronary heart disease (CAD), apoplexy and peripheral arterial disease.Referring to Schwartz C.J., wait people's " Pathogenesis of theatherosclerotic lesion.Implications for diabetes mellitus, ", Diabetes Care15:1156-1167 (1992); Stamler J., Deng people's " Diabetes; other risk factors; and12-yr cardiovascular mortality for men screened in the Multiple RiskFactor Intervention Trial. ", Diabetes Care 16:434-444 (1993).Atherosclerosis has been explained the death that in fact 80% North America diabetics is arranged, and is equivalent to 1/3rd of the general crowd's death in whole North Americas, and the crowd that is in hospital who surpasses 75% diabetic complication is because cardiovascular disease.Referring to ADA, " Consensus statement:role ofcardiovascular risk factors in prevention and treatment of macrovasculardisease in diabetes; ", Diabetes Care 16:72-78 (1993).

In the decline of general American population cardiac patient mortality rate owing to the minimizing of cardiovascular morbidity factor and the improvement of disease treatment.Yet, do not embody the decline of observed deaths from heart disease rate with change of age in non-diabetic people in the diabetics, and the situation that mortality rate increases among the women of diabetes occurred suffering from.Referring to Gu K, wait people's " Diabetes and decline in heart disease mortality in U.S.adults, ", JAMA281:1291-1297 (1999).Also have report to say that diabetics has coronary artery and cerebrovascular atherosclerosis more widely than age and sex-matched non-diabetic contrast crowd.Referring to Robertson W.B. ， ﹠amp; Strong J.P., " Atherosclerosis in persons withhypertension and diabetesmellitus, ", Lab Invest 18:538-551 (1968).In addition, there is report to say that diabetics has and manyly relates to the coronary vasodilator pathological changes and Geng Duo fills the air the distributivity atherosclerotic lesions.Referring to WallerB.F., Deng the people " Status of the coronary arteries atnecropsy in diabetes mellitus with onset after age 30 years.Analysis of 229diabetic patients with and without clinical evidence of coronary heartdisease and comparison to 183 control subjects; ", Am JMed 69:498-506 (1980).

With the comparative study of diabetics with corresponding matched group, also report has the diabetics of suffering from CAD of the heart catheterization, angioplasty or the cononary artery bypass that have experienced the treatment acute myocardial infarction to suffer from even more serious near-end and terminal CAD significantly by in a large number.Referring to Granger C.B., Deng the people " Outcome of patients with diabetesmellitus and acute myocardial infarction treated with thrombolytic agents.The Thrombolysis and Angioplasty in Myocardial Infarction (TAMI) StudyGroup; ", JAm Coll Cardiol 21:920-925 (1993); Stein B., Deng the people " Influence of diabetes mellitus on early and late outcome afterpercutaneous transluminal coronary angioplasty; ", Circulation 91:979-989 (1995); Barzilay J.I., Deng the people " Coronary artery disease and coronary arterybypass grafting in diabetic patients aged＞or=65 years[from theCoronary Artery Surgery Study (CASS) Registry]; ", Am J Cardiol 74:334-339 (1994)).The evidence of obduction and blood vessel perspective also shows the ulcer speckle and the thrombotic remarkable increase of diabetics.Referring to Davies M.J., wait people's " Factorsinfluencing the presence or absence of acute coronary artery thrombi insudden ischemic death, ", Eur Heart J 10; 203-208 (1989); Silva J.A. waits people " Unstable angina.A comparison of angioscopic findings betweendiabetic and nondiabeticpatients, ", Circulation 92:1731-1736 (1995).

CAD causes causing type 2 diabetes mellitus patient's death, no matter be during which of diabetes in.Referring to Stamler I., Deng the people " Diabetes; other risk factors; and 12-yrcardiovascular mortality for men screened in the Multiple Risk FactorIntervention Trial; ", Diabetes Care 16:434-444 (1993); Donahue R.P. ， ﹠amp; Orchard T.J., " Diabetes mellitus and macrovascular complications.Anepidemiological perspective, ", Diabetes Care 15:1141-1155 (1992).The danger that increases cardiovascular disease especially in women crowd clearly.Referring to Barrett Connor E.L., Deng the people " Why is diabetes mellitus a stronger risk factor for fatal ischemicheart disease in women than in men? The Rancho Bemardo Study; ", JAMA265:627-631 (1991).The generation of CAD does not limit the particular type of diabetes, and it is all very general in 1 type and type 2 diabetes mellitus, and the mortality rate of cardiovascular disease significantly increased after 30 years old.Referring to KrolewskiA.S., Deng people's " Magnitude and determinants of coronaryartery disease in juvenile-onset; insulin-dependent diabetesmellitus, ", Am JCardiol 59:750-75 5 (1987).CAD incidence rate fast rise after being reported in 40 years old in the research in the time of 55 years old, has 35% masculinity and femininity patient to die from CAD in the type 1 diabetes, the mortality rate of its CAD is higher than non-diabetic people of the same age far away.

Type 1 diabetes patient's diabetic nephropathy also increases the concurrent sickness rate of CAD.Nephropathy causes the aggravation of accumulating of AGEs in body circulation and tissue, and causes similarly serious renal dysfunction.Referring to Makita Z., wait people's " Advanced glycosylation end products inpatients with diabetic nephropathy, ", N Engl J Med 325:836-842 (1991).In reaching the nephropathy change diabetics in late period, general mortality rate also is higher than the non-diabetic people of kindred circumstances.In all diabeticss, the mortality rate of the myocardial infarction of relative given age 1 year after making a definite diagnosis is 89 times of general population.Referring to Geerlings W., wait people's " Combined report on regular dialysis and transplantation in Europe, XXI, ", Nephrol Dial Transplant 64]: 5-29 (1991).Also have report to claim that the most conventional cause of the death of the diabetics of renal transplantation is CAD, have 40% to be among such patient the dead because of this.Referring to Lemmers M.J. ， ﹠amp; Barry J.M., " Major role for arterial disease inmorbidity and mortality after kidney transplantation in diabeticrecipients, ", Diabetes Care 14:295-301 (1991).

The degree and the persistent period that have confirmed hyperglycemia are the principal elements of type 2 diabetes mellitus microvascular complication morbidity.Referring to The Diabetes Control and Complications TrialResearch Group, " The effect of intensive treatment of diabetes on thedevelopment and progression of long-term complications ininsulin-dependent diabetes mellitus; ", N EngJ Med 329:977-986 (1993).Yet, the order of severity of trunk complication not fully aware of and the degree of diabetes or the relation between the persistent period, it is tangible that the CAD sickness rate of saying the type 2 diabetes mellitus patient of new diagnosis according to reports generally improves.Referring to Uusitupa M., Deng the people " Prevalence of coronary heartdisease; left ventricular failure and hypertension in middle-aged; newlydiagnosed type2 (non-insulin dependent) diabetic subjects; ", Diabetologia28:22-27 (1985).Also have report to say that the glucose tolerance that reduces also can cause the rising of cardiovascular disease incidence rate, although it has reduced hyperglycemia.Referring to Fuller J.H., wait people's " Coronary-heart-disease risk and impaired glucose tolerance.TheWhitehall study, ", Lancet 1:1373-1376 (1980).

It also is worldwide trend that the onset diabetes rate rises.The case number of type 2 diabetes mellitus reached 135,000,000 in 2000, and will surpass 300,000,000 in 2025.These increase relevant with the increase of people's life-span prolongation, obese people and inferior socioeconomics.World's statement-of-health in 1997 referring to WHO.As a result of, the mortality rate of diabetes rises in nearest 10 years to some extent, and the mortality rate of cardiovascular disease, apoplexy and malignancy disease remains unchanged or decreases.Referring to U.S. health research center.The reason of type 2 diabetes mellitus death comprises cardiovascular disease, 58%; Cerebrovascular disease, 12%; Nephropathy, 3%; Diabetic coma, 1%; And malignant tumor, 11%.

The further feature of diabetic cardiopathy is at the even more serious CAD of young patient, 4 times of heart failure incidence rates that amount increases, back acute myocardial infarction and left ventricular hypertrophy and the increase of unbecoming property.Referring to Struthers A.D. ， ﹠amp; Morris A.D., Lancet 359:1430-2 (2002).The increase of the unbecoming property of mortality rate among the type 2 diabetes mellitus patient be presented at also that the back acute myocardial infarction takes place 24 hours.Emergent interventional therapy can improve this danger.Referring to Malmberg K., BrMed J 314:1512-5 (1997).

PCT application No.PCT/NZ99/00161 (publishes with WO00/18392,2000.04.06) relate to treating and bring out easily and/or suffer the mammal of diabetes so that the method that its trunk and microvascular lesions alleviate, it comprises, except the treatment of glucose level control, also has the control at least one the fixing time to for example copper.Its determination and analysis method applies for that at PCT No.PCT/NZ99/00160 (publishes with WO00/18891,2000.04.06) the middle description.Different therapeutic agents are then described in PCT/NZ99/00161.Comprising copper chelator.

The natural metal that exists in health, many be cell necessary (Cu for example, Fe, Mn, Ni, Zn).Yet all metals all are virose when high concentration.The deleterious reason of metal can cause that with metal oxidative stress is relevant, the transition metal that redox active is particularly arranged, it can (for example admit or provide electronics, Fe2+/3+, Cu+/2 ±), cause increasing of free radical cause damage (referring to people such as Jones " Evidence for the generation ofhydroxyl radicals from a chromium (V) intermediate isolated from thereaction of chromate with glutathione; ", Biochim.Biophys.Acta 286:652-655 (1991); Li, Y.﹠amp; Trush, M.A., " DNA damage resulting from theoxidation of hydroquinone by copper:role for a Cu (II)/Cu (I) redox cycleand reactive oxygen generation; ", Carcinogenes 7:1303-1311 (1993)).Metal can be replaced other essential metal or enzyme, destroys the function of these molecules and therefore has toxicity.Some metal ions (for example, Hg+ and Cu+) are very easy to and the mercapto groups reaction, influence proteinic 26S Proteasome Structure and Function.

Here, the patient of type 2 diabetes mellitus or abnormal glucose metabolism causes heart failure especially easily, and the disease of other arterial tree.Existing report is said the influence of dying from cardiovascular disease in western countries above 50% type 2 diabetes mellitus patient.Referring to Stamler, wait people's Diabetes Care16:434-44 (1993).Also have report to say that the glucose intolerance of the low degree of being determined by glucose tolerance test (glucose tolerance reduces, or " IGT ") still can cause the increase of sudden death danger.Referring to Balkau, wait people's Lancet 354:1968-9 (1999).In the long time, suppose the increase that it reflects coronary atherosclerosis sickness rate and myocardial infarction in the diabetics.Yet evidence shows that under the situation that does not have atherosclerotic coronary heart disease, the glycosuria condition of disease causes specific heart failure or cardiomyopathy.

Cardiac function can be assessed by measuring ejection fraction usually.Normal left ventricle can eject the blood volume of 50% ED volume at least when pumping each time.The common left ventricle of the patient of systole heart failure can only eject less than 30%, and compensatory increases ED volume.Carry out in not having the diabetics of tangible congestive heart failure that normal left ventricle contractile function (LV ejection fraction) has been observed in hematodinamics research but unusual diastolic function shows left ventricle diastole or perfusion injury.Referring to Regan, wait people's J Gun.Invest.60:885-99 (1977).In nearest research, there be not 60% among the type 2 diabetes mellitus patient of the heart failure performance on the clinical meaning to have diastolic filling to show unusually, its assessment is undertaken by ultrasoundcardiogram.Referring to Poirier, wait people's Diabetes Care 24:5-10 (2001).Diagnosis is finished by for example non-damage determination method.In not having the patient of mitral stenosis, the Bicuspid valve relaxing period blood flow that utilizes doppler echocardiography to measure can be directly used in the perfusion situation of measuring left ventricle.The most conventional algoscopy is the AlE ratio.Normal early stage diastolic filling is fast, and the speed that it is characterized by E-wave is about 1 meter per second.The diastolic filling in late period that atrial systole produces only is a submember, its A type wave propagation velocity is that the chances are 0.5 meter per second.This has provided normal AIE ratio, is about 0.5.For diastolic dysfunction, early stage diastolic filling is impaired, and atrial systole provides compensatory to increase, and the AlE ratio increases to and surpasses 2.0.

No matter the treatment of diabetic cardiomyopathy reverses or improves, and all is difficult, and to select be limited.Strict control to blood sugar level can prevent or reverse heart failure, but this is feasible at the ventricular failure commitment just.Angiotensin-convertion enzyme inhibitor such as mercaptomethyl propionyl proline can improve the survival of heart failure, particularly to serious systole heart failure and the exponential patient of grazing shot blood.Yet, have many therapys of not recommending diabetic cardiomyopathy.For example, the contractility medicine can improve the contraction of failure heart.But the heart of simple diastolic dysfunction is normal contraction, and be sure of that the contractility medicine can increase ARR possibility.In addition, the vasodilation that can reduce afterload and improve the emptying of ventricle also can be used, because it is normal to penetrate blood exponential sum end-diastolic dimension.The reduction of afterload may worsen cardiac function because of producing outflow obstruction.

Diuretic is the main medicine of treatment heart failure, and it is storing and reducing filling pressure and be effective by control salt and water.But it is incompatible using diuretic in the diastolic dysfunction treatment, and wherein Zhe Zhong cardiac pump function will depend on high filling pressure to keep cardiac output.Venectasia medicine such as nitrate can be used for the treatment of systole heart failure very effectively by reducing preload and filling pressure, and tolerance is lower for the relaxing period patients with heart failure but should understand.It is all normal usually to penetrate the blood exponential sum end systolic volume, and the reduction of any preload all can cause cardiac output significantly to descend.They at last, also relate to the application of receptor blocking agent aspect heart failure, because may worsen pumping function.Also relate to the administration of receptor blocking agent to diabetics, described patient may cause serious hypoglycemic situation with sulfonylureas medicine and insulin.

Therefore, be appreciated that disease and the mechanism that comprises the diabetes long-term complications relevant with heart disease and long-term complications according to different hearts, trunk system, blood capillary system, be very complicated and passed through and study for a long period of time, and unclear the disclosure, the safety and effectiveness of its treatment is not understood yet.The demand that therefore described treatment is arranged is as the explanation in description of the present invention and claims.

Will also be understood that needs a kind of pharmaceutical composition, its can the addressing cardiovascular damage that causes of disease, disorder or the symptom of tree (comprising heart) and corresponding organ (for example retina, kidney, neural or the like), it comprises, relates to or about for example raising or the level of unwanted copper, as the level of free copper in the acellular that raises.The compositions that Therapeutic Method described here also provides the prolongation of the controlled release of low dosage and/or low dosage to discharge, it is used to reverse and/or improve the structural damage of suffering from or not suffering from the experimenter of diabetes, it has the copper level that can reduce with treatment heart, trunk system, blood capillary systemic disease and/or long-term diabetic complication, and comprises the damage of cardiac structure.Cardiac structure damage includes but not limited to that the deposition of the expansion of forfeiture, ECS of atrophy, myocardial cell and extracellular matrix increases (and the consequence that is caused) and/or is selected from is the coronary artery structural damage (reaching the consequence that is caused) of intermediate layer damage (Musclar layer) and theca interna (endodermis) at least, contractile function, diastolic function, contractility, recoil feature and penetrate the blood index.

Can treat with method and composition of the present invention with organ diseases associated, disorder and the symptom of cardiovascular tree and/or dependence, it comprises, for example any or multiple following treatment of diseases: (1) cardiomyopathy (cardiomyopathy or myocarditis) is as idiopathic cardiomyopathy, the metabolic cardiomyopathy that comprises diabetic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy and hypertensive cerebral cardiomyopathy; (2) for example aorta, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery He popliteal tremulous pulse of the atherosclerosis (trunk systemic disease) of main blood vessel; (3) poison, drug-induced, and metabolism (comprise the hypertension of little blood vessel and/or diabetes (blood capillary systemic disease) as retina small artery, glomerulus small artery, neural blood vessel small artery, heart small artery and and eye, kidney, heart and maincenter and the relevant blood vessel of peripheral nervous system capillary bed; And the atherosclerosis zone speckle of (4) main blood vessel such as aorta, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery He popliteal tremulous pulse breaks.

Summary of the invention

The present invention is a part based on as novel dosage and dosage form at the treatment of effective reduction free copper, for example treats or prevents trunk as herein described, blood capillary, and/or poisoning/metabolic disease, and process of tissue reparation.The metabolism of this and experimenter's glucose is irrelevant, with whether to relate to Fructosamine oxidase in these diseases also irrelevant.The invention still further relates to be used for the treatment of with diabetics in have a redox active the transiting state metal ion accumulate the dosage form of relevant cardiovascular disease.

Under physiological condition, thus to the damage of Target organ by stem cell perception at a distance to the damage location migration and help the reparation of 26S Proteasome Structure and Function through differentiation of stem cells.Treatment as described herein can also slow down particularly copper accumulating in the cardiac muscle of diabetics or vascular tissue of oxidation-reduction quality transition metal with dosage and dosage form, do not wish to be bound by theory, it is believed that this is accumulated is to follow the influence that is subjected to stem cell migration and suppress the regenerated of normal structure.The situation of the normal biological behaviour of the rising of copper level inhibition undifferentiated cell and diabetes is irrelevant in the tissue, though this situation is very common in the mammal that comprises the people that suffers from diabetes.

The glucose tolerance reduction that symptom that occurs in described diabetes and/or normal stem cell response suppress can cause the damage of normal structure response, and use treatment as described herein and can improve this situation, comprise following content with the level that dosage and dosage form reduce copper:

1. heart failure.The significant orthogenesis that can occur heart tissue in a couple of days behind the heart transplant operation.Possible mechanism is the migration of the stem cell of heart outside, and the cell differentiation that reaches then forms various heart cells, comprises myocardial cell, endotheliocyte and coronary vasodilator cell.Accumulating of our verified copper in heart tissue may these regenerative responses of grievous injury, and can application examples such as copper chelator in acute intravenous therapy, be used for the treatment of heart failure including but not limited to the diabetic heart failure.

2. acute myocardial infarction (AMI).AMI often follows proliferation of cells in the ventricular muscles, for example AMI can occur in described diabetes.The rising of oxidation-reduction quality transition metal level can suppress the normal stem cell response, causes the structural damage and the functional reparation of damaged tissue.The mechanism of the impairment of cardiac function in diabetics is for example be sure of the toxic action that the transition metal in the tissue kinetics is accumulated, and responds the damage that causes tissue regeneration by suppressing from the outside to regulate the normal stem cell that physiological tissue's regeneration produces to the damaged tissues migration.The treatment of AMI for example for diabetics as herein described, can give described copper chelator by acute mode (if necessary, adopting parenteral administration) or chronic mode and be improved.

3. wound healing and ulcer.The repair process of normal structure needs the intervention of active stem cell, and it can influence the reparation of each different layers of blood vessel.Transition metal (particularly copper) accumulating in vascular tissue causes the tissue injury of diabetic character, comprise that the operation or the repair in trauma of wound and ulcer surface enlarge and more after not good.The treating diabetes that the application copper chelator carries out before operation or in the tissue injury as herein described can also advantageously be used dosage as described herein and dosage form.If too much transition metal is removed from blood vessel before operation, the operation of diabetics just has better result.Can finish this purpose by acute (parenteral introduction treatment) and/or chronic mode (oral administration treatment) before the actual operation.

4. infect the tissue injury that causes.Metainfective normal structure repair process need can migrate to damaged tissue so that the intervention of the active stem cell of its regeneration and reparation, for example, and to the regeneration and the reparation of each different layer of blood vessel.The reparation meeting of these tissue injurys is impaired because of being suppressed stem cell response, and is caused as oxidation-reduction quality transition metal (particularly copper) accumulating in tissue, for example, and in blood vessel wall.In diabetics, the reparation of tissue injury comprises that for example metainfective reparation can be improved with dosage and dosage form by using treatment as described herein.

5. diabetic injury of kidney.Copper chelator by giving dosage of the present invention and dosage form has the recovery of the healing that the renal failure treatment of conditions can be by normal structure to improve the reproduction condition of organ to diabetes and other, and the recovery of the healing of normal structure is by making normal migration and the differentiation of stem cell realize.

Yet, even the mammal of non-diabetic type with do not have in the mammal of unusual glucose mechanism, the reduction of extracellular copper level also is favourable, the reduced levels of copper can cause the alleviating of tissue injury of copper mediation, and/or improves tissue repair by recovering the response of normal structure stem cell.

In the research of the rat model of described application streptozotocin type diabetes (STZ), find that the animal center of severe diabetes mellitus is dirty and tissue injury's incidence rate coronary tissue is all very high here, and with the situation of this inference the pure man.In one aspect, the present invention has illustrated and has reduced the method for suffering from or do not suffer from experimenter's free copper level of diabetes, the patient who does not particularly suffer from Wilson's disease, it has the copper level that can reduce, and this reduction is to obtain by the reagent that can reduce patient's copper level that gives effective dose.

Preferred copper chelator is the triethyl group tetramine, comprises triethyl group tetramine acid-addition salts, and active metabolite, comprises for example N-acetyl triethyl group tetramine and analog, derivant and prodrug.The other title of triethyl group tetramine comprises N, N '-two (2-amino-ethyl)-1,2-ethane two-amine; Trien (" TETA "); 1,8-diaminourea-3,6-diaza octane; 3,6-diaza octane-1,8-diamidogen; 1,4,7,10-four azepine decane; Trientine; TECZA; And triolefin.In a specific embodiment, the triethyl group tetramine does not have alkalescence (for example as the acid-addition salts form).

In another embodiment, the triethyl group tetramine can be modified, that is, can be the analog or the derivant (or the analog or the derivant of the triethyl group tetramine metabolite of copper chelating, for example N-acetyl triethyl tetramine) of triethyl group tetramine.The derivant of triethyl group tetramine or triethyl group tetramine salt or its analog comprise what those were modified by Polyethylene Glycol (PEG).The structure of PEG is HO-(CH ₂-CH ₂-O-) _n-H.It can be the neutral polyethers of straight or branched, and different molecular weight can be arranged.The analog of triethyl group tetramine comprises the chemical compound that the one or more NH groups in the triethyl group tetramine are replaced by sulphur atom.Other analog comprise the triethyl group tetramine be modified to additional one or more extra-CH ₂The chemical compound of group.The chemical formula of triethyl group tetramine is NH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH ₂Its empirical formula is C ₆N ₄H ₁₈The example of triethyl group tetramine analog comprises:

1.SH-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH ₂，

2.SH-CH ₂-CH ₂-S-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH ₂，

3.NH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-S-CH ₂-CH ₂-SH，

4.NH ₂-CH ₂-CH ₂-S-CH ₂-CH ₂-S-CH ₂-CH ₂-SH，

5.SH-CH ₂-CH ₂-S-CH ₂-CH ₂-S-CH ₂-CH ₂-SH，

6.NH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH ₂，

7.SH-CH ₂-CH ₂-NH-CH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH ₂，

8.SH-CH ₂-CH ₂-S-CH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-NH ₂，

9.NH ₂-CH ₂-CH ₂-NH-CH ₂-CH ₂-CH ₂-S-CH ₂-CH ₂-SH，

10.NH ₂-CH ₂-CH ₂-S-CH ₂-CH ₂-CH ₂-S-CH ₂-CH ₂-SH，

11.SH-CH ₂-CH ₂-S-CH ₂-CH ₂-CH ₂-S-CH ₂-CH ₂-SH，

12. or the like.

One or more oh groups also can replace one or more amine groups, generate triethyl group tetramine analog (one or more nitrogen-atoms by or do not replaced by one or more sulphur atoms).Other analog comprises non-annularity and cyclic analogs, is represented by following general formula I and general formula I I.

In another embodiment, the triethyl group tetramine is as the copper chelating metabolite release of the prodrug of triethyl group tetramine or triethyl group tetramine.

The salt of triethyl group tetramine (optional can be the salt of the copper chelating metabolite of the prodrug of triethyl group tetramine or triethyl group tetramine) comprises acid-addition salts in a specific embodiment, as suitable inorganic or organic acid salt.The salt of triethyl group tetramine (acid-addition salts, for example disalt triethylenetetraminehexaacetic acid urotropine) can be used as copper chelator, can get rid of copper in body by the complex of can be easily being discharged by kidney that forms stable solubility with copper.

Another aspect of the present invention provides following a kind of method, (1) comprehensively or part improve or reverse damage (for example atrophy of at least a or multiple patient's cardiac structure, myocyte's forfeiture, ECS expands, and/or the increase of extrtacellular matrix deposition (and consequence), and/or (2) improve one or more contractile functions comprehensively or partly, diastolic function, contractility, recoil feature and ejection fraction are (for example by ultrasonic mensuration, MRI or other imaging technique are determined), and/or improve or the reverse cardiac muscle comprehensively or partly (3), the trunk disease, the damage of the disease diseases such as (and consequences) of the atherosclerotic plaque rupture damage of microvascular disease and/or main blood vessel, and/or (4) comprehensively or part improve or reverse by diabetic nephropathy, diabetic nephropathy, copper is accumulated and/or damage that injury of renal artery causes kidney.This method can comprise:

(i) the diagnosis mammal may suffer from the damage that can be enhanced and/or reverse to small part, and

(ii) feed the compositions of animal triethyl group tetramine as described herein activating agent.

In a specific embodiment, compositions is can be the dosage form that the experimenter provides lower effective dose of " QID " that compare the Wilson's disease therapeutic scheme and less pulsile irradiation dose.

Another aspect of the present invention comprises the method for all or part of improvement or reverse, it is used for (I) and suffers from the people of diabetes or the animal of other trouble diabetes, or (II) have people or other animal of the copper level of the increase (and the consequence that causes) of the expansion that can reduce (" experimenter ") one or more atrophys, myocyte forfeiture, ECS and/or extrtacellular matrix deposition and/or coronary artery structural damage, comprise the coronary artery structural damage (reaching the consequence that is caused) of intermediate layer damage (Musclar layer) and theca interna (endodermis).Described method comprises or comprises to experimenter's administration or automedication slowly or continue the dosage form of the amount that enough chelated coppers are provided that discharges, described dosage form contains triethyl group tetramine activating agent, the metabolite of the prodrug of the salt of the salt of at least a triethyl group tetramine, prodrug or prodrug, analog or analog or salt and/or triethyl group tetramine or the salt of metabolite or prodrug include but not limited to N-acetyl triethyl group tetramine and salt thereof and prodrug (" triethyl group tetramine activating agent ").

Described experimenter treats as vulnerable crowd before treatment in a specific embodiment.

Another aspect of the present invention is the method that comprises all or part of improvement or reverse, it is used for one or more systole malfunctions of experimenter, the relaxing period malfunction, contractility, recoil feature that shortage needs and/or the exponential function of blood of penetrating that needs (can be by ultrasonic mensuration, MRI or other imaging technique are determined), cardiomyopathy, the trunk disease, the atherosclerotic plaque rupture (and the consequence that causes) of microvascular disease and microvascular disease and main blood vessel, described experimenter can be that (I) suffers from diabetic subjects, also can be that (II) has the experimenter that can reduce copper level, described method comprises for example low dosage of the amount of enough chelated coppers that effective treatment is provided to the experimenter, slowly and/or the dosage form of controlled release, described dosage form comprises one or more copper chelators, for example one or more triethyl group tetramine activating agents.

The disease of usually said usefulness tissue substance of the present invention and handling procedure treatment, disorderly and symptom includes but not limited to one or more of the following stated: diabetic cardiomyopathy, diabetic acute coronary syndrome (for example myocardial infarction MI), the diabetic hypertension cardiomyopathy, reduce (IGT) relevant acute coronary syndrome with glucose tolerance, with fasting glucose damage (IFG) relevant acute coronary syndrome, the hypertensive cerebral cardiomyopathy relevant with IGT, the hypertensive cerebral cardiomyopathy relevant with IFG, the ischemic cardiomyopathy relevant with IGT, the ischemic cardiomyopathy relevant with IFG, with the relevant ischemic cardiomyopathy of coronary heart disease coronary atherosclerosis (CHD), with the irrelevant acute coronary syndrome of glucose metabolism, with the irrelevant hypertensive cerebral cardiomyopathy of glucose metabolism, with the irrelevant ischemic cardiomyopathy (not considering whether be the ischemic cardiomyopathy relevant) of glucose metabolism with the coronary heart disease coronary atherosclerosis, and one or more tree-shaped angiopathys, comprise aorta, carotid artery, cerebrovascular, coronary vasodilator, renal blood vessels, retinal vessel, vasa nervorum, the ilium blood vessel, femur blood vessel popliteal portion blood vessel, the disease of small artery tree and capillary bed.

The further aspect of the present invention comprises the application of the dosage form of at least a triethyl group tetramine activating agent and other suitable material, be used for that preparation is used for comprehensively or part is improved or reverse (I) suffer from diabetes or (II) can reduce copper level the experimenter with one or more contractile functions, diastolic function, contractility, recoil characteristics and penetrate the blood index (can be by ultrasonic mensuration, MRI or other imaging technique are determined), and/or one or more come from by diabetic nephropathy to small part, diabetic nephropathy and/or copper are accumulated kidney, and/or the damage that causes of injury of renal artery, and/or be selected from one or more atrophys, the myocardial cell forfeiture, the damage of the cardiac structure that the deposition of ECS expansion and extracellular matrix increases, and/or the damage coronarius that is selected from is that the damage of intermediate layer (Musclar layer) and theca interna (endodermis) the slow release relevant or injury in treating that has nothing to do is put dosage form at least.

Another aspect of the present invention provides a kind of experimenter's of processing method, described experimenter has one or more symptoms as described herein, this method comprises that parenteral administration contains the compositions of the copper chelator for the treatment of effective dose, wherein treat effective dose be meant approximately every dose and/or every day 5mg-1100mg.

Copper chelator is a triethyl group tetramine activating agent in a specific embodiment.Triethyl group tetramine activating agent comprises the salt or the prodrug of salt, triethyl group tetramine analog or this analog of salt, triethyl group tetramine prodrug or this prodrug of triethyl group tetramine, and/or the salt of the metabolite of at least a triethyl group tetramine or this metabolite or prodrug, include but not limited to the salt and the prodrug of N-acetyl triethyl group tetramine and N-acetyl triethyl group tetramine.Triethyl group tetramine activating agent also comprises the analog of general formula I and II.

In a specific embodiment, the triethyl group tetramine activating agent of other treatment effective dose includes but not limited to the triethyl group tetramine, triethyl group tetramine salt, the triethyl group tetramine analog of general formula I and II, or the like, its effective dose comprises 10mg-1100mg, 10mg-1000mg, 10mg-900mg, 20mg-800mg, 30mg-700mg, 40mg-600mg, 50mg-500mg, 50mg-450mg, from the extremely about 400mg of 50-100mg, from the extremely about 300mg of 50-100mg, 110-290mg, 120-280mg, 130-270mg, 140-260mg, 150-250mg, 160-240mg, 170-230mg, 180-220mg, 190-210mg, and/or any other amount in illustrated scope.

Compositions can comprise for example solution, suspending agent, Emulsion according to the efficient requirement of parenteral administration, can be by subcutaneous, vein, intramuscular, intradermal, intrasternal injection or infusion techniques administration.

Preparation can further comprise the material of any or multiple the following stated: buffer agent, for example acetate, phosphate, citrate or glutamate, Glu buffer agent with the final pH value scope that obtains preparation greatly about 5.0-9.5, carbohydrate or polyhydric alcohol regulator, can be selected from for example m-cresol, benzyl alcohol, methyl, ethyl, the antimicrobial preservative of propyl group and butyl p-Hydroxybenzoate (paraben) class and phenol, and stabilizing agent.

Use enough water for injection to obtain the solution of desired concn.If necessary, sodium chloride and other adjuvant also can be used.But these adjuvants must be able to be kept the overall stability of triethyl group tetramine activating agent.

Preparation of the present invention should be isoosmotic substantially.Isosmotic solution can be defined as and contain certain density electrolyte, non-electrolyte or its combination so that can form the osmotic pressure that equates in its introducing mammalian tissues." basic wait ooze " meaning is ± 20% with interior isotonicity, preferably in ± 10%.The product of preparation can be included in the container, for example is typically in medicine bottle, socket, prefilled syringe or the disposable shaft of a writing brush.

Another aspect of the present invention provides the compositions of parenteral introduction, and said composition comprises the copper chelator for the treatment of effective dose, and it can have the experimenter of one or more symptoms as described below.

These symptoms comprise diabetic cardiomyopathy, diabetic acute coronary syndrome (myocardial infarction-MI) for example, the diabetic hypertension cardiomyopathy, reduce (IGT) relevant acute coronary syndrome with glucose tolerance, with fasting glucose damage (IFG) relevant acute coronary syndrome, reduce (IGT) relevant hypertensive cerebral cardiomyopathy with glucose tolerance, with fasting glucose damage (IFG) relevant hypertensive cerebral cardiomyopathy, reduce (IGT) relevant ischemic cardiomyopathy with glucose tolerance, with fasting glucose damage (IFG) relevant ischemic cardiomyopathy, with the relevant ischemic cardiomyopathy of coronary heart disease (CHD), cardiac muscle disease (cardiomyopathy or myocarditis) comprises idiopathic cardiomyopathy, metabolic cardiomyopathy (comprises diabetic cardiomyopathy, alcoholic cardiomyopathy, drug-induced property cardiomyopathy, ischemic cardiomyopathy and hypertensive cerebral cardiomyopathy), with the irrelevant acute coronary syndrome of abnormal glucose metabolism, with the irrelevant hypertensive cerebral cardiomyopathy of abnormal glucose metabolism, with the irrelevant ischemic cardiomyopathy (not considering whether ischemic cardiomyopathy is relevant with coronary heart disease) of abnormal glucose metabolism and the disease of one or more vascular trees, comprise aorta, carotid artery and comprise the tremulous pulse cerebral arteries, coronary artery, renal artery, arteria retina, iliac artery, femoral artery popliteal tremulous pulse, vasa nervorum, small artery tree and capillary bed are in interior disease, the atherosclerosis such as the aorta of main blood vessel (trunk disease), coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery is with the disease of popliteal tremulous pulse, include but not limited to atrophy, myocyte's forfeiture, the deposition of ECS expansion and extracellular matrix increases the cardiac structure damage of (and the consequence that causes) and/or is selected from the coronary artery structural damage of the damage (and the consequence that causes) that is intermediate layer (Musclar layer) and/or theca interna (endodermis) at least, the plaque rupture such as the aorta of the atherosclerotic lesions of main blood vessel, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery is with the disease of popliteal tremulous pulse, the systole malfunction, diastolic dysfunction, the contractility disorder, recoil feature and penetrate the blood index, toxicity, drug-induced and Developmental and Metabolic Disorder comprises that the diabetic disease (microvascular disease) of hypertension and/or little blood vessel is as the retina small artery, the glomerulus small artery, vasa nervorum, heart small artery and relevant eye, kidney, the capillary bed of heart and maincenter and peripheral nervous system.

Copper chelator is a triethyl group tetramine active agent in a specific embodiment.Triethyl group tetramine active agent comprises salt or the active metabolite of prodrug and/or at least a triethyl group tetramine or the salt or the prodrug of this metabolite of salt, triethyl group tetramine analog or this analog of salt, triethyl group tetramine prodrug or this prodrug of triethyl group tetramine, includes but not limited to the salt and the prodrug of N-acetyl triethyl group tetramine and N-acetyl triethyl group tetramine.

The copper chelator of treatment effective dose, for example, one or more triethyl group tetramine activating agents include but not limited to triethyl group tetramine analog of triethyl group tetramine, triethyl group tetramine salt, general formula I and II or the like, its effective dose is about every day of 5mg-1200mg.Other is treated effective dosage range and comprises 10mg-1100mg, 10mg-1000mg, 10mg-900mg, 20mg-800mg, 30mg-700mg, 40mg-600mg, 50mg-500mg, 50mg-450mg, from the extremely about 400mg of 50-100mg, from the extremely about 300mg of 50-100mg, 110-290mg, 120-280mg, 130-270mg, 140-260mg, 150-250mg, 160-240mg, 170-230mg, 180-220mg, 190-210mg, and/or any other amount in illustrated scope.

According to the efficient requirement of parenteral administration, compositions can comprise for example solution, suspending agent, Emulsion, can be by subcutaneous, vein, intramuscular, intradermal, intrasternal injection or infusion techniques administration.

Preparation can further comprise the material of any or multiple the following stated: buffer agent, for example acetate, phosphate, citrate or glutamate, Glu buffer agent with the final pH value scope that obtains preparation greatly about 5.0-9.5, carbohydrate or polyhydric alcohol regulator, can be selected from m-cresol, benzyl alcohol, methyl, ethyl, the antimicrobial preservative of propyl group and butyl parabens and phenol, and stabilizing agent.

The copper chelator that another aspect of the present invention provides the treatment effective dose has the purposes aspect experimenter's the medicine of one or more following symptoms in preparation treatment: diabetic cardiomyopathy, diabetic acute coronary syndrome (myocardial infarction-MI) for example, the diabetic hypertension cardiomyopathy, reduce (IGT) relevant acute coronary syndrome with glucose tolerance, with fasting glucose damage (IFG) relevant acute coronary syndrome, reduce (IGT) relevant hypertensive cerebral cardiomyopathy with glucose tolerance, with fasting glucose damage (IFG) relevant hypertensive cerebral cardiomyopathy, reduce (IGT) relevant ischemic cardiomyopathy with glucose tolerance, with fasting glucose damage (IFG) relevant ischemic cardiomyopathy, with the relevant ischemic cardiomyopathy of coronary heart disease (CHD), cardiac muscle disease (cardiomyopathy or myocarditis) comprises idiopathic cardiomyopathy, metabolic cardiomyopathy (comprises diabetic cardiomyopathy, alcoholic cardiomyopathy, drug-induced property cardiomyopathy, ischemic cardiomyopathy and hypertensive cerebral cardiomyopathy), with the irrelevant acute coronary syndrome of abnormal glucose metabolism, with the irrelevant hypertensive cerebral cardiomyopathy of abnormal glucose metabolism, with the irrelevant ischemic cardiomyopathy (not considering whether ischemic cardiomyopathy is relevant with coronary heart disease) of abnormal glucose metabolism and the disease of one or more vascular trees, comprise aorta, carotid artery and comprise the tremulous pulse cerebral arteries, coronary artery, renal artery, arteria retina, iliac artery, femoral artery popliteal tremulous pulse, vasa nervorum, small artery tree and capillary bed are in interior disease, the atherosclerosis such as the aorta of main blood vessel (trunk disease), coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery is with the disease of popliteal tremulous pulse, include but not limited to atrophy, myocyte's forfeiture, the deposition of ECS expansion and extracellular matrix increases the cardiac structure damage of (and the consequence that causes) and/or is selected from the coronary artery structural damage of the damage (and the consequence that causes) that is intermediate layer (Musclar layer) and/or theca interna (endodermis) at least, the plaque rupture such as the aorta of the atherosclerotic lesions of main blood vessel, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery is with the disease of popliteal tremulous pulse, the systole malfunction, diastolic dysfunction, the contractility disorder, recoil feature and penetrate the blood index, toxicity, drug-induced and Developmental and Metabolic Disorder comprises that the diabetic disease (microvascular disease) of hypertension and/or little blood vessel is as the retina small artery, the glomerulus small artery, vasa nervorum, heart small artery and relevant eye, kidney, the capillary bed of heart and maincenter and peripheral nervous system.

Copper chelator is a triethyl group tetramine activating agent in a specific embodiment.Triethyl group tetramine activating agent comprises salt or the active metabolite of prodrug and/or at least a triethyl group tetramine or the salt or the prodrug of this metabolite of salt, triethyl group tetramine analog or this analog of salt, triethyl group tetramine prodrug or this prodrug of triethyl group tetramine, includes but not limited to the salt and the prodrug of N-acetyl triethyl group tetramine and N-acetyl triethyl group tetramine.

The copper chelator of treatment effective dose, for example, triethyl group tetramine activating agent includes but not limited to triethyl group tetramine analog of triethyl group tetramine, triethyl group tetramine salt, general formula I and II or the like, its effective dose is about every day of 5mg-1200mg.Other is treated effective dosage range and comprises 10mg-1100mg, 10mg-1000mg, 10mg-900mg, 20mg-800mg, 30mg-700mg, 40mg-600mg, 50mg-500mg, 50mg-450mg, from the extremely about 400mg of 50-100mg, from the extremely about 300mg of 50-100mg, 110-290mg, 120-280mg, 130-270mg, 140-260mg, 150-250mg, 160-240mg, 170-230mg, 180-220mg, 190-210mg, and/or any other amount in illustrated scope.

Preparation of the present invention should be isoosmotic.Isosmotic solution may be defined as and contains certain density electrolyte, non-electrolyte or its combination so that can form the osmotic pressure that equates in its introducing mammalian tissues." basic wait ooze " meaning is ± 20% with interior isotonicity, preferably in ± 10%.The product of preparation can be included in the container, for example is typically in medicine bottle, socket, prefilled syringe or the disposable shaft of a writing brush.

Here, parenteral administration includes but not limited to one or more following route of administration: administration in the subcutaneous administration, intravenously administrable, intramuscular administration, intraperitoneal administration, breastbone, intra-articular administration or breastbone inner injection or infusion techniques aqueous or the non-aqueous solution or the suspension of aseptic injection (for example as); Nose administration is as sucking spray delivery; Topical is as with Emulsion or ointment form; Or vagina administration.

Therapeutic Method can be monitored by the situation of copper in the 24 hours periodic analysis urine.Urine must be collected with not copper bearing glass drying oven.If the amount of copper thinks then that in the 0.5-1.0 milligram quantities patient is in ideal negative balance of copper state in the urine that 24 hours periods are collected.

One aspect of the present invention provides to handle has for example experimenter's of one or more symptoms as herein described method, comprise through a kind of compositions of parenteral route administration, said composition contains the copper chelator for the treatment of effective dose, the treatment effective dose of described parenteral administration be every dose dosage range at about 0.1mg/kg-40mg/kg, the body weight that is based on the experimenter is calculated.

In another embodiment, the copper chelator of treatment effective dose, for example, triethyl group tetramine activating agent, include but not limited to triethyl group tetramine analog of triethyl group tetramine, triethyl group tetramine salt, general formula I and II or the like, its treatment effective dose is about every day of 5mg-1200mg.Other treat effective dosage range comprise 10mg-1100mg, 10mg-1000mg, 10mg-900mg, 20mg-800mg, 30mg-700mg, 40mg-600mg, 50mg-500mg, 50mg-450mg, from 50-100mg to about 400mg, from 50-100mg to approximately 300mg, 110-290mg, 120-280mg, 130-270mg, 140-260mg, 150-250mg, 160-240mg, 170-230mg, 180-220mg, 190-210mg and/or any other illustrated scope.

The further aspect of the present invention is to comprise the percutaneous patch, liner, encapsulation or binder (" adhesive plaster "), it can combine with experimenter's adhering skin or alternate manner, described patch can discharge one or more triethyl group tetramine activating agents of effective dose when bestowing the experimenter, described experimenter can be (1) diabetics or (II) copper level can reduce with comprehensively or part improve or reverse one or more systole malfunctions, diastolic dysfunction, contractility is unusual, the Back-flushing apparatus dysfunction and penetrate blood index obstacle (can be by ultrasonic mensuration, MRI or other imaging technique are determined) and/or one or more are at least by diabetic nephropathy, glycosuria gorge property nephropathy and/or kidney folding copper are accumulated the damage that causes, and/or be arteriorenal damage at least, and/or be selected from one or more atrophys, myocyte's forfeiture, the deposition of ECS expansion and extracellular matrix increases the cardiac structure damage of (and the consequence that is caused), and/or is selected from the patient of coronary artery structural damage of the damage (reaching the consequence that is caused) that is intermediate layer (Musclar layer) and theca interna (endodermis) at least.

Another aspect of the present invention comprises a kind of finished product of manufacturing, it comprises a container, the dosage form as CR, SR and/or ER that contains one or more activating agents wherein is housed, or the CR, the SR that contain the acceptable copper chelator of pharmacy and/or the dosage form of ER are housed, described copper chelator includes but not limited to one or more acceptable triethyl group tetramine activating agents; And be used for comprehensively or the explanation of experimenter's disease is improved and/or reversed to part, wherein the experimenter is (I) diabetics, or (II) copper level can slow down the experimenter of one or more above-mentioned diseases.

Another aspect of the present invention is to comprise the manufactured goods that contain packaging material; CR, the SR and/or the ER dosage form that in packaging material, comprise the acceptable triethyl group tetramine of one or more pharmacy activating agent, packaging material label wherein, it illustrates that described dosage form can be used for improving, reversing and/or recover experimenter's health, described experimenter is (I) diabetics, or (II) copper level can slow down the experimenter of any or multiple the above disease.

In a specific embodiment of dosage form, effective dose and/or dosage regimen relate to the triethyl group tetramine activating agent of effective daily dose that can offer the experimenter, and (for example the salt as the dihydrochloride of triethyl group tetramine calculates, do not consider whether contain this salt in the dosage form units) be 4g or lower every day, even oral, dosage also is 1mg-4g every day.

In another specific embodiment, oral release dosage (accumulation is calculated or alternate manner) scope is 200mg-4g every day.In the further specific embodiment, daily dose is 1.2g or lower.

On the other hand, be that the dosage (not considering the amount in the dosage device) that provides for the experimenter is 1mg-1.2g every day in the salt of the dihydrochloride of triethyl group tetramine or other material described here.If oral administration dosage is 200mg-1.2g every day.

In the further specific embodiment, triethyl group tetramine activating agent is that 7.2-7.6 (preferred pH is 7.4 ± 0.1) discharges with the pH value in the form of administration unit.

In another dosage form for example in the specific embodiment of triethyl group tetramine activating agent, for example the release of the dihydrochloride of the triethyl group tetramine of slow release formulation makes the result who always is less than the 250mg oral administered dosage form that is used for Wilson's disease at the intravital activating agent of experimenter.

For example in the specific embodiment of the slow release formulation of triethyl group tetramine activating agent, the dihydrochloride of triethyl group tetramine activating agent such as triethyl group tetramine is suitable for administration once a day, can slow in vivo or controlled and lasting release at another.The dihydrochloride of the triethyl group tetramine of its release was no more than 10% under the environment of about＜4.5 acid pH in 5 hours, and in vivo or the dihydrochloride of the triethyl group tetramine that discharges in a controlled manner in the external dissolving in 12 hours at pH environment approximately＜6.5 down above 50%.

The for example method of one or more triethyl group tetramine activating agents that gives effective dose with the form of delayed release preparation (DR), slow delivery formulations (SR), extended release preparation (ER), sustained release preparation (CR) and/or repeat function preparation (RA) is provided in another aspect of the present invention.In a specific embodiment, DR, SR, ER, RA or CR preparation are applicable to any aforesaid disease of treatment, include but not limited to heart failure, diabetic cardiopathy, acute coronary syndrome, hypertensive heart disease, ischemic heart desease, coronary artery disease, peripheral arterial disease, Wilson's disease or any type of cancer.DR, SR, ER, RA or CR preparation can comprise effective dosage device and give the experimenter, dosage is approximately at least a triethyl group tetramine activating agent of every dose of 1mg-600mg, and in the further specific embodiment, TDD is from 5g to 1mg, in certain persistent period, to keep the blood drug level that triethyl group tetramine activating agent needs, preferably kept at least about 18-24 hour.

Another aspect of the present invention is for example to be a kind of preparation of triethyl group tetramine activating agent at least, the blood drug level of the triethyl group tetramine activating agent that it can remain unchanged in the long time, and can in subject, remove copper effectively with one or more symptoms described herein, described symptom includes but not limited to, heart failure, diabetic cardiopathy, acute coronary syndrome, hypertensive heart disease, ischemic heart desease, coronary artery disease, peripheral arterial disease, Wilson's disease or any type of cancer.

Another aspect of the present invention comprises a kind of device, it comprises one or more triethyl group tetramine activating agents and can be used for treating one or more symptoms as herein described in the matrix device of integral body, include but not limited to heart failure, diabetic cardiopathy, acute coronary syndrome, hypertensive heart disease, ischemic heart desease, coronary artery disease, peripheral arterial disease, Wilson's disease or any type of cancer.

In a specific embodiment of integrated substrate device, in dispersive soluble matrix, comprise described one or more triethyl group tetramine activating agents, described one or more triethyl group tetramine activating agents in substrate, dissolve or swelling after can increase action effect.The integrated substrate device can include but not limited to the adjuvant that one or more are following: hyprolose (BP) or HPC (USP); Hydroxypropyl emthylcellulose (BP, USP); Methylcellulose (BP, USP); Carboxymethylcellulose calcium (BP, USP); Acrylate copolymer or carboxypolymethylene (Carbopol) or carbomer (BP, USP); Or the glucuronic acid ester polymer of straight chain such as alginic acid (BP, USP), those microgranules that are mixed with from the reunion system of alginic acid (and salt)-gelatin gels for example, or those are by the liposome of alginic acid and poly-L-Lysine thin film encapsulation.In addition, described integrated substrate comprises one or more triethyl group tetramine activating agents in the substrate that is dissolved in dissolubility, and described one or more triethyl group tetramine activating agents work aqueous solvent enters substrate and dissolves triethyl group tetramine granule by minim channel after.

In the further specific embodiment, integrated substrate comprises for example described one or more triethyl group tetramine active agent particles in lipidic matrix or insoluble polymer substrate, its include but not limited to by Brazil wax (BP, USP); Medium chain triglyceride such as fractionated coconut oil (BP) or saturated triglyceride culture medium (PhEur); Or cellulose ethylether or ethyl cellulose (BP, USP) preparation of Xing Chenging.Lipid can account for the 20-40%w/w of hydrophobic solid material in the amount of described integrated substrate.Lipid can be kept perfectly in dispose procedure.

In another specific embodiment, described device is comprising outside for example described one or more triethyl group tetramine activating agents, also comprise one or more following materials: channel agent (channeling agent), as sodium chloride or one or more sugar, it can go out from preparation in leaching, form aqueous micro channel (blood capillary), solvent can enter thus and medicine is released.

Perhaps, device is any hydrophilic polymer substrate, wherein said one or more for example triethyl group tetramine activating agent be to concentrate with the form of any water-swellable hydrophilic polymer with mixture.

The content that for example is included in the triethyl group tetramine activating agent in the hydrophilic polymer substrate is 20-80% (w/w).

In a specific embodiment, hydrophilic polymer substrate also comprises any or multiple following substances outside one or more triethyl group tetramine activating agents: gel dressing agent such as one or more sugar, counter ion, pH buffer agent, surfactant, lubricant such as magnesium stearate and/or fluidizer such as silicon dioxide colloid.

Another aspect of the present invention comprises various devices, and it comprises for example described one or more triethyl group tetramine activating agents of effective dose, and it includes or contains the film of the rate controlled of surrounding medicine storage place, and contains galactose and microcrystalline Cellulose.The ratio of galactose and microcrystalline Cellulose can be such as about 60: 40.

The clinical trial of the following stated shows that the equal divided dose of 1.2g every day of triethyl group tetramine can effectively keep (relate to moment levels of drugs) in vivo in order to improve and/or to reverse the purpose of cardiac structure damage and/or coronary artery injury and the high dose level of long-term needs.So every day 1.2g dosage can be by using 300mg the capsule of hydrochlorate of triethyl group tetramine provide, this capsule was taken in half an hour ante cibum, two of two of administrations in morning and administrations in evening.

The mensuration of free copper [amount that equals total plasma copper deducts the bonded copper of ceruloplasmin] can be applied in Merck ﹠amp; The operation that discloses in the capsular tables of data (www.Merck.com) of the SYPRINERO of Co Inc (salt of the dihydrochloride of triethyl group tetramine) is finished: " the index of reliable monitor therapy is the free copper of determining in serum, and its value equals the poor of fixed total copper amount and the bonded copper of ceruloplasmin in wherein explanation.The experimenter who fully treats has free copper in the serum usually less than 10mcg/dL.Therapeutic Method can be monitored by the situation of analyzing copper in the urine in 24 hours.Urine must be collected with not copper bearing glass drying oven.Because low copper diet can keep the absorption of copper to be lower than 1 milligram of every day, if the amount of experimenter's copper in the urine that 24 hours periods are collected then is ideal negative balance of copper state in the 0.5-1.0 milligram quantities ".

Description of drawings

We rely on the STZ rat model and philtrum is studied the salt of triethyl group tetramine dihydrochloride, and wish to further describe the present invention by following accompanying drawing:

Figure 1 shows that the homaluria thing response of diabetes and non-diabetic animal increases triethyl group tetramine or isopyknic saline of dosage, and wherein the homaluria thing of diabetes and non-diabetic animal response increases the triethyl group tetramine (floors of dosage; In 75 μ l saline 0.1,1.0,10,100mg.kg ^-1Then use the normal saline washing of 125 μ l, inject by the time according to the direction of arrow) or isopyknic saline (top value), and on behalf of 15 minutes urine, each point collect the cycle (referring to the detailed method of embodiment 2); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 2 shows that non-diabetic and diabetic animal acceptance increase triethyl group tetramine or isopyknic brinish homaluria thing of dosage, wherein diabetes (top value) and non-diabetic rat (floors) accept to increase the triethyl group tetramine of dosage the homaluria thing (in 75 μ l saline 0.1,1.0,10,100mg.kg ^-1Then use the normal saline washing of 125 μ l, inject by the time according to the direction of arrow) or isopyknic saline, and on behalf of 15 minutes urine, each point collect the cycle (referring to the detailed method of embodiment 2); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 3 shows that diabetes and non-diabetic animals received increase the triethyl group tetramine of dosage or the copper Excreta in isopyknic brinish urine, wherein diabetes (top value) and non-diabetic rat (floors) accept to increase copper Excreta in the urine of triethyl group tetramine of dosage (in 75 μ l saline 0.1,1.0,10,100mg.kg ^-1Then use the normal saline washing of 125 μ l, inject by the time according to the direction of arrow) or isopyknic saline, and on behalf of 15 minutes urine, each point collect the cycle (referring to the detailed method of embodiment 2); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 4 shows the information identical as accompanying drawing 18, and the cupruresis thing of every gram the weight of animals is described, wherein the response of the cupruresis thing of every gram body weight of diabetes and non-diabetic animal increase dosage the triethyl group tetramine (floors: in 75 μ l saline 0.1,1.0,10,100mg.kg ^-1Then use the normal saline washing of 125 μ l, inject by the time according to the direction of arrow) or isopyknic saline (top value), and on behalf of 15 minutes urine, each point collect the cycle (referring to the detailed method of embodiment 2); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 5 is presented at the total copper bar discharge that gives saline or medicine in non-diabetic and the diabetic animal, wherein total cupruresis thing (μ mol) giving saline (black streaking, n=7) or give triethyl group tetramine (shaded stripe, n=7) non-diabetic animal, or give saline (grey striped, n=7) or give the triethyl group tetramine (the informal voucher stricture of vagina is in diabetic animal n=7); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 6 shows total copper Excreta of accepting triethyl group tetramine or brinish animal per gram body weight, is wherein accepting triethyl group tetramine (non-diabetic: shaded stripe, n=7; Diabetes: the informal voucher stricture of vagina, n=7) or saline (non-diabetic: black streaking, n=7; Diabetes: grey striped, total cupruresis amount (μ mol.gBW of every gram body weight in animal n=7) ^-1); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 7 is presented in the triethyl group tetramine that accept to increase dosage or isopyknic brinish diabetes and the non-diabetic animal excretion of ferrum in the urine, wherein accept to increase dosage the triethyl group tetramine (in 75 μ l saline 0.1,1.0,10,100mg.kg ^-1Then use the normal saline washing of 125 μ l, according to the direction of arrow by time injection) or the urine ferrum Excreta of isopyknic saline diabetes rat (top value) and non-diabetic rat (floors), and each puts the urine collection cycle (referring to the detailed method of embodiment 2) of representing 15 minutes; Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 8 shows the urine ferrum Excreta of diabetes and non-diabetic animals received triethyl group tetramine or brinish every gram body weight, wherein the cupruresis thing of every gram body weight of diabetes and non-diabetic animal response increase dosage the triethyl group tetramine (floors: in 75 μ l saline 0.1,1.0,10,100mg.kg ^-1Then use the normal saline washing of 125 μ l, inject by the time according to the direction of arrow) or isopyknic saline (top value), and on behalf of 15 minutes urine, each point collect the cycle (referring to the detailed method of embodiment 2); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 9 is presented at the total urine ferrum excretion that gives saline or medicine in non-diabetic and the diabetic animal, wherein total urine ferrum Excreta (μ mol) is giving saline (black streaking, n=7) or give triethyl group tetramine (shaded stripe, n=7) non-diabetic animal, and give saline (grey striped, n=7) or give the triethyl group tetramine (the informal voucher stricture of vagina is in diabetic animal n=7); Error shows SEM and P value describe whether have significance (P＜0.05).

Figure 10 shows total urine ferrum Excreta of accepting triethyl group tetramine or brinish animal per gram body weight, is wherein accepting triethyl group tetramine (non-diabetic: shaded stripe, n=7; Diabetes: the informal voucher stricture of vagina, n=7) or saline (non-diabetic: black streaking, n=7; Diabetes: grey striped, every gram body weight (μ mol.gBW in animal n=7) ^-1) total urine ferrum excretion; Error shows SEM and P value describe whether have significance (P≤0.05).

Figure 11 demonstrations give 10mg.kg continuously ^-1(A) and behind the triethyl group tetramine pill of 100 (B) by AAS (△) and EPR (▲) mensuration urine [Cu], as shown in Figure 19; (illustration) is from the epr signal indication Cu of 75 minutes urine background correction ^IIThe existence of-triethyl group tetramine; ^*,P＜0.05, ^*, P＜0.01 compared with the control.

Figure 12 is forms, and copper and the ferrum Excreta of triethyl group tetramine or brinish animal accepted in its contrast, and the application mix linear model carries out statistical analysis.

The weight of animals in the experiment of Figure 13 demonstration embodiment 5 changes in time.

Animal glucose level in the experiment of Figure 14 demonstration embodiment 5 changes in time.

Figure 15 is kinemic charts of demonstration animal of measuring among the embodiment 5.

Figure 16 is charts of the demonstration animal coronary flow of mensuration among the embodiment 5.

Figure 17 is the demonstration of mensuration among the embodiment 5 charts by the standardized coronary flow of final cardiac weight.

Figure 18 is charts of the demonstration animal ABF of mensuration among the embodiment 5.

Figure 19 is the demonstration animal of mensuration among the embodiment 5 charts for the maximum positive change rate of the pressure of each cardiac cycle (contraction) ventricle.

Figure 20 is the demonstration animal of mensuration among the embodiment 5 charts for the MAX DES of the pressure of each cardiac cycle (diastole) ventricle.

Figure 21 shows that each load in animal of measuring among the embodiment 5 finishes the percentage ratio that the back keeps cardiac function.

Figure 22 shows STZ-diabetes rat and the LV-myocardial structural of non-diabetic control rats after 7 all oral triethyl group tetramines are treated that matches, and wherein carries out the heart section after functional study.Each image is represented 5 independently sections of each heart, and each treatment is totally three hearts.A-d is, the LV section of 120-μ M is dyeed (phalloidin-488, orange) to actin and jointly to β ₁The laser focusing image of the immunostaining of-integrin (the paired secondary antibody of CY5-, aubergine) (scale striped=33 μ m), the untreated matched group of a.; B. untreated diabetic groups; C. the diabetic groups of triethyl group tetramine treatment; D. the non-diabetic matched group handled of triethyl group tetramine.E-h. corresponding to the TEM image of the painted 70-nM of uranium acetate/lead citrate section (scale striped=158nm); E. untreated matched group; F. untreated diabetic groups; G. the diabetic groups of triethyl group tetramine treatment; H. the non-diabetic matched group handled of triethyl group tetramine.

Figure 23 shows the effect of the people LV quality of six months oral triethyl group tetramine treatment T2DM, triethyl group tetramine (600mg wherein, twice of every day) or corresponding placebo gives diabetics (n=15) or corresponding contrast (n=15) is to compare research, wherein LV mass discrepancy (g in double blinding (double-blind) test; Meansigma methods and 95% confidence interval) measure with the MRI of labelling heart.

The excremental effect of urine Cu that Figure 24 shows at random, double blinding, controlled trial contrast the male of non-complex T2DM and corresponding non-diabetic matched group behind oral triethyl group tetramine and the placebo is wherein urinated Cu Excreta (μ mol.2h ^-1First day (as baseline) and the 7th day experimenter with oral triethyl group tetramine of single agent 2.4-g and corresponding placebo see Table 9, the T2DM of placebo treatment, zero, the matched group of placebo treatment, ●, the T2DM of triethyl group tetramine treatment,, the matched group of triethyl group tetramine treatment, ■.The Cu Excreta of the T2DM of triethyl group tetramine treatment is obviously greater than the non-diabetic matched group (P＜0.05) with the treatment of triethyl group tetramine.

Figure 25 shows the response of mean arterial pressure (MAP) in diabetes and non-diabetic animal, is used in the 10mg.kg of 75 μ l ^-1Triethyl group tetramine+125 μ l normal saline washings (or saline of equal volume).The meansigma methods of data in 1 minute of the point that each some representative was collected in per 2 seconds.The time of administration (or saline) guides in the direction of arrows.Error shows SEM, and

Figure 26 shows the scanning of 15 days ultraviolet-visible spectrum of triethyl group tetramine preparation stored and adds copper to form triethyl group tetramine-copper complex.Scanning was the 0th day (control formulation) and carried out in the 15th day.Have three preparations that contain the triethyl group tetramine, deposit in the dark place for one under 4 ℃, another deposits in the dark place under room temperature (21 ℃), at room temperature deposits in the daylight environment for the 3rd.Add copper after finishing spectral scan.

Detailed Description Of The Invention

We have described the STZ rat model that is used to study human diabetes and non-diabetic experimenter, and the minimizing of free copper can comprehensively or part be improved or the damage of reverse cardiac structure.This comprises following damage: because the deposition of atrophy, myocardial cell forfeiture, ECS expansion and extracellular matrix increases (and the consequence that causes), and coronary artery structural damage (and the consequence that causes).For confirming that the reverse effect of STZ rat damage as further description, has been found the relevant dose for the people, relate to the removing of copper in the urine.In addition, the damage meeting sensitization of cardiac structure stem cell at a distance under physiological condition, it can migrate to damage location, and the differentiation of stem cell takes place, and, can promote the reparation of 26S Proteasome Structure and Function that is.Yet, confirmed that redox active transition metal, particularly copper accumulating in the heart tissue of diabetic subjects and coronary artery can suppress the normal structure regeneration function of finishing because of the stem cell migration.In other words, the rising of copper level suppresses the normal biological behaviour of these undifferentiated cells in the tissue.Even in the non-diabetic mammal, (for example suffer from type 2 diabetes mellitus) and do not having in the mammal of abnormal glucose metabolism (for example not having IGT or IFG), the damage that the decline of extracellular copper can help reducing and/or reverse is relevant with copper.For example, the regeneration by the response of normal structure stem cell improves tissue repair comprehensively or partly.

The evidence of 2 phase oranons demonstrates positive findings.Yet when comparing for the site of action pattern of dynamic mode and recent findings with its medicine, the dosage scheme does not reach the best.The active component for example bioavailability of dihydrochloride behind oral administration of triethyl group tetramine is lower (＜10%), and this is owing to absorption difference, and first pass metabolism is arranged.The dihydrochloride of triethyl group tetramine and metabolite thereof, N-acetyl-triethyl group tetramine hydrochloride can both combine with copper, but the sequestering activity of N-acetyl-triethyl group tetramine hydrochloride significantly is lower than triethyl group tetramine dihydrochloride according to reports.Referring to Kodama H., wait people's Life Sciences 61:899-907 (1997).In addition, food, mineral supplement and other medicines are unfavorable for the absorption of triethyl group tetramine dihydrochloride.The half-life of various copper chelators, for example can treat or reverse the triethyl group tetramine of heart failure and coronary heart disease, have only relatively short about 2 hours action time.Ideal triethyl group tetramine should use under its maximum tolerated dose in present treatment, and the scheme of application dose should be suitable for the characteristics of its pharmacokinetics and action site.Blood drug level for oral administration triethyl group tetramine, referring to Miyazaki, K., Deng the people " Determination of trientinein plasma of subjects with high-performance liquidchromatography; ", ChenzPharm Bull 38:1035-38 (1998).Heart failure and/or coronary heart disease experimenter adopt multiple dosage regimen often.Based on the above reason, the route of administration of the dosage of copper chelator, form formula and/or described dosage and goods needs to improve.

The present invention relates to and provide new copper chelator, for example dosage of triethyl group tetramine activating agent and dosage form, and the route of administration of various dosage and dosage form.Triethyl group tetramine activating agent comprises the salt and the prodrug of salt, triethyl group tetramine analog and the described analog of the prodrug of salt, triethyl group tetramine of triethyl group tetramine, triethyl group tetramine and described prodrug, and/or the salt of the metabolite of triethyl group tetramine and described metabolite and prodrug, include but not limited to N-acetyl-triethyl group tetramine, and the salt and the prodrug of N-acetyl triethyl group tetramine.Be sure of not bound by theory, dosage and dosage form and route of administration provide beyond thought comprehensively or part improve and reverse beneficial effect aspect described disease, disorder and the symptom herein, and be sure of that copper plays an important role therein.

Wilson's disease is the defectives of a kind of genetic liver and gall to the drainage aspect of copper.Copper accumulate and the toxicity of copper causes the disease of liver, and in the part patient, cause brain injury.The big frequently-occurring disease of patient shows as the sacred disease or the dystropy of hepatopathy, movement disorder type in 10-40 year, and usually concurrent.Wilson's disease can effectively be treated by oral copper chelator.Confirmed copper chelator main defecate of passing through in Wilson's disease, effectively (or absorption suppresses) takes place in chelation at enteral, or passes through to allow unnecessary copper through urine or the excretory part Restoration Mechanism of gallbladder antiperspirant, or the combination of the two.Referring to Siegemund R, Deng the people " Mode of actionof triethylenetetramine dihydrochloride on copper metabolism inWilson ' sdisease; ", ActaNeurol Scand.83 (6): 364-6 (June 1991).

On the contrary, experiment as described herein demonstrates unexpectedly, gives copper chelator triethyl group tetramine dihydrochloride and does not cause the excretory increase of copper in feces in for example non-Wilson's disease patient.Referring to embodiment 9 and table 11.The drainage of the unnecessary copper of handling with copper chelator of non-Wilson's disease experimenter at first is by urine rather than feces.Referring to embodiment 8 and accompanying drawing 12.These data have been supported following viewpoint: the dosage of whole body administration (parenteral administration) copper chelator is lower than oral administration, perhaps the dosage of sustained release administration copper chelator is lower than oral administration, or oral administration more low dosage can avoid undesirable first pass effect, so that more active component can play a role, has the beneficial effect of describing significantly here outside intestinal.This comprises that the administration of described dosage and dosage form compares direct digestive tract administration, and measurable release (comprising intramuscular administration, intraperitoneal administration, subcutaneous administration and intravenously administrable) in blood circulation can be provided.Therefore, chemical compound can also be made the injection (comprising that bolus injection is penetrated or continuous infusion) of parenteral administration and can be present in the unit preparation of the ampoule, prefilled syringe, small-sized dense notes container or the multi-agent container that add antiseptic.

According to the present invention, copper chelator is the dosage and the dosage form of triethyl group tetramine for example, for the blood drug level of keeping hope with organize level, can make efficiently and in body, remove copper through urine, and than the oral administration preparation of low dosage more, it can more effectively treat generation and progress increase or the disease that undesirable copper causes on the various pathology.Described disease includes but not limited to the following stated: the cancer of heart failure, diabetic cardiopathy, acute coronary syndrome, hypertensive heart disease, ischemic heart desease, coronary heart disease, peripheral arterial disease and the treatment of available copper chelating agen.

The triethyl group tetramine has alkaline part, contains a plurality of nitrogen, can be transformed into many suitable acid-addition salts with acid, for example, the triethyl group tetramine of equivalent as calculated and acid are reacted in atent solvent, as in ethanol or water, if and dosage form is distilled when needing exsiccant salt.Available acid can be the acid that can produce physiologically acceptable salt.Nitrogenous copper chelator such as triethyl group tetramine activating agent are for example, the triethyl group tetramine, form that can salt discharges (as acid-addition salts, triethyl group tetramine dihydrochloride), and as copper chelator, can help easily to remove copper from kidney in the body by forming stable soluble complex.Can use mineral acid, for example sulphuric acid, nitric acid, halogen acids example hydrochloric acid or hydrobromic acid, phosphoric acid such as orthophosphoric acid, sulfamic acid.Here also non exhaustive.Other organic acid also can use, particularly aliphatic, alicyclic, aryl is aliphatic (araliphatic), aromatic series or heterocycle, list-or polynary carboxyl, sulfonic group or vitriolic acid (for example formic acid, acetic acid, propanoic acid, neopentanoic acid, diethacetic acid, malonic acid, succinic acid, 1,5-pentanedicarboxylic acid., fumaric acid, maleic acid, lactic acid, tartaric acid, malic acid, citric acid, gluconic acid, ascorbic acid, nicotinic acid .gamma.-pyridinecarboxylic acid, methanesulfonic acid, ethionic acid, 2-hydroxyl methanesulfonic acid, benzenesulfonic acid, right-toluenesulfonic acid, naphthalene list and disulfonic acid and lauryl sulfate).Those skilled in the art can prepare suitable salt form.Nitrogenous copper chelator such as triethyl group tetramine activating agent, for example the triethyl group tetramine can also form the form of quaternary ammonium salt, and wherein nitrogen-atoms inserts suitable organic group, as alkyl, thiazolinyl, alkynyl or aralkyl.This nitrogenous copper chelator is solution and/or form of suspension in a specific embodiment, wherein can contain buffer agent, and its pH value is near neutral, far below the value of the pH14 of triethyl group tetramine solution.

Other triethyl group tetramine activating agent comprises the derivant of triethyl group tetramine activating agent, and for example, the triethyl group tetramine combines with Picolinic Acid (2-nicotinic acid).These derivants comprise the salt of triethyl group tetramine picoline and triethyl group tetramine picoline, for example hydrochlorate of triethyl group tetramine picoline.The salt that also comprises triethyl group tetramine two-picoline and triethyl group tetramine two-picoline, for example, triethyl group tetramine two-picoline hydrochlorate.The Picolinic Acid group can be used conventional chemical technology and link triethyl group tetramine, for example one or more CH ₂The group part.Those skilled in the art can prepare other appropriate derivative, for example, triethyl group tetramine-PEG derivant, it can be used for improving the particular dosage form of the oral administration of bioavailability.

Other triethyl group tetramine activating agent comprises the activating agent of triethyl group tetramine analog.Such analog comprises ring-type and the represented analog of acyclic following general formula:

Formula I

The non-annularity analog of triethyl group tetramine can be following based on the described four-heteroatomic non-annularity analog of above general formula I, X1 wherein, and X2, X3 and X4 independently are selected from N respectively, and S or O atom make

(a) for the series of four nitrogen, promptly work as X1, X2, when X3 and X4 are N, so: R1, R2, R3, R4, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; And, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R3, R4, R5 or R6 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of total pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide, C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(b) for the series of first kind of three nitrogen, promptly work as X1, X2, X3 are N, and X4 is when being S or O, and so: R6 does not exist; R1, R2, R3, R4, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R3, R4, R5 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide, C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(c) for the series of second kind of three nitrogen, promptly work as X1, X2 and X4 are N, and X3 is when being O or S, and so: R4 does not exist; R1, R2, R3, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R3, R5 or R6 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide, C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(d) for the series of first kind of phenodiazine, promptly working as X2 and X3 is N, and X1 and X4 be when being O or S, and so: R1, R6 do not exist; R2, R3, R4 and R5 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R2, R3, R4 or R5 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide, C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(e) for the series of second kind of phenodiazine, promptly working as X1 and X3 is N, and X2 and X4 be when being O or S, and so: R3, R6 do not exist; R1, R2, R4 and R5 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R4 or R5 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(f) for the series of the third phenodiazine, promptly working as X1 and X2 is N, and X3 and X4 be when being O or S, and so: R4, R6 do not exist; R1, R2, R3 and R5 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R3 or R5 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(g) for the series of the 4th kind of phenodiazine, promptly working as X1 and X4 is N, and X2 and X3 be when being O or S, and so: R3, R4 do not exist; R1, R2, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R5, or R6 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH--peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11 or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

The second, for the analog of four-heteroatomic circular sequence, R1 and R6 are joined together to form (CR13R14) n4 by bridged group, and X1, and X2, X3 and X4 independently are selected from N respectively, S or, O makes

(a) for the series of four nitrogen, promptly work as X1, X2, when X3 and X4 are N, so: R2, R3, R4 and R5 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2, n3 and n4 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11, R12, R13 and R14 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R2, R3, R4, or R5 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide, C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, R12, R13, or R14 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(b) for the series of three nitrogen, promptly work as X1, X2, X3 are N, and X4 is when being S or O, and so: R5 does not exist; R2, R3 and R4 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2, n3 and n4 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11, R12, R13 and R14 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R2, R3, or R4 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, R12, R13, or R14 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(c) for the series of first kind of phenodiazine, promptly working as X2 and X3 is N, and X1 and X4 be when being O or S, and so: R2 and R5 do not exist; R3 and R4 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2, n3 and n4 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11, R12, R13 and R14 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or two R3 and R4 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, R12, R13 or R14 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(d) for the series of second kind of phenodiazine, promptly working as X1 and X3 is N, and X2 and X4 be when being O or S, and so: R3 and R5 do not exist; And R2 and R4 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2, n3 and n4 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11, R12, R13 and R14 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or two R2, or R4 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, R12, R13 or R14 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(e) for the series of a nitrogen, promptly working as X1 is N, and X2, when X3 and X4 are O or S, so: R3, R4 and R5 do not exist; R2 is independently selected from H, CH ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2, n3 and n4 independently are selected from 2 or 3 respectively; And R7, R8, R9, R10, R11, R12, R13 and R14 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, R2 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, R12, R13 or R14 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

Formula II

As three of general formula I I-heteroatomic non-annularity analog, X1 wherein, X2 and X3 independently are selected from N respectively, and S or O atom make

(a) for the series of three nitrogen, promptly work as X1, when X2 and X3 are N, so: R1, R2, R3, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1 and n2 independently are selected from 2 or 3 respectively; With, R7, R8, R9 and R10 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R3, R5 or R6 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, or R10 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(b) for the series of first phenodiazine, promptly working as X1 and X3 is N, and X2 is when being S or O, and so: R3 does not exist; R1, R2, R3, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1 and n2 independently are selected from 2 or 3 respectively; With, R7, R8, R9 and R10 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R5, R6 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9 or R10 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(c) for the series of second kind of phenodiazine, promptly working as X1 and X2 is N, and X3 is when being O or S, and so: R3 does not exist; R1, R2, R5 and R6 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1 and n2 independently are selected from 2 or 3 respectively; With, R7, R8, R9 and R10 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R1, R2, R5, or R6 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, or R10 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

Second kind as three of general formula I I-heteroatomic non-annularity analog, and wherein R1 and R6 link together by bridged group, forms (CR11R12) n3, and X1, and X2 and X3 independently are selected from N respectively, and S or O atom make

(a) for the series of three nitrogen, promptly work as X1, when X2 and X3 are N, so: R2, R3 and R5 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or several R2, R3, or R5 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(b) for the series of phenodiazine, promptly work as X1, X2 is N, and X3 is when being S or O, and so: R5 does not exist; R2 and R3 independently are selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11, R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, one or two R2 or R3 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

(c) for the series of a nitrogen, promptly when X1 be N, and X2 and X3 be when being O or S, so: R3 and R5 do not exist; R2 is selected from H, CH respectively ₃, the alkyl of the straight or branched of C2-C10, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aromatic radical, single, two, three, four and five aromatic radicals that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl, CH ₂COOH, CH ₂SO ₃H, CH ₂PO (OH) ₂, CH ₂P (CH ₃) O (OH); N1, n2 and n3 independently are selected from 2 or 3 respectively; With, R7, R8, R9, R10, R11 and R12 independently are selected from H, CH respectively ₃C2-C10 straight or branched alkyl, C3-C10 cycloalkyl, C1-C6 alkyl C3-C10 cycloalkyl, aryl, single, two, three, four and five aryl that replace, heteroaryl, fused-aryl, the C1-C6 alkylaryl, C1-C6 alkyl list, two, three, four and five aryl that replace, C1-C5 miscellaneous alkyl aryl, C1-C6 alkyl fused-aryl.In addition, R2 can be functionalized can be attached to peptide, protein, Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.Furtherly, one or several R7, R8, R9, R10, R11, or R12 can be functionalized can link peptide, protein Polyethylene Glycol and other can modify the chemical group of pharmacokinetics, drug release characteristics and/or half-life.The example of these functionalized groups includes but not limited to C1-C10 alkyl-CO-peptide, C1-C10 alkyl-CO-protein, C1-C10 alkyl-CO-PEG, C1-C10 alkyl-NH-peptide, C1-C10 alkyl-NH-protein, C1-C10 alkyl-NH-CO-PEG, C1-C10 alkyl-S-peptide and C1-C10 alkyl-S-protein.

Analog of the present invention can be synthetic by arbitrary method well known in the art, separation, purification obtain.

The present invention includes controlled release or other medicines dosage and pharmaceutical dosage form carry preparaton and device, wherein comprise one or more for example copper chelators of triethyl group tetramine or its salt.The present invention includes for example dosage and dosage form, at least be oral administration,, percutaneous dosing, topical application, suppository discharge, mucosa discharges, injection (comprising subcutaneous administration, intramuscular administration, heeling-in administration and intravenously administrable (bolus injection, slowly intravenous injection and intravenous drip)), infusion device (comprise implantable infusion device, comprise active and passive), suck or be blown into administration, buccal administration, sublingual administration and administration through eye.

Described dosage, the disease that dosage form and route of administration are used comprises diabetic cardiomyopathy, diabetic acute coronary syndrome (for example myocardial infarction MI), the diabetic hypertension cardiomyopathy, reduce (IGT) relevant acute coronary syndrome with glucose tolerance, with fasting glucose damage (IFG) relevant acute coronary syndrome, the hypertensive cerebral cardiomyopathy relevant with IGT, the hypertensive cerebral cardiomyopathy relevant with IFG, the ischemic cardiomyopathy relevant with IGT, the ischemic cardiomyopathy relevant with IFG, with the relevant ischemic cardiomyopathy of coronary heart disease coronary atherosclerosis (CHD), cardiac muscle disease (cardiomyopathy or myocarditis) comprises idiopathic cardiomyopathy, metabolic cardiomyopathy (comprises diabetic cardiomyopathy, alcoholic cardiomyopathy, drug-induced property cardiomyopathy, ischemic cardiomyopathy and hypertensive cerebral cardiomyopathy), with the irrelevant acute coronary syndrome of abnormal glucose metabolism, with the irrelevant hypertensive cerebral cardiomyopathy of abnormal glucose metabolism, with the irrelevant ischemic cardiomyopathy (not considering whether ischemic cardiomyopathy is relevant with coronary heart disease) of abnormal glucose metabolism and the disease of one or more vascular trees, comprise aorta, carotid artery and comprise the tremulous pulse cerebral arteries, coronary artery, renal artery, arteria retina, iliac artery, femoral artery popliteal tremulous pulse, vasa nervorum, small artery tree and capillary bed are in interior disease, the atherosclerosis such as the aorta of main blood vessel (trunk disease), coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery is with the disease of popliteal tremulous pulse, include but not limited to atrophy, myocyte's forfeiture, the deposition of ECS expansion and extracellular matrix increases the cardiac structure damage of (and the consequence that causes) and/or is selected from the coronary artery structural damage of the damage (and the consequence that causes) that is intermediate layer (Musclar layer) and/or theca interna (endodermis) at least, the plaque rupture such as the aorta of the atherosclerotic lesions of main blood vessel, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery is with the disease of popliteal tremulous pulse, the systole malfunction, diastolic dysfunction, the contractility disorder, recoil feature and penetrate the blood index, toxicity, drug-induced and Developmental and Metabolic Disorder comprises that the diabetic disease (microvascular disease) of hypertension and/or little blood vessel is as the retina small artery, the glomerulus small artery, vasa nervorum, heart small artery and relevant eye, kidney, the disease of the capillary bed of heart and maincenter and peripheral nervous system.Therefore, the present invention's dosage and dosage form of also having indicated the copper chelator of one or more new for example triethyl group tetramines or its salt is used for people described here or other mammiferous treatment of diseases.Described disease can be effectively treated in the application of these dosage, dosage form and device, can be used for people and other mammiferous administration.

The invention provides and comprise one or more for example drug release dosage of the copper chelator of triethyl group tetramine or its salt.Therefore, the present invention partly is meant the clear blood drug level of new release dosage to obtain best bioavailability and to keep therapeutic domain that contains one or more as the copper chelator of triethyl group tetramine, the action time that comprises prolongation, and cause the increase of holding time of the dense medicine of blood medicine of one or more copper chelators such as triethyl group tetramine or its salt, guaranteed ideal therapeutic dose scope at site of action.The sustained release preparation also provides the optimum medicine concentration at site of action, and has reduced treatment cycle.

The present invention also provides and comprises one or more for example the drug conveying preparaton and devices of the copper chelator of one or more triethyl group tetramine activating agents, include but not limited to triethyl group tetramine, triethyl group tetramine dihydrochloride or the acceptable salt of other pharmacy, this preparaton is suitable for cyclical administration, comprise administration once a day, provide the long lasting copper chelator of the controlled and/or low dosage of the low dosage that discharges in vivo, and the drainage of copper chelator is through homaluria.

The present invention also provides and comprises one or more for example the drug release preparaton and devices of the copper chelator of one or more triethyl group tetramine activating agents, include but not limited to triethyl group tetramine, triethyl group tetramine dihydrochloride or the acceptable salt of other pharmacy, be suitable for cyclical administration dosage, comprise administration once a day, provide the copper chelator of the bioavailability that increases, and the drainage of copper chelator is through homaluria.

The example that is used to discharge the dosage that controlled delivery of pharmaceutical agents of the present invention discharges can be referring to Sweetman, S.C. (Ed.) .Martindale.The Complete Drug Reference, 33rd Edition, Pharmaceutical Press, Chicago, 2002,2483 pp.; Aulton, M.E. (Ed.) Pharmaceutics.The?Science?of?Dosage?Form?Design.ChurchillLivingstone，Edinburgh，2000，734?pp.；and，Ansel，H.C.，Allen，L.V.andPopovich，N.G.Pharmaceutical?Dosage?Forms?and?Drug?Delivery?Systems，7th?Ed.，Lippincott?1999，676?pp.。The adjuvant that is used for preparing delivery system all has description at many publications, all are conventional technology for those skilled in the art, referring to Kibbe, E.H.Handbook of Pharmaceutical Excipients, 3rd Ed., AmericanPharmaceutical Association, Washington, 2000,665 pp..American Pharmacopeia also provides the example of oral sustained release dosage form, comprises those preparation tablet and capsular adjuvants.For example, referring to American Pharmacopeia 23/ National Formulary 18, American Pharmacopeia committee, Inc., Rockville MD, has also described the particular detection of tablet that the mensuration prolongation discharges and delay discharges and capsular burst size and has tested at 1995 (being called USP here).Be used to measure the USP test that prolongation discharges and delay discharges and be based on of the stripping of the interior medicine of test period from dosage device.Various detecting instruments and rule of operation can be referring to USP.Some monograph comprises the specific criteria of complying with used test, device and operation.Embodiment has provided the release that aspirin for example prolongs aspirin in the release tablet (as referring to Ansel, H.C., Allen, L.V.and Popovich, N.G.PharmaceuticalDosage Forms and Drug Delivery Systems, 7th Ed., Lippincott 1999, p.237).The standard of the homogeneity that slow releasing tablet and capsule must be described according to USP routine dose unit.The homogeneity of dosage device can determine that weight differential method or content uniformity method are as the description in USP by two kinds of methods.Further relating to the analysis that prolongs release dosage form is provided (referring to Guidance for Industry.Extended release oral dosage forms:development by F.D.A, evaluation, and application of in vitro/in vivo correlations.Rockville, MD: center for Drug Evaluation and Research, FDA Food and Drug Administration, 1997).The compliance of dosage regimen is always necessary, is in order to draw best therapeutic scheme.When with BID (one day twice), TID (one day three times), QID (one day four times), Deng the treatment Wilson's disease of using so far triethyl group tetramine dosage the multi-dose oral dosage regimen relatively, the present invention recognizes another advantage of the dosage device that above-mentioned emission levels can be provided, and it is that the more triethyl group tetramine dosage of low dosage is arranged.

The present invention also comprises various one or more for example delivery systems of the copper chelator of triethyl group tetramine or its salt that are used to carry.Therefore, the invention describes the novel medicament induction system.These comprise that mitigation release dosage form of the present invention (MR) comprises delayed release dosage forms (DR); Sustained action dosage form (PA); Controlled release dosage form (CR); Prolong release dosage form (ER); Timing release dosage form (TR); And extended release formulations (LA).Most cases is, these terms are used to describe peroral dosage form, but the term rate controlled is carried the delivery system that can be applicable to certain type, and this conveying is by the feature control of device rather than by physiology or environmental condition decision, as the gastrointestinal tract pH value, or medicine is in time that gastrointestinal tract moves.These preparatons influence following aspect: (1) delays total drug release in the certain hour after administration, (2) short drug release at interval after administration, (3) medicine slowly discharges with controlled speed under the domination of induction system, (4) medicine discharges with invariable speed, and/or the release time of the remarkable length of the medicine of (5) more conventional preparaton.Wherein " mitigation ", " delay ", " slowly ", " prolongation ", " regularly ", " long-acting ", " controlled " and/or " prolongation " release dosage form here can be any suitable release dosage forms.

One or more for example the advantage of the administration preparaton of the copper chelator of triethyl group tetramine or its salt comprise that for the experimenter be easily; The compliance that increases and reach stable levels of drugs with maximum every days of twice administration; Long-time constant blood concentration; Prophylactic agent toxicity; And the removing of particularly failing in the treatment at night.Slow release of the present invention is put dosage form and is comprised the dosage form of medicine based on the release characteristic of time, process and/or medicine-feeding part, these be routine or rapid release dosage form can not finish.Referring to for example Bogner, R.H.Bioavailability and bioequivalenceof extended-release oral dosage forms.U.S Pharmacist 22 (Suppl.): 3-12 (1997); Scale-up of oral extended-release drug delivery systems:partI, anoverview.Pharmaceutical Manufacturing 2:23-27 (1985).Prolongation release dosage form of the present invention for example comprise FDA Food and Drug Administration (F.D.A.) described those, it is with conventional dosage form, as solution, or rapid release puts dosage form and compares, and can reduce the frequency of administration.Referring to Bogner, R.H.Bioavailability and bioequivalence of extended-releaseoral dosage forms.US Pharmacist 22 (Suppl.): 3-12 (1997); Guidance forindustry.Oral dosage forms:development, evaluation, and application ofthe invitro/in vivo correlations.Rockville, MD: center for Drug Evaluation and Research, FDA Food and Drug Administration (1997).The active dosage form of repetition of the present invention comprises the dosage form that for example contains two single-dose things, and one is rapid release, and another is a slow release.In prolonging release dosage form, can be prepared into bilayer tablet, one deck is a rapid release, another layer is a slow release.Directed release dosage form of the present invention for example comprises that those are convenient to drug release and for specific absorption or just concentrate in health zone, tissue or position with the orientation of medicine active function.

An embodiment is the oral delivery dosage form, be tablet, capsule, lozenge etc., or liquid dosage form such as syrup, aqueous pharmaceutical, Emulsion etc., it can provide the release of active ingredients that can keep certain persistent period for example one or more chemical compound of the present invention and preparatons.

Carry the unitary embodiment of transdermic absorbent amount of The compounds of this invention and preparaton to comprise percutaneous patch, skin binder or the like.

Carry the embodiment of the topical dosage device of The compounds of this invention and preparaton to comprise lotion, be coated with rod, spray, ointment, paste, Emulsion, gel etc., it is directly through skin or by the vehicle administration, it discharges when being delivered to active component in the subject slowly, and described vehicle comprises liner, paster etc.

The unitary embodiment of suppository dosage of conveying The compounds of this invention and preparaton comprises the dosage form of any solid dosage forms, particularly rectum, vagina and the urethra administration that can insert the health hole.

Carry the embodiment that wears the mucosa delivery dosage device of The compounds of this invention and preparaton to comprise deposition property solution such as being used for coloclysis, vaginal suppository, tampon, emulsifiable paste, gel, paste, foam, spray solution, powder, wherein contain and well known to a person skilled in the art that suitable Sheng carries the carrier of active substance.

Carry the embodiment of the drug administration by injection dosage device of The compounds of this invention and preparaton to comprise the bolus injection of single agent or multi-agent, can be through intravenous injection, subcutaneous injection and intramuscular injection, or Orally-administrable.

Carry the storage storehouse unitary embodiment of dosage of The compounds of this invention and preparaton to comprise piller or little cylinder or the solid dosage forms that contains active component, wherein active component places Biodegradable polymeric substrate, micro-emulsion stroma, liposome substrate, or seals with the microcapsule form.

Carry the embodiment of the infusion device of The compounds of this invention and preparaton to comprise the injection pump that contains just like one or more copper chelators of triethyl group tetramine or its salt, can also comprise implantable drug efflux pump with the dosage or the stable status administration of needs.Implantable infusion device of the present invention comprises any solid form, and wherein active substance is encapsulated in or is scattered in the Biodegradable polymeric, or synthetic polymer, silicone, silicone rubber, silicone rubber or similar polymer.

Carry the suction of The compounds of this invention and preparaton or be blown into the unitary embodiment of dosage and comprise and containing in the acceptable aqueous of medicine or organic solvent or its mixed solution and/or compositions suspension and/or powder.

Carry the unitary embodiment of buccal dosage of The compounds of this invention and preparaton to comprise lozenge, tablet etc., in the acceptable aqueous of medicine or organic solvent or its mixed solution and/or compositions suspension and/or powder.

Carry the embodiment of the sublingual administration dosage device of The compounds of this invention and preparaton to comprise lozenge, tablet etc., in the acceptable aqueous of medicine or organic solvent or its mixed solution and/or compositions suspension and/or powder.

Carry the embodiment of the administration through eye dosage device of The compounds of this invention and preparaton to be included in the acceptable aqueous of medicine or organic solvent or its mixed solution and/or suspension, or the compositions of implant.

The invention provides the dosage conveyer device, and comprise one or more for example preparatons of the copper chelator of triethyl group tetramine or its salt, with one or more suitable aniones to form slow dissolved complex in body fluid only.One comprise one or more for example the example of the slow release formulation of the copper chelator of triethyl group tetramine or its salt be by active component being combined in certain complex, the complex (for example referring to Merck Index12th Ed., 9221) that forms of the anion of those and various forms tannic acid for example.The dissolving of these complex depends on the environment pH value.Rate of dissolution provides the prolongation of medicine to discharge slowly.For example, the tannate of triethyl group tetramine can provide this performance, and can be used for the treatment of and copper increase diseases associated disease.The example of equivalence product referring to those commodity compound recipe tannic acid phenylephrine dosage Rynatan by name (Wallace: referring to Madan, P.L., " Sustained release dosageforms, " U.S.Pharmacist 15:39-50 (1990); Ryna-12 S, which contains a mixture of mepyramine tannatewith phenylephrine tannate, Martindale 33rd Ed., 2080.4) material.

The present invention also comprises and contains one or more for example coating globule, granule or microspheres of the copper chelator of triethyl group tetramine or its salt.Therefore, the present invention also provides a kind of one or more for example methods of the sustained release performance of the copper chelator of triethyl group tetramine or its salt that obtains, and is that medicine is placed coating globule, granule or microsphere.Like this one or more for example preparaton of the copper chelator of triethyl group tetramine or its salt can be used for treating people or the corresponding disease of other mammal.In such system, medicine distributes in globule, piller, granule or other specific system.Use conventional pan coating or air suspension packaging technique, the medicine substrate solution places on the inert seed or globule or microcrystalline Cellulose bead that is formed by sugar and starch.Crystal seed general diameter scope is at the 425-850 micron, the microcrystalline cellulose bead then is (referring to Ansel at the 170-600 micron, H.C., Allen, L.V.and Popovich, N.G.Pharmaceutical Dosage Forms andDrug Delivery Systems, 7th Ed., Lippincott 1999, p.232).The microcrystalline Cellulose bead is considered to (referring to Celphere microcrystalline cellulosespheres.Philadelphia:FMC Corporation, 1996) more durable than sugared core.The preparation method of suitable drug release microsphere open (referring to Arshady, R.Microspheres and microcapsules:asurvey of manufacturing techniques.1:suspension and cross-linking.Polymer Eng Sci 30:1746-1758 (1989); Also can be referring to Arshady, R.Micro-spheres and microcapsules:a survey of manufacturing techniques.2:coacervation.Polymer Eng Sci 30:905-914 (1990); Also can be) referring to Arshady R.Microspheres and micro-capsules:a survey of manufacturing techniques.3:solvent evaporation.Polymer Eng Sci 30:915-924 (1990).In heavy dose of exemplary drugs, initial particulate material can be formed by medicine itself.Part in these granules can keep not the coating state so that the rapid release of medicine to be provided.Other granule (about 2/3rds to 3/4ths) carries out coating with fluent material, as Cera Flava, Brazil wax, glyceryl monostearate, spermol or cellulosic material such as ethyl cellulose (seeing below).Then, the mixing of different-thickness coated granules obtains a mixture, and it has ideal drug release characteristics.Coating material can be with one or more dyeings with granule or the globule (by the depth of color) of distinguishing different-thickness and the difference that product is provided.Mix suitable after, granule can place capsule or tabletting.Various coating system all is available commercially, wherein have based on aqueous and with ethyl cellulose and plasticizer as coating material (for example, AquacoatTM[FMC Corporation, Philadelphia] and SurereleaseTM[Colorcon]; Aquacoat aqueous polymericdispersion.Philadelphia:FMC Corporation, 1991; Surerelease aqueouscontrolled release coating system.West Point, PA:Colorcon, 1990; Butler, J., Cumming, I, Brown, J.et al.A novel multiunit controlled-releasesystem.Pharm Tech 22:122-138 (1998); Yazici, E., Oner, L., Kas, H.S.﹠amp; Hincal, A.A.Phenytoin sodium microspheres:bench scale formulation, process characterization and release kinetics.Pharmaceut Dev Technol 1:175-183 (1996)).Based on the coating system of aqueous eliminated with based on the system of organic solvent relevant danger and environment.Can contrast the coating method (referring to Hogan, J.E.Aqueous versus organic solvent coating.IntJPharm Tech Prod Manufacture3:17-20 (1982)) of water and organic solvent.The difference of coating thickness and coating material type can influence the speed of medicine solution pervasion coating in body fluid.Usually, coating is thick more, and osmotic resistance is big more, and drug release and dissolving delay more.Be typically the coating globule of 1mm diameter.Normally combination has three or four release groups, wherein surpasses 100 globules and is loaded in (referring to Madan, P.L.Sustained release dosage forms.U.S.Pharmacist 15:39-50 (1990)) in the dosage device.This provides different continuing or prolongation rate of release and needed coating globule in gastrointestinal tract fragment orientation.An example of this type of dosage form be SpansuleTM (SmithKline BeechamCorporation, U.K.).Can be used for the example that water-insoluble slowly discharges the film forming polymer in intermediate layer (being used for piller, bead or label) and comprise ethyl cellulose, polyvinyl acetate, Eudragit  RS, (each Eudragit  RS and Eudragit  RL are ammonio methacrylate copolymer) such as Eudragit  RL.Rate of release can combine by forming material such as lactose, mannitol, Sorbitol etc. with suitable water solublity hole, or is controlled by coatings thickness.Multiple tablet comprises the small pieces of microspheric form compacting, and its diameter is 3-4mm, and the release characteristics that can place gelatine capsule to obtain suiting.Each capsule can contain 8-10 small pieces, some not coating be used for rapid release, the prolong drug that is used for of other coating discharges.

Following method can be used for producing induction system, and this induction system comprises one or more for example copper chelator slow release release dosage forms of triethyl group tetramine or its salt or other triethyl group tetramine activating agent, is suitable for people and other mammal oral administration.Here need two fundamental mechanisms to finish the slow release of drug conveying.These have changed the dissolubility and the dispersibility of medicine and adjuvant.In this article, for example, can use four processes, carry out simultaneously or carry out in succession.As described below: (i) Zhuan Zhi hydration (for example swelling of substrate); (ii) water diffuses into device; The (iii) controlled or delay dissolving of medicine; And (iv) dissolved drug is controlled or postpone diffusion and go out.Discharging continuously is zero order kinetics, and is that diffusion or infiltration by constant rate of speed forms.The slow release release dosage form is generally suitable for a kind of in following three type systematics: whole or single matrix type; Storage storehouse or film control type; Or osmotic pump system.Each all comprises following composition: active medicine; Release control agent; The substrate regulator; The medicament adjusting agent; Replenish coating materials; Preparaton adjuvant with routine, as well known to those skilled in the art consult (referring to for example Kibble A.H (ed.) Handbook of Pharmaceutical Excipients, 3rd Edition, AmericanPharmaceutical Association, 2000,665 pp.).

Oral administered dosage form for chemical compound of the present invention and preparaton, the effect of prolong drug can be by influencing speed that medicine discharges and/or reaching (referring to Bogner, R.H.Bioavailability and bioequivalenceof extended-release oral dosage forms.US Pharmacist 22 (Suppl.): 3-12 (1997)) by slowing down medicine by the gastrointestinal time from dosage form.The drug release rate of solid dosage forms can be regulated by technology as described below: 1) act on the dissolubility that medicine is regulated medicine by using coating barrier control biological fluid; 2) diffusion of control medicine from dosage form; And 3) medicine or its pharmaceutically barrier and chemical reaction or the power of influence between the biological fluid of specific site.Such system also has explanation here.On the one hand, as the Digestion of releasing mechanism, to active component carry out coating or the parcel can slow down Digestion or the dispersion in intestinal.But the speed utilized of activating agent is the function of the digestion rate of dispersed substance.Therefore, the action effect of rate of release and medicament can be according to the experimenter to the difference of the digestion power of material and difference.On the other hand, as disclosed in the U.S. patent No.3247066, activating agent disperses in the water solublity colloid, uses rupturable plasticity, non-digesting material coating then, and it can permeate because of the diffusion of water.After ingesting and food carries out gastrointestinal tract, the water in the body fluid passes coating to be disperseed to enter to cause colloidal swelling.Coating breaks because of the colloid swelling, and all the elements thing of activating agent is released.Though the rate of release variation is very little between the different experimenters, the initial blood drug level of gross activity agent is very high, and descends rapidly in time.

U.S. patent No.3115441 has disclosed the method for another kind of encapsulation, be used for the conveying of chemical compound of the present invention and preparaton, the coating that approaches fast with filmogen and nontoxic hydrophobic material at first of the granule of activating agent wherein carries out coating continuously with material that can organic solvent-resistant then.Coated granule is mixed with the activating agent of coating not, and mixture is made tablet immediately, and the gained tablet is that the sheet with coating places the not substrate of the activating agent of coating.The tablet that makes with this method has the advantage of rapid release chemical compound of the present invention and preparaton because host material (comprising initial dosage) dissolves fast in the back of ingesting.

Another aspect, as at U.S. patent No.4025613, provide a kind of chemical compound of the present invention of improvement and the blood level of preparaton, this is that dry back forms the coating of cellulose acetate outside the tablet that forms because of the granule (before the tabletting) that simply the non-aqueous solution thin film of cellulose acetate is applied to activating agent and untreated active agent particle.According to film coating, those skilled in the art can select suitable film former: cellulose selects the polymer and the copolymer of derivant such as hydroxypropyl emthylcellulose (HPMC), ethyl cellulose, acetyl O-phthalic acid cellulose, cellulose acetopropionate, tricarboxylic acid cellulose (trimelliate), methacrylate and derivant thereof.Film former can with following component mend together into: plasticizer (as high-molecular weight Polyethylene Glycol, polybasic ester such as citric acid or phthalic acid), filler (as Pulvis Talci, metal oxides such as titanium dioxide), be selected from the pigment that those can be used for medicine and food industry.

The another kind of agent for slow releasing type of chemical compound of the present invention and preparaton is any suitable osmosis system, and it has the semipermeable membrane of cellulose acetate, acetylbutyrylcellulose, cellulose acetate propionate, with the release of control activating agent.These can be filmed the dispersion coating and not change rate of release by the use intestinal.An example of such osmosis system is the osmotic pumps device, can be the Oros of Alza company (U.S.A.) ^TMDevice.This system comprises a label, and semipermeable membrane in its outsourcing, on the hole of the 0.4mm diameter that is formed by laser beam is arranged.Label has two-layer, and one deck contains medicine (active layer), and another layer contains polymeric penetrating agent (promoting layer).Label is made up of active medicine, filler, viscosity modifier and solubilizing agent.This system operates by the osmotic pressure principle.This system is suitable for the release of the medicine of relative broad range, comprises triethyl group tetramine or its salt.Art for coating is simple, and release is zero order kinetics.When taking tablet, semipermeable membrane allows waterborne liquid to enter from stomach in the label, dissolving or suspended drug.When pressure increases to permeable formation, it extrudes drug solution or pumps to the tablet edge from the aperture.Have only drug solution (non-soluble drug is not all right) can pass the aperture of tablet.This system per hour only needs several dripping to enter in the tablet.The function of the speed of stream and tablet depends on the existence of osmotic gradient between the content of double-layer tablet and the liquid in the gastrointestinal tract in the waterborne liquid.Drug release is constant at osmotic gradient to be successive down basically.Drug release rate can be by changing surface area, compositions the thickness of film and/or the diameter in aperture change.Drug release rate is not subjected to the influence of gastrointestinal tract acidity, basicity, feeding conditioned disjunction gastrointestinal motility power.The active component of inanimate object is kept perfectly in the intestinal transfer process in the tablet, and discharges from feces as insoluble refuse.The example that other this technology is used can be referring to GlucotrolXL Extended Release Tablets (Pfizer Inc.) and Procardia XL ExtendedRelease Tablets (Pfizer Inc.; See, Martindale 33rd Ed., p.2051.3).

The present invention also is provided for discharging the releasing device of The compounds of this invention and preparaton, the substrate of its using integral for example comprises slowly aggressivity or hydrophilic polymer substrate, with one or more for example the copper chelator of triethyl group tetramine or its salt be pressed into or imbed in the described substrate.

The integrated substrate device that is used to discharge chemical compound of the present invention and preparaton comprises that those form with following system, and for example: (I), drug particles is scattered in the dissolvable matrix, and wherein effect increases after stromatolysis or the swelling; Example comprises hydrophilic colloid substrate such as hydroxypropyl cellulose (BP) or hydroxypropyl cellulose (USP); Hydroxypropyl emthylcellulose (HPMC; BP, USP); Methylcellulose (MC; BP, USP); Carboxymethylcellulose calcium (calcium CMC; BP, USP); Acrylate copolymer or carboxylic polymethylene (carbopol (Carbopol)) or carbomer (BP, USP); Or straight chain grape uronic acid polymer such as alginic acid (BP, USP), for example those microparticles by alginic acid (alginate)-gelatin hydrocolloid reunion system form, or those are by alginic acid and the film-coated liposome of poly-L-lysine.Medicine discharges when polymers swell, and it forms hypothallus, can control therefore waterborne liquid also controls the diffusion rate in this system from medicine to the diffusion of label.In such system, drug release rate depends on the natural torsion resistance of the passage in the gel, and the viscosity of liquid, can obtain different release dynamics, zero order kinetics for example, or with the bonded first order kinetics of pulse release.If gel is not crosslinked, have one more weak, the interchain contact of revocable polymer, it is to depend on the secondary bonding.For such device, can finish the high useful load of active medicine, and frequent effectively mixing.This device comprises the medicine (w/w) of 20-80%, and the gel regulator, and it can strengthen the diffusion of medicine; The example of such regulator comprises the sugar that can increase hydration speed, can influence the pH buffer agent of crosslinked ion and the Ionized level of energy impact polymer.Hydrophilic matrix device except containing medicine and hydrophilic matrix, also typically contain pH buffer agent, surfactant, counter ion, lubricant such as magnesium stearate (BP, USP) and fluidizer such as silica sol (USP; Colloidal silica anhydrous, BP); (II), drug particles is dissolved in the insoluble matrix, and its Chinese medicine enters substrate by solvent, and normally passing hole channel enters, and dissolved substance granule and obtaining.Example comprises lipidic matrix or the substrate formed system of insoluble polymer, comprises by Brazil wax (BP; USP) preparation of Xing Chenging; Medium chain triglyceride such as fractionated Oleum Cocois (BP) or triglyceride saturated media (PhEur); Or cellulosic ether or ethyl cellulose (BP, USP).Lipidic matrix is easy to and preparation simply, and can be mixed with following powdered ingredients: lipid (20-40% hydrophobic solid w/w) is kept perfectly in dispose procedure; Medicine; Channel agent such as sodium chloride or sugar can leach from preparaton, form aqueous micro channel (blood capillary), are released by the micro channel medicine.In the another one system, use insoluble polymer substrate, medicine is imbedded in the inertia insoluble polymer and by waterborne liquid and is leached release, and this liquid diffuses in the granule core by passage, thus medicine can discharge from device.Rate of release is controlled by suppression degree, granular size, natural performance and corresponding auxiliary material (w/w).The example of such device is Ferrous Gradumet (Martindale 33rd Ed., 1360.3).The example that is further adapted for insoluble matrix is an inert plastic substrate.By this method, triethyl group tetramine activating agent and plastic material are made granule, and for example polyethylene, polyvinyl acetate or polymethacrylates and their mixture are pressed into tablet then.In case ingest, medicine from inert plastic substrate by diffusion slowly discharge (referring to Bodmeier, R.﹠amp; Paeratakul, O., " Drug releasefrom laminated polymeric films prepared from aqueous latexes, " J PharmSci 79:32-26 (1990); Laghoueg, N. waits people " Oral polymer-drug deviceswith a core and an erodable shell for constant drug delivery, ", Int J Pharm50:133-139 (1989); Buckton, G. waits " The influence of surfactants ondrug release from acrylic matrices. " Int J Pharm 74:153-158 (1991) of people).The compacting of tablet forms substrate or plastic form, and it can ooze drop and pass through to keep in the gastrointestinal process its shape at medicine.The rapid release part of medicine can be pressed into tablet surface.Inert tablet substrate is the refuse of medicine, passes through defecate.The example of the dosage form of this type is Gradumet (Abbott; Referring to Ferro-Gradumet, Martindale 33rd Ed., p.1860.4).

Further use chemical compound of the present invention and preparaton are combined with polymeric matrix in unsettled (pendent) adnexa (referring to Scholsky, K.M.﹠amp; Fitch, R.M.Controlled release of pendant bioactive materials from acrylic polymercolloids.J Controlled Release 3:87-108 (1986)).In these devices, medicine is by the ester that is connected with the polyacrylate latex particle and combination, and its preparation is to finish by aqueous emulsion polymerization.

Further the specific embodiment combines the dosage form of chemical compound of the present invention and preparaton, its Chinese medicine and biocompatible polymer (itself are by acyl chlorides and medicine: the prepared in reaction of isobutene. acyl chlorides and methoxybenzoic acid sodium) Zhi Bei polyanhydride bonding from the anhydride that replaces for example by unsettled chemical bond, be used to form the substrate (Eudragit RL) of secondary polymerization thing, discharge (referring to Chaffi by hydrolysis in intestinal juice, N., Montheard, J.P.﹠amp; Vergnaud, J.M.Release of 2-aminothiazole from polymeric carriers.Int J Pharm 67:265-274 (1992)).

Forming the suitable hydrophilic matrix that is used for The compounds of this invention and preparaton, the polymer of selection must form gelatinous layer fast, and its speed is enough to protect tablet core to avoid too fast by digest and decompose.And the ratio of polymer in the rising preparaton, the increase of gel viscosity can cause the speed of drug diffusion and release to descend (referring to Formulating for controlledrelease with Methocel Premium cellulose ethers.Midland, MI:DowChemical Company, 1995).Usually, the HPMC of 20% (w/w) can form the rate of release of the prolongation release tablet preparaton of satisfied medicine.Yet, for all preparatons, must consider the effect that other preparaton composition is possible, such as filler, tablet binder and disintegrating agent.The example of the patented product that the prolongation of application HPMC hydrophilic matrix preparation discharges is an Oramorph SR (roxatidine; Referring to Martindale 33rd Ed., p.2014.4).

Bilayer tablet can be prepared into and contain one or more chemical compound of the present invention and preparatons, and wherein one deck contains unconjugated medicine as the rapid release layer, and another layer contains the medicine of imbedding hydrophilic matrix as prolonging releasing layer.Tri-layer tablets also can prepare with similar methods, and two skins contain medicine as the rapid release layer.Some its kernels of commercially available tablet contain the medicine that prolongs release, but are encapsulated in the medicine that outer shell then contains rapid release.

The present invention also provides for example complex that forms of one or more chemical compounds of the present invention and preparaton and ion exchange resin of active component, and this complex can tabletting, encapsulated or be suspended in the aqueous carrier.The release of activating agent depends on partial pH value and electrolyte concentration, and the selection of such ion exchange resin is to be preferable over the resin that activating agent is discharged in gastral relevant position.The present invention also provides the conveyer device of having incorporated this complex into.For example, the slow release formulation of triethyl group tetramine can obtain by triethyl group tetramine and anion exchange resin complexation are merged.Triethyl group tetramine solution can be by ion exchange resin column by replacing H ₃O ⁺Ion forms complex.Resin-triethyl group tetramine complex is with after scouring, and can tabletting, encapsulated or be suspended in the aqueous carrier.The release of triethyl group tetramine depends on the pH value and the electrolyte concentration of gastro-intestinal Fluid.Be released in the tart gastric juice than many in the intestinal fluid of low sour environment.The example of the prolongation delivery formulations of another this type is to provide (Medeva by hydrocodone polistirex and chorpheniramine polistirex suspension; Tussionex PennkineticExtended Release Suspension, referring to Martindale 33rd Ed., p.2145.2), and by Duromine resin capsule (Pharmanex; P.1916.1) Ionamin Capsules provides referring to Martindale 33rdEd..Such resin-triethyl group tetramine surfactant system can be in addition in conjunction with the polymer barrier coating outside the deionization switching technology with become the pearl technology.Initial dosage is from the part of coating not, and all the other are the globules from coating.Coating does not dissolve, and drug release can continue above 12 hours because of ion exchange.It is very little to comprise particulate medicine, and the formation that can suspend can have liquid dosage form and the solid dosage forms that prolongs release characteristics.Such preparation can also be applicable to the administration of the storage storehouse dosage form of for example intramuscular injection.

The present invention also provides a kind of one or more for example methods of the slow releasing preparation of the copper chelator of triethyl group tetramine or its salt for preparing, and this method is undertaken by microencapsulation.The preparation of described microencapsulation can be used for treating people and other mammal that needs the copper chelator treatment.Microencapsulation is following process, can be encapsulated in the molecule by this process solid, liquid and even gas, finishes by forming film coating at material surface, and microencapsulation method can be referring to U.S. patent No.3,488,418; 3,391,416 and 3,155,590.Gelatin (BP USP) can form material as the coating wall of microencapsulation preparation usually, and synthetic polymer such as polyvinyl alcohol (USP), ethyl cellulose (BP, USP), polrvinyl chloride and other material also can be used (referring to Zentner, G.M., Rork, G.S.﹠amp; Himmelstein, K.J.Osmotic flow through controlledporosity films:an approach to delivery of water soluble compounds.JControlled Release 2:217-229 (1985); Fites, A.L., Banker, G.S.﹠amp; Smolen, V.F.Controlled drug release through polymeric films.J PharmSci59:610-613 (1970); Samuelov, Y., Donbrow, M.﹠amp; Friedman, M.Sustained release of drugs from ethylcellulose-polyethylene glycol filmsand kinetics of drug release.J Pharm Sci 68:325-329 (1979)).

The encapsulated water that is dissolved in that at first is the coating wall material such as described gelatin.One or more for example the copper chelator of triethyl group tetramine or its salt add subsequently, biphase mixture fully stirs.When the material of encapsulation has reached the granular size that needs, add the solution of another kind of material, its can be arabic gum (BP, USP).Additional materials be select to have concentrated gelatin (polymer) to fine droplet ability.These drops (aggregate) form solid triethyl group tetramine granule outer thin film or coating subsequently, the result forms the residual water in the coating wall material or the minimum interfacial tension of solvent, make and to form firm continuous films coating (referring to Ansel on the granule, H.C., Allen, L.V. and Popovich, N.G.Pharmaceutical Dosage Forms and DrugDelivery Systems, 7th Ed., Lippincott 1999, p.233).Final dry microcapsule is free-pouring, discrete coated granule.With respect to total particle weight, the coating wall material is usually at 2-20% (w/w).Coated granule mixes the tablet of making suitable dosage with additive of tablet subsequently.The rate of release of different triethyl group tetramines can be used for the polymer of coating by changing the ratio of label-coating wall, or the method for microencapsulation and obtain (for example referring to Yazici, E., Oner, L., Kas, H.S.﹠amp; Hincal, A.A.Phenytoin sodium microspheres:bench scaleformulation, process characterization and release kinetics.Pharmaceut DevTechnol 1996; 1:175-183).

An advantage of microencapsulation be with dosage one or more for example the copper chelator of triethyl group tetramine or its salt be divided into a plurality of little dosage devices, can extensively be distributed in the gastrointestinal tract, increase the absorption of medicine (referring to Yazici et al., supra) by reducing local drug concentration.The example of the prolongation release dosage form of microencapsulation that can be commercially available be potassium chloride (Micro-KExten-caps, Wyeth-Ayerst, Martindale 33rd Ed., p1968.1).Other comprises that those medicines are incorporated into aggregation colloid granule or the middle storage storehouse that forms of microcapsule (microgranule, microsphere or nanoparticles) and matrix device (referring to Douglas, S.J., Deng the people " Nanoparticles in drugdelivery; ", C.R.C.Crit Rev Therap Drug Carrier Syst 3:233-261 (1987); Oppenheim, R.C., " Solid colloidal drug delivery systems:nanoparticles. " Int J Pharm 8:217-234 (1981); Higuchi, T. " Mechanism ofsustained action medication:theoretical analysis of rate of release of soliddrugs dispersed in solidmatrices. " J Pharm Sci 52:1145-1149 (1963)).

The present invention also comprises and contains one or more for example repeat function tablets of the copper chelator of triethyl group tetramine or its salt.Comprise that further preparation is applicable to mammiferous one or more methods of the slow release formulation of the copper chelator of triethyl group tetramine or its salt for example of treatment people or other, but be by providing in the tablet that the triethyl group tetramine is incorporated into repeat function.Preparing such tablet makes and then can discharge second dosage by initial drug dose rapid release.This tablet has the rapid release dosage layer as shell or coating, and the second dosage layer is separated by having slow chemosmotic coating barrier in the kernel of tablet.Usually, the medicine of kernel was exposed in the body fluid after administration in 4-6 hour and discharges.The example of the product of this type is by Repetabs (Schering Inc.) alleged occurrence.The repeat function dosage form is suitable for one or more for example administrations of the copper chelator of triethyl group tetramine or its salt, and suitable disease includes but not limited to chronic disease such as heart failure, diabetic cardiopathy, acute coronary syndrome, hypertensive heart disease, ischemic heart desease, coronary heart disease, peripheral arterial disease or any type of cancer.The drug release of this form absorbs fast owing to it and drains the release that is specially adapted to the triethyl group tetramine.

The present invention also comprise contain one or more for example the copper chelator of triethyl group tetramine or its salt postpone the peroral dosage form that discharges.One or more for example the release of the peroral dosage form of the copper chelator of triethyl group tetramine or its salt can postpone wittingly to discharge, arrive intestinal portion up to medicine, its mode is an enteric coating for example.Enteric coating self is not to discharge the effective ways that triethyl group tetramine for example or its salt comprise the copper chelator of triethyl group tetramine dihydrochloride, and reason is that such coating system can not provide persistent therapeutic effect behind the drug release.Enteric coating need dissolve or disintegrate in the environment of alkalescence.The existence of food can increase the pH value in the stomach.Therefore, the triethyl group tetramine dihydrochloride of enteric coating and food absorb jointly or have under one's belt under the situation of food, all can cause the loss of drug dose and the generation of undesirable side reaction.And, statement of facts, triethyl group tetramine dihydrochloride can cause the generation of gastrointestinal side effect, so need a delivery system, it can provide the release in the long time in a predetermined manner of the salt of in check triethyl group tetramine dihydrochloride or the acceptable triethyl group tetramine of other pharmacy.

When carrying prescription or device in conjunction with one or more other preparations described herein, enteric coating also can be used for the present invention.The advantage of this releasing pattern is to have reduced the part experimenter's that the triethyl group tetramine may cause gastrointestinal irritation.Enteric coating can be a time dependence, pH-is dependent, wherein in the lower enteral disintegrate of acidity, and in the intestinal transfer process, corroded by moisture in time, or enzyme is dependent, wherein catalyzing hydrolysis and going bad (referring to Muhammad under the effect of intestinal enzyme, N.A., Deng people's " Modifying the release properties ofEudragitL30D, ", Drug Dev Ind Pharm.17:2497-2509 (1991)).Being used for enteric coated tablet and capsular plurality of reagents all is that the art technology philtrum is known, and the fat, fatty acid, wax, Lac and the cellulose acetate phthalate that comprise triglyceride are arranged, and more enteric coating preparation can find in USP.

The present invention also comprises and contains one or more for example delivery devices of the film control system of the copper chelator of triethyl group tetramine or its salt.Such device comprises the rate controlled thin film that surrounds drug depot.Behind the oral administration, thin film gradually can be by liquid infiltration but can not be etched or swelling.Drug depot can be made conventional tablet, or comprises a plurality of unitary microgranule pillers, its with can swelling after liquid contacts.Need not to change inner osmotic pressure is solubilized nuclear core, therefore avoids the destruction of thin film, typically contains 60: 40 lactulose: the mixture of microcrystalline Cellulose (w/w).Medicine discharges by biphase process, comprises the diffusion of waterborne liquid in substrate, then is that medicine is to extramatrical diffusion.Multiple-unit thin film control system typically comprises the unit of a plurality of separations.Can contain the discrete film-coated spherical bead of usefulness rate controlled, and can be encapsulated in that (such examples of formulations comprises contac Contac 400 in the hard gelatin shell; Martindale 33rd Ed., 1790.1 and Feostat Feospan; Martindale33rd Ed., p.1859.4).Perhaps, multiple-unit thin film control system can be pressed into tablet (mistaprel Suscard for example; Martindale 33rd Ed., p.2115.1).The another kind of mode of this technology of using comprises a kind of device, and wherein drug coating is on inertia sugar ball, and its preparation is to use conventional matrix system to finish by the extruding nodularization.The advantage of this system comprises accelerate gastrointestinal road through-rate, can't cause the loss of drug dose.This device can also once be carried more than a kind of medicine ideally.

Preferred oral delivery is meant the sustained release form of one or more chemical compounds of the present invention and preparaton, it is a matrix structure, described matrix structure adopts the form of film coating round, wherein comprise one or more copper chelators of triethyl group tetramine or its salt such as triethyl group tetramine dihydrochloride for example as active component, and non-water-soluble nodularization reagent.Term " round " is meant spheroidal particle pharmaceutically, typically has a diameter from 0.01mm-4mm.Nodularization reagent can be the acceptable material of any pharmacy, but mixes globulate with active component.Microcrystalline Cellulose preferably.Suitable microcrystalline Cellulose comprises for example Avicel PH 101 (trade mark, FMC Corp.).Preferred aspect according to the present invention, the bead of film coating comprise 70%-99%'s (weight ratio), particularly the nodularization reagent, particularly microcrystalline Cellulose of 80%-95% (weight ratio).Except activating agent and nodularization reagent, bead can also contain binding agent.Suitable bonding as low viscous water-soluble polymer, is well known to those skilled in the art.Suitable bonding is the polyvinylpyrrolidone of the various degree of polymerization particularly.Yet the low alkylcellulose of water soluble hydroxy is preferred as hydroxypropyl cellulose.(or alternative) in addition, bead can comprise insoluble polymer, particularly acrylic polymer, ACR, as methacrylate-ethyl acrylate copolymer or ethyl cellulose.Other intensifier or binding agent comprise: lipid, comprising vegetable oil (Oleum Gossypii semen, Oleum sesami and Oleum Arachidis hypogaeae semen) and derivant (hydrogenated oils such as castor oil hydrogenated, glycerol, Wax such as natural Brazil wax or natural Cera Flava, synthetic wax such as cetyl esters wax, amphiprotic substance such as ethylene oxide polymer (high-molecular weight polyoxyethylene glycol, molecular weight is at 4000-100000) or the copolymer (poloxamer) of ethylene oxide and propylene oxide, cellulosic class material (cellulose, hydroxypropyl emthylcellulose, hydroxypropyl cellulose, the semisynthetic derivant of hydroxy methocel high molecular high viscosity resins) or any other polysaccharide such as alginic acid, polymer class material such as acrylate copolymer (as carbomer), and inorganic matter class material such as silica sol, bentonite.

For the active component suitable diluent in piller, bead or the nuclear core for example microcrystalline Cellulose, lactose, dicalcium phosphate, calcium carbonate, calcium sulfate, sucrose, dextrates, dextrin, glucose, dicalcium phosphate dihydrate, Kaolin, magnesium carbonate, magnesium oxide, maltodextrin, cellulose, microcrystalline Cellulose, Sorbitol, starch, pregelatinized starch, Pulvis Talci, tricalcium phosphate and lactose are arranged.Examples of suitable lubricants has for example magnesium stearate and sodium stearyl fumarate.Suitable bonding is for example hydroxypropyl emthylcellulose, polyvidone (polyvidone) and methylcellulose.

Suitable bonding can comprise: arabic gum, tragakanta, guar gum, alginic acid, sodium alginate, sodium carboxymethyl cellulose, dextrin, gelatin, hydroxyethyl-cellulose, hydroxypropyl cellulose, liquid glucose, magnesium and aluminum.Suitable disintegrants has starch, primojel, crospovidone and croscarmellose sodium.Suitable surfactant is poloxamer 188 , Tween 80 and sodium lauryl sulfate.Suitable fluidizer is a Pulvis Talci colloid anhydride silica.Operable examples of suitable lubricants can be slip agents (as anhydrous silicate, magnesium trisilicate, magnesium silicate, cellulose, starch, Pulvis Talci or tricalcium phosphate) or lubricant (as calcium stearate, hydrogenated vegetable oil, paraffin, magnesium stearate, Polyethylene Glycol, sodium benzoate, sodium lauryl sulfate, fumaric acid, stearic acid or zinc stearate and Pulvis Talci).Suitable water-soluble polymer is the PEG of molecular weight in the 1000-6000 scope.

Postpone to discharge the tablet, piller, bead or the nuclear core self that use, except containing filler and binding agent, also contain other adjuvant, particularly lubricant and antiplastering aid, and disintegrating agent.The example of lubricant and antiplastering aid is higher fatty acids and their alkali metal and alkali salt, as calcium stearate.Suitable disintegrants is those chemical inertness agent particularly.The preferably crosslinked polyvinylpyrrolidone of disintegrating agent, crosslinked sodium carboxymethyl cellulose and carboxylic amylcose acetate sodium.

In the body of controlled way and in the dissolution in vitro, oral dosage device is preferably carried the copper chelator that surpasses 50% for example triethyl group tetramine dihydrochloride time in 12 hours in pH value＜6.5.Other preparaton and dosage form are as described below.

Further the specific embodiment of the present invention comprises one or more for example dosage forms of the delivery system incorporates of the copper chelator of triethyl group tetramine or its salt and percutaneous dosing, described in describing below those: Transdermal Drug Delivery Systems, Chapter 10.In:Ansel, H.C., Allen, L.V.and Popovich, N.G.Pharmaceutical Dosage Forms andDrug Delivery Systems, 7th Ed., Lippincott 1999, pp.263-278.The medicine that the induction system of percutaneous dosing helps percutaneous therapeutic dose enters body circulation performance effect, can be with reference to (Stoughton, R.D.Percutaneous absorption.Toxicol Appl Pharmacol7:1-8 (1965)).The evidence of the drug absorption of percutaneous can be measured blood level by the clinical response of experimenter after the administration, measures excretion of drug and/or the metabolite in urine and determines.For impart transdermal drug delivery,, then be considered to ideal (Black, C.D., " Transdermal drug delivery systems, ", U.S.Pharm 1:49 (1982)) if medicine enters blood through skin and do not accumulate at skin layer.The pharmaceutical formulation that is suitable for percutaneous release is well known to those skilled in the art, in some lists of references description is arranged, as people such as Ansel (supra).Known method by percutaneous approach enhancing drug conveying comprises chemical transdermal enhancer, wherein be the permeability that increases skin by the cuticular physicochemical properties of reversible damage or other change, with reduce its opposing to drug diffusion (referring to Shah, V.P., Peck, C.C.﹠amp; Williams, R.L.Skin penetration enhancement:clinical pharmacological and regulatoryconside ratio ns.In:Walters, K.A.﹠amp; Hadgraft, J. (Eds.) Pharmaceuticalskin penet ratio n enhancement.New York:Dekker, 1993).Effectively other change schemes have the increase that activity or degeneration by solvent cause skin liver horny layer hydration, and/or in the variation of the lipid and the lipoprotein structure of intercellular passage (referring to Walters K.A., " Percutaneous absorption and transdermaltherapy, " Pharm Tech 10:30-42 (1986)).The penetrating reinforcing agent of skin of the triethyl group tetramine preparaton in being suitable for transdermal drug delivery systems can be selected following listed material: acetone, laurocapram (Laurocapram, 1-positive dodecyl aza cyclohepta-2-ketone), acetic acid dimethylamide, dimethyl formamide, dimethyl sulfoxide, ethanol, oleic acid, Polyethylene Glycol, propylene glycol and sodium lauryl sulfate.The penetrating reinforcing agent of the skin that further provides can in the publication of routine, find by those skilled in the art (referring to Osborne, D.W. ， ﹠amp; Henke, J.J., " Skin penetration enhancers cited in thetechnical literature, " Pharm Tech 21:50-66 (1997); Rolf, D., " Chemical andphysical methods of enhancing transdermal drug delivery, " Pharm Tech 12:130-139 (1988)).

Except chemical mode, can also strengthen the percutaneous release and the infiltration of The compounds of this invention and preparaton with physical method.These comprise iontophoresis and phonophoresis method.Iontophoresis comprises using electric field makes chemical substance see through the drug release of skin membrane.Described method is applicable to the release of many medicines.Correspondingly, another specific embodiment of the present invention comprise one or more for example the copper chelator of triethyl group tetramine or its salt answer iontophoretically or phonophoresis method to make suitable preparaton.One or more for example the copper chelator of triethyl group tetramine or its salt answer iontophoretically or phonophoresis method to make the form that suitable preparaton can be gel, Emulsion or lotion.Impart transdermal drug delivery can be applied to other system, adheres to induction system (for example from the Latitude of 3M as whole delivery system, drug osmotic ^TMThe medicine attachment systems), active medicament release device and film control system.Total system is in conjunction with activating agent substrate, and it comprises polymeric material, activating agent can be scattered in before and after it two-layer between.Drug osmotic adheres to induction system and comprises mucoadhesive polymers, and one or more chemical compounds of the present invention and preparaton and adjuvant all are combined in the mucoadhesive polymers.The active transport device combines with active agent reservoir, and in liquid or gel, thin film can be used for rate controlled usually, as advancing activating agent to pass the power of thin film.Film control transdermal delivery system generally includes the active agent reservoir of liquid form or gel form, as rate controlled, support, adhere to and/or the thin film of protective layer.Percutaneous carries dosage form to comprise that those replace the triethyl group tetramine, the active component of triethyl group tetramine dihydrochloride or the acceptable salt of other pharmacy preferably, and its example in transdermal delivery system is referring to U.S. patent No.6,193,996 and 6,262,121.

The topical of chemical compound of the present invention and preparaton can be prepared into mixture or other pharmacy preparaton is used in many ways, includes but not limited to lotion, Emulsion, gel, bar rod, spray, ointment and paste.These product types can comprise multiple preparaton type, include but not limited to solution, Emulsion, gel, solid dosage and liposome.If topical compositions is made aerosol and sprayed and bestow skin, in liquid composite, can add propellant.Conventional suitable propellant all can use.The example of topical compositions is referring to U.S. patent No.5,602,125,6,426,362 and 6,420,411.

The present invention also comprises sustained release forms, can be the variant of various peroral dosage forms, and this variant is adapted to the purposes of suppository or other parenteral administration.When with the suppository form rectally, these compositionss can be by with one or more chemical compounds of the present invention and preparaton and suitable mixed the making of nonirritating adjuvant, be solid cocoa butter, synthetic glyceride or Polyethylene Glycol at normal temperatures for example, it can liquefy and/or dissolve at internal rectum.Suppository is generally solid dosage forms, is used for inserting the body bore, comprises rectum, vagina and once in a while in urethra, can be long-acting or slowly discharges.Suppository comprises substrate, and described substrate includes but not limited to the material as alginic acid, and its release that can prolong pharmacy activity component reaches a few hours (5-7 hour).These substrate can be divided into two big classes and the 3rd mixed group by characteristic: 1) fat or oleaginous base, 2) water solublity or the blendable substrate of water and 3) mixed type substrate, the normally mixing of lipotropy and hydroaropic substance.Fat or oleaginous base comprise hydrogenated fatty acid such as the palm-kernel oil and the Oleum Gossypii semen of vegetable oil, fatty material, comprise glycerol and high molecular weight fatty acid, as Palmic acid and stearic acid, and cocoa butter, also can use, wherein phenol and chloral hydrate have reduced the fusing point of cocoa butter, and firming agent such as cetyl esters wax (about 20%) or Cera Flava (about 4%) can add to keep the solid-state form of suppository.Other substrate comprises commercially available product such as Fattibase (from Petiolus Trachycarpi, Petiolus Trachycarpi nuclear and the triglyceride of Oleum Cocois and the glyceryl monostearate and the Myrj 45 (poloxyl stearate) of self emulsifying), Wecobee and Witepsol substrate.Water-soluble base is glycerin gelatine normally, and the blendable substrate of water is Polyethylene Glycol normally.Mixed type substrate comprises oil and water solublity or water miscibility material.An example of described substrate is Myrj 52 and polyoxyethylene glycol and ethylene glycol freely.

The mucosa of wearing of chemical compound of the present invention and preparaton is carried and can be used any mucosa thin film, is generally used for the administration of intranasal, oral cavity buccal, vagina and rectal tissue.

The dosage of the present invention that is applicable to nose administration can be with the liquid form administration, for example nasal mist, nasal drop, or by aerosol apparatus with the aerosol form administration, comprise the solution of aqueous or butyrous active component.Nose administration, wherein carrier is that solid preparaton comprises the coarse powder with certain particle diameter, and for example diameter is less than 100 microns, preferably less than 50 microns, it is the mode administration with the snuffing medicament, and the container that is about to be equipped with powder is pressed close to the mode administration of nasal cavity with quick suction.Liquid composite can use built-in gas atomization administration, and the solution of described spraying can directly suck from sprayer unit, and sprayer unit can attach face shield, tent or intermittent pressure breathing assistor.Solution, suspension or powder composition can per os or nose administrations, carry out drug conveying with suitable manner.Preparaton can be made aqueous solution such as saline solution, the solution that uses benzyl alcohol or other suitable preservatives, increase absorption enhancer, fluorocarbon and/or other the known solubilized or the dispersible material of bioavailability.

The present invention also provides and comprises one or more for example preparatons of discharging of the prolongation that is suitable for parenteral administration of the copper chelator of triethyl group tetramine or its salt.The pharmaceutically active rate elongation of drug administration by injection can obtain in several ways, comprising: crystal formation or unformed medicament forms with dissolution characteristics of prolongation; The slow dissolving of the chemical complex of medicine; The solution or the suspension of the medicine of (as oil) in the carrier or vehicle that slowly absorb; The granular size that medicine increases in suspension; Or the slow erosion of the medicine microspheres of being injected is (for example referring to Friess, W., Lee, G.and Groves, M.J.Insoluble collagen matrices for prolongeddelivery of proteins.Pharmaceut Dev Technol 1:185-193 (1996)).For example the various forms of persistent period of insulin partly are based on its physical form (unformed or crystal formation), with the formation of the complex of additive reagent, with and dosage form (solution or suspension).

Copper chelator need be made stable, the safe drugs compositions that gives the patient.Copper chelator is a triethyl group tetramine activating agent.Said composition can be according to preparing by the conventional method of a certain amount of triethyl group tetramine activating agent being dissolved or be suspended in the diluent.Described amount is that every ml diluent has triethyl group tetramine activating agent 0.1-1000mg.Acetate, phosphate, citrate or glutamate, Glu buffer can add so that the pH value of final composition at 5.0-9.5; Optional can add carbohydrate or polyhydric alcohol regulator, and antiseptic, be selected from m-cresol, benzyl alcohol, parabens and phenol that methyl, ethyl, propyl group and butyl replace.The water for injection of capacity is used to obtain the solution concentration of needs.If necessary, additional regulator such as sodium chloride and other adjuvant also can exist.Described adjuvant must can be kept all performances of triethyl group tetramine activating agent.

Term buffer agent, buffer solution refer to particularly aqueous solution of system with reference to hydrogen ion concentration or pH value, in the ability that pH value changes of resisting behind adding acid or the alkali or after the solubilizer dilution.The characteristic of buffer solution is to tolerate the variation that adds pH value little behind acid or the alkali, and often with weak acid and salt thereof, or the form of weak base and salt thereof exists.An example of this system is acetic acid and sodium acetate.The variation of pH value is very little, as long as the hydrion that adds can be not too much, buffer system can both balance out it.

The stability of parenteral administration preparaton of the present invention can be enhanced in the scope of about 5.0-9.5 by keeping pH value.Other pH value scope for example comprises 5.5-9.0, or 6.0-8.5, or 6.5-8.0, or 7.0 to 7.5.

The buffer agent of using among the present invention is selected from following any, and for example acetate buffer agent, phosphoric acid buffer agent or glutamic acid buffer agent most preferably are phosphoric acid buffer agents.

Carrier or adjuvant can be used for making things convenient for administration.The example of carrier or adjuvant comprises calcium carbonate, calcium phosphate, various sugar such as lactose, glucose or sucrose, or each kind of starch, cellulose derivative, gelatin, the solvent that Polyethylene Glycol and physiology are compatible.

Preparaton of the present invention can comprise stabilizing agent, but will emphasize that it is optional.If but comprise that can be used for stabilizing agent of the present invention is carbohydrate or polyhydric alcohol.Polyhydric alcohol comprises Sorbitol, mannitol, glycerol and Polyethylene Glycol (PEGs).Carbohydrate has mannose, ribose, trehalose, maltose, inosite, lactose, galactose, arabinose or lactose.

Suitable stabilizing agent for example comprises that polyhydric alcohol such as Sorbitol, mannitol, inositol, glycerol, xylitol and polypropylene/glycol copolymer and various molecular weight are 200,400,1450,3350,4000,6000 and 8000 Polyethylene Glycol (PEG).

The antimicrobial that American Pharmacopeia (USP) indicates antibacterial or antifungal concentration must join in the container of preparaton of multiple dose.Enough concentration must be arranged in use preventing retraction partial content thing when using hypodermic needle, or the breeding of the microorganism that brings when using other administering mode such as pen type injection.Antimicrobial will be assessed to guarantee compatible with other all the components, and their activity also will assess determining specific reagent, described reagent in a kind of preparaton effectively and invalid in another kind of preparaton.Be easy to determine that a kind of specific reagent is effective in a preparaton, and invalid in another preparaton.

In common pharmacy practice, antiseptic can prevent or suppress microbial growth, and can join in the pharmaceutical formulation that needs this purpose, goes bad to avoid preparaton to be subjected to the influence of microorganism.Although but the consumption of antiseptic is not a lot, can influence the overall stability of triethyl group tetramine activating agent.Therefore, selection is than difficulty.

The amount ranges of antiseptic is at 0.005-1.0% (w/v) among the present invention, preferably for every kind of antiseptic, separately or the consumption during use in conjunction be: benzyl alcohol (0.1-1.0%), m-cresol (0.1-0.6%), or phenol (0.1-0.8%), the perhaps combination of methyl (0.05-0.25%) and ethyl or propyl group or butyl (0.005%-0.03%) p-Hydroxybenzoate.P-Hydroxybenzoate is the lower alkyl esters of P-hydroxybenzoic acid.

The detailed description of every kind of antiseptic can reach " Pharmaceutical Dosage Forms:Parenteral Medications, Vol.1,1992, Avis et al. " referring to " Remington ' s PharmaceuticalSciences ".For these purposes, the salt of the triethyl group tetramine dihydrochloride of crystal formation can be used for parenteral administration (comprising subcutaneous injection, intravenous injection, intramuscular injection, intradermal injection or infusion techniques) or comprise the preparaton of the dosage device of conventional nontoxic pharmaceutical acceptable carrier, adjuvant and media by the suction spray delivery.

Also having needs adding sodium chloride or other salt to adjust the tension force of pharmaceutical formulation, and this depends on the tonicity contributor of selection.Yet this is selectable components and the specific preparaton that depends on selection.The parenteral administration preparaton must be to wait to ooze or roughly wait to ooze, otherwise will cause significant stimulation and pain in administered area.

Required isotonicity can add sodium chloride or other pharmacy acceptable agents reaches, as glucose, boric acid, sodium tartrate, propylene glycol, polyhydric alcohol (as mannitol and sorbitol) or other inorganic or organic solute.Usually, compositions is that blood etc. with the experimenter oozes.

If necessary, the parenteral administration preparaton can add the thickening agent thickening, as methylcellulose.Preparaton can be made oil-in-water or water-in-oil emulsion form.The acceptable emulsifying agent of any pharmacy can use, for example arabic gum powder, nonionic surfactant or ionic surface active agent.

Can also add suitable dispersant or suspending agent, comprise that the aqueous suspension agent is as synthetic and natural gum, i.e. tragakanta, arabic gum, alginate, glucosan, sodium carboxymethyl cellulose, methylcellulose, polyvinylpyrrolidone or gelatin.

The carrier of the product of most important parenteral administration is a water.The water of appropriate amount must can be used for parenteral administration through distillation or reverse osmosis.Only in this way, could from water, fully isolate the pollutant of various solids, liquid, gas.Water for injection is preferred aqueous carrier, can be used for pharmaceutical formulation of the present invention.Water can be with the nitrogen cleaning to get rid of oxygen or the oxygen-derived free radicals in the water.

The preparaton of parenteral administration of the present invention can also contain other composition.These supplementary elements can comprise wetting agent, oils and fats (plant for example; resemble Oleum sesami, Oleum Arachidis hypogaeae semen or olive oil), analgesic, emulsifying agent, antioxidant, extender, tonicity contributor, metal ion, oily carrier, protein (for example human serum albumin, gelatin or protein) and amphion (for example aminoacid resembles betanin, taurine, arginine, glycine, lysine and histidine).Such supplementary element can not have adverse influence to the overall stability of pharmaceutical formulation of the present invention certainly.

Container also is a complete part of injection, and can think a component, because do not have container not dissolve fully or any influence can not arranged to liquid wherein fully, particularly when liquid is aqueous.Therefore, particularly must carry out based on it being contained compositions, solution that carries and the treatment that will carry out the container selection of injection.

In order to make hypodermic needle enter multiple dose vials, and keep sealing when withdrawing from syringe needle, each bottle all seals with the aluminum ring with rubber stopper.

The stopper of vial, West 4416/50,4416/50 (Teflon faced) and 4406/40 for example, Abbott 5139 or other any stopper that is equal to can be used for the sealing of dosage bottle of the present invention.These stoppers all will pass through the complete test of bottle stopper, can stand the test of at least 100 injections such as bottle stopper.

Every kind of composition of pharmaceutical formulation described above all is well known to those skilled in the art, and can be referring to " Pharmaceutical Dosage Forms ": Parenteral Medications, Vol.1,2nd ed., Avis et al.Ed., Mercel Dekker, New York, N.Y.1992, the document quotes in full in this for referencial use.

The preparation process of above-mentioned preparaton comprises chemical combination, aseptic filtration and filling step.The chemical combination process can for example comprise by particular order dissolves, and at first dissolves as antiseptic, follows by stabilizing agent/tonicity contributor, and buffer agent is triethyl group tetramine activating agent then, or simultaneously whole composition dissolvings is formed the preparaton of parenteral administration.The example of a method of the preparaton of preparation parenteral administration be water with for example triethyl group tetramine dihydrochloride dissolving of triethyl group tetramine activity form, and the gained mixture is diluted to 154mM in phosphate buffered saline(PBS).

Perhaps, parenteral route preparaton of the present invention can be prepared from by mixed each component after the step of routine.For example, the component of selection can mix in the device of blender or other standard, obtains spissated mixture, adds water, thickening agent, buffer agent, 5% human serum albumin or the tensile solute adjustment of additional regulation and control obtain final concentration and viscosity.

Perhaps, triethyl group tetramine activating agent can add solvent and be reconstructed in use with drying solid and/or form of powder packing, obtains the preparaton of the parenteral administration of reconstruct of the present invention.

Preparation process also comprises suitable sterilization process.Typical sterilization process comprises filtration, steam treated (damp and hot), dry heat treatment, gas treatment (for example oxirane, formaldehyde, chlorine dioxide, expoxy propane, beta-propiolactone, ozone, nitrochloroform, peracetic acid MB etc.), radiation treatment and aseptic process.

Suitable parenteral administration approach comprises injection or the like in intramuscular injection, intravenous injection, subcutaneous injection, intradermal injection, intra-articular injection, the sheath.Subcutaneous injection route of administration preferably.The mucosa release administration also is fine.Dosage and dosage depend on experimenter's body weight and health status.

The parenteral administration approach comprises intravenously administrable, intramuscular administration, intraperitoneal administration, percutaneous dosing and subcutaneous administration.

Except the mode of above-described prolong drug effect, can also finish by control drug release speed and persistent period, for example the medication infusion pump of application machine control carries out.

The agent of pharmacy acceptable activity, for example one or more can be with the form administration of drug depot injection, to obtain the lasting release of activating agent as the copper chelator of triethyl group tetramine or its salt such as triethyl group tetramine dihydrochloride.Active component can be pressed into piller or small column carries out the implantation of subcutaneous or intramuscular.Piller or small column can be with suitable biodegradable polymeric coating, with the release mode that needing to obtain.Active component can also micropillization.The micropill of the activating agent of use Biodegradable polymeric can be designed to the release mode of rate of release needing to obtain of needs.Perhaps, the injectable drug reservoir type can be made by forming the microcapsule substrate of main matter in Biodegradable polymeric such as polylactic acid-polyglycolic acid lactide.According to medicine and polymer ratio, and the character of used specific polymer, rate of drug release is controlled.The example of other Biodegradable polymeric comprises poe and polyanhydride.Injectable drug depot preparaton can also be by placing liposome to be prepared from medicine, and the example comprises unilamellar vesicle, large unilamellar vesicles liposome and multilamellar chamber liposome.Liposome can form by various phospholipid such as cholesterol, stearmide or GranulestinLecithin.Injectable drug storage storehouse preparaton can also be by forming drug encapsulation in microemulsion that can be compatible with bodily tissue.The example can be with reference to U.S. patent application No.6,410,041 and 6,362,190.

The present invention also provides infused drug to carry preparaton and device, includes but not limited to implantable infusion device.Implantable infusion device can use inert material such as above-mentioned Biodegradable polymeric or synthetic silicone for example the polymer produced of silicone rubber or other Dow-Corning company obtain.Polymer can load activating agent and adjuvant.Implantable infusion device can also carry out coating or part coating, and wherein coating contains the polymer that loads activating agent and adjuvant.Implantable infusion device like this can also be by the method preparation of U.S. patent No.6309380, by with containing in the body compatible and biodegradable or bio-absorbable or bioerodible liquid or gel solution described device being carried out coating, wherein said solution contains the active component that comprises required dosage and the polymer of adjuvant.Solution adheres to film forming on described device, form implantable drug release medical apparatus.

Implantable infusion device can also be prepared from the spot at the activating agent place that comprises solid matrix, can be referring to U.S. patent No.6120789, and the document quotes in full in this as a reference.Implantable infusion device can be passive transport or active transport.Have active implantable infusion device and can comprise active agent reservoir, make activating agent discharge the device in storage storehouse, for example permeable membrane and promotion activating agent leave the driving device in storage storehouse.Active implantable infusion device like this can be by the signal enabling of outside, as the description in WO 02/45779, wherein implantable infusion device includes a system that is used for release bioactive agent, comprise the exterior active unit, can activate the user operation of implantable infusion device by needs, comprise a controller, be used to stop demand blocking before stopping at interval.The example of active implantable infusion device comprises implantable drug efflux pump.Implantable drug efflux pump comprises delivery system for example miniature, computerized, program control, that can recharge, and with the conduit that can insert target organ, described target organ is spinal cord or blood vessel normally.Referring to Medtronic Inc.Publications:UC9603124 ENNP-2687,1997; UC199503941b EN NP-2347182577-101,2000; UC199801017a EN NP3273a182600-101,2000; UC200002512 EN NP4050,2000; UC199900546b EN NP-3678 EN, 2000.Minneapolis, Minn:Medtronic Inc; 1997-2000.Many pumps all have two parts: the part that can inject for medicine, another finishes the part of the analysis of bolus injection or the interior liquid of conduit for directly being connected with conduit.Implantable medication infusion pump (the program control pump of SynchroMed EL and Synchromed; Medtronic) can be used for the infusion of morphine sulfate in the long-term sheath, with the treatment chronic intractable pain; The infusion fluorodeoxyuridine is with treatment cancer in situ or metastatic carcinoma in the blood vessel; Intrathecal injection (baclofen injection) is to treat serious spasm; Long-term epidural infusion morphine sulfate is with the treatment chronic intractable pain; Infusion amycin, cisplatin or methotrexate are with the treatment metastatic carcinoma in the long-term blood vessel; And long-term venoclysis clindamycin is with treatment osteomyelitis.Such pump can also be used for one or more copper chelators of triethyl group tetramine or its salt for example of the long-term infusion of the administration of needed dosage or stable state.A kind of typical implantable medication infusion pump form (program control pump of Synchromed EL; Medtronic) be that reaching of coated titanium roughly is discous, diameter is 85.2mm, and thickness is 22.86mm, and weight is 185g, contains the drug depot of 10ml, and according to operating position, the thionyl chloride lithium battery life-span is 6-7.Downloadable memory storage comprises the drug release parameter of programming and the medicine surplus of calculating, its can with the medicine surplus of reality relatively with accuracy near the pump function, but the actual pump function of overstepping the time limit record not.Pump is implanted in left side or the right side stomach wall usually.Other can be used for pump of the present invention and comprises portable disposable injection pump (PDIPs).In addition, implantable infusion device can be used the liposome induction system, and as the small unilamellar vesicles liposome, large unilamellar vesicles liposome, and multilamelar liposome can form by various phospholipid materials, for example cholesterol, stearmide or GranulestinLecithin.

The present invention also comprises the eye medicinal preparation that postpone to discharge, comprising one or more copper chelators of triethyl group tetramine or its salt for example.The arteria retina disease causes blood plasma to ooze out and finally causes diabetic retinopathy is the first cause of diabetics impaired vision and blind.The triethyl group tetramine can be treated the diabetic arterial disease effectively.The invention provides the ophthalmic preparation of triethyl group tetramine, be applicable to the arteria retina disease that the human therapy diabetes cause.Described administration forms partial medicine high concentration, is suitable for the arteria retina disease of diabetes and the treatment of diabetic retinopathy.

The problem that ophthalmic solution uses is the quick loss of the medicine that causes because of nictation and tear.Maximum 80% drug dose can be by tear and nasolacrimal duct internal loss in 5 minutes.The treatment that prolongs can be finished by the time of contact that increases medicine and anterior corneal surface.This can require to increase the viscosity of solution; The slow dissolved eye suspension of drug application granule; Use slow dispersive ophthalmic ointment; Or application ophthalmic implant.Human eye use one or more for example the preparation of the copper chelator of triethyl group tetramine or its salt can use synthetic high-molecular weight cross linked polymer, for example those acrylate copolymers (for example carbopol 940) or gelling carbohydrate gum (Gelrite; With reference to Merck Index 12th Ed., 4389), the material (for example, using among the Inc.) of the gel that formation contacts with precorneal tear film at Timoptic-XE by Merck.

The further specific embodiment of the present invention comprises the ophthalmic preparation that comprises triethyl group tetramine implant that postpones release, as OCUSERT system (Alza Inc.).Typically, such implant is oval-shaped, and size is about 13.4mm * 5.4mm * 0.3mm (thickness).This implant is flexible, and a pastille kernel is arranged, and is being coated hydrophobic acetate ethylene copolymer film, makes medicine spread with constant speed.The white edge of device contains the titanium dioxide of adularescent, and it is the inert substance that can distinguish.Drug diffusion speed can be controlled by polymeric compositions, film thickness and drug solubility.First few after the implantation hour, drug release than after fast, to obtain initial drug concentration level.Drug-containing implants can be positioned in the conjunctival sac, and the time of the release medicine that continues 7 days can typically be arranged when treatment diabetic retinal diseases.Another kind of ophthalmic implant is bar-shaped, comprises the water-soluble structure of hydroxypropyl cellulose, wherein contains the triethyl group tetramine.In this implant of treatment diabetic retinal diseases once a day or place the conjunctival cul-de-sac position of eye for twice.Softening and the slowly dissolving of this implant discharges medicine and absorbs with tear.Another example of this device is provided by Lacrisert Lacrisert (Merck Inc.).

For the targeted system, activating agent is isolating or concentrate in regional area in vivo, tissue or site, absorbs or plays a role.

The present invention also provides drug dose to carry preparaton and device to increase the bioavailability of triethyl group tetramine activating agent.This can be by adding or discharging dosage or device realization in conjunction with above-described dosage.

Although good water-solubility is arranged, the triethyl group tetramine is very poor in gastral absorption, and bioavailability is very incomplete, and very irregular, and is widely different between different people.The triethyl group tetramine activating agent of treatment effective dose is the level of triethyl group tetramine in blood that can provide suitable.By increasing the bioavailability of triethyl group tetramine activating agent, can reduce using dosage to reach the treatment level of triethyl group tetramine activating agent.

The increase of triethyl group tetramine bioavailability can or form bioavailability or the enhanced preparaton realization of trap by triethyl group tetramine activating agent and one or more bioavailability or trap reinforcing agent formation complex.

The present invention provides other to be used to strengthen the reagent of bioavailability or trap for the preparaton of triethyl group tetramine activating agent.Such bioavailability or trap reinforcing agent include but not limited to for example butter of various surfactants such as various triglyceride, monoglyceride such as stearic acid and vegetable oil and ester, fatty acid ester, propylene glycol ester, polysorbate, sodium lauryl sulfate, sorbitol ester, aerosol OT, and other material.By changing the surfactant properties of release vehicle, can make activating agent the more gastrointestinal tract contact of longer time be arranged to increase absorption and to reduce side effect.The further example of such reagent comprises carrier molecule such as cyclodextrin and derivant thereof, and its character of knowing is the physicochemical properties that can change drug molecule as chelating agent.For example, cyclodextrin can be stablized (stablizing of thermodynamics and oxidisability aspect) or reduce the volatilization of activating agent, the dissolubility after the complexation of change activating agent.Cyclodextrin is a kind of ring molecule that comprises the Glucopyranose. ring element and form bent anchor ring structure.Cyclodextrin molecular inside is hydrophobic, and the outside is hydrophilic, and this makes cyclodextrin molecular possess water solublity.Dissolubility changes with the replacement of the outside oh group of cyclodextrin molecular.Similarly, inner hydrophobicity also can change with replacement, though inner hydrophobicity is to regulate in the hole of molecule.This adjusting is called complexation between the molecule, and generates inclusion complex.The example of cyclodextrin derivative comprises sulfo-butyl cyclodextrin, maltose cyclodextrin, hydroxypropyl cyclodextrin and their salt.The inclusion complex of triethyl group tetramine and carrier molecule such as cyclodextrin can reduce the consumption that the triethyl group tetramine reaches therapeutic effect because of increasing bioavailability.

The invention provides the microemulsion of the triethyl group tetramine activating agent preparaton that increases bioavailability.Microemulsion is a kind of solution of flowable stable uniform, is made up of four kinds of main components, is respectively aqueous favoring, lipophilic phase, at least a surfactant (SA) and at least a cosurfactant (CoSA).Surfactant is a kind of chemical substance that has two kinds of groups, and one is polarity or ionic with water strong affinity is arranged that another is to contain long or short aliphatic chain, is hydrophobic.These hydrophilic chemical substances can form microgranule in aqueous or oily solution.That suitable surfactant comprises is single-, two and triglyceride, and Polyethylene Glycol (PEG) single-and diester.Cosurfactant is also referred to as " cosurfactant " sometimes, is a kind of chemical substance with hydrophobic property, can promote the mutual dissolving of water and oil phase in the microemulsion.The example of suitable cosurfactant comprises ethyl diethylene glycol, propylene glycol lauryl, polyglycerol acrylate and relevant material.

The present invention provides various polymer for triethyl group tetramine activating agent preparaton, by increasing the adhesiveness of mucomembranous surface, reduces activating agent hydrolysis or enzymolysis speed, and the surface area of increase active agent particle is to increase bioavailability.Suitable polymers can be natural or synthetic, can be biodegradable or not biodegradable.The conveying of low-molecular-weight activating agent such as triethyl group tetramine activating agent can be finished by the diffusion or the degraded of polymer system.Representational natural polymer comprises zein, casein, gelatin, glutelin, serum albumin and the collagen of protein such as zein, improvement, polysaccharide such as cellulose, glucosan and poly-hyaluronic acid.Preferred usually degraded of synthetic polymer and the better material of release usefulness.Representational synthetic polymer comprises poly-phosphorus nitrence (polyphosphazenes), polyvinyl alcohol, polyamide, Merlon, polyacrylate, polyolefin, polyacrylamide, polyalkenylalcohols, polyoxyalkylene, polyene terephthalate, polyvinylether, polyvinyl ester, polyethylene halogen, polyvinylpyrrolidone, polyglycolide, polysiloxanes, polyurethanes and their copolymer.Suitable polyacrylate comprises poly-(methylmethacrylate), poly-(ethyl methacrylate), poly-(methacrylate butyl ester), poly-(methacrylate isobutyl), poly-(methacrylate hexyl ester), poly-(methacrylate isodecyl ester), poly-(methacrylate Lauryl Ester), poly-(methacrylate phenylester), poly-(acrylic acid methyl ester .), poly-(isopropylacrylic acid methyl ester and poly-(octadecyl acrylate).Manually modified natural polymer comprises cellulose derivative such as alkylcellulose, hydroxy alkyl cellulose, cellulose ether, cellulose esters and NC Nitroncellulose.The example of suitable cellulose derivative comprises methylcellulose, ethyl cellulose, hyprolose, hydroxypropyl emthylcellulose, hydroxyl fourth methylcellulose, cellulose acetate, cellulose propionate, acetylbutyrylcellulose, cellulose acetate phthalate, carboxymethyl cellulose, Triafol T and sodium cellulose sulfate.Above-described each polymer can be commercially available, as Sigma Chemical Co., St.Louis, Mo., Polysciences, Warrenton, Pa., Aldrich Chemical Co., Milwaukee, Wis., Fluka, Ronkonkoma, N.Y., and BioRad, Richmond, Calif., maybe can use standard technique to synthesize preparation by the monomer that obtains from above-mentioned supplier.Above-described polymer can be divided into biodegradable, abiotic degradable and bioadhesive polymer, below is described in more detail.Representational synthetic degradable polymer comprises polyhydroxy acid such as polylactide, polyglycolide and copolymer thereof, poly-(ethylene terephthalate), poly-(butic acid), poly-(valeric acid), poly-(lactide (lactide) is caprolactone altogether), polyanhydride, poly-ortho position Ester and their mixture and copolymer.Representational natural biological degradable polymer comprises polysaccharide such as alginate, glucosan, cellulose, collagen and their chemical derivative (displacement of chemical group, addition, for example alkylation, alkenyl, hydroxylating, oxidation and other modification well known to those skilled in the art), protein such as albumin, zein and their copolymer and mixture, it can combine application separately or with synthetic polymer.Usually, these materials can be in vivo by enzyme hydrolysis or be exposed to water, its surface or skeleton are etched.The example of abiotic degradable polymer comprises vinyl acetate, poly-(methyl) acrylic acid, polyamide, polyethylene, polypropylene, polystyrene, polrvinyl chloride, polyethylene phenol and their copolymer and mixture.Hydrophilic polymer and hydrogel have bio-adhesive properties.Include the hydrophilic polymer of carboxylic group (for example poly-[acrylic acid]), possess best bio-adhesive properties.When needing the bioadhesion of soft tissue, the polymer that contains the carboxylic group of maximum concentration is preferred.Various cellulose derivatives such as sodium alginate, carboxymethyl cellulose, hydroxy methocel and methylcellulose also have good bio-adhesive properties.Some are water miscible in these bioadhesion materials, and other are hydrogels.Polymer such as hydroxypropyl emthylcellulose acetic acid succinate (HPMCAS), acetic acid-1,2,4-benzenetricarboxylic acid cellulose (CAT), cellulose acetate phthalate (CAP), hyprolose acetic acid phthalic acid ester (HPCAP), hydroxypropyl emthylcellulose acetic acid phthalic acid ester (HPMCAP) and methylcellulose acetic acid phthalic acid ester (MCAP) can be used to strengthen bioavailability of medicament when complexation.Quick bio erosion depolymerization compound is as poly-(lactide-co-glycolide), polyanhydride and poly-ortho position Ester, and its carboxylic group is exposed to outer surface, also can be used for the bioadhesion delivery system.In addition, contain polymer such as the polyanhydride and the polyester of labile bond, have hydrolysing activity, its hydrolytic degradation speed changes with the simple change of the chain of polymer usually.In degraded, these materials expose carboxylic group at its outer surface, and therefore can be used for the bioadhesion delivery system.

Other reagent that can increase bioavailability or trap can be used to promote or suppress the transhipment of medicine at gastrointestinal mucosa.For example, the blood flow in the gastrointestinal tract is the factor of decision gastrointestinal Chinese medicine trap and bioavailability, so the reagent such as the vasodilation of energy increasing blood flow can increase the absorption of the medicine of oral administration.Vasodilation can combine with other medicines.For example, publish in the document 106335 at EPO, record coronary vasodilator diltiazem increases oral bioavailability and is no more than 20% bioavailability of medicament, as epinephrine beta blocker (for example Propranolol), Catecholamine matter (as dopamine), Benzodiazepine analog derivative (for example stable), vasodilation (sorbide nitrate for example, nitroglycerine or n-Amyl nitrite), cardiac tonic or antidiabetic, bronchodilator (for example tetrahydroisoquinoline), hemorrhage (for example sulfonic acid carbazole chromium), spasmolytic (for example thiophene piperazine (timepidium) halogenide) and anti-tussive agents (as Tipepidine).Therefore vasodilation constitutes the another kind of reagent that can strengthen triethyl group tetramine bioavailability.

Other mechanism that increases the bioavailability of chemical compound of the present invention and preparaton comprises that the active transport of counter-rotating suppresses mechanism.For example, think that now the active transport mechanism at intestinal epithelial cell is p-glycoprotein transporting mechanism, the counter-rotating that it promotes substance transportation can make diffusion or transhipment enter epithelial material and return in the intestinal chamber.Can infer that the p-glycoprotein on the intestinal epithelial cell can be used as protectiveness counter-rotating pump, can prevent from diffusion or be transported to epithelial noxious substance absorption to enter the body circulation.A disadvantageous aspect of p-glycoprotein is its utilization that can also prevent useful material, is the operational medicine of p-glycoprotein counter-rotating movement system just as some.The inhibitory action of p-glycoprotein can cause that less medicine returns the intestinal chamber, and therefore increases the medication amount of transhipment by gut epithelium, and can increase the final concentration of blood medicine.Various p-glycoprotein inhibitors all are to know in the prior art.These comprise watermiscible vitamin E; Polyethylene Glycol; The poloxamer that comprises Pluronic F-68; Polyethylene glycol oxide; The castor oil derivatives that comprises Cremophor EL and CremophorRH 40; Chrysin, (+)-distylin; Naringenin; Daflon; Quercetin or the like.

Inference can increase the bioavailability of described triethyl group tetramine activating agent to for example inhibition of the active transport system of triethyl group tetramine activating agent of reversing.

Surprisingly, as shown in embodiment 2 and accompanying drawing 3 and 4, triethyl group tetramine dihydrochloride can be removed the intravital Cu of diabetes rat effectively, and the effective dose that used dosage is thought far below prior art.As the Cu Excreta that in accompanying drawing 3, particularly can see in the accompanying drawing 4 by weight standardization, in the diabetes rat urine at administration triethyl group tetramine 0.1mg.kg ^-1The Cu Excreta of (the minimum dosage in the research herein) is significantly more than the brinish diabetes rat of administration.

These data show include but not limited to that the triethyl group tetramine activating agent of triethyl group tetramine analog that triethyl group tetramine, triethyl group tetramine salt, general formula I and II represent etc. can be lower than 1.2g.d ^-1Dosage treat the human heart disease effectively.Effectively dosage can be used (120mg.d for example by 1/10,1/100,1/1000 order ^-1, 12mg.d ^-1, or 1.2mg.d ^-1).

The invention provides the conveying preparaton and the device of the low dosage that comprises one or more triethyl group tetramine activating agents, include but not limited to the triethyl group tetramine analog of triethyl group tetramine, triethyl group tetramine salt, general formula I and II etc., give with effective dosage, for example dosage range is 0.01mg.kg ^-1-5mg.kg ^-1, 0.01mg.kg ^-1-4.5mg.kg ^-1, 0.02mg.kg ^-1-4mg.kg ^-1, 0.02-3.5mg.kg ^-1, 0.02-3mg.kg ^-1, 0.05-2.5mg.kg ^-1, 0.05-2mg.kg ^-1, 0.05-0.1mg.kg ^-1To 5mg.kg ^-1, 0.05-0.1mg.kg ^-1To 4mg.kg ^-1, 0.05-0.1mg.kg ^-1To 3mg.kg ^-1, 0.05-0.1mg.kg ^-1To 2mg.kg ^-1, 0.05-0.1mg.kg ^-1To 1mg.kg ^-1, and/or any other value in this scope.

Any this type of dosage of any route of administration or form of medication all has description here.Be appreciated that it is that any dosage described herein is carried preparaton or device, particularly oral administration, when available or desired, can be used for conveying preparaton or device with any administration.For example, can use the parenteral administration mode and give dosage form of the present invention, or with specific peroral dosage form administration, as slow release release dosage form, prolongation release dosage form, delayed release dosage forms, agent for slow releasing type or repeat function peroral dosage form.

Another aspect of the present invention is based on the result of study to the excretory STZ rat of the copper level that is equal to the people, and described dosage form contains and is lower than 250mg triethyl group tetramine dihydrochloride (or triethyl group tetramine activating agent of representing with triethyl group tetramine dihydrochloride).Can use the capsule of the triethyl group tetramine activating agent that is lower than 250mg triethyl group tetramine dihydrochloride or equivalence or the dosage form of tablet or any suitable form.

" danger " described here refers to the ill possible assessment of mammal, as at JAMA, May 16 calendar year 2001, Volume 285 No.19, described in the 2486-2497, wherein age, T-CHOL, HDL cholesterol, systolic pressure are considered in the dangerous scoring of Framingham, hypertension therapeutic and whether smoking is also related to can add that the glucose of mentioned any situation is unusual here.

" rising " described here is the rising about copper level in the mammal, and for example the people comprises unwanted copper level, as the removing of the copper of therapeutic purposes, and/or at least about 10mcg free copper/dL serum, use Merck ﹠amp; The assay method of Co Inc. is measured.

Histological evidence shows with the treatment of triethyl group tetramine after six months, the protection of the Wistar rat heart that diabetes damages (cardiomyopathy) cause occurs, judges by the histology.The dosage of the triethyl group tetramine that needs will be studied the drainage of copper and ferrum in the urine, for example studies the excretory difference of diabetes and non-diabetic animal.For example, contrast at the copper of normal and diabetes rat and the drainage pattern of ferrum behind the acute intravenously administrable triethyl group tetramine.In addition, whether acute intravenously administrable triethyl group tetramine exists the side effect of cardiovascular aspect to determine.

In order to understand the present invention better, following experimental section will be introduced.Following experiment just is used to illustrate the present invention, and limits the present invention never in any form.

Embodiment 1

The baseline physiological data of the rat that this embodiment is used for determining that streptozotocin (streptozotocin) (STZ) is handled and the contrast of diabetes and non-diabetic rat baseline physiological data.

The method of this research that is useful on is is all checked and approved through University of Auckland animal Ethics Committee, and consistent with New Zealand's animal protection regulations and detailed rules and regulations (The Animals Protection Act andRegulations of New Zealand).

For inducing diabetes, (n=28,303 ± 2.9g) are divided into diabetes and non-diabetic group to male Wistar rat at random.Anesthesia (5% Hal and 2l.min ^-1O ₂) after, the animal via tail vein of diabetic groups is accepted streptozotocin (STZ, the 55mg.kg of single agent ^-1(body weight), Sigma; St.Louis, 0.5ml saline solution administration MO).The isopyknic saline of non-diabetic animals received.After the injection, two groups of rat stable breedings under condition of similarity, and normal rat food (food 86 pillers are provided; New Zealand's dried foodstuff, Auckland, NZ) and deionized water.Inject under study for action behind the STZ/ saline and to measure blood glucose and body weight in three days, jede Woche once then.Diabetes rat shows as excessive thirst, polyuria and hyperglycemia (＞11mmol.l ^-1, AdvantageII, Roche Diagnostics, NZ Ltd).

The result is as follows.Consider the influence of STZ to blood glucose and body weight, three days blood glucose is increased to 25 ± 2mmol.l behind the injection STZ ^-1(table 1).Even eat more food every day, diabetic animal is also many than non-diabetic group body weight weightlessness in behind the injection STZ/ saline continuous 44 days.Experiment diabetes on the same day and non-diabetic animal blood glucose level are respectively 24 ± 1 and 5 ± 0mmol.l ^-1And body weight is 264 ± 7g and 434 ± 9g.

Blood glucose, body weight and the food consumption of table 1. diabetes contrast non-diabetic animal

	Diabetic groups	The non-diabetic group
	Diabetic groups	The non-diabetic group	Body weight before the injection STZ/ saline	????303±3g	????303±3g
Three days blood glucose behind the injection STZ/ saline	??? ^*25±2mmol.l ^-1	????5±0.2mmol.l ^-1	Body weight before the injection STZ/ saline	????303±3g	????303±3g
Three days blood glucose behind the injection STZ/ saline	??? ^*25±2mmol.l ^-1	????5±0.2mmol.l ^-1	Day food consumption	??? ^*58±1g	????28±1g
The blood glucose of experiment day	??? ^*24±1mmol.l ^-1	????5±0.2mmol.l ^-1	Day food consumption	??? ^*58±1g	????28±1g
The blood glucose of experiment day	??? ^*24±1mmol.l ^-1	????5±0.2mmol.l ^-1	The body weight of experiment day	??? ^*2647g	????434±9g

Diabetic animal n=14, non-diabetic animal n=14.Listed numerical value is ± the SEM meansigma methods. ^*Expression has significant difference (P＜0.05).

Therefore, the result shows that STZ handles the blood sugar increasing that causes diabetic groups, and food ration increases, and loses weight.

Embodiment 2

This embodiment assesses acute vein increases the diabetes of triethyl group tetramine of dosage and copper and the drainage of ferrum in urine of non-diabetic group rat.

Give six to seven weeks (average 44 ± 1 days) behind the STZ, animal contrasts or the drug study record.Overnight fasting before all animal surgeries, but still arbitrarily feed deionized water.Hal and 2l.min with 3-5% ^-1O ₂Give and keep anesthesia.(Texas USA) carries out intubate with perfusion of saline PE 50 conduits to femoral artery and vein for MikrotipTM 1.4F, Millar Instruments with the solid pressure transducer.Ureter exposes through the center line laparotomy, with polyethylene catheter (outer dia 0.9mm, inside diameter 0.5mm) intubate, and sew up wound.The animal that plugs in conduit breathes 70-80 time at the ventilation per minute, and additional O ₂(pressure control aerarium, Kent Scientific, Connecticut, USA).Regulate breathing rate and the intrinsic pressure (10-15cmH of tide ₂O) to keep CO in the tide ₂Be pressed in 35-40mmHg (SC-300 CO ₂Monitor, PryonCorporation, Wisconsin, USA).Make body temperature remain on 37 ℃ with hot plate in operation and the experimentation.The liquid loss of estimating replenishes 154mmol.l by vein ^-1NaCl solution, additional speed is 5ml.kg ^-1.h ^-1

Stablized after the operation 20 minutes, and began to experimentize.Intravenously administrable triethyl group tetramine, the concentration that increases in next hour administration surpass 60 seconds (0.1,1.0,10 and 100mg.kg ^-1In the saline of 75 μ l, and with the normal saline washing of 125 μ l).Matched group is accepted isopyknic saline.Urine was to be collected in experiment in the cycle in the polyethylene epindorf pipe of weighing in advance with 15 minutes.When finishing, experiment passes through cardiac puncture acquisition terminal blood sample, and separation of serum, be stored under-80 ℃ up to analyzing.With quick center line breastbone thoracotomy isolating cardiac, and carry out following process.

Mean arterial pressure (MAP), heart rate (HR, can from the MAP waveform, obtain), oxygen saturation (Nonin 8600V pulse oximeter, Nonin Medical Inc., Minnesota USA) will carry out successive monitoring with central body temperature in whole experiment, use PowerLab/16s data acquisition module (AD Instruments, Australia).Calibrated signal is presented on the screen, and preserves as the 2s meansigma methods of each variable.

Urine and fabric analysis are following to be carried out.Instrument: be furnished with Perkin Elmer (PE) Model 3100 atomic absorption spectrophotometers of PE HGA-600 graphite furnace and PEAS-60 automatic sampler, be used for the mensuration of urine Cu and Fe.Use the deuterium background correction.Use the hollow cathode lamp (Perkin Elmer Corporation) of Cu or Fe and operation under 10W (Cu) or 15W (Fe).324.8nm atomic spectral line be used for Cu, and the atomic spectral line of 248.3nm is used for Fe.The slit width of Cu and Fe all is 0.7nm.The pipe that pyrolysis applies graphite is used for all analyses.Volume injected is 20 μ l.Typical graphite furnace temperature conditions is as follows:

GF-AAS temperature program

Process	Temperature ℃	?RamP/s	?Hold/s	Inner flow velocity/ml.min ^-1
Process	Temperature ℃	?RamP/s	?Hold/s	Inner flow velocity/ml.min ^-1	Dry pretreatment atomization-Cu/Fe post processing	?90 ?120 ?1250 ^*?20 ?2300/2500 ?2600	?1 ?60 ?20 ?1 ?1 ?1	?5 ?5 ?10 ?10 ?8 ?5	?300 ?300 ?300 ?300 ?0 ?300

^*Pretreatment temperature is 1050 ℃, is used for the analysis (referring to embodiment 3) of tissue digestion

Reagent: all reagent are all used highest purity, are analytically pure at least.The standard operation solution of the Cu of GF-AAS and Fe obtains 1000mg.l by stepwise dilution ^-1(Spectrosol standard solution; BDH).The purification of water is finished with the water system of Millipore Milli-Q ultra-purity, and resistivity value is measured as 18M Ω.

The urine sample pretreatment: urine collecting is in the 1.5ml microtest tube of weighing in advance (eppendorf).Again after the weighing, urine specimen is centrifugal, the supernatant HNO of the Aristar level of 0.02M 69% ₃Be diluted to 25: 1.Before entering the GF-AAS analysis, sample is stored down at 4 ℃.Store sample if desired and surpass fortnight, lyophilizing, and-20 ℃ of maintenances down. Serum: the terminal blood sample is centrifugal, and serum is stored by the urine mode before analysis.Trace metal was collected in the experiment last moment in the serum in the blood sample, the following equation of the computing application of renal clearance:

Make following statistical analysis.All numerical value all use ± and SEM meansigma methods and P value＜0.05 expression have the significance of statistical significance.Azygous t-check is used to detect the weight of diabetic groups and matched group and the difference of glucose at first.For the response of drugs compared, use variance analysis carry out statistical analysis (v.6.1 statistical value sees Windows, SAS Institute Inc., Calfornia, USA).The mixed model that statistical analysis is then used duplicate detection variance analysis ANOVA carries out (referring to embodiment 4).

The result is as follows.For cardiovascular variation during the infusion, the baseline values of the MAP of contrast does not have significant difference (99 ± 4mmHg) before the infusion between diabetic groups and non-diabetic treated animal.HR is markedly inferior to non-diabetic group (being respectively 287 ± 11 and 364 ± 9bpm, P＜0.001) in diabetic groups.Infusion triethyl group tetramine or saline is to the not influence of these variablees, and except under maximal dose, wherein MAP reduced to 19 ± 4mmHg in 2 minutes after administration, and level returned to administration in 10 minutes before.It is stable that body temperature and oxygen saturation keep in experimentation.

About the homaluria thing, except at maximum drug dose (100mg.kg ^-1) or equal-volume saline (accompanying drawing 16) under, the excretory urine of diabetic animal is obviously more than the non-diabetic group.Administration 100mg.kg ^-1The triethyl group tetramine compare and give isopyknic brinish non-diabetic group, can also increase the urinary excretion (accompanying drawing 17) of non-diabetic treated animal.This influence is not found in the diabetic animal group.

Analysis about the homaluria response medicine curve of Cu and Fe shows, on all dosage, accepts the diabetes of medicine and the excretory Cu of non-diabetic animal all more than only accepting brinish group of equal-volume (accompanying drawing 18).For the weight of proofreading and correct the diabetic groups animal influences, and therefore carry out the contrast between more diabetes and non-diabetic animal, the excretion rate of trace element also will calculate by every gram body weight.Copper bar discharge contrast non-diabetic animal was high significantly after accompanying drawing 19 demonstration diabetic animals were accepted medicine.Identical situation also occurs in the contrast of brinish group of acceptance, but influence is not very remarkable.

The drainage of total copper contrast the brinish matched group of acceptance in during experiment whole in the diabetes of accepting the triethyl group tetramine and non-diabetic treated animal significant increase (accompanying drawing 20).The diabetic animal of accepting medicine is calculated by every gram body weight and is compared the excretory copper of non-diabetic group and also want many.(accompanying drawing 21) also observed in identical significance influence in giving brinish animal groups.

In comparison, the diabetes of accepting the triethyl group tetramine are compared with the drainage of ferrum in the non-diabetic animal and are accepted the brinish animal of equal-volume and do not increase (accompanying drawing 22).The analysis of every gram body weight shows that accepting brinish diabetic groups animal drains obviously more ferrum than non-diabetic group, but this situation is in the diabetes of accepting the triethyl group tetramine and non-diabetic group and not obvious (accompanying drawing 23).The drainage of accepting total ferrum in the diabetes of medicine and the non-diabetic treated animal with accept brinish group and zero difference (accompanying drawing 24).Consistent with the analysis of dose response curve, the ferrum excretion of accepting the every gram body weight of brinish diabetic animal is apparently higher than the non-diabetic animal, but this phenomenon is not found (accompanying drawing 25) in triethyl group tetramine group.

Electron paramagnetic resonance spectrum shows that the urine Cu of the animal of Drug therapy has mainly formed triethyl group tetramine-Cu ^II(accompanying drawing 28) illustrated that the Cu that increases in the tissue of diabetes rat mainly is a bivalence.These data show the rat Cu of serious hyperglycemia ^IIIncrease, and can be through optionally chelation drainage.

Renal clearance about serum content and Cu and Fe does not wherein have significant difference on the serum copper content, compared remarkable increase (table 2) with the brinish diabetic animal of acceptance on the renal clearance of the diabetic animal of accepting medicine.Identical situation also has in the non-diabetic animal groups, but this trend is not very remarkable (P=0.056) on statistical significance.On the serum content of ferrum or renal clearance, then there is not any influence.

Table 2. is in accept medicine or brinish diabetes and non-diabetic animal

Serum content and the renal clearance of Cu and Fe

	1.1.a.a.1 diabetes	1.1.a.a.1 diabetes	1.1.a.a.2 non-diabetic	1.1.a.a.2 non-diabetic
	1.1.a.a.1 diabetes	1.1.a.a.1 diabetes	1.1.a.a.2 non-diabetic	1.1.a.a.2 non-diabetic		Triethyl group tetramine n=6	Saline n=7	Triethyl group tetramine n=4	Saline n=7
Levels of serum cu (μ g. μ l ^-1×10 ^-4)	7.56±0.06	????9.07±1.74	????7.11±0.41	??7.56±0.62		Triethyl group tetramine n=6	Saline n=7	Triethyl group tetramine n=4	Saline n=7
Levels of serum cu (μ g. μ l ^-1×10 ^-4)	7.56±0.06	????9.07±1.74	????7.11±0.41	??7.56±0.62
Serum Fe (μ g. μ l ^-1×10 ^-4)	35.7±7.98	????63.2±16.4	????33.6±1.62	??31.4±8.17
Serum Fe (μ g. μ l ^-1×10 ^-4)	35.7±7.98	????63.2±16.4	????33.6±1.62	??31.4±8.17
Cu renal clearance (μ l.min ^-1)	^*28.5±4.8	???1.66±0.82	????19.9±6.4	??0.58±0.28
Cu renal clearance (μ l.min ^-1)	^*28.5±4.8	???1.66±0.82	????19.9±6.4	??0.58±0.28	Fe renal clearance (μ l.min ^-1)	0.25±0.07	???0.38±0.15	????0.46±0.22	??0.11±0.03

Data are meansigma methods ± SEM. ^*Asterisk is illustrated in the diabetic animal of accepting the triethyl group tetramine and there were significant differences between the brinish diabetic animal of equal-volume (P＜0.05) accepting.

In brief, acute intravenously administrable triethyl group tetramine is compared the excretion that the saline control group significantly increases total copper of diabetic groups and non-diabetic group.And after acute vein increased the triethyl group tetramine of dosage, the copper bar discharge that diabetic animal is compared non-diabetic animal per gram body weight significantly increased.On the contrary, accept the diabetic animal of medicine and compare the brinish matched group of acceptance with the non-diabetic animal, the excretion of total ferrum does not have significant difference.

Embodiment 3

This embodiment is used for determining that acute vein increases the triethyl group tetramine of dosage to the copper of the heart tissue of normal and diabetes and the influence of ferrum content.

Method is as follows.Description among spectrophotometric analysis such as the embodiment 2.Cu, Fe and Zn in the digestion tissue measure (Hamilton, New Zealand) in the Hill laboratory, use PE Sciex Elan-6000 and PE Sciex Elan-6100 DRC ICP-MS.Operating parameter such as following table are listed.

The Instrument operation parameter of ICP-MS

Parameter	Numerical value
Parameter	Numerical value	The repeated sample absorptivity is scanned/repeated to inductively coupled plasma RF energy argon plasma gas flow rate argon assist gas flow velocity argon spray gas flow velocity interface sample taper hole and orifice diameter separator taper hole and orifice diameter data acquisition parameters scan mode sampling time	? ??1500W ??15l.min ^-1??1.2l.min ^-1??0.89l.min ^-1Ni/1.1mm Ni/0.9mm peak value jump 30ms (Cu, Zn)/100ms (Fe) 20 3 1ml.min^-1

Reagent is as follows.The liver of standard reference materials 1577b cattle derives from standard and technology association (National Institute of Standards and Technology) of country and is used to assess the effect of tissue digestion.The result who obtains is as follows:

The GF-AAS of NIST SRM 1577b Hepar Bovis seu Bubali * and the result of ICP-MS

Element	Determined value	??GF-AAS	??ICP-MS
Element	Determined value	??GF-AAS	??ICP-MS	????Cu ????Fe ????Zn	????160±8 ????184±15 ????127±16	??142±12 ??182±21 ??-	??164±12 ??166±14 ??155±42

^*The measurement unit of expression dry matter is μ g.g ^-1

The sample pretreatment is as follows. Heart: after exsomatizing, clean and remove unnecessary tissue, remove unnecessary blood, blot, record ventricle weight in wet base with buffer.Utilize the titanium instrument to cut left ventricle muscle, place a 5.0ml polystyrene tube of weighing in advance.The sample lyophilized overnight is to constant weight, adds 69% the HNO of the 0.45ml of analytical pure level ₃Sample tube was 65 ℃ of following heating in water bath 60 minutes.This 4.5ml that takes a sample adds milli-Q H ₂O.Gained solution dilution 2: 1 is to reduce HNO ₃Concentration, make it to be lower than ICP-MS and analyze the maximum that is allowed.

The result is as follows.About the metal content of heart tissue, the wet heart weight of diabetic animal is significantly less than the non-diabetic animal, and the ratio of heart/body weight increases (seeing Table 3).Cu and Fe content have also been analyzed from part animal hearts tissue.Diabetes and the non-diabetic group of accepting saline or triethyl group tetramine do not have significant difference on the copper content.The ferrum content of accepting brinish non-diabetic group is obviously than the height (seeing Table 3) of accepting brinish diabetic groups.

Table 3: the cardiac weight of diabetes and non-diabetic animal, heart/body weight ratio and

The contrast of heart tissue trace meter content

	Diabetic groups	The non-diabetic group
	Diabetic groups	The non-diabetic group	Wet heart weight	???? ^*0.78±0.02g	??1.00±0.02g
Heart/body weight weight ratio	???? ^*2.93±0.05mg.g ^-1	??2.30±0.03mg.g ^-1	Wet heart weight	???? ^*0.78±0.02g	??1.00±0.02g
Heart/body weight weight ratio	???? ^*2.93±0.05mg.g ^-1	??2.30±0.03mg.g ^-1	Cu content μ g.g in the dry tissue ^-1The triethyl group tetramine is handled saline treatment	????24.7±1.5 ????21.3±0.9	??27.1±1.0 ??27.2±0.7
Fe content μ g.g in the dry tissue ^-1The triethyl group tetramine is handled saline treatment	????186±46 ????180±35	??235±39 ??274±30		????24.7±1.5 ????21.3±0.9	??27.1±1.0 ??27.2±0.7

Diabetic animal: n=14; Non-diabetic animal: n=14.Numerical value is ± the SEM meansigma methods. ^*Asterisk represents that there were significant differences between diabetic animal and non-diabetic animal (P＜0.05). represents to accept that there were significant differences between brinish diabetes and non-diabetic animal (P＜0.05).

In brief, confirmed that triethyl group tetramine that acute vein gives recruitment does not have remarkable influence to the copper content of diabetes and normal heart tissue.

Embodiment 4

In this embodiment, the data among the above embodiment 1-3 are done mixed linear model.

Method is as follows.About the statistical analysis of application mix linear model, the data of each dosage level are all analyzed (PROC MIXED with mixed linear model; SAS, Version 8).This model comprise diabetes, medicine and between influence each other as fixed effect, the time, rat was as the object of data set as replication.Suppose liking fully independently.Complete model is suitable for each data set of using maximum likelihood estimate (REML), is suitable for mixed linear model (being effect mould fixed and at random).Mixed model is the general popularization of standard linear model, can be used to analyze the data of various variablees.Significance level is 0.05 in the whole detection.The result is as follows.

For copper, suffer from the excretory copper level of rats with diabetes significantly high (referring to accompanying drawing 27) on all dosage levels.The copper bar of diabetes rat baseline is let out also apparently higher than the non-diabetic rat.Medicine group and saline group do not have difference on baseline values.Influence each other significantly in the model is at dosage level 1.0mg.kg ^-1And it is higher.The existence of significance illustrates that a kind of variation of effect is subjected to alternative the influence.Therefore, the significance between diabetes and the medicine factor influences each other the copper bar discharge is increased.

For ferrum, the excretory ferrum of accepting brinish diabetes rat is significantly higher than other dosage level.This causes, and all factors on average significantly increase at all dosage waters in the model.

In brief, the homaluria of the acute effect of cardiovascular system and copper and ferrum is studied in diabetes of anesthesia (streptozotocin inductive 6 week diabetes) and non-diabetic rat to intravenously administrable triethyl group tetramine.Animal is divided into four groups: diabetes+triethyl group tetramine, diabetes+saline, non-diabetic+triethyl group tetramine, non-diabetic+saline.Medicine or isopyknic saline per hour by the dosed administration of gaining in strength (0.1,1.0,10,100mg.kg ^-1), urine of collection in per 15 minutes in experiment.Take blood sample at last and obtain heart tissue.Urine analysis shows: under (1) all dosage, accept the diabetes of medicine and non-diabetic animal ratio and accept the brinish animal of equal-volume and drain more Cu (μ mol); (2) for the analysis of every gram body weight, drainage (the μ mol.gBW of the diabetic animal copper of every kind of triethyl group tetramine dosage ^-1) obviously higher than non-diabetic animal.Same situation also has in the saline group, but is not all very remarkable at each dosage; (3) for most dosage, it is more than the group of accepting medicine that diabetic animal is accepted the drainage (μ mol) of brinish group of ferrum.In the drainage of non-diabetic group ferrum, there is not difference between saline group or the triethyl group tetramine group; (4) analysis of every gram body weight is presented at diabetes and the drainage of the ferrum between the non-diabetic animal of accepting the triethyl group tetramine does not have difference.By every gram weighing machine, it is more than non-diabetic to accept brinish diabetic animal ferrum excretion; (5) the heart tissue analysis shows that total copper content of diabetes and non-diabetic animal does not have significant difference, and medicine is to heart ferrum and the also not influence of copper content; (6) calculating of renal clearance shows that the copper removing amount of the diabetic animal of accepting the triethyl group tetramine is significantly higher than the brinish diabetic animal of acceptance.Identical situation also exists in the non-diabetic animal, but is not very remarkable.The triethyl group tetramine is to the not influence of removing of ferrum.

Acute giving do not found cardiovascular side effect behind the triethyl group tetramine.The treatment of triethyl group tetramine has increased the drainage of the copper of diabetes and non-diabetic animal effectively.Give the amount of excretory every gram body weight of the urine copper behind the triethyl group tetramine, diabetic animal will be more than the non-diabetic animal.The triethyl group tetramine can not increase the drainage of diabetes or non-diabetic animal ferrum.

Embodiment 5

Carry out the experiment that relevant triethyl group tetramine recovers the effect of STZ diabetes rat cardiac function.As mentioned above, histological evidence shows the heart that can protect the diabetes Wistar rat (diabetic cardiomyopathy) of heart and injury with the treatment of triethyl group tetramine.Yet, and do not know the improvement whether histological improvement can bring cardiac function.

This experiment is the cardiac function of the tetramine treatment of contrast triethyl group or untreated STZ diabetes rat and normal rat, uses the heart model that exsomatizes.

Method is as follows.The careful care of animal for research " laboratory animal maintenance rule " (National Society for Medical Research), this research is approved by University of Auckland animal Ethics Committee.

The male albinism Wistar rat of weight 330-430g is divided into four groups, and is as shown in table 4.

Table 4. experiment grouping

Group	Code name	??N	Treatment
Group	Code name	??N	Treatment	The A group	??STZ	??8	The diabetes in 13 weeks
The B group	??STZ/D7	??8	The diabetes in 13 weeks (Drug therapy 7-13 week)	The A group	??STZ	??8	The diabetes in 13 weeks
The B group	??STZ/D7	??8	The diabetes in 13 weeks (Drug therapy 7-13 week)	The C group	??Sham	??9	The non-diabetic contrast
The D group	??Sham/D7	??11	Non-diabetic contrast (Drug therapy 7-13 week)	The C group	??Sham	??9	The non-diabetic contrast

The STZ=streptozotocin; The triethyl group tetramine treatment in continuous 7 weeks of D7=, initial from experiment beginning 6 all backs.

Diabetes give streptozotocin by vein and induce (STZ; Sigma; St.Louis, MO).All rats carry out of short duration suction anesthesia (sucking: the oxygen of 5% Hal and 2L/min, and keep the oxygen of 2% Hal and 2L/min).It is that 0.9% saline solution with 0.5ml is from tail vein injection that two diabetic groups are accepted single agent vein bolus injection STZ (57mg/kg body weight).Isopyknic 0.9% saline solution of the animals received of non-diabetic placebo treatment.Normal diet (food 86 balls are freely absorbed in diabetes and the paired stable breeding of non-diabetic rat; The drying food of New Zealand, Auckland NZ) is also freely absorbed deionized water.Every cage has two water bottles, gives the chance that rat absorbs drinking-water or medicine on an equal basis.Animal ambient temperature of living in is 21 ℃, humidity 60%, and standard mouse cage sawdust flooring, change every day.

Measure blood glucose (Advantage II, RocheDiagnostics, NZ Ltd) from the blood sample that the most advanced and sophisticated blood capillary of afterbody extracts.The sampling simultaneously of all groups.Behind injection STZ/ saline, measured blood glucose and body weight on the 3rd day, and measure once weekly under study for action subsequently.To have excessive thirst, polyuria and hyperglycemia (＞11mmol.L ^-1) determine diabetes.

In the drug treatment of diabetic group, the triethyl group tetramine gives every cage with water way with 50mg/L concentration.The drinking-water that contains the triethyl group tetramine is from giving continuously in the 7th week, up to the 13rd weekend animal be condemned to death.Be less than the Sham/D7 non-diabetic group of diabetic groups for drinking-water, the corresponding adjustment of drug level in its drinking-water makes it to consume the medicine of organizing roughly the same dosage with STZ/D7.The medication amount of average absorption every day of triethyl group tetramine treatment animal is 8-11mg.

When medicine begins to take in diabetic groups, wish that diabetic animal has cardiomyopathy,, and in known references, confirmed as (data not shown) of initial institute prediction.Referring to Rodrigues B, et al., Diabetes 37 (10): 1358-64 (1988).

Experiment last day, anesthetized animal (oxygen of 5% Hal and 2L/min), and give heparin (500IU.kg through the tail vein ^-1) (Weddel Pharmaceutical Ltd., London).Gather the blood sample of 2ml from postcava, the sharp separation heart also immerses in Ke-Han Er Shi (Krebs-Henseleit) bicarbonate buffer of ice bath active to keep it to shrink.Heart is with being placed in the stripped heart perfusion device.

The quick ligation of the aortic root of heart is on the aortic cannulation of device for casting.(Langendorff) perfusion of driving in the wrong direction is at static pressure 100cm H ₂O and temperature are to carry out under 37 ℃, keep 5 minutes, finish through the cannulation of pulmonary venous left atrium.Then at filling pressure 10cmH ₂To pour into buffer under the O flows to left atrium from aorta inoperative (Langendorff) is prepared to be converted into cardiac Working Model.Left ventricle is at static pressure (afterload) 76cm H ₂Penetrate from the trend aortic cannulation under the O (55.9mmHg).Infusion liquid is that (mM:KCl 4.7, CaCl for KHB ₂2.3, KH ₂PO ₄1.2, MgSO ₄1.2 NaCl 118, and NaHCO ₃25), pH is 7.4, contains the glucose of 11mM, and charges into 95% O continuously ₂: 5% CO ₂Buffer also can be streamlined filter and go into (8 μ m during beginning, the cellulose acetate of 0.4 μ m filtration then; Sartorius, Germany).The temperature of device for casting is kept with water interlayer, the temperature continuous monitoring of buffer, and in filling process, remain on 37 ℃.

(Becton Dickson, Utah USA) are inserted in the left ventricle through the top of heart with conventional insertion syringe needle the 24g plastics venous cannula of improvement.This intubate is connected in SP844 piezo-electric pressure sensor (AD device) subsequently and goes up with the continuous monitoring left ventricular pressure.Aortic pressure by carry out with the pressure transducer on the side shoot of aortic cannulation continuous monitoring (Statham Model P23XL, Gould Inc., CA, USA).(England) frequency is 300bpm to heartthrob for Digitimer Ltd, Heredfordshire, by being connected in Supraaortic electrode and pulmonary vein intubate, uses superthreshold voltage to form, and the pulse that square wave takes place is 5-ms.

Aorta stream by linear cmf record (Transonic T206, Ithaca, NY, USA) and the time point of coronary flow by the Coronary vein record flows out at 30 seconds collecting amounts and measure.

The existing many descriptions of the various heart working devices that use, as Neely, JR waits the people, Am JPhysiol 212:804-14 (1967).Improved device can be measured the cardiac function (accompanying drawing 14 and accompanying drawing 15) under the different preload pressure.The structure of corresponding device thereof is finished, and the height that flows to the buffer of heart can change by a series of scales of reconstruct mode. and for preload, aortal outlet tube can also increase height so that the afterload pressure of various definition to be provided.The afterload height is with mm Hg definition, is consistent with the regulation of publication.

All data from pressure transducer and flow probe are all collected (Powerlab16s data acquisition machine; AD Instruments, Australia).The data processing function of this device is used to calculate the one-level derivative (ventricle and aorta) of two pressure waves.Final cardiac function data comprise:

Cardiac output ^*ABF; Coronary flow; Left ventricle summit/aortal pressure; The maximum rate of ventricular pressure (+dP/dt) ^*The maximum rate that ventricular diastole is pressed (dP/dt) ^*The maximum rate of aortic pressure (aorta+dP/dt); The maximum rate of aortic diastolic pressure (aorta-dP/dt).[ ^*The amount of cardiac output (CO) buffer that to be the unit interval pumped by heart comprises the amount that the amount that pumped by aorta and coronary vasodilator pump.This is the sign of whole cardiac functions. ^*+ dP/dt is ventricle rate of change (or aortic pressure) and relevant with ventricular systole power (contractility).Be used in the contractility (Textbookof Medical Physiology, Ed.A.Guyton.Saunders company 1986) of preload more different hearts when identical.-dP/dt is the ventricular diastole rate measured value of generally acknowledging].

The experiment separated into two parts, first is fixing afterload and change preload, second portion is to follow fast after first, and fixing preload and change afterload.

Fixing afterload and change preload: after cannulation was finished, heart was at 10cm H ₂O atrium filling pressure and 76cm H ₂Balance is 6 minutes under the O afterload.Arterial pulse is inserted and risen to left ventricular pressure force transducer intubate during this time.In case heart is stable, the atrium filling pressure is reduced to 5cmH ₂O is more gradually with 2.5cm H ₂The step-length of O raises, and reaches maximum 20cmH after 7 step-lengths ₂O.Preload kept 2 minutes during each filling pressure, and internal pressure keeps stable and measures coronary flow during this period.When the experiment of pro-load variations was finished, afterload changed experimental section and will begin rapidly.

Fixing preload and change afterload: in this part experiment, filling pressure (preload) is set in 10cm H ₂O, and afterload is from 76cm H ₂O (55.9mm Hg) begins to increase, and each increasing continues 2 minutes, increases altogether 9 times.The maximum (afterload) that each individual heart can the limit be born depends on the maximum afterload value 145cm H that can reach ₂O (106.66mm Hg), or the measured value when recording aortic flow and becoming 0ml/min.Then a kind of situation, heart is considered to " nonfunction ".Be (for example long-term ischemia or the valve damage) of determining that this depletion is functional really rather than other reason causes that all hearts are all got back to initial perfusion condition (preload 10cm H ₂O; Afterload 75cm H ₂O) keep 4 minutes to be sure of the recovery of function.This process last, heart makes it stop jumping with the cold KCl (24mM) of contrary perfusion 4ml.Remove atrium and blood vessel residue, blot heart and weigh.Ventricle is along the midline incision of heart top and coronary sulcus.The using miniature caliper is measured ventricle wall thickness (Absolute Digimatic, Mitutoyo Corp, Japan).

Data from Powerlab are extracted by the electron scanning steady component with each step generation from record of average 1 minute interval.Will from every group result in conjunction with and the analysis of cardiac functional parameter between difference (aortic flow, cardiac flow, MLVDP, LV or aorta+/-dP/dt).The mixed model that application is similar to replication is probed into the difference under the different preload conditions of repeated observation and each seminar is done contrast (SAS v8.1, SAS Institute Inc, Cary NC).Application maximum likelihood value can cause the loss of data of randomness.The meansigma methods of significance and repercussion effect can further be used the method validation of Tukey, and keep the error rate of pairing 5%.All detections all are two tails.The remaining application Proc Liftest (SAS V8.2) that analyzes finishes.The difference of weight change parameter between one way analysis of variance is used to detect not on the same group.Tukey ' s detects the difference that is used to contrast between each group.Except as otherwise noted, in each chart ^*Expression p＜0.05=STZ v STZ/D7, #.p＜0.05=STZ/D7 v Sham/D7.

Animal weight the results are shown in Table 5 when showing the experiment end.Diabetic animal has about 50% less than corresponding normal group animal.The percentage ratio change curve of the weight of each experimental group is seen accompanying drawing 5, and wherein arrow represents to begin the treatment of triethyl group tetramine.

Initial and the final the weight of animals of table 5. (meansigma methods ± SD)

^*P＜0.05

The blood glucose value of three groups of rats is seen accompanying drawing 6.Usually, diabetes will be set up in STZ injection back and determine in 3-5 days.Placebo Sham and Sham/D7 matched group keep blood glucose normal in experimentation.The matched group of contrast therapy group and non-treatment, the blood glucose situation after healing with medicine does not have difference (p=ns).

The measurement of final cardiac weight and ventricle wall thickness sees Table 6." heart: body weight " ratio of the animal for the treatment of diabetes group has little still significant the improvement.Contrast non-diabetic treatment group, the ratio of " the ventricle wall thickness: body weight " for the treatment of diabetes group has the tendency of improvement, but does not reach the significance effect.

Fixing afterload and change preload

Performance parameter (the STZ diabetic groups of the graphical presentation heart of accompanying drawing 7-12; STZ diabetes+medicine; With the placebo treatment matched group), the atrium filling pressure (5-20cmH that is increasing ₂O, preload) and constant afterload 75cm H ₂Under the situation of O.All results are meansigma methods ± SEM.Except as otherwise noted, has only relevant STZ/D7 other group mark that there were significant differences in each chart; ^*Expression p＜0.05 is for STZ v STZ/D7; #p＜0.05 is for STZ/D7 v Sham/D7.Except as otherwise noted, STZ/D7 v Sham or Sham/D7 are no significances.

Cardiac output (accompanying drawing 7) is the summation of aortic flow (accompanying drawing 10) and coronary blood flow (accompanying drawing 8).Because there were significant differences on final weight for the heart of matched group and experimental group, coronary blood flow also is with respect to the normalized blood flow of cardiac weight (accompanying drawing 9) (annotate: coronary blood flow with respect to the ratio of cardiac muscle weight, reaches the ratio with respect to cardiac weight usually).

The final cardiac weight (g) of table 6. and every gram the weight of animals (BW) (meansigma methods ±)

^*P＜0.05

§=with STZ STZ/D7 group there were significant differences p＜0.05

The one-level derivative of pressure curve has provided the rate of change of ventricular pressure between each cardiac cycle, and with maximum positive change rate value (+dP/dt) make chart, see accompanying drawing 11.Corresponding maximum diastolic rate (dP/dt) is seen accompanying drawing 12.The result that similar demonstration improves cardiac function can draw (result is unlisted) from the data that the aortic pressure intubate derives.

Fixedly preload and change of load

Under the condition of the increase afterload of constant preload, but the ability that evaluate cardiac reply afterload increases.The curve of function remnants, the remaining amount of heart that promptly still has aortic flow behind each afterload is referring to accompanying drawing 13.

The administration of triethyl group tetramine with for the treatment matched group compare, improved the cardiac function of STZ diabetes rat.For example, be in a ratio of the treatment matched group, cardiac output, ventricular systole and diastole and arteria coronaria blood flow all are improved in triethyl group tetramine treatment diabetes rat.

Embodiment 6

This embodiment is used for further assessing the effect of acute administration triethyl group tetramine to heart tissue by the histology of assessment left ventricle (LV).

Method is as follows.After the functional analysis, by laser focusing (LCM; Accompanying drawing 29a-d) and transmission electron microscopy (TEM; Accompanying drawing 29e-h) the histology aspect of research LV.For LCM, the LV section is dyeed altogether with phalloidin and is formed visible actin, and β-integrin, as the labelling of ECS.Referring to Ding B, Deng the people " Left ventricular hypertrophyin ascending aortic stenosis in mice:anoikis and the progression to earlyfailure; ", Circulation 101:2854-2862 (2000).

For each treatment, check with LCM and TEM from 5 sections of per 3 hearts.For LCM, LV section fixing (4% paraformaldehyde, 24 hours); Implant in (6% agar); The vibration section (120pm, Campden); Filamentous actin dyeing (Phalloidin-488, Molecular Probes) and β ₁-alpha 2 integrin antibodies and goat antirabbit and the dyeing conjugated secondary antibody of CY% (1: 200; Ding B, " Left ventricular hypertrophy inascending aortic stenosis in mice:anoikis and the progression to earlyfailure, " Circulation 101:2854-2862 (2000) Deng the people); And develop (TCS-SP2, Leica).For TEM, behind the sample fixing (1: 1 v/v 1%w/v 0s0 M 0s0 M PBS); Dyeing (aqueous acetic acid uranyl (2%w/v 20mm), is citrate (3mm) then); Section (70nm); And develop (CM-12, Phillips).

The result is as follows.Copper chelator normalization LV in diabetes rat.(accompanying drawing 29a) compared with the control, diabetes cause the change of tangible myocardial structural, are labeled as the myocardial cell disappearance; Residue sarcostyle attenuation and destroyed; The decline of actin filament density; Expansion (accompanying drawing 29b) with interstice.These find existing report.Referring to Jackson CV, " Afunctional and ultrastructural analysis of experimental diabetic ratmyocardium:manifestation of acardiomyopathy, " Diabetes 34:876-883 (1985) Deng the people.By labelling contrast, the cardiac muscular tissue after the treatment of triethyl group tetramine make moderate progress (accompanying drawing 29c).Importantly, the orientation of myocardial cell and volume, and their actin are standardized observed-dP in studying with function assessment to a great extent _LV/ dt is consistent.The treatment of triethyl group tetramine reverses the expansion of heart ECM.The ND cardiac muscle that the triethyl group tetramine is handled is normal (accompanying drawing 29d) aspect LCM, the side effect of the LV configuration aspects that expression not can observe.Therefore, the Cu chelating can recover the normal structure structure of cardiac muscle basically, but does not eliminate hyperglycemia.The importance that these data provide the above-described cardiac function of structurally associated to recover.

TEM is consistent with LCM to a great extent.(accompanying drawing 29e) compared with the control, diabetes cause myocardial damage, feature is the myocardial cell disappearance, and tangible myocytolysis is arranged; The destruction of residual myocardium cell shows as the mitochondrion enlargement, and is fairly obvious; And the expansion of markd interstice (accompanying drawing 29f).These find existing report.Referring to Jackson CV, et al., " Afunctional and ultrastructural analysis of experimental diabetic ratmyocardium:manifestation of acardiomyopathy, " Diabetes 34:876-883 (1985).Oral triethyl group tetramine causes the substance recovery of the LV structure of diabetes, and a large amount of increases and normalized myocyte's orientation are arranged; Recover normal structure of mitochondria; And narrow down (the accompanying drawing 29g) of the ECS of labelling.These data declaration hyperglycemia-inductive Cu ^IIAccumulation can cause the mitochondrial fuctionning obstacle.Referring to Brownlee M, " Biochemistry andmolecular cell biology of diabetic complications, " Nature 414:813-820 (2001).Triethyl group tetramine treatment and TEM ND cardiac muscle normal (accompanying drawing 29h).Therefore, the triethyl group tetramine is treated the hyperglycemia-inductive myocardial damage of standardized cell and intercellular substance two aspects.Conclusion is got up, and the research of these microcosmic provides significant evidence, and promptly optionally the Cu chelation can be improved the LV structure substantially, even in serious chronic hyperglycemia.

In brief, confirmed the blood sugar concentration not obviously influence (as expected) of the treatment of (1) triethyl group tetramine for two diabetic groups; (2) diabetic groups is not treated in contrast, and the diabetic groups for the treatment of with the triethyl group tetramine has little but significantly in the improvement aspect (cardiac weight)/(body weight) ratio; (3) increase and afterload when constant when preload, cardiac output is worth to recover for Sham.All be improved for aorta and coronary blood flow in medication therapy groups; (4) ventricular systole and diastole all have significant improvement in medication therapy groups.This improvement has recovered function to a certain extent, but does not have significant difference between medication therapy groups and Sham matched group; (5) variation of the pressure of aorta sensor determination shows that also the diabetic groups of Drug therapy compares improve (data are unlisted) of function with untreated diabetic groups; (6) increase and preload when constant when afterload, observe with untreated diabetic groups and compare, the obvious improvement of the diabetic groups of Drug therapy cardiac function under high afterload.When 50% do not treat the heart failure of diabetic groups the time, have the heart of the diabetes of about 90% triethyl group tetramine treatment to still have good function; (7) compare with the heart of untreated diabetes, the heart of the diabetes of response medicine treatment shows the improvement of many variate-values: the exponential improvement of cardiac output, aortic flow, coronary blood flow and ventricular systole and diastole; (8) intact animal's medication therapy groups does not have the side effect of heart aspect; And (9) histological observation (TEM and LCM) has also shown the improvement with the rat heart organizational structure after the treatment of triethyl group tetramine.

The STZ diabetes rat improves the measured value of several cardiac functions significantly with the treatment of triethyl group tetramine.Can also reach a conclusion the improvement of the comprehensive cardiac function of Wistar rat of suffering from 6 weeks of diabetes in oral 7 weeks of triethyl group tetramine.This improve be retracted the improving of function (+dP/dT) and the minimizing of ventricle wall hardness (dP/dT) confirm.The triethyl group tetramine is to the also tangible improvement of heart of the diabetes of the afterload of treatment tolerance increase.

Embodiment 7

This embodiment is used to assess slow administration triethyl group tetramine to diabetes and non-diabetic experimenter's the cardiac structure and the influence of function.

Method is as follows.Research to the people is approved by public ethics and adjusting committee (institutional ethicsand regulatory committees).The absorption of triethyl group tetramine and drainage, report (referring to MiyazakiK with plasma concentration one time graph behind the representational oral triethyl group tetramine is existing, etal., " Determination of trientine in plasma of patients withhigh-performance liquid chromatography, " Chem.Pharm.Bull.38:1035-1038 (1990)).

Fill in the experimenter (30-70 year) of application form if following situation is arranged then be suitable for research: the HbA of T2DM _Ic＞7%; Cardiac ejection fraction (ultrasoundcardiogram) 〉=45% has tangible diastolic dysfunction, but does not have regional wall motion unusual; Not used other new medicine in 6 months; Normal electrocardiogram (sinus rhythm, normal PR interval, normal T shape ripple and QRS configuration, and normal isoelectric level st section electrocardiogram); With the blind placebo treatment of list greater than 90% obedience, 2 time-of-weeks.The women is required it is postclimacteric, or makes it infertile or do not have suckling and non-gestation with enough contraceptive devices.If the experimenter is sub-standard, or have: morbid obesity (B.M.I. 〉=45kg.m ²) Tl DM; Tangible valvular heart disease history; Tangible autonomic neuropathy; Ventricular wall motion is unusual; Multiple drug allergy history; Drug abuse; Laboratory tests abnormality at random; Or MRI contraindication etc. is arranged, then be not suitable for experiment.

Before the stochastical sampling, potential suitable experimenter joins in twice on the one the capsular treatment of two comforts of single blind stage of 4 weeks, and through the ultrasound cardiogram screening, if the damage of regional wall motion abnormalities or LV contractile function (ejection fraction＜50%) is then got rid of.In addition, the assessment of LV diastolic filling is to use Bicuspid valve influx doppler instrument (preload reduction) to finish, and has diastolic filling unusual to be sure of the experimenter; Normal people is not selected into.Before taking food, standard compliant and experimenter that have no reason to get rid of accepts triethyl group tetramine (600mg, every day twice, accumulated dose 1.2g.d at random ^-1) or two Cebo-Capses that are equal to, adopt the double-blind method parallel laboratory test.Carry out specified treatment with the maintenance balance, and give experimenter at random continuously reposefully.Double-blind treatment continues 6 months.

When baseline and after treating 6 months, use cardiac MRI and measure the LV quality, use the phased array surface coils to carry out with identical 1.5T scanner (Siemens Vision) in dorsal position.The image that has that application segmentation pulse train obtains expecting in the section of 6 minor axises and 3 major axis is shared (11-19 frames.slice ^-1) gated cardiac electric image (TR 8ms; TE 5ms; 10 ° of flip angles; Visual field 280-350mm).The acquisition of each section is the respiratory control period between 15-19 beat pulse.Short-axis slice strides across left ventricle from the top to the bottom, slice thickness 8mm, gap 2-6mm mutually.60 ° of interval locations that long axis slices equates at about long axis of left ventricle.Cardiac MRI provides the assessment of accurate and reproducible LV quality and volume.The quality of LV and the calculating of volume are that application-oriented point model carries out, and its process can accurately be measured quality and volume.In brief, the visceral pericardium and the endocardium interface of the LV wall that the three-dimensional mathematical model of LV is suitable for cutting into slices are studied simultaneously, then use the mathematics integration method with Model Calculation quality and volume (quality=wall body is long-pending * 1.05g.ml ^-1).All measurements are all finished in the data of the collection at 6 the end of month by an experimenter.Interpretation of result is carried out heart, uses the random data of the close method of maximum likelihood in mixed model and handles, and measures the average of the method for least square adjustment at edge.The variation of baseline is compared between the treatment group of mixed model.Owing to have only 2 groups to have main effect not have reciprocal influence, so do not use such process.In other analysis, the influence of the difference between the treatment group of baseline is thought to make a variation mutually with other model clinically.All P values all are to calculate by the significance,statistical that the 2-tail detects, and keep 5% significance level.The therapeutic effect of clear and definite variable is used the rules of Mantel and Haenzel and is measured (SAS v8.01, SAS Institute).

Table 7 shows 30 long-term type 2 diabetes mellitus experimenters' essential information.Not significantly coronary artery disease and unusual diabetogenous function clinically in the research of the long-term oral triethyl group tetramine dihydrochloride of, placebo at random, double blinding at 6 months.

Table 7: research participant's feature

	Placebo	Triethyl group tetramine dihydrochloride
	Placebo	Triethyl group tetramine dihydrochloride	N	?15	??15
Mean age	54 (scope 43-64)	52 (scope 33-69)	N	?15	??15
Mean age	54 (scope 43-64)	52 (scope 33-69)	Women %	?44％	??56％
Diabetes ill average times	?10(1-24)	??8(1-21)	Women %	?44％	??56％
Diabetes ill average times	?10(1-24)	??8(1-21)	Average weight index (kg/m ²)(SD)	?32(5)	??34(5)
Hypertension %	?64％	??80％	Average weight index (kg/m ²)(SD)	?32(5)	??34(5)
Hypertension %	?64％	??80％	Average %HbA _1C(SD)	?9.3(1.3)	??9.3(2.0)
Initial left ventricular mass (g) (SD)	?202.2(53.1)	??207.5(48.7)	Average %HbA _1C(SD)	?9.3(1.3)	??9.3(2.0)

Triethyl group tetramine (600mg, twice of every day, adult Weir Xun Shi disease experimenter's low dose applications, referring to Dahlman T, et al., " Long-term treatment of Wilson ' s diseasewith triethylene tetramine dihydrochloride (trientine); " Quart.J Med 88:609-616 (1995)) or 6 months diabetes adult group of placebo orally give (n=15/ group: table 7), also cooperate Drug therapy to comprise: receptor blocking agent in equivalence, calcium antagonist, the ACE-inhibitor, cholesterol reduces medicine, antiplatelet drug and antidiabetic.The LV quality responds into picture by labelled molecule, and (MRI is referring to Bottini PB, et al., " Magnetic resonanceimaging compared to echocardiography to assess left ventricular mass inthe hypertensivepatient, " Am.J Hypertens 8:221-228 (1995)) measures at baseline and 6 months triethyl group tetramine treatment backs.According to expectation like that, diabetes have significant LVH at first, and are consistent with previous report.Referring to Struthers AD ﹠amp; Morris AD, " Screening forand treating left-ventricular abnormalities in diabetes mellitus:a new wayof reducing cardiac deaths, " Lancet 359:1430-1432 (2002).

The result shows that the triethyl group tetramine reverses type 2 diabetes mellitus experimenter's LVH.The cardiac MRI scanning of baseline and 6 months shows the remarkable reduction of LV quality.The meansigma methods of the LV of the diabetic subjects of the treatment of 6 months triethyl group tetramines significantly reduces by 5%, and placebo then has 3% raising (accompanying drawing 33); The LV quality keeps high significance influence for the index of body surface area, does not shrink or diastolic pressure (table 8) and can not change.Therefore, the triethyl group tetramine causes the regression of intensive LV quality and does not change blood pressure or urine amount (accompanying drawing 32).There is not the significantly side effect relevant between triethyl group tetramine treatment in 6 months with medicine.

Long-term triethyl group tetramine treatment improvement human heart 26S Proteasome Structure and Function

The therapeutic outcome of table 8. triethyl group tetramine

	Placebo	The treatment of triethyl group tetramine
	Placebo	The treatment of triethyl group tetramine	Urine copper (μ mol.l ^-1)	????0.67 ????(-1.16-2.49)	????-0.83 ????(-2.4-0.74)
Systolic pressure (mmHg)	????-1.9 ????(-10.6-6.8)	????-3.5 ????(-9.5-1.8)	Urine copper (μ mol.l ^-1)	????0.67 ????(-1.16-2.49)	????-0.83 ????(-2.4-0.74)
Systolic pressure (mmHg)	????-1.9 ????(-10.6-6.8)	????-3.5 ????(-9.5-1.8)	Diastolic pressure (mmHg)	????-4.5 ????(-9.0-0.01)	????-3.9 ????(-13.4-6.5)
Left ventricular mass/body surface area (g.m ^-2)	????+3.49 ????(0.63-7.61)	????-5.56 ^**????(-9.64-1.48)	Diastolic pressure (mmHg)	????-4.5 ????(-9.0-0.01)	????-3.9 ????(-13.4-6.5)

The difference of main treatment variable (6 months-baseline, meansigma methods (95% confidence interval ^*, P＜0.05 pair. and placebo ^*, P＜0.01 pair. and placebo).

Heart shows the remarkable decline of LV quality in the MRI of baseline and 6 months scanning.

In brief, 6 months triethyl group tetramine of administration all has improvement to the human heart 26S Proteasome Structure and Function.

Embodiment 8

This embodiment assesses the diabetes of long term administration triethyl group tetramine and non-diabetic experimenter's urine metal Excreta.

Method is as follows.To people's research through public ethics with regulate the approval of committee.We measure the urine metal Excreta of the male subject of T2DM or the contrast of corresponding non-diabetic, and baseline information sees Table 9, at random, carry out in experiment double blinding, placebo.Simple T 2DM male subject (table 9) was through the element balance research in related fully metabolism unit in 12 days.All F﹠B are provided.Measure the trace element (Ca, Mg, Zn, Fe, Cu, Mn, Mo, Cr and Se) that (ICP MS) always takes in (two food method) every day and drain (urine and feces).Baseline determination carried out in first 6 days, oral triethyl group tetramine (2.4g, once a day) or corresponding placebo with after 2 * 2 random double blind tests, metal loss be determined at next 6 days.

Table 9: research participant's feature

	Placebo	Triethyl group tetramine treatment contrast	The placebo diabetic groups	Triethyl group tetramine treatment diabetic groups
	Placebo	Triethyl group tetramine treatment contrast	The placebo diabetic groups	Triethyl group tetramine treatment diabetic groups	The average diabetes of mean age n fasting in age glucose plasma (mmol.l ^-1) average HbA1C (%) Body Mass Index (kg.m ^-2)	??42(32-53) ??10 ??- ??4.7±0.3 ? ??5.4±0.2 ??24.6±3.5	????52(30-68) ????10 ????- ????5.0±0.4 ? ????5.0±0.3 ????27.9±5.2	????51(32-66) ????10 ????5.9(1-13) ????11.5±3.8 ? ????9.9±2.7 ????32.9±4.5	????50(30-64) ????10 ????7.5(1-34) ????10.8±4.3 ? ????9.1±1.6 ????30.4±3.1

(average ± S.E.M, except as otherwise noted); F.b.g., HbA _1CSignificant high in diabetes with B.M.I..

The result shows among the type 2 diabetes mellitus experimenter of the oral triethyl group tetramine treatment of being lost in of Cu in the urine to be increased.The urine amount of medicine group and matched group is identical.Cu loss in basic 2 hours is measured (accompanying drawing 32) to diabetic groups (n=20) and corresponding matched group (n=20) in first day 10 hours; The 1-6 day that is lost in of every day is measured.

Baseline urine Cu drains in diabetes comparison, and high (meansigma methods of diabetes is 0.257 μ mol.d according to significant ^-1Contrast, 0.196; P＜0.001).

2 hours urine Cu excretions of triethyl group tetramine and placebo were measured (2.4g once a day) once more in the time of the 7th day in same experimenter, oral drugs or placebo (n=10/ group), the triethyl group tetramine all increases urine Cu to two groups, but the diabetic groups discharge rate is wanted fast (accompanying drawing 30; P＜0.05).The triethyl group tetramine does not increase the drainage of Fe is corresponding, though the base concentration of diabetes increases (P＜0.001 to some extent with respect to contrast; The result does not show).Therefore, the triethyl group tetramine produces the response of similar urine Cu the people of T1DM rat and T2DM.It is 5.8 μ mol.d in T2DM that the urine Cu that average triethyl group tetramine produces drains ^-1, and in the non-diabetic contrast, be 4.1 μ mol.d ^-1, 40% increase is arranged.The Cu of this concordance explanation general ^IIBe increased in the diabetic subjects extensively and exist.

In brief, long term administration triethyl group tetramine has all increased the urine copper level in diabetic groups and non-diabetic group, but the discharge rate in diabetic groups is faster.Do not increase urine Fe is corresponding and use the triethyl group tetramine.Therefore, triethyl group tetramine generation rat type 1 diabetes and people's type 2 diabetes mellitus are similarly urinated the copper response.

Embodiment 9

This embodiment is used for determining the influence of oral triethyl group tetramine (triethyl group tetramine dihydrochloride) administration to the metal of diabetes and non-diabetic person's metal object defecate.Method is as follows.

With oral triethyl group tetramine (2.4g, once a day) or placebo give to suffer from accordingly the people or the matched group (n=10/ group) of type 2 diabetes mellitus (T2DM).Carry out the research of total metal balance in the associated metabolic unit.Total defecation is collected every day, and totally 12 days, lyophilization, and analyze Cu, Fe, Zn, Ca, Mg, Mn, Cr, Mb and the Se that wherein contains with ICP-MS.Baseline determination carried out in first 6 days, and after oral triethyl group tetramine or the placebo, in 2 * 2 random double blind tests, being lost in another 6 days of metal measured.

The result is as follows.In the average every day feces copper be lost in the triethyl group tetramine and placebo group there is no significant difference, the Cu output of diabetes and matched group, is zero difference also.It is unexpected (seeing Table 11) that the triethyl group tetramine is drained the nothing influence to excrement Cu, and obviously opposite with the report of Wilson ' s disease, reports excrement Cu there and drains increase.

The drainage of table 11 feces copper

Average Cu loss (mg/ days)	Before the treatment (Pre-Tment)	Treatment back (Post-Tment)
Average Cu loss (mg/ days)	Before the treatment (Pre-Tment)	Treatment back (Post-Tment)	Diabetes-placebo (n=10) contrast-placebo (n=10) diabetes-medicine (n=10) contrast-medicine (n=10)	??1.914503965 ??1.670142101 ??1.869867293 ??2.19850868	??1.937921277 ??2.078654892 ??1.965342334 ??2.045467014
SEM: diabetes-PrePlac SEM: contrast-PrePlac SEM: diabetes-preceding medicine SEM: contrast-preceding medicine	??0.122570307 ??0.1765707 ??0.228263465 ??0.209289978	??0.178995736 ??0.209400786 ??0.144463056 ??0.124516832		??1.914503965 ??1.670142101 ??1.869867293 ??2.19850868	??1.937921277 ??2.078654892 ??1.965342334 ??2.045467014

Reference value
Reference value		Ishikawa etc. (2001): contrast	????-1.00mg/d
(1988) such as Kenzie Pamall: contrast	????-1.30mg/d	Ishikawa etc. (2001): contrast	????-1.00mg/d
(1988) such as Kenzie Pamall: contrast	????-1.30mg/d	Contrast such as Kosaka H (2001)	????53.5μg/d

It is similar that the feces of other metal is discharged.Diabetes and non-diabetic person do not have detectable Zn, Fe, Ca, Mg, Mn, Cr, the influence of the discharge horizontal of Mb or Se.In brief, in the people of normal person and use T2DM, the triethyl group tetramine does not increase the defecate of Cu or other metal.Therefore, the triethyl group tetramine can't work by the discharge that increases feces Cu in T2DM.On the other hand, the previous triethyl group tetramine that studies show that increases the homaluria of Cu.Gather, these results show that the triethyl group tetramine can remove intravital Cu by the loss that increases copper in the urine.Therefore, the triethyl group tetramine of whole body activity form is that the present invention is preferred

The specific embodiment.

People's data and the aggregation of data of above-described rat are got up, illustrate that long-acting Cu chelation can cause the remarkable regeneration of the heart of diabetes damage.The triethyl group tetramine reverses heart failure of severe diabetes mellitus rat and the damage of LV significantly.And oral triethyl group tetramine significantly improved type 2 diabetes mellitus experimenter's left ventricular hypertrophy in 6 months.Suffer from rats with diabetes and people whole body Cu is arranged ^IIThe rising of level can be by using the Cu selectivity chelator, and the triethyl group tetramine is treated.

Embodiment 10

This embodiment is used to assess the effect of copper chelator of the variable concentrations of the male diabetes of anesthesia and non-diabetic Wistar rat parenteral administration, and method is the copper level of measuring in the urine.

The stock solution of the vein preparaton of the various triethyl group tetramine dihydrochlorides that contain variable concentrations is prepared in 0.9% saline, and stores 4 months down at 4 ℃, does not have perceptible rotten generation.The concentration of storing preparaton is: 0.67mg/ml, 6.7mg/ml, 67mg/ml, and 670mg/ml.Preparaton gives rat subsequently, and dosage is 0.1mg/kg 1mg/kg, 10mg/kg, and t100mg/kg gives animal respectively.

STZ administration 6-7 is (average out to 44 ± 1 days) after week, and animal contrasts or drug study.Fasting and spend the night but can arbitrarily feed deionized water before all animal surgeries.With 3-5% Hal and 2l.min ^-1O ₂Anaesthetize.(Texas USA) carries out intubate with perfusion of saline PE 50 conduits to femoral artery and vein for MikrotipTM 1.4F, Millar Instruments with the solid pressure transducer.Ureter exposes through the center line laparotomy, with polyethylene catheter (outer dia 0.9mm, inside diameter 0.5mm) intubate, and sew up wound.The animal that plugs in conduit breathes 70-80 time at the ventilation per minute, and additional O ₂(pressure control aerarium, Kent Scientific, Connecticut, USA).Regulate breathing rate and intrinsic pressure (the 10-15cm H of tide ₂O) to keep CO in the tide ₂Be pressed in 35-40mmHg (SC-300 CO ₂Monitor, Pryon Corporation, Wisconsin, USA).Control body temperature at 37 ℃ with hot plate in operation and the experimentation.The liquid loss of estimating replenishes 154mmol.l by vein ^-1NaCl solution, additional speed is 5ml.kg ^-1.h ^-1

Mean arterial pressure (MAP), heart rate (HR, can from the MAP waveform, obtain), oxygen saturation (Nonin 8600V pulse oximeter, Nonin Medical Inc., Minnesota USA) will carry out successive monitoring with central body temperature in whole experiment, use PowerLab/16s data acquisition module (AD Instruments, Australia).Calibrated signal is presented on the screen, and preserves as two meansigma methodss of each variable.

After operation and stablizing 20 minutes, begin to experimentize.Intravenously administrable triethyl group tetramine, the concentration that increases in next hour administration surpass 60 seconds (0.1,1.0,10 and 100mg.kg ^-1In the saline of 75 μ l, and with the normal saline washing of 125 μ l).Matched group is accepted isopyknic saline.Urine was to collect in experiment in the cycle with 15 minutes.

The sample pretreatment is following to be carried out.Urine: urine collecting is in the 1.5ml microtest tube of weighing in advance (eppendorf).Again weighing, urine specimen is centrifugal, the supernatant HNO of the Aristar level of 0.02M 69% ₃Be diluted to 25: 1.Before entering the GF-AAS analysis, sample is stored down at 4 ℃.Store sample if desired and surpass fortnight, lyophilizing, and-20 ℃ of maintenances down. Blood Clearly: the terminal blood sample is centrifugal, and serum is stored by the urine mode before analysis.The trace metal was collected in the experiment last moment in the serum in the blood sample, the following equation of the computing application of renal clearance:

The result is as follows.For cardiovascular, the acute infusion of triethyl group tetramine is gone out and is had a negative impact.Figure 25 does not have disadvantageous cardiovascular effect after being presented at infusion, although the instantaneous decline of blood pressure occurred when 1000mg/kg.The maximum of blood pressure drops is 19 ± 4mmHg in this variation, the (not shown) but rat was restored in 10 minutes.

In brief, the concentration range of acute intravenously administrable triethyl group tetramine is from 0.1mg/kg, 1mg/kg, 10mg/kg and blood pressure is had no significant effect up to 100mg/kg.And triethyl group tetramine preparaton can be effectively as copper chelator when intravenously administrable, and the triethyl group tetramine is preserved the activity that still kept copper chelator in 4 months down at 4 ℃ in saline.

Embodiment 11

This embodiment assesses triethyl group tetramine dosage and stores the stability of back about the copper sequestering power.

The 100mM triethyl group tetramine HCl solution of standard prepares in deionized water (MilliQ).Sample in the dark 4 ℃ down with 21 ℃ of following dark places and the 3rd sample under 21 ℃ of daylight, store.

The 0th day initial ultraviolet-visible spectrum of measuring preparaton taked the sample solution of 20 μ l equal portions then on the 15th day.The TRIS buffer of 960 μ l 50mM of each sample adding equal portions and the copper nitrate (100mM-Orion Research Inc) of 20 μ l standards.Under the 700-210nm wavelength, measure the combination stability of triethyl group tetramine preparaton.Referring to accompanying drawing 26, illustrated that this preparaton copper sequestering power of 15 day time does not have perceptible variation.And also do not have being chelated with disadvantageous perceptible effect under the room temperature daylight, the triethyl group tetramine is stable in solution as copper chelator.

***

Here with reference to or all patents, publication, scientific and technical article, the network information or other document mentioned and material all to be that those skilled in the art can introduce of the present invention, and the file of each reference and material all in full mode quote here as a reference.The applicant keeps and will be combined in right in the description from arbitrary and whole optional material of above-mentioned patent, publication, scientific and technical article, the network information, digitized information and other list of references or file and information.

This patent is described to comprise all claim.And, comprise that original rights requires and from the claim in arbitrary and all priority texts, these description parts that all can be fully incorporated in the application as a reference, and the applicant keeps description part or any other parts that these arbitrary and all claim are combined in the application's description.

Claim is explained according to law.But, complexity that claim or its part are understood not under any circumstance, any adjustment when carrying out this patent, claim or its part done or change and cause the forfeiture of any right because of declaring or recognizing.

The feature combination in any form that description is all.Therefore, except as otherwise noted, each disclosed feature all just one be equal to or the example of similar feature.

Be appreciated that aforesaid detailed description is used for proof but be not to limit protection scope of the present invention, and with the formal definition of claim scope.Therefore, in sum, though should be appreciated that with certain embodiments and be illustrated, various corresponding variations all do not deviate from the spirit and scope of the present invention.Others of the present invention, advantage, improvement are all within the protection domain of following claim.Except describing with specific claim, the present invention can not be subjected to any restriction.

Specific method described here and compositions to be preferred embodiment being illustrated, and not as the qualification to protection domain of the present invention.Other theme, aspect and embodiment can be that those skilled in the art are available according to description, are also contained within spirit of the present invention and the protection domain.It will be apparent to one skilled in the art that various replacements or modification, also do not deviate from the spirit and scope of the present invention.The present invention can be illustrative puts into practice these not special descriptions lacking or limit under the situation of some key element.Therefore, in the present invention, term " comprises ", " comprising ", " containing " etc. be open qualification.Procedure of the present invention also can variable sequence of steps be put into practice, and does not need to limit especially explanation.

Any described feature that is equal to can't be got rid of in term described here and express to be descriptive and indefiniteness, should admit that each possible modification is also within protection scope of the present invention.Therefore, some preferred embodiment and optionally features have been disclosed especially, all modifications and change and all be that those skilled in the art can expect and be included in as within the described scope of claim of the present invention though be appreciated that the present invention.

The invention describes broad and general content.Each falls into the disclosed special case of this generality and subordinate concept all can form a part of the present invention.This comprises the general description of the present invention that negative restriction is arranged with good conditionsi and that remove any material of the present invention in the general range, and no matter whether described material is mentioned especially herein.

Term " one " and " being somebody's turn to do " of it is also understood that the single form of stating here comprise plural form, unless existing definite the description.Term " X and/or Y " refers to " X " or " Y ", and perhaps " X " and " Y ", noun all contains its odd number and plural form.In addition, feature of the present invention or aspect all are to describe by the mode of Markush group, and those skilled in the art can assert the pair group formal description that the present invention also organizes with individual form or Markush.

Other specific embodiment comprises in the claims.Patentability of the present invention does not limit with certain embodiments or the specific embodiment or ad hoc approach and/or content disclosed herein.Do not limited, unless such explanation is illustrated in the description of the application's description especially with any auditor of patent, trade mark department or the explanation of any other civil servant or employee's any way yet.

Claims

1. one kind is used for preventing or improving the experimenter and organize the Treatment injury method, and wherein said experimenter does not suffer from Wilson's disease, and this method comprises that the parenteral route approach gives the copper chelator that described experimenter treats effective dose, and its scope is greatly about 5mg-1100mg.

2. method as claimed in claim 1, wherein said copper chelator is to give described experimenter through the parenteral route approach, is selected from diabetic cardiopathy with processing, the diabetic acute coronary syndrome, the diabetic hypertension cardiomyopathy, reduce relevant acute coronary syndrome with glucose tolerance, with the relevant acute coronary syndrome of fasting glucose damage, reduce relevant hypertensive cerebral cardiomyopathy with glucose tolerance, with the relevant hypertensive cerebral cardiomyopathy of fasting glucose damage, the disease of ischemic cardiomyopathy relevant or the ischemic cardiomyopathy relevant with the damage of fasting glucose with the glucose tolerance reduction, symptom or disorder.

3. method as claimed in claim 1, wherein said copper chelator is to give described experimenter through the parenteral route approach, is selected from myocardial infarction with processing, the ischemic cardiomyopathy relevant with the coronary heart disease coronary atherosclerosis, cardiomyopathy, myocarditis, idiopathic cardiomyopathy, metabolic cardiomyopathy, alcoholic cardiomyopathy, drug-induced cardiomyopathy, ischemic cardiomyopathy and hypertensive cerebral cardiomyopathy, with the irrelevant acute coronary syndrome of glucose metabolism, with the irrelevant hypertensive cerebral cardiomyopathy of glucose metabolism, or with the disease of the irrelevant ischemic cardiomyopathy of glucose metabolism, symptom or disorder.

4. method as claimed in claim 1, wherein said copper chelator is to give described experimenter through the parenteral route approach, be selected from one or more following diseases with processing, symptom or disorder, comprise arotic disease, the tree-shaped angiopathy of carotid disease, comprise cerebrovascular, coronary vasodilator, renal blood vessels, retinal vessel, the ilium blood vessel, femur blood vessel popliteal portion blood vessel, vasa nervorum, the arterial disease of small artery tree and capillary bed comprises aorta, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, the atherosclerosis of the main blood vessel of femoral artery Huo popliteal tremulous pulse.

5. method as claimed in claim 1, wherein said copper chelator are to give described experimenter through the parenteral route approach, are selected from disease, symptom or the disorder of cardiac structure damage with processing.

6. method as claimed in claim 5, wherein said cardiac structure damage are that the deposition that is selected from atrophy, myocardial cell forfeiture, ECS expansion or extracellular matrix increases.

7. method as claimed in claim 1, wherein said copper chelator are to give described experimenter through the parenteral route approach, are selected from disease, symptom or the disorder of coronary artery structural damage with processing.

8. method as claimed in claim 7, wherein said coronary artery structural damage is selected from the damage of middle level structure or theca interna.

9. method as claimed in claim 1, wherein said copper chelator are to give described experimenter through the parenteral route approach, comprise disease, symptom or the disorder of the atherosclerotic plaque rupture damage of one or more main blood vessels with processing.

10. method as claimed in claim 9, wherein said main blood vessel are selected from aorta, coronary artery, carotid artery, cerebral arteries, renal artery, iliac artery, femoral artery Huo popliteal tremulous pulse.

11. method as claimed in claim 1, wherein said copper chelator is to give described experimenter through the parenteral route approach, comprises heart contraction malfunction, diastole malfunction, shrinks disorderly, as to recoil feature disorder or injection period dysfunction disease, symptom or disorder with processing.

12. method as claimed in claim 1, wherein said copper chelator are to give described experimenter through the parenteral route approach, comprise disease, symptom or the disorder of microvascular disease with processing.

13. method as claim 12, wherein said microvascular disease comprises that one or more are selected from retina small artery, glomerulus small artery, vasa nervorum, myocardium small artery and relevant eye kidney portion, heart, the disease of the blood vessel of the capillary bed of central nervous system or peripheral nervous system.

14. the process of claim 1 wherein that described copper chelator gives with single dose or fractionated dose.

15. method as claimed in claim 1, the described copper chelator of the about 1100mg of wherein said about 5mg-with every day single dose or fractionated dose give.

16. method as claimed in claim 1, wherein said copper chelator are the triethyl group tetramines.

17. method as claimed in claim 1, wherein said copper chelator are the salt of triethyl group tetramine.

18. method as claimed in claim 1, wherein said copper chelator are the derivants of triethyl group tetramine.

19. method as claimed in claim 1, wherein said copper chelator are the analog of triethyl group tetramine.

20. method as claimed in claim 1, wherein said copper chelator are the prodrug of triethyl group tetramine.

21. as each method of claim 1-20, wherein said administration is by being selected from percutaneous dosing, topical application, suppository administration, mucosa delivery, inhalation, spraying into administration, giving through the approach of cheek administration, sublingual administration or administration through eye.

22. as each method of claim 1-20, wherein said administration is a drug administration by injection.

23. the method for claim 22, wherein said injection are meant subcutaneous injection, intramuscular injection, heeling-in administration or intravenous injection.

24. as the method for claim 23, wherein said intravenous injection is bolus injection or intravenous drip.

25. as each method of claim 1-20, wherein said administration is finished by infusion device.

26. as the method for claim 25, wherein said infusion device is passive infusion or the active infusion device of implanting.

27. delivered dose unit or dosage preparaton comprise the copper chelator and the acceptable delivery vehicles of pharmacy for the treatment of effective dose, described dosage unit can be that the experimenter carries the described copper chelator that surpasses 10%w/w.

28. as the unit of claim 27, wherein dosage device is an orally give, and the described dosage that surpasses 10%w/w to be oral back be transferred to amount the body circulation from intestinal.

29. as the dosage device of claim 28, wherein copper chelator is a triethyl group tetramine activating agent.

30. as the dosage device of claim 29, wherein copper chelator is the triethyl group tetramine.

31. as the dosage device of claim 29, wherein copper chelator is the acceptable salt of pharmacy of triethyl group tetramine.

32. as the dosage device of claim 29, wherein copper chelator is the prodrug of triethyl group tetramine.

33. as the dosage device of claim 29, wherein copper chelator is the analog of triethyl group tetramine.

34. each described dosage device of claim 28-33, wherein drug conveying carrier loads or enters body circulation amount to increase medicine from experimenter's enteral in conjunction with at least a agent delivery.

35. as the unit of claim 34, wherein at least a agent delivery is one or more synthetic and/or natural polymers.

36. as the unit of claim 35, wherein at least a agent delivery is one or more bioadhesive polymers.

37. as the unit of claim 35, wherein at least a agent delivery is one or more passive diffusion reagent.

38. as the unit of claim 35, wherein at least a agent delivery is one or more active transport reagent.

39. as the unit of claim 35, wherein at least a agent delivery is one or more promoted type active transport reagent.

40. as each described unit of claim 28-39, wherein copper chelator is blended with drug conveying carrier.

41. as each described unit of claim 28-40, it is the dosage form that enteric coating, intestinal are implanted and/or intestinal comprises.

42. as each described unit of claim 28-41, it is a slow release type.

43. as the unit of claim 42, unit wherein has the nuclear core of the slow release of enteric coating coating.

44. the unit of claim 42 or 43, it comprises no caryogram capsule.

45. as each described unit of claim 28-44, wherein surpass 50% the acceptable chelating agen of treatment in 12 hours from the dosage device stripping in gastrointestinal tract.

46. as each described unit of claim 28-45, it is to have to be used for the repeat function dosage form of stocking that level discharges.

47. as each described unit of claim 28-46, wherein the amount of the copper chelator in dosage device is lower than 300mg.

48. as the unit of claim 47, wherein the amount of the copper chelator in dosage device is lower than 250mg.

49. as the unit of claim 48, wherein the amount of the copper chelator in dosage device is lower than 240mg.

50. as the unit of claim 49, wherein the amount of the copper chelator in dosage device is at 120-140mg.

51. as each described unit of claim 28-50, the copper chelator that wherein surpasses 15%w/w can discharge from intestinal.

52. as the unit of claim 51, the copper chelator that wherein surpasses 20%w/w can discharge.

53. as the unit of claim 52, the copper chelator that wherein surpasses 25%w/w can discharge.

54. as the unit of claim 53, the copper chelator that wherein surpasses 30%w/w can discharge.

55. as the unit or the preparaton of claim 27, it is a parenteral administration.

56. as the dosage device or the preparaton of claim 55, wherein treating acceptable copper chelator is triethyl group tetramine activating agent.

57. as the dosage device or the preparaton of claim 56, wherein treating acceptable copper chelator is the triethyl group tetramine.

58., wherein treat the salt that acceptable copper chelator is the triethyl group tetramine as the dosage device or the preparaton of claim 56.

59., wherein treat the prodrug that acceptable copper chelator is the triethyl group tetramine as the dosage device or the preparaton of claim 56.

60., wherein treat the analog that acceptable copper chelator is the triethyl group tetramine as the dosage device or the preparaton of claim 56.

61. as each unit of claim 55-60, wherein dosage device is a percutaneous dosing.

62. as the dosage device of claim 61, its be can with experimenter's adhering skin or the bonded percutaneous patch of alternate manner, liner, encapsulation or binder.

63. as each preparaton of claim 55-60, it is the topical preparaton.

64. as claim 61,62 or 63 dosage device or preparaton, wherein at least 20% copper chelator can be released in the middle of the body circulation.

65. as the unit of claim 55, wherein said dosage device is a sublingual administration.

66. as the dosage device of claim 65, wherein at least 20% copper chelator can be released in the middle of the body circulation.

67. as the unit of claim 27, wherein said dosage device is a suppository form.

68. as the dosage device of claim 67, wherein at least 20% copper chelator can be released in the middle of the body circulation.

69. as the dosage preparaton of claim 55, it is the injectable administration.

70. as the preparaton of claim 69, wherein the copper chelator of 50%w/w can be released in the middle of the body circulation at least.

71. as the preparaton of claim 69 or 70, it is an intravenously administrable.

72. as the preparaton of claim 69 or 70, it is a subcutaneous administration.

73. as the preparaton of claim 69 or 70, it is an intramuscular administration.

74. as the dosage device or the preparaton of claim 51, it is implantation of storing or the form of storing injection.

75. as the unit or the preparaton of claim 74, wherein the copper chelator of 20%w/w can be released in the middle of the body circulation at least.

76. as the unit or the preparaton of claim 28, it can be carried by suction apparatus.

77. as the unit or the preparaton of claim 76, wherein the copper chelator of 20%w/w can be released in the middle of the body circulation at least.

78. as the preparaton of claim 51, but it is the preparaton of administration through eye.

79. as each described dosage device of claim 27-78 or dosage preparaton as the application in each described method of claim 1-26.

80. add each the described dosage device of claim 27-79 or the application in each described disease, symptom or the disorder in treating of dosage preparaton of label or description packing as claim 1-26.

81. dosage device or dosage preparaton as claim 80 wherein require administration once a day.

82. copper chelator and other material are preparing as the application in each described dosage device of claim 27-81 or the dosage preparaton.

83. as the described application of claim 82, it is used for the processing purposes described in each as claim 1-26.