FR2882259A1 - Use of a controlled release losartan oral dosage form, to decrease the inter individual gap of standard deviation of maximum concentration of the losartan, independent of administration of losartan before or after the meals - Google Patents

Abstract

Use of a oral dosage form (A) comprising a coating or a matrix containing losartan (I) and allowing controlled release of (I), before or after meals, to decrease the inter individual gap of standard deviation of maximum concentration of (I) (C max), which results in a low variability of effectiveness of (A), when compared to a dosage form with immediate release of (I). Independent claims are included for: (1) a modified release oral dosage form (A) of losartan (I), comprising micro-units (II) containing (I), where (II) has an average diameter of 50-1000 (preferably 150-500) mu m, and carboxylic acid metabolite of (I) (E3174) has a specific plasma profile (i.e. C18h(i)=C18h (preferably 2.0 C18h(i)=C18h=C max(i)/2), where C18h is the plasma concentration of E3174 after 18 hour of administering (A), C18h(i) is the plasma concentration of E3174 obtained after administering immediate release form, C max is the maximum plasma concentration of E3174 after the administration of (A) and C max(i) is the maximum plasma concentration of E3174 obtained after administering immediate release form); and (2) a micro particle.

Description

ORAL PHARMACEUTICAL FORM MULTIMICROPARTICULAR A

MODIFIED LIBERATION OF LOSARTAN

  Field of the Invention The field of the present invention is that of the oral modified-release losartan pharmaceutical forms, and related treatments and methods of administration.

  Losartan Overview Losartan (or losartan potassium) is an angiotensin II (AT1) receptor antagonist. It is active orally and intervenes in the regulation of hypertension by acting on the renin-angiotensin system.

  Its formula is as follows: potassium [2-butyl-4-chloro-1- [4- [2- (1H-tetrazol-5-yl) phenyl] benzyl] -1H-imidazol-5-yl] methanol.

  There are many salts or esters of this product that are pharmaceutically effective and acceptable. Thus, throughout this specification, the term "losartan" refers to losartan per se and / or at least one of its pharmaceutically acceptable salts or esters.

  Angiotensin II receptor antagonists, such as losartan, are also referred to as Angiotensin Receptor Blockers (ARBs). ARBs can be combined with a diuretic (hydrochlorothiazide) to increase their effectiveness.

  Losartan is particularly used in the treatment of the following pathologies: E essential hypertension, E treatment of renal insufficiency in patients with type 2 diabetes with proteinuria, E reduction of cardiovascular morbidity and mortality in hypertensive patients with left ventricular hypertrophy (most often in combination with a thiazide diuretic), É congestive heart failure, E polyglobulia of renal transplant patients.

  Losartan, administered orally, undergoes an important first-pass metabolism at the level of the cytochrome P450 enzymatic system. It is converted, in part, to a carboxylic acid (E-3174), a more potent active metabolite than the parent drug losartan, which is considered as a prodrug.

  The problem The ARBs, in particular losartan, are most often administered orally, in tablet form, at a rate of once a day. But, it turns out that such a treatment is imperfect. Indeed, it happens that the targeted control of the blood pressure is not or is poorly obtained, or is obtained in a non-reproducible manner. Side effects are sometimes observed.

  The underlying problems include: Problem 1: In most patients, the dosage is 50 mg or 100 mg once a day.

  However, some authors [The Angiotensin II type 1 receptor antagonists: a new ciass of antihypertensive drugs, Bauer et al., Arch. Inter. Med. 1960, 1995, 155, 13, p1361-1368] describe taking a dose of 50 mg twice daily as being more effective than taking a single dose of 100mg.

  Thus, for about 20% of patients, a daily intake of, for example, 100 mg, does not allow effective treatment and two doses per day (2 times 50 mg) are required.

  This imperfect performance of a single daily administration is explained by the fact that the blood pressure of the patients after oral administration of losartan is closely related to the plasma concentration of the active metabolite E-3174. However, only 12 hours after a single daily dose, the active plasma concentration E-3174 e; t already very weak. Indeed, the decrease in plasma concentration of E-3174 occurs as early as 2 to 4 hours after setting; moreover, this decay is rapid: the half-life time of the E-3174 is 69 h. It is therefore recommended to administer this medication twice a day. However, it is commonly accepted that a dosage involving several doses per day is not most desirable in terms of compliance and thus effectiveness of treatment.

  It is therefore desirable to have a modified-release form of losartan. which prolongs the time of bio-absorption and allows to administer the drug only once a day. However, such forms pose the problems discussed below.

  Problem 2: The guarantee of therapeutic safety is a major issue, especially for antihypertensives such as losartan. Indeed, it is essential to have an oral drug designed so that once ingested, the active ingredient it contains is released into the gastrointestinal tract and bioabsorbed in its absorption window. Otherwise, the dose of active ingredient is removed with intestinal transit without being absorbed properly. It does not produce the expected therapeutic effect. In the case of losartan, the blood pressure of the patient who has swallowed the tablet is not reduced, which considerably increases the risk of infarction and thus jeopardizes the patient's life.

  The literature describes gastro-retentive sustained-release tablets of losartan. The tablet swells in the stomach to a size which, when the pylorus is closed (that is to say in the nourished state), prevents its gastric emptying. The active ingredient is thus released progressively upstream of its absorption window located in the upper parts of the small intestine. It can therefore be absorbed correctly ..

  However, for a significant fraction of patients, pylorus closure may be erratic. In addition, if the patient does not follow the dosing instructions and ingests the tablet before meals or at the beginning of the meal before the pylorus is closed, it is possible that the swallowed tablet does not stay in the stomach and is evacuated. quickly without having released the losartan upstream of its bio-absorption window.

  These sustained-release gastro-retentive forms are therefore not safe since losartan is not necessarily bioabsorbed whether the patient is fed or fasting.

  It is therefore crucial for a modified-release oral form to be able to ensure that once the oral drug is ingested, the losartan is bioabsorbed, whether the patient is fed or fasting.

  Problem 3: An additional problem is associated with the modified release forms of losartan. This active ingredient has a solubility in water which varies greatly depending on the pH (see Table 1 below).

  pH 1.4 2.0 4.5 6.8 9.8 Solubility (g / L) 1 0.6 0.01 10> 5C0 Table 1: Evolution of the aqueous solubility of losartan potassium as a function of pH.

  However, fasting gastric pH is 1.4, while it is 5 after a meal. Thus, in losartan-modified-release forms for which the release of losartan is either pH-dependent (enteric coating) or dependent on the solubility of the active ingredient, the release kinetics may vary depending on whether the patient is fasting or not. .

  Accordingly, it would be ideal to have an oral pharmaceutical form of losartan which is administrable once a day; which is more effective than the once-a-day forms of immediate release; which ensures that once the oral pharmaceutical form ingested, the active principle it contains is released into the gastrointestinal tract and bioabsorbed in its gastrointestinal absorption window, and that the patient is at the fed or fasting state, that is to say which allows a good reproducibility of the plasma concentration, by limiting - even by suppressing - the harmful effects of the interindividual variability of the gastric emptying, ^ and which overcomes the problem of the variability of the solubility in function Ju pH of losartan.

  Prior Art Monolithic Forms Patent application WO-A-03/035039 discloses a controlled release dosage form of losartan. The basis of the invention according to WO-A-03/035039 is to provide a gastro-retentive galenic form administrable once a day.

  This dosage form consists of a "bioadhesive" gastrorespirant tablet capable of swelling to a sufficient size to be resected in the fed stomach.This controlled release galenic form of losartan is large in size, monolithic. and multilayer (2, optionally 3) based on polymers of hydroxypropylmethylcellulose (HPMC) or ethylene oxide (PEO) type capable of swelling in the gastric medium, losartan can be in the form of a single ring or of a plurality of particles (page 8, lines 29, 30) included in a compressed HPMC / PEO polymer matrix A non-active layer formed by HPMCIPEO swelling polymers can be applied to this matrix (or active layer) by compression also.

  The pharmacokinetic parameters, measured in the dog, of the two gastro-retentive forms exemplified are given in Table 2 below:

Table 2

  Parameters Release Release Immediate release controlled by gastro-controlled gastro-retention GR1 GR2 AUC (ng / ml.h) 486 133 590 202 461 176 Cmax (ng / ml) 224 58.5 105 31.7 72 24.1 Tmax (h) 0 , 88 0.25 2.5 0.58 5.25 0.5 GR time (h) / 7.6 2.5 6.8 0.5 Cmax = peak plasma concentration after oral administration Tmax = time elapsed after oral administration and corresponding to Cmax GR = gastroretention First, the gastro-retentive sustained-release tablet according to WO-A-03/035039 is defective in terms of guarantee of therapeutic safety (problem N 2 vacuum supra) . Indeed, it is not guaranteed that, in 100% of cases, once the oral drug ingested, the losartan it contains is released and bioabsorbed in its window of absoiption. The expected therapeutic action is therefore not produced and this puts the life of the patient at risk. In particular, depending on whether the patient is in the fed state or fasting state, the gastro-retaining tablet according to WO-A03 / 035039 can escape the stomach prematurely and be evacuated rapidly without having released the losartan, which is not therefore not bioabsorbed and thus does not produce the desired effect on the limitation of blood pressure. This refers to the major disadvantage of interindividual variability of gastric emptying of monolithic gastro-retentive forms.

  In addition, this gastro-retentive tablet may have a large size. It can not be broken down to facilitate ingestion without impairing the modified release characteristics of losartan. It is therefore difficult for patients who have difficulty swallowing, and even less for children or infants who can not swallow more and who, in addition, require an adjustment of the dose administered according to their weight.

  In addition, it is difficult to mix losartan with one or more active ingredients in the same tablet and it is even more difficult to adjust independently the release times of the various active ingredients.

  In addition, with a losartan tablet, one can not rule out the risk of tissue damage by local overconcentration of losartan, which is well known to be aggressive.

  In addition, since the solubility of losartan varies with pH, it is clear that losartan contained in the "tablet" form according to WO-A-03/035039 does not have the same release kinetics as the patient is fasting or not.

  Thus, inevitably, unacceptable therapeutic risks persist for gastro-retentive tablets according to WO-A03 / 035039.

  Multimicroparticulate Forms PCT patent application WO-A-03/020243 discloses tablets or capsules comprising an anticholesterol agent, an angiotensin II receptor antagonist (ARB), aspirin and, optionally, vitamin B6 or B12 or folate. This formulation is intended for the prevention of cardiovascular risk in patients with high cardiovascular risk. The ARB may be losartan. The ARB, like the other active ingredients, can be in the form of beads, particles or granules (eg 14-26 mesh: 7001410 m) coated (enteric coating: EUDRAGIT L 30D-55 and diethylphthalate). to allow delayed or prolonged release of ARB.

  This technical proposal aims essentially to isolate the different active ingredients from each other in order to improve their stability. In no case does this proposal teach how to increase the bio-absorption time of losartan and therefore does not solve the aforementioned technical problems.

  In this context, it is first of all the plaintiff's merit to have identified the aforementioned problems and its causes. Thus, without linking it to the theory, the Applicant has formulated the hypothesis that the insufficient efficacy of the once-a-day treatment of oral losartan could be related to the bio-absorption time. the E-3174 active metabolite and the inter-individual variability of gastric emptying and, consequently, the variability of bio-absorption of losartan.

  Objectives Based on these observations, the Applicant has set the following objectives.

  The essential objective of the invention is to remedy the shortcomings and disadvantages of the prior art.

  Another essential object of the invention is to provide an oral pharmaceutical form of losartan which, once ingested, allows the losartan it contains to be released into the gastrointestinal tract and bioabsorbed into its absorption window.

  Another essential objective of the invention is to provide an oral pharmaceutical form of losartan, which reduces the interindividual variability of the in vivo absorption of losartan, which is a direct consequence of the sensitivity of certain oral dosage forms to the interindividual variability of gastric emptying.

  Another essential object of the invention is to provide an oral pharmaceutical form of losartan, administrable once a day and at least as effective as the once-daily release forms currently in use.

  Another essential object of the invention is to provide an oral pharmaceutical form of losartan which, when administered once a day, is therapeutically effective, for example, for more than 80% of patients.

  Another essential objective of the invention is to provide an oral pharmaceutical form of losartan having an in vitro dissolution profile independent of the losartan dose.

  Another essential objective of the invention is to provide an oral pharmaceutical form of losartan having the same weight composition regardless of the therapeutic dose of losartan targeted.

  Another essential object of the invention is to provide an oral pharmaceutical form of losartan, administrable once a day and adapted to patients having difficulties to swallow, especially to children or infants who can not not only swallow and which, moreover, require adjustment of the dose administered according to their weight.

  Another essential objective of the invention is to provide an oral pharmaceutical form of losartan, administrable once a day and which offers the possibility of mixing losartan with one or more active ingredients in the same oral form, with the possibility of adjusting easily and independently the time of release of the different active ingredients.

  Another essential object of the invention is to provide an oral pharmaceutical form of losartan, administrable once a day which limits the risk of tissue damage by local overconcentration of losartan.

  Another essential objective of the invention is to provide an oral pharmaceutical form of losartan, which is administrable once a day and which, despite the variability of the solubility of losartan in water as a function of pH, releases losartan according to the same kinetics whether the patient is fasting or not.

  Another essential objective of the invention is to provide an oral pharmaceutical form of losartan, which may exist in various galenic presentations, including in particular: tablet, sachet, oral suspension, capsule ...

  Brief description of the invention

  To achieve these objectives, among others, the present invention provides a novel losartan-modified oral pharmaceutical dosage form characterized in that it comprises a plurality of microunits containing losartan, in that the average diameter (Dm m) micro-units is between 50 and 1000, preferably 100 and 600, and more preferably still between 150 and 500, -p and in that it allows to obtain, after taking, a defined plasma profile as follows: a.

  C18h * <C18h preferably 1.5.C18h * C18h Cmax * 12 more preferably still; 2.0.C18h * C18h Cmax * 12 b.

  1.1.Tmax * Tmax Tmax preferably 1,2.Tmax * and more preferably 1, 5.Tmax * Tmax and more preferably 1.7. Tmax * Tmax 5 6.Tmax with o C18h representing the plasma concentration of the active metabolite (E 3174) of losartan, 18h after taking, É C18h * representing the plasma concentration of E 3174 obtained under the same conditions as C18h, with a form immediate-release oral pharmaceutical composition, containing the same dose of losartan, where C max represents the maximum plasma concentration of E 3174 after taking, T max representing the time elapsed after taking and which corresponds to C max, Cmax * representing the maximum plasma concentration of E 3174 obtained under the same conditions as Cmax, with a reference oral immediate release pharmaceutical form, containing the same dose of losartan, Tmax * representing the time which elapsed after the setting and which corresponds to Cmax *.

  Advantageously, this pharmaceutical form is designed so that the micro-units, once ingested, are dispersed and individualized when they reach the stomach, which guarantees a regular and progressive gastric emptying of the micro-units, at the same time. fed state as fasting, and thus ultimately a release of losartan in its window astrointestinal bioabsorption.

  For the purposes of the invention, the expression "dispersed and individualized" means that the micro-units containing losartan are not trapped in a matrix when they arrive: in the stomach just after ingestion. The micro-units spread in the stomach immediately after entering the stomach (for example in less than two minutes).

detailed description

  The definition of "losartan" given above may be advantageously supplemented by that mentioned in WO-A-03/035039 (page 3, line 28 to page 4, line 18).

  By "modified release" is meant herein a release of losartan by a pharmaceutical formulation, such release occurring at a rate less than that of a "Immediate Release" formulation of reference FLI *, such as a conventional tablet or capsule to be swallowed. Such a modified release formulation may, for example, include an immediate release phase and a slow release phase. Modified release formulations are well known in the art; see for example Remington: The Science and Practice of Pharmacy, 19th Edition, Mack Publishing Co. Pennsylvania, USA.

  By "Immediate Release" is meant in the present disclosure, the release by FLI of most of the amount of losartan in a relatively short time, for example at least 80% in one hour, preferably in thirty minutes, after oral ingestion. Examples of such FLIs include conventional swallowing tablets, dispersible tablets, chewable tablets, unit dose sachets and capsules.

  The comparison of the parameters C18h and C18h *, Cmax and Cmax * as well as Tmax and Tmax * is made in a statistically significant manner and under the same conditions and at the same dose of losartan.

  According to the invention, the micro-units denote: microparticles coated with at least one coating allowing the modified release of losartan and losartan immediate release microgranules. The advantages of the invention include the following: This once-daily oral dosage form of losartan ensures that once the oral pharmaceutical form is ingested, the losartan it contains is released into the gastrointestinal tract and bioabsorbed in its absorption window.

  This oral pharmaceutical form of losartan, which can be administered once a day, ensures that once the oral pharmaceutical form is ingested, the losartan it contains will not pass in front of its bioabsorption window without being released.

   This once-daily oral dosage form of losartan ensures that once the oral dosage form is ingested, the losartan it contains will be released regardless of the open or closed state of the pylorus.

  This once-daily oral dosage form of losartan is at least as effective as the one-day-once-a-day forms currently used.

   > This once-daily oral dosage form of losartan has little or no effect on the phenomenon of interindividual variability in gastric emptying and ultimately the in vivo absorption of losartan and its active metabolite E 3174.

  This oral pharmaceutical form of losartan is therapeutically effective for example for more than 80% of patients, when administered once a day.

  This losartan oral pharmaceutical form, which can be administered once a day and comprises modified-release losartan micro-units, derives some of its advantages from the small size (50-1000 m) of these micro-units and their large number (eg several thousands per dose), which allows a gradual and well-controlled gastric emptying, regardless of food intake by patients.

  This oral pharmaceutical form of losartan, which is administrable once a day, makes it possible to increase the Tmax of losartan as well as the duration during which the losartan plasma concentration is greater than the losartan plasma concentration below which the losartan is therapeutically ineffective. 11.

   This oral pharmaceutical form of losartan, having an in vitro dissolution profile, independent of the dose of losartan.

  This oral pharmaceutical form of losartan may have the same weight composition regardless of the dose of losartan it contains.

  This oral pharmaceutical form of losartan, which is administered once a day, is suitable for patients who have difficulty swallowing, especially children or infants who can not only swallow but which, in addition, require the dose administered according to their weight.

  This oral pharmaceutical form of losartan, administrable once a day, offers the possibility of mixing losartan with one or more other active ingredients in the same oral form, the respective release times of these different active ingredients being easily adjusted independently of each other.

   This losartan oral pharmaceutical form, which is administrable once a day, despite the variability of the water solubility of losartan as a function of pH, can release losartan according to the same kinetics whether or not the patient is fasting.

  This oral pharmaceutical form of losartan may exist in various galenical presentations, including in particular: tablet, sachet, oral suspension, capsule, etc.

  The oral dosage form according to the invention consists of a large number (for example of the order of one to several thousand) of micro-units (microparticles or microparticles of losartan), this multiplicity ensuring statistically good reproducibility of the transit kinetics of losartan throughout the gastrointestinal tract, and hence good bioavailability control and efficacy.

    The use of a mixture of microparticles with different modified release profiles makes it possible to produce release profiles having several waves of release or ensuring, by appropriate adjustment of the various fractions, a constant level of plasma concentration of losartan.

   > The sensitivity to the variability of gastric emptying is less, because the emptying, which is carried out here on a large number of particles is statistically more reproducible; - The contact of the tissues with a high dose of losartan (dumping dose) is avoided. Each microunity contains only a very small dose of losartan. This eliminates the risk of tissue damage by local overconcentration of aggressive losartan.

  This pharmaceutical form does not induce degradation of losartan and preserves the polymorphism of the starting losartan.

   * Their size between 50 and 1000 m and the characteristics of their possible coating allows micro-units to increase their transit time in the upper parts of the gastrointestinal tract, which ensures an increase in the transit time of the losartan in front of its absorption window and maximizes the bioavailability of losartan.

  Preferably, at least a portion of the micro-units are individually microparticles consisting of a core which comprises losartan and which is coated with at least one coating for the modified release of losartan.

  Regarding microparticle-type microparticles, it should be noted that their coating controlling the modified release of Losartan essentially comprises pharmaceutically acceptable excipients.

  It may also be very advantageous for at least a portion of the microunits of the pharmaceutical form according to the invention to be constituted by micro granules with immediate release of losartan.

  Preferably, the oral pharmaceutical form according to the invention is characterized in that the CV variability (in%) of the area under the curve (ASC) giving the evolution I the plasma concentration to the active metabolite E 3174, as a function of time (T) after setting is less than or equal to 200%, preferably 150%, and more preferably still 120%, of the corresponding CV * variability (in%) of the area under the curve (ASC * ) giving the evolution of the plasma concentration of the active metabolite E 31'14 as a function of time (T) after taking, under the same conditions, a standard oral pharmaceutical form with immediate release of reference *, containing the same dose of losartan, that is to say: CV 1.5.CV *, preferably CV S 1,2.CV *.

  The pharmacokinetic parameters CV, ASC are well known to those skilled in the art.

  The comparison of the modified-release form of losartan according to the invention with FLI *, and in particular the parameters CV and CV *, ASC and ASC *, is made statistically significantly, under the same conditions and at the same dose. of losartan.

  All in vitro dissolution profiles, which are discussed in this paper, are carried out according to the indications of the European Pharmacopoeia 4th edition entitled: "Dissolution test of solid oral forms": type II dissolutest performed under SINK conditions maintained at 37 ° C. and stirred at 100 rpm.

  According to a first embodiment of the invention, the oral pharmaceutical form has an in vitro dissolution profile such that:% of losartan are released between 1 and 24h, preferably between 2 and 12h, and even more preferably between 2 and 12h. 8h, after the administration.

  Advantageously, the oral pharmaceutical form according to the first embodiment of the invention is characterized in that the rate of release of losartan in vitro in a dissolution test is independent of the pH.

  The pHs more specifically concerned are physiological pHs, for example those ranging from 1 to 7.

  This remarkable property of the oral pharmaceutical forms according to the first embodiment of the invention is all the more interesting for losartan, as the latter is known for its solubility in water which is very dependent on pH, as has been the case. recalled supra.

  The composition of the coating of the microparticles according to the first embodiment corresponds, advantageously, to one of the following two families A and B. Family AA-At least one film-forming polymer (P1) insoluble in the liquids of the tract, present at from 50 to 90, preferably from 50 to 80 by weight on a dry basis relative to the total weight of the coating composition and consisting of at least one non-water-soluble derivative of the cellulose; 2A-at least one nitrogen-containing polymer (P2) present in a proportion of 2 to 25, preferably 5 to 15% by weight on a dry basis relative to the total weight of the coating composition and consisting of at least one polyacrylamide and / or poly-N-vinylamide and / or polyNvinyl-lactam; 3A-at least one plasticizer present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and constituted by at least one of the following compounds: esters of glycerol, phthalates, citrates, sebzacates, esters of cetyl alcohol, castor oil; 4A -at least one surfactant and / or lubricant, present in a proportion of 2 to 2.0, preferably 4 to 15% by weight, on a dry basis relative to the total weight of the coating composition and selected from among the surfactants; anionic actives, and / or among nonionic surfactants, and / or among lubricating agents; said agent may comprise a single or a mixture of the aforesaid products; Family B: 1B -at least one film-forming polymer insoluble in the liquids of the gastrointestinal tract, 2B -at least one water-soluble polymer, 3B at least one plasticizer, 4B -and optionally at least one surfactant / lubricant preferably consisting of minus an anionic surfactant and / or at least one nonionic surfactant.

  According to a preferred embodiment of the invention, the Aet B families in which the constituents of the coating composition are chosen are as follows: Family A 1A - ethylcellulose and / or cellulose acetate; 2A - polyacrylamide and / or polyvinylpyrroliclone; 3A - castor oil; 4A - alkali or alkaline earth fatty acid salts, stearic and / or oleic acid being preferred, polyoxyethylenated sorbitan ester, derived from castor oil polyoxyethyl, stearate ileate, preferably calcium, magnesium, aluminum or zinc, stearyl fumarate, preferably sodium glycerol behenate; taken by themselves or mixed together; Family B: 1B non-water-soluble derivatives of cellulose, with ethylcellulose and / or cellulose acetate being particularly preferred, acrylic derivatives, polyvinylacetates, and mixtures thereof. 2B

  water-soluble derivatives of cellulose, polyacrylamides, poly-N-vinylamides, poly-N-vinyl-lactams, polyvinyl alcohols (PVAs), polyoxyethylenes (POE), polyvinylpyrrolidones (PVP) (the latter being preferred), and their mixtures; 3B glycerol and its esters, preferably in the following subgroup: acetylated glycerides, glycerolmonostearate, glyceryl-triacetate, glyceroltributyrate, phthalates, preferably in the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate, citrates, preferably in the following subgroup: acetyl tributyl citrate, acetyltriethyl citrate, tributyl citrate, triethyl citrate, sebacates, preferably in the following subgroup: diethyl sebacate, dibutyl sebacate, adipates, azelates, benzoates, vegetable oils, fumarates, preferably diethyl fumarate, malates, preferably diethyl malate, oxalates, preferably diethyl oxalate, succinates; preferably dibutylsuccinate, butyrates, esters of cetyl alcohol, salicylic acid, triacetin, malonates, preferably diethylmalonate, cutin, castor oil (the latter being particularly preferred), and their mixtures; 4B the alkali or alkaline earth fatty acid salts, stearic and / or oleic acid being preferred, polyoxyethylenated oils preferably polyoxyethylated hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymers, polyoxyethylenated sorbitan esters, polyoxyethylenated castor oil, stearates, preferably calcium, magnesium, aluminum or zinc, stearyl fumarates, preferably sodium, glycerol behenate, and mixtures thereof.

  Preferably, the coating film is constituted by a single layer, the mass of which represents from 1 to 50% by weight, preferably from 5 to 40% by weight, of the total mass of the microparticles.

  Other details and examples of compositions and methods for obtaining the microparticles according to the first embodiment according to the invention are given in WO-A-03/084518, the contents of which are incorporated herein by reference.

  For more qualitative and quantitative data regarding the family A coating composition, reference is made to EP-B-0 709 087, the contents of which are incorporated herein by reference.

  According to a second embodiment of the invention, the oral pharmaceutical form is such that: - the release of losartan, is governed by two distinct mechanisms of triggering, one being based on a variation of pH and the other allowing release of the AP, after a predetermined time of residence in the stomach; at constant pH 1.4, the dissolution profile comprises a latency phase with a duration of less than or equal to 7 hours, preferably less than or equal to 5 hours, and more preferably still between 1 to 5 hours, and the passage pH 1.4 to pH 7.0, leads to a start release phase without latency.

  According to the second embodiment of the invention, the oral pharmaceutical form may have an in vitro dissolution profile as indicated below: less than 20% of the losartan are released after 2 heares at pH = 1, 4; at least 50% of the losartan are released after 16 hours at pH = 1.4.

  Advantageously, the losartan-modified-release microparticles, according to the second embodiment of the invention, have the following specificities: the coating allowing the modified release of losartan comprises a composite material comprising: at least one hydrophilic polymer I carrier of ionized groups at neutral pH, É at least one hydrophobic compound II; 4 representing a mass fraction (% by weight relative to the total mass of the microparticles) <40; and O their average diameter is less than 2000 m, and preferably between 50 and 800 m and, more preferably still, between 100 and 600 m.

  According to another advantageous characteristic, the composite material I-II of the coating allowing the modified release of losartan, is such that: 4 the weight ratio I1 / 1, is between 0.2 and 1.5, preferably between 0.5 and 4 and the hydrophobic compound II is selected from the crystallized products in the solid state and having a melting temperature Tfli> 40 C, preferably Tm 50 C, and more preferably still 40 C T1I 90 C.

  According to one preferred embodiment, the hydrophilic polymer I is chosen from: (i) copolymers of (meth) acrylic acid and (meth) acrylic acid alkyl ester and mixtures thereof; -I. b cellulose derivatives, preferably cellulose acetates, cellulosic phthalates, cellulosic succinates and mixtures thereof, and more preferably hydroxypropylmethylcellulose phthalates, hydroxypropylmethylcellulose acetates, silicone pacifiers; hydroxypropyl methylcelluloses and mixtures thereof; and their mixtures.

  More preferred polymers I are copolymers of (meth) acrylic acid and alkyl (e.g. C 1 -C 6) alkyl esters of (meth) acrylic acid. These copolymers come out, for example, of the type marketed by the company R.5hm Pharma Polymers under the registered trademarks EUDRAGIT, L and S series (as for example the EUDRA ("I am L100, 5100, L30 D-55 and L100-55) These copolymers are anionic enteric copolymers and are soluble in aqueous media at pH levels higher than those found in the stomach.

  Still according to the preferred embodiment, the compound II is chosen from the following group of products: II.a vegetable waxes taken alone or in mixtures with each other; II.b hydrogenated vegetable oils taken alone or mixed with each other; II. c mono and / or di and / or tri esters of glycerol and at least one fatty acid; II.d mixtures of monoesters, diesters and triesters of glycerol and at least one fatty acid; II.e and their mixtures.

  Even more preferably, the compound II is chosen from the following group of products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glycerol behenate, hydrogenated castor oil, tristearin, tripalmitine, trimyristine, yellow wax, hard fat, or fat for use as suppository bases, anhydrous milk fat, lanolin, glycerol palmitostearate, glycerol stearate, lauryl macrogolglycerides, cetyl alcohol, polyglycerol diisostearate, diethylene glycol monostearate, ethylene glycol monostearate, Omega 3 and any mixture thereof, preferably in the following sub-group of products: hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glycerol behenate, hydrogenated castor oil, tristearin , tripalmitine, trimyristine and any mixture of them.

  In practice and without being limiting, it is preferred that the compound II be chosen: O in the group of products marketed under the following brands: Dynasan, Cutina, Hydrobase, Dub, Castorwax, Croduret, Compritol, Sterotex, Lubritab, Apifil , Akofine, Softtisan, Hydrocote, Livopol, Super Hartclan, MGLA, Corona, Protalan, Akosoft, Akosol, Crema, Massupol, Novata, Suppocire, Wecobee, Witepsol, Lanolin, Incromega, Estai am, Suppoweiss, Gelucire, Precirol, Emulcire, Plurol diisostearic, Geleol, Hydrin, Monthyl and mixtures thereof; O and in the additive group whose codes are the following: E 901, E 907, E 903 and mixtures thereof; And preferably in the group of products sold under the following brand names: Dynasan P60, Dynasan 114, Dynasan 116, Dynasan 118, Cutina HR, Hydrobase 66-68, Dub HPH, Compritol 888, Sterotex NF, Sterotex K, Lubritab and their mixtures.

  According to another advantageous feature of the invention, the coating allowing the modified release of losartan is free of talc.

  Advantageously, the coating of the microparticles may comprise, in addition to the essential constituents I and II, other conventional ingredients known to those skilled in the art, such as, in particular: dyes, plasticizers, for example dibutyl sebacate, hydrophilic compounds, for example cellulose and its derivatives or polyvinylpyrrolidone and its derivatives, and mixtures thereof.

  Without limitation, and in an even more preferred embodiment, the coating of the losartan-modified-release microparticles comprises a single composite coating film I-II.

  Other details and examples of compositions and methods for obtaining the microparticles according to the second embodiment of the invention are given in WO-A-03/030878, the content of which is incorporated herein by reference.

  From a quantitative point of view, the monolayer of encapsulant may represent, for example, at most 40%, preferably at most 30% by weight of the microparticles. Such a limited rate of coating makes it possible to produce pharmaceutical units each containing a high dose of losartan, without exceeding a prohibitive size with regard to swallowing. The observance and therefore the success of the treatment can only be improved.

  According to a third embodiment of the invention, the oral pharmaceutical form according to the invention comprises at least two populations of microparticles with modified release of losartan. Each losartan-modified-release microparticle population may be in accordance with the first or second embodiment of the invention. According to a variant -2 of the second embodiment of the invention combined with the third embodiment, the pharmaceutical form oral formulation according to the invention comprises at least two populations of microparticles having different dissolution profiles, for at least a pH value between 1.4 and 7.4.

  According to a variant -2iI of the second embodiment of the invention combined with the third embodiment, the oral pharmaceutical form according to the invention comprises at least two populations of microparticles with modified release of losartan differing by their respective triggering pH.

  According to yet another variant -2iii of the second embodiment of the invention combined with the third embodiment, the oral pharmaceutical form according to the invention comprises at least two populations of microparticles with a controlled release of losartan differing in their tripping times. respectively.

  According to a fourth embodiment of the invention, the oral pharmaceutical form according to the invention comprises at least one population of microparticles with modified release of losartan and at least one population of microgranules with immediate release of losartan.

  According to a variant -2iv- of the second embodiment of the invention combined with the fourth embodiment, the oral pharmaceutical form according to the invention comp end: -> at least one population of microgranules immediate release of losartan; at least one population P1 of modified-release microparticles of losartan, and at least one population P2 of microparticles with modified release of losartan; and, furthermore, the respective release pH values of P1 and P2 differ by at least 0.5 pH units, preferably by at least 0.8 pH units, and more preferably by at least 0.9 pH unit.

  Advantageously, the respective triggering pHs of the different populations of modified-release microparticles of losartan are between 5 and 7.

  According to a variant -2v- of the second embodiment of the invention combined with the fourth embodiment, the oral pharmaceutical form according to the invention comprises: at least one population of microgranules with immediate release of losartan; at least one population P1 'of microparticles with modified release of losartan, whose triggering pH is equal to 5.5; and at least one population P2 'of modified-release losartan microparticles, whose triggering pH is between 6.0 inclusive and 6.5 inclusive.

  The P1, P2, P1 'and P2' populations of the -2iv- and -2v- variants of the second embodiment include losartan-modified-release microparticles, obtained according to the second embodiment of the invention.

  To illustrate the variants of the invention according to which microunits with immediate release of losartan are present in the pharmaceutical form according to the invention, it may be specified that these variants may correspond to the cases where this pharmaceutical form comprises for example at least one population of losartan immediate release microgranules, whose behavior in an in vitro dissolution test is such that at least 80% of losartan is released in 1 hour at any pH between 1.4 and 7.4.

  When the oral pharmaceutical form according to the first embodiment comprises losartan-modified-release microparticles, the dissolution profiles of said microparticles between pH 1 and pH 5 are similar, according to the similarity factor f2 calculated as indicated in the directive of the FDA SUPAC-MR Modified Release Solid Oral Dosage Forms, ie since f2 50%. The oral dosage forms according to the invention may comprise at least one other active ingredient different from losartan. The abbreviation PA will hereinafter denote indifferently one or more active ingredients different from losartan.

  The in vivo or in vitro release of the AP may be immediate or modified. PA may be contained in micro-units of the immediate release microparticles type PA or the modified release microparticles of PA.

  This AP can be chosen, among others, from the group comprising diuretics, beta-blockers, angiotensin converting inhibitors, Sodium channel blockers, alpha-blockers, alpha-beta blockers, vasodilators, alpha antagonists and adrenergic neuronal blockers.

  For more details on these additional PAs, reference may be made, for example, to page 4, line 19 - page 4, line 31 of WO-A-03/035039.

  Losartan exists in several crystalline forms, one of which is particularly crucial for pharmaceutical activity, namely crystalline form 1. It is important that it be preserved. Thus, the process used to produce the pharmaceutical form according to the invention makes it possible to preserve losartan in its initial crystalline form. In the pharmaceutical form according to the invention, for example at least 50% of the losartan is in its crystalline form I. The microparticles according to the invention may have several structures.

  Thus, according to a first form of microparticle structure, at least a portion of the losartan-modified-release microparticles of the oral pharmaceutical form each comprise: a ring containing losartan and at least one coating encasing the core and allowing the modified release of said losartan.

  According to a second form of microparticle structure, at least a portion of said losartan modified-release microparticles of the pharmaceutical form, each comprises: -3 a nucleus comprising: o a neutral core, and o at least one active layer comprising losartan and coating the neutral core, and at least one coating coating the core and allowing the modified release of losartan.

  Advantageously, the proportion of losartan in the micro-units (expressed as% by weight on a dry basis relative to the total mass of the micro-units) is between 5 and 80, preferably between 10 and 70, and more preferably still between 15 and 60.

  According to one possibility, losartan immediate release microgranules are uncoated nuclei of modified losartan microparticles.

  As regards the preparation of the microparticles according to the invention, this refers to microencapsulation techniques accessible to those skilled in the art, the main of which are summarized in the article by C. DUVERNEY and JP BENOIT in "L'actualité chimique December 1986. More specifically, the technique considered is microencapsulation by film coating, leading to individualized "reservoir" systems as opposed to matrix systems.

  For more details, reference is made to EP-B-0 953 359.

  The losartan particles of desired particle size and necessary for the production of the microparticles according to the invention can be pure losartan crystals and / or pretreated by one of the conventional techniques in the field, such as granulation, for example. presence of at least one conventional binder and / or an agent that modifies the intrinsic solubility characteristics of losartan. Losartan can for example be deposited on the core by the techniques known to those skilled in the art, for example the "spray coating" technique in a fluidized air bed or shaped in the wet granulation, compaction , extrusion - spheronization ...

  Advantageously, the oral pharmaceutical form according to the invention is in the form of a single daily oral dose comprising from 1000 to 500000 micro-units containing losartan.

  More specifically, the oral pharmaceutical form according to the invention may be in the form of a single oral daily dose comprising from 1000 to 500000 microparticles with modified release of losartan.

  The oral pharmaceutical form according to the invention may be provided in the form of a sachet of microparticle powder, liquid suspension of microparticles, tablet obtained from microparticles, or capsule containing microparticles.

  According to another of its objects, the invention relates to the use of the modified-release microparticles of losartan as defined above and possibly microgranules with immediate release of losartan as defined above, for the preparation of microparticulate oral dosage forms, pharmaceutical or dietetic, preferably in the form of advantageously orodispersible tablets, powders or capsules. 2: 3

  According to another of its objects, the invention is directed to microparticles per se as defined above.

  According to another of its objects, the invention is directed to a method of therapeutic treatment of hypertension characterized in that it consists in administering, preferably in a single daily oral dose, the pharmaceutical form as defined above.

Description of the figures:

  FIG. 1 represents the in vitro dissolution profile at pH 6.8 of the losartan-modified microparticles according to example 2: FIG. 2 represents the in vitro dissolution profile at pH 1.4; 4.5 and 6.8 of the losartan-modified microparticles according to Example 2. FIG. 3 represents the in vitro dissolution profile at pH 6.8 of the modified-release microparticles of losartan according to Example 2 for doses of losartan. varying between 10 and 200mg.

  FIG. 4 represents the in vitro clissolution profile at pH 1, 4 and 6.8 of the losartan-modified microparticles according to example 3; FIG. 5 represents the in vitro dissolution profile at pH 1.4 and 6; 8 is the in vitro dissolution profile at pH 1.4 of the losartan-modified microparticles according to Example 4 for doses of losartan ranging from and 200mg.

  In all the figures, the dissolution profile corresponds to the weight percentage of dissolved losartan (D) as a function of time (T) in hours.

  The dissolution profiles are carried out according to the indications of the European Pharmacopoeia 4th edition entitled: "Dissolution test of solid oral forms": dissolutest of type II carried out under SINK conditions maintained at 37 ° C. and stirred at 100 rpm.

EXAMPLES

  In the following examples, the excipients are designated under their commercial name. Correspondence with the chemical name can be found in the table below: Trade Name Chemical Name / Monograph Cremophor RH 40 Macrogolglyceroli hydroxystearas Klucel EF Hydroxypropyl cellulose Plasdone K29 / 32 Povidone Eudragit L100-55 Poly (methacrylic acid, ethyl acrylate) 1: 1 Eudragit 5100 Poly (methacrylic acid, methyl methacrylate) 1: 2 Example 1: Preparation of losartan potassium granules 810 g of losartan potassium and 90 g of Klucel EF (Aqualon) are dispersed in 2,000 g of isopropanol. The suspension is sprayed on 100 g of neutral microspheres (Asahi-5 Kasei) in a Glatt GPCG1 coater spray.

  The granulate obtained has a concentration of losartan potassium of 81%.

  Example 2: Preparation of losartan potassium microparticles 200 g of ethyl cellulose (Ethocel Premium / Dow), 15 g of Plasdone K29 / 32 (ISP), 10 g of Cremophor RH 40 (BASF) and 25 g of castor oil are dispersed in a mixture of 60% isopropanol and 40% acetone. This solution is sprayed on 750 g of losartan potasium granulate (prepared in Example 1).

  The microparticles obtained are then placed in a size 2 gelatin capsule. The dose of losartan potassium per capsule was fixed in this test at 100 mg (165 mg of microparticles). This capsule is the final form of the drug.

  The capsule containing the microparticles was tested in a type II dissolutest according to the Pharmacopoeia at 37 C and with stirring at 100 rpm at pH 6.8 (0.05 M KH 2 PO 4 / NaOH). See Figure 1.

  It is found that the release of losartan potassium is prolonged for a period of about 5 hours, which makes it possible, during the administration of such a medicament, to increase the bio-absorption times.

  The capsule containing the microparticles was tested in a type II dissolutest according to the Pharmacopoeia at 37 C and with stirring at 100 rpm at pH 1.4 (HCl); 4.5 (KH 2 PO 4 / NaOH) and 6.8 (KH 2 PO 4 / NaOH). See Figure 2.

  It is found that the release of losartan is almost independent of the pH of the dissolution medium, which makes it possible to have a non-pH-dependent in vivo release of the gastric fluids.

  In order to study the influence of the dose of losartan Potassium on the dissolution profile, the release of losartan by the microparticles was determined for a dose of 10, 25, 50, 100, 150 and 200 mg of active ingredient in dissolutest. type II according to the Pharmacopoeia at 37 C and with stirring at 100 rpm pH 6.8 (KH2PO4 / NaOH). See Fig. 3. The dissolution profile is independent of the dose of losartan.

  Example 3: Preparation of microparticles of losartan potassium g of hydrogenated cottonseed oil (Penwest) and 150 g of Eudragit L100-55 (RShn-) are dissolved hot in isopropanol. The solution is sprayed on 750 g of losartan potasium granules (prepared in Example 1).

  The microparticles obtained are then placed in a gelatin capsule of size 2. The dose of losartan potassium per capsule was fixed in this test at 100 mg (165 mg of microparticles). This capsule is the final form of the drug.

  The capsule containing the microparticles was tested in a type II dissolutest according to the Pharmacopoeia at 37 C and with stirring at 100 rpm at pH 1.4 (HCl) and at pH 6.8 (0.05 M KH 2 PO 4 / NaOH). See Figure 4.

  It is noted that the release of losartan potassium is delayed and prolonged for a period of about 5 hours, which allows the administration of such a drug to increase the bioabsorption times.

  It is found that the release of potassium is immediate at pH 6.8, which makes it possible during the administration of the drug to have a strong absorption of the active principle in the upper part of the small intestine.

  Example 4: Preparation of losartan potassium microparticles 100 g of hydrogenated cottonseed oil (Penwest), 50 g of Eudragit L100-55 (Rohm) and 100 g of Eudragit 5100 (Rdhm) are dissolved in hot water in isopropanol. The solution is sprayed on 750 g of losartan potasium granules (prepared in Example 1).

  The microparticles obtained are then placed in a size 2 gelatin capsule. The dose of losartan potassium per capsule was fixed in this test at 100 mg (165 mg of microparticles). This capsule is the final form of the drug.

  The capsule containing the microparticles was tested in a type II dissolutest according to the Pharmacopoeia at 37 ° C. and with stirring at 100 rpm at pH 1.4 (I-ICI) and at pH 6.8 (0.05 M KH 2 PO 4 / NaOH). ). See Figure 4.

  It is found that the release of losartan potassium is delayed and prolonged for a period of about 10 hours, which allows the administration of such a drug to increase the bioabsorption times.

  It is found that the release of potassium is immediate at pH 6.8 which allows during the administration of the drug to have a strong absorption of the active ingredient in the upper part of the small intestine.

  In order to study the influence of the dose of losartan Potassium on the dissolution profile, the release of losartan by the microparticles was determined for a dose of 10, 25, 50, 100, 150 and 200 mg of active ingredient in dissolutest of type II according to the Pharmacopoeia at 37 ° C. and with stirring at 100 rpm at pH 1.4 (KH 2 PO 4 / NaOH). See Figure 6.

  The dissolution profile is independent of the dose of losartan.

  Example 5: Preparation of microparticles of losartan potassium The microparticles obtained in Example 4, 280 g of lactose, 40 g of crospovidone and 15 g of magnesium stearate are mixed using an ERWEKA laboratory mixer.

  Tablets consisting of 500 mg of the above mixture are prepared using a KORSCH tablet press. These tablets are the final form of the drug.

  The in vitro dissolution profile at pH 1.4 (HCl) of the tablets thus prepared is identical to that of the capsules of Example 4 (see FIG. 5).

  It is found that the release of losartan potassium is delayed and prolonged for a period of about 10 hours, which makes it possible, during the administration of such a medicament, to increase the bioabsorption times and to respect at best the chronobiology of the patient.

FLAMEL 0100 FR 05 50476 27

Claims (25)

  1. A modified-release oral pharmaceutical dosage form of losartan characterized in that it comprises a plurality of micro-units containing losartan, in that the average diameter (Dm in m) of the micro-units is between 50 and 1000, preferably 100 and 600, and more preferably between 150 and 500, * and in that it allows to obtain, after taking, a plasma profile defined as follows: -a- C18h * C18h of preferably 1.5.C18h * 5 C18h 5 Cmax * / 2 and more preferably still; 2.0.C18h * <C18h 5 Cmax * 12 -b-1, l.Tmax * S Tmax preferably 1,2.Tmax * 5 Tmax and more preferably 1,5.Tmax * Tmax more preferably 1,7 .Tmax * 5 Tmax 6.Tmax with o C18h representing the plasma concentration of the active metabolite (E 3174) of losartan, 18h after taking, o C18h * representing the plasma concentration of E 3174 obtained under the same conditions as C 18h, with a reference oral immediate-release pharmaceutical form, containing the same dose of losartan, where C max represents the maximum plasma concentration of E 3174 after taking, where T max represents the time that elapsed after taking and which corresponds to C max, o Cmax * representing the maximum plasma concentration of E 3174 obtained under the same conditions as Cmax, with a reference oral immediate release pharmaceutical form, containing the same dose of losartan, É Tmax * representing the time which elapsed after the taking and which corresponds to Cmax *. 30 35   FLAMEL 0100 - EN 05 50476 28 2. Oral pharmaceutical form according to claim 1, characterized in that at least a portion of the microunits are microparticles each consisting of a core which comprises losartan and which is coated with at least one coating allowing the modified release of losartan.   3. oral pharmaceutical form according to one of claims 1 and 2, characterized in that at least a portion of the micro-units it comprises, is formed by microgranules immediate release losartan.   4. Oral pharmaceutical form according to claim 3, characterized by an in vitro dissolution profile such that: losartan% are released between 1 and 24h, preferably between 2 and 12h, and even more preferably between 2 and 8h, after administration.   5. Oral pharmaceutical form according to one of claims 1 and 2, characterized in that the release of losartan, is governed by two separate mechanisms of triggering, one being based on a pH change and the other allowing the release losartan, after a predetermined time of residence in the stomach; at a constant pH 1.4, the dissolution profile comprises a latency phase with a duration of less than or equal to 7 hours, preferably less than or equal to 5 hours, and more preferably still between 1 to 5 hours, and the passage of pH 1.4 at pH 7.0, leads to an early release phase without latency.   6. oral pharmaceutical form according to claim 5, characterized in that its dissolution profile, measured in an in vitro dissolution test, is as indicated below: less than 20% of the losartan are released after 2 hours at pH = 1.4; at least 50% of losartan are released after 16 hours at pH = 1.4.   7. Oral pharmaceutical form according to any one of the preceding claims, characterized in that the CV variability (in%) of the area under the curve (ASC) giving the evolution of the plasma concentration to the active metabolite E 3174, in time (T) after setting, is less than or equal to 200%, preferably 150%, and more preferably 120%, of the corresponding CV * variability (in%). ) the area under the curve (AUC *) giving the change in plasma concentration to the active metabolite E 3174, as a function of time (T) after taking, under the same conditions, an oral pharmaceutical release form immediate reference *, containing the same dose of losartan, ie: CV 2.0.CV *, preferably CV 1.5.CV *, and more preferably still CV 1.1.CV *.   8. Oral pharmaceutical form according to one of claims 1, 2 or 4, characterized in that the rate of release of losartan in vitro in a dissolution test, is independent of the pH.   9. oral pharmaceutical form according to claim 8 and optionally claim 6, characterized in that the dissolution profiles of the microparticles between pH 1 and pH 5 are similar.   10. oral pharmaceutical form according to any one of claims 1 to 9, characterized in that it comprises at least two populations of microparticles according to claim 2.   11. Oral pharmaceutical form according to any one of claims 1 to 10, characterized in that it comprises at least one population of microparticles according to claim 2 and at least one population of microgranules according to claim 3.   12. oral pharmaceutical form according to claim 5 and optionally claim 6 or 10, characterized in that it comprises at least two populations of microparticles having different dissolution profiles, for at least a pH value between 1.4 and 7.4.   13. oral pharmaceutical form according to claim 5 and optionally one of claims 6, 10 and 12, characterized in that it comprises at least two populations of modified release microparticles losartan differing by their respective trigger pH.   14. Oral pharmaceutical form according to claim 5 and optionally one of claims 6, 10, 12 and 13, characterized in that it comprises at least two populations of microparticles modified release of active ingredient differ by their respective trigger times .   FLAMEL 0100 EN 05 50476 30 15. Oral pharmaceutical form according to claim 5 and optionally one of claims 6, 10, 12 to 14, characterized in that it comprises: at least one population of microgranules with immediate release of losartan ; at least one population P 1 of losartan-modified release microparticles, and o at least one P2 population of modified-release losartan microparticles; and in that the respective triggering pHs of P1 and P2 differ by at least 0.5 pH units, preferably by at least 0.8 pH units, and more preferably by at least 0. , 9 pH unit.   16. Oral pharmaceutical form according to claim 5 and optionally one of claims 10, 12 to 15, characterized in that the respective triggering pH of the different populations of modified-release microparticles of losartan are between 5 and 7.   17. Oral pharmaceutical form according to claim 5 and optionally one of claims 10 to 16, characterized in that it comprises: E at least one population of micro-granules immediate release of losartan; at least one population of losartan-modified microparticles with a triggering pH of 5.5; and o at least one population P2 'of modified release losartan microparticles, whose triggering pH is between 6.0 inclusive and 6.5 inclusive.   21. oral pharmaceutical form according to any one of claims 3 to 16 characterized in that it comprises at least one population of microgranules immediate release of losartan, whose behavior in an in vitro dissolution test is such that at least 80% losartan are released in 1 hour at any pH between 1.4 and 7.4.   22. Oral pharmaceutical form according to any one of the preceding claims, characterized in that at least 50% of the losartan is in its crystalline form I. FLUORAL oral form according to one of claims 2 at 19, characterized in that at least a portion of the losartan-modified-release microparticles each comprise: E a ring containing losartan and E at least one coating coating the core and allowing the modified release of said losartan.   21. An oral pharmaceutical form according to any one of claims 2 to 19, characterized in that at least a portion of said losartan-modified-release microparticles each comprise: a nucleus comprising: a neutral core, at least one an active layer comprising losartan and coating the neutral core; and at least one coating coating the core and allowing the modified release of losartan.   22. Oral pharmaceutical form according to any one of the preceding claims, characterized in that the proportion of losartan in the micro-units (expressed as% by weight on a dry basis relative to the total mass of micro-units) is between 5 and 80, preferably between 10 and 70, and more preferably between 15 and 60.   23. Oral pharmaceutical form according to claim 3 and optionally according to any one of claims 4 to 22 characterized in that losartan immediate release microgranules are uncoated microparticle cores according to claim 3.   24. Oral pharmaceutical form according to any one of the preceding claims, characterized in that it is in the form of a daily oral single dose comprising 1000 to 500000 micro-units containing losartan.   25. Oral pharmaceutical form according to any one of the preceding claims, characterized in that it is in the form of a daily oral single dose comprising from 1000 to 500000 microparticles with modified release of losartan.   26. Oral pharmaceutical form according to any one of the preceding claims characterized in that it is in the form of a bag of micro-unit powder, liquid suspension of microparticles, tablet obtained from micro-units, or capsule containing micro-units.   27. Use of the modified release microparticles of losartan as defined in any one of claims 1 to 26 and optionally microgranules immediate release of losartan as defined in any one of claims 3 to 26, for the preparation of microparticulate, pharmaceutical or dietetic oral dosage forms, preferably in the form of advantageously orodispersible tablets, powders or capsules.   28. Use of the losartan-modified-release microparticles as defined in any one of claims 1 to 27 and optionally losartan immediate release microgranules as defined in any one of claims 3 to 27, for the preparation of a therapeutically safe, microparticulate oral pharmaceutical form so designed that once said pharmaceutical form is ingested, the microparticles which it comprises are dispersed and individualized when they reach the stomach, allowing these microparticles to be subjected to a regular and progressive gastric emptying, whether the patient is fed or fasted during the taking, thus guaranteeing a release of losartan in its gastrointestinal window of bioabsorption 29. Microparticles as defined in any one of the claims 2 to 28. 25 30