CN101132782A

CN101132782A - Orally tanken medicament preparation of losartan

Info

Publication number: CN101132782A
Application number: CNA2006800069250A
Authority: CN
Inventors: 卡特琳·卡斯唐; 弗洛朗斯·甘贝尔托; 雷米·梅吕埃克斯; 热拉尔·苏拉
Original assignee: Flamel Technologies SA
Current assignee: Flamel Technologies SA
Priority date: 2005-02-21
Filing date: 2006-02-21
Publication date: 2008-02-27
Also published as: FR2882259A1

Abstract

The invention concerns oral pharmaceutical forms of losartan, as well as related treatments and delivery methods. The invention concerns the use, in an oral pharmaceutical form comprising losartan, of a coating or a matrix including said losartan and enabling said losartan to be released in controlled manner, such that said form administered to subjects results, whether the patients have eaten or not, in reducing the standard deviation among individuals of Cmax, thereby ensuring a very low variability of the efficacy and therapeutic safety of the pharmaceutical form, compared to a pharmaceutical form of losartan with immediate release administered to the same sample of subjects, at a similar dose. The invention also concerns an oral pharmaceutical form of losartan capable of being administered once a day, at least as efficient as the other forms taken once daily and than the forms taken twice daily. The invention is thus an oral pharmaceutical form with modified release of losartan comprising a plurality of micro-units of losartan (mean diameter: 20-1000 [mu]m) enabling, after being taken, a plasmatic profile of the type as those shown in figure 10 to be obtained.

Description

The oral Pharmaceutical dosage forms of losartan

Technical field

The field of the invention is the oral Pharmaceutical dosage forms of losartan treatment and the medication relevant with it.

Background technology

General aspect

Losartan (or Losartan Potassium) is a kind of angiotensin ii receptor antagonist (an AT1 type).It is oral effective, and participates in regulating hypertension by acting on renin-angiotensin system.

Its structural formula is as follows:

2-butyl-4-chloro-1-[4-[2-(1H-tetrazolium-5-yl) phenyl] benzyl]-1H-imidazoles-5-yl } methanol.

Exist pharmacy effectively and some salt or the ester of acceptable this product.Therefore, in whole description, term " losartan " expression losartan itself and/or at least a its salt, ester or the acceptable form of other pharmacy.

Losartan can with diuretic (Hydrochlorothiazide) combination, or with other has the drug regimen of cardiac vascular activity arbitrarily, increasing its effect,

Especially, losartan is used to treat following pathology:

● the constitutional arterial hypertension,

● treat at the renal insufficiency of suffering under the albuminuretic type 2 diabetes mellitus situation,

● reduce the hyperpietic's who suffers from left ventricular hypertrophy cardiovascular morbidity and mortality rate (common and thiazide diuretic combination),

● congested cardiac insufficiency,

● the erythrocytosis of renal transplant recipients.

The oral administration losartan in cytochrome P 450 enzymes system through first pass metabolism widely.It partly changes a kind of carboxylic acid (EXP3174) into, and a kind of than the more effective active metabolite of parent molecule losartan, therefore, losartan is regarded as prodrug.

The definition of " losartan " that above provides can advantageously be replenished by those that mention among the WO-A-03/035039 (page 3 the 28th walks to page 4 the 18th row).

Based on this description, term " losartan " represent its pharmacy can accept form at least any, comprise its metabolite.

Problem

For pharmaceutical dosage form arbitrarily, especially for the peroral dosage form of losartan, the quality of treatment and the assurance of repeatability are major requirements.

Yet; following phenomenon may occur: some oral Pharmaceutical dosage forms of losartan can not satisfy this requirement; therefore; for identical treatment dosage form with the same dose oral administration; some patient benefits from enough and effectively treatment protection; and some other patient can not obtain suitable treatment, and/or more seriously, become the victim of dangerous side-effects.

These oral Pharmaceutical dosage forms of losartan produce unsettled blood plasma feature, can not guarantee that a kind of all is Therapeutic Method uniform, effective and that can tolerate to all patients.

But for being administered once every day or repeatedly the oral Pharmaceutical dosage forms of release immediately (IRF) can be observed these important disadvantages.

Especially, observe, behind the oral IR pharmaceutical dosage form of administration losartan, patient for 5% to 25%, the plasma concentration feature that obtains causes the early stage peak plasma concentration of large amplitude, and for Most patients, the plasma concentration feature of acquisition causes peak plasma concentration (Cmax) to occur slower and has less amplitude.The significant difference of this characteristic can be divided into the patient two types of populations: another colony (Ps) that has the colony (Pr) of " fast " feature and have " slowly " feature.

Have too early and can bring serious consequence with a large amount of these high variability that discharge these antihypertensive losartans.

At first, having very, the patient of the early stage peak concentration of large amplitude will suffer serious hypotension.

The second, finally, extremely low losartan concentration level reflects the early stage reduction of plasma concentration behind peak value during twice administration.Therefore, after standing to be equivalent to the too high losartan concentration of peak value, the patient Pr of colony will treat not enough in the end during twice administration fast.

At last, this high variability makes the doctor limit prescribed dose, and some patient can not obtain correct treatment.

Also can prevent the establishment or the administrative approval of the low dosage dosage form that medicine is useful:

● the fact is: owing to have the above-mentioned variability of mentioning for the known dosage form of prior art, confirmation can not prove in a kind of mode that satisfies the requirement of registration management office (double blind clinical studies demonstrates statistics to placebo or reference group and goes up significant difference), the low dosage dosage form for specific crowd for example child have therapeutic value;

● another example of this class an open question is for being used for the treatment of the hypertensive low dosage antihypertensive of weak expression type, can demonstrate hypotensive accidental outbreak to this patient, for example upright position hypotension: it can be manifested by the excessive release (if it can not cause danger) of low dosage ARB dosage form via chance, can increase the weight of the danger of hypotension outbreak.

Therefore, obtain the useful oral Pharmaceutical dosage forms of losartan, it is useful particularly obtaining the every day form of administration, and it can avoid the unstability of the plasma concentration feature that two kinds of patients exist.In other words, described pharmaceutical dosage form produces the plasma concentration feature of homogeneous, is favourable and there is not a large amount of and/or the early stage and/or rapid release of losartan.Therefore, this purpose is different from the dosage form that searching delays to discharge losartan.

And ARB, particularly losartan press oral administration once a day with tablet usually.Yet, confirm that this treatment is undesirable.Especially, the known expection control that is difficult to or can not obtains at all arterial pressure perhaps obtains in irreproducible mode.Also observe side effect once in a while.

Potential problem is following (1,2,3) especially:

1) in Most patients, dosage is 50mg or 100mg, once a day.Yet, some author [The Angiotensin II type 1 receptor antagonists:a new class ofantihypertensive drugs, Bauer etc., Arch.Inter.Med.1995,155,13, p1361-1368] described and taken in every day twice, each dosage 50mg, it is more effective to take in 100mg dosage than single.

Therefore, the patient for about 20% for example takes in that 100mg can not treat effectively every day, and it is essential taking in two doses (twice, each 50mg) every day.

The effect of this single administration every day weakens can be by following facts explain: the plasma concentration of patient's arterial pressure and active metabolite E-3174 is closely related behind the oral administration losartan.Yet after the single daily dose is taken in only 12 hours, the plasma concentration of activating agent E-3174 was very low.Especially, the reduction of the plasma concentration of E-3174 appears in 2 to 4 hours that dosage takes in; In addition, this is reduced to fast: the half-life of E-3174 is 6-9 hour.

Therefore, recommend twice of this medicine of administration every day.Yet acceptable usually is that the dosage of taking in every day does not several times have in the dosage of expecting most according to patient's compliance and therapeutic efficiency.

Therefore, go for to have and slow down the dosage form that discharges losartan, it has prolonged the bio-absorbable time, and medicine only is administered once every day.Yet these dosage forms well known in the prior art have caused the problem of listing hereinafter.

2) guaranteeing to treat safety is the main challenge of antihypertensive such as losartan.Reason has basic importance for it for obtaining to be designed to following oral drugs: in case picked-up, its effective ingredient that comprises discharges into gastrointestinal tract, and bio-absorbable in its absorption window, otherwise effective ingredient dosage is not absorbed just along with intestinal movement is discharged by correct.Therefore, it can not produce desired therapeutic effect.With regard to losartan, the patient's of the tablet of swallowing arterial pressure does not reduce, and it has increased the danger of infarction considerably, and therefore, its life with the patient places danger.

Document description the losartan tablet that keeps of the stomach that delays to discharge.Described tablet is expanded to a certain size under one's belt, and when pylorus is closed (, under the state on the feed), prevented its gastric emptying.Therefore, described effective ingredient discharges gradually in the upstream of its absorption window, and described absorption window is positioned at the top of small intestinal.Therefore, it can correctly be absorbed.

Yet for the part patient who can not ignore, closing of pylorus may be unsettled.And, if the patient does not strictly follow dosage regulation, and take in tablet before the dining pylorus is closed before or when having meal beginning, stop is not under one's belt for the tablet of swallowing, it does not discharge losartan in the upstream of its bio-absorbable window as yet, has just been discharged apace.

Therefore, it is insecure that these stomaches that delay to discharge keep dosage form, because losartan is not necessarily biological absorbable, no matter whether the patient is in feed or fasting state.

Therefore, in a single day be to guarantee to take in oral drugs for what slow down liberation port oral dosage form key, losartan is just by bio-absorbable, and no matter whether the patient is in feed or fasting state.

3) slowing down of losartan another problem has appearred in the release dosage form.The water solublity of this effective ingredient is along with pH changes and greatly variation (referring to following the 12nd page table).

Now, under fasting state, the pH of stomach is 1.4, and after dining, it is 5.Therefore, slowing down in the release dosage form of losartan, the dissolubility of effective ingredient is perhaps depended in the release of losartan or depend on pH (enteric coating), and its release dynamics can whether fasting changes according to described patient.

Therefore, perfect condition is for obtaining a kind of oral Pharmaceutical dosage forms of losartan:

It causes the plasma concentration feature of homogeneous ■, and not a large amount of and/or early stage and/or rapid release losartan;

It can be administered once ■ every day;

Its " take in once every day " dosage form than release immediately of ■ is more effective;

It is in case take in oral Pharmaceutical dosage forms for ■, its effective ingredient that comprises discharges into gastrointestinal tract, bio-absorbable in the gastrointestinal absorption window, no matter the patient is under feed or the fasting state, that is, its by restriction (or even eliminate) between individuality the ill-effect of gastric emptying variability obtained good plasma concentration repeatability.

■ and, overcome the losartan dissolubility variability problem relevant with pH.

Prior art

Monolithic oral Pharmaceutical dosage forms and multiparticulates oral Pharmaceutical dosage forms are known.

The monolithic dosage form

Patent application WO-A-98/24411 has described a kind of Therapeutic Method that uses buspirone, it comprises a kind of galenic dosage form (for example tablet or capsule) that discharges immediately of oral administration, described dosage form comprises the nefazodone of buspirone and capacity, thereby increased the bioavailability of buspirone, and reduced its removing, the formation of metabolite and the variability of pharmacokinetic parameter.This combination of nefazodone and buspirone be considered to overcome can not be by disclosed buspirone in US-B-5431922 control/delay the problem that delivery formulations solves, it has the major defect (referring to page 3 the 7th to 16 row of WO-A-98/24411) that causes high-caliber pharmacokinetic parameter variability.

Patent USB-6248359 discloses a kind of multi-disc system that uses oxibutynin to treat urinary incontinence.This system is included in second tablet that (for example less than 6 hours) discharge first tablet of oxibutynin and (18 to 24 hours) discharge oxibutynin in the time of a prolongation in the short-term.After the oxibutynin treatment, this system shows as the variability that can compensate between individuality.For example, these tablets are made up of the tablet of each self-contained oxibutynin medicated core and which floor coating.

The monolithic dosage form of WO-A-98/24411 and US-B-6248359 does not relate to losartan.

The multiparticulates dosage form

Patent application PCT WO-A-96/11675 has described the microcapsule that is used for the medicinal of oral administration and/or nutrition effective ingredient (AP), and it has the size that is less than or equal to 1000 μ m.These microcapsules are by forming with the coating material coated granules, and (polyvinylpyrrolidone: form by mixture PVP) by film forming polymer (ethyl cellulose), hydrophobic plasticizer (Oleum Ricini), surfactant and/or lubricant (magnesium stearate) and polymer with nitrogen for described coating material itself.These microcapsules are characterised in that it has the ability that long-time (at least 5 hours) stop in small intestinal, and it makes during its residence time, and the absorption elapsed time of AP is longer than the natural delivery time in small intestinal.

Patent application PCT WO-A-03/030878 has described a kind of system that is used to postpone, control and regularly discharge AP, it is characterized in that having and cause the dual mechanism that AP discharges: " time-dependency " discharges, it is causing under the immovable situation of pH after controlled time under one's belt, " pH-dependency " discharges, and its increase by pH causes after the galenical dosage form enters intestinal.These have diameter is that 200 to 600 microns microcapsule is characterised in that coating membrane is the combination based on Eudragit  base polymer A and hydrophobic compound B, the fusing point that for example has is 40 to 90 ℃, and the ratio of B/A is 0.2 to 1.5 vegetable wax (Lubritab ).

All these known oral Pharmaceutical dosage forms all can not provide and meet following assurance: repeatability between the individuality of plasma concentration feature, the treatment of having eliminated in the dangerous of early stage and a large amount of release and the interval of the All Time between two doses is taken in covers.

Therefore, improved described peroral dosage form.

Therefore, according to inventor's knowledge, prior art lacks can provide any technical scheme that begins to solve this problem of oral Pharmaceutical dosage forms that causes unstable blood plasma feature.

Summary of the invention

Based on these observed results, the inventor oneself has set following purpose:

Main purpose of the present invention is for overcoming the deficiencies in the prior art and shortcoming.

Another main purpose of the present invention is for proposing to be used for controlling the new purposes of the mode (coating or the substrate that comprise losartan) of losartan release at oral Pharmaceutical dosage forms, to satisfy at least a above-mentioned purpose, particularly reduced variability between the individuality of blood plasma feature.

Another main purpose of the present invention is for proposing the new purposes of oral Pharmaceutical dosage forms, and described oral Pharmaceutical dosage forms comprises and is used to control the mode that losartan discharges, and described mode is coating or the substrate that comprises losartan, to satisfy at least a above-mentioned purpose.

Another main purpose of the present invention is to propose to be used for controlling the new purposes of the mode (coating or the substrate that comprise losartan) of losartan release at oral Pharmaceutical dosage forms, with standard deviation between the individuality of maximum blood plasma after the reduction administration.

Another main purpose of the present invention is the new purposes of proposing oral Pharmaceutical dosage forms, described oral Pharmaceutical dosage forms comprises and is used to control the mode that losartan discharges, described mode is coating or the matrix type that comprises losartan, with variability between the individuality that reduces blood plasma feature after the administration, particularly reduce standard deviation between the individuality of maximal plasma concentration.

A main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, uses it to obtain with respect to proposing different patients' more uniform and more reproducible therapeutic properties in the prior art.

Another main purpose of the present invention is the method that has proposed to be used to reduce standard deviation between the individuality of Cmax Cmax of blood plasma feature.

Another main purpose of the present invention is the oral Pharmaceutical dosage forms that has proposed a kind of losartan, it has reduced variability between the individuality of blood plasma feature of oral Pharmaceutical dosage forms of known losartan, especially for fear of two kinds of blood plasma features occurring: dangerous Pr of colony of " fast " feature and the Ps of colony of " slowly " feature.

Another main purpose of the present invention is for proposing to be used to reduce and even eliminate the method for the quick Pr of colony.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, it can provide the assurance of treatment safety aspect: eliminated some patient danger too early and/or a large amount of and/or the rapid release losartan, and the treatment in the whole interval covers between two doses is taken in.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, and it makes the patient not emit the too high any risk of plasma concentration of losartan, thereby makes the patient avoid the relevant accident of any medicine.

Another main purpose of the present invention is to have proposed a kind of method that reduces the peak/paddy ratio of the plasma concentration of losartan.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, in case with its picked-up, losartan that can will comprise discharges into gastrointestinal tract, and in its absorption window bio-absorbable.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, and it can be administered once every day, and dosage form once a day that discharges immediately with present use is effective equally at least for it.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, and when be administered once every day, it was for example effective for treatment for the patient who surpasses 80%.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, and it has the external stripping feature that does not rely on losartan dosage.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, and it has the identical weight composition irrelevant with the expection therapeutic dose of losartan.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, it can be administered once every day, its inconvenient patient that is suitable for swallowing is especially for not only not swallowing but also need adjusting the child or the baby of dosage according to their body weight.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, it can be administered once every day, and provide losartan and one or more effective ingredient, and can be easily and regulate release time of various effective ingredient independently in the blended probability of same peroral dosage form.

Another main purpose of the present invention provides a kind of oral Pharmaceutical dosage forms of losartan, but is administered once its every day, and has limited the danger by the too high lesion tissue that causes of losartan local concentration.

Another main purpose of the present invention has provided a kind of oral Pharmaceutical dosage forms of losartan, but be administered once its every day, and, although the dissolution variability of losartan in water is relevant with pH, but losartan discharges according to identical kinetics, no matter whether fasting of described patient.

Another main purpose of the present invention is for providing a kind of oral Pharmaceutical dosage forms of losartan, and it can be present in the various galenic dosage forms, comprises especially: tablet, sachet, can drink suspension, capsule etc.

Another main purpose of the present invention provides a kind of Therapeutic Method, and it comprises a kind of oral Pharmaceutical dosage forms that satisfies at least a above-mentioned therapeutic purposes of use.

The improvement of above-mentioned all purposes is with reference to the oral Pharmaceutical dosage forms of release immediately of losartan.

Summary of the invention

In context, the applicant:

～recognize:

The dissolubility of ■ losartan greatly changes as the function of the pH of stomach,

The pH of ■ stomach has very big difference, and its source is variable, depends on multiple uncontrollable parameter, particularly: feed or fasting shape body, interindividual variation, influence the effect etc. of the medicine of these gastrointestinal conditions.

～hypothesis is proposed: the non-reproducibility of different patients' therapeutic quality may be relevant relevant with stomach pH with the dissolubility of losartan, and described pH is in the same individual and the variable of the dosage of Different Individual absorption time correlation.

～and, at last, imagine a kind of technical scheme that limits and even eliminate this dependency, this scheme is for recommending to use coating or the substrate that comprises losartan, its can reduce and even eliminate the quick blood plasma feature Pr of colony and can avoid losartan too early and/or a large amount of and/or rapid release and irrelevant with gastric acidity, it has the character of variability between the individuality that reduces the blood plasma feature.In this case, at first,, improved the safety for the treatment of by the illeffects that prevents the oral administration losartan for the patient of a certain class, the second, promoted therapeutic effect.

Therefore, the present invention has realized above-mentioned purpose, wherein, and by proposing:

■ comprises the coating or the purposes of substrate in oral Pharmaceutical dosage forms of losartan, described coating or substrate can make the losartan sustained release, this dosage form of oral administration is to individual specimen, no matter described individuality is feed or fasting state, the capital causes that standard deviation reduces between the individuality of Cmax, with respect to the pharmaceutical dosage form of release immediately of the losartan that is administered to the same individual sample with same dose, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety; And/or

■ comprises the coating or the purposes of substrate in the preparation oral Pharmaceutical dosage forms of losartan, described coating or substrate can make the losartan sustained release, in this dosage form of oral administration to individual specimen, no matter described individuality is feed or fasting state, the capital causes that standard deviation reduces between the individuality of Cmax, with respect to the pharmaceutical dosage form of release immediately of the losartan that is administered to this same individual sample with same dose, it can guarantee the variability of lower efficacy of drugs and safety.

Therefore, defined the present invention, wherein under experimental condition, described pharmaceutical dosage form has been administered orally to individual specimen, those that described experimental condition can be for providing in the following embodiments by the reference clinical trial.This clinical trial has defined the present invention by the specific pharmacokinetic properties that obtains under experimental condition.Yet the present invention is not limited to implement under the clinical trial condition of these references.

Can reduce and even eliminate the unstability of the plasma concentration feature of Different Individual according to purposes of the present invention, in this case, to avoid:

● at first, avoided the too early release of AP, thereby, avoided plasma concentration too high with side effect and

● the second, avoided any treatment that may lack between the two doses absorption to cover.

Therefore, exploitation and outstanding technical role are not the prolongations of release time according to the present invention, but have reduced the disadvantageous treatment variability to the patient.Therefore, the present invention can guarantee effect and bigger treatment safety preferably.

The invention allows for a kind of oral Pharmaceutical dosage forms that slows down release of losartan of novelty, it can be wherein a kind of who uses in such use, and limits by claim 31 or 32.

Advantageously, in case this pharmaceutical dosage form is designed to take in, described micro-unit can be disperseed and individuation when their arrive in stomach, its can guarantee on the feed or under the fasting state micro-unit uniformly and gastric emptying progressively, thereby, finally in gastrointestinal bio-absorbable window, discharge losartan.

For the purposes of the present invention, term " disperses and individuation " to refer to that they do not sink in the substrate when losartan base micro-unit just arrives in the stomach after absorption.In case described micro-unit arrives in the stomach, it disperses under one's belt (for example less than two minutes).

Detailed Description Of The Invention

The definition of " losartan " that above provides can be advantageously by replenishing that in WO-A-03/035039 (page 3 the 28th walks to page 4 the 18th row) mentioned.

In this manual, term " discharges immediately " and refers to discharging by immediate release dosage form (IRF) in the short time relatively by most of losartans, for example:

After the oral absorption of ■, at least 80% in one hour, preferably discharges in vivo in 30 minutes;

■ or in external dissolution test, under any pH between 1.4 to 7.4, at least 80% losartan preferably discharged in 30 minutes in 1 hour;

In this manual, all strippings in the research are characterized as according to the indication that is called " dissolution test of solid oral dosage form " among the European Pharmacopea the 4th edition and carry out: at 37 ℃ with carry out II class dissolution test under the SINK condition that 100rpm stirs.

But the example of these IRF comprises standard film dispersible tablet, chewable tablet, sachet and the capsule of swallowing.

In this manual, term " sustained release " expression discharges losartan by oral Pharmaceutical dosage forms, and the pH of this release of carrying out in vivo and stomach has nothing to do, according to than reference IRF ^*" immediately discharge " slower speed of preparation carry out.These sustained release preparations can comprise, for example rapid release mutually with slow release mutually.The sustained release preparation is well-known in the art: referring to, Remington:The scienceand practice of pharmacy for example, 19 ^ThEdition, Mack publishing Co.Pennsylvania, USA.Described sustained release can be slow release and/or controlled release especially, perhaps discharges for postponing.

In this manual, term " slows down release (modified release) ", and expression discharges losartan by pharmaceutical preparation, this release is carried out standard film that described immediate release formulation is for example swallowed or capsule with " discharging immediately " the slower speed of preparation than reference IRF*.This delivery formulations that slows down can comprise, for example rapid release mutually with slow release mutually.This delivery formulations that slows down is well-known in the art: referring to, Remington:The science and practice of pharmacy for example, 19th edition, Mackpublishing Co.Pennsylvania, USA.

The pharmacokinetic parameter that the present invention considers is what define in following manner.After described pharmaceutical dosage form is administered orally to N individual specimen, measure each patient's individual plasma concentration feature, depict conventional individual pharmacokinetics parameter according to this feature: Tmax, Cmax, C24h:

Tmax is the time that plasma concentration reaches its maximum Cmax,

C24h is 24 hours a plasma concentration after the administration.

According to these individual parameters, those skilled in the art calculate the meansigma methods and the standard deviation thereof of these parameters routinely.The more detailed description of relevant these parameter discussion will be found in following book: Pharmacokinetics and Pharmacodynamic Data Analysis 3rd ed., J.Gabrelsson etc., Kristianstads Bocktryckeri AB, Sweden, 2000.

The pH of stomach is the variable value of essence in the pH scope of pH 1.2 to pH 5.5.Especially can be observed this variation for same individual and Different Individual under feed or the fasting state.In addition, some patient who heals with medicine has changed the pH of stomach " manually ".During for example, with proton pump inhibitor (for example omeprazole) or antacid is exactly this situation.

The applicant recognizes that dissolubility depends on that to a great extent the losartan of the pH of stomach can cause different patients' unsettled plasma concentration feature.

The applicant can not provide sufficient explanation to this phenomenon, and what can propose is that the variability of this plasma concentration feature is changed along with the pH of stomach by the dissolubility of losartan and changes institute and cause.This phenomenon former is because in order to be absorbed, losartan at first must be dissolved.Therefore, this dissolving step depends on the pH of stomach to a great extent.Therefore, for the losartan of same dose, according to the pH of patient's stomach, in some patient, losartan can fully and apace dissolve, and perhaps, on the contrary, in other patients, it is insoluble in the stomach.

Therefore, it is contemplated that, depend on the losartan of the pH (seeing table) of stomach to a great extent for dissolubility, dissolubility and final plasma concentration feature exist than big difference in Different Individual, and for same individual, have one day difference with another day.

pH	Dissolubility g/l under 37 ℃
pH	Dissolubility g/l under 37 ℃	1.4	1
2.0	0.6	1.4	1
2.0	0.6	3.0	0.10
4.5	0.12	3.0	0.10
4.5	0.12	5.0	0.3

6.0	1.2
6.0	1.2	6.8	10
8.5	＞550	6.8	10

Therefore, as showing among the embodiment 7 hereinafter, cause Cmax in Different Individual, to change by coefficient＞10 (70 to 800ng/ml) to the conventional IRF of the losartan of 20 individual specimen administration 100mg dosage.

The unstability of this plasma concentration feature can reflect as the appearance by two kinds of feature colonies in reference embodiment: colony (Pr) and slowly colony (Ps) fast.

For quick colony, the too early release of losartan has three very disadvantageous consequences:

(a) patient of colony stands dangerous side effect fast, and such as hypotension, its early stage plasma concentration with losartan is too high relevant.

(b) existence of these danger can cause prescribed dose to be restricted, and it can make some patient lose sufficient treatment.

(c) for quick feature, the interval end of plasma concentration between twice administration is very low.Therefore, these patients' treatment covers not enough.

For the purposes of the present invention, after term " Pr of colony fast " was illustrated in the IRF of administration losartan, all the individual Tmax under the feed state were less than 1.5 hours.For this quick Pr of colony, the maximal plasma concentration of losartan early reaches, and obtains high value usually.

Therefore, one of fundamental of the present invention is to use or advise comprising the purposes that is used for the treatment of purpose of the oral Pharmaceutical dosage forms of losartan, described losartan is contained in coating or the substrate, described coating or matrix design become to make the losartan sustained release, therefore, this dosage form of oral administration is to individual specimen, no matter described individuality is feed or fasting state, the capital causes that standard deviation reduces between the individuality of Cmax, with respect to the pharmaceutical dosage form of release immediately that is administered to this same individual sample losartan with same dose, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety.

Standard deviation reduces the factor (f) and is defined as IRF ^*The ratio of the respective standard deviation of the dosage form that the standard deviation of the Cmax of dosage form is relevant with purposes of the present invention.

Preferably, the factor (f) that reduces of standard deviation is between the individuality of Cmax: f 〉=1.2, and preferred f 〉=1.75, and more preferably f is between 2.5 to 20.

Described coating or the described substrate purposes in the preparation oral Pharmaceutical dosage forms also is a target of the present invention.

The oral Pharmaceutical dosage forms relevant with described purposes also is full ripe (fledged) purpose of the present invention.

Therefore, the applicant finds, losartan with sustained release film coating, perhaps is included in losartan in the sustained release substrate, can eliminate or reduce the unstability of the release characteristic of losartan Different Individual.

The present invention is to the purposes of the optimization losartan particular importance that seems, it is administered once individually every day, but it has the erratic behavior of described blood plasma feature.Therefore, target master of the present invention is if it were not for prolonging release time, and at first is to have reduced the disadvantageous treatment variability to the patient.Therefore, the present invention can guarantee effect and treatment safety preferably.

In a word, the creationary prestige of applicant is mainly based on the following fact: it clearly is familiar with and has solved the problem of losartan according to the pH variability dissolving variability of the pH stomach function regulating of stomach.From these invisible factors, the applicant has proposed to be used to limit the new and creationary purposes of the known conventional method of these factor affecting.These methods are coating membrane or the inclusion substrate that is used for losartan.Even make under the high situation of the dissolubility of losartan at the pH of patient's stomach, they have prevented under one's belt fast and early stage release.

According to another favourable scheme of the present invention, described pharmaceutical dosage form can utilize all types of one or more dosage units (for example volume unit of tablet, capsule, powder or solution) administration every day, do not comprise and comprise every dose of system that takes in several tablets, wherein at least a of these tablets is the tablet with rapid release effective ingredient (less than 6 hours), and these tablets is at least a for having the tablet that delays to discharge identical effective ingredient (18 to 24 hours).

Utilization coating and/or losartan is included in the dissolubility variation relevant that can weaken losartan in the substrate on the losartan granule with pH.Therefore, when being 1 between 3 the time at pH, dissolubility has changed 10 times, and the preparation of purposes can obtain the release in vitro feature (D of the losartan relevant with time T (in hour) according to the present invention, %), it seldom depends on pH or does not rely on pH (referring to accompanying drawing 2).

Advantageously, described coating or matrix design become to make it can make the losartan sustained release, at first avoided any too early and/or a large amount of of losartan and/or discharge fast and any deleterious plasma concentration of losartan is too high subsequently, secondly it can guarantee that the treatment of two doses between taking in covers.

According to according to purposes of the present invention, the coating of described pharmaceutical dosage form or matrix design become to make average peak/paddy amplitude modulation of the metabolite EXP3174 that average peak/paddy amplitude modulation that this dosage form of oral administration individual specimen can cause the blood plasma feature of metabolite EXP3174 produces less than the same individual sample of the immediate release dosage form of the losartan of accepting same dose.

For the purposes of the present invention, the peak of plasma concentration feature/paddy amplitude modulation defines by the ratio Cmax/C24h of metabolite EXP3174.

According to purposes of the present invention, the coating of described pharmaceutical dosage form or matrix design become to make this dosage form of oral administration individual specimen can cause the variability of peak/paddy amplitude modulation of the metabolite EXP3174 that the variability of the peak/paddy amplitude modulation of the blood plasma feature of metabolite EXP3174 produces less than the same individual sample of the immediate release dosage form of the losartan of accepting same dose.

For the purposes of the present invention, the variability of the peak of plasma concentration feature/paddy key width of cloth defines by the standard deviation of the ratio Cmax/C24h of metabolite EXP3174.

The blood plasma feature that obtains is more even.Individual variability has reduced.

In noticeable mode, the present invention also proposes:

The coating or the purposes of substrate in comprising the oral Pharmaceutical dosage forms of losartan that comprise losartan, the release of described coating or substrate controlled release losartan, make this pharmaceutical dosage form of oral administration individual specimen (for example state under) on the feed can cause the reduction or the disappearance of individual blood plasma feature, the Tmax of described individual blood plasma feature is from being less than or equal to 1 hour, and preferably be less than or equal to 1.5 hours, the Tmax that advantageously arrives individual blood plasma feature was greater than 1 hour, and be preferably more than 1.5 hours, with respect to the pharmaceutical dosage form of release immediately with same dose administration same individual sample (for example state under) on the feed losartan, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety;

The coating or the purposes of substrate in the preparation pharmaceutical dosage form that perhaps comprise losartan, the release of described coating or substrate controlled release losartan, after the oral administration individual specimen (for example state under) on the feed, this pharmaceutical dosage form can cause the reduction or the disappearance of individual blood plasma feature, the Tmax of described individual blood plasma feature is from being less than or equal to 1 hour, and preferably be less than or equal to 1.5 hours, the Tmax that advantageously arrives individual blood plasma feature was greater than 1 hour, and be preferably more than 1.5 hours, with respect to the pharmaceutical dosage form of release immediately with same dose administration same individual sample (for example state under) on the feed losartan, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety;

In some patients, for example more than or equal to 15, and be preferably more than or equal 20, under the losartan of the same terms and same dose, the sustained release dosage form of losartan more used according to the invention and immediate release dosage form (IRF ^*), the pharmacokinetic parameter of its standard deviation particularly.

According to a modification, the present invention also relates to:

■ comprises the coating or the purposes of substrate in comprising the oral Pharmaceutical dosage forms of losartan of losartan, with respect to the pharmaceutical dosage form of the release immediately IRF that is administered to this same individual sample losartan with same dose ^*,, it reduces the variability of this pharmaceutical dosage form of administration blood plasma feature during the individual specimen, with respect to the pharmaceutical dosage form of the release immediately IRF that is administered to this same individual sample losartan with same dose ^*, it has guaranteed the effect of this pharmaceutical dosage form and the lower variability of treatment safety;

■ or comprise the coating of losartan or the purposes of substrate in the preparation oral Pharmaceutical dosage forms is with respect to the pharmaceutical dosage form of the release immediately IRF that is administered to this same individual sample losartan with same dose ^*, it causes the reduction of this pharmaceutical dosage form of administration variability of blood plasma feature during the individual specimen, with respect to the pharmaceutical dosage form of the release immediately IRF that is administered to this same individual sample losartan with same dose ^*, it can guarantee the effect of this pharmaceutical dosage form and the lower variability of treatment safety;

According to purposes of the present invention, the drug target dosage form can comprise the losartan of micro-unit form, and it can be especially:

The ■ microgranule, it is made up of the medicated core that comprises losartan separately, and it can make the coatings coating (being also referred to as the microgranule of coating hereinafter) of losartan sustained release with one deck at least;

■ and/or micropill, it is made up of substrate separately, and described substrate comprises losartan, and can make losartan sustained release (being also referred to as the substrate micropill hereinafter);

■ and/or the losartan micropill that discharges immediately.

According to purposes of the present invention, the target oral Pharmaceutical dosage forms can be any dosage form well known by persons skilled in the art,, is capsule, sachet, the suspension that comprises the losartan micro-unit or tablet especially that is.

These tablets can for

■ (i) comprises the tablet of losartan micro-unit,

■ (ii) or not contains the tablet of microgranule and/or micropill, described microgranule is made up of the medicated core that comprises losartan separately, it uses the coatings of one deck at least coating that can make the losartan sustained release, and described microgranule is separately by comprising losartan and the substrate of losartan sustained release being formed.

These tablets (ii) can be for matrix tablet or the coated tablet of respectively doing for oneself.

The average diameter (Dm represents with μ m) of losartan micro-unit (coated particle of sustained release and/or substrate micropill or the micropill that discharges immediately) is preferably less than 1000, preferably between 50 to 800, more preferably between 50 to 500.

Advantageously, according to purposes of the present invention, the oral Pharmaceutical dosage forms of expection can obtain to be defined as following blood plasma feature after dosage is taken in:

Cmax/C24h≤Cmax ^*/C24h ^*

Preferred 1.5 * Cmax/C24h≤Cmax ^*/ C24h ^*

And more preferably 2.0 * Cmax/C24h≤Cmax ^*/ C24h ^*

Wherein

℃ 24h is illustrated in dosage and takes in back 24 hours, the mean plasma concentration of the active metabolite EXP3174 of losartan,

℃ 24h ^*Be illustrated under the same terms as C24h, discharge the mean plasma concentration of the EXP3174 that oral Pharmaceutical dosage forms obtains immediately with the object of reference of losartan that comprises same dose,

℃ max is illustrated in the average maximal plasma concentration that dosage is taken in back EXP3174,

℃ max ^*Be illustrated under the same terms as Cmax, discharge the average maximal plasma concentration of the EXP3174 that oral Pharmaceutical dosage forms obtains immediately with the object of reference of losartan that comprises same dose,

According to first embodiment, described oral Pharmaceutical dosage forms comprises coating or substrate micropill, and it is 1 to 24 hour that the external stripping feature that has [D% (t)] can make after the administration time t (70%) when the losartan that discharges 70% finishes, preferred 2 to 12 hours, and more preferably 2 to 8 hours.

According to a favorable characteristics of this first embodiment, for time t be 2 hours between the t (70%), preferably 1 hour to the arbitrary value between the t (70%), the percentage ratio of (release) losartan of stripping [D% (t)] 〉=35 * t/t (70%).

Preferably, the oral Pharmaceutical dosage forms according to first embodiment is characterised in that the in-vitro release rate of losartan and pH are irrelevant in the stripping experiment.

Xiang Guan pH value is physiology pH under one's belt more especially, for example from 1 to 7.

Advantageously be equivalent to one of following two A families and B according to each coating of the microgranule of first embodiment or the compositions of each substrate:

A familyAt least a film forming polymer (P1) that is insoluble to gastro-intestinal Fluid of A-1-exists ratio (solid weight %) for respect to 50 to 90 of coated composition gross mass, and is preferred 50 to 80, and it comprises at least a water-insoluble cellulose derivative especially;

At least a polymer with nitrogen of A-2-(P2), there is ratio (solid weight %) in it is with respect to 2 to 25 of coated composition gross mass, preferred 5 to 15, and by at least a polyacrylamide and/or a kind of poly--N-ethernamine and/or a kind of poly N-ethylene lactams form;

At least a plasticizer of A-3-, having ratio (solid weight %) is with respect to 2 to 20 of coated composition gross mass, be preferably 4 to 15 solid weight, and by at least a composition the in the following compounds: glyceride type, O-phthalic acids, citric acid ester type, sebacic acid ester, spermol esters, Oleum Ricini;

At least a surfactant of A-4-and/or lubricant exist ratio (solid weight %) for being equivalent to 2 to 20 of coated composition gross weight, and be preferred 4 to 15, and be selected from anion surfactant and/or nonionic surfactant and/or lubricant; Described reagent can comprise only a kind of or its mixture of above-mentioned product.

The example of compd A-1, A-2, A-3 and A-4 is following quoting:

A-1: ethyl cellulose and/or cellulose acetate;

A-2: polyacrylamide and/or polyvinylpyrrolidone;

A-3: Oleum Ricini;

A-4: preferred stearic acid of fatty acid and/or oleic alkali metal or alkali salt, the polyoxyethylene ester of anhydro sorbitol, castor oil derivatives, stearate, preferred calcium stearate, magnesium stearate, aluminium stearate or zinc stearate.

B family:

B1-at least a in gastro-intestinal Fluid insoluble film forming polymer,

At least a water-soluble polymer of B2-,

At least a plasticizer of B3-,

B4-and randomly at least a surfactant/lubricant, it preferably is made up of at least a anion surfactant and/or at least a non-ionic surface active agent.

The example of compd B 1, B2, B3 and B4 is following quoting:

B1：

The water-insoluble cellulose derivative, special preferred, ethyl and/or cellulose acetate,

Acrylic acid derivative,

Polyvinyl acetate,

And composition thereof.

B2：

Water-soluble cellulose derivative,

Polyacrylamide,

It is poly--the N-ethernamine,

It is poly--the N-vinyl lactam,

Polyvinyl alcohol (PVA),

Polyoxyethylene (POE),

Polyvinylpyrrolidone (PVP) (latter is preferred),

And composition thereof;

B3：

Glycerol and ester thereof, preferred following subclass: acetylation glyceride, glyceryl monostearate, glyceryl triacetate, glycerin tributyrate,

Phthalic acid ester, preferred following subclass: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,

Citrate, preferred following subclass: tributyl 2-acetylcitrate, acetyl triethyl citrate, tributyl citrate, triethyl citrate,

Sebacate, preferred following subclass: ethyl sebacate, dibutyl sebacate,

Adipate ester,

Azelate,

Benzoate,

Vegetable oil,

Fumarate, preferred DEF,

Malate, the preferably apple diethyl phthalate,

Oxalate, preferred ethyl oxalate,

Succinate, preferred dibutyl succinate,

Butyrate,

The spermaceti alcohol ester,

Salicylic acid,

Malonate, preferred diethyl malonate,

Oleum Ricini (this is particularly preferred),

And composition thereof;

B4：

The preferred stearic acid of fatty acid and/or oleic alkali metal or alkali salt,

Polyoxyethylene oil, polyoxyethylene hydrogenated Oleum Ricini preferably,

Polyoxyethylene-polyoxypropylene copolymer,

Sorbitan ethoxylate,

Castor oil derivatives,

Stearate, preferred calcium stearate, magnesium stearate, aluminium stearate or zinc stearate,

The stearoyl-fumarate ester, preferred sodium stearyl fumarate,

Behenic acid glyceride,

And composition thereof.

Preferably, described coating is made up of a coatings, and its quality accounts for 1% to 50% weight of microgranule gross mass, preferred 5% to 40% weight.

Provided acquisition among the WO-A-03/084518 according to the compositions of the microgranule of first embodiment of the present invention and other detailed description and the example of method, its content is integrated with this description with way of reference.

For the further qualitative and quantitative relevant A1﹠amp of family; The detailed description of the coated composition of A2 can be respectively with reference to European patent EP-B-0709087 and patent application WO-A-2004/010984, and its content is integrated with this description with way of reference.

According to second embodiment, described oral Pharmaceutical dosage forms at first comprises coated particle and/or substrate micropill, and makes:

The release of zero losartan is subjected to the control of two different triggering mechanisms, and a kind of pH that is based on changes, and another kind makes losartan keep under one's belt discharging after one period predetermined time of staying;

Zero under 1.4 constant pH, and described stripping feature comprises that having the persistent period is less than or equal to 7 hours, preferably is less than or equal to 5 hours, and lag phase of 1 to 5 hour more preferably,

Zero and cause release period from pH 1.4 to pH 7.0, and without any time delay.

Advantageously, the stripping feature of in external dissolution test, measuring that has following demonstration according to the oral Pharmaceutical dosage forms of this second mode:

Zero discharges after pH is 1.4 times 2 hours less than 20% losartan;

Zero at least 50% losartan discharges after pH is 1.4 times 16 hours.

According to another preferable feature, comprise the losartan microgranule of sustained release according to the oral Pharmaceutical dosage forms of this second mode, it causes pH value is 6.0 to 6.5, and comprises endpoint value.

Advantageously, the losartan microgranule according to the sustained release of second embodiment has following specific feature:

-make the coating of losartan sustained release or substrate comprise composite

Zero comprises:

-at least a hydrophilic polymer I, it has can be ionized under neutral pH

Group,

-at least a hydrophobic compound II;

The mass fraction (with respect to the % of microgranule gross mass)≤40 of zero expression; With

-their average diameter is less than 1000 μ m, is preferably 50 to 800 μ m, more preferably 50 to 500 μ m.

According to another favourable feature, make the coating of losartan sustained release or groundmass composite material I-II be:

-weight ratio II/I is 0.2 to 1.5, and is preferred 0.5 to 1.0,

-being selected under solid-state with hydrophobic compound II is crystalline product, its fusing point T _FII〉=40 ℃, T preferably _FII〉=50 ℃, and 40 ℃≤T more preferably _FII≤ 90 ℃.

According to one preferred embodiment, described hydrophilic polymer I is selected from:

The acrylic acid copolymer of-I.a (methyl) and (methyl) acrylic acid Arrcostab and composition thereof;

-I.b cellulose derivative, preferred cellulose acetate, cellulose phthalate, cellulose hemisuccinate salt and composition thereof, and more preferably hydroxypropylmethyl cellulose phthalate, hydroxypropyl methylcellulose acetas and hydroxypropyl methylcellulose succinate and composition thereof;

-and composition thereof.

More preferably, polymer I is (methyl) acrylic acid copolymer and (methyl) acrylic acid Arrcostab (for example C1-C6 alkyl).These copolymers are for example to be sold by the R  hm PharmaPolymers of company, the serial L of registered trade mark Eudragit  and S (for example Eudragit  L100, S100, L30D-55 and L100-55).These copolymers are anionic enteric copolymer, and it is under greater than the pH value of stomach pH in the water soluble medium.

Still according to preferred embodiment, Compound I I is selected from following group of products:

The II.a vegetable wax mixes separately or mutually and uses;

The II.b hydrogenated vegetable oil mixes separately or mutually and uses;

The glyceryl list of at least a fatty acid of II.c-and/or two-and/or triester;

The mixture of glyceryl monoesters, diester and the triester of at least a fatty acid of II.d;

II.e and composition thereof.

More preferably, Compound I I is selected from following group of products: cotmar, hydrogenated soybean oil, hydrogenated palm oil, behenic acid glyceride, castor oil hydrogenated, tristearin, glyceryl tripalmitate, trimyristin (trimyristine), Cera Flava, as hard lipid or fat, anhydrous lactitol system fat, lanoline, palmitostearate, tristerin, lauryl polyethyleneglycol glyceride, spermol, polyglyceryl diisopstearate, diglycol stearate, glycol stearate, ω 3 and any mixture thereof of suppository base.

Preferably be selected from following group of products: cotmar, hydrogenated soybean oil, hydrogenated palm oil, behenic acid glyceride, castor oil hydrogenated, tristearin, glyceryl tripalmitate (tripalmitine), trimyristin (trimyristine) and any mixture thereof.

In practice, without limitation, Compound I I preferably is selected from:

-with following trade name product sold: Dynasan , Cutina , Hydrobase , Dub , Castorwax , Croduret , Compritol , Sterotex , Lubritab , Apifil , Akofine , Softtisan , Hydrocote , Livopol , Super Hartolan , MGLA , Corona , Protalan , Akosoft , Akosol , Cremao , Massupol , Novata , Suppocire , Wecobee , Witepsol , Lanolin , Incromega , Estaram , Suppoweiss , Gelucire , Precirol , Emulcire , Plurol diisost é arique , Geleol , Hydrine , Monthyle  and composition thereof;

-and be selected from the following additive group of symbol: E 901, E 907, E 903 and composition thereof;

-and preferably be selected from following trade name product sold group: Dynasan  P60, Dynasan  114, Dynasan  116, Dynasan  118, Cutina  HR, Hydrobase  66-68, Dub  HPH, Compritol  888, Sterotex  NF, Sterotex  K, Lubritab  and composition thereof.

According to another favourable feature of the present invention, can make the coating of losartan sustained release or substrate not contain Talcum.

Advantageously, except that key component I and II, the coating of microgranule or substrate also comprise other standard analysis well known by persons skilled in the art, especially such as:

Zero dyestuff,

Zero plasticizer, dibutyl sebacate for example,

Zero hydrophilic compounds, for example cellulose and derivant thereof or polyvinylpyrrolidone and derivant thereof,

Zero and composition thereof.

Without limitation, according to a preferred embodiment, described coatings by the losartan microgranule of the sustained release of coating only comprises the compound coating film I-II of one deck.

Provided among the WO-A-03/030878 and obtained the compositions of microgranule second embodiment of the invention and other detailed description and the example of method, its content is incorporated this description into way of reference.

Quantitatively, but described coating monolayer typical example and preferably is no more than the microgranule of 30% weight as being no more than 40%.The content of this qualification of coating can produce the galenical unit, and it comprises the losartan of high dose respectively, and does not have to surpass the particle diameter about forbidding swallowing.Thereby, undoubtedly improved the compliance of treatment and the successful property of treatment.

According to the 3rd embodiment, oral Pharmaceutical dosage forms comprises at least two kinds of microgranules.The losartan microgranule of every kind of sustained release can be consistent with above-mentioned first or second embodiment.

According to a modification-2i-of second embodiment and the 3rd embodiment combination, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention comprises that at least two classes have the microgranule of different stripping features, and the pH value of at least one class is between 1.4 to 7.4.

According to a modification-2ii-of second embodiment and the 3rd embodiment combination, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention comprises the losartan microgranule of at least two kinds of sustained release, and it has different separately initiation pH value.

According to another modification-2iii-of second embodiment and the 3rd embodiment combination, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention comprises the losartan microgranule of at least two kinds of sustained release, and it has the different separately initiation time.

According to the 4th embodiment, the oral Pharmaceutical dosage forms that uses in according to the present invention comprises the losartan microgranule and at least a losartan microgranule that discharges immediately of at least a sustained release;

According to a modification-2iv-of second embodiment and the 4th embodiment combination, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention comprises:

→ at least a losartan the micropill that discharges immediately;

The losartan microgranule P of → at least a sustained release ₁And

The losartan microgranule P of → at least a sustained release ₂,

And P ₁And P ₂The pH value of initiation separately differ at least 0.5 pH unit, preferred at least 0.8 pH unit, and more preferably at least 0.9 pH unit.

Advantageously, the pH value of initiation separately of the losartan microgranule of various sustained release is between 5 and 7.

According to a modification-2v-of second embodiment and the 4th embodiment combination, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention comprises:

→ at least a losartan the micropill that discharges immediately;

The losartan microgranule P of → at least a sustained release ₁', it causes pH value and equals 5.5; With

The losartan microgranule P of → at least a sustained release ₂', it causes pH value is between 6 to 6.5, and comprises endpoint value.

Modification-the 2iv-of second embodiment and-the kind P of 2v- ₁, P ₂, P ₁' and P ₂' comprise the losartan microgranule of the sustained release that obtains according to second embodiment.

In order to set forth modification of the present invention, the losartan micro-unit that discharges immediately according to this modification is present in the oral Pharmaceutical dosage forms that uses in purposes according to the present invention, can be pointed out that these modification are equivalent to the situation that this pharmaceutical dosage form comprises for example at least a losartan micropill that discharges immediately.

When the oral Pharmaceutical dosage forms that uses in according to first embodiment comprises the losartan microgranule of sustained release, according to the similar factors f2 that as shown in FDA directive SUPAC-MR-Modified Release Solid OralDosage Forms, calculates, the stripping feature class of described microgranule between pH 1 to pH 5 seemingly, that is, it is f2 〉=50%.

The oral Pharmaceutical dosage forms of using in purposes according to the present invention can comprise at least a effective ingredient that is different from losartan.Have no difference ground, abbreviation AP will represent hereinafter that one or more are different from the effective ingredient of losartan.

In the body of AP or release in vitro can be immediately or control.AP can be included in the micro-unit of the micro-pill type that discharges AP immediately or in the microgranule of sustained release AP.

This AP can be selected from diuretic, beta-Blocking agent, inhibitor, sodium channel inhibitor, α-Zu Zhiji, alpha-beta-blocker, vasodilation, alpha antagonist and epinephrine neuron blocker especially.

In order to be described in further detail relevant these other effective ingredient,, the page 4 the 19th of reference example such as WO-A-03/035039 goes but walking to page 4 the 31st.

The microgranule of above-mentioned target coating can have several structures.

Therefore, according to first kind of form of coated particle structure, the losartan microgranule of the sustained release of some oral Pharmaceutical dosage forms comprises separately at least:

→ one medicated core that comprises losartan and

→ one deck covers the coating of described medicated core at least, and it makes described losartan sustained release.

Therefore, according to second kind of form of coated particle structure, the losartan microgranule of the described sustained release of some oral Pharmaceutical dosage forms comprises separately at least:

→ medicated core, it comprises:

01 neutral medicated core and

Zero at least one active layer, it comprises losartan and the described neutral medicated core of coating,

→ covering the coating of described medicated core with at least one, it makes the losartan sustained release.

Advantageously, the ratio (be expressed as weight percent solids with respect to micro-unit gross mass) of losartan in micro-unit is 5 to 80, and be preferred 10 to 70, and more preferably 15 to 70.

According to a kind of probability, the losartan micropill of Shi Fanging is the not coating medicated core of the losartan microgranule of sustained release immediately.

Shown in before, the present invention relates to the oral Pharmaceutical dosage forms of those common aforesaid particular group.The pharmaceutical dosage form of particular group is the micro-unit that comprises that the losartan microgranule by coating forms.The various pharmaceutical dosage forms of every kind of particular group for as the losartan that in claim 31 or 32, characterizes slow down the release oral Pharmaceutical dosage forms.

In case pharmaceutical dosage form as claimed in claim 31 is designed to take in micro-unit, when their arrived stomach, micro-unit was disperseed and individuation, no matter on the feed or under the fasting state, it can guarantee the uniform and gastric emptying progressively of micro-unit, thereby finally discharges losartan at its gastrointestinal bio-absorbable window.

In context as the pharmaceutical dosage form of claim 31 or 32:

● described micro-unit is represented:

Zero usefulness at least one deck can make losartan slow down release the coatings coating microgranule and

The zero losartan micropill that discharges immediately;

Zero does not contain separately by the microgranule that comprises losartan and the substrate (being also referred to as the substrate micropill hereinafter) of losartan sustained release is formed;

● statement " disperses and individuation " to refer to that they do not sink in the substrate when losartan base micro-unit enters in the stomach after absorption.They just disperse (for example, in less than two minutes) under one's belt in case described micro-unit arrives wherein.

Advantage as the pharmaceutical dosage form of claim 31 or 32 is following especially:

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day is ingested in case guarantee this oral Pharmaceutical dosage forms, and the losartan that can will comprise discharges into gastrointestinal tract, and in its absorption window bio-absorbable;

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day is ingested in case guarantee this oral Pharmaceutical dosage forms, and its losartan that comprises can be through before its bio-absorbable window with being released;

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day is ingested in case guarantee this oral Pharmaceutical dosage forms, and its losartan that comprises will be released, and irrelevant with the state that opens or closes of pylorus;

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day is with the dosage form once a day that discharges the immediately equivalence at least of present use;

There is not or only seldom exists following phenomenon in this oral Pharmaceutical dosage forms of-the losartan that can be administered once every day: absorb in the final body of gastric emptying and losartan and the interindividual variation of active metabolite E3174.

This oral Pharmaceutical dosage forms of-losartan is that therapeutics is effective, and is for example when be administered once every day, effective above 80% patient;

-can be administered once and comprise this oral Pharmaceutical dosage forms of the losartan of the losartan micro-unit of slowing down release every day, have the small particle diameter (50-1000 μ m) of these micro-units and the advantage of a large amount of (for example every doses is thousands of), it allows progressively and fine controlled gastric emptying, and is irrelevant with patient's dietary intake;

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day can increase the Tmax of losartan and the period that blood plasma losartan concentration is higher than blood plasma benchmark losartan concentration, and losartan is failed to respond to any medical treatment under blood plasma benchmark losartan concentration;

The external stripping feature of this oral Pharmaceutical dosage forms of-losartan and the dosage indifference of losartan;

This oral Pharmaceutical dosage forms of-losartan can have identical weight and form the dosage indifference of the losartan that comprises with it;

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day inconvenient patient that is suitable for swallowing is especially for not only not swallowing but also need adjusting the child or the baby of dosage with their body weight;

This oral Pharmaceutical dosage forms of-losartan that can be administered once every day, the probability that losartan and one or more other effective ingredient is mixed into same peroral dosage form is provided, can be easy to the release time separately of these plurality of active ingredients regulate, and with irrelevant each other;

But this oral Pharmaceutical dosage forms of the losartan that is administered once-every day, although losartan dissolution variability in water is relevant with pH, it can discharge according to identical kinetics, no matter whether fasting of described patient;

This oral Pharmaceutical dosage forms of-losartan can be present in the various galenic dosage forms, comprises especially: tablet, sachet, can drink suspension, capsule etc.

-oral galenic dosage form according to the present invention is made up of the micro-unit (losartan microgranule or micropill) of a large amount of (for example from about 1,000 to several thousand), this multiplicity has been guaranteed to spread all over whole gastrointestinal losartan from statistics and has been transmitted dynamic (dynamical) well reproduced, therefore, the good control of bioavailability and effect have preferably been guaranteed;

-use has the different particle mixtures that slows down release characteristic and can produce following release characteristic: have several release waveforms, perhaps utilize and suitably regulate the plasma concentration that various composition branch rates have been guaranteed the losartan of constant level;

-reduced sensitivity, because the gastric emptying that takes place is more reproducible on the statistics on a large amount of granules to the gastric emptying variability;

-avoided contacting of tissue and high dose losartan (" dosage coming down in torrents ").Especially, each micro-unit only comprises very small amount of losartan.Therefore, this has overcome because the too high danger that makes lesion tissue of local concentration of corrosive losartan;

-this pharmaceutical dosage form does not cause any degraded of losartan, has kept the polymorphic of initial losartan;

-when suitable, the characteristic of the particle diameter of 50 to 1000 μ m and their coating makes micro-unit increase their transmission times in upper gastro-intestinal tract, it can guarantee to increase the time that losartan passed through before its absorption window, thereby makes the bioavailability maximization of losartan.

Preferably, at least some micro-units as claim 31 or 32 described these pharmaceutical dosage forms are the microgranule that each free medicated core is formed, and described medicated core comprises losartan and can make losartan slow down the coatings coating of release with one deck at least.

Micro-unit about as the particle type of claim 31 or 32 described pharmaceutical dosage forms should be noted that, can control the coating that losartan slows down release and comprise the acceptable excipient of pharmacy basically.

For some micro-unit at least of claim 31 or 32 described pharmaceutical dosage forms, it is made up of the losartan micropill that discharges immediately also is very favorable.

Preferably, be characterised in that as claim 31 or 32 described pharmaceutical dosage forms: the plasma concentration area under curve (AUC of active metabolite E3174 after the object of reference of taking in the losartan that comprises same dose as the variability CV (%) of the plasma concentration area under curve (AUC) of time (T) function for dosage under the same conditions that dosage is taken in back active metabolite E3174 discharges oral Pharmaceutical dosage forms immediately as time (T) function ^*) corresponding variability CV ^*(%) be less than or equal to 200%, preferred 150%, and more preferably 120%, i.e. CV≤2.0 * CV ^*, CV≤1.5 * CV ^*, and preferred CV≤1.2 * CV ^*

Pharmacokinetic parameter CV and AUC are well known to those skilled in the art.

Slow down release dosage form and IRF according to losartan of the present invention ^*Comparison, particularly parameters C V and CV ^*, AUC and AUC ^*Relatively be under the identical condition with under identical losartan dosage, carry out in the significant mode of statistics.

The external stripping feature of all that relate to is according to Europeanpharmacopea in this manual, the 4th edition, name is called: " Test of the dissolution of solid oral forms ": remain on 37 ℃ SINK condition and stir with 100rpm under the II type dissolution test carried out carry out.

According to first embodiment, can make as the external stripping feature that has at claim 31 or 32 described pharmaceutical dosage forms: 70% losartan is after the administration between 1 to 24 hour, preferably between 2 to 12 hours, and more preferably discharges between 2 to 8 hours.

Advantageously, in first embodiment, the pharmaceutical dosage form described in claim 31 or 32 is characterised in that the in-vitro release rate of losartan in dissolution test and pH have nothing to do.

More particularly Xiang Guan pH value is the physiological pH value of stomach, for example those of from 1 to 7.

As the described pharmaceutical dosage form of claim 31 in first embodiment to merit attention character more useful to losartan because the dissolubility of known losartan in water greatly depends on pH, as mentioned above.

In first embodiment, advantageously consistent with one of two A of family of above-mentioned definition and B as claim 31 or the 32 described compositionss that are used for coating (coating membrane) microgranule.

In first embodiment, consistent as those of claim 31 or the 32 described coatings (coating membrane) that are used for microgranule and the logical family that is used for micro-unit of the present invention as mentioned above.

Relevant in first embodiment, be to obtain detailed description and example, and about the qualitative and quantitative data of the coated composition of A family, situation also is like this as the compositions and the method for claim 31 or 32 described these microgranules.

According to second embodiment, pharmaceutical dosage form as claimed in claim 31 be so so that:

The release of → losartan is subjected to two kinds of independent initiation mechanism controls, and a kind of pH that is based on changes, and another kind makes AP keep under one's belt discharging after one period predetermined time of staying;

→ under 1.4 constant pH, described dissolving characteristic comprises that having the persistent period is less than or equal to 7 hours, preferably is less than or equal to 5 hours, and lag phase of 1 to 5 hour more preferably,

And can cause release period from pH 1.4 to pH 7.0, and not have lag time.

In order to illustrate in greater detail second embodiment, with reference to the above-mentioned explanation of second embodiment of the micro-unit of the logical family of the present invention.

Similarly, each situation all can directly be changed, and be suitable for as claim 31 or 32 described pharmaceutical dosage forms, described situation is pointed out hereinbefore, its micro-unit with the logical family of the present invention is relevant, described micro-unit from " the 3rd embodiment " extremely according to the probability of its " the losartan micropill of Shi Fanging is the medicated core of not coating that slows down the losartan microgranule of release immediately ".

There are several crystal forms in losartan, and one of them is crucial especially for pharmaceutically active, i.e. crystalline form I.Importantly keep the latter.Therefore, the method that is used to prepare pharmaceutical dosage form according to the present invention can keep the initial crystal form of losartan.In pharmaceutical dosage form of the present invention, for example, at least 50% losartan is its crystalline form I.

About preparing the microgranule of coating of the present invention, it relates to the accessible microencapsulation technology of those skilled in the art, and former reason C.Duverney wherein and J.P.Benoit summarize in the article of in December, 1986 at " L ' actualit é chimique ".More particularly, the technology in the consideration causes " bank " system of the individuation opposite with matrix system for to use the coating membrane microencapsulation.

But more detailed description referenced patent EP-B-0953359.

Can and/or there be at least a standard binders in the losartan granule for preparing the essential desired particle size standard of microgranule of the present invention and/or be used to improve one of the conventional method that stands under the situation of reagent of intrinsic dissolution feature of losartan via this area pretreated crystal for pure losartan crystal, and described conventional method is granulation for example.Losartan can, for example via method known to those skilled in the art, for example " spray coating " deposition techniques in the fluidization air bed is on medicated core, or by formation such as wet grain methods, compression method, extruding-round as a ball.

Advantageously, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention is the dosage form of single oral dose every day, and described dosage comprises 1000 to 500000 micro-units that contain losartan.

More particularly, the oral Pharmaceutical dosage forms that uses in purposes according to the present invention can be the dosage form of single oral dose every day, and described dosage comprises the losartan microgranule of 1000 to 500000 sustained release.

Can provide with the liquid suspension of the losartan microgranule of the powder sachet of the losartan microgranule of sustained release, sustained release, the tablet of losartan microgranule that may comprise sustained release or the capsule that comprises the losartan microgranule of sustained release according to oral Pharmaceutical dosage forms of the present invention.

One object of the present invention also be as according to described in the context of purposes of the present invention and itself and the irrelevant oral Pharmaceutical dosage forms of the purposes of expection.

According to another purpose, the present invention relates to the losartan microgranule of sustained release as defined above and the optional as defined above losartan microgranule that discharges immediately at the preparation microgranule medicinal or diet with oral galenic dosage form in purposes, described oral lid human relations dosage form is preferably and advantageously is a mouthful dispersible Tabules or powder or capsule.

According to another purpose, the present invention relates to losartan microgranule and/or the micropill and the optional as defined above purposes of the losartan micropill that discharges immediately in the microgranular oral Pharmaceutical dosage forms of preparation therapeutics safety of sustained release as defined above, described dosage form design becomes in case absorbed described pharmaceutical dosage form, it microgranule that comprises can disperse and individuation when they arrive stomach, this makes these microgranules suffer uniformly and gastric emptying progressively, no matter described patient is feed or fasting state during dosage is taken in, but thereby guaranteed the release of losartan in its gastrointestinal biology absorption window, it participates in the variability of the blood plasma feature of reduction losartan.

According to another purpose, the present invention relates to coated particle and/or substrate micropill itself as defined above.

According to other purpose, the present invention relates to:

■ is used for the treatment of hypertensive Therapeutic Method, it is characterized in that it comprises the pharmaceutical dosage form that uses with single oral dose every day administration preferably in as defined above according to purposes of the present invention;

■ is used for the reproducible method of the mankind or animal oral medication, it is characterized in that it consists essentially of the pharmaceutical dosage form that oral administration comprises losartan, described losartan is included in coating or the substrate, described coating or substrate comprise losartan and make described losartan sustained release, therefore, this dosage form of oral administration is to individual specimen, no matter described individuality is feed or fasting state, the capital causes that standard deviation reduces between the individuality of Cmax, with respect to the pharmaceutical dosage form of release immediately that is administered to same individual sample losartan with same dose, it can guarantee the lower variability of efficacy of drugs and therapeutics safety.

■ is used for the reproducible method of the mankind or animal oral medication, it is characterized in that, this method is that basically oral administration comprises the pharmaceutical dosage form of losartan, described losartan is included in coating or the substrate, described coating or substrate give this pharmaceutical dosage form such character, make this dosage form of oral administration to individual specimen, no matter described individuality is feed or fasting state, the capital causes the reduction or the disappearance of individual blood plasma feature, the Tmax of described individual blood plasma feature is from being less than or equal to 1 hour, and preferably be less than or equal to 1.5 hours, the Tmax that advantageously arrives individual blood plasma feature was greater than 1 hour, and be preferably more than 1.5 hours, discharge the losartan pharmaceutical dosage form immediately with respect to administration same individual sample, it can guarantee the effect of pharmaceutical dosage form and the low variability of treatment safety;

■ is used for the reproducible method of the mankind or animal oral medication, it is characterized in that it consists essentially of the pharmaceutical dosage form that oral administration comprises losartan, described losartan is included in coating or the substrate, with respect to the pharmaceutical dosage form that discharges immediately that is administered to same individual sample losartan, reduced the variability of blood plasma feature during this pharmaceutical dosage form of administration individual specimen, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety;

■ is used for the reproducible method of the mankind or animal oral medication, it is characterized in that it consists essentially of the pharmaceutical dosage form that oral administration comprises losartan, the dissolubility of losartan depends on the pH of stomach, losartan is included in coating or the substrate and can gives this pharmaceutical dosage form such character, so that this dosage form of oral administration is to individual specimen, can cause the reduction of variation coefficient between the individuality of Tmax, discharge pharmaceutical dosage form immediately with respect to the losartan that is administered to this same individual sample same dose, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety.

Description of drawings

Zero Fig. 1 represents the external stripping feature of losartan microgranule under pH 6.8 according to the sustained release of embodiment 2;

Zero Fig. 2 represents the external stripping feature of losartan microgranule under pH 1.4,4.5 and 6.8 according to the sustained release of embodiment 2;

Zero Fig. 3 represents the external stripping feature of losartan microgranule under pH 6.8 according to the sustained release of embodiment 2, and the dosage of losartan is between 10 to 200mg;

Zero Fig. 4 represents the external stripping feature of losartan microgranule under pH 1.4 and 6.8 according to the sustained release of embodiment 3;

Zero Fig. 5 represents the external stripping feature of losartan microgranule under pH 1.4 and 6.8 according to the sustained release of embodiment 4;

Zero Fig. 6 represents the external stripping feature of losartan microgranule under pH 1.4 according to the sustained release of embodiment 4, and the dosage of losartan is between 10 to 200mg;

Zero Fig. 7 represents the external stripping feature of losartan microgranule under pH 6.8 according to the sustained release of embodiment 5;

Zero Fig. 8 is illustrated in the individual pharmacokinetics feature of losartan behind the drug-delivery preparation C1, and described formulation C 1 does not comprise in the context of the present invention.Will be noted that quick Pr of colony and the slowly existence of the Ps of colony among Fig. 8.

Zero Fig. 9 is illustrated in the individual pharmacokinetics feature of EXP3174 behind the drug-delivery preparation C1, and described formulation C 1 does not comprise in the context of the present invention.Will be noted that quick Pr of colony and the slowly existence of the Ps of colony among Fig. 9.

Zero Figure 10 be illustrated in administration according to the preparation M1 of embodiment 2 after the individual pharmacokinetics feature of losartan, described preparation M1 comprises in the context of the present invention.To notice that said preparation M1 causes the single slow Ps of colony of plasma concentration feature.

Zero Figure 11 represents the individual pharmacokinetics feature of EXP3174 after administration is according to the preparation M1 of embodiment 2;

Zero Figure 12 represents the individual pharmacokinetics feature of losartan after administration is according to the preparation M2 of embodiment 4;

Zero Figure 13 represents the individual pharmacokinetics feature of EXP3174 after administration is according to the preparation M2 of embodiment 4;

In whole accompanying drawings, stripping feature and conduct in hour the percetage by weight (D) of losartan of stripping of time (t) function consistent.

The specific embodiment

In the following embodiments, excipient is for to represent as its trade name.It sees table with the corresponding of chemical name:

Trade name	Chemical name/special topic
Trade name	Chemical name/special topic	Cremophor RH
40	The polyethylene glycol glycerol hydroxy stearic acid ester	Cremophor RH
40	The polyethylene glycol glycerol hydroxy stearic acid ester	Klucel EF	Hydroxypropyl cellulose
Plasdone K29/32	Polyvidone	Klucel EF	Hydroxypropyl cellulose
Plasdone K29/32	Polyvidone	Eudragit L100-55	Poly-(methacrylic acid, ethyl acrylate) 1: 1
Eudragit S100	Poly-(methacrylic acid, methylmethacrylate) 1: 2	Eudragit L100-55	Poly-(methacrylic acid, ethyl acrylate) 1: 1

Embodiment 1: the preparation of Losartan Potassium micropill

The Klucel EF  (Aqualon) of 810g Losartan Potassium and 90g is dispersed in the isopropyl alcohol of 3000g.In Glatt GPCG1 flush coater, this suspension is sprayed on neutrality (Asahi-Kasei) microsphere of 100g.

The Losartan Potassium concentration of gained micropill is 81%.

Embodiment 2: the preparation of Losartan Potassium microgranule

The Oleum Ricini of the Cremophor RH 40 (BASF) of PlasdoneK29/32  (ISP), the 10g of the ethyl cellulose (Ethocel 20 Premium/Dow) of 200g, 15g and 25g is dispersed in the mixture that 60% isopropyl alcohol and 40% acetone forms.With this solution spray (preparation in embodiment 1) on the Losartan Potassium micropill of 750g.

Then, the gained microgranule is placed the gelatine capsule of No. 2 sizes.In this experiment, the dosage setting of Losartan Potassium is 100mg (being the microgranule of 165mg) in each capsule.This capsule has constituted the final dosage form of medicine.

In II type dissolution experiment, at 37 ℃ with at pH 6.8 (0.05MKH according to Pharmacopea ₂PO ₄/ stir with 100rpm under NaOH) and test the capsule that comprises described microgranule.Referring to Fig. 1.

In II type dissolution experiment, at 37 ℃ with at pH 1.4 (HCl) according to Pharmacopea; 4.5 (KH ₂PO ₄/ NaOH) and 6.8 (KH ₂PO ₄/ stir with 100rpm under NaOH) and test the capsule that comprises described microgranule.Referring to Fig. 2.

The release of finding losartan is in fact irrelevant with the pH of dissolution medium, and this makes the proper interior pH that does not rely on gastric juice that discharges.

For the influence of the dosage of studying Losartan Potassium, in II type dissolution experiment, at 37 ℃ with at pH6.8 (KH according to Pharmacopea to the stripping feature ₂PO ₄/ dosage that stir to measure effective ingredient with 100rpm under NaOH) is 10,25,50,100,150 and the release of the losartan of the microgranule of 200mg.Referring to Fig. 3.The dosage indifference of described stripping feature and losartan.

Embodiment 3: the preparation of Losartan Potassium microgranule

(L100-55 (R  hm) is dissolved in the hot isopropyl alcohol with the cotmar (Penwest) of 100g and the Eudragit  of 150g.This solution spray (is prepared in embodiment 1) on the Losartan Potassium micropill of 750g.

In II type dissolution experiment, at 37 ℃ with at pH 1.4 (HCl) with at 6.8 (0.05M KH according to Pharmacopea ₂PO ₄/ stir with 100rpm under NaOH) and test the capsule that comprises described microgranule.Referring to Fig. 4.

Embodiment 4: the preparation of Losartan Potassium microgranule

With the cotmar (Penwest) of 100g, the Eudragit  S100 (R  hm) of the Eudragit  L100-55 of 50g (R  hm) and 100g is dissolved in the hot isopropyl alcohol.This solution spray (is prepared in embodiment 1) on the Losartan Potassium micropill of 750g.

In II type dissolution experiment, at 37 ℃ with at pH 1.4 (HCl) with at 6.8 (0.05M KH according to Pharmacopea ₂PO ₄/ stir with 100rpm under NaOH) and test the capsule that comprises described microgranule.Referring to Fig. 5.For the influence of the dosage of studying Losartan Potassium, in II type dissolution experiment, at 37 ℃ with at pH 1.4 (KH according to Pharmacopea to the stripping feature ₂PO ₄/ dosage that stir to measure effective ingredient with 100rpm under NaOH) is 10,25,50,100,150 and the release of the losartan of the microgranule of 200mg.Referring to Fig. 6.The dosage indifference of described stripping feature and losartan.

Embodiment 5: the preparation of Losartan Potassium microgranule

The Cremophor RH 40 (BASF) of PlasdoneK29/32  (ISP), the 6g of the ethyl cellulose (Ethocel 20Premium/Dow) of 120g, 9g and 15 Oleum Ricini are dispersed in the mixture of being made up of 60% isopropyl alcohol and 40% acetone.This solution spray (is prepared in embodiment 1) on the Losartan Potassium micropill of 850g.

Then, the gained microgranule is placed the gelatine capsule of No. 2 sizes.In this experiment, the dosage setting of Losartan Potassium is 100mg (being the microgranule of 145mg) in each capsule.This capsule has constituted the final dosage form of medicine.

In II type dissolution experiment, at 37 ℃ with at pH6.8 (0.05MKH according to Pharmacopea ₂PO ₄/ stir with 100rpm under NaOH) and test the capsule that comprises described microgranule.Referring to Fig. 7.

Embodiment 6: based on the tablet of Losartan Potassium microgranule

Use the Erweka laboratory stirrer that the microgranule of 165g gained in embodiment 4, the lactose of 280g, the crospovidone of 40g and the magnesium stearate of 15g are mixed.

Use the preparation of Korsch tablet machine to comprise the tablet of the said mixture of 500mg dosage.These tablets constitute the final dosage form of medicine.

The external stripping feature of the tablet that makes thus under pH 1.4 (HCl) is identical with the capsule of embodiment 4.Referring to Fig. 5.

As can be seen hangover of Losartan Potassium and delaying to about 10 hours time, it makes has increased the bio-absorbable time during this medicine of administration, and meets patient's chronobiology best.

Embodiment 7: data in the body

The pharmaceutical dosage form that uses

100mg Cozaar  sheet (trade name) C1

Pharmaceutical dosage form M1 according to the losartan of embodiment 2

Pharmaceutical dosage form M2 according to the losartan of embodiment 4

The test explanation

During orthogonal experiment research,, the preparation M1 of

embodiment

2 and 4 and M2 and formulation C 1 are administered to 20 healthy volunteers once a day with the dosage of 100mg after the meal early.In the time: measured the plasma concentration of losartan and EXP3174 (active metabolite that it is main) after the administration in 0-0.25-0.5-0.75-1-1.5-2-3-4-6-8-10-12-16-18-20-24-36-48 hour.

Pharmacokinetics result

The individual pharmacokinetics feature of losartan behind administration M1, M2 and the C1 has been described respectively among Figure 10,12 and 8.The individual pharmacokinetics feature of metabolite EXP3174 behind administration M1, M2 and C1 has been described respectively among Figure 11,13 and 9.

Notice that the formulation C 1 that is not included in the context of the invention causes the losartan of two types (Pr and slowly Ps fast) and the plasma concentration feature of metabolite EXP3174 thereof.

Notice that also formulation C 1 causes the Cmax (high standard deviation) that distributes non-constant width.

On the other hand, only cause the feature of a kind of slow type Ps, and cause the cmax value of substandard deviation according to preparation M1 of the present invention and M2.

Behind administration C1, M1 and the M2, for the feature of losartan, the Tmax that individual amount distributes provided in following table 1 less than 1 and 1.5 hour:

Table 1

Treatment	Individual amount (%)
	Individual amount (%)		Tmax≤1h	Tmax≤1.5h
	C1 M1 M2	2(10％) 0(0％) 0(0％)	Tmax≤1h	Tmax≤1.5h	4(20％) 0(0％) 1(5％)

Find,, can reduce individual ratio considerably with short Tmax according to preparation M1 of the present invention and M2 with respect to reference formulation C 1.

Average pharmacokinetic parameter ± SD of losartan (Cmax and Tmax) and metabolite EXP3174 (Cmax, Tmax, C24h, Cmax/C24h) thereof provides in the following table 2.

Table 2

	Losartan			EXP3174
	Losartan			EXP3174					Treatment	Cmax (ng/mL)	Tmax (h)	AUC _0-48h ng/(mLxh)	Cmax (ng/mL)	Tmax (h)	AUC _0-48h (ng/mLxh)	C24h (ng/mL)	C24h/Cmax
C1	226± 159	3.5± 1.6	699±201	434± 176	5.7± 1.8	3265± 1067	26±14	21±14	Treatment	Cmax (ng/mL)	Tmax (h)	AUC _0-48h ng/(mLxh)	Cmax (ng/mL)	Tmax (h)	AUC _0-48h (ng/mLxh)	C24h (ng/mL)	C24h/Cmax
C1	226± 159	3.5± 1.6	699±201	434± 176	5.7± 1.8	3265± 1067	26±14	21±14	M1	96±35	3.6± 0.8	481±136	235± 94	6.5±1 .1	2311±714	25±15	11±6
M2	118±53	4.5± 2.3	559±165	298± 125	7.4±2 .9	2748±802	29±18	13±9	M1	96±35	3.6± 0.8	481±136	235± 94	6.5±1 .1	2311±714	25±15	11±6

Find, with respect to not belonging to of the present invention with reference to formulation C 1, according to preparation M1 of the present invention and M2 can:

A) standard deviation of minimizing cmax value

B) amplitude modulation of minimizing average peak/paddy

C) standard deviation of minimizing peak/paddy amplitude modulation.

Claims

1. the coating or the purposes of substrate in comprising the oral Pharmaceutical dosage forms of losartan that comprise losartan, described coating or substrate can make described losartan sustained release, this dosage form of oral administration is to individual specimen, no matter described individuality is feed or fasting state, the capital causes that standard deviation reduces between the individuality of Cmax, with respect to the pharmaceutical dosage form of release immediately of the losartan that is administered to this same individual sample with same dose, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety.

2. be included in the purposes of losartan in the preparation oral Pharmaceutical dosage forms in coating or the substrate, described coating or substrate can make described losartan sustained release, in this dosage form of oral administration to individual specimen, no matter described individuality is feed or fasting state, the capital causes that standard deviation reduces between the individuality of Cmax, with respect to the pharmaceutical dosage form of release immediately of the losartan that is administered to this same individual sample with same dose, it can guarantee the effect of pharmaceutical dosage form and the lower variability of treatment safety.

3. claim 1 or 2 described purposes is characterized in that the factor (f) that standard deviation reduces between the individuality of Cmax is defined as follows: f 〉=1.2; Preferred f 〉=1.75, and more preferably f is 2.5 to 20.

4. at least one described purposes in the aforementioned claim, the coating or the matrix design that it is characterized in that described pharmaceutical dosage form become to make its sustained release losartan, at first avoided any too early and/or a large amount of of losartan and/or discharge fast and any deleterious plasma concentration of losartan is too high subsequently, next has guaranteed that the treatment of two doses between taking in covers.

5. at least one described purposes in the aforementioned claim is characterized in that the coating of described pharmaceutical dosage form or matrix design become to make this dosage form of oral administration individual specimen can cause the average peak/paddy amplitude modulation of the average peak/paddy amplitude modulation of the blood plasma feature of metabolite EXP3174 less than the metabolite EXP3174 of the same individual sample generation of the immediate release dosage form of the losartan of accepting same dose.

6. at least one described purposes in the aforementioned claim is characterized in that the coating of described pharmaceutical dosage form or matrix design become to make this dosage form of oral administration individual specimen can cause the variability of peak/paddy amplitude modulation of the metabolite EXP3174 that the variability of the peak/paddy amplitude modulation of the blood plasma feature of metabolite EXP3174 produces less than the individuals with same sample of the immediate release dosage form of the losartan of accepting same dose.

7. at least one described purposes is characterized in that described oral Pharmaceutical dosage forms comprises the losartan of micro-unit form in the aforementioned claim, and it can be:

The microgranule that ■ is made up of the medicated core that comprises losartan separately, it can make the coatings coating of losartan sustained release with one deck at least;

■ and/or separately by comprising losartan and can making the substrate composed micropill of losartan sustained release;

■ and/or the losartan micropill that discharges immediately.

8. as at least one described purposes in the claim 1 to 6, it is characterized in that described oral Pharmaceutical dosage forms is a tablet, described tablet does not contain to be made up of the medicated core that comprises losartan separately and can to make the microgranule of the coatings coating of losartan sustained release with one deck at least, and/or does not contain independent by comprising losartan and can making the substrate composed micropill of losartan sustained release.

9. at least one described purposes in the aforementioned claim is characterized in that described pharmaceutical dosage form can obtain to be defined as following blood plasma feature after dosage is taken in:

Cmax/C24h≤Cmax ^*/C24h ^*

Preferred 1.5 * Cmax/C24h≤Cmax ^*/ C24h ^*

More preferably 2.0 * Cmax/C24h≤Cmax ^*/ C24h ^*

Wherein:

° C24h is illustrated in dosage and takes in back 24 hours, the mean plasma concentration of the active metabolite EXP3174 of losartan,

° C24h ^*Be illustrated under the same terms as C24h, discharge the mean plasma concentration of the EXP3174 that oral Pharmaceutical dosage forms obtains immediately with the object of reference of losartan that comprises same dose,

° Cmax is illustrated in the average maximal plasma concentration that dosage is taken in back EXP3 174,

° Cmax ^*Be illustrated under the same terms as Cmax, discharge the average maximal plasma concentration of the EXP3174 of oral Pharmaceutical dosage forms acquisition with the object of reference of the losartan that comprises same dose immediately.

10. purposes as claimed in claim 7, it is characterized in that described oral Pharmaceutical dosage forms comprises microgranule, and it is 1 to 24 hour that the dissolution in vitro feature that has [D% (t)] can make after the administration time t (70%) when the losartan that discharges 70% finishes, preferred 2 to 12 hours, and even more preferably 2 to 8 hours.

11. purposes as claimed in claim 10, the dissolution in vitro feature [D% (t)] that it is characterized in that oral Pharmaceutical dosage forms was: for 2 hours arbitrary values to the described time t of t (70%), preferably for 1 hour arbitrary value to the described time t of t (70%), the percentage ratio of dissolved (release) losartan [D% (t)] 〉=35 * t/t (70%).

12. at least one described purposes in the aforementioned claim is characterized in that the rate of release of losartan in extracorporeal dissoluting test and pH are irrelevant.

13. purposes as claimed in claim 7 is characterized in that described oral Pharmaceutical dosage forms is for making:

The release of-losartan is subjected to two independent initiation mechanism controls, and a kind of pH that is based on changes, and another kind makes losartan keep under one's belt discharging after one period predetermined time of staying;

-under 1.4 constant pH, described dissolving characteristic comprises that having the persistent period is less than or equal to 7 hours, preferably is less than or equal to 5 hours, and lag phase of 1 to 5 hour more preferably,

-and can cause release period from pH1.4 to pH7.0, and do not have lag time.

14. purposes as claimed in claim 13 is characterized in that described oral Pharmaceutical dosage forms has the dissolving characteristic of measuring as follows in extracorporeal dissoluting test:

Under ° pH1.4, the losartan less than 20% discharged after 2 hours;

Under ° pH1.4, at least 50% losartan discharged after 16 hours.

15. purposes as claimed in claim 13 is characterized in that described oral Pharmaceutical dosage forms comprises the losartan microgranule of sustained release, it causes pH is 6.0 to 6.5, and comprises endpoint value.

16., it is characterized in that described oral Pharmaceutical dosage forms comprises at least two kinds of microgranules as described purposes in claim 7 and 10 to 15.

17., it is characterized in that described oral Pharmaceutical dosage forms comprises at least a sustained release microgranule and/or micropill and/or at least a micropill that discharges immediately as described purposes in claim 7 and 10 to 16.

18. as described purposes in claim 7 and 13 to 17, it is characterized in that described oral Pharmaceutical dosage forms comprises at least two kinds of sustained release microgranules and/or micropill, they have different dissolving characteristics with regard at least one pH value between 1.4 to 7.4.

19. as described purposes in claim 7 and 13 to 18, it is characterized in that described oral Pharmaceutical dosage forms comprises at least two kinds of sustained release microgranules and/or micropill, they have different separately initiation pH.

20. as described purposes in claim 7 and 13 to 19, it is characterized in that described oral Pharmaceutical dosage forms comprises at least two kinds of sustained release losartan microgranules and/or micropill, they have the different separately initiation time.

21., it is characterized in that described oral Pharmaceutical dosage forms comprises as described purposes in claim 7 and 13 to 20:

° at least a losartan micropill that discharges immediately;

The losartan microgranule and/or the micropill P of ° at least a sustained release ₁And

The losartan microgranule and/or the micropill P of ° at least a sustained release ₂,

And P ₁And P ₂The pH of initiation separately differ at least 0.5 pH unit, preferably at least 0.8 pH unit, more preferably at least 0.9 pH unit.

22., it is characterized in that the losartan microgranule of various sustained release and/or the pH of initiation separately of micropill are 5 to 7 as described purposes in claim 7 and 13 to 21.

23., it is characterized in that described oral Pharmaceutical dosage forms comprises as described purposes in claim 7 and 13 to 22:

° at least a losartan micropill that discharges immediately;

The losartan microgranule and/or the micropill P of ° at least a sustained release ₁', it causes pH and equals 5.5; With

The losartan microgranule and/or the micropill P of ° at least a sustained release ₂', it causes pH is 6 to 6.5, and comprises endpoint value.

24. as described purposes in the claim 7 to 23, it is characterized in that described oral Pharmaceutical dosage forms comprises at least a losartan micropill that discharges immediately, its character in extracorporeal dissoluting test is to make losartan release in 1 hour under any pH between 1.4 to 7.4 of at least 80%.

25. as described purposes in the claim 7 to 24, it is characterized in that described oral Pharmaceutical dosage forms is the form of single oral dose every day, described dosage comprises 1000 to 500000 micro-units that contain losartan.

26. as described purposes in the claim 7 to 25, it is characterized in that described oral Pharmaceutical dosage forms is the form of single oral dose every day, described dosage comprises the losartan microgranule and/or the micropill of 1000 to 500000 sustained release.

27. described purposes in the claim is characterized in that described oral Pharmaceutical dosage forms is powder sachet, liquid suspension, tablet or capsular form as described above.

28. a described purposes in the aforementioned claim is characterized in that described pharmaceutical dosage form comprises at least a effective constituents A P that is different from losartan.

29. as at least one purposes in claim 7 and 10 to 12, it is characterized in that described pharmaceutical dosage form comprises sustained release losartan microgranule and/or micropill, the coating or the base composition that are used for this microgranule and/or micropill are selected from the group that comprises prescription A and prescription B, and be as described below:

Prescription A

At least a film forming polymer of A-1-(P1), it is insoluble in gastro-intestinal Fluid, exist ratio to count with respect to 50% to 90% of coated composition gross mass by solid weight, preferred 50% to 80%, and it comprises at least a water-insoluble cellulose derivative especially;

At least a polymer with nitrogen of A-2-(P2), it exists ratio to count with respect to 2% to 25% of coated composition gross mass by solid weight, preferred 5% to 15%, and by at least a polyacrylamide and/or a kind of poly--the N-vinylamine and/or a kind of poly--the N-vinyl lactam forms;

At least a plasticizer of A-3-, it exists ratio to count with respect to 2% to 20% of coated composition gross mass by solid weight, preferred 4% to 15%, and form by at least a following chemical compound: glyceride, phthalic acid ester, citrate, sebacate, spermaceti alcohol ester, Oleum Ricini;

At least a surfactant of A-4-and/or lubricant, exist ratio to count with respect to 2% to 20% of coated composition gross mass by solid weight, preferred 4% to 15%, it is selected from anion surfactant and/or nonionic surfactant and/or lubricant; Described reagent can comprise only a kind of above-mentioned product or its mixture;

Or

Prescription B

At least a film forming polymer of B1-, it is insoluble in gastro-intestinal Fluid,

At least a water-soluble polymer of B2-,

At least a plasticizer of B3-,

30. at least one described purposes in the claim 7 to 29, the average diameter (Dm represents with μ m) that it is characterized in that the losartan microgranule and/or the micropill of described sustained release be less than 1000, and be preferred 50 to 800, and more preferably 50 to 500.

31. a losartan oral Pharmaceutical dosage forms that slows down release is characterized in that

→ it comprises a plurality of micro-units that comprise losartan,

The average diameter of → described micro-unit (Dm represents with μ m) is 50 to 1000, and is preferred 100 to 600, more preferably 150 to 500,

→ and its blood plasma feature that can after dosage be taken in, obtain as give a definition:

C18h ^*≤C18h

Preferred 1.5 * C18h ^*≤ C18h≤Cmax ^*/ 2

More preferably 2.0 * C18h ^*≤ C18h≤Cmax ^*/ 2

Wherein

° C18h is illustrated in dosage and takes in back 18 hours, the plasma concentration of the active metabolite of losartan (E3174),

° C18h ^*Be illustrated under the same terms as C18h, discharge the plasma concentration of the E3174 that oral Pharmaceutical dosage forms obtains immediately with the object of reference of losartan that comprises same dose,

° Cmax is illustrated in the maximal plasma concentration that dosage is taken in back E3174,

° Cmax ^*Be illustrated under the same terms as Cmax, discharge the maximal plasma concentration of the E3174 of oral Pharmaceutical dosage forms acquisition with the object of reference of the losartan that comprises same dose immediately.

32. a losartan oral Pharmaceutical dosage forms that slows down release is characterized in that

→ it comprises a plurality of micro-units that comprise losartan,

The average diameter of → micro-unit (Dm represents with μ m) is 50 to 1000, and is preferred 100 to 600, more preferably 150 to 500,

-a- C18h ^*≤C18h

Preferred 1.5 * C18h ^*≤ C18h≤Cmax ^*/ 2

More preferably 2.0 * C18h ^*≤ C18h≤Cmax ^*/ 2

-b- 1.1×Tmax ^*≤Tmax

Preferred 1.2 * Tmax ^*≤ Tmax

More preferably 1.5 * Tmax ^*≤ Tmax

And more preferably 1.7 * Tmax ^*≤ Tmax≤6 * Tmax

Wherein

° Tmax is illustrated in the time that passes after dosage is taken in, and it is corresponding with Cmax,

° Cmax ^*Be illustrated under the same terms as Cmax, discharge the maximal plasma concentration of the E3174 that oral Pharmaceutical dosage forms obtains immediately with the object of reference of losartan that comprises same dose,

° Tmax ^*Be illustrated in the time that passes after dosage is taken in, itself and Cmax ^*Corresponding.

33. claim 31 or 32 described oral Pharmaceutical dosage forms is characterized in that some micro-unit is a microgranule at least, described microgranule is made up of the medicated core that can comprise losartan individually, and this medicated core is used at least, and one deck can make losartan slow down the coatings coating of release.

34. each described oral Pharmaceutical dosage forms in the claim 31 to 33 is characterized in that some micro-unit comprises the losartan micropill that discharges immediately at least.

35. the described oral Pharmaceutical dosage forms of claim 34 is characterized in that dissolution in vitro is characterized as: 70% losartan is release in 1 to 24 hour after administration, preferably at 2 to 12 hours, more preferably at 2 to 8 hours.

36. described oral Pharmaceutical dosage forms in claim 31 or 32 and 33 is characterized in that:

-under 1.4 constant pH, described dissolving characteristic comprises that having the persistent period is less than or equal to 7 hours, preferably is less than or equal to 5 hours, more preferably 1 to 5 hour lag phase;

-and can cause release period from pH1.4 to pH7.0, and do not have lag time.

37. each described oral Pharmaceutical dosage forms in claim 36 and the claim 40 to 46 is characterized in that it has the dissolving characteristic by extracorporeal dissoluting test mensuration as follows:

Under ° pH1.4, the losartan less than 20% discharged after 2 hours;

Under ° pH1.4, at least 50% losartan discharged after 16 hours.

38. each described oral Pharmaceutical dosage forms in the claim 31 to 37 is characterized in that the plasma concentration area under curve (AUC as time (T) function of active metabolite E3174 after the object of reference of taking in the losartan that comprises same dose as the variability CV (%) of the plasma concentration area under curve (AUC) of time (T) function for dosage under the same conditions that dosage is taken in back active metabolite E3174 discharges oral Pharmaceutical dosage forms immediately ^*) corresponding variability CV ^*(%) be less than or equal to 200%, preferred 150%, more preferably 120%, i.e. CV≤2.0 * CV ^*, CV≤1.5 * CV ^*, and preferred CV≤1.2 * CV ^*

39. described oral Pharmaceutical dosage forms in the claim 31,33 or 35 is characterized in that in-vitro release rate and the pH of losartan in solubility test is irrelevant.

40. the described oral Pharmaceutical dosage forms of claim 39 is characterized in that the dissolving characteristic between pH1 to pH5 of described microgranule is similar.

41. each described oral Pharmaceutical dosage forms in the claim 31 to 40 is characterized in that it comprises at least two kinds of microgranules as claimed in claim 33.

42. each described oral Pharmaceutical dosage forms in the claim 31 to 41 is characterized in that it comprises at least a microgranule as claimed in claim 33 and at least a micropill as claimed in claim 34.

43., it is characterized in that it comprises at least two kinds of microgranules that have different dissolving characteristics under at least a pH value between 1.4 to 7.4 as claim 36 and the optional described oral Pharmaceutical dosage forms of claim 41.

44. as each described oral Pharmaceutical dosage forms in claim 36 and the claim 41 to 43, it is characterized in that it comprises at least two kinds of losartan microgranules that slow down release, described two kinds of microgranules have different separately initiation pH.

45. as each described oral Pharmaceutical dosage forms in claim 36 and the claim 41,43 and 44, it is characterized in that it comprises that at least two kinds of effective ingredient slow down the microgranule of release, described two kinds of microgranules have the different separately initiation time.

46. each described oral Pharmaceutical dosage forms in claim 36 and claim 41 and 43 to 45 is characterized in that it comprises:

° at least a losartan micropill that discharges immediately;

° at least a losartan microgranule P that slows down release ₁And

° at least a losartan microgranule P that slows down release ₂,

47., it is characterized in that the various pH of initiation separately that slow down the losartan microgranule of release are 5 to 7 as each described oral Pharmaceutical dosage forms in claim 36 and claim 41 and 43 to 46.

48., it is characterized in that it comprises as each described oral Pharmaceutical dosage forms in claim 36 and the claim 41 to 47:

° at least a losartan micropill that discharges immediately;

° at least a losartan microgranule P that slows down release ₁', it causes pH and equals 5.5; With

° at least a losartan microgranule P that slows down release ₂', it causes pH is 6 to 6.5, and comprises endpoint value.

49. each described oral Pharmaceutical dosage forms in the claim 34 to 48, it is characterized in that it comprises at least a losartan micropill that discharges immediately, its character in extracorporeal dissoluting test is to make losartan release in 1 hour under any pH between 1.4 to 7.4 of at least 80%.

50. each described oral Pharmaceutical dosage forms in the claim 31 to 49 is characterized in that at least 50% losartan is its crystal form I.

51., it is characterized in that at least some losartan microgranule that slows down release comprises separately as described oral Pharmaceutical dosage forms in the claim 33 to 50:

Comprise losartan medicated core and

At least one covers the coating of described medicated core, and it makes described losartan slow down release.

52., it is characterized in that some described losartan microgranule that slows down release comprises separately at least as each described oral Pharmaceutical dosage forms in the claim 32 to 50:

Medicated core, it comprises:

Neutral medicated core,

At least one deck active layer, it comprises losartan and the described neutral medicated core of coating,

At least one deck covers the coating of described medicated core, and it makes losartan slow down release.

53. each described oral Pharmaceutical dosage forms in the aforementioned claim is characterized in that the ratio (be expressed as weight percent solids with respect to micro-unit gross mass) of losartan in micro-unit is 5 to 80, and is preferred 10 to 70, more preferably 15 to 60.

54., it is characterized in that the microgranule medicated core of the described losartan micropill that discharges immediately for the not coating described in claim 34 as each described oral Pharmaceutical dosage forms in claim 33 and the claim 34 to 52.

55. each described oral Pharmaceutical dosage forms in the claim is characterized in that it is the form of single oral dose every day as described above, described dosage comprises 1000 to 500000 micro-units that contain losartan.

56. each described oral pharmaceutical form in the claim is characterized in that it is the form of single oral dose every day as described above, described dosage comprises 1000 to 500000 losartan microgranules that slow down release.

57., it is characterized in that it is the powder sachet of micro-unit, the liquid suspension of microgranule, the capsule that derives from the tablet of micro-unit or comprise micro-unit as each described oral Pharmaceutical dosage forms in the claim 31 to 56.

58. as the losartan microgranule that slows down release that defines in each in the claim 31 to 57 and as the losartan micropill that discharges immediately that defines in the claim 34 to 57 each at preparation medicine or diet with the purposes in the microparticulate oral medical herbs dosage form, described oral medical herbs dosage form is preferably and advantageously is a mouthful dispersible tablet form or powder or capsule.

59. as the losartan microgranule that slows down release that defines in each in the claim 31 to 58 with as the purposes of the losartan micropill that discharges immediately in the microgranular oral Pharmaceutical dosage forms of preparation therapeutics safety of each definition in the claim 34 to 58, described dosage form design becomes in case absorbed described pharmaceutical dosage form, it microgranule that comprises is disperseed and by individuation when their arrive stomach, it makes these microgranules carry out uniformly and gastric emptying progressively, no matter described patient is feed or fasting state during dosage is taken in, thereby but has guaranteed the release of losartan in its gastrointestinal biology absorption window.

60. the microgranule of each definition in the claim as described above.