CN100584333C - Pharmaceutical composition of liver disease - Google Patents

Abstract

The invention provides a composition and method for treatment of a subject suffering from liver disease comprising the oral administration of a slow release formulation of calcium channel blocker such as diltiazem and thiamine which is also an antioxidant which is relatively hydrophilic when compared with the calcium channel blocker.

Description

The pharmaceutical composition of treatment hepatopathy

Invention field

The present invention relates to the supportive Therapeutic Method of hepatopathy and complication thereof, described complication comprises liver cirrhosis and portal hypertension.Specifically, the present invention is used for non-pernicious hepatopathy, comprises viral hepatitis or toxic hepatitis, wherein, except that the damage that the protopathy process causes, the direct or indirect damage trigger cell swelling again to liver plasma membrane, anoxia and a series of incidents of liver function damage that the protopathy that continues process takes place.

Background of invention

Hepatopathy comprises toxic hepatitis, as alcoholic hepatitis and liver cirrhosis, modal viral hepatitis hepatitis C and comparatively rare be the immunity hepatopathy of feature with the chronic inflammatory disease.

Improving the treatment of liver function and make great efforts always to carry out after the treatment of protopathy process, is the effort that target is improved liver function but many different ingredients with pathological process have been arranged.A kind of key method that adopts is to use antioxidant, and this starts from herb extract silymarin and silibinin (referring to Flora etc., 1998).Yet, the effect of silymarin disappointing (Angulo etc., 2000) in alcoholic liver disease, and it may cause hepatotoxic effect (Bass; 1999).Tocopherol, dipyridamole (Novikov etc., 1991 have been used recently; Vargas etc., 2001) and the modern antioxidant (Vaidya etc., 1996) of many synthetic or natural generations.

Comprising calcium blockers verapamil, diltiazem and amlodipine (Mason etc., 1999), also comprise nitrendipine (Thurman and colleague, 1998).At first, it is believed that these medicaments directly act on hepatocyte and enter with blocking-up calcium, act on excitable tissues (Liang and Thurman, 1992) such as myocardium and tremulous pulse just as them, do not have the medicine target-valtage-gated calcium channel in the excitable tissue yet people readily recognize that liver.Therefore, if these drug effects in liver, they need play a role with different approach.Therefore find that many calcium blockerses also are effective anti-oxidants (Heo etc., 1997).

The expansible Hepatic artery of calcium channel blocker is transported to liver with increase oxygenated blood (McLean, 1998) was once proposed.Yet, verapamil, diltiazem (Liang and Thurman, 1992; Romero and colleague, 1994) and the protective effect of medicine such as other calcium blockers occur in the isolated cell.The calcium blockers that gives with low dose oral also confirms the effect of hepatic artery blood flow.Shown that diltiazem is to liver blood capillary blood flow invalid (Marteau and colleague, 1988).

The thiamine concentration that hepatitis absorbs in impaired so its blood of the ability of thiamine is difficult to measure usually.Therefore mitochondrial energy produces and is badly damaged in the ill liver cell.

Here the discussion to background of invention is in order to explain content of the present invention.Do not think to admit that all data mentioned of priority date in any claim are disclosed, known or the part of general knowledge.

Summary of the invention

We have found that the effect of calcium channel blocker (especially diltiazem) and the effect interaction of vitamin B thiamine can effectively improve hepatopathy, calcium channel blocker wherein is to mitochondrion performance calcium blocking effect, having the antioxidant effect and be lipophilic relatively, is hydrophilic relatively antioxidant and compare calcium channel blocker vitamin B thiamine.Although thiamine is invalid usually for diseased cells, we think that the calcium channel blocker that has these characteristics simultaneously helps thiamine to play a role, the protection cell membrane, and continue produce power when cell is sustained damage.

According to the present invention, we provide a kind of treatment to suffer from the method for the object of hepatopathy, this method comprises and giving: (i) have the oral slow-releasing preparation of the lipophilic relatively calcium channel blocker of antioxidant effect, and (ii) compare the hydrophilic relatively vitamin B thiamine that is all antioxidant of calcium channel blocker.

The present invention (i) also is provided thus the lipophilic relatively calcium channel blocker with antioxidant effect with (ii) compare the hydrophilic relatively vitamin B thiamine that is all antioxidant of calcium channel blocker gives to be used for the treatment of hepatopathy simultaneously by the compositions that is used for the slow release calcium channel blocker at one or more in preparation medicine in application.

The present invention also provides and has been used for the treatment of or the pharmaceutical composition of prevention of liver disease, and it comprises lipophilic relatively calcium channel blocker that (i) have an antioxidant effect and (ii) compares the hydrophilic relatively vitamin B thiamine that is all antioxidant of calcium channel blocker.Described pharmaceutical composition is slow releasing composition normally.

Because many medicines that are fit to this treatments are vasoactive or have systemic effect (can avoid if medicine preferentially concentrates in the liver), therefore need liver selectivity slow releasing preparation.The calcium channel blocker delivery rate that the low dosage slow releasing preparation preferably provides will be enough in portal vein, provide clinical effectively but be lower than the blood levels that clinical effect level desired level is provided in peripheral circulation, thereby the delivery rate that liver is had the selectivity effect is provided.

Thiamine can give separately or give simultaneously, but preferred and calcium channel blocker gives in same composition.

Thiamine is known as vitamin B, as mitochondrion protecting agent, promptly as the cofactor of pyruvic dehydrogenase, also is a kind of hydrophilic antioxidant in mitochondrion.It is used to malnutrition patient and some Patients with Viral Hepatitis.Add in having the calcium antagonist of antioxidant properties that thiamine has also improved the facilitation that vitamin produces the mitochondrion self-energy and himself is in intracellular antioxidant effect.

Detailed Description Of The Invention

Method of the present invention comprises lipophilic relatively calcium channel blocker with antioxidant effect and compares the hydrophilic relatively antioxidant thiamine of calcium channel blocker.

The administration daily dose of preferred calcium channel blocker is lower than half (more preferably less than 1/3rd) of the prescribed dose of treatment cardiovascular disease.The prescribed dose of treatment cardiovascular disease is provided in the prescription drugs doctor handbook.The dosage (MIMS annual report Australian fascicle (Australian Edition of MIMS Annual 2002) in 2002) of the calcium channel blocker that comprises diltiazem that our especially preferred Australia approval is used.The optimal dose of the diltiazem of approval is the 180-240 mg/day.

Preferred calcium channel blocker is lipophilic to guarantee that they can infiltrate the cell depths and arrive in the cell membrane, and their therapeutic efficiency occurs in the place that free radical works like this.On the contrary, the medicine that plays a role in kytoplasm or cellular environment needs more hydrophilic.The most of calcium blocking agents that comprise verapamil, diltiazem, amlodipine and nitrendipine have film and stablize effect, stablize medicine but the short half-life of diltiazem and verapamil makes these medicines be suitable as the liver selective membrane more.Preferred medicament is the diltiazem that gives as slow releasing preparation, and its dosage is lower than 70mg/ days, preferably is lower than 50 mg/day.These dosage are far below being used for the treatment of angina and hypertensive drug dose.Diltiazem can be the form of hydrochlorate or other pharmaceutically acceptable salt.

Preferred calcium channel blocker will be membrane stabilizer (or combination medicament), and it is powerful to some key components of film destroy process.Preferred calcium channel blocker will work as antioxidant in the born of the same parents and in the film, and restriction calcium enters mitochondrion, and suppresses activity of phospholipase, and promote or the energy of keeping cell produces.In addition, these act on still continuation effect when preferably cellular pH descends between anaerobic phase.Integrate, we think that these effects can alleviate cellular swelling and anoxia, therefore can improve liver function.We find that diltiazem is particularly preferred based on these.

Diltiazem, suitable-(+)-3-(acetoxyl group)-5-[2-(dimethylamino) ethyl]-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepine Zhuo (benzothiazepin)-4 (5H)-ketone, being called " diltiazem " in the literary composition, is a kind of benzothiazine derivative with calcium antagonist activity.So far, diltiazem is used for blocking smooth muscle and the inflow of intramyocardial calcium ion by clinical, so has powerful cardiovascular effect.Shown that diltiazem can be used for relieve chronic cardiopathic symptom, especially angina pectoris, myocardial ischemia and hypertension, and shown low side effect sickness rate.In these were used, diltiazem was that the capsule form that 30,60,90 and 120 milligrams diltiazem agent form and intensity are 60,90,120,180,240 and 300 milligrams is used with intensity.Diltiazem can intensity be the injectable forms use of 5 mg/ml also.

The diltiazem therapy that is used for the treatment of cardiovascular disease starts from each 30 milligrams of every day 4 times.Dosage is elevated to the 180-240 mg/day gradually, reaches 360 mg/day sometimes, divide to give for three times or four times, and 1-2 days at interval, up to obtaining optimum response.The a large amount of metabolism diltiazems of liver.Use information according to the specialty that Marion Merrell Dow Inc. delivers, the diltiazem in the CARDIZEM.RTM. board tablet has 80% to be absorbed approximately, and experiences first pass effect widely, compares with intravenous administration, and its absolute bioavailability is about 40%.Single oral dose is that the CARDIZEM.RTM. diltiazem sheet of 30-120 milligram reached plasma peaks after administration 2-3 hour.Occurring detectable blood plasma level explanation CARDIZEM.RTM. diltiazem sheet after the administration in 30-60 minute is easy to absorb.The plasma clearance half-life after the single or multiple administration is about 3.5 hours.CARDIZEM.RTM. the treatment blood levels of diltiazem sheet appears as the 50-200 nanograms/milliliter.

Compare with the prior art preparation of calcium channel blocker, be considered to hinder the head that effectively treats the medicine (as diltiazem) of cardiovascular disease to cross removing and when the treatment hepatopathy, become advantage, because it can make the clinical efficacy of medicine be limited to liver.Therefore, preferred especially calcium channel blocker exists with low dosage with as slow releasing preparation, so that clinical effective blood levels is provided in portal vein, and is lower than the dosage that clinical effect level required dosage is provided in peripheral circulation.Therefore, method and composition of the present invention can provide the delivery rate that liver is had selection effect.

The method of protecting the liver of this employing diltiazem associating thiamine is applicable to any hepatic disease state of oxidized dose of cell membrane or oxidizing process constitutional or secondary injury.Adopt the liver selective preparation of these lipotropy membrane stabilizers to can be used as the means of supplementing out economy of the treatment of protopathy.

When suitable, these hepatoprotectives can or be prepared jointly with the common prescription of other the oral antiviral agents that is used for mainly treating treatment of diseases agent such as ribavirin or being used for the treatment of hepatitis C.

Therefore, the present invention provides also that a kind of at least a activating agent that is selected from portal hypertension medicine and antiviral agents is treated or the method for prevention of liver disease by giving, and wherein said at least a activating agent gives with lipotropy membrane stabilizer and antioxidant such as the diltiazem liver selective preparation with hydrophilic antioxidant such as thiamine.

Two kinds of films are stablized component, and promptly calcium channel blocker adds hydrophilic antioxidant thiamine and can prepare jointly or give with independent compositions.Medicament can identical approach gives (especially orally give) or gives with different approaches.For example, but a kind of activating agent intravenous or parenteral give, and calcium channel blocker (membrane stabilizer) but or other medicament orally give.

In method and composition of the present invention, thiamine can use example hydrochloric acid salt or other pharmaceutically acceptable derivates by salt form.

In particularly preferred embodiment of the present invention, at least a medicament that is selected from portal hypertension medicine and antiviral agents and calcium channel blocker and thiamine are prepared jointly.

Most preferred antiviral agents is a ribavirin, and it can (and preferred) be used in combination with interferon.Therefore, another embodiment of the invention provides a kind of method for the treatment of viral hepatitis, and this method comprises with ribavirin and preferably also has interferon to give the liver selective preparation of membrane stabilizer jointly.

Ribavirin and membrane stabilizer preferred oral give, and more preferably prepare with every kind of medicament of sustained release jointly.The preferred parenteral of interferon is given and give providing effect level during co-administered.

In another embodiment, the invention provides the method for a kind of treatment or prevention toxic hepatitis (for example alcoholic hepatitis), this method comprises the liver selective preparation that gives lipotropy calcium channel blocker and thiamine jointly.Particularly advantageously be that hydrophilic thiamine and calcium channel blocker component are prepared jointly.Therefore, in preferred embodiments, we provide a kind of compositions for the treatment of toxic hepatitis, comprise the liver selective preparation of calcium channel blocker such as diltiazem and relative hydrophilic medicament thiamine in the said composition.

Preferred calcium channel blocker is a diltiazem, and its dosage is the 20-70 mg/day, more preferably the 25-50 mg/day.

When using thiamine, preferably the amount with transmissibility 1-5 mg/day, better 1-3 mg/day exists.In indivedual cases, comprise acute treatment, can adopt the higher dosage that reaches 20 mg/day according to attending doctor's judgement.

When with the ribavirin therapy viral hepatitis, the dosage of conventional formulation can be up to 1200 mg/day, and the dosage of liver selective preparation is lower than 500 mg/day.

In the description and claim of this description, word " comprises " and the version of this speech is not got rid of other additive, component, integer or step as " comprising " and " containing " expression.

According to the present invention, we provide a kind of pharmacotherapy, comprise giving the liver that is formed by calcium channel blocker selective preparation, calcium channel blocker is a kind of lipophilic relatively antioxidant, and its consumption is enough to provide depression effect to suppress phospholipase simultaneously to the mitochondrial calcium passage.This lipotropy medicament can add or not add hydrophilic antioxidant prescription, with in the kytoplasm of cell or cellular environment and produce extra antioxidant effect in the cell membrane.Use vitamin thiamine can produce the supplementary cords plastochondria effect as the pyruvic dehydrogenase cofactor in mitochondrion, help energy to produce like this.(wherein cell membrane is by constitutional or the damage of Secondary cases process when liver is subjected to any type of chronic nonmalignant disease damage; cause swelling of liver cell to stop portal venous flow and cause the liver anoxia) time, can adopt this therapy to can be used to the liver protecting and keep liver function.

The combination that we have found that calcium channel blocker and thiamine can provide the film stabilizing effect.Term " film is stable " is promptly created many years ago, is used for defining local anesthesia effect and other film effect of Beta-3 adrenergic antagonist.This term comprises various film effects now, and this needs independent sign (Smith, 1982) again.

The disease that is suitable for Therapeutic Method of the present invention comprises that the lasting hepar damnification and the liver of viral hepatitis (comprising hepatitis C), alcoholic liver disease, liver cirrhosis, toxic hepatitis, autoimmune hepatitis, chemotherapy or the radiation period of form of ownership wear out.

The chronic hepatopathy pathology

The carrying out property decline of liver plasma membrane 26S Proteasome Structure and Function is the key reason of the chronic non-pernicious hepatopathy of nearly all form.The effect that it can damage liver function comprehensively, cause cell death and replenish or strengthen the protopathy process.

Film fails or goes to stablize and caused by at least 6 kinds of correlated processes, and one of them common feature is to produce free radical (superoxide anion, hydroxyl etc.) thereby and the Oxidation of their cell membrane phospholipid generation lysophosphatide.

At first, the protopathy process can produce free radical.In comprising the viral hepatitis of hepatitis C, free radical is not by virus but (Patrick, 1999 that the immune system that is activated by response viral infection in the health produces; Jain etc., 2002; Loguercio and Federico, 2003).

Immune system acts on the virulent tissue of growth, thereby the phospholipid oxidation of phospholipid especially hepatocyte adventitia is changed the 26S Proteasome Structure and Function that makes film, increases the permeability of film to water, sodium ion and calcium ion.This swelling of process inducing cell and calcium overload raise intracellular free calcium level and surpass physiological level.Similarly process also occurs in alcoholic liver disease, toxic hepatitis, autoimmune hepatitis, chemotherapy and the aging liver, makes the cell membrane oxidation, causes the cellular swelling and produces calcium overload.

Secondly, membrane permeability changes the swelling that causes and has increased blood flow by liver and the resistance by portal system.Liver tends to reduce blood flow especially when the cellular swelling takes place, and this is that the blood supply major part of liver is passed through portal system with low pressure, and is the venous blood of low oxygen content owing to compare other organ.Even if the slightest blood flow suppresses all can cause the liver anoxia, this is enough to make the damage of liver function to surpass the damage that the protopathy process causes.

The 3rd, carrying out property anoxia makes in the born of the same parents and Intramitochondrial NADPH ₂Level raises.This has stimulated free-radical generating again, and is different with the free radical that produces in the extracellular by immunity or poisonous effect, and the free radical of Chan Shenging is in cell and mitochondrion like this.Therefore, immunity or toxic reaction cause film impaired from outside to inside, and anoxia causes film from inside to outside impaired immediately.

The 4th, the calcium ion level raises and activates the interior ion gated calcium channel of mitochondrial membrane (black lipid membrane), and calcium preferentially is concentrated in the mitochondrion.This makes mitochondrial function from the preferential row's calcium of energy generation becoming.Consequently, the interior calcium concentration rising of mitochondrion has increased anoxybiotic effect and the NADPH that further raise between anaerobic phase ₂Level.

The 5th, calcium level raises and promotes NADPH in the mitochondrion ₂Produce free radical.Therefore, carrying out property film fails or goes stable speed to increase with mitochondrial calcium accumulation process.

The 6th, calcium level raises and has activated phospholipase in the mitochondrion, and it has caused secondary destruction to whole hepatocellular cell membrane again.

These six kinds of processes interact and cause the film oxidation of carrying out property and functional disorder, cellular swelling, anoxia, calcium accumulation, phospholipase activation, liver function damage, finally cause cell death.

For produce effect in the hepatocyte of the process damage that is subjected to anoxia or other oxidation cell membrane phospholipid, liver-protective film stabilizing effect need satisfy following standard:

This medicament should be as antioxidant to absorb or to destroy the high NADPH that takes place when anoxia and other oxidative damage form ₂The inductive free radical of level.

This medicament should be in forming the cell that free radical and free radical just producing damage and in the film protection of performance film and antioxidant effect.

This medicament works as antioxidant the mitochondrion planted agent.

This medicament should suppress the mitochondrial calcium passage to reduce the NADPH that takes place between anaerobic phase ₂Level raises.

This medicament should allow mitochondrion to continue to make ATP under the situation of cell calcium overload.

This medicament should prevent the phospholipase activation that calcium concentration raises and causes.

The blood supply that should prevent this medicament or reduce cellular swelling and cell membrane oxidation change cause reduces.

Some calcium blocking agents that comprise the D-diltiazem demonstrate all these characteristics, yet the protective effect of any this type of medicament and known calcium blockers are irrelevant to body circulation vasorelaxation action, and irrelevant with the variation of oxygenate arterial blood supply.

The specific calcium delivery passage (Spalletti-Cernia etc., 2002) that the response calcium channel blocker is arranged in the mitochondrial membrane (black lipid membrane).As if though these passages are ion gates rather than valtage-gated, their feature is identical with passage in the excitable tissue, and this can explain why they respond medicine such as verapamil, diltiazem and amlodipine.When the upborne cellular calcium concentration of mitochondrial calcium passage activated, the direct effect of this mitochondrial calcium carrier frequency channel break was that restriction calcium enters mitochondrion, thus the protection mitochondrial function.Restriction calcium enters the activity (Draper etc., 2004) that has reduced phospholipase, although this also may be a kind of direct effect of medicine to this kind of enzyme system.

As the film liver protectant, membrane stabilizer need be lipophilic relatively for effectively.The free radical target that is produced by protopathy process or anoxia is the phospholipid in the cell membrane.Conclude that thus antioxidant activity must that is to say in the hurtful film of free radical to operate in lipid bilayer.Similarly, the film protective agent must protect black lipid membrane (mitochondrial membrane) to suppress the ion gated calcium channel in these films.Yet we propose, and intracytoplasmic effect is provided when being provided by the hydrophilic antioxidant has increased total anti-oxidation protection.Though required pivotal role is to prevent the destruction of free radical in cell membrane (comprising mitochondrial membrane), during it also helps and the free radical in kytoplasm or the hydrophilic component.

Lipotropy also makes medicament have to be suitable as the required feature of liver selective preparation.It requires medicament to have the short liver metabolism half-life, and from descending by being easy to be absorbed by gastrointestinal tract wall after gastrointestinal capsule or the release of other preparation.The lipotropy medicament facilitates penetration of cell membrane and therefore satisfies these standards.Anyly select and antioxidant or other stabilizing agent with hydrophilic active needs gentle lipophilic to satisfy these requirements to half-life and gastrointestinal absorption with its water-wet behavior.Thiamine satisfies these requirements.

The second method of improving liver function is to give the vitamin B thiamine.Thiamine helps the mitochondrion produce power as the cofactor of cyclophorase-pyruvic dehydrogenase.Known alcohol hepatopathy patient may lack this kind of enzyme, also knows Patients with Viral Hepatitis may be benefited from its administration (Wallace and Weeks, 2001).The antioxidant properties (Lukienko etc., 2000) of thiamine has also been described in nearest research.Different with diltiazem, thiamine is a kind of hydrophilic relatively molecule.

It is key component of the present invention as the liver selective preparation that lipophilic and hydrophilic film are stablized medicine.

The requirement of sending of liver alternative medicine gives short medicine of half-life with low dosage and with slow release or controlled release preparation, so that medicine is in a few hours, slowly discharges in preferred 24 hours.Pass after the intestines and stomach wall, medicine arrives the less relatively portal system of volume and is brought into liver.In liver, most of medicine is removed from circulation through metabolism, and remaining medicine enters the much bigger systemic circulation of volume.So just obtained stable Concentraton gradient, wherein, the drug level in liver and the Portal circulation is higher more than 5 times than systemic circulation concentration.The gained Concentraton gradient may be higher in liver cirrhosis or the slow disease of other Portal circulation, yet, can compensate this effect by between Portal circulation and systemic circulation, setting up effective collateral vessel.

Under many treatment situations, need limit drug sending to target organ.This particular importance when medicine has the side effect relevant with other pharmacological properties.For simultaneously also being for the calcium channel blocker membrane stabilizer of (with effective vasodilation), its liver selects treatment to avoid or minimized unwanted vasodilation and heart effect, has therefore improved toleration and acceptability.The liver selectivity is sent the total daily dose that makes medicine simultaneously and is reduced to obtaining the systemic effect 20-25% of required total whole-body dose usually.

For diltiazem, be generally the 120-360 mg/day for obtaining the required dosage of systemic effect when being used for the treatment of angina pectoris and hypertension, and 50 milligrams of every days or diltiazem dosage still less will be kept the curative effect to liver, and will be then invalid to the health other parts.

Have these characteristics and comprise and or not can be used for protecting liver in the following situation with the membrane stabilizer of the diltiazem that carries out the liver selectivity and send with the common preparation of thiamine:

Viral hepatitis comprises the hepatitis of B-mode, third type or other form

Alcoholic hepatitis

Liver cirrhosis

Portal hypertension

The non-pernicious hepatopathy of other form that causes by toxin, medicine and abnormal immune state

Hepatic insufficiency in the chemotherapy

Hepatic insufficiency after the radiotherapy

Liver is aging

In viral hepatitis, the immediate cause of damage liver plasma membrane is the immunity of organism (Loguercio and Federico, 2003) of the existing virus of response.This causes producing the cell membrane (Jain etc., 2002) of free radical and damaging cells surface and cell interior.Hence one can see that, is essential antiviral therapy although use to add or do not add the interferon of ribavirin (or relevant molecule), also need protection or reverse that immunologic process causes to hepatocellular damage.Therefore, the liver selective membrane stabilizing agent that has antioxidant and mitochondrion effect simultaneously is replenishing of main treatment.In addition, can't bear costliness for those and kill the virus for the people of treatment, maybe can alleviate or the relevant molecule of controlling symptoms is treated and become the selection that can afford with liver selective membrane stabilizing agent such as diltiazem.Therefore the liver selective membrane stabilizing agent that adds or do not add thiamine can be used as the monotherapy prescription, can write out a prescription with interferon and ribavirin or with other suitable antiviral therapy, perhaps can write out a prescription, give together thereby these two kinds of medicines or all medicines can be used as the liver selective preparation with other oral administration composition of ribavirin or antiviral therapy.

Thiamine (vitamin B1) treatment has been used for the treatment of alcoholic liver disease, and this is can occur the vitamin shortage usually owing to suffer from the patient of this disease.Thiamine works as the coenzyme of the reaction of some fracture carbon-carbon bonds, and these reactions comprise the crucial metabolic process (Wilson, 1998) in the liver mitochondrion.Except improving malnutrition, can also improve the drug-induced mitochondrial injury of hepatitis B or hepatitis C patient (Kontorinis and Dieterich, 2003) with the thiamine treatment.Other staff show that the liver cirrhosis patient that is caused by alcoholic liver disease and hepatitis C thiamin deficiency can occur usually, but the hepatitis C patient who liver cirrhosis do not occur then can (Levy and colleague thereof, 2002).Yet thiamine has shown the liver function (Wallace and Weeks, 2001) that can improve hepatitis B patient.These research worker are also pointed out, and vitamin may have protective effect to the mitochondrial function of Patients with Viral Hepatitis.The crucial composition of other of thiamine protective effect is its anti-oxidation characteristics, because its hydrophilic feature, this specific character shows activity in kytoplasm.

Evidence shows that as mitochondrion protecting agent, thiamine (vitamin) is treated Patients with Viral Hepatitis (Wallace AE and Weeks WB, 2001), and the liver cirrhosis patient that especially hepatitis C is caused (Levy etc., 2002) is helpful.Common prescription of liver selective membrane stabilizing agent and thiamine or common preparation may be helpful to these patients.We think that especially the makeup energy facilitation of thiamine and antioxidation thereof and membrane stabilizer provide an important advantage together.

In alcoholic hepatitis, have three kinds of pathological effects at least in running.At first, ethanol itself has caused that wherein film is by the oxidation reaction of radical damage.Water enters cell with ion by present permeable film and causes cellular swelling and relative anoxia.In addition, the common malnutrition of chronic alcoholic liver patient, thiamin deficiency can damage mitochondrial effect.For these patients, best Therapeutic Method is to give up ethanol to give suitable nutrient simultaneously, comprises giving thiamine, and has antioxidation and the inhibiting liver selective membrane of mitochondrial calcium stabilizing agent simultaneously as the additional use of main treatment.This medicament can be used as the monotherapy prescription, can write out a prescription with thiamine, perhaps can prepare jointly with thiamine, thereby these two kinds of medicaments can give together as the liver selective preparation.

In portal hypertension and liver cirrhosis patient, immediate treatment is the rectification of basic pathogenic hepatopathy, be the reduction of blood flow to pylic vascular resistance then, perhaps the portal venous flow that carries out with Propranolol or other non-selective beta-adrenergic antagonist can reduce.Therefore, having the inhibiting liver selective membrane of antioxidation and mitochondrial calcium stabilizing agent simultaneously is replenishing of this main treatment.This medicament can be used as the monotherapy prescription, perhaps writes out a prescription with Propranolol.

In the hepatopathy of other form of the hepar damnification in comprising toxic hepatitis, autoallergic and systemic chemotherapy process, the attack that reaches extracellular oxidant and radical pair hepatocyte cell membrane in the cell is the main pathomechanism of disease.This causes the cellular swelling again, induces anoxia and produce free radical for the second time in whole cell and mitochondrion.Radiotherapy also can produce free radical.Although this may be the key mechanism of target on cancer organ when must or have a mind to shine liver, the normal physiologic of portal vein low-pressure injection makes this organ be easy to anoxia and deterioration especially.Therefore, have the inhibiting liver selective membrane of antioxidation and mitochondrial calcium stabilizing agent simultaneously and be drug withdrawal or stop to replenish of toxin, treatment immunological diseases, systemic chemotherapy treatment, or replenishing after the radiotherapy.

In aged liver, the oxidation susceptibility of liver weakens, so liver protecting himself exempts from the ability reduction of naturally occurring Oxidation influence in the diet.These variations relate to mitochondrion and kytoplasm function simultaneously, make that easier generation cellular swelling of liver, slight anoxia and function are impaired.Therefore, have the inhibiting liver selective membrane of antioxidation and mitochondrial calcium stabilizing agent simultaneously and can be used for treating aged liver to help to keep the liver function that liver function has the impaired gerontal patient of any degree.

That give as monotherapy, that write out a prescription with other medicament or with the common preparation of other medicament have antiopxidant effect, mitochondrial calcium suppresses and this protective effect of the membrane stabilizer of anti-activity of phospholipase can prevent or reduce the Oxidation of radical pair cell membrane, produce lysophosphatide and the whole cell membrane that destroys subsequently.In this way, be subject to hepatocellular cell membrane that free radical attacks and can keep sodium and water impermeable when anoxia, consequently light the and anoxia of cellular swelling degree is carried out slowlyer.In addition, remaining permeability and mitochondrial calcium depression effect can protect cell to avoid calcium overload and mitochondrial function is impaired, thereby suppresses to produce free radical in the mitochondrion, and compares untreated anoxia hepatocyte and more can keep hepatocellular metabolic function.

The interaction of diltiazem and thiamine

We think that diltiazem and the thiamine anti-oxidation efficacy in cell membrane (diltiazem) and kytoplasm (thiamine) is addition, and may be independently.

Because it is very little or invalid that this medicine seems effect to healthy people, but the effect of diltiazem is activated when calcium overload, so in the mitochondrion different situations can appear.On the contrary, as if along with calcium concentration in the mitochondrion raises, the effect of thiamine in NM is suppressed or lost efficacy.Therefore, diltiazem makes thiamine continue the performance effect under the disease situation to the protective effect of mitochondrial calcium content.Therefore, diltiazem and thiamine are collaborative or promote in Intramitochondrial effect.

The combination of diltiazem and thiamine takes place with at least 4 kinds of approach ill hepatocellular effect.They are additions to the anti-oxidation efficacy of full cell.Effect is collaborative or promotes in their mitochondrion.Paired cell and mitochondrion effect are complementary.

Slow releasing preparation

Many technology that active agents slowly discharges from oral Preparation that influence are arranged.These methods can comprise: the technology that postpones capsule, tablet or other carrier disintegrate; Postpone capsule, tablet or the dissolved technology of other carrier; And activating agent combined with polymer or other macromole so that discharge the technology that absorption just takes place from polymer or other macromole up to this material.The technology that realizes these different release methods is different, and comprises the aging method of knowing, and as the Lac coatings, and adopts synthetic and cellulosic polymer or employing that the more modern technology of the film coating at least one hole is arranged.

Dosage form of the present invention can be a controlled release form.The releasing mechanism of these dosage forms can and/or corrode control by diffusion.In some embodiments, described preparation comprises the many granules of polymer coating, polymer coated tablet or small pieces (minitablet) or hydrophilic skeleton sheet.

Stablize the medicine slow releasing preparation as the film of hepatoprotective and can be designed to after administration, discharge medicine in about 6-24 hour, thereby can be administered once every day and make liver to continue to be exposed in the medicine.In some embodiments, the preparation that discharges medicine in a long time can contain one or more and regularly discharge component and cover with influence time.

The present invention relates to following discovery; the i.e. protective effect of the low dosage membrane stabilizer that gives as slow releasing preparation (comprising that dosage is lower than the diltiazem of 50 mg/day) is by the direct protective action mediation to liver self rather than vascular system; medicine enters cell as lipophilic antioxidant and protects cell membrane and mitochondrial membrane exempts from phospholipid Oxygenation damage, and it works as the mitochondrial calcium antagonist.

Slow releasing composition can be the type of reporting in the past that is used for the treatment of cardiovascular disease, but the dosage of diltiazem is reduced to the 20-70 mg/day.As mentioned above, it is the 1-20 mg/day that this slow releasing composition will preferably also contain dosage, the thiamine of preferred 1-5 mg/day.But said composition gives 1 time every day, give every day 2 times or more times number, but gives 1 preferred especially every day.

United States Patent(USP) Nos. 4721619,4891230,4917899 and 521921 disclose the diltiazem preparation that needs per 12 hours to give 1 time (be every day 2 times).United States Patent(USP) Nos. 4894240 and 5002776 discloses the diltiazem preparation that needs per 24 hours to give 1 time (be every day 1 time).For obtaining disclosed stripping curve in these patents, disclosed preparation need wrap up the multilayer film of the central plate heart and will contain organic acid in the active tablet heart and/or multilayer film.Disclosed appropriate organic has adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid and tartaric acid in these patents.Professional purpose information according to Marion Merrell Dow Inc. issue, CARDIZEM.RTM.CD diltiazem capsule is a kind of lasting release diltiazem capsule that contains 120,180,240 or 300 milligrams of diltiazem hydrochlorides, and recommended doses is 1 capsule every day.Similarly, for obtaining 24-hour diltiazem release profiles, the piller in the CARDIZEM.RTM.CD diltiazem capsule contains the multilayer film of the organic acid fumaric acid and the parcel central plate heart.According to above-mentioned patent, piller is essential dry a few hours after the neutralization of coating process.

Be applicable to that another kind of method of the present invention is described in United States Patent (USP) 5 834 024 (Heinicke etc.), it adopts the combination of short retardation and long retardation diltiazem pill evenly to discharge diltiazem in 24 hours.

In an embodiment of the present composition, slow releasing composition comprises the sheet heart and one or more layers polymer coating that contains diltiazem.The sheet heart can contain and preferably contain the thiamine component.The sheet heart can form on inert material such as sugared ball seed.Sheet also can use pharmaceutically acceptable binding agent such as hydroxypropyl cellulose in the heart.One or more layers coating can comprise diltiazem and the permeable polymer of water and diltiazem and the polymer of water to being difficult to permeate.

An example of diltiazem permeable polymer is from acrylate and methacrylate and the synthetic cationic polymer of low concentration quaternary ammonium group, known have EUDRAGIT RL (Rohm Pharma GmbH manufacturing) ethyl cellulose, cellulose acetate, cellulose propionate is (low, in or high molecular), cellulose acetate propionate, acetylbutyrylcellulose, cellulose acetate phthalate, Triafol T, poly-(methyl methacrylate), poly-(ethyl methacrylate), poly-(butyl methacrylate), poly-(isobutyl methacrylate), poly-(N-Hexyl methacrylate), poly-(isodecyl methacrylate), poly-(lauryl methacrylate), poly-(phenyl methacrylate), poly-(acrylic acid methyl ester .), poly-(isopropyl acrylate), poly-(Isobutyl 2-propenoate), poly-(acrylic acid stearyl), poly-(ethylene), low-density is gathered (ethylene), high density is gathered (ethylene), poly-(propylene), poly-(oxirane), poly-(terephthalic acids vinyl acetate), poly-(vinyl isobutyl ether), poly-(vinyl acetate), poly-(vinyl chloride) or polyurethane, or wherein any two or more mixture.The suitable natural polymer of the difficult infiltration of water and diltiazem or resin comprise Lac, chitosan, gum sandarac (gumjuniper) or two or more mixture wherein.

The material of the difficult infiltration of diltiazem and water comprises cationic polymer, (RohmPharma GmbH makes to be known as EUDRAGIT RS, because EUDRAGIT RS contains less amino therefore than EUDRAGIT RL poor permeability) ethyl cellulose, cellulose acetate, cellulose propionate is (low, in or high molecular), cellulose acetate propionate, acetylbutyrylcellulose, cellulose acetate phthalate, Triafol T, poly-(methyl methacrylate), poly-(ethyl methacrylate), poly-(butyl methacrylate), poly-(isobutyl methacrylate), poly-(N-Hexyl methacrylate), poly-(isodecyl methacrylate), poly-(lauryl methacrylate), poly-(phenyl methacrylate), poly-(acrylic acid methyl ester .), poly-(isopropyl acrylate), poly-(Isobutyl 2-propenoate), poly-(acrylic acid stearyl), poly-(ethylene), low-density is gathered (ethylene), high density is gathered (ethylene), poly-(propylene), poly-(oxirane), poly-(terephthalic acids vinyl acetate), poly-(vinyl isobutyl ether), poly-(vinyl acetate), poly-(vinyl chloride) or polyurethane, or wherein any two or more mixture.The suitable natural polymer of the difficult infiltration of water and diltiazem or resin comprise Lac, chitosan, gum sandarac or two or more mixture wherein.

Except these polymer, coatings also contains lubricant and wetting agent.Preferred lubricant is a Talcum, and wetting agent is a sodium lauryl sulfate.

The suitable succedaneum of sodium lauryl sulfate can comprise arabic gum, benzalkonium chloride, cetomacrogol emulsifying wax, cetostearyl alcohol, spermol, cholesterol, diethanolamine, docusate sodium, sodium stearate, emulsifing wax, glyceryl monostearate, hydroxypropyl cellulose, lanolin alcohol, lecithin, mineral oil, ethanolamine, poloxamer, polyoxyethylene alkyl ether, castor oil derivatives, polyoxyethylene sorbitan fatty acid ester, Myrj 45, propylene glycol alginate, sorbitan ester, stearyl alcohol and triethanolamine, perhaps above-mentioned any two or more mixture.

The steatitic suitable succedaneum that can comprise in the coating comprises calcium stearate, silica sol, glycerol, magnesium stearate, mineral oil, Polyethylene Glycol, zinc stearate, aluminium stearate or above-mentioned any two or more mixture.

Should contain in the coating plasticizer with the elasticity and the stability that improve polymeric film and during preventing long term storage polymer penetration sexually revise.This variation may influence drug release rate.Suitable conventional plasticizer comprises acetylated monoglyceride; acetyl tributyl citrate; acetyl triethyl citrate; Oleum Ricini; citrate; dibutyl phthalate; dibutyl sebacate; ethyl oxalate; diethyl malate; DEF; diethyl phthalate; diethyl succinate; diethyl malonate; diethyl tartrate.; dimethyl phthalate; glycerol; glycerol; triacetin; the glycerol tributyl; mineral oil and lanolin alcohol; vaseline and lanolin alcohol; phthalic acid ester; Polyethylene Glycol; propylene glycol; vegetable oil; Oleum sesami; glyceryl triacetate; tributyl citrate; triethyl citrate and tributyl 2-acetylcitrate, perhaps above-mentioned any two or more mixture.Triethyl citrate is a preferred plasticizer of the present invention.

Perhaps or in addition, the sheet heart or coating can contain organic acid, as adipic acid, ascorbic acid, citric acid, fumaric acid, malic acid, succinic acid, tartaric acid and fumaric acid.

Another kind of controlled release method is the film coating that uses at least one hole at the sheet that comprises activating agent in the heart.Among this US 6,866,866 that is arranged in people such as Chen description is arranged, it can every day 1 time dosage SRM is provided.Chen etc. are also at United States Patent (USP) 6,524, have described the diltiazem slow releasing preparation in 620, and it can be used for low dose group compound of the present invention with the treatment hepatopathy.

Referring now to following examples the present invention is described.Should be understood that these embodiment are just in order to set forth the present invention rather than will to limit the scope of the invention by any way.

Embodiment

Embodiment 1

The hepatoprotective effect of in vitro study-diltiazem

On piglets liver microsomes film, study the protective effect of diltiazem cell membrane available from female little pig liver in 3 ages in week.Handled the microsome component 1 hour at 37 ℃ with vasoactive D diltiazem or blood vessel non-activity L-diltiazem (0-1000 μ M), use then radical-forming agent AAPH (2,2 '-azo is two-(2-amidine propane) dihydrochloride) handled 1 hour.Cultivate the centrifugal microsome mixture of back 2000rpm to remove excessive AAPH and diltiazem.Utilize the degree of commercially available dichlorofluorescein (dichlorofluoresen) (DCF, 10 μ 15 minutes) then by the lipid peroxidation in the microsomal membrane of fluorescence measurement reactive oxygen species mediation.Analyze image.The result of image analysis shows that shown in the active reduction of DCF during the inductive free radical of AAPH discharges, the D-diltiazem produces the oxidation of dose dependent film to be suppressed, and the L-diltiazem is not like this.

The DCF activity that the inductive free radical of AAPH discharges in the microsome that table 1 D-diltiazem is handled

These research explanations that entrusted by the inventor and undertaken by F professor Burczynski of University of Winnipeg, the characteristic that protects the liver of diltiazem has nothing to do with its blood vessel pharmacological property.In adopting the parallel study of H2O2 as radical-forming agent, diltiazem does not grant asylum.Therefore can reach a conclusion, H2O2 in kytoplasm, work (aqueous favoring) rather than lipophilic film or its near.

Embodiment 2

Diltiazem adds the hepatoprotective effect of thiamine

As mentioned above, the piglets from 4 health obtains liver microsomes.Microsome is kept at-80 ℃ up to research.Microsome concentration is 1 mg/ml.Diltiazem concentration is 50 and 500 μ M, and the thiamine concentration of test comprises 10,50 and 100 μ M.Radical-forming agent AAPH is 1mM.As mentioned above, this research detects the liver lipid peroxidation product by the fluorescence activity of analyzing the DCFH dyestuff with flat bed reader.

By the description of manufacturer, DCF-DA handled 2 hours with 2M NaOH and MeOH, seemingly obtained the DCFH of form in the born of the same parents then with the HCl neutralization.Hepatomicrosome is diluted to 1 mg/ml with phosphate-buffered saline (PBS).The diltiazem of microsome and various concentration, thiamine or its are combined in 37 ℃ and cultivated 1 hour.The contrast microsome is cultivated with PBS (no drug treating).The microsome mixture is cultivated 1 hour to start the lipid peroxidation of free yl induction, 1 hour by a definite date at 37 ℃ with 1mMAAPH then.Cultivate the back with the centrifugal microsome mixture of the super centrifuge tube 2000rpm of 5000MWCO, repeat twice of this process to remove any AAPH and medicine with PBS.Lipid was cultivated 15 minutes with 10 μ M DCFH by snperoxiaized microsome and is write down fluorescence activity with the fluorescence flat bed reader.

Table 1 has shown the result (n=6) of all researchs.In microsome, add thiamine and continue to reduce fluorescence activity (promptly suppressing free radical discharges).It seems generally, in thiamine, add diltiazem and further reduced fluorescence activity (p＜0.05).The active reduction all is significant when low dosage and high dose diltiazem.Add diltiazem and make the fluorescence activity reduction more, this reduction addition seemingly.

Table 2. diltiazem and thiamine are to the inhibitory action of fluorescence activity (free radical release).

These study explanation, and diltiazem and thiamine can act on cell cytoplasm and microsomal membrane, isolating hepatocyte are had the antioxidation and the protective effect of addition.

Embodiment 3

Diltiazem adds thiamine to mitochondrial hepatoprotective effect

Can carry out mitochondrion and suppress the influence that research produces energy with the combination that detects diltiazem and thiamine.

Detect the integrity of thereby the mitochondrial inhibition of rat being determined they by the ability of measuring ADP and stimulating oxygen to generate.Also detected the generation of ATP in the mitochondrion as another comparative study.

Can stimulate diseased cells by the calcium concentration that improves infusion liquid.The work that can detect thiamine, diltiazem and their combination respectively produces in order to confirm the energy that diltiazem helps to improve diseased cells.In fact, because the thiamine thiamine is invalid so be used in combination and be considered to synergism can be provided to the mitochondrion of diseased cells.

Embodiment 4

Hepatoprotective effect in the patient

Following clinical trial is used for studying and verifying the hepatoprotective effect of low dosage slow release diltiazem.

Clinical trial

This research has been raised 10 or abovely do not accept antiviral therapy or to the unresponsive hepatitis C patients of the interferon therapy that is with or without ribavirin, contain the effect of the slow releasing preparation of 25 milligrams and 50 milligrams diltiazems with detection.Confirm that by the rising of plasma A LT (alanine aminotransferase) concentration each patient has stable but unusual liver function.Pay special attention to not have the patient of HIV infection or have obvious ethanol to take in the patient of problem.Every kind of preparation gives 14 days with dosage once a day.

With objective and subjectively measure the hepatoprotective effect of low dosage slow release diltiazem, the variation of objective measurement assessment ALT level, the fatigue of subjective measurement assess patient and health status to liver.In formal clinical trial, the latter will need double blinding-placebo-controlled study, carry out suitable questionnaire survey to assess quality of life.

According to clinical research personnel's judgement, this research can allow the patient with 50 mg/day of dosage when 25 mg/day are increased to that treatment finished in 14 days.Yet, have than large effect with its expection higher dosage, it would be better to that the different efficacies of thinking between these dosage more likely is the function of individual disease severity, wherein more serious being limited in to portal venous flow produced higher drug level in the liver, therefore also produced the chance of using than low dosage.

Can expect that 25 milligrams and 50 milligrams of liver selectivity diltiazem preparations can be reduced to normal level with the ALT level, so drowsiness and tired situation still less also will appear in the patient when its liver function is improved.

Common prescription and combination treatment

Because using the liver selective membrane stabilizing agent with anti-oxidation efficacy and mitochondrial calcium inhibition effect (as diltiazem) is a kind of replacement therapy, therefore the liver selective preparation of this medicine can be write out a prescription with antiviral therapy (as ribavirin) when the treatment viral hepatitis usually, when the treatment alcoholic hepatitis, can write out a prescription, perhaps when the treatment portal hypertension, can write out a prescription with Propranolol with thiamine.

Embodiment 5

The controlled release preparation of calcium channel blocker and relative hydrophilic antioxidant

Can prepare following controlled release preparation:

The sheet heart

Medicine is formed: the mixture of 2-70 weight % diltiazem (20-70mg) and thiamine (1-20mg)

Binding agent: 3-98 weight %

Coating

Membrane polymer: 50-99%

Fluidizer: 0-40%

Plasticizer: 0-30%

Embodiment 6

Can be according to United States Patent (USP) 5,834, the following low dosage slow releasing preparation that discharged at 12 hours of 024 method preparation:

The sheet heart

Diltiazem: 30mg

Thiamine: 3mg

Hydroxypropyl cellulose 3.5g

Sugar ball 28g

Coating

Eudragit?RL：0.5g

Eudragit?RS：6.8g

Triethyl citrate 0.7g

Sodium lauryl sulfate 0.2g

Talcum 4.1g

Embodiment 7

Following slow release capsule preparation can be used the method manufacturing of United States Patent (USP) 6,074,669.

Embodiment 8

According to United States Patent (USP) 5,616,345 method prepares the sustained release preparation of diltiazem and thiamine.

Grind to obtain uniform powder with diltiazem hydrochloride (250 gram), thiamine hydrochloride (25 gram), adipic acid (0.5 kilogram) and Talcum (0.100 kilogram) mixing and by the No.50 mesh sieve.

Can be in the standard coating pan with following coating solution with powder coated in starch/sugared seed (diameter 0.6-0.71 millimeter) (0.5 kilogram):

Seed wraps up with the coating solution of prescribed volume, spills the mixture of powders of predetermined weight then.The seed of dry coationg and repeat coating steps and use up then up to powder.The seed drying that will contain the coating of the active tablet heart then spends the night to remove all trace solvent.

The piller active tablet heart that available then coating solution parcel makes, shown in coating solution constitute by following composition:

The coating solution of each coating can be every kilogram of capsuled seed 5 ml solns.

Reference material

Angulo?P，Patel?T，Jorgensen?RA，Therneau?TM，Lindor?KD.

Silymarin in the treatment patients with primary biliary cirrhosis with a suboptimalresponse to ursodeoxycholic acid (silymarin is used for the treatment of the constitutional gallbladder sclerosis patient who ursodesoxycholic acid is had time good reaction).

Hepatology32:897-900, Hepatology 33:483-4.2001 is seen in 2000 comments

Bass?NM.

Is there any use for nontraditional or alternative therapies in patients with chronic liverdisease? can (unconventional therapy or alternative medicine be used for chronic hepatitis patients?)

Curr?Gastroenterol?Rep?1：50-6，1999。

Draper?DW，Harris?VG，Culver?CA，Laster?SM.

Calcium and its role in the nuclear translocation and activation of cytosolicphospholipase A (2) in cells rendered sensitive to TNF-induced apoptosis bycycloheximide (calcium and the effect of cycloheximide activation cytosol phospholipase A (2) at nuclear translocation and in thereof) to the cell of the inductive apoptotic sensitivity of TNF.

J?Immunol.172：2416-23，2004

Flora?K，Hahn?M，Rosen?H，Benner?K.

Milk thistle (Silybum marianum) for the therapy of liver diseases (Herba Silybi mariani is used for the treatment of hepatopathy).

Am J Gastroenterol93:139-43,1998 comments are seen Am J Gastroenterol94:545-6,1999.

Jain?SK，Pemberton?PW，Smith?A，McMahon?RF，Burrows?PC，Aboutwerat?A，Warnes?T?W.

The Oxidative stress in chronic hepatitis C:not just a feature of late stage disease (oxidative stress in the chronic hepatitis C: the feature of being not only terminal illness).

J?Hepatol.36：805-11，2002。

Kontorinis N and Dieterich D.

Hepatoxicity of antiretroviral therapy (hepatotoxicity of antiretroviral therapy).

AIDS?Rev.5：36-43，2003。

Levy S, Herve C, Delacoux E and Erlinger s.

Thiamine deficiency in hepatitis C virus and alcohol-related hepatopathy s (thiamin deficiency in the relevant hepatopathy of hepatitis C virus) with ethanol

Dig?Dis?Sci?47：543-8，2002

Loguercio?C，Federico?A.

Oxidative stress in viral and alcoholic hepatitis (oxidative stress of viral hepatitis and alcoholic hepatitis).

Free?Radic?Biol?Med.34：1-10，2003

Lukienko Pl, Mel ' nichenko NG, Zverinskii IV and Zabrodskava SV

Antioxidant properties of thiamine (anti-oxidation characteristics of thiamine)

Bull?Exp?Bio?Med?130：874-6，2000

McLean?AJ.

Method for the treatment of liver disease and like indications with vasodilating agents (with the method for vasodilation treatment hepatopathy and similar indication)

United States Patent (USP) 5.854.233,1991-12-29.

Novikov?KN，Herrera?M，Pascual?C，Gonzalez?R

The antioxidative activity of drugs in the liver microsomal system of rats (medicine is to the antioxidant activity of rat liver microsome system)

Nauchnve?Doki?Vvss?Shkolv?Biol?Nauki.12：19-27，1991。

Patrick?L.

Hepatitis C:epidemiology and review of complementary/alternative medicinetreatments (hepatitis C: epidemiology and additional/alternative medicine treatment are looked back).

Altern?Med?Rev?4：220-38.1999

Smith?HJ.

The need to redefine membrane-stabilizing actiVity of beta-adrenergic receptorantagonists (redefining the necessity of Beta-3 adrenergic receptor antagonist film stabilizing active)

J?Mol?Cell?Cardiol.14：495-500，1982。

Spalletti-Cernia D, D ' Agnano I, Sorrentino, R.Zupi, G, Vecchio G, Portella G and Laccetti P.

Varapamil reverts resistance to drug-induced apoptosis in Ki-ras-transformed cells byaltering the cell membrane and the mitochondrial transmembrane potentials (verapamil recovers the drug-induced apoptosis of Ki-ras transformant by changing cell membrane and mitochondrion transmembrane potential)

Oncol?Res.13：25-35，2002

Thurman?RG，Apel?ED，Lemasters?JJ

Protective effect of nitrendipine against hypoxic jnjury in perfused livers fromethanol-treated rats (nitrendipine is to Ethanol Treatment rat perfusion liver Anoxia of Isolated)

J Cardiovasc Pharmacol12 (supplementary issues 4), S113-6,1988.

Vaidya?AB，Antarkar?DS，Doshi?JC，Bhatt?AD，Ramesh?V，Vora?PV，Perissond?D，BaxiAJ，Kale?PM

Picrorhiza kurroa (Kutaki) Royle ex Benth as a hepatoprotective agent--experimental﹠amp; Clinical studies (Rhizoma Coptidis is as hepatoprotective-test and clinical research)

J?Postgrad?Med?42：105-8，1996。

Vargas?F，Cheng?AT，Velutini?G，Marcano?E，Sanchez?Y，Fraile?G，Velasquez?M.

In vitro antioxidant and photo-oxidant properties of dipyridamole (the antioxidation in vitro characteristic of persantin and photooxidation characteristic)

Int?J?Toxicol.20：363-8，2001。

Wallace AE and Weeks WB.

Thiamine treatment of chronic hepatitis B infection (thiamine treatment chronic hepatitis B infects)

Am?J?Gastroenterol?96：864-8，2001。

Wilson，JD.

Vitamin deficiency and excess (vitamin deficiency and excessive)

Harrison ' s principles of Internal MedicineMcGraw-Hill, Health Professions Division publishes, and 1998.

Claims (10)

1. diltiazem and thiamine are used to make the purposes that the liver protecting is not suffered from non-pernicious hepatopathy or prevented the oral drugs that non-pernicious hepatopathy further worsens; described non-pernicious hepatopathy is selected from: viral hepatitis; alcoholic hepatitis; liver cirrhosis; portal hypertension; and by toxin; the non-pernicious hepatopathy of other form that medicine and abnormal immune state cause; wherein said medicine discharges medicine in 6-24 hour after administration; described medicine is the slow releasing preparation that comprises diltiazem and thiamine, and the unit dose that described medicine comprises contains 20-70 milligram diltiazem and 1-20 milligram thiamine.

2. purposes as claimed in claim 1 is characterized in that, wherein, the ratio of diltiazem and thiamine is 80: 1-5: 1.

3. purposes as claimed in claim 1 is characterized in that, described hepatopathy is selected from hepatitis that alcoholic hepatitis, liver cirrhosis, portal hypertension, infection cause and is the immunity hepatopathy of feature with the chronic inflammatory disease.

4. purposes as claimed in claim 1 is characterized in that described hepatopathy is selected from hepatitis B or hepatitis C.

5. purposes as claimed in claim 2 is characterized in that, described hepatopathy is the toxic hepatitis as acute and chronic pharmacotherapy side effect.

6. the pharmaceutical composition of the treatment or the controlled release composition form of prevention of liver disease, described compositions comprises: (i) diltiazem and (ii) thiamine, described controlled release composition discharges diltiazem on 6 to the 24 hours ground, back of taking medicine, and the unit dose that described compositions comprises contains 20-70 milligram diltiazem and 1-20 milligram thiamine.

7. pharmaceutical composition as claimed in claim 6 is characterized in that, the form of described controlled release composition is selected from the many granules of polymer coating, polymer coated tablet and hydrophilic skeleton sheet.

8. pharmaceutical composition as claimed in claim 7, wherein, described polymer coated tablet is the polymer coating small pieces.

9. pharmaceutical composition as claimed in claim 6, its form are capsule or tablet.

10. pharmaceutical composition as claimed in claim 6, its form are the capsule sheet.