CN1226166A

CN1226166A - Formulation and method for treating congestive heart failure

Info

Publication number: CN1226166A
Application number: CN97196854A
Authority: CN
Inventors: 小J·L·麦奈
Original assignee: Eli Lilly and Co
Current assignee: Eli Lilly and Co
Priority date: 1996-06-06
Filing date: 1997-06-05
Publication date: 1999-08-18
Also published as: IL126966A0; EA199900006A1; NO985695L; WO1997046241A1; JP2000511906A; KR20000016406A; AU3233197A; YU55998A; ZA974978B; NO985695D0; TR199802496T2; EP0914128A1; CZ397698A3; BR9709546A; CA2256720A1; PL330637A1; HUP0003885A2

Abstract

This invention provides a method for treating congestive heart failure comprising administering an effective amount of 4-chloro-5-(imidazoline-2-ylamino)-6-methoxy-2-methylpyrimidine in an oral or implant nonimmediate release formulation and nonimmediate release formulations.

Description

The preparation and the method that are used for the treatment of congestive heart failure

Relevant application reference

The application is the patent application serial number No.08/659 that submits on June 6 of 1996,463 part continuation application.

Invention field

The invention belongs to pharmacology and pharmaceutical chemistry field, the preparation and the method for use 4-chloro-5-(imidazoline-2-base is amino)-6-methoxyl group-2-methylpyrimidine treatment congestive heart failure is provided.

Background of invention

Congestive heart failure (CHF) may be defined as heart does not have ability with the suitable nutrition of enough blood supplys with discharge the metabolism needs that refuse satisfies periphery.What this noun was described is a kind of concurrent compound symptom, may comprise dyspnea, fatigue, pulmonary congestion, cardiac dilatation and periphery edema.CHF is the final result of long-term or serious heart or circulatory disturbance.It often is to be caused by underlying cause: long-term hypertension, acute myocardial infarction, valve disease, primary cardiac myopathy, and multiple secondary injury.The sickness rate of CHF just constantly increases, and is the common cause that the over-65s patient is in hospital.

Early stage at this syndrome, heart and periphery regulatory mechanism all begin to play a role, so that help the phase beginning depletion of compensation heart.For example, heart rates increases, and left ventricular volume and pressure may rise, and heart may enlarge and/or become loose (being called as remodeling process (remodeling process) now).In periphery, blood is volume gain, sodium and hydropexis, and the active reflexive increase of sympathetic nervous system improved tremulous pulse and intravenous tension, and increased the contractility of heart.At first, as the active result who increases of sympathetic nervous system, the neuro hormone in the blood plasma improves comprehensively, comprising: norepinephrine, renin, neuropeptide tyrosine (NPY), angiotensin II, aldosterone, vassopressin, and atrial natriuretic factor.These compensatories changes concur, so that keep the hemoperfusion supply of life basis as brain and heart.The formation though these effective mechanism may have been evolved originally, be used to prevent acute blood volume forfeiture (for example hemorrhage), but, under the situation of chronic CHF, activate compensatory mechanism (particularly sympathetic nervous system) constantly, may play blanketing to effective cardiac function, make cardiac ejection more difficult.And the peripheral nervous hormone improves inadequately, will impel many sxs of CHF, for example pulmonary edema and periphery edema, dilutional hyponatremia and hypokalemia.

The particularly activation of neurohormonal system impels keeping of regenerative feedback loop, and this is continued the circulation that causes patient condition further to fail.For example, increase orthosympathetic tensity and may directly cause increasing heart rates, cause that the myocyte who causes promoting myocardial cell remodeling (remodeling) is downright bad and loose, increase wall tension force, and cause the diastole sexual dysfunction that causes promoting heart failure.The activity that increases sympathetic nervous system can also the stimulation of renal upper parathyrine, the release of norepinephrine and renin, and this further increases the resistance to Ve again conversely, and has reduced the blood flow to kidney.The latter is as to the further stimulation of renin-angiotensin system and work, and this circulation is continued.Clinically, clearly realize that now that patient CHF has the sympathetic nervous system activity of increase and the norepinephrine and the renin of high plasma concentration, and recognizes, neurohormonal excessive raising is an important prognosis factor.

The complexity of this syndrome has been impelled it has been carried out many pharmacology's exploratory developments.Its scope relates to the medicine from direct cardiac stimulus, as Folium Digitalis Purpureae, and beta-2-agonists and phosphodiesterase inhibitor, to the peripheral vascular chemical compound that directly relaxes, as nitrate, some calcium channel blocker, α-Zu Zhiji and direct acting vasodilation such as hydralazine.But, in treatment CHF, use and to work in some way and interrupt the medicament of above-mentioned positive feedback loop, reached best so far result.As if suppress over-drastic neuro hormone activates beneficial especially.Therefore, ACE inhibitor is useful adjuvant to treatment, nearly all this patient is recommended now.Recently interesting especially to the test of beta-Blocking agent, because think for a long time always, directly disturb sympathetic nervous system CHF is more worsened to stimulating contractility and the compensation of keeping blood pressure, in fact, particularly for ischemic heart disease decentraction myopathy, use this class medicament to prove useful carefully.And some beta-Blocking agent such as bucindolol and carvedilol also may make blood plasma medium vessels tonin protoenzyme and norepinephrine reduce.Even so, best Drug therapy example also only makes survival rate improve about 10-15%, and total M ﹠ M of CHF still makes us dull.In fact situation is, for New York heart association III degree and IV degree patient CHF, even carry out optimal Folium Digitalis Purpureae and ACE inhibitor treatment, the metabolism turnover rate of the norepinephrine of CNS and periphery has still improved significantly.

A lot of clinicians begin to think that CHF is a kind of neuro hormone disorder disease.Therefore, work by CNS and interrupt the sympatheticotonia state and the medicament to ill heart and peripheral nervous hormonal stimulation followed may have favorable influence to patient's CHF M ﹠ M.What is interesting is, never did test fully for this hypothesis.Once clonidine was carried out clinical trial, but only taken in 13 patients, and treatment time is also relatively lacked (12 week), Giles etc., Angiology, 38,537-548, (1987).Yet, reported favourable trend, comprise that heart rate descends, ejection fraction increases and functional status improves.

Activate the importance of sympathetic nervous system based at present known about local and general to the CHF pathophysiology, advised moxonidine as the effective healing potion of potentiality, Mangiapane etc., FASEB.9,265 (1 995), Michel etc., J.Cardiovasc, Pharmacol.20.Supp.4.524-530, (1992).

Systolic blood pressure and diastolic blood pressure raise, and for cardiovascular disease such as myocardial infarction, coronary artery disease and apoplexy are principal risk factor.Though recognize clearly, hypertension is relevant especially with the danger of apoplexy, seldom recognizes, hypertension also is important risk to coronary heart disease, raises of equal importance with serum lipids.Hypertension generally is defined as systolic pressure and/or diastolic pressure is increased to above 140/90mmHg, is modal cardiovascular disease.Only, there are about 2-4 10,000,000 people need treat hypertension in the U.S..Present available therapeutic agent comprises, converting enzyme inhibitor, diuretic, vasodilation, beta-Blocking agent, anti-sympathetic dose of maincenter, and Ca ⁺⁺Channel antagonist.Blood pressure is with vascular resistance, blood vessel inner capacities, cardiac output and vasoconstriction state and change.Many physiologys system is relevant with the homoiostasis of regulating the blood vessel internal volume, mainly is to discharge salt and water by kidney.Cardiac output not only had been subjected to the heart intrinsic factor to regulate but also be subjected to the adjusting of external factor, regulated by sympathetic nervous system.The vasoconstriction state depends on following factors: blood vessel intrinsic factor, sympathetic nervous system, the relaxation factor of endotheliocyte, renin-angiotensin system (RAS) and body fluid balance.RAS is main means, and by it, health is to body fluid, and ionogen balance and blood pressure are controlled.It is the part of the Homeostatic mechanism of complexity, and this mechanism relates to multiple hormone, enzyme, and spontaneous signal activity.The key end product of the physiology of RAS is the octapeptide angiotensin II.Can regard the original system of high development as the physiology of RAS is activated, be in order to prevent that body from losing blood volume suddenly or more little by little losing sodium and the system of evolutionary development.Therefore, angiotensin II improves the pressure of inculcating to the life basic part, and promotes the heavily absorption to sodium and water.A kind of influence in back is to take place by the effect to kidney of aldosterone and vassopressin.

The overactivity of local RAS may cause the terminal organ relevant with chronic hypertension not normal.For example, known that angiotensin II is the important medium of smooth muscle cell growth and differentiation.Therefore, angiotensin II may mediate the proliferation response of blood vessel, and it is accompanied by mechanically (being angiopoiesis) or improves systemic blood pressure for a long time and the injured blood vessel wall.Notice that as top angiotensin II is the important regulator of glomerule function, the overactivity of RAS is undoubtedly an important factor to the formation and development of nephropathy such as glycosuria nephropathy and ultra-filtration glomerule nephropathy.

Two kinds of enzymes, renin and angiotensin converting enzyme (ACE) they are the basic factors that produces angiotensin II, they are distributed in whole body widely.Though renin and preceding renin are to be synthesized in nearly glomerule (JG) cell of kidney, and discharge into blood circulation,, early data shows that consumingly it distributes widely.For example, renin and/or its mRNA in following tissue, have been found: brain, blood vessel, antepituitary, adrenal cortex, kidney, ovary, uterus and heart.Renin is subjected to angiotensin II and glomerule pressure raises and the feedback of sodium load increase suppresses.

ACE finds the main dipeptidyl carboxypeptidase relevant with the pulmonary capillary lining cell.As renin, it also has distribution widely, is positioned blood vessel, heart, kidney, intestinal and liver.The ACE mediation is removed its terminal dipeptides from hypertensin, the also easypro kassinin kinin degraded of catalysis blood vessel.In angiotensin II synthetic, ACE is not the speed limiting factor.And ACE shortage specificity, only require the tripeptide sequence (as long as intermediary aminoacid is not proline) that has free carboxy.Thereby multiple endogenous peptide is the substrate of this enzyme, comprises enkephalin, P material and the lysine-blood vessel kassinin kinin that relaxes.

The release of renin from the nearly bead of kidney (JG) cell is subjected to angiotensin II to the direct acting inhibition of JG cell.Angiotensin II also stimulates the aldosterone secretion, thereby increases sodium retention and the drainage of increase potassium in the kidney.By increasing sodium retention, the blood vessel inner capacities is increased, and therefore suppress the angiotensin secretion.These feedback circuits can be divided into long loop (volume), short loop (circulation angiotensin II) and ultrashort loop (angiotensin II in the JG cell).Many pharmacological modulation agent are excretory activator of renin or deactivator.It is more particularly, many that to be used for the treatment of hypertensive medicine all be the secretion that changes renin directly or indirectly.This effect may be offset or be strengthened the effect that is used for the treatment of hypertension drug.

Renin and hypertensinogen also are positioned in blood vessel wall and the brain.This is called as the outer renin of kidney-angiotensin system (RAS).Therefore, the hyperpietic hangs down the renin level, with and non-reacted to physiological stimulation of renin secretion, may be covered owing to there is the outer renin system of very effective blood vessel.

Disturb the medicament of renin-angiotensin system, be used to treat hypertension more than 15 years.

Before about 14 years, clinical treatment is pushed out than successful angiotensin converting enzyme (ACE) inhibitor and comes into the market, and has become the main pillar of treatment moderate to severe hypertension.These inhibitor can be used as single agent and use, and perhaps merge with diuretic and use (consider the physiology of renin angiotensin system, it is rational doing like this).This is will cause the renin secretion to increase (as volume control) because capacity and salt reduce, so suppressing the angiotensin system may bring high blood pressure down more.

Central action antihypertensive moxonidine, 1991 in Germany by examining.The receptor pharmaceutical research shows that moxonidine is a kind of selective agonist to inboard medullary substance imidazoline 1-receptor.

Use mainly to α ₂Though-adrenoceptor agonists such as clonidine effectively, show the side effect of high rate, as calmness, and xerostomia and other nonspecific action.These side effect can be used presynaptic in the CNS and postsynaptic α ₂The stimulation of-adrenoceptor is explained.Further studies show that, central action medicine such as clonidine and moxonidine, be by to imidazoline receptor in conjunction with their antihypertensive function of performance, and side effect is because to α ₂The effect of-receptor is brought out.The difference of clinical tolerance between moxonidine and the clonidine can also not be to α to imidazoline receptor according to moxonidine ₂-receptor has bigger selectivity to explain.

Since 1991 in Germany by since examining, the immediate release dosage form administration to moxonidine has accumulated clinical experience quite widely.Moxonidine almost is absorbed (absorbing＞90%) fully from gastrointestinal tract, and bioavaliability is 88%, and this medicine can not put aside during repeat administration.The absorption and the bioavaliability of ingesting simultaneously to moxonidine do not have remarkable influence.Plasma half-life (t _1/2) be 2-3 hour.Take in after the moxonidine 0.2mg maximal plasma concentration (C _Max) be 1-3ng/ml.Maximum blood plasma level appeared at after the administration in 30-180 minute.Different with plasma half-life, its antihypertensive function persistent period (reaching 24 hours) may be since moxonidine due to the lower clearance rate of its maincenter agency part (deep-seated chamber).Moxonidine has 7% low plasma protein combination, is eliminated with prototype by the kidney approach more than 60%.For patient with renal dysfunction, peak serum concentration (C _Max), plasma half-life and 0-24 hour plasma concentration area under a curve (AUC _0-24) all increased, but depot action does not take place.

Proved that moxonidine is the antihypertensive drug with very good toleration.There is the patient of 2-15% that its typical side effect xerostomia takes place, but can improves usually along with continuing treatment.Other side effect such as tired, headache and dizzyly only occur in a few patients.After the acute experiment administration, moxonidine has reduced plasma norepinephrine and Adrenaline Concentration, and the activity of blood plasma renin has also reduced.Moxonidine is to the not influence of circadian rhythm of blood pressure.Stop not see rebound phenomenon after the treatment.Use separately and with other antihypertensive drug, diuretic for example, calcium antagonist and ACE inhibitor merge to be used, and moxonidine all is the antihypertensive drug with well tolerable property.

Verified moxonidine is the medicine that is fit to the hypertension driver.With regard to its metabolizing parameters, it is neutral, and does not cause respiration inhibition, and this antihypertensive therapy to the asthmatic patient is important.

Show that in clinical research the 0.2-0.4mg moxonidine is effective every day of a dosage range, 10-20% can bring high blood pressure down.Reach 2 years voluntary participation research and reach in 6 months the comparative study, proved the resisting hypertension effect of moxonidine.

In once research more early, moxonidine is with the dosage of 0.2mg once a day, perhaps every day 2 0.2mg dosed administration, and blood pressure has reduced by 27/19 or 29/15mmHg from baseline respectively.To the patient in 2 years of 49 tracking tests, the similar blood pressure that has obtained 27/16mmHg reduces, and proves that its antihypertensive function dosage does not weaken along with the time, drug resistance promptly do not occur.

141 patients have been carried out 12 months treatment, and dosage wherein is to adjust one by one, so that obtain the target diastolic pressure less than 95mmHg, mean blood pressure drops to 151/88mmHg from 173/103mmHg.With 0.2mg moxonidine once a day, treated 82 patients (58.2%) effectively, 53 patients (37.6%) need 0.2mg moxonidine every day 2 times, in addition: 1 patient 0.1mg every day, 4 patient 0.6mg every day, 1 patient 0.8mg every day.Most humans blood pressure in 3 weeks of beginning moxonidine treatment back is controlled, and maintenance is stablized during whole 1 year research in.

The proof moxonidine is the effective and safe antihypertensive agents that can improve quality of life in to 9295 hyperpietics' a observational study.Treat after 12 weeks, blood pressure has reduced, and heart rate reduces a little, and per minute reduces 3 times.Except uric acid, glucose, triglyceride and cholesterol have outside the minimizing slightly, and the clinical inspection parameter of testing remains unchanged.6.9% patient report side effect.

According to the result of Framingham Heart research,, be the most common reason of CHF poor prognosis by the left ventricular hypertrophy that hypertension causes.

Desirablely be, antihypertensive drug can induce myocardial hypertrophy to reply, and myocardial hypertrophy usually can cause heart failure.Evidence suggests that causing somatomedin is the Therapeutic Method that norepinephrine and angiotensin II reduce, induce left ventricular hypertrophy to reply.In once less research, 20 hypertensive patients antihypertensive function and the regressive evaluation of left ventricular hypertrophy have been carried out.After moxonidine treatment 6 months, blood pressure drops, left ventricle thickness at interval is reduced to 19.1mm (average) significantly from 22.5mm.

Be used for the treatment of hypertensive medicine, particularly ACE inhibitor, important further to the treatment congestive heart failure.These medicines generally all have the peripheral action position, therefore can be by improving the sympathetic system activity or stimulating renin-angiotensin-aldosterone system to cause reverse regulating action.

The cardiovascular self-adjusting system can be with the drug-induced change of compensatory reflex mechanism antagonism.The central drugs with function can be avoided the reverse regulating action of compensatory, particularly avoids increasing the sympathetic system tense situation, the pathogeny that this tense situation may change the hypertensive cerebral organ and continue to work.In view of the patient of most of hypertensive patients and congestive heart failure has the sympathetic system activity that increases, control these two kinds of indications with the central drugs with function and it seems it is rational.

Moxonidine increases cardiac output simultaneously to the vascular resistance that the hypertensive patient reduces whole body.These hemodynamic changes may have useful effect to suffering from symptomatic congestive heart failure patients.

To being arterial hypertension basically, around the patient who perhaps has a congestive heart failure carries out in the treatment of the voluntary participation research, patient accepts the 0.2-0.4mg moxonidine every day, single therapy or with the other medicines combined treatment, moxonidine is the immediate release dosage form that market is buied.Acute give the 0.1mg moxonidine after and around the treatment after, under resting state and kinestate, measure blood pressure and left ventricular ejection fraction.As described six patients that suffer from CHF in casuistics.Wherein 2 patients to penetrate the blood index poorer.Wherein demonstrate adverse consequences after 1 people's acute experiment administration, do not accept the long term administration treatment.Wherein 2 patients' result does not change substantially.1 patient demonstrates tangible improvement in acute experiment administration and long term administration treatment.Another also suffers from the patient of arterial hypertension, only demonstrate the slight improvement of left ventricular ejection fraction owing to the moxonidine treatment, but hypertension has obtained better controlled, thereby this patient continues to treat with 0.2mg moxonidine one twice-daily.In these patients, do not see that treatment has consistent reaction to moxonidine.

In single dose administration research, the immediate release dosage form moxonidine of buying with market is measured hematodinamics when static and motion suffering from patient's administration of congestive heart failure, and to regulating the effect of related hormones with hematodinamics.

In the research of a voluntary participation, comprise 10 patients, all suffer from congestive heart failure (NYHA III degree).Moxonidine is with the dosage single oral administration of 0.4mg.Hematodinamics and neuro humor parameter under resting state and the kinestate are measured in before the oral medicine and the back 1,2 and 3 hour of taking medicine.By means of the Swan-Ganz catheterization, measure resting state and press lung pressure index and cardiac output in the energy meter motor process.

Right ventricle does not see that with the lung pressure index clinical relevant change is arranged.Cardiac output and heart rate descend a little, and stroke volume has increased.After taking in moxonidine, the resistance of resting state and the visible general blood vessel of kinestate and pulmonary vascular resistance all have statistics not significance reduce.In these normotensive patients, no matter static and at the largest motion state, blood pressure all with time-the dependency mode descends.About to neurohumoral effect, all observe the active reduction of blood plasma renin at quiescent condition and largest motion state.

Observed resting state and between moving period the plasma norepinephrine level obviously reduce, thereby record plasma epinephrine less decline is only arranged.Also observing blood plasma angiotensin II level behind the absorption moxonidine obviously reduces.In the test of this single dose administration, do not record that aldosterone has any relevant change with ANF in the blood plasma.

These discoveries show, moxonidine to the hemodynamic parameter of congestive heart failure patients without any deleterious effects.Though cardiac output and stroke volume in fact still remain unchanged, pressure index has the trend of reduction.Acute oral gives after the moxonidine, does not see neurohumoral reverse regulating action.According to evaluation to its side effect and experiment parameter, show that moxonidine is safe to heart failure patient single dose administration 0.4mg afterwards, and can be well tolerable.

It is unexpected that discovery be, gives 4-chloro-5-(imidazoline-2-base is amino)-6-methoxyl group-2-methylpyrimidine of present commercially available dosage form (immediate release dosage form) to patient CHF, and moxonidine causes that the undulatory property that the sympathetic system activity is difficult to accept reduces.The back was observed once big and of short duration reduction in 1-3 hour taking medicine.The intensity of peak action and transient continuous time all are undesirable.Unless obviously this peak strength can reduce, can prolong action time, and do not cause owing to the inherent problem of repeatedly taking medicine, otherwise moxonidine can not be realized as the potentiality effect of congestive heart failure healing potion., and, also can not foretell hypertensive laboratory and clinical experience according to the moxonidine that has accumulated, to patient's CHF administration, will can not cause the more persistent reduction of sympathetic system activity with the existing commercially available dosage form of moxonidine to patient's CHF limited experience.

Summary of the invention

The application requires the invention of patent protection that a kind of method for the treatment of congestive heart failure is provided, and comprises that the mammal to this treatment of needs gives effective dose moxonidine or its pharmaceutics acceptable salt of non-immediate release dosage form.

The present invention also provides the pharmaceutical preparation that comprises effective dose moxonidine or its pharmaceutics acceptable salt, itself and one or more carrier, and diluent or excipient composition make it the non-moxonidine of promptly releasing.

The present invention further provides a kind of method and formulation, provide 6-16 hour average blood plasma to remove the half-life.

And then, the invention provides a kind of method and formulation, be provided 2.5-5 hour the average time that reaches maximal plasma concentration.

Detailed Description Of The Invention

Compound 4-chloro-5-(imidazoline-2-base amino)-6-methoxyl group-2-methylpyrimidine (moxonidine) is known, and in U.S. Patent No. 4,323, and existing description the in 570 all is incorporated herein by reference in this this patent.

Compound 4-chloro-5-(imidazoline-2-base amino)-6-methoxyl group-2-methylpyrimidine generally can be by U.S. Patent No. 4,323, disclosed method preparation in 570.Preferably, (imidazoline-2-base is amino)-6-methoxyl group-2-methylpyrimidine can be by being prepared as follows for 4-chloro-5-.

Ethenylamidine hydrochloride Diethyl malonate 4,6-dihydroxy-2-methylpyrimidine

4,6-dihydroxy-2-methyl-5-nitro pyrimidine 4,6-two chloro-2-methyl-5-nitro pyrimidines

Raney nickel 5-amino-4,6-two chloro-2-methylpyrimidines

N-acetyl imidazole quinoline-2-ketone N-(1-acetyl imidazole quinoline-2-subunit)-4,6-two chloro-2-methyl-5-pyrimidinamine

4-chloro-N-(imidazolidine-2-subunit)-6-methoxyl group-2-methyl-5-pyrimidinamine

By at room temperature making acetic anhydride and 2-imidazolone prepared in reaction N-acetyl imidazole quinoline-2-ketone.This reactant mixture was heated 90 minutes between 80 ℃-100 ℃, be cooled to about 10 ℃-10 ℃ then, obtain N-acetyl imidazole quinoline-2-ketone.

First intermediate 4,6-dihydroxy-2-methylpyrimidine amine can synthesize by prepare Sodium ethylate in position from sodium and dehydrated alcohol in blanket of nitrogen.Add ethenylamidine hydrochloride and diethyl malonate; And this reactant mixture is heated to boils 2-5 hour, obtain 4,6-dihydroxy-2-methylpyrimidine.

Second intermediate 4,6-dihydroxy-2-methyl-5-nitro pyrimidine can pass through then with 4, and 6-dihydroxy-2-methylpyrimidine is added to lentamente in the reactant mixture of fuming nitric aicd in acetic acid and synthesizes.Add 4, after the 6-dihydroxy-the 2-methylpyrimidine is finished, begin to stir this reactant mixture half an hour to 2 hour immediately, obtain 4,6-dihydroxy-2-methyl-5-nitro pyrimidine.

After Nitrification is finished, under agitation make phosphorus oxychloride (POCl ₃) and 4,6-dihydroxy-2-methyl-5-nitro pyrimidine chemical combination.Drip diethylaniline to this mixture, rate of addition should make the temperature of reactant mixture keep below about 40 ℃.After adding, reaction mixture refluxed was heated 1-3 hour, under vacuum, distill then, obtain the 3rd intermediate 4,6-two chloro-2-methyl-5-nitro pyrimidines.

The 3rd intermediate 4,6-two chloro-2-methyl-5-nitro pyrimidines with the 10%-30% solution form in toluene, are hydrogenated under Raney nickel catalysis and form corresponding compounds 4, and 6-two chloro-2-methyl-5-aminopyrimidines are as the 4th intermediate.

The 5th intermediate N (1-acetyl imidazole quinoline-2-subunit)-4 then; 6-two chloro-5-pyrimidinamine; can prepare as follows: make phosphorus oxychloride; N-acetyl imidazole quinoline-2-ketone and 5-amino-4; 6-two chloro-2-methylpyrimidine chemical combination; be heated to and boil, continue 2-4 hour, stir then and be cooled to room temperature.

End product 4-chloro-N-(imidazoline-2-subunit)-6-methoxyl group-2-methyl-5-pyrimidinamine can synthesize by at first preparing Feldalat NM in position from absolute methanol and sodium.Add the 5th intermediate N (1-acetyl imidazole quinoline-2-subunit)-4,6-two chloro-2-methyl-5-pyrimidinamine, and this reactant mixture is heated to boiling.Be heated to back 15 minutes to 1 hour of boiling at reactant mixture, add Feldalat NM once more, and make reactant mixture keep boiling 15 minutes to 1 hour, obtain 4-chloro-N-(imidazoline-2-subunit)-6-methoxyl group-2-methyl-5-pyrimidinamine.

Can progressively obtain this several intermediate by standard technique well known to those skilled in the art.The various reactants and the reagent that are used for this building-up process can be buied, and perhaps by standard method well known to those skilled in the art, produce easily from the raw material of buying.

Should be understood that this chemical compound of the present invention can be used as prototype and is separated, perhaps can use conventional method and be converted to acid addition salt.As described above, the present invention also comprises the acceptable salt of the pharmaceutics of moxonidine.Moxonidine can generate the acceptable salt of pharmaceutics with any reaction in many avirulent inorganic or organic acid.The acid that is generally used for forming acid addition salt is mineral acid, for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulphuric acid, phosphoric acid etc., and organic acid, for example right-toluenesulfonic acid, methanesulfonic acid, oxalic acid, right-bromo-benzene sulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid etc.Therefore, the example of some pharmaceutics acceptable salts has sulfate like this, pyrosulfate, disulfate, sulphite, bisulfites, phosphate, a hydrogen orthophosphate, dihydrogen orthophosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, caprate, caprylate, acrylates, formates, isobutyrate, caproate, enanthate, propiolate, oxalates, malonate, succinate, suberate, sebacate, fumarate, maleate, butine-1,4-disalt, hexin-1,6-disalt, benzoate, chloro benzoate, ar-Toluic acid salt, dinitro-benzoate, hydroxy benzoate, methoxybenzoic acid salt, phthalate, sulfonate, xylyl sulfonate, phenylacetic acid salt, phenylpropionic acid salt, phenylbutyric acid salt, citrate, lactate, gamma hydroxybutyrate, glycollate, tartrate, mesylate, propane sulfonic acid salt, naphthalene-1-sulfonate, naphthalene-2-sulfonic acid salt, mandelate etc.The preferred acceptable acid addition salt of pharmaceutics is those and mineral acid, example hydrochloric acid, the salt that hydrobromic acid and sulphuric acid form.

With noun " effective dose " expression 4-chloro-5-(imidazoline-2-base is amino)-6-methoxyl group-2-methylpyrimidine, perhaps a kind of dosage of its pharmaceutics acceptable salt, this dosage can alleviate or releasing and congestive heart failure, hypertension, or the two relevant one or more symptoms or situation.Noun " treatment " comprises treatment and the prevention to this symptom and specified conditions as used herein, in case this therapeutical effect is established, will alleviate or eliminate this situation." plasma clearance half-life " refers to, after single agent administration in the blood plasma amount of moxonidine reduce by 50% required time, will be called as t sometimes in this plasma clearance half-life _1/2" reach the time of maximal plasma concentration " and refer to after the moxonidine list agent administration and reach the required time of Cmax in the blood plasma.Except as otherwise noted, " on average " refers to the geometric mean of described value when joining with the time correlation that reaches maximal plasma concentration with the plasma clearance half-life.The program of measuring the moxonidine plasma concentration is as described below.

Chemical compound of the present invention is that a kind of proof is to I basically ₁Receptor surpasses α ₂The optionally I of adrenoreceptor ₁-imidazoline part.In the saturated combination experiment to cattle ventral horn medullary substance (bovine rostralventrolateral medulla, (bovine RVLM)), moxonidine shows to have greater than 20 times, is preferably more than 30 times selective value (α ₂The K in site _i(μ M)/I ₁The K in site _i(μ M)), at this K _iIt is the inhibition affinity costant.Certainly, K _iBe inversely proportional to affinity, like this, lower K _iValue shows to have higher affinity.Therefore, selective value is high more, and the selectivity of chemical compound is strong more.By contrast, the selective value of clonidine in cattle RVLM is less than 4.Detailed experiments program and result are referring to Ernsberger etc., J.Pharmacol Exp.Ther.264.172-182 (1993).

Noun " mammal " means high vertebrates Class Mammalia as used herein.This noun " mammal " includes, but are not limited to the mankind.The dosage of this chemical compound generally is about 0.001-5.0mg every day, but dosage single heavy dose gives this day as a rule, and the judgement of being responsible for this case doctor is depended in perhaps gradation administration.Preferred dosage scope is about 0.01-2.0mg every day; May be that preferred other dosage ranges are about 0.005-2.0mg every day in some cases, about 0.1-2.0mg, about 0.05-0.8mg, and particularly preferred dosage range is about 0.05-2.0mg every day.Should be understood that, often be to determine according to the judgement through Guan doctor to given patient's dosage, and dosage also changes based on following factors; Patient's body weight, the fat or thin characteristics of patient, the feature of selected specific compound (free alkali or salt), the order of severity of patient symptom, and the psychological factor that may influence patient's physiological reaction.

Medicine always is mixed with the dosage form of medicament basically, so that manageable drug dose can be provided, and gives patient meticulous and drug products that be easy to manage.

Though might directly give 4-chloro-5-(imidazoline-2-base is amino)-6-methoxyl group-2-methylpyrimidine, but, preferably use its non-pharmaceutical dosage forms of promptly releasing, said preparation comprises one or more pharmaceutics acceptable carriers, diluent or excipient, and this chemical compound or the acceptable salt of its pharmaceutics.This preparation will contain this chemical compound of about 0.01%-99% by weight.

When preparation preparation of the present invention, normally use the routine techniques and the program of useful in preparing drug formulations, active component is mixed with at least a carrier, or with at least a carrier dilution, perhaps be encapsulated in the carrier, this package carrier can be a capsule, sachet, the form of paper mold or other container.When carrier was used as diluent, it can be for active component starts shipment the dress body, solid, semisolid or the liquid substance of excipient or medium effect.Like this, said preparation can be following form: tablet, granule, pill, powder, lozenge, little wafer, cachet, elixir, Emulsion, solution, syrup, suspension, aerosol (as solid or in liquid medium) and soft and hard gelatine capsule.

The carrier that is fit to, the example of diluent and excipient comprises: lactose, glucose, sucrose, sorbitol, mannitol, starch, arabic gum, calcium phosphate, alginate, liquid paraffin, calcium silicates, microcrystalline Cellulose, polyvinylpyrrolidone, cellulose, tragakanta, gelatin, syrup, methylcellulose, methyl-and propyl group-hydroxybenzoate, vegetable oil such as olive oil, injectable organic ester such as ethyl oleate, Talcum, magnesium stearate, water and mineral oil.Said preparation can also comprise wetting agent, lubricant, emulsifying agent, and suspending agent, antiseptic, sweeting agent, aromatizing agent, stabilizing agent or aromatic.Preparation of the present invention can be prepared by means of technology well known in the art, causes the non-release immediately of its active component.Preparation of the present invention can be mixed with and be used for the non-immediate release dosage form of active component oral or the implantation administration.

In non-immediate release dosage form, the release of medicine from its dosage form is the speed conditioning step in the kinetics model of drug release-absorption-elimination.This is different from immediate release dosage form, and it is its speed conditioning step that immediate release dosage form is crossed over biomembranous drug absorption.The non-drug delivery system of promptly releasing is divided into four types: (1) postpones to discharge, and (2) slowly discharge, and (3) site specific discharges and (4) receptor discharges.

In general, postponing delivery system is that those adopt repeatedly the system of administration at interval, and institute's administered agents is to mix the into i.e. unit of releasing of single dosage forms from one or more.The example that postpones delivery system comprises the tablet and the capsule of repeat function, and enteric coated tablets, wherein is to hold layer coating by resistance to reach the purpose that regularly discharges.

Slow release send delivery system to comprise controlled release and prolongs two kinds of releases.In general, slow-released system comprises and can make drug slow discharge surpass any drug delivery system of certain time expand.When this system can keep in blood or the target tissue relatively constant levels of drugs, can think controlled release system.When this system can prolong action time and surpass conventional when sending the action time of delivery system, can think to prolong delivery system.

Site specific and receptor delivery system refer to medicine and directly aim at desirable biology of position.Under the situation that site specific discharges, target is specific organ or tissue.Similarly, under the situation that receptor discharges, target is the special receptor of medicine in certain organs or tissue.

The typical oral non-form of promptly releasing comprises diffusion system and dissolution system.For diffusion system, the rate of release of medicine depends on that it passes through the polymeric diffusion of water-insoluble.Two types diffusion is arranged usually, drug core is wrapped in wherein reservoir, and dissolving or dispersive medicine spread all over the substrate of whole inertia polymer substrate therein substantially equably by the polymer film.In actual applications, many systems that utilize diffusion also may depend on dissolution to a certain extent and decide rate of release.

The common practice that is used to form the reservoir system comprises, the drug particles dress made microcapsule and with whole tablet or granule pressed coated.Usually formed a system by the drug particles of microencapsulation coating, at this, medicine is packaged in the coated film, and is comprised in the core of microcapsule.Typical drug release comprises the cohesive process of dissolving and diffusion, and wherein dissolution is the process of sustained release speed.Hardened gelatin, methyl and ethyl cellulose, poly-hydroxyl methacrylate, hydroxypropyl cellulose, polyvinyl acetate and various wax are arranged as barrier coating membrane material independent or associating usually.

For matrix system, mainly contain 3 class materials and usually be used to prepare this matrix system, comprise insoluble plastics, hydrophilic polymer and fatty compound.Adopted plastic matrix comprises acrylic acid methyl ester .-methylmethacrylate, polrvinyl chloride and polyethylene.Hydrophilic polymer comprises methylcellulose, hydroxypropyl cellulose and sodium carboxymethyl cellulose.Fatty compound comprises various waxes such as Brazil wax, and glyceryl tristearate.Can prepare these matrix systems by means of method well known to those skilled in the art.These preparation methoies generally comprise mixes medicine with host material, then this mixture is pressed into tablet.When using wax material, generally be that medicine is dispersed in the wax of fusing, it is condensed, make granule and be pressed into core.When adopting other non-when being release system, a part of medicine can be utilized immediately as basal dose, remainder will discharge in the slow release mode.This generally is to realize by basal dose being placed in the coating on the tablet for matrix system.Can be coated with this coating by compression coating or by conventional disc type or the outstanding coating method (conventional pan or air suspension coating) of gas.

Dissolution system is the product of highly soluble medicine with low dissolution velocity normally.There is several method can reach the purpose that reduces dissolution velocity; comprise active component is made suitable salt or derivant; by giving the medicine coating with slow dissolved material; perhaps by medicine being mixed in the tablet with slow molten carrier; the dissolution system of microencapsulation can be coated with medicine microgranule or granule by the slow insoluble polymer may bag with all thickness, perhaps by the medicine microencapsulation is prepared.The most frequently used microencapsulation method is a cohesion, and it comprises a kind of hydroaropic substance is added in the colloidal state suspension.Can be selected from multiple natural and synthetic polymer as the hydroaropic substance of coating material, comprise Lac, wax, starch, cellulose acetate, phthalic acid ester or butyrate, polyvinylpyrrolidone, and polrvinyl chloride.After the coating material dissolving, the medicine in the microcapsule can dissolved immediately or absorption.Therefore, can be by the thickness of adjusting coating and the release that dissolution velocity is controlled medicine.For example, about 30% by the content of coating material is changed to from about 3% of gross weight, can make thickness from becoming 200 μ m less than 1 μ m.By adopting the coating of different-thickness, generally be 3 or 4 μ m, active component will be released with the time that different preliminary elections is determined, and the delay release action is provided.Certainly, tablet can directly be pressed into by the microgranule of coating, in perhaps incapsulating.

The stromatolysis system prepares by the gentle molten polymer support of medicine is pressed into tablet.Usually there are two kinds of methods can prepare the drug-polymer microgranule, coagulation and dispersion method.When adopting coagulation, be that medicine is mixed with polymer or wax material, be cooled then or cold sieve or spraying are condensed.When adopting water dispersion, be that medicine-polymer mixture is directly sprayed into or put into water, collect the microgranule that forms then.

Osmosis system also can utilize, and is as the driving force that impels drug release with osmotic pressure at this.This system generally is made up of the drug core of the semipermeable membrane parcel that contains 1 or several holes.This film allows water to diffuse into core, and still, the position that does not allow medicine to pass through except that hole discharges.Examples of material as semipermeable membrane comprises polyvinyl alcohol, polyurethane, cellulose acetate, ethyl cellulose, and polrvinyl chloride.

Another system comprises ion exchange resin.This resinoid is the water-insoluble cross linked polymer that salt-forming group is contained at the repetition position on polymer chain.By in chromatographic column, making medicine contact pressure resin or this active agents is incorporated into resin repeatedly by making resin and drug solution Long contact time.Ionic environment is depended in the release of medicine from medicine-resin complexes, just pH value in the gastrointestinal tract and electrolyte concentration, and drug release also depends on the characteristic of resin.By with gastrointestinal tract in the ion exchange of suitable electric charge, the drug molecule that is attached on the resin is discharged, can infiltrate thereupon absorb this from the resin free drug molecule.In general, diffusion velocity is by diffusion area, and the degree of diffusion path length and resin crosslinks is controlled.By to this medicine-resin complexes coating, rate of release is further changed.

The prevailing administration type that is used for the treatment of parenterai administration slow releasing pharmaceutical is intramuscular injection, to the implantation of subcutaneous tissue and various body cavitys, and the transdermal administration method.In general, intramuscular injection comprises that medicine and another kind of molecule form a kind of insoluble complex.On this meaning, this medicine-molecular complex is as a reservoir in the injection site, is used to make medicine to discharge towards periphery.Macromolecular example comprises biopolymer such as antibody and protein, the perhaps polymer of synthetic such as polyvinylpyrrolidone and Polyethylene Glycol.

Can also make between medicine and the micromolecule and form complex.When drug molecule was bigger than the stitching agent molecule, binding constant was bigger, and this complex is more stable.This example than micromolecule comprises the zinc molecule, can randomly be suspended in gelatin solution or the fluid.The another kind of dosage form that is used for intramuscular injection is an aqueous suspension.By changing its viscosity and particle size, can obtain stable active component suspension.The another kind of common method that reduces dissolution velocity is to reduce the saturation solubility of medicine.This can pass through to form the salt and the prodrug derivatives of less dissolubility, and realizes by the polymorphic crystal form of using this active component.

Another kind method is to use oil solution or oil suspension.Those skilled in the art will recognize, those medicines with suitable oily dissolubility and ideal Distribution characteristic are suitable for this method most.The example that can be used for the oil of intramuscular injection comprises Oleum sesami, olive oil, Oleum Arachidis hypogaeae semen, Semen Maydis oil, almond oil, Oleum Gossypii semen and Oleum Ricini.For oil suspension, drug microparticles must at first be dissolved in oil phase, distributes then to enter water-based.

Can also use emulsion to comprise the emulsion of oil-in-water emulsion or water-in-oil emulsion.

Implant contains the polymeric material that stops medicine, can implanted subcutaneous or various body cavity in.Certainly, employed polymeric material must be biocompatibility with nontoxic, typically can be from following selection: hydrogel, silane, polyethylene, ethylene vinyl acetate copolymer and biodegradable polymer.Hydrogel generally is a kind of swelliong power that has in water, and can keep having in its structure the polymeric material more than 20% water, but it can not be dissolved in water.Small molecular weight material can diffuse through hydrogel.Concrete hydrogel example comprises, polyhydroxy alkyl methacrylate, polyacrylamide and PMAm, polyvinylpyrrolidone, polyvinyl alcohol, and various compound polyelectrolyte.

The implantable system that replenishes comprises subcutaneous method for implantation and intravaginal method for implantation.

Transdermal drug absorbs, and more generally is called as transdermal system, generally comprises to use microporous membrane as the speed controlling barrier layer.Microporous membrane is the thin film with the different-thickness from a few μ m to a few dust pore diameter ranges.The example for preparing the raw material of this film comprises regenerated cellulose, celluloid/cellulose acetate, Triafol T, polypropylene, Merlon and politef.The barrier properties of these different films depends on preparation method, is full of the substrate of micropore, micro-pore diameter, void fraction percent, and hole tortuosity.

At United States Patent (USP) 4,201, a kind of embodiment of transdermal system is disclosed in 211.

The targeted delivery of drugs system comprises nanoparticles and liposome.Nanoparticles is the example that is called as the colloid drug delivery system jointly.Other member of this system comprises microcapsule, nanocapsule, macromolecular complex, polymer globules, microsphere and liposome.In general, nanoparticles is the microgranule that contains dispersion medicine of a kind of diameter 200-500nm.The material that is used to prepare nanoparticles is sterilizable, and is avirulent and biodegradable.Example comprises albumin, ethyl cellulose, casein and gelatin.Generally can prepare by the agglutination that is similar to the bag microcapsule.

Liposome generally is by phospholipid, and when being disperseed by aqueous medium, phospholipid expands, aquation, and form the multicell concentric bilayer vesicle of separating lipid bilayer with the aqueous medium layer.Phospholipid can also form the multiple structure except that liposome in being dispersed in water the time, depends on the mole ratio of lipid to water.When the ratio of hanging down, preferentially form liposome structure.The real physical characteristics of liposome depends on pH, the bivalent cation of ionic strength and existence.They demonstrate hypotonicity to ion and polar substances, but when raising during temperature, can take place to change mutually and change its permeability.Polar medicine is trapped in aqueous phase, and nonpolar medicine combines with the lipid bilayer of vesicle.When polar medicine breaks when lipid bilayer, or can discharge, but nonpolar medicine keeps combining with lipid bilayer, up to by temperature or be exposed to lipoprotein and lipid bilayer disintegrated just can be released by osmosis.Certainly, liposome has been the effect of carrier or activating agent.

Depend on medication, preparation of the present invention can be formulated into non-(being slow release) tablet of promptly releasing, capsule, the injection that parenteral uses, gel, suspension that orally uses or elixir, perhaps suppository.Preferably said composition is mixed with unit dosage form, each dosage contains the active component of appropriate amount, can provide 0.01-3.0mg to the patient, more generally is 0.05-2.0mg, active component.Noun " unit dosage form " refers to the physics unit independently that is suitable as people and other mammalian subject single dose, each unit contains the active substance of scheduled volume, this active matter quality can produce desired treatment or preventive effect as calculated, and it is relevant with administration once a day that requires or gradation administration, this active substance also with one or more medicament carriers that is fit to, diluent or excipient combination, thus slow releasing function provided to active component.For slow releasing preparation, this unit dosage form can contain the 0.01-5.0mg active component.The preferred preparation of the present invention is oral or implantable non-immediate release formulations, and this preparation has closed 0.01-3.0mg, or the 0.05-2.0mg active component, forms a unit dosage form jointly with the pharmaceutics acceptable carrier.Most preferably oral non-immediate release formulations.

Non-immediate release formulations of the present invention will provide the moxonidine of prevention or therapeutic dose to patient, so that can reach, keep the active component of effective dose then, and side effect be little.These preparations will realize that the space orientation of better moxonidine and time discharge particularly time release.Certainly, spatial relationships is to making medicament aim at specific organ or tissue, and the time discharges the speed that refers to control drug release.

Non-immediate release formulations of the present invention will provide following a kind or several advantage that is better than known immediate release formulations: 1) reduce to minimum or eliminate the compliance of patients problem; 2) use less active component total amount; 3) reduce to minimum or eliminate local side effects; 4) reduce to minimum or eliminate systemic side effects; 5) the active less height fluctuation of active component during life-time service; 6) the depot action minimum of active agents during life-time service; 7) improve therapeutic effect; 8) controlling symptoms more promptly; 9) reduce the fluctuation of levels of drugs, provide stronger control symptom; And 10) cost saving.

Certainly, compliance of patients is essential and important factor to the success of all automedication treatments.

Can expect that non-immediate release formulations of the present invention will provide more constant levels of drugs.For healthy people, reach maximum plasma concentration time (t _Max) geometrical mean should be about 2.5 hours-5.0 hours, preferably 2.5-4.0 hour, having plasma clearance half-life geometrical mean simultaneously approximately was 6.0 hours-16.0 hours, preferably 7.0-15.0 hour.Therefore, the non-unit dosage form of promptly releasing described herein will consider be used, once a day or secondary administration every day.

At least can buy moxonidine in Germany and Austria at present, be promptly to release the agent tablet as 0.2,0.3 and 0.4mg dosage of antihypertensive agents.What exemplify below is the complete preparation of the present 0.3mg tablet of selling.For the tablet of 0.2mg and 0.4mg, its lactose content of scalable makes it to hold more or less active component content.

Preparation-product description

Pink film-coated 105mg tablet contains the moxonidine 0.3mg as active component.

Active component [mg]

Moxonidine 0.30

Other composition

Lactose 95.700

Ketopyrrolidine 0.700

Crosslinked ketopyrrolidine 3.000

Magnesium stearate 0.300

Hydroxypropyl methylcellulose 2910 1.300

Water solublity ethyl cellulose 1.200

Polyethylene glycol 6000 0.250

Talcum 0.975

Red iron oxide 0.025

Titanium dioxide 1.250

The moxonidine preparation that existing market is sold provides rapidly, and the active component of release immediately has t _MaxGeometrical mean 0.5-3.0 hour, had plasma clearance half-life geometrical mean 2.0-3.5 hour.

For the present invention will be described more fully, will provide some to believe that to moxonidine be useful example of formulations below.These embodiment only are illustrative, do not plan scope of the present invention is limited.In following patent, disclose some and it is believed that the slow releasing preparation useful: United States Patent(USP) Nos. 4,140,755 the present invention; 4,218,433; 4,389,393; 4,839,177; 4,865,849,489; 4,892,742; 4,933,186 and 5,422,123.Wherein most preferred preparation be those in U.S. Patent No. 5,422, disclosed preparation in 123.

Clinical trial protocol and result

Obtained about pharmacokinetics and the pharmacodynamics data of moxonidine from congestive heart failure patients placebo.Systolic blood pressure (SSBP) change during with moxonidine group and placebo group patient peace and quiet and the change of plasma norepinephrine (PNE) concentration are used to estimate the effect of moxonidine, and predict suitable dosage regimen.Existing report shows, gives the moxonidine of maximum 0.6mg to the patient of essential hypertension (HTN), and 24 hours internal energy introduction blood pressures significantly reduce after the administration, do not have too high secondary hypotension incidence rate.After the single 0.25mg administration, patient's CHF pharmacokinetics and pharmacodynamics are with former (the Kirch et al.J.Clin.Pharmacol.30.1088-1095 (1990) that compares to essential hypertension people report

Testing program

The research design general introduction:

At randomization, double-blind method in the II clinical trial phase of placebo, gives moxonidine to the patient who suffers from functional New York heart association (NYHA) II-III degree CHF.Have only the patient who accepts consistent dose angiotensin converting enzyme ACE inhibitor, the patient who has perhaps stopped original ACE treatment is eligible.Patient also may accept Folium Digitalis Purpureae, and diuretic and other medicines are used for the treatment of CHF, as long as dosage is stable before beginning one's study.Research is by single blind screening phase in 2 weeks, and the phase is carried out in 4 all double-blind method administrations and 8 all double-blind methods phase of keeping is formed.

The patient who only meets following whole standards just can be included in this research:

[1] suffers from lasting clinically chronic medium severity NYHA II-III degree CHF's

Patient.

[2] year man or the woman of order between 21-79.

[3] left ventricular ejection fraction is the patient of 40% (2 times), preceding 1 of research beginning

Carried out radionuclide cardiovascular imaging inspection within month, quantitatively echo imaging inspection

Look into, or the angiocardiography inspection.[4] patient accepts, or has stopped the ACE inhibitor treatment to CHF in advance.Sick

The people may take Folium Digitalis Purpureae or diuretic, perhaps takes this two.Be used to control

Treat the Folium Digitalis Purpureae of CHF, the dosage of diuretic and other medicines in 2 weeks is at least

Stable.Owing to following any reason, patient will be excluded outside this research: myocardial infarction took place in [1] in nearest 90 days.[2] the significant constitutional valve of hematodinamics blocks or flow pass (for example, blocks

Mitral stenosis, aortic stenosis, unsymmetry barrier film hypertrophy, or action is lost

The repairing valve of transferring), diastolic function seriously descends, perhaps the congenital heart of complex

Disease of ZANG-organs.[3] activeness myocarditis.[4] incident of fainting took place, supposition may be life-threatening arrhythmia (Secondary cases

Arrhythmia comprises perishability ventricle tachycardia, is not the mark of getting rid of

Accurate).[5] in the near future, the probability of the cardiac operation done is arranged, comprise heart transplantation.[6] although treatment still has unstability chest angor when static (be defined as angor),

Perhaps serious persistence angor (show effect more than the secondary average every day).[7] systolic blood pressure 90mmHg (secondary was measured after reposing 10 minutes), or

The person has secondary hypotension.[8] begin that unsteered hypertension is arranged before adding is tested (3 180mmHg of systolic pressure,

3 105mmHg of diastolic pressure) measure after reposing 10 minutes.[9] severe pulmonary disease (FEV ₁/ FVC ₂Minor peaks 50, expectorant flow velocity＜200ml/ second,

Or FVC＜expection 60%), or pulmonary heart disease.[10] cerebrovascular disease (for example serious carotid artery stenosis), this disease is because blood pressure

Reducing may concurrent or performance instability.[11] (for example, the systemic red yabbi of the collagen angiopathy except that rheumatoid arthritis

Skin ulcer, polyarteritis tumor, scleroderma).[12] suspect that serious renal artery stenosis is arranged, perhaps seriously to reduce (be kreatinin to renal function

＞160μM/L)。

[13] malignant tumor, except the skin carcinoma of surgical healing, original position cancer, or diagnosis entity

The situation of 5 years releasing diseases after the tumor.

That [14] need make immunosuppressant therapy (is used for non-lethal disease such as joint with steroid

Not being excluded of scorching treatment).

[15] Yu Ding participant may can not adhere to test owing to following reason: in the chronic ethanol

Poison has no fixed address, or the medicine addiction is arranged.

[16] serious constitutional hepatic disease.

[17] because in fact other mortality disease or state cause predetermined participant's expection

Can not finish test.

[18] Huai Yun women or the conceived women of possibility by qualified method contraception.

[19] used beta blocker at nearest 3 months.

[20] in 1 month, used moxonidine.

[21] use other experimental drug simultaneously.

[22] participated in this test before.

Must all meet exclusion standard with visit Japan (at random) beginning to participate in test and the 3rd.

In addition, if also the 3rd patient who meets following standard in visit Japan (at random)

Be excluded outside test:

[23] between the 1st and the 3rd time is followed up a case by regular visits to the placebo medicine lacked wrongly and comply with

Property (less than the doctor's advice medicine 90%)

Sequentially each test dose group is studied.Six moxonidine dosage groups have been estimated altogether.The determining initial moxonidine level and reach second with the interval in 1 week of dosage group increases dosage.It is mode administration with once a day that medicine to be studied begins.

The order search time is arranged as follows;

The screening phase (single blind method, 2 weeks): appropriateness is identified and to the compliance of placebo medicine.

(double-blind method, 4 weeks) are carried out the phase in administration: to wait to study first dosed administration 1 of medicine

After week, giving second increases dosage.

Keep the phase (double-blind method, 8 weeks): 4 weeks did 2 times at interval and follow up a case by regular visits to, during this period Mosso

It is constant in maximum dose level that the Buddhist nun decides administration.

1 time-of-week is defined as 5-9 days.

Progress arrangement for each patient's search time is listed in the table 1.

Table 1

Each patient's search time arrangement

The search time variable screening administration phase of carrying out phase is kept expectation research medicine placebo placebo placebo

2 weeks of 1,2,33 persistent period of moxonidine moxonidine dosing step were followed up a case by regular visits to number of times 1,23 in 4 all 8 weeks ^a, 4 ^b, 5 ^b, 6 ^a7 ^c, 8 ^{A, c} ^aEvaluation in 8 hours day (research day) ^bEstimated in 4 hours day (an only I stage) ^cFollow up a case by regular visits to and to remove from for the 7th, 8 time in the I stage.

The the 3rd, the 6 and the 8th is evaluation in 8 hours day (be called as the the 1st, the 2 and the 3rd research day) with visiting Japan, and in this day, up to before the administration of internal medicine clinic, waits that dosage every day that grinds medicine is concealed earlier, and the tracked observation of patient is 8 hours after the administration.During this period of time, carry out physiology's observation, observe the side effect of bringing out, take blood sample to do clinical laboratory and measure, and detect wherein neuroendocrine medium and drug concentrations to be studied.The 4th and the 5th follow-up period between, patient accepts administration in the internal medicine clinic, and stays in the clinic after each administration and observed 4 hours.

During studying, begin sequentially 6 moxonidine dosage groups to be studied with the 1st dosage group.For each dosage group, specify 2 patients to accept active medicine to be studied randomly, 1 patient accepts placebo.Plan 3 patients weekly adds research.When the patient who accepts the 6th dosage group moxonidine or placebo randomly being finished (the administration phase of keeping finishes) when following up a case by regular visits to for the 8th time, research finishes, and after this patient dismisses.

Strengthen gradually from the size of the 1st dosage group to the 6 dosage group dosage.The dosage minimum that each dosage group begins gives 2 maximal dose process steps continuously, and intermediate phase is every 1 week.

Table 2

The moxonidine dosing step is according to dosage organized mg/ day,

2 0.1 0.2 0.2 0.3 0.3 0.4 last 3 0.1 0.2 0.3 0.4 0.6 0.6 order of administration see Table 3 in the middle of 123456 beginnings 1 0.1 0.1 0.1 0.1 0.2 0.2 of moxonidine dosage group dosing step.

Table 3

The dosage sequential dose week number grouping of moxonidine ^a01234567891 0.1mg 0.1mg 0.1mg ^b0.1mg ^c2 0.1mg 0.2mg 0.2mg ^b0.2mg ^c3 0.1mg 0.2mg 0.3mg ^b0.3mg ^c4 0.1mg 0.3mg 0.4mg ^b0.4mg ^c5 0.2mg 0.3mg 0.6mg ^b0.6mg ^c6 0.2mg 0.4mg 0.6mg ^b0.6mg ^c ^aSpecify 2 patients to accept active medicine to be studied at random for every group, 1 patient accepts placebo. ^bPatient accepts 2 weeks of maximal dose. ^cPatient continues to accept in other 8 weeks the maximal dose moxonidine of this dosage group.

The source of dosage and medication material

Moxonidine and placebo tablet are offered hospital pharmacy, be distributed to patient by enough follow up a case by regular visits to quantity at interval at every turn then, 0.1mg the moxodine tablet identical with the placebo tablet appearance, and by the proper proportion combination, so that guarantee required dosage (dosage that comprises secondary administration every day if desired), be easy to comply with, and keep not knowing.Noun in this scheme " dosage " refer to gave in one day wait to study the medicinal tablet total amount.Use the preparation of selling at present, as previously described the content adjustment of lactose is made it to adapt to and contain or do not contain active component.Screening:

Patient gives the 1st dosage placebo in the internal medicine clinic, and gives enough placebo medicines between the 1st time and the 2nd follow-up period, and be administered once every day.Medicine to be studied is administered once every day, in the morning single-dose (6).Administration is carried out and is kept:

After the 3rd time was followed up a case by regular visits to randomization, each patient gave 1 dosage moxonidine (0.1 or 0.2mg) or placebo between the 3rd follow-up period.The 3rd is Japan-China one day of 3 evaluations in 8 hours in this scheme implementation process with visit Japan (the 1st research day), this day medicine to be studied in the internal medicine clinic, patient carried out safety evaluation and laboratory inspection in tracked 8 hours.In addition, the 4th and the 5th with the also administration in the internal medicine clinic of visiting Japan, after the administration patient was observed 4 hours.The the 6th and the 8th also is evaluation in 8 hours day with visit Japan (the 2nd and the 3rd research day), at the daily dose of this day concealment administration in the internal medicine clinic, and, the tracked observation of patient reaches 8 hours then.Each 4 hours and 8 hours evaluation days, patient just gave the medicine of their every day when administration in the clinic.The 3rd with visiting Japan the 7th, provide once enough moxonidines of medication every day or placebo medicine to patient, up to follow up a case by regular visits to next time with the every day of visiting Japan.

Single dose (6) is taken once a day and is waited to study medicine and placebo in the morning, unless the secondary hypotension sign is arranged, otherwise prove that then the sub-service administration is reasonable, the result is the dose regimen of secondary every day.

The evaluation of pesticide effectiveness comprises following project:

The plasma concentration of neuroendocrine medium (norepinephrine, the atrial natriuretic peptide of N-end).

Life signal (crouch systolic blood pressure and diastolic blood pressure when quiet, and heartbeat rate).

The diuresis amount of formulation of doctor's advice reduces.

After 3 researchs day (the the 3rd, the 6 and the 8th with visiting Japan) are waited to study medicine about 0,0.5,1,1.5,2,4,6 and 8 hours, blood drawing was used to wait to study the drug plasma concentration analysis.With gas chromatography/mass spectrometry assay drug plasma concentration.Normally, get aliquot human plasma (1.0ml), add 25.0 μ l (10pg/ μ l internal work liquid) internal standard liquid (Clonidine.HCl).Under alkali condition, each sample extraction in ethyl acetate, is isolated organic layer, abandon plasma layer.Reuse 0.5MHCl strips to sample, and abandons organic layer.Then under alkali condition with sample extraction in dichloromethane, abandon aqueous layer, make organic layer dry under nitrogen current.With exsiccant sample residues with 3,5 pairs of (trifluoromethyl) Benzenecarbonyl chloride. derivatizations, evaporation dryings under nitrogen once more.Add 50 μ l acetonitriles and rebuild sample, and be transferred in the gas chromatogram sampling plastic bottle, to GC/MS system injection application of sample (1 μ l).Pharmacokinetics

Except as otherwise noted, " on average " refer to geometric average.First dose of 8 patients CHF (the 3rd with visiting Japan) are given to make plasma concentration-time graph behind the 0.1mg moxonidine, and evaluate.Absorb fast (average t _Max: 0.75 hour), it is slightly biphasic that plasma concentration descends.The clear rate in average oral corridor is 28.03L/ hour, and on average removing the half-life is 3.28 hours.

To (the average t of the former report of the absorptance of moxonidine to the hypertensive patient _Max: 1.07 hours) faster.Compare with the hypertensive patient (CL:43.58 L/ hour, t _1/2: 2.01 hours), patient's CHF the clear rate in oral corridor is lower and the half-life is longer.Clear rate in corridor and the difference of half-life may be because the difference (69 years old patient's CHF mean age, 49 years old patient's HTN mean age) of age and renal function between two colonies.With respect to patient HTN who gives similar dosage, Absorption and long half-life can produce higher C to CHF crowd faster to moxonidine _MaxYet,, estimate that even with 2 times method every day, the depot action of moxonidine is very little to behind patient's CHF repetitively administered according to the 3rd deduction of moxonidine plasma concentration when visiting Japan.During expectation secondary administration every day, peak value is 20: 1 to the ratio of valley.

Data in the past proves, patient HTN, has the time warping between medicine peak serum concentration (1 hour) and the maximum effect (4-6 hour).And action time is than a lot of according to the length of plasma half-life prediction.The observation of two aspects shows that all medicine in the blood plasma and CNS action site carry out balance lentamente.

Pharmacodynamics

Follow up a case by regular visits to the change of resting state systolic blood pressure (SSBP) the 3rd time in the 1st stage from baseline (T=0) to 2 hours:

Table 4

The systolic blood pressure of resting state

The percentage rate that the absolute magnitude that patient's number changes changes

Placebo

101????????????-10??????????????-8.3

107????????????-10??????????????-10

201???????25????21.7

205???????10?????7.7

301???????20????15.4

303????????5?????5.0

Meansigma methods 6.7 5.2

Moxonidine 0.1mg

102???????10???????7.7

103??????-60??????-42.8

104???????10???????7.7

105??????-10??????-10

202???????0????????0

203???????0????????0

206??????-10??????-6.9

302??????-15??????-12

307??????-5???????-4.3

Meansigma methods-8.9-6.7

Table 4 is presented at absolute magnitude and the percentage rate that the 1st research day (the 6th with visiting Japan) resting state systolic blood pressure changes from the predose baseline.Have 6 patients to accept placebo, 9 patients accept the 0.1mg moxonidine.Peak action appearred after administration in 2 hours.Observe SSBP trend of rising (average 6.7mmHg) in placebo group.This variation may be owing to the effect of the ACE inhibitor of coming the clinic to take morning has before been disappeared.Compare with placebo, moxonidine has caused SSBP decline, and mean difference is-15.6mmHg (11.9%).

Be consistent with previous data to hypertension (HTN) patient, observe also that the blood pressure peak value descends and the moxonidine plasma peak concentration between time warping.But (5 hours) of being compared patient HTN patient's CHF the time that reaches peak action (3 hours) are short.And patient's CHF blood pressure drops persistent period is shorter.Take medicine and returned to the preceding SSBP that takes medicine in back 8 hours.After short acting duration indication repeat administration every day or 2 administrations every day, depot action is very little.The change of norepinephrine in the blood plasma (PNE):

Table 5 shows that respectively organize patient takes medicine after (0.1mg), absolute value and percentage rate that plasma norepinephrine concentration baseline to 2 before take medicine hour changes.These data are that the clinical experiment program with standard obtains.

Table 5

The I stage the 3rd with visiting Japan, from baseline time (t=0)

The change of 2 hours norepinephrine to the administration

Norepinephrine

Patient's number changes absolute magnitude and changes percentage rate

Placebo

101?????????????40??????????????6.7

107????????????144?????????????40.9

201?????????????48?????????????23.5

205????????????104?????????????15.1

301?????????????40?????????????10.6

303???????????-124????????????-16.8

Meansigma methods 42.0 13.3 moxonidine 0.1mg

102????????????-62?????????????-27.7

103????????????-168????????????-30.1

104????????????-142????????????-37.2

105????????????-360????????????-42.1

202????????????-92?????????????-17.1

203????????????-6??????????????-1.8

206????????????-50?????????????-15.2

302?????????????24??????????????6.9

307?????????????22??????????????9.6

Meansigma methods-92.7-17.2

The 3rd with the moxonidine 0.1mg administration of visiting Japan after 2 hours, caused the reduction of PNE meansigma methods maximum.After the administration 2 hours, reduce with respect to placebo PNE and to surpass 30%.Acting duration is shorter.After the administration 4 hours, the PNE of moxonidine group turned back to baseline values.Prove with the effect of the representative experimenter's that visits Japan moxonidine the 3rd and the 6th PNE, the 3rd with the patient that visits Japan to the not reaction of 0.1mg dosage.And with visiting Japan 0.3mg dosage is had strong reaction the 6th.But, raise with respect to baseline with the PNE before the administration of visiting Japan the 6th.Similarly situation is, accept among 8 patients of moxonidine 5 the 6th with the baseline PNE that visits Japan, raise with the baseline PNE that visits Japan with respect to the 3rd, and among 5 experimenters that accept placebo only 1 be like this.

(6 hours) that reach time (2 hours) the comparison patient HTN report that the maximum PNE of patient CHF reduces are shorter.The acting duration prompting that patient CHF is short, 2 administrations of moxonidine administration every day and every day can not suppress the interval that PNE surpasses 24 hours constantly.After accepting the 0.1mg moxonidine 2 times every day, representative experimenter's PNE time course, almost completely overlapping with the PNE time course of (the 3rd with visiting Japan) behind the first time 0.1mg dosed administration.

With the moxonidine promptly released to patient CHF administration every day 0.1-0.6mg or every day 2 0.1-0.2mg, do not cause that the sympathetic activity that surpasses dosage range continues to descend, but observe many experimenters big and of short duration decline was arranged after administration in 1-3 hour.It is desirable to, the low valley phase that this administering mode should be behind chronic administration produces significantly the inhibition to PNE, does not cause the blood pressure excessive descent action time on the peak.These targets may by the increase dosage (above 0.6mg/ days) of every day, and shorten dosing interval and realize with the immediate release formulations of present sale.But hour acting duration of the 4-8 behind the 0.1-0.6mg dosed administration shows, best dosing interval may be every day 4 times at least.But every day, 4 administrations may be unpractiaca, because compliance of patients is a problem, and may be still relevant to the ratio of low valley effect with the peak effect.For example, patient can cause benefiting from this active agents to the not compliance of multiple dosing mode, and may strengthen the ratio of peak effect to the effect of low valley.

Based on top described, and, as seen, reduce the effect ratio of peak simultaneously, require moxonidine by non-immediate release formulations administration to the valley in order to provide lasting sympathetic nerve to suppress in these other data of not enumerating.Because 1-3 hour observed sympathetic activity rapidly and of short duration reduction after the moxonidine administration, may cause secondary hypotension, so also may improve the side effect state of moxonidine by non-immediate release formulations.

The following examples will the invention will be further described.

The composition of embodiment 1 prescription

		The mg/ sheet
		The mg/ sheet	Interior powder	Moxonidine	????0.535
	HPMC2910,3mPas	????0.565	Interior powder	Moxonidine	????0.535
	HPMC2910,3mPas	????0.565		Calcium phosphate	????27.80
	Lactose	????27.80		Calcium phosphate	????27.80
	Lactose	????27.80	Outer powder	HPMC2208	????42.90
	Magnesium stearate	????0.40	Outer powder	HPMC2208	????42.90
	Magnesium stearate	????0.40	Coating	Do not have
Gross mass		???100.00	Coating	Do not have

Reactive compound delay to discharge the principle that is based on hydrocolloid substrate.This substrate is by hydroxypropyl emthylcellulose, and HPMC2208 (15000mPas is in the time of 2%, 20 ℃) forms.The mixture of lactose and calcium phosphate is as carrier.

By changing the release of the proportion control reactive compound between these three kinds of compositions.

The batch quantity analysis test shows that this prescription is extremely sensitive to the change that mixes number of times.Increasing the mixing number of times has the lubricant of causing skewness, causes the not enough tendency of tablet hardness.

Embodiment 1

Preparation steps

Powder in planetary-type mixer, mixing;

The system granule;

50 ℃ of dried overnight in the basin;

With vibration grain machine, sieve aperture-1mm, preparation dry powder;

Add outer powder, roll and mixed 30 minutes;

Tabletting.

Embodiment 1 batch quantity analysis

Parameter
Parameter		-in batches	1000g
The quality uniformity (minimum-maximum; Meansigma methods)	97.0-103.0mg meansigma methods=100.0mg	-in batches	1000g
The quality uniformity (minimum-maximum; Meansigma methods)	97.0-103.0mg meansigma methods=100.0mg	Measure evenness	Meansigma methods=0.5173mg
Hardness	67-76N	Measure evenness	Meansigma methods=0.5173mg
Hardness	67-76N	Dissolving: (in vitro tests) (Ph.Eur.2 ^ndEd.V.5.4, agitator indication is digital 1,900ml water is at 37 ℃, rotating speed 100rpm)	2 hours: 36.2% 4 hours: 62.9% 8 hours: 96.9%

Embodiment 2

Eye disk is arranged	The mg/ sheet
Eye disk is arranged	The mg/ sheet	Interior powder	Moxonidine	??0.535
HPMC2910,3mPas	??0.550	Interior powder	Moxonidine	??0.535
HPMC2910,3mPas	??0.550		Calcium phosphate	??27.800
Lactose	??27.615		Calcium phosphate	??27.800
Lactose	??27.615		HPMC2208	??4.900
Ethanol	??15.000		HPMC2208	??4.900
Ethanol	??15.000		Water	??3.000
Dichloromethane	??15.000		Water	??3.000
Dichloromethane	??15.000	Outer powder	HPMC2208	??38.000
Magnesium stearate	??0.600	Outer powder	HPMC2208	??38.000
Magnesium stearate	??0.600	Coating	Macrogol 2000 0	??0.454
HPMC2910,3mPas	??0.906	Coating	Macrogol 2000 0	??0.454
HPMC2910,3mPas	??0.906		Pulvis Talci	??0.280
Titanium dioxide	??0.120		Pulvis Talci	??0.280
Titanium dioxide	??0.120		Azorubine E122	??0.240

The interior powder of coating	Moxonidine	?0.100
The interior powder of coating	Moxonidine	?0.100		Lactose	?177.900
	Ketopyrrolidine	?1.400		Lactose	?177.900
	Ketopyrrolidine	?1.400		Ethanol	?16.000
	Water	?3.200		Ethanol	?16.000
	Water	?3.200		Dichloromethane	?16.000
The outer powder of coating	Corn starch	?10.000		Dichloromethane	?16.000
The outer powder of coating	Corn starch	?10.000		Crosslinked ketopyrrolidine	?10.000
	Magnesium stearate	?0.600		Crosslinked ketopyrrolidine	?10.000
	Magnesium stearate	?0.600	Outer coatings	Macrogol 2000 0	?1.34
	?HPMC2910,3mPas	?3.14	Outer coatings	Macrogol 2000 0	?1.34
	?HPMC2910,3mPas	?3.14	Gross mass		?304.00

Eye disk (0.635mg) is arranged

Because there is the therapeutical effect (data is unlisted) that delays in embodiment 1, decision combines slow releasing preparation with initial dose.Prove (unlisted) if any data, compare that 1 hour visible significant blood pressure reduces after administration with the immediate-release tablet formulations of moxonidine standard at this.

" eye disk being arranged " is a kind of tablet of special pressed coated: the garden forming core heart (diameter 6mm) compacting of biconvex is entered section " U " shape, and in the round coating of 9mm diameter, core is not wrapped up fully.

Coating contains the initial dose (0.1mg) of immediate release dosage form.It can be in 30-95 disintegrate in second, because high-load disintegrate reinforcing agent (crosslinked ketopyrrolidine 5%, corn starch 5%) is arranged.

The part (0.535mg) of slow release is housed in the core.The needed HPMC2208 of a small amount of slow release (maximum 5%) is mixed in the outer powder as carrier, can promote granule to absorb the liquid of q.s.

Make moistureproof coating to tablet at last.

Embodiment 2

The preparation steps moxonidine has eye disk

Powder in the blender in planetary-type mixer;

The system granule;

Coil interior 50 ℃ of dried overnight;

Vibration granulator with sieve aperture 0.75mm prepares dry powder;

Add outer powder, roll and mix 30 minutes (HPMC20 minute+magnesium stearate 10 minutes

Clock)

Tabletting;

Be coated with core by means of spray pistol (0.8mm nozzle) with 15% suspension bag;

Powder in planetary-type mixer, mixing;

The system granule;

Coil interior 50 ℃ of dried overnight;

Vibration granulator with sieve aperture 0.75mm prepares dry powder;

Add outer powder, roll and mixed 30 minutes;

Tabletting;

Be coated with core by means of spray pistol (0.8mm nozzle) with 10% suspension bag.

Embodiment 2

Batch quantity analysis

Parameter	Moxonidine-have eye disk
Parameter	Moxonidine-have eye disk	Batch size	5000g
The quality uniformity (minimum-maximum; Meansigma methods)	293.2-309.2mg meansigma methods=303.8mg	Batch size	5000g
The quality uniformity (minimum-maximum; Meansigma methods)	293.2-309.2mg meansigma methods=303.8mg	Measure meansigma methods	Meansigma methods=0.6236mg
Hardness	36-48N	Measure meansigma methods	Meansigma methods=0.6236mg
Hardness	36-48N	Disintegration time	30-95 second (coating)
Dissolving: (in vitro tests) (Ph.Eur.2 ^ndEd V.5.4, agitator, indication is digital 1,900ml water, at 37 ℃, rotating speed 100rpm)	2 hours: 52.6% 4 hours: 73.0% 8 hours: 96.4%	Disintegration time	30-95 second (coating)

With being substantially similar to the program described in the following embodiment 3-6, preparation and coating are as at the described preparation from embodiment 3-1 to 3-5 of embodiment 3-6.

Embodiment 3-1

Moxonidine	????0.5％
Moxonidine	????0.5％	Ketopyrrolidine	????-
Calcium phosphate	????37.7％	Ketopyrrolidine	????-
Calcium phosphate	????37.7％	Lactose	????37.7％
????HPMC2208	????23.5％	Lactose	????37.7％
????HPMC2208	????23.5％	Magnesium stearate	????0.6％

Embodiment 3-2

Moxonidine	????0.5％
Moxonidine	????0.5％	Ketopyrrolidine	????0.5％
Calcium phosphate	????37.7％	Ketopyrrolidine	????0.5％
Calcium phosphate	????37.7％	Lactose	????37.7％
????HPMC2208	????18％	Lactose	????37.7％
????HPMC2208	????18％	Magnesium stearate	????0.6％

Embodiment 3-3

Moxonidine	????0.5％
Moxonidine	????0.5％	Ketopyrrolidine	????0.5％
Calcium phosphate	????86.4％	Ketopyrrolidine	????0.5％
Calcium phosphate	????86.4％	Lactose	??????-
????HPMC2208	????12％	Lactose	??????-
????HPMC2208	????12％	Magnesium stearate	????0.6％

Embodiment 3-4

Moxonidine	????0.5％
Moxonidine	????0.5％	Ketopyrrolidine	????0.5％
Calcium phosphate	????91.4％	Ketopyrrolidine	????0.5％
Calcium phosphate	????91.4％	Lactose	?????-
????HPMC2208	????7.0％	Lactose	?????-
????HPMC2208	????7.0％	Magnesium stearate	????0.6％

Embodiment 3-5

Moxonidine	????0.5％
Moxonidine	????0.5％	Ketopyrrolidine	????0.5％
Calcium phosphate	????88.4％	Ketopyrrolidine	????0.5％
Calcium phosphate	????88.4％	Lactose	??????-
????HPMC2208	????10.0％	Lactose	??????-
????HPMC2208	????10.0％	Magnesium stearate	????0.6％

Embodiment 3-6

Interior powder	Moxonidine	Mg/ sheet 0.5
Interior powder	Moxonidine	Mg/ sheet 0.5	Ketopyrrolidine	??????0.625
	Calcium phosphate	??????110.625	Ketopyrrolidine	??????0.625
	Calcium phosphate	??????110.625
Outer powder	????HPMC2208	??????12.500
Outer powder	????HPMC2208	??????12.500	Magnesium stearate	??????0.750
Coating	Polyethylene glycol 6000	??????0.25	Magnesium stearate	??????0.750
Coating	Polyethylene glycol 6000	??????0.25	????HPMC2910,6mPas	??????1.30
	Pulvis Talci	??????1.00	????HPMC2910,6mPas	??????1.30
	Pulvis Talci	??????1.00	Titanium dioxide	??????1.225
	Yellow iron oxide	??????0.025	Titanium dioxide	??????1.225
	Yellow iron oxide	??????0.025	30% ethyl cellulose aqueous suspensions	??????1.200
Gross mass		??????130.00	30% ethyl cellulose aqueous suspensions	??????1.200

Powder in embodiment 3 preparation steps are mixed in planetary-type mixer; The system granule; Coil interior 50 ℃ of dried overnight; Vibration granulator with sieve aperture-1mm prepares dry powder; Add outer powder, roll and mixed 30 minutes; Tabletting; With 12.5% suspension core being made the aqueous bag by means of spray pistol (0.8mm nozzle) is coated with.

Embodiment 3-6

Batch quantity analysis

Parameter
Parameter		Batch size	2000g
The quality uniformity (minimum-maximum; Meansigma methods)	128.9-132.3mg meansigma methods-130.2mg	Batch size	2000g
The quality uniformity (minimum-maximum; Meansigma methods)	128.9-132.3mg meansigma methods-130.2mg	Measurement range, meansigma methods	(0.429-0.539mg minimum-maximum) meansigma methods=0.513mg
Hardness	77-80N	Measurement range, meansigma methods	(0.429-0.539mg minimum-maximum) meansigma methods=0.513mg
Hardness	77-80N
Dissolving: (in vitro tests) (Ph.Eur.2 ^ndEd.V.5.4, agitator, indication number 1,900mL water, at 37 ℃, rotating speed 100rpm)	2 hours: 66.0% 4 hours: 85.7% 8 hours: 108.9%

In the clinical research limited, the preparation of embodiment 1,2 and 3-6 has been carried out estimating (data does not list) to the hypertensive patient.

	Embodiment A relatively:	The mg/ sheet
	Embodiment A relatively:	The mg/ sheet	0.25mg moxonidine is promptly released agent
	Interior powder	1% moxonidine grinds in lactose in ketopyrrolidine in lactose (superfine)	0.25mg moxonidine is promptly released agent		????20.0 ?????0.7 ????96.0
Outer powder	Interior powder		Crosslinked ketopyrrolidine magnesium stearate	?????3.0 ?????0.3	????20.0 ?????0.7 ????96.0
Outer powder	Coating	Polyethylene glycol 6000 HPMC2910,3mPas Pulvis Talci titanium dioxide red iron oxide 30% ethyl cellulose aqueous suspensions	Crosslinked ketopyrrolidine magnesium stearate	?????3.0 ?????0.3	????0.25 ????1.30 ??0.9975 ????1.25 ??0.0025 ????1.20
Gross mass	Coating			??125.00	????0.25 ????1.30 ??0.9975 ????1.25 ??0.0025 ????1.20

In with 8 researchs that the hypertensive patient was done, preparation and the 0.25mg immediate-release tablet formulations (Comparative Example A An) of embodiment 1 compared.Measure plasma drug level with known GC/MS method.

During with the preparation of embodiment 1, reached maximal plasma concentration after the administration in 2-3 hour.Compare with embodiment A, (2.25 ± 1ng) improve 60% to need higher dosage to cause the plasma concentration maximum.These dynamics datas are consistent with the blood pressure reduction.Embodiment 1 preparation is compared with the embodiment A preparation, and the maximum of systolic blood pressure and diastolic blood pressure descends high by 50%, occurs in after the administration 5-6 hour.For two kinds of moxonidine preparations, be defined as diastolic blood pressure during this period and descend and do not have action time more than or equal to 10mmHg marked difference.Xerostomia is also identical with tired degree.Two kinds of preparations all there is good tolerability.

In the clinical research that the volunteer with 4 health carries out,, " eye disk is arranged " of embodiment 2 compared with 0.25mg immediate-release tablet formulations (Comparative Example A An) with regard to its dynamic behavior.Measure blood plasma Chinese medicine concentration with known GC/MS method.Referring to for example Kirch etc., J.Clin.Pharmacol.30,1088-1095 (1990), Trenk etc., J.Clin.Pharmacol.27,988-993 (1987) and Kirch etc., Clinical Pharmacokinetics, 15,245-253 (1988).

Compare with the embodiment A tablet, " eye disk is arranged " excited the persistent period of 2.5 times blood plasma level above 1ng/ml, and maximum plasma concentration almost remains unchanged.The time started of effect is not subjected to the influence of initial dose basically.

Data difference is big because patient's number is few, so think that the time parameter evaluation that blood pressure is reduced is unsuitable.

The research of carrying out with 2 volunteers only relates to the kinetics data of embodiment 3-6 preparation, is reported as follows together with the limited clinical dynamics data that obtains above.

The moxonidine preparation	T-max [hour]	?????c-max ????[ng/ml]	?????AUC ??[h ^*ng/ml]	Relative bioavaliability ^*
The moxonidine preparation	T-max [hour]	?????c-max ????[ng/ml]	?????AUC ??[h ^*ng/ml]	Relative bioavaliability ^*	Embodiment A (0.25mg)	????1	????1.35	????7.42	Do not obtain
Embodiment 1	????4	????2.25	????18.49	109％	Embodiment A (0.25mg)	????1	????1.35	????7.42	Do not obtain
Embodiment 1	????4	????2.25	????18.49	109％	Embodiment 2	????1	????1.48	????10.30	72％
Embodiment 3-6	????1	????1.22	????7.41	Do not obtain	Embodiment 2	????1	????1.48	????10.30	72％

^*Bioavaliability can be by the theoretical AUC value of the same dosage of basis of calculation dosage form relatively

Determine.AUC value=100% of immediate release formulations.

Basically according to United States Patent (USP) 5,422, the program described in 123 has prepared embodiment 4 (4-1 and 4-2), 5 and 6 tri-layer tablets, and this patent all is introduced into reference at this.

Embodiment 4-1

The spherical set compound

Component

The mg/ sheet

1% moxonidine in lactose	????30．0
1% moxonidine in lactose	????30．0	Glyceryl Behenate (Compritol 888 ATO)	????31.9
Lactose powder H ₂O	????78.13	Glyceryl Behenate (Compritol 888 ATO)	????31.9
Lactose powder H ₂O	????78.13	Magnesium stearate	????3.0
Hydroxypropyl emthylcellulose (MethocelE50)	????38.25	Magnesium stearate	????3.0
Hydroxypropyl emthylcellulose (MethocelE50)	????38.25	Hydroxypropyl emthylcellulose (Methocel K4M)	????39.88
Hydroxypropyl emthylcellulose (Methocel K100M)	????60.O	Hydroxypropyl emthylcellulose (Methocel K4M)	????39.88
Hydroxypropyl emthylcellulose (Methocel K100M)	????60.O	Polyvinylpyrrolidone (Plasdone K29-32)	????13.5
Silica sol (Syloid 244)	????2.0	Polyvinylpyrrolidone (Plasdone K29-32)	????13.5
Silica sol (Syloid 244)	????2.0	Yellow iron oxide	????0.35

Tablet total weight amount: 297.01 diameters (mm): 8 thickness (mm): 62

Embodiment 4-2

Spherical set compound component mg/ sheet

1% moxonidine in lactose	????30．0
1% moxonidine in lactose	????30．0	Glyceryl Behenate (Compritol 888 ATO)	????20.0
Lactose powder H ₂O	????56.5	Glyceryl Behenate (Compritol 888 ATO)	????20.0
Lactose powder H ₂O	????56.5	Magnesium stearate	????3.0
Hydroxypropyl emthylcellulose (Methocel E50)		Magnesium stearate	????3.0
Hydroxypropyl emthylcellulose (Methocel E50)		Hydroxypropyl emthylcellulose (Methocel K4M)
Hydroxypropyl emthylcellulose (Methocel K100M)	????170.0	Hydroxypropyl emthylcellulose (Methocel K4M)
Hydroxypropyl emthylcellulose (Methocel K100M)	????170.0	Polyvinylpyrrolidone (Plasdone K29-32)	????15.0
Silica sol (Syloid 244)	????2．0	Polyvinylpyrrolidone (Plasdone K29-32)	????15.0
Silica sol (Syloid 244)	????2．0	Yellow iron oxide	????0.5

Tablet total weight amount: 297.0 diameters (mm): 8 thickness (mm): 6.2

Embodiment 5

Spherical set compound component mg/ sheet

	????0.1mg
	????0.1mg	1% moxonidine in lactose	????10.0
Glyceryl Behenate (Compritol888ATO)	????27.0	1% moxonidine in lactose	????10.0
Glyceryl Behenate (Compritol888ATO)	????27.0	Lactose powder H ₂O	????99.76
Magnesium stearate	????3.0	Lactose powder H ₂O	????99.76
Magnesium stearate	????3.0	Hydroxypropyl emthylcellulose (Methocel E50)	????-
Hydroxypropyl emthylcellulose (Methocel K4M)	????79.76	Hydroxypropyl emthylcellulose (Methocel E50)	????-
Hydroxypropyl emthylcellulose (Methocel K4M)	????79.76	Hydroxypropyl emthylcellulose (Methocel K100M)	????60.0
Polyvinylpyrrolidone (Plasdone K29-32)	????15.0	Hydroxypropyl emthylcellulose (Methocel K100M)	????60.0
Polyvinylpyrrolidone (Plasdone K29-32)	????15.0	Silica sol (Syloid244)	????2.0
Yellow iron oxide	????0.5	Silica sol (Syloid244)	????2.0

Tablet total weight amount: 297.02 diameters (mm): 8 thickness (mm): 6.2

Embodiment 6

Spherical set compound component mg/ sheet (theoretical weight)

	????0.3?mg
	????0.3?mg	1% moxonidine in lactose	????30.0
Glyceryl Behenate (Compritol888 ATO)	????27.0	1% moxonidine in lactose	????30.0
Glyceryl Behenate (Compritol888 ATO)	????27.0	Lactose powder H ₂O	????79.76
Magnesium stearate	????3.0	Lactose powder H ₂O	????79.76
Magnesium stearate	????3.0	Hydroxypropyl emthylcellulose (Methocel E50)	????-
Hydroxypropyl emthylcellulose (Methocel K4M)	????79.76	Hydroxypropyl emthylcellulose (Methocel E50)	????-
Hydroxypropyl emthylcellulose (Methocel K4M)	????79.76	Hydroxypropyl emthylcellulose (Methocel K100M)	????60.0
Polyvinylpyrrolidone (Plasdone K29-32)	????15.0	Hydroxypropyl emthylcellulose (Methocel K100M)	????60.0
Polyvinylpyrrolidone (Plasdone K29-32)	????15.0	Silica sol (Syloid244)	????2.0
Yellow iron oxide	????0.5	Silica sol (Syloid244)	????2.0

Tablet total weight amount: 297.02 diameters (mm): 8 thickness (mm): 6.2

Embodiment 6

The barrier layer mixture

The mg/ sheet	Raw material
The mg/ sheet	Raw material	????39.88	Hydroxypropyl emthylcellulose (Methocel K4M Premium ^)
????39.88	The lactose powder, water	????39.88	Hydroxypropyl emthylcellulose (Methocel K4M Premium ^)
????39.88	The lactose powder, water	????13.50	Mountain Yu acid glyceride (Compritol888ATO ^)
????5.00	Polyvinylpyrrolidone (Plasdone K29-32 ^)	????13.50	Mountain Yu acid glyceride (Compritol888ATO ^)
????5.00	Polyvinylpyrrolidone (Plasdone K29-32 ^)	????0.25	Yellow iron oxide
????1.00	Magnesium stearate	????0.25	Yellow iron oxide
????1.00	Magnesium stearate	????0.50	Silica sol (Aerosil200 ^)
????100.00		????0.50	Silica sol (Aerosil200 ^)

Embodiment 6

Active mixture

The mg/ sheet	Raw material
The mg/ sheet	Raw material	30.00	1% moxonidine in lactose
60.00	Hydroxypropyl emthylcellulose (Methocel K100M Premium ^)	30.00	1% moxonidine in lactose
60.00	Hydroxypropyl emthylcellulose (Methocel K100M Premium ^)	5.00	Polyvinylpyrrolidone (Plasdone K29-32 ^)
1.00	Magnesium stearate	5.00	Polyvinylpyrrolidone (Plasdone K29-32 ^)
1.00	Magnesium stearate	1.00	Silica sol (Aerosil200 ^)
97.00		1.00	Silica sol (Aerosil200 ^)

Drug release in vitro tests (Ph.Eur, 2nd Ed.V.5.4. agitator set 2,500ml water, 100rpm.37 ℃).

After 2 hours	23％
After 2 hours	23％	After 4 hours	39％
After 8 hours	65％	After 4 hours	39％
After 8 hours	65％	After 10 hours	77％
After 12 hours	86％	After 10 hours	77％
After 12 hours	86％	After 16 hours	96％

In limited clinical trial to embodiment 4-1,4-2,5 and 6 preparation is estimated.

The purpose of these researchs is that (1) provides bioavaliability behind the moxonidine preparation single-dose of four kinds of different sustained release relatively food is measured to wherein a kind of influence of preparation with 5 additional experimenters in data and (2).With these preparations,, contain promptly releasing of 0.2mg moxonidine with commercially available every and compare with reference to preparation (Comparative Examples B) with 3 administrations of 0.3mg tablet administration 3 times and 0.1mg 1 time.Material and method

Use the embodiment 4-1 of every 0.3mg moxonidine, 4-2 and 6 preparations and embodiment 5 preparations that contain the 0.1mg moxonidine.

This research is with voluntarily, and mode is at random carried out, and administration is 1 time after one night of fasting, and 7 days the EXPERIMENTAL DESIGN that washes out is formed during by 5 researchs.To comprise Comparative Examples B, embodiment 6, and 4 research cycles are carried out in 4 crossing designs (four-way Crossoverdesign) of embodiment 4-2 and embodiment 5 preparations, and in the 5th interval, identical experimenter accepts 1 administration of embodiment 4-1 preparation.Research colony is by 10 health, and the men and women experimenter who keeps a diet forms.The preparation of embodiment 6 is also tested in parallel group that is made up of other 5 experimenters, and these 5 experimenters took medicine after the meal in the higher fatty acid morning of edible U.S. food Drug Administration (FDA) standard.

During each research, the experimenter is with 1 oral administration of 240ml room temperature tap water.For quantitative, gathered 15 blood samples in the different time to moxonidine: for Embodiment B preparation relatively, the preceding and blood sampling in 12 hours after administration of administration, for preparation of the present invention, the preceding and blood sampling in 22 hours after administration of administration.With GC/MS method as described below, measure the plasma concentration of moxonidine with the quantitation limit (LOQ) of 0.025ng/ml.

Get aliquot human plasma (1.0ml), add 25.0 μ l (10pg/ μ l internal work liquid) internal standard liquid (clonidine hydrochloride).Under alkali condition, each sample base is got in the ethyl acetate, isolate organic layer, abandon plasma layer.Reuse 0.5MHCl strips to sample, abandons organic layer.Under alkali condition, the sample base is got in the dichloromethane then, abandoned aqueous layer, make organic layer dry under nitrogen current.With exsiccant sample residues with 3.5 pairs of (trifluoromethyl) Benzenecarbonyl chloride. derivatization treatment after, evaporation drying under nitrogen once more.Add 50 μ l acetonitriles and rebuild sample, and be transferred in the gas chromatogram sampler plastic bottle, to GC/MS system injection application of sample (1 μ l).

According to the actual content shown in the following Table 1, the experimental data of preparation is normalized to the 0.3mg moxonidine.It is 0.2mg that the actual content of supposing object of reference equals scalar quantity.

The demarcation of each preparation of table 1. and actual moxonidine content.

The actual content of preparation is the 94-109% that demarcates content.

Preparation	Demarcate content (mg)	Actual content (mg)
Preparation	Demarcate content (mg)	Actual content (mg)	Comparative Examples B	????0.200	0.200 supposition
Embodiment 4-1	????0.300	????0.287	Comparative Examples B	????0.200	0.200 supposition
Embodiment 4-1	????0.300	????0.287	Embodiment 6	????0.300	????0.282
Embodiment 4-2	????0.300	????0.327	Embodiment 6	????0.300	????0.282
Embodiment 4-2	????0.300	????0.327	Embodiment 5	????0.300	????0.300

Obtain the maximal plasma concentration (C of each preparation from the DS of content calibration _Max).The applicable line trapezoidal rule, calculating reaches the plasma drug level of last quantitative concentrations to the area (AUC under the time graph _{0-t is last}).By logarithm-straight line being transformed concentration the latter end of time graph is done the rectilinear regression processing, can calculate apparent removing speed constant (λ), and the AUC that can be used for extrapolating is to infinitely great (AUC _0-∝).The stationary state time T _50%CmaxBeing equivalent to during this period, plasma concentration is higher than C _Max50% interval.

According to the following expression upper limit (F _{(1) relatively}) and lower limit (F _{(2) relatively}) dual mode, can calculate each preparation of the present invention to the relative bioavaliability of preparation B relatively.

1. relative (the 1)=AUC of F _{0-∝ executes example}/ AUC _{0-∝ Comparative Examples B}

2. F _{(2) relatively}=[AUC _{0-t final time embodiment}+ (C _{Final time embodiment}/ λ _{The Comparative Examples B preparation})]/AUC _{0-∝ Comparative Examples B}At this because dose difference, wherein AUC _{0-∝ Comparative Examples B}Be normalized to 0.3mg.

Use the ANOVA (pairwise ANOVA) of antithesis, transform C according to logarithm _MaxAnd AUC _{The 0-t final time}Be worth, can calculate the point estimate and the 90% confidence level scope of average ratio between each preparation of the present invention.When 90% confidence level scope of this logarithmetics data rate drops between the 0.8-1.25, the preparation that can conclude embodiment 6 and 5 is a bioequivalence.Result and discussion:

Made the curve of the individual plasma concentration of the experimenter who compares preparation and preparation of the present invention the time.An experimenter (with the administration of embodiment 4-2 preparation) is at 6 and 12 hours plasma concentration high numerical value that shows abnormality, and has pair PK parameter and meansigma methods that corresponding tremendous influence is arranged.These two concentration have been got rid of from data set with from PK analyzes.

The PK parameter is listed in the table 3 of table 2.In this research PK parameter (numerical value bracket in) of observed Comparative Examples B is similar to and reports in the document (1): C _Max± 0.32 1.29 (2.14 ± 0.4) ng/ml, t _Max0.74 ± 0.35 (intermediate value 0.5) hour, AUC _{The 0-t final time}± 1.9 4.1 (5.8 ± 0.2) ngh/ml, and t _1/22.12 ± 0.58 (2.06 ± 0.10) hour.All preparations of the present invention all show than immediate release formulations (C _Max3.2 ± 0.4ng/ml is through the dosage standardization) much lower C _MaxValue, and the longer persistent period of blood plasma level is arranged, in vitro tests, discharge consistent more lentamente with them.Compare with immediate release formulations, all preparations of the present invention all have extraordinary relative bioavaliability.

But the intraindividual variability of seeing in this research of moxonidine experimenter generally is that AUC compares C _MaxLittle.The half experimenter demonstrates C _MaxRelatively large variability is arranged.For AUC, only 1 experimenter shows the variability higher than other experimenters.

Because embodiment 6 preparations to fasting state and to the feed state test, be in different experimenters, to carry out, so this PK parameter can not directly compare.But it seems that them be in identical scope, and the AUC value of the state of just taking food is slightly lower.

It is eclipsed that the pharmaceutical concentration-time curve of the preparation of the preparation of embodiment 6 (0.3mg) and embodiment 5 (0.1mg gives 3) shows, and shows the two bioequivalence.

Table 2: the PK parameter catalog that fasting is handled." meansigma methods " is to C _Max, AUC

And F _RelativelyRefer to geometric mean, to t _MaxAnd t50%c _MaxRefer to intermediate value.Sample

Product number: 10

Parameter (unit)	Treatment agent	Meansigma methods	Aberration rate	Minima	Maximum
Parameter (unit)	Treatment agent	Meansigma methods	Aberration rate	Minima	Maximum	C _max(ng/ml)	Embodiment B embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????2.14 ????0.69 ????0.57 ????0.54 ????0.54	???40 ???24 ???21 ???20 ???14	??0.96 ??0.44 ??0.42 ??0.38 ??0.46	??3.46 ??0.95 ??0.81 ??0.83 ??0.72
t _max(h)	Embodiment B embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????0.50 ????3.50 ????3.50 ????3.00 ????3.00		??0.50 ??2.00 ??3.00 ??2.00 ??1.00	??2.00 ??6.00 ??4.00 ??4.00 ??6.00	C _max(ng/ml)		????2.14 ????0.69 ????0.57 ????0.54 ????0.54	???40 ???24 ???21 ???20 ???14	??0.96 ??0.44 ??0.42 ??0.38 ??0.46	??3.46 ??0.95 ??0.81 ??0.83 ??0.72
t _max(h)		????0.50 ????3.50 ????3.50 ????3.00 ????3.00		??0.50 ??2.00 ??3.00 ??2.00 ??1.00	??2.00 ??6.00 ??4.00 ??4.00 ??6.00	AUC _{The 0-t final time}(ng/mloh)	Embodiment B embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????5.81 ????7.50 ????6.78 ????6.02 ????6.48	???19 ???18 ???20 ???14 ???11	??4.51 ??5.70 ??5.29 ??4.90 ??5.40	??8.01 ??10.2 ??9.73 ??7.45 ??7.46
AUC _0-∝(ng/mloh)	Embodiment B embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????8.91 ????9.03 ????8.25 ????8.49 ????8.62	???18 ???21 ???24 ???28 ???20	??4.60 ??7.13 ??5.83 ??5.52 ??6.92	??8.10 ??14.2 ??12.4 ??12.5 ??12.7	AUC _{The 0-t final time}(ng/mloh)		????5.81 ????7.50 ????6.78 ????6.02 ????6.48	???19 ???18 ???20 ???14 ???11	??4.51 ??5.70 ??5.29 ??4.90 ??5.40	??8.01 ??10.2 ??9.73 ??7.45 ??7.46

t _50％Cmax(h)	Embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????9.0 ????12.0 ????7.0 ????10.5		????5.0 ????6.0 ????3.0 ????5.0	????11.0 ????15.5 ????15.5 ????15.0
t _50％Cmax(h)	Embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????9.0 ????12.0 ????7.0 ????10.5		????5.0 ????6.0 ????3.0 ????5.0	????11.0 ????15.5 ????15.5 ????15.0	F _{(1) relatively}	Embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????101 ????93 ????95 ????97	????11 ????17 ????31 ????12	????81 ????68 ????63 ????75	????117 ????123 ????169 ????118
F _{(2) relatively}	Embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????89 ????80 ????73 ????77	????12 ????14 ????18 ????12	????70 ????66 ????57 ????63	????110 ????102 ????99 ????89	F _{(1) relatively}	Embodiment 4-1 embodiment 6 embodiment 4-2 embodiment 5	????101 ????93 ????95 ????97	????11 ????17 ????31 ????12	????81 ????68 ????63 ????75	????117 ????123 ????169 ????118

Table 3: the PK parameter catalog that feed is handled." meansigma methods " is to C _MaxRefer to geometric mean with AUC, to t _MaxRefer to intermediate value.Sample number: 5

Parameter (unit)	Treatment agent	Meansigma methods	Aberration rate (%)	Minima	Maximum
Parameter (unit)	Treatment agent	Meansigma methods	Aberration rate (%)	Minima	Maximum	C _max(ng/ml)	Embodiment 6	?0.61	????24	??0.48	??0.86
t _max(h)	Embodiment 6	?4.00		??2.00	??6.00	C _max(ng/ml)	Embodiment 6	?0.61	????24	??0.48	??0.86
t _max(h)	Embodiment 6	?4.00		??2.00	??6.00	AUC _{The o-t final time}(ng/mloh)	Embodiment 6	?5.77	????22	??4.27	??7.77
?AUC _0-∞(ng/mloh)	Embodiment 6	?6.63	????17	??5.45	??7.9	AUC _{The o-t final time}(ng/mloh)	Embodiment 6	?5.77	????22	??4.27	??7.77

With commercially available all 4 moxonidine preparations of the present invention of promptly releasing with reference to the preparation contrast test, all demonstrate the distribution curve of the drug level of plateau after 1 administration to the time.All preparations of the present invention have also been realized C _MaxThe reducing of variability between the experimenter, and extraordinary relative bioavaliability.And all preparations of the present invention are only observed considerably less side effect.

Give between 3 the preparation of embodiment 5 difference of not seeing significance,statistical at embodiment 6 preparations that contain the 0.3mg moxonidine and every 0.1mg.The preparation of embodiment 4-1 is compared with the preparation of embodiment 4-2 and 6, and the former has higher plasma concentration and absorbs faster, thereby causes that higher relative bioavaliability is arranged.

Claims

1. a method for the treatment of congestive heart failure comprises the non-immediate release formulations that the mammal of this treatment of needs is given the oral of effective dose moxonidine or its pharmaceutics acceptable salt or implantation.

2. the process of claim 1 wherein that described preparation is to contain the moxonidine of about 0.01mg-3.0mg or the unit dosage form of its pharmaceutics acceptable salt.

3. the method for claim 2, non-immediate release formulations wherein is a peroral dosage form.

4. the method for claim 3, peroral dosage form wherein is a kind of delay delivery system or slow-released system.

5. the method for claim 4, peroral dosage form wherein is a kind of slow-released system.

6. the method for claim 5, wherein said slow-released system are a kind of controlled release system or time-delay delivery system.

7. the method for claim 3, wherein said peroral dosage form is a kind of diffusion system or dissolution system, or the combining form of the two.

8. the method for claim 7, peroral dosage form wherein is a kind of diffusion system.

9. the method for claim 8, wherein said diffusion system is a kind of reservoir system or matrix system.

10. oral or an implant pharmaceutical preparation comprises effective dose moxonidine or the acceptable salt of its pharmaceutics, combines with one or more carriers, diluent or excipient, so that the non-moxonidine of promptly releasing is provided.

11. the preparation of claim 10, wherein said non-immediate release formulations is a peroral dosage form.

12. the preparation of claim 11, wherein said preparation is the moxonidine or the acceptable salt of its pharmaceutics of about 0.01mg-3.0mg unit dose.

13. the preparation of claim 12, peroral dosage form wherein are a kind of delay delivery system or slow-released system.

14. the preparation of claim 13, peroral dosage form wherein are a kind of slow-released systems.

15. the preparation of claim 14, slow-released system wherein are a kind of controlled release system or time-delay delivery system.

16. the preparation of claim 12, peroral dosage form wherein are a kind of diffusion system or dissolution system, or the combining form of the two.

17. the preparation of claim 16, peroral dosage form wherein are a kind of diffusion systems.

18. the preparation of claim 17, diffusion system wherein are a kind of reservoir system or matrix system.

19. the preparation of claim 18, diffusion system wherein are a kind of matrix systems.

20. the preparation of claim 19 comprises 0-40% lactose by weight, 0-85% calcium phosphate; The 9-65% hydroxypropyl emthylcellulose; With 0.05-2.0% moxonidine or the acceptable salt of its pharmaceutics, and randomly contain one or more diluent, excipient, and carrier, condition be exist at least in lactose and the calcium phosphate a kind of.

21. the preparation of claim 20, peroral dosage form wherein are a kind of tablets, it comprises the core that is placed in the barrier excipient, wherein

A) described core comprises by core weight:

The 9-40% lactose;

0-40% calcium phosphate;

The 9-65% hydroxypropyl emthylcellulose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate and

0.05-2.0% moxonidine, or the acceptable salt of its pharmaceutics, and

Randomly contain one or more diluent, excipient, and carrier,

B) described barrier excipient contains by barrier excipient weight:

The 30-50% hydroxypropyl emthylcellulose;

The 30-50% lactose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0-0.1% moxonidine; And

Randomly contain one or more diluent, excipient, and carrier, wherein said barrier excipient partly is wrapped in the surface of described core.

22. an oral non-immediate release formulations contains moxonidine or the acceptable salt of its pharmaceutics, combines with one or more diluent, excipient and carrier, makes it to have average 6-16 hour plasma clearance half-life.

23. the preparation of claim 22, it is 7-15 hour that wherein said average blood plasma is removed the half-life.

24. an oral non-immediate release formulations contains moxonidine or the acceptable salt of its pharmaceutics, with one or more diluent, excipient and carrier combine, and make it to have 2.5-5 hour the average time that reaches maximum plasma concentration.

25. the preparation of claim 24, be 2.5-4.0 hour the wherein said average time that reaches maximum plasma concentration.

26. method for the treatment of congestive heart failure, comprise mammal to this treatment of needs, give effective dose moxonidine or the acceptable salt of its pharmaceutics,, provide 6-16 hour average blood plasma to remove the half-life with a kind of oral non-preparation administration of promptly releasing.

27. the method for claim 26, it is 7-15 hour that wherein said average blood plasma is removed the half-life.

28. the hypertensive method of treatment comprises the mammal to this treatment of needs, gives effective dose moxonidine or the acceptable salt of its pharmaceutics, with a kind of oral non-preparation administration of promptly releasing, provides 6-16 hour average blood plasma to remove the half-life.

29. the method for claim 28, it is 7-15 hour that wherein said average blood plasma is removed the half-life.

30. method for the treatment of congestive heart failure, comprise mammal to this treatment of needs, give effective dose moxonidine or the acceptable salt of its pharmaceutics,, provide 2.5-5 hour the average time that reaches maximum plasma concentration with a kind of oral non-preparation administration of promptly releasing.

31. the method for claim 30, be 2.5-4.0 hour the wherein said average time that reaches maximum plasma concentration.

32. hypertensive method of treatment, comprise mammal to this treatment of needs, give effective dose moxonidine or the acceptable salt of its pharmaceutics,, provide 2.5-5 hour the average time that reaches maximum plasma concentration with a kind of oral non-preparation administration of promptly releasing.

33. the method for claim 32, be 2.5-4.0 hour the wherein said average time that reaches maximum plasma concentration.

34.4-chloro-5-(imidazoline-2-base (amino))-6-methoxyl group-2-methylpyrimidine, or its pharmaceutics acceptable salt preparation a kind of oral non-be purposes in the release thing.

35. the purposes of claim 34, wherein said medicine is to be used for the treatment of congestive heart failure.

36. oral or an implant pharmaceutical preparation comprises effective dose moxonidine or the acceptable salt of its pharmaceutics, combines with one or more carriers, diluent or excipient, so that the non-moxonidine of promptly releasing is provided.

37. the preparation of claim 36, wherein said non-immediate release formulations is a peroral dosage form.

38. the preparation of claim 37, wherein said preparation are the unit dosage forms that contains about 0.01-2.0mg moxonidine or its pharmaceutics acceptable salt.

39. the preparation of claim 38, peroral dosage form wherein are a kind of delay delivery system or slow-released system.

40. the preparation of claim 39, wherein said slow-released system are a kind of controlled release system or time-delay delivery system.

41. the preparation of claim 38, peroral dosage form wherein are a kind of diffusion system or dissolution system, or the combining form of the two.

42. the preparation of claim 41, wherein said diffusion system are a kind of reservoir system or matrix system.

43. the preparation of claim 42 contains 0-40% lactose by weight; 0-85% calcium phosphate; The 9-65% hydroxypropyl emthylcellulose; With the 0.05-2.0% moxonidine, and randomly contain one or more diluent, excipient, and carrier, condition is at least a existence of lactose and calcium phosphate.

44. the preparation of claim 43, peroral dosage form wherein are a kind of tablets, it contains the core that places in the barrier excipient, wherein

A) described core comprises by core weight:

The 9-40% lactose;

0-40% calcium phosphate;

The 9-65% hydroxypropyl emthylcellulose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0.05-2.0% moxonidine, and

Randomly contain one or more diluent, excipient, and carrier;

B) described barrier excipient contains by barrier excipient weight:

The 30-50% hydroxypropyl emthylcellulose;

The 30-50% lactose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0-0.1% moxonidine, and

Randomly contain one or more diluent, excipient, and carrier; Wherein said barrier excipient partly wraps up the surface of described core.

45. a pharmaceutical preparation that is suitable for treating congestive heart failure contains 4-chloro-5-(imidazoline-2-base (amino))-6-methoxyl group-2-methylpyrimidine as active component, or the acceptable salt of its pharmaceutics.

46. oral or an implant pharmaceutical preparation comprises effective dose moxonidine or the acceptable salt of its pharmaceutics, combines with one or more carriers, diluent or excipient, so that the non-moxonidine of promptly releasing is provided.

47. the preparation of claim 46, wherein said non-immediate release formulations is a peroral dosage form.

48. the preparation of claim 47, wherein said preparation is the unit dosage form of about 0.01mg-2.0mg moxonidine or its pharmaceutics acceptable salt.

49. the preparation of claim 48 contains 0-40% lactose by weight; 0-85% calcium phosphate; The 9-65% hydroxypropyl emthylcellulose; With the 0.05-1.5% moxonidine, and randomly contain one or more diluent, excipient, and carrier, condition is at least a existence of lactose and calcium phosphate.

50. the preparation of claim 49, peroral dosage form wherein are a kind of tablets, it contains the core that is placed in the barrier excipient, wherein

A) described core comprises by core weight:

The 9-40% lactose;

0-40% calcium phosphate;

The 9-65% hydroxypropyl emthylcellulose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0.05-2.0% moxonidine, and

Randomly contain one or more diluent, excipient, and carrier; With

B) described barrier excipient contains by barrier excipient weight:

The 30-50% hydroxypropyl emthylcellulose;

The 30-50% lactose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0-0.1% moxonidine, and

51. a method for the treatment of congestive heart failure comprises the oral non-immediate release formulations that ill patient is given 4-chloro-5-(imidazoline-2-base (amino))-6-methoxyl group-2-methylpyrimidine or its pharmaceutics acceptable salt.

52. oral or an implant pharmaceutical preparation comprises effective dose moxonidine or the acceptable salt of its pharmaceutics, with one or more carriers, diluent or excipient combination are so that provide the non-moxonidine of promptly releasing.

53. the preparation of claim 52, wherein said non-immediate release formulations is a peroral dosage form.

54. the preparation of claim 53, wherein said preparation are the unit dosage forms that contains about 0.01mg-3.0mg moxonidine or pharmaceutics acceptable salt.

55. the preparation of claim 54, peroral dosage form wherein are a kind of delay delivery system or slow-released system.

56. the preparation of claim 55, peroral dosage form wherein are a kind of slow-released systems.

57. the preparation of claim 56, peroral dosage form wherein are a kind of diffusion system or dissolution system, or the combining form of the two.

58. the preparation of claim 57, wherein said diffusion system are a kind of reservoir system or matrix system.

59. the preparation of claim 58 contains 0-40% lactose by weight; 0-85% calcium phosphate; The 9-65% hydroxypropyl emthylcellulose; With the 0.05-2.0% moxonidine, and randomly contain one or more diluent, excipient, and carrier, condition is at least a existence of lactose and calcium phosphate.

60. the preparation of claim 59, peroral dosage form wherein are a kind of tablets, it contains the core that is placed in the barrier excipient, wherein

A) described core comprises by core weight:

The 9-40% lactose;

0-40% calcium phosphate;

The 9-65% hydroxypropyl emthylcellulose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0.05-2.0% moxonidine, and

Randomly contain one or more diluent, excipient, and carrier;

B) described barrier excipient contains by barrier excipient weight:

The 30-50% hydroxypropyl emthylcellulose;

The 30-50% lactose;

The 2-8% polyvinylpyrrolidone;

The 0.1-2% magnesium stearate; With

The 0-0.1% moxonidine, and

Randomly contain one or more diluent, excipient, and carrier; Wherein this barrier excipient partly wraps up the surface of described core.