Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
  • A61K31/4164—1,3-Diazoles
  • A61K31/417—Imidazole-alkylamines, e.g. histamine, phentolamine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
  • A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P9/00—Drugs for disorders of the cardiovascular system
  • A61P9/12—Antihypertensives
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
  • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
  • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
  • A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings

Definitions

• the field of the present invention is that of oral pharmaceutical forms of losartan, as well as treatments and methods of administration thereof.
• Losartan is an angiotensin II receptor antagonist (AT1 type). It is active orally and intervenes in the regulation of hypertension by acting on the renin-angiotensin system.
• Losartan may be combined with a diuretic (hydrochlorothiazide) to increase its effectiveness, or any other drug with cardiovascular activity.
• Losartan is particularly used in the treatment of the following pathologies: • essential hypertension,
• Losartan administered orally, undergoes an important first-pass metabolism at the level of the cytochrome P450 enzymatic system. It is converted, in part, into a carboxylic acid (EXP3174), a more potent active metabolite than the parent molecule losartan, which is considered as a prodrug.
• EXP3174 carboxylic acid
• losartan a more potent active metabolite than the parent molecule losartan, which is considered as a prodrug.
• 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).
• losartan refers to losartan in at least one of its pharmaceutically acceptable forms, including its metabolites.
• the early decay of the plasma concentration after the peak results in a very low level of losartan concentration at the end of the period between two administrations.
• the patients of the fast population Pr are inadequately treated at the end of the period between two administrations.
• ARBs especially losartan
• losartan are most often administered orally, in tablet form, 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.
• a daily intake of, for example, 100 mg does not allow effective treatment and two doses per day (2 times 50 mg) are required.
• 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.
• pylorus closure may be erratic.
• the patient does not follow the dosing instructions and ingests the tablet before the meal 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.
• the patent application WO-A-98/24411 describes a method of therapeutic treatment with buspirone of orally administering an immediate release dosage form (eg tablet or capsule) comprising both a buspirone and a sufficient amount of nefazodone, in order to increase the bioavailability of buspirone and to decrease its elimination, metabolite formation as well as variability in pharmacokinetic parameters.
• an immediate release dosage form eg tablet or capsule
• nefazodone with buspirone is believed to address the unresolved problem of controlled / sustained release formulations of buspirone disclosed in US-B-5,431,922, which have the major disadvantage of inducing a high level of variability in pharmacokinetic parameters ( see page 3, lines 7 to 16 of WO-A-98/24411).
• US-B-6,248,359 discloses a multi-tablet system for the treatment of urinary incontinence using oxybutynin.
• the system includes a 1 tablet that releases oxybutynin over a short period of time (eg less than 6 hours) and a 2 nd tablet that releases oxybutynin over an extended period of time (18-24 hours).
• This system is presented as allowing to compensate for interindividual variability, in response to therapy using oxybutynin.
• These tablets consist for example of tablets each comprising an oxybutynin core and several coatings.
• microcapsules for the oral administration of medicinal and / or nutritional active principles (PA), the size of which is less than or equal to 1000 ⁇ m.
• These microcapsules consist of particles which are coated with a coating material consisting of a mixture of a polymeric film-forming derivative (ethylcellulose), a hydrophobic plasticizer (castor oil), a surfactant and / or lubricant (magnesium stearate) and a nitrogenous polymer (polyvinylpyrrolidone: PVP).
• PVP polyvinylpyrrolidone
• PCT Patent Application WO-A-03/030878 discloses a delayed release system, controlled and certain PA, characterized by a dual mechanism for triggering the release of AP: release "dependent time” triggered after a period of time controlled in the stomach, without pH change and release "pH dependent” triggered by a rise in pH, when the galenic form enters the intestine.
• These microcapsules with a diameter of between 200 and 600 microns are characterized by a coating film based on a hydrophilic polymer A of the EUDRAGIT® type combined with a hydrophobic compound B, such as a vegetable wax (LUBRITAB®) with a melting temperature. between 40 and 90 ° C, the ratio B / A between 0.2 and 1.5.
• the essential objective of the invention is to remedy the shortcomings and disadvantages of the prior art.
• Another essential objective of the invention is to propose, in the oral pharmaceutical forms, a new use of the means for controlling the release of losartan (coating or matrix containing losartan) so as to satisfy at least one of the objectives. above, and in particular to reduce the interindividual variability of plasma profiles.
• Another essential objective of the invention is to propose a new use of the oral pharmaceutical forms comprising means for controlling the release of losartan of the coating or matrix type containing losartan, so as to satisfy at least one of the following objectives. -above.
• Another essential objective of the invention is to propose, in the oral pharmaceutical forms, a new use of the means for controlling the release of losartan (coating or matrix containing losartan), in order to reduce the interindividual standard deviation of the plasma concentration. maximum after administration.
• Another essential objective of the invention is to propose a new use of oral pharmaceutical forms comprising means for controlling the release of losartan of the coating or matrix type containing losartan, in order to reduce the interindividual variability of the plasma profiles and, in particular, to reduce the interindividual standard deviation of peak plasma concentration after administration.
• An essential object of the invention is to provide an oral pharmaceutical form of losartan which is used in such a way that it gives access to a more uniform and reproducible quality of treatment from one patient to another, with respect to this which is proposed in the prior art.
• Another essential objective of the present invention is to propose a means for reducing the interindividual standard deviation of the maximum concentration Cmax of the plasma profile.
• Another essential objective of the invention is to provide an oral pharmaceutical form of losartan which makes it possible to reduce the interindividual variability of the plasma profiles of the known oral pharmaceutical forms of losartan, in particular to prevent the appearance of two populations of plasma profiles: a population Pr at risk of "fast" profiles and a population Pl of "slow” profiles.
• Another essential objective of the present invention is to propose a means for reducing or even suppressing the fast population Pr.
• Another essential objective of the invention is to provide an oral pharmaceutical form of losartan which offers a guarantee in terms of therapeutic safety: risk for certain patients of premature and / or massive and / or rapid release of losartan and therapeutic coverage over the entire time interval between two doses.
• Another essential objective of the invention is to provide an oral pharmaceutical form of losartan which preserves patients from any risk of plasmatic overconcentration of losartan and thus protect them from any drug accident.
• Another essential objective of the invention is to provide a means for reducing the peak / valley ratio of losartan plasma concentrations.
• 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 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, administrable once a day and adapted to patients having difficulty swallowing, especially to children or infants who can not only not swallow and who in addition, 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 release times 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, administrable once a day and which, despite the variability of the solubility losartan in water as a function of pH, releases losartan according to the same kinetics, whether or not the patient is fasting.
• 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 and the like.
• Another essential object of the invention is to provide a therapeutic method of employing an oral dosage form that satisfies at least one of the above therapeutic objectives.
• That losartan has a solubility which varies greatly according to the gastric pH, • and that this gastric pH is subjected to a great variability of varied origin and dependent on various uncontrollable parameters, in particular: nourished state or fasting, interindividual variability, action of a drug influencing these gastrointestinal conditions, etc., to have hypothesized that the non-reproducibility of the quality of treatment from one patient to another could be related to the dependence of the solubility of the patient.
• losartan vis-à-vis the gastric pH, variable depending on the timing of the taking in the same subject and from one subject to another ⁇ and finally to have imagined a technical solution to limit or even eliminate this dependence, this solution consisting in recommending the implementation of a coating or a matrix containing losartan able to reduce or even suppress the Pr population of rapid plasma profiles and to avoid premature release e and / or massive and / or rapid losartan irrespective of gastric acidity, which is likely to reduce the interindividual variability of plasma profiles.
• the therapeutic safety is improved by preventing the deleterious effects of the oral administration of losartan for a certain patient population, and, on the other hand, the therapeutic efficacy is promoted.
• the present invention achieves the above objectives, among others, by providing: "the use, in an oral pharmaceutical form comprising losartan, a coating or matrix including said losartan and allowing the controlled release of said losartan, to ensure that this form administered orally to a sample of subjects lead, regardless of the fed or fasting state of the subjects, the decrease in the gap interindividual type of Cmax, which makes it possible to ensure a lower variability of the efficacy and the therapeutic safety of the pharmaceutical form compared to an immediate-release pharmaceutical form of losartan administered to this same sample of subjects, to the same dose; and / or "and / or the use of losartan contained in a coating or in a matrix allowing the controlled release of said losartan, to manufacture an oral pharmaceutical form which, after oral administration to a sample of subjects, leads, whatever the fed or fasted subjects, the decrease in the inter-individual standard deviation of Cmax, which makes it possible to ensure a lower variability in the efficacy and therapeutic safety of the pharmaceutical form compared to a particular form.
• the invention is thus defined through a reference clinical test in which the pharmaceutical form is administered orally to a sample of subjects, under experimental conditions which may be those given in the examples below.
• This clinical test defines the invention by the pharmacodynamic properties obtained specifically under the conditions of the test.
• the invention is not limited to an implementation under the conditions of this reference clinical test.
• the use according to the invention makes it possible to reduce or even eliminate the erratic character of the plasma concentration profiles from one subject to another and, in so doing, to avoid:
• the technical function exploited and highlighted in accordance with the invention is not the extension of the release time, but rather the reduction of the variability of the treatment that is harmful to the patient.
• the invention makes it possible to guarantee better efficacy and greater therapeutic safety.
• the present invention also provides a novel oral dosage form with modified release of losartan, which may be one of those used in the above-mentioned use and defined by claim 31 or 32.
• this pharmaceutical form is designed in such a way that the micro-units, once ingested, are dispersed and individualized when they reach the stomach, which guarantees a regular and progressive gastric emptying of microorganisms. units, in the fed state as fasting, and thus in fine a release of losartan in its gastrointestinal window of bioabsorption.
• the expression "dispersed and individualized” means that losartan micro-units are not trapped in a matrix when they arrive in the stomach just after their ingestion.
• the micro-units spread in the stomach immediately after entering the stomach (for example in less than two minutes).
• immediate Release is meant in this disclosure the release by an Immediate Release Form (FLI) of most of the amount of losartan in a relatively short time, for example:
• At least 80% are released in vivo in one hour, preferably in thirty minutes after oral ingestion.
• losartan is released in 1 hour, preferably in 30 minutes, at any pH between 1.4 and 7.4 in an in vitro dissolution test.
• SINK maintained at 37 ° C and stirred at 100 rpm.
• FLIs include conventional swallowing tablets, dispersible tablets, chewable tablets, sachets and capsules.
• controlled release is meant in the present disclosure, a release of losartan by an oral pharmaceutical formulation, this release being effected in vivo independently of the gastric pH and at a rate lower than that of a formulation "Liberation Immediate "FLI reference *.
• a controlled release formulation may, for example, include an immediate release phase and a slow release phase.
• Controlled release formulations are well known in the art; see, eg, Remington: The science and practice of pharmacy, I9 th edition, Mack publishing Co. Pennsylvania, USA.
• the controlled release may be in particular a prolonged and / or controlled release, even delayed.
• modified release is meant in the present disclosure, a release of losartan by a pharmaceutical formulation, this release being effected at a speed less than that of a FLI * "Immediate Release” formulation, such as a conventional tablet or capsule to be swallowed.
• 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, eg, Remington: The science and practice of pharmacy, I9 th edition, Mack publishing Co. Pennsylvania, USA.
• the pharmacokinetic parameters referred to in the present invention are defined as follows. After oral administration of the dosage form to a sample of N subjects, the individual plasma concentration profile is measured on each patient, from which the individual individual pharmacokinetic parameters are derived: Tmax, Cmax, C24h:
• Tmax is the time after which the plasma concentration reaches its maximum Cmax.
• C24h is the plasma concentration 24 hours after administration.
• the gastric pH is an intrinsically variable variable in a pH range from pH 1.2 to pH 5.5. This variation is observed for the same individual, particularly according to the state fed or fasted, and from one individual to another.
• some patients may be treated with drugs that "artificially" alter gastric pH. This is the case, for example, with proton pump inhibitors (eg omeprazole) or antacids.
• a traditional losartan FLI administered at a dose of 100 mg to a sample of 20 subjects leads to a Cmax varying from one individual to another, by a factor> (70 to 800 ng / ml).
• This erratic character of the plasma concentration profiles can be translated, as in the example invoked, by the appearance of two populations of profiles: the fast (Pr) population and the slow population (Pl).
• the term "rapid population Pr" refers to all individuals for whom, in the fed state, after administration of a losartan FLI, Tmax is less than 1.5 hours. For this fast population Pr, the peak plasma concentration of losartan is reached early and usually takes a high value.
• one of the essential elements of the invention is to use or propose the therapeutic use of an oral dosage form comprising losartan contained in a coating or matrix designed to control controlled release.
• losartan to ensure that this dosage form administered orally to a sample of subjects, lead, regardless of the fed state or fasting subjects, a decrease in the inter-individual standard deviation of Cmax, which allows to ensure a lower variability in the efficacy and therapeutic safety of the pharmaceutical form compared to an immediate-release pharmaceutical form of losartan administered to this same sample of subjects, at the same dose.
• the factor (f) for decreasing the standard deviation is defined by the ratio of the standard deviation of the Cmax of the FLI * form to the corresponding standard deviation of the form concerned by the use according to the invention.
• the factor (f) for decreasing the inter-individual standard deviation of Cmax is such that: f> 1.2; preferably f> 1.75, and even more preferably f is between 2.5 and 20.
• the use of the aforesaid coating or matrix for producing such an oral pharmaceutical form is also covered by the invention.
• the oral pharmaceutical form concerned with the aforesaid uses is also an object in its own right of the present invention.
• This invention appears particularly important for optimizing the use of losartan which can, by itself, be administered once a day, but which suffers from this erratic behavior of the plasma profiles.
• the purpose of the invention is not primarily the extension of the release time, but especially the reduction of the variability of the treatment that is harmful to the patient.
• the invention makes it possible to guarantee better efficacy and therapeutic safety.
• the inventive merit of the applicant is essentially based on having clearly identified and posed the problem of the variability of the solubility of losartan according to the gastric pH and the variability of the latter.
• the plaintiff proposed a new and inventive use of general means known to limit the influence of these factors. These means are the coating membrane or the inclusion matrix of losartan. They prevent its rapid and early release into the stomach, even in patients with gastric pH such that the solubility of losartan is high.
• the pharmaceutical form can be administered daily via one or more dosage units of all types (eg tablet, capsule, volume unit of powder or liquid), to the excluding multiple-dose tablet systems, in which at least one of these tablets is a fast-release tablet of the active ingredient (less than six hours) and at least one of these tablets is a sustained-release tablet same active ingredient (18 to 24 hours).
• dosage units of all types eg tablet, capsule, volume unit of powder or liquid
• the pharmaceutical form can be administered daily via one or more dosage units of all types (eg tablet, capsule, volume unit of powder or liquid), to the excluding multiple-dose tablet systems, in which at least one of these tablets is a fast-release tablet of the active ingredient (less than six hours) and at least one of these tablets is a sustained-release tablet same active ingredient (18 to 24 hours).
• the coating or the matrix is designed so that it allows the controlled release of losartan, on the one hand, to prevent premature and / or massive and / or rapid release of losartan and subsequently any plasma overconcentration of losartan. deleterious and, on the other hand, to ensure therapeutic coverage between two doses.
• the coating or matrix of the pharmaceutical form is designed such that the oral administration of this form, to a sample of subjects, leads to a peak / valley average modulation of the profiles.
• EXP3174 less than the mean peak / valley modulation of the EXP3174 metabolite of the same sample of subjects given the same dose of an immediate-release form of losartan.
• the peak / valley modulation of the plasma concentration profiles is defined by the average of the Cmax / C24h ratio of the EXP3174 metabolite.
• the coating or the matrix of the pharmaceutical form is designed so that the oral administration of this form, to a sample of subjects, leads to a variability of the peak / valley modulation.
• profiles EXP3174 which is less than the variability of the peak / valley modulation of the EXP3174 metabolite, from the same sample of subjects given the same dose of an immediate-release form of losartan.
• the variability of the peak / valley modulation of the plasma concentration profiles is defined by the standard deviation of the Cmax / C24h ratio of the EXP3174 metabolite.
• the plasma profiles obtained are more homogeneous. Their interindividual variability is reduced.
• the invention also proposes:
• an oral pharmaceutical form comprising losartan, a coating or a matrix comprising said losartan and allowing the controlled release of losartan, to ensure that said pharmaceutical form administered orally to a sample of subjects (eg in the fed state), lead to the decrease in the number or the disappearance of individual plasma profiles having a Tmax less than or equal to one hour, preferably less than or equal to 1.5 hours, in favor of plasma profiles individuals having a Tmax greater than one hour, preferably greater than 1.5 hours, which makes it possible to ensure a lower variability of the efficacy and the therapeutic safety of the pharmaceutical form, compared to a pharmaceutical release form. immediate losartan administered to this same sample of subjects (eg in the fed state) at the same dose.
• the invention also aims at: "the use, in an oral pharmaceutical form comprising losartan, a coating or a matrix including said losartan, for reducing the variability of the plasma profiles during administration of this pharmaceutical form to a sample of subjects, compared to an immediate release pharmaceutical formulation FLI * of losartan administered to this same sample of subjects, at the same dose, which makes it possible to ensure a lower variability of the efficacy and the therapeutic safety of the pharmaceutical form, relative to a losartan FLI * immediate-release pharmaceutical form administered to the same sample of subjects, at the same dose, or the use of losartan contained in a coating or in a matrix, to manufacture a pharmaceutical form leading to a reduction in the variability of plasma profiles when administering this pharmaceutical form to a sample of subjects, compared to an immediate release pharmaceutical formulation FLI * of losartan administered to this same sample of subjects, at the same dose, which makes it possible to ensure a lower variability in efficacy and therapeutic safety of the pharmaceutical form, relative to an immediate-release pharmaceutical dosage form losartan administered to the
• the pharmaceutical form contemplated in the use according to the invention may contain losartan in the form of micro-units, which may be in particular: "microparticles each consisting of a heart which comprises losartan and which is coated with at least one coating for controlled release of losartan (also hereinafter referred to as coated microparticles); and / or microgranules individually consisting of a matrix which includes losartan and which permits the controlled release of losartan (also referred to hereinafter). matrix microgranules); and / or losartan immediate release microgranules.
• micro-units may be in particular: "microparticles each consisting of a heart which comprises losartan and which is coated with at least one coating for controlled release of losartan (also hereinafter referred to as coated microparticles); and / or microgranules individually consisting of a matrix which includes losartan and which permits the controlled release of losartan (also referred to hereinafter).
• matrix microgranules and / or
• the oral pharmaceutical form contemplated in the use according to the invention may be any of the forms known to those skilled in the art, namely in particular capsules, sachets, suspensions containing micro-units of losartan or else tablets. These tablets can be
• microparticle-free tablets each consisting of a core comprising losartan and being coated with at least one coating for controlled release of losartan, and / or free of microgranules individually consisting of a matrix including losartan and allowing the controlled release of losartan.
• These tablets (ii) may be matrix tablets or individually coated tablets.
• the losartan micro-units (coated microparticles and / or controlled-release matrix microgranules or immediate release microgranules) preferably have a mean diameter (Dm in ⁇ m) of the micro-units of less than 1000, preferably between 50 and 800, and even more preferably between 50 and 500.
• the oral pharmaceutical form contemplated in the use according to the invention makes it possible, after taking, to obtain a plasma profile defined as follows:
• ° Cmax * representing the maximum average plasma concentration of EXP3174 obtained under the same conditions as Cmax, with a standard oral immediate release pharmaceutical form, containing the same dose of losartan.
• the oral dosage form comprises coated or matrix microparticles and has an in vitro dissolution profile [Cd / o (t)] such that: time t (70%) after administration and at The end of which 70% of the losartan are released, is between 1 and 24 hours, preferably between 2 and 12 hours, and even more preferably between 2 and 8 hours.
• the oral pharmaceutical form according to the first embodiment 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 the physiological pH in the stomach, for example those ranging from 1 to 7.
• composition of the individual coating or of the individual matrix of the microparticles according to the first embodiment corresponds, advantageously, to one of the following two families A and B:
• A-4-at least one surfactant and / or lubricant present (% by weight on a dry basis) in a proportion of 2 to 20, preferably 4 to 15 by weight on a dry basis relative to the total mass of the composition coating and selected from anionic surfactants, and / or from nonionic surfactants, and / or from lubricating agents; said agent may comprise a single or a mixture of the aforesaid products;
• A-I ethylcellulose and / or cellulose acetate
• A-2 polyacrylamide and / or polyvinylpyrrolidone
• A-3 castor oil
• A-4 alkali or alkaline earth fatty acid salt, stearic and / or oleic acid being preferred, polyoxyethylenated sorbitan ester, derived from polyoxyethylenated castor oil, stearate, preferably calcium, magnesium, aluminum or zinc, Family B:
• At least one film-forming polymer that is insoluble in the liquids of the gastrointestinal tract At least one film-forming polymer that is insoluble in the liquids of the gastrointestinal tract
• At least one surfactant / lubricant preferably consisting of at least one anionic surfactant and / or at least one nonionic surfactant.
• non-water-soluble derivatives of cellulose with ethylcellulose and / or cellulose acetate being particularly preferred,
• PVA polyvinyl alcohols
• PVP polyvinylpyrrolidones
• glycerol and its esters preferably in the following subgroup: acetylated glycerides, glycerolmonostearate, glyceryl triacetate, glycerol tributrate, phthalates, preferably in the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate,
• citrates preferably in the following subgroup: acetyltributylcitrate, acetyltriethylcitrate, tributylcitrate, triethylcitrate,
• the sebacates preferably in the following subgroup: diethylsébaçate, dibutylsébaçate,
• fumarates preferably diethylfumarate
• malates preferably diethyl malate
• oxalates preferably diethyloxalate, succinates; preferably the dibutylsuccinate,
• malonates preferably diethyl malonate, castor oil (the latter being particularly preferred),
• alkaline or alkaline earth salts of the fatty acids, stearic and / or oleic acid being preferred,
• polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil
• polyoxyethylenesorbitan esters polyoxyethylenated castor oil derivatives
• stearates preferably calcium, magnesium, aluminum or zinc,
• stearyl fumarates preferably sodium
• the coating coating 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.
• 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.
• the oral pharmaceutical form comprises coated microparticles and / or matrix microparticles, and, on the other hand, 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 the release of losartan after a predetermined time of residence in the stomach;
• 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 transition from pH 1.4 to pH 7.0, leads to an early release phase without latency.
• the oral pharmaceutical form according to this second embodiment comprises controlled release microparticles of losartan whose triggering pH is between 6.0 inclusive and 6.5 inclusive.
• losartan controlled release microparticles according to the second embodiment, have the following specificities:
• the coating or matrix for controlled release of losartan comprises a composite material
• At least one hydrophobic compound II at least one hydrophobic compound II; ° representing a mass fraction (% by weight relative to the total mass of the microparticles) ⁇ 40;
• Their average diameter is less than 1000 microns, and preferably between 50 and 800 microns and, more preferably, between 50 and 500 microns.
• the composite material I-II of the coating or matrix allowing the controlled release of losartan is such that:
• the weight ratio II / I is between 0.2 and 1.5, preferably between 0.5 and 1.0
• the hydrophobic compound II is selected from crystallized products in the solid state and having a melting temperature Tf ⁇ ⁇ 40 ° C, preferably Tf ⁇ ⁇ 50 ° C, and more preferably still 40 ° C ⁇ T ffl ⁇ 90 ° vs.
• the hydrophilic polymer I is chosen from:
• Lb cellulose derivatives preferably cellulose acetates, cellulosic phthalates, cellulosic succinates and mixtures thereof, and more preferably still hydroxypropylmethylcellulose phthalates, hydroxypropylmethylcellulose acetates, succinates hydroxypropyl methylcelluloses and mixtures thereof; and their mixtures.
• the most 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 are, for example, of the type sold by Rohm.
• EUDRAGIT® Pharma Polymers under the trademarks EUDRAGIT®, L and S series (eg EUDRAGIT® LlOO, S100, L30 D-55 and L100-55). These copolymers are anionic enteric copolymers and soluble in aqueous medium at pH levels higher than those encountered in the stomach.
• the compound II is chosen from the following group of products:
• Vegetable waxes taken by themselves or in mixtures with each other; Hydrogenated vegetable oils taken by themselves or mixed together;
• 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 mix of them, preferably in the following sub-group of hydrogenated cottonseed oil, hydrogenated soybean oil, hydrogenated palm oil, glycerol behenate, hydrogenated castor oil, tristearin, tripalmitine, trimyristin and any mixture of them.
• the compound II be chosen: 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 Hartolan®, MGLA®, Corona®, Protalan®, Akosoft®, Akosol®, Cremao®, Massupol®, Novata®, Suppocire®, Wecobee®, Witepsol®, Lanolin®, Incromega®, Estaram®, Suppo Stamms®, Gelucire®, Precirol®, Emulcire®, Diisostearic Plurol®, Geleol®, Hydrine®, Monthyle® and mixtures thereof; as well as in the additive group whose codes are the following: E 901, E 907, E 90
• the coating or matrix allowing the controlled release of losartan is free of talc.
• the coating or the matrix 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 dibutylsébaçate, o hydrophilic compounds, such as for example cellulose and its derivatives or polyvinylpirrolidone and its derivatives, o and mixtures thereof.
• the coating of losartan controlled release coated microparticles comprises a single composite coating film I-II.
• 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.
• the oral pharmaceutical form comprises at least two populations of microparticles.
• Each losartan controlled release microparticle population may be in accordance with the first or second embodiment presented above.
• the oral pharmaceutical form used in the use according to the invention comprises at least two populations of microparticles having different dissolution profiles, for at least a pH value of between 1.4 and 7.4.
• the oral pharmaceutical form used in the use according to the invention comprises at least two populations of microparticles controlled release of losartan differing in their pH of respective trips.
• the oral pharmaceutical form according to the invention comprises at least two populations of microparticles with controlled release of losartan differing by their respective tripping times.
• the oral pharmaceutical form implemented in the use according to the invention comprises at least one population of microparticles with controlled release of losartan and at least one population of microgranules with immediate release of losartan.
• the oral pharmaceutical form implemented in the use according to the invention comprises:
• At least one population of micro-granules with immediate release of losartan At least one population of micro-granules with immediate release of losartan
• the respective triggering pHs of the different populations of microparticles with controlled release of losartan are between 5 and 7.
• the oral pharmaceutical form implemented in the use according to the invention comprises:
• At least one population of micro-granules with immediate release of losartan At least one population P 1 'of microparticles with controlled release of losartan whose triggering pH is equal to 5.5; and
• Populations P 1, P 2, P 2 Pi'et 'of -2iv- -2v- variants and the 2 nd embodiment comprise controlled release microparticles of losartan, obtained according to the 2nd "16 embodiment.
• the oral pharmaceutical form used in the use according to the first embodiment comprises losartan controlled release microparticles
• the dissolution profiles of said microparticles between pH 1 and pH 5 are similar, according to similarity factor f2 calculated as indicated in the directive of the
• the oral pharmaceutical forms used in the use 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 controlled.
• PA may be contained in micro-units of the immediate release microgranule type of AP or in microparticles with controlled release of AP.
• This AP can be chosen, among others, from the group comprising diuretics, beta-blockers, inhibitors, sodium channel blockers, alpha-blockers, alpha-beta-blockers, vasodilators, alpha-antagonists and neuron-adrenergic blockers.
• coated microparticles referred to above may have several structures.
• At least a portion of the microparticles with controlled release of losartan of the oral pharmaceutical form each comprise: ⁇ a heart containing losartan and
• At least a part of said microparticles with controlled release of losartan of the oral pharmaceutical form each comprises: a core comprising: a neutral core, and at least one active layer comprising losartan and coating the neutral heart, and at least one coating coating the heart and allowing the controlled release of losartan.
• the proportion of losartan in the micro-units is between 5 and 80, preferably between 10 and 75, and more preferably still between 15 and 70.
• losartan immediate release microgranules are uncoated cores of losartan controlled release microparticles.
• the invention also aims at a specific group of oral pharmaceutical forms from those described above in general.
• the pharmaceutical forms of the specific group are those comprising micro-units formed by losartan-coated microparticles.
• Each pharmaceutical form of this specific group is a modified-release oral pharmaceutical dosage form of losartan as characterized in claim 31 or 32.
• This pharmaceutical form according to claim 31 is designed so that the micro-units, once ingested, are dispersed and individualized when they enter the stomach, which guarantees a regular and progressive gastric emptying of the micro-units, in the fed state as fasting, and thus ultimately a release of losartan in its gastrointestinal window of bioabsorption.
• micro-granules with immediate release of losartan ° excluding microgranules individually consisting of a matrix that includes losartan and that allows the controlled release of losartan (also hereinafter referred to as matrix microgranules);
• Disposable and individualized means that losartan micro-units are not trapped in a matrix when they enter the stomach immediately after ingestion. The micro-units spread in the stomach immediately after entering the stomach (for example in less than two minutes).
• This once-daily oral dosage form of losartan ensures that once the oral pharmaceutical form is ingested, the losartan it contains is released. in the gastrointestinal tract and bioabsorbed in its absorption window.
• This oral pharmaceutical form of losartan which is administrable 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 pharmaceutical form is ingested, the losartan it contains will be released regardless of the open or closed state of the pylorus.
• This once-a-day oral dosage form of losartan is at least as effective as the one-day-once-a-day forms currently used.
• This losartan oral pharmaceutical form which is administrable once a day, is not or only slightly subject to the phenomenon of inter-individual variability of gastric emptying and ultimately to 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 is administered once a day and comprises modified-release losartan micro-units, draws part of its advantages of the reduced size (50-1000 ⁇ m) of these micro-units and their large number (eg several thousand per dose), which allows a gradual and well-controlled gastric emptying, regardless of food intake by patients.
• This losartan oral pharmaceutical form, which is administered once a day makes it possible to increase the losartan T max and the duration during which the losartan plasma concentration is greater than the losartan plasma concentration below which the losartan is therapeutically ineffective.
• This oral pharmaceutical form of losartan exhibits 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, 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 adaptation of the dose administered according to their weight.
• This oral pharmaceutical form of losartan which is 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 able to be easily adjusted, independently one another.
• This losartan oral pharmaceutical form which is administrable once a day, despite the variability of the losartan solubility in water 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 galenic 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 thousand to several thousand) of micro-units (microparticles or microparticles of losartan), this multiplicity ensuring statistically a good reproducibility. the transit kinetics of losartan throughout the gastrointestinal tract, and hence good bioavailability control and efficacy.
• This pharmaceutical form does not induce degradation of losartan and preserves the polymorphism of the starting losartan.
• Their size between 50 and 1000 ⁇ m as well as the characteristics of their possible coating allows the micro-units to increase their transit time in the upper parts of the gastrointestinal tract, which ensures an increase in the duration of passage of the losartan in front of its absorption window and maximizes the bioavailability of losartan.
• micro-units of this pharmaceutical form according to claim 31 or 32 are individually microparticles consisting of a core which comprises losartan and which is coated with at least one coating allowing the modified release of losartan.
• microparticle-type microparticles of this pharmaceutical form according to claim 31 or 32 it should be noted that their coating controlling the modified release of losartan essentially comprises pharmaceutically acceptable excipients.
• micro-units of the pharmaceutical form according to claim 31 or 32 can also be very advantageous for at least a portion of the micro-units of the pharmaceutical form according to claim 31 or 32 to consist of immediate release microgranules of losartan.
• the pharmaceutical form according to claim 31 or 32 is characterized in that the CV variability (in%) of the area under the curve (AUC or AUC) of the plasma concentration of 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 variability CV * (in%) of the area under the curve
• AUC * of the plasma concentration of the active metabolite E 3174, as a function of time (T) after taking, under the same conditions, a reference oral immediate release pharmaceutical form *, containing the same dose of losartan, c is to say:
• CV ⁇ 1.5 x CV * preferably CV ⁇ 1.2 x CV *.
• the pharmaceutical form according to claim 31 or 32 has an in vitro dissolution profile such that: 70% of losartan is released between 1 and 24 hours, preferably between 2 and 12 hours, and even more preferentially between 2 and 8h, after the administration.
• the pharmaceutical form according to claim 31 or 32 in its first embodiment, 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 gastric physiological pH, for example those ranging from 1 to 7.
• composition of the coating (film coating) of the microparticles according to claim 31 or 32, their first embodiment, corresponds, advantageously, to one of two families A and B as defined above.
• the coating (film coating) of the microparticles according to claim 31 or 32, in their first embodiment, is as described above for the general family of micro-units according to the invention.
• the pharmaceutical form according to claim 31 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 the release of PA, after a predetermined time of residence in the stomach;
• 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 and 5 hours, and the passage pH 1.4 to pH 7.0 leads to an early release phase with no latency.
• the process used to produce the pharmaceutical form according to the invention makes it possible to preserve losartan in its initial crystalline form.
• the pharmaceutical form according to the invention for example at least 50% of the losartan is in its crystalline form I.
• 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 example the "spray coating" technique in fluidized air bed or shaped by wet granulation, compaction, extrusion-spheronization ...
• the oral pharmaceutical form used in the use according to the invention is in the form of a single daily oral dose comprising from 1000 to 500000 micro-units containing losartan.
• the oral pharmaceutical form used in the use according to the invention may be in the form of a daily oral single dose comprising from 1000 to 500000 microparticles with controlled release of losartan.
• the oral pharmaceutical form according to the invention can be provided in the form of a pouch of microparticle powder with controlled release of losartan, liquid suspension of microparticles with controlled release of losartan, tablet containing or not losartan controlled release microparticles, or capsule containing microparticles with controlled release of losartan.
• the present invention also relates to the oral pharmaceutical form, as described above in the context of the use according to the invention, taken as such regardless of the intended use.
• the invention relates to the use of controlled release microparticles of losartan as defined above and possibly microgranules immediate release of losartan as defined above, for the preparation of oral dosage forms microparticulate, pharmaceutical or dietetic, preferably in the form of advantageously orodispersible tablets, powders or capsules.
• the invention relates to the use of microparticles and / or microgranules with controlled release of losartan as defined above and possibly microgranules with immediate release of losartan as defined above, for the preparation of a therapeutically safe, microparticulate oral pharmaceutical form designed so that, once said pharmaceutical form is ingested, the microparticles which it comprises are dispersed and individualized when they reach the stomach, which allows these microparticles to be subjected to a regular and progressive gastric emptying, whether the patient is fed or fasted while taking, thereby guaranteeing the release of losartan in its gastrointestinal window. bioabsorption and may be involved in decreasing the variability of losartan plasma profiles.
• the invention relates to coated microparticles and / or matrix microgranules per se as defined above.
• the invention aims at:
• a method of therapeutic treatment of hypertension characterized in that it consists in administering, preferably in a single daily oral dose, the pharmaceutical form used in the use according to the invention as defined above;
• a reproducible method of human or animal therapeutic treatment by the oral route characterized in that it consists essentially in orally administering a pharmaceutical form comprising losartan contained in a coating or in a matrix including said losartan and allowing the controlled release of said losartan, for to ensure that this form administered orally to a sample of subjects leads, regardless of the fed or fasting state of the subjects, to the decrease in the inter-individual standard deviation of Cmax, which makes it possible to ensure a lower variability of the efficacy and therapeutic safety of the pharmaceutical form, relative to an immediate-release pharmaceutical dosage form of losartan administered to this same sample of subjects, at the same dose;
• a reproducible method of human or animal therapeutic treatment by the oral route characterized in that it consists essentially in orally administering a pharmaceutical form comprising losartan contained in a coating or in a matrix which confers on this pharmaceutical form properties such that oral administration of this pharmaceutical form, in the fed state, to a sample of subjects, leading to the decrease in the number or the disappearance of the individual plasma profiles having a Tmax less than or equal to one hour, preferably less than or equal to 1 , 5 hours, in favor of individual plasma profiles having a Tmax greater than one hour, preferably greater than 1.5 hours, which makes it possible to ensure a lower variability in the efficacy and therapeutic safety of the pharmaceutical form. , compared to an immediate-release pharmaceutical form of losartan administered to this same sample number of subjects;
• a reproducible method of human or animal therapeutic treatment by the oral route characterized in that it consists essentially in orally administering a pharmaceutical form comprising losartan contained in a coating or in a matrix, in order to reduce the variability of the plasma profiles during administration of this pharmaceutical form to a sample of subjects, as compared to a pharmaceutical form to immediate release of losartan administered to this same sample of subjects, which ensures a lower variability in the efficacy and therapeutic safety of the pharmaceutical form;
• a reproducible method of human or animal therapeutic treatment by the oral route characterized in that it consists essentially in orally administering a pharmaceutical form comprising losartan whose solubility is dependent on the gastric pH, the losartan being contained in a coating or in a matrix which confers on this pharmaceutical form such properties that the oral administration of this pharmaceutical form to a sample of subjects leads to a reduction of the interindividual coefficient of variation of Tmax with respect to an immediate-release pharmaceutical dosage form of losartan administered to this same sample of subjects, at the same dose, which makes it possible to ensure a lower variability of the efficacy and the therapeutic safety of the pharmaceutical form.
• FIG. 1 represents the in vitro dissolution profile at pH 6.8 of the microparticles with controlled release of losartan according to example 2;
• Figure 2 shows the in vitro dissolution profile at pH 1.4; 4.5 and 6.8 controlled-release microparticles of losartan according to Example 2
• FIG. 3 represents the in vitro dissolution profile at pH 6.8 of the microparticles with controlled release of losartan according to Example 2 for doses of losartan varying between
• FIG. 4 represents the in vitro dissolution profile at pH 1.4 and 6.8 of the microparticles with controlled release of losartan according to example 3.
• FIG. 5 represents the in vitro dissolution profile at pH 1.4 and 6. 8
• FIG. 6 represents the in vitro dissolution profile at pH 1.4 of the controlled release microparticles of losartan according to Example 4 for doses of losartan varying between
• FIG. 7 represents the in vitro dissolution profile at pH 6.8 of the controlled release microparticles of losartan according to example 5.
• FIG. 8 represents the individual pharmacokinetic profiles of losartan after administration of the Cl formulation, which does not enter not within the scope of the invention. Note in this figure 8 the existence of a fast population Pr and a slow population Pl.
• Figure 9 shows the individual pharmacokinetic profiles of EXP3174 after administration of the Cl formulation, which is outside the scope of the invention. It will be noted in this figure 8, the existence of a fast population Pr and a slow population P1.
• Figure 10 shows the individual pharmacokinetic profiles of losartan after administration of the formulation M1 according to Example 2, which falls within the scope of the invention. It will be noted that this formulation Ml leads to a single slow population
• Figure 11 shows the individual pharmacokinetic profiles of EXP3174 after administration of the M1 formulation according to Example 2.
• Figure 12 shows the individual pharmacokinetic profiles of losartan after administration of the M2 formulation according to Example 4.
• Figure 13 represents the individual pharmacokinetic profiles of EXP3174 after administration of Formulation M2 according to Example 4.
• the dissolution profile corresponds to the percentage by weight of dissolved losartan (D) as a function of time (t) in hours.
• the granulate obtained has a concentration of losartan potassium of 81%.
• Example 2 Preparation of Microparticles of Losartan Potassium
• 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 (ie 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 pH 6.8 (KH 2 PO 4 0.05M / NaOH). See Figure 1.
• 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 allows a release in vivo does not depend on the pH of the gastric fluids.
• 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 a dissolute. type II according to the Pharmacopoeia at 37 ° C and with stirring at 100 rpm pH 6.8 (KH 2 PO 4 / NaOH).
• the dissolution profile is independent of the dose of losartan.
• 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 (ie 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 pH 6.8 (KH 2 PO 4). 0.05M / NaOH). See Figure 5.
• the dissolution profile is independent of the dose of losartan.
• 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 (ie 145 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 pH 6.8 (KH 2 PO 4 0.05M / NaOH). See Figure 7.
• Example 6 Tablet made from microparticles of losartan potassium 165 g of the microparticles obtained in Example 4, 280 g of lactose, 40 g of crospovidone and 15 g of magnesium stearate are mixed using a laboratory mixer Erweka. 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.
• losartan potassium is delayed and prolonged for a period of approximately 10 hours, which makes it possible, during the administration of such a medicinal product, to increase the bio-absorption times and to respect at best the chronobiology of the drug. patient.
• Formulations M1 and M2 of Examples 2 and 4, and Formulation Cl are administered once daily, at a dose of 100 mg, after breakfast, to 20 healthy volunteers in a crossover study.
• the plasma concentrations of losartan and EXP3174 (its principal active metabolite) are measured at the following times: 0-0.25-0.5-0.75-1-
• the formulations M1 and M2 according to the invention lead to a single slow population P1 of profiles and to a small standard deviation of Cmax.
• the distribution of the population which shows, for the losartan profile after administration of Cl, M1 and M2, a Tmax of less than 1 and 1.5 hours is reported in Table 1 below:
• formulations M1 and M2 according to the invention make it possible to reduce considerably the proportion of individuals having a short Tmax compared to the reference form C1.
• the formulations M1 and M2 according to the invention allow a) to reduce the standard deviation of the Cmax b) to reduce the peak / valley modulation average c) to reduce the standard deviation of peak / valley modulation

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