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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • 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
  • A61P25/00—Drugs for disorders of the nervous system
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
  • A61P31/12—Antivirals
  • A61P31/20—Antivirals for DNA viruses
  • A61P31/22—Antivirals for DNA viruses for herpes viruses
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P35/00—Antineoplastic agents
• • 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

Definitions

• the field of the present invention is that of oral pharmaceutical forms of active principle (s) -PA- whose solubility varies greatly depending on the conditions of gastric pH, as well as treatments and methods of administration related thereto.
• PA active principle
• AP denotes PA per se and / or at least one of its salts, esters or other pharmaceutically acceptable forms, including its metabolites.
• 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 problem of the high level of variability in pharmacokinetic parameters observed for the controlled release / extended release formulations of buspirone disclosed in US-B-5,431,922 (see page 3, lines 7-16 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 TABLET nd that releases oxybutynin over an extended period of time (18-24 hours).
• This system is presented to compensate for interindividual variability in response to therapy with oxybutynin.
• These tablets include for example each a heart of oxybutynin and several coatings.
• Oxybutynin has a high solubility in acidic medium. This solubility does not vary greatly depending on the conditions of gastric pH.
• 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 coated with a coating material, itself constituted by a mixture of a film-forming polymer (ethylcellulose), a hydrophobic plasticizer (castor oil), a surfactant and / or or lubricant (magnesium stearate) and a nitrogenous polymer (PolyVinylPyrrolidone: PVP).
• a coating material itself constituted by a mixture of a film-forming polymer (ethylcellulose), a hydrophobic plasticizer (castor oil), a surfactant and / or or lubricant (magnesium stearate) and a nitrogenous polymer (PolyVinylPyrrolidone: PVP).
• PVP nitrogenous polymer
• 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 PA: 1) release "dependent time” triggered after a controlled duration in the stomach, without pH change and 2) "pH-dependent” release 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 being between 0.2 and 1.5.
• US-A-2005/0059667 relates to a sustained-release formulation of ranolazine in the form of tablets obtained by compression of granules.
• Each granule is for example based on ranolazine, at least one partially pH-dependent binder such as methacrylic acid copolymer (EUDRAGIT® L 100-55), microcrystalline cellulose, polyvinylpyrrolidone, methyl ester copolymer of methacrylic acid and methacrylic acid ethyl ester (EUDRAGIT® NE 30D).
• the granules are mixed with magnesium stearate and croscarmellose sodium for compression. Tablets may be enteric coated or OPADRY® based.
• the partially pH-dependent binder such as the methacrylic acid copolymer
• This formulation can be administered orally twice daily and can control the dissolution rate of ranolazine and maintain the plasma concentration between 550 and 7500 ngbase / mL.
• the problem of ranolazine is to have a high solubility at low gastric pH.
• Ranolazine has a short plasma half-life. This high solubility at low gastric pH results in rapid absorption and elimination of ranolazine as well as undesirable plasma fluctuations and a short duration of action. As a result, oral administrations must be frequent to obtain adequate treatment.
• the invention according to US-A-2005/0059667 claims to remedy this by advocating the administration once or twice a day of the above-described formulation, which is supposed to allow the achievement of effective plasma concentrations for the treatment of angina breasts .
• US-B-5,576,533 discloses oral pharmaceutical forms comprising a multiplicity of controlled release micro-granules of furosemide, individually coated with a mucoadhesive membrane. These dosage forms are presented as reducing inter- and / or intra-individual variability.
• None of these known oral dosage forms are presented as offering a guarantee in terms of inter and / or intra-individual reproducibility of the plasma concentration profile with the suppression of the risk of premature and massive release and therapeutic coverage over the entire body. time interval between two shots. Said oral forms can therefore be improved.
• An essential objective of the invention is to provide an oral pharmaceutical form of PA that is used in such a way that it gives access to a more uniform and reproducible treatment quality from one patient to another and / or for one patient. patient, compared to what is proposed in the prior art.
• Another essential objective of the present invention is to propose a means for reducing the inter and / or intra-individual standard deviation of the maximum concentration C max and / or the time of transition to the maximum concentration, T max, Plasma concentration profile.
• Another essential objective of the invention is to provide an oral pharmaceutical form of AP which makes it possible to reduce the inter and / or intra-individual variability of the plasma concentration profiles of the known oral pharmaceutical forms of PA, in particular to prevent the appearance of a "fast" population, at risk, for which the plasma profile has a high and early peak concentration.
• Another essential objective of the invention is to provide an oral pharmaceutical form of PA which offers a guarantee in terms of therapeutic safety: risk elimination for certain patients of massive and / or rapid release of AP and therapeutic coverage over the entire interval time between two shots.
• Another essential objective of the invention is to provide an oral pharmaceutical form of PA which preserves the patients from any risk of plasma overconcentration of AP and thus protect them from any drug accident.
• Another essential objective of the invention is to propose a means for reducing the peak / valley ratio of plasma PA concentrations.
• Another essential objective of the invention is to provide an oral pharmaceutical form of AP which makes it possible to reduce the inter and / or intra-individual variability of the plasma concentration profiles of the known oral pharmaceutical forms of PA, in particular to prevent the appearance two populations of plasma concentration profiles: a population Pr at risk of "fast” profiles and a population P1 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 propose, for the oral pharmaceutical forms, a new use of the PA release control means (coating or matrix containing the PA) so as to satisfy at least one of the objectives. above, and in particular to reduce the inter and / or intra-individual variability of plasma profiles.
• Another essential objective of the invention is to propose a new use of the oral pharmaceutical forms comprising PA-type release means of the coating type or matrix containing the AP, so as to satisfy at least one of the objectives mentioned above. -above.
• Another essential objective of the invention is to propose, for the oral pharmaceutical forms, a new use of the means for controlling the release of PA (coating or matrix containing PA), to reduce inter and / or intra-individual variability in plasma concentration profiles and, in particular, to reduce the inter and / or intra-individual standard deviation of the maximum plasma concentration after administration.
• PA coating or matrix containing PA
• Another essential objective of the invention is to propose a new use of oral pharmaceutical forms comprising means of controlling the release of PA of the coating or matrix type containing PA, in order to reduce the inter- and / or intra-individual variability of the Plasma concentration profiles and, in particular, reduce the inter and / or intra-individual standard deviation of the maximum plasma concentration after administration.
• 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.
• this variability of the gastric pH depends on various uncontrollable parameters, in particular: nourished state or fasting, time of the catch, inter and / or intra-individual variability, action of a drug influencing these gastrointestinal conditions ... ⁇ 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 the PA adapted to reduce or to suppress the population Pr of fast plasma profiles and to avoid the premature and / or massive and / or rapid release of the AP regardless of the gastric acidity, which is likely to reduce the inter and / or intra-individual variability Plasma concentration profiles.
• the present invention achieves the above objectives, among others, by providing:
• an oral pharmaceutical form comprising at least one PA whose solubility varies by a factor of at least 3, preferably at least 10 and, more preferably, at least 30 under conditions of gastric pH between 1.0 and 5.5, preferably between 1.5 and 5.0, a coating or matrix including said PA and allowing the controlled release of said
• PA to ensure that this form administered orally to a sample of human subjects lead, regardless of the fed state or fasting subjects, the decrease in the standard deviation inter and / or intra-individual Cmax and / or Tmax, which makes it possible to ensure a lower variability of the efficacy and the therapeutic safety of the pharmaceutical form, compared with an immediate release pharmaceutical form of PA administered to this same sample of subjects, the same dose;
• PA contained in a coated form or in a matrix allowing the controlled release of this PA the solubility of which varies by a factor of at least 3, preferably at least 10 and, more preferably, at least 30 at a pH of 1.0 to 5.5, preferably 1.5 to 5.0, to make an oral dosage form which, after oral administration to a sample of human subjects, lead, regardless of the fed or fasting state of the subjects, to the reduction of the inter and / or intra-individual standard deviation of Cmax and / or Tmax, which makes it possible to ensure a lower variability of the efficacy and therapeutic safety of the pharmaceutical form, compared to an immediate-release pharmaceutical form of PA administered to the same sample of subjects, at the same dose.
• the invention thus relates to pharmaceutical forms containing at least one PA whose solubility varies greatly depending on the gastric pH.
• the invention is thus defined through a reference clinical test in which the pharmaceutical form is administered orally to a sample of human subjects, under experimental conditions which may be those given in the examples below.
• This clinical test defines the invention by the pharmacokinetic 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 nature of the plasma concentration profiles from one subject to another and, in so doing, to avoid, on the one hand, the premature release of the AP. and, by the same token, a plasma overconcentration with the secondary effects that this entails and, on the other hand, any possible lack of therapeutic coverage between two doses.
• 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.
• Gastric pH is an inherently variable variable in a pH range of pH 1.0 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 alter the gastric pH. This is the case, for example, with proton pump inhibitors (eg omeprazole) or antacids.
• an AP whose solubility strongly depends on the gastric pH, the solubilization, thus ultimately the plasma concentration profile, undergoes large variations from one individual to another, and, for the same individual, one day to another.
• an immediate-release form (FLI cf definition infra) of PA 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 greater than (70 to 800 ng / ml).
• the profiles of the fast population are those for which a high peak plasma is observed very early.
• one of the essential elements of the invention is to use or propose the therapeutic use of an oral pharmaceutical form comprising PA contained in a coated form or in a matrix designed to regulate the release. controlled, so that this pharmaceutical form orally administered to a sample of human subjects, lead, regardless of the fed state or fasting subjects, to a decrease in the standard deviation inter and / or intra Cmax, which ensures a lower variability of the efficacy and therapeutic safety of the pharmaceutical form, compared to an immediate-release PA dosage form administered to this same sample of subjects, at a single dose.
• the implementation of the aforesaid coating or the aforesaid matrix for manufacturing such an oral pharmaceutical form is also covered by the invention.
• the oral pharmaceutical form concerned by the above-mentioned uses is also an object in its own right of the present invention.
• This invention appears particularly important for optimizing the use of AP 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 the fact of having clearly identified and posed the problem of the variability of the solubility of the AP according to the gastric pH and the variability of the latter.
• the plaintiff has 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 matrix containing the PA. They prevent its rapid and early release into the stomach, even in patients with gastric pH such that the solubility of PA is high.
• a PA whose solubility varies greatly according to the gastric pH is, within the meaning of the present invention, an AP whose solubility varies by a factor of at least 3, preferably at least 10 and, more preferably still, at least 30 under conditions of gastric pH between 1.0 and 5.5, preferably between 1.5 and 5.0. This solubility is measured in an aqueous medium at 37 ° C., maintained at the pH considered.
• the term "pharmaceutical” pharmaceutical form designates a form in which at least a fraction of the AP is released by passing through a continuous membrane (or film) which controls its diffusion towards the outside.
• a continuous membrane or film
• matrix pharmaceutical form, is meant in the present disclosure a pharmaceutical form in which the AP is dispersed in a solid continuous phase (the matrix) consisting of pharmaceutically acceptable excipients, this phase not being coated with a membrane (or film) continuously controlling the diffusion of the AP.
• immediate Release is meant in this disclosure the release by an Immediate Release Form (FLI) of most of the amount of AP in a relatively short time, for example:
• At least 70% of the AP are released in vivo in one hour, preferably in thirty minutes after oral ingestion.
• the AP are released in 1 hour, preferably in 30 minutes, at any pH between 1.4 and 6.8 in an in vitro dissolution test.
• controlled release form is meant herein a form in which at least a fraction of the AP is released at a rate less than or equal to the rate of an immediate release form. This fraction may be, for example between 1 and 100%, preferably between 10 and 100%, and more preferably between 30 and 100%.
• a controlled release formulation may, for example, include an immediate release phase and a slow or delayed release phase.
• Controlled release formulations are well known in the art; see, eg, Remington: The science and practice of pharmacy, 19th Edition, Mack publishing Co. Pennsylvania, USA.
• the controlled release can be in particular a prolonged and / or delayed release.
• 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 human subjects, the individual plasma concentration profile is measured on each patient, from which the traditional individual pharmacokinetic parameters are derived: Tmax, Cmax, C24h,:
• Tmax is the time after which the plasma concentration reaches its maximum, Cmax.
• PA whose solubility varies greatly according to the gastric pH, are AP whose dispersion of a dose D in a volume of water 100 ml at 37 ° C, does not allow, in equilibrium, a total solubilization of the dose D for at least a gastric pH value of between 1 and 5.5.
• PA whose solubility varies greatly according to the gastric pH are PA whose dispersion of a dose D in a volume of water of 100 ml at 37 ° C. C, ⁇ does not allow, in equilibrium, a total solubilization of the dose D for at least a gastric pH value of between 1 and 5.5;
• the pharmaceutical form is defined by a number of daily intake (s) identical to that of an immediate release pharmaceutical form comprising the same dose PA.
• This third mode just like the first two, illustrates the fact that the purpose of the invention is not the extension of the PA release time, but the reduction of the variability.
• the AP solubilization test characterizes the invention, but also makes it possible to select the PAs concerned by the invention and subject to the problem of the dependence of the solubility of PA on the gastric pH.
• the PAs concerned by the invention are those having a solubility strongly dependent on gastric pH and, for example, are selected from the group comprising the following PA families: proton pump inhibitors, angiotensin II receptor antagonists [ or ARB (Angiotensin Receptor Blocker)], antiulcer, antidiabetic, anticoagulant, antithrombotic, lipid-lowering, antiarrhythmic, vasodilator, antianginal, antihypertensive, vasoprotective, fertility promoter, inducer and uterine inhibitor, contraceptive, antibiotic, antifungal, antiviral, anticancer, antiinflammatory, analgesic, antiepileptic, antiparkinsonian, neuroleptic, hypnotic, anxiolytic, psychostimulant, anti-migraine, antidepressant, antitussive, antihistaminic or antiallergic, agents to fight against insufficiency congestive heart disease, angina pectoris, left ventricular hypertrophy, cardiac arrhythmi
• ARBs are preferred, and more particularly ARBs selected from the subgroup comprising:
• Irbesartan Olmesartan, Eprosartan, Candesartan, Candesartan cilexetil, Valsartan, Telmisartan, Zolasartin, Tasosartan.
• the ARBs may be combined with at least one co-active ingredient chosen from diuretics (hydrochlorothiazide), beta-blockers, angiotensin converting enzyme inhibitors, sodium channel blockers, alpha-blockers, alpha-beta-blockers, vasodilators, alpha-antagonists and neuron-adrenergic blockers.
• diuretics hydrochlorothiazide
• beta-blockers angiotensin converting enzyme inhibitors
• sodium channel blockers alpha-blockers, alpha-beta-blockers, vasodilators, alpha-antagonists and neuron-adrenergic blockers.
• PAs whose solubility is highly dependent on pH and which belong to the nonlimiting group of compounds selected from the group of the following compounds: acetylsalicylic acid, carbamazepine pentoxifylline, prazosin, acyclovir, nifedipine, diltiazem, naproxen, ibuprofen, flurbiprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, fentiazac, estradiol valerate, metoprolol, sulpiride, captopril, cimetidine, zidovudine, nicardipine, terfenadine, atenolol, salbutamol, carbamazepine, ranitidine, enalapril, simvastatin, fluoxetine , alprazolam, famotidine,
• the AP does not include diuretics.
• 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 C max is such that f> 1.05; preferably f> 1.5, and still more preferably f is between 2.0 and 20.
• 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 active substance (less than six hours) tablet and at least one other tablet is a sustained-release tablet of the same active ingredient (18 to 24 hours).
• dosage units of all types eg tablet, capsule, volume unit of powder or liquid
• the excluding multiple-dose tablet systems in which at least one of these tablets is a fast-release active substance (less than six hours) tablet and at least one other tablet is a sustained-release tablet of the same active ingredient (18 to 24 hours).
• the coating or the matrix are designed such that they allow the controlled release of the PA, on the one hand, to avoid any premature and / or massive and / or rapid release of the PA and subsequently any plasma overconcentration in PA. deleterious and, on the other hand, to ensure therapeutic coverage between two doses.
• the coating is non-mucoadhesive within the meaning of US Pat. No. 5,571,533.
• the core of the extended release microparticles of PA is not lipophilic, that is to say, for example, that it does not contain one or more excipients having an HLB overall less than 8.
• the average peak / valley-average-VLP modulation of the plasma profile of an AP is defined as follows: on each of the individual plasma profiles, the maximum individual concentration cmax 'and the concentration cT are measured. T hours after single oral administration.
• the MPV is the arithmetic mean of the individual ratios cmax '/ cT'.
• the concentration used to calculate the MPV will be replaced by the measured ex concentration x hours after oral administration, where x is the latest time at which a concentration can be measured. greater than the detection limit of the method used. In this case, x is less than 12 hours after single administration.
• the coating or the matrix of the pharmaceutical form are designed so that the oral administration of this form, to a sample of human subjects, leads to a peak / valley modulation (MPV). ) mean AP plasma concentration profiles, lower than the peak / average PA modulation of the same sample of subjects given the same dose of an immediate-release form of AP.
• MPV peak / valley modulation
• the reduction of the peak / valley modulation of the plasma concentration profiles is given, for example, by the g factor of reduction of the peak / valley modulation.
• the factor g is defined by the ratio of the peak / valley modulation of the FLI * form to the peak / valley modulation of the form concerned by the use according to the invention.
• the reduction factor g of the peak / valley modulation is such that: g>1.05; preferably g> 1.5, and still more preferably g is between 2.5 and 20.
• the coating or the matrix of the pharmaceutical form are designed such that the oral administration of this form, to a sample of human subjects, leads to a variability of the peak modulation. Plasma PA profile valley, less than the variability of PA peak / valley modulation, of the same sample of subjects given the same dose of an immediate-release form of AP.
• the reduction of the variability of the peak / valley modulation of the plasma concentration profiles is given, for example, by the reduction factor g 'of the standard deviation of the peak / valley modulation.
• the factor g ' is defined by the ratio of the standard deviation of the peak / valley modulation of the FLI * form to the standard deviation of the peak / valley modulation of the form concerned by the use according to the invention. .
• the factor g 'of decreasing the standard deviation of the peak / valley modulation is such that: g'> 1.05; preferably g '> 1.5, and still more preferably g' is between 2.5 and 20.
• the plasma profiles obtained are more homogeneous. Their inter- and / or intra-individual variability is reduced.
• the invention also proposes:
• an oral pharmaceutical form comprising PA, a coating or a matrix including said PA allowing the controlled release of PA, so that this pharmaceutical form administered orally, to a sample of human subjects (by example), leads to a decrease in the number or 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 the 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 the therapeutic safety of the pharmaceutical form, compared with an immediate-release pharmaceutical form of PA administered to this same sample of subjects (for example in the fed state) at the same dose.
• PA contained in a coated form or in a matrix allowing the controlled release of PA, to manufacture a pharmaceutical form which, after oral administration to a sample of human subjects (for example in the fed state), lead to a decrease in the number or disappearance of individual plasma profiles with 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 of the efficiency and the therapeutic safety of the pharmaceutical form, compared to an immediate-release pharmaceutical form of PA administered to the same sample of subjects (for example in the fed state), at the same dose.
• the comparison can be carried out by means of a reference clinical test in which the drug is administered orally to a sample of N human subjects, preferably N> 20 or 30 subjects.
• the individual plasma concentration profile is then measured on each of the volunteers, from which the individual pharmacokinetic parameters such as the Tmax time at the end of which the plasma concentration reaches its maximum and the value of this maximum concentration Cmax are obtained. From these individual parameters, those skilled in the art traditionally calculate the average values of these parameters and their standard deviations. Further details on the discussion of these parameters can be found in: Pharmacokinetics and pharmacodynamics Data Analysis 3rd ed., J. Gabrelsson et al., Kristianstads Bocktryckeri AB, Sweden, 2000.
• the experimental conditions of the reference clinical test may be for example, the following: administration of the form (capsule or tablet or suspension) once a day, at a given dose, after breakfast, to 20 healthy volunteers in a crossover study.
• Plasma PA concentrations are, for example, measured at the following times: 0 - 0.25 - 0.5 - 0.75 - 1 - 1.5 - 2 - 3 - 4 - 6 - 8 - 10 - 12 - 16 - 18 - 20 - 24 - 36 - 48 hours post-administration.
• This clinical test defines the invention by the pharmacokinetic properties obtained specifically under the conditions of the test. However, the invention is not limited to an implementation under the conditions of this reference clinical test.
• the invention also aims at: "the use, in an oral pharmaceutical form comprising PA, a coating or a matrix including said PA, 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 form FLI * of PA administered to the same sample of subjects, at the same dose, which allows to ensure a lower variability of the efficacy and therapeutic safety of the pharmaceutical form, compared to an immediate release pharmaceutical form FLI * of PA administered to this same sample of subjects, at the same dose.
• the pharmaceutical form contemplated in the use according to the invention may contain PA in the form of micro-units, which can be in particular:
• micro-particles individually consisting of a core which comprises PA and which is coated with at least one coating allowing the controlled release of PA (also hereinafter referred to as coated microparticles);
• micro-granules individually consisting of a matrix which includes PA and which allows controlled release of PA (also hereinafter referred to as matrix micro-granules);
• 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 PA or still tablets. These tablets may be "(i) tablets containing micro-units of AP,
• microparticle-free tablets each consisting of a core comprising PA and being coated with at least one coating allowing controlled release of the AP, and / or free of micro-granules individually consisting of a matrix including PA and allowing controlled release of AP;
• These tablets (ii) may be matrix tablets or individually coated tablets.
• the PA micro-units coated microparticles and / or controlled-release matrix micro-granules or immediate-release micro-granules
• 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 / C24h ⁇ Cmax * / C24h * preferably 1.5 x Cmax / C24h ⁇ Cmax * / C24h * and even more preferably 2.0 x Cmax / C24h ⁇ Cmax * / C24h * with
• ° C24h representing the average plasma concentration of AP, 24 hours after taking, ° C24h * representing the average plasma concentration of PA obtained under the same conditions as C24h, with a standard oral immediate release pharmaceutical form, containing the same dose of AP ,
• ° Cmax * representing the maximum mean plasma concentration of PA obtained under the same conditions as Cmax, with a standard oral immediate release pharmaceutical form, containing the same dose of AP.
• the oral pharmaceutical form comprises coated or matrix microparticles and has an in vitro dissolution profile such that: time t (70%) after administration and at the end of which 70% of the AP are released, is between 1 and 24, preferably between 2 and 12h, and even more preferably between 2 and 8h.
• the percentage of dissolved PA is greater than or equal to 35 t / t (70%).
• 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: Family A
• 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, stearates, preferably calcium, magnesium, aluminum or zinc,
• At least one film-forming polymer which is insoluble in the liquids of the gastrointestinal tract At least one film-forming polymer which 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.
• Bl non-water-soluble derivatives of cellulose, ethylcellulose and / or cellulose acetate being particularly preferred, acrylic polymers, polyvinylacetates, and mixtures thereof.
• B2 water-soluble derivatives of cellulose, polyacrylamides, poly-N-vinylamides, poly-N-vinyl-lactams, polyvinyl alcohols (PVA), polyoxyethylenes (POE), polyvinylpyrrolidones (PVP) (the latter being preferred), and mixtures thereof;
• PVA polyvinyl alcohols
• POE polyoxyethylenes
• PVP polyvinylpyrrolidones
• B3 glycerol and its esters, preferably in the following subgroup: acetylated glycerides, glycerylmonostearate, glyceryl triacetate, glyceryl tributylate, phthalates, preferably in the following subgroup: dibutyl phthalate, diethyl phthalate, dimethyl phthalate, dioctyl phthalate, 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 diethylfumarate, malates, preferably diethylmalate, oxalates, preferably diethyloxalate, succinates; preferably di
• polyoxyethylenated oils preferably polyoxyethylenated 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.
• 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 on the one hand, comprises coated microparticles and / or micro-matrix particles, and, on the other hand, is such that: the release of the PA, is governed by two distinct mechanisms of triggering, one being based on a pH change and the other allowing the release of PA, after a predetermined time of residence in the stomach;
• the dissolution profile comprises a latency phase 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 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 PA, whose triggering pH is between 5.0 and 7.0 inclusive.
• the oral pharmaceutical form according to this second embodiment comprises controlled-release microparticles of PA, whose triggering pH is between 6.0 inclusive and 6.5 inclusive.
• microparticles with controlled release of PA have the following specificities:
• O the coating or matrix allowing the controlled release of the PA comprises a composite material
• At least one hydrophilic polymer I carrying ionized groups at neutral pH At least one hydrophilic polymer I carrying ionized groups at neutral pH
• At least one hydrophobic compound II representing a mass fraction (% by weight relative to the total mass of the microparticles) ⁇ 40;
• O their average diameter is less than 1000 microns, and preferably between 50 and 800 microns and, more preferably still, between 50 and 500 microns.
• the composite material I-II of the coating or matrix allowing the controlled release of the PA is such that:
• the weight ratio TU1 is between 0.2 and 1.5, preferably between 0.5 and
• the hydrophobic compound II is selected from crystallized products in the solid state and having a melting temperature Tf ⁇ ⁇ 40 ° C, preferably TQ I ⁇
• the hydrophilic polymer I is chosen from: - The copolymers of (meth) acrylic acid and of alkyl ester of acid
• Cellulose derivatives preferably cellulose acetates, cellulose phthalates, cellulosic succinates and mixtures thereof, and more preferably still hydroxypropylmethylcellulose phthalates, hydroxypropylmethylcellulose acetates, hydroxypropylmethylcellulose succinates and mixtures thereof; - and their mixtures.
• Even more preferred polymers are copolymers of (meth) acrylic acid and (C 1 -C 6) alkyl esters of (meth) acrylic acid. These copolymers are, for example, of the type marketed by Rohm Pharma Polymers under the registered trademarks EUDRAGIT®, L and S series (as for example EUDRAGIT® LlOO, SlOO, 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 alone or mixed together;
• Mono and / or di and / or triester esters of glycerol and at least one fatty acid ILd mixtures of monoesters, diesters and triesters of glycerol and at least one fatty acid; ILe and mixtures thereof.
• 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.
• Dynasan® P60 Dynasan® 114, Dynasan® 116, Dynasan® 118, Cutina® HR, Hydrobase® 66-68, Dub® HPH, Compritol® 888, Sterotex® NF, Sterotex® K, Lubritab® and mixtures thereof.
• the coating or the matrix allowing the controlled release of PA are 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 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 the controlled release PA coated microparticles comprises a single composite coating film I-II. Further details and examples of compositions and processes for obtaining the microparticles according to the second embodiment of the invention are given in WO-A-03/030878, the contents of which are 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 dosage units each containing a high dose of PA, 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 population of controlled release microparticles of PA may be in accordance with the first or second embodiment presented above.
• the oral pharmaceutical form implemented in the use according to the invention comprises at least two populations of microparticles having different dissolution profiles, for at least one pH value between 1.4 and 7.4.
• the oral pharmaceutical form implemented in the use according to the invention comprises at least two populations of microparticles with controlled release of PA differing by their respective trigger pH.
• the oral pharmaceutical form according to the invention comprises at least two populations of microparticles with controlled release of PA differing in their respective tripping times.
• the oral pharmaceutical form used in the use according to the invention comprises at least one population of microparticles with controlled release of AP and at least one population of microparticles with immediate release of PA. .
• the oral pharmaceutical form implemented in the use according to the invention comprises:
• At least one population of micro-granules with immediate release of AP At least one population of micro-granules with immediate release of AP
• At least one population P1 of microparticles with controlled release of PA At least one population P1 of microparticles with controlled release of PA
• At least one population P2 of microparticles with controlled release of PA; and, furthermore, the respective release 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.
• the respective triggering pHs of the different populations of microparticles with controlled release of AP are between 5 and 7.
• the oral pharmaceutical form used in the use according to the invention comprises: at least one population of micro-granules with immediate release of PA;
• At least one population Pl 'of microparticles with controlled release of PA whose triggering pH is equal to 5.5
• At least one population P2 'of microparticles with controlled release of AP whose triggering pH is between 6.0 inclusive and 6.5 inclusive.
• the population Pl, P2, Pl 'and P2' of -2iv- -2v- variants and the 2 nd embodiment comprise micro-particulate controlled release of AP obtained under the 2 nd embodiment.
• micro-units with immediate release of PA are present in the oral pharmaceutical form implemented in the use according to the invention
• these variants may correspond to the cases where this
• the pharmaceutical form comprises, for example, at least one population of micro granules with immediate release of AP.
• the oral pharmaceutical form used in the use according to the first embodiment comprises controlled-release microparticles of PA
• the dissolution profiles of said microparticles between pH 1 and pH 5 are similar, depending on the similarity f2 calculated as stated in the FDA guideline SUPAC-MR - Modified Release Solid Oral Dosage Forms, ie since f2> 50%.
• the coated microparticles referred to above may have several structures.
• a first form of structure of the coated microparticles at least a part of the microparticles with controlled release of PA of the oral pharmaceutical form, each comprises:
• At least a part of said controlled-release microparticles of PA of the oral pharmaceutical form each comprises: ⁇ a core comprising: o a neutral core, and o at least one layer active agent comprising AP and coating the neutral core, ⁇ and at least one coating coating the core and allowing the controlled release of the
• the proportion of PA 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 75, and more preferably still between 15 and 70.
• the immediate-release microgranules of PA are uncoated nuclei of microparticles with controlled release of AP.
• microencapsulation techniques accessible to those skilled in the art, the main ones of which are summarized in the article by C. DUVERNEY and JP BENOIT in "Chemical News", December 1986. More specifically, the technique considered is microencapsulation by film coating, leading to individualized "reservoir” systems as opposed to matrix systems.
• the particles of PA of desired particle size and necessary for the production of the microparticles according to the invention can be pure PA crystals and / or pretreated by one of the conventional techniques in the field, such as granulation, for example. the presence of at least one conventional binder and / or an agent modifying the intrinsic solubility characteristics of PA.
• the PA may, 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 by wet granulation, compacting, 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 500,000 micro-units containing PA.
• 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 500,000 microparticles with controlled release of AP.
• the oral pharmaceutical form according to the invention may be provided in the form of a bag of controlled release microparticulate powder of PA, of a liquid suspension or of a suspension for reconstituting controlled-release microparticles of PA, tablet containing or not containing controlled-release microparticles of PA, or capsule containing microparticles with controlled release of AP.
• the present invention also relates to the oral pharmaceutical form, as described above in the context of the use according to the invention and taken as such regardless of the use according to the present invention.
• the invention aims at the use of microparticles with controlled release of AP as defined above and optionally immediate release micro granules of PA as defined above, for the preparation microparticulate, pharmaceutical or dietetic oral dosage forms, preferably in the form of advantageously orodispersible tablets, powders or capsules.
• the invention relates to the use of microparticles and / or microparticles with controlled release of PA as defined above and optionally microparticles with immediate release of PA such as defined above, for the preparation of a therapeutically safe, microparticulate oral dosage form designed such that, once said pharmaceutical form is ingested, the microparticles which it comprises are dispersed and individualized when they arrive in the stomach, which allows 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 the PAd in his gastrointestinal window of bioabsorption and able to participate decrease in the variability of PA plasma concentration profiles.
• the invention relates to coated microparticles and / or matrix micro-granules per se as defined above.
• the invention aims at:
• a method of therapeutic treatment 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 PA contained in a coated form or in a matrix and allowing the controlled release of said AP, so that this form administered orally to a sample of human subjects leads, irrespective of the fed or fasting state of the subjects, to the reduction of the inter and / or intra-individual standard deviation of Cmax and / or Tmax, which makes it possible to ensure a lower variability in the efficacy and the therapeutic safety of the pharmaceutical form, compared to an immediate-release pharmaceutical form of PA 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 PA 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 disappearance of the individual plasma concentration profiles having
• 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 PA contained in a coated form or in a matrix, in order to reduce the variability of the plasma profiles during oral administration of this dosage form to a sample of subjects, compared to an immediate-release PA dosage form administered to this same sample of subjects, thereby ensuring a lower variability in efficacy and therapeutic safety 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 PA whose solubility is dependent on the gastric pH, the PA being contained in a coated form or in a matrix which confer on this pharmaceutical form properties such that the oral administration of this pharmaceutical form to a sample of subjects leads to a reduction of the inter and / or intra-individual variation coefficient of Tmax with respect to a pharmaceutical release form immediate PA administered to the same sample of subjects, at the same dose, which ensures a lower variability of the effectiveness and therapeutic safety of the pharmaceutical form.
• Example 1 Solubility of irbesartan as a function of pH
• Step 1
• the granulate obtained has an Irbesartan concentration of 70%.
• Eprosartan varies greatly in the gastric pH range
• Step 1
• eprosartan 950 g of eprosartan and 30 g of Povidone (Plasdone K29 / 32) are premixed dry in the tank of a high shear granulator (Aeromatic PMAl) for 5 minutes. This powder mixture is then granulated with water (200 g). The granules are dried at 40 ° C. in a ventilated oven and then calibrated on a 500 ⁇ m grid. The 200-500 ⁇ m fraction is sieved. The granulate obtained has an eprosartan concentration of 95%. 2nd step :
• Step 1 800 g of acyclovir, 100 g of lactose, 50 g of Povidone (Plasdone K29 / 32) and 50 g of magnesium stearate are premixed dry in a wheel mixer. Tablets consisting of 250 mg of the above mixture are prepared using a KORSCH tablet press.
• ethylcellulose Ethylcellulose N7 / Aqualon
• 8 g of Klucel EF2® Hydroxypropyl cellulose / Aqualon
• 7 g of Lutrol F-68 Polyxamer 188 / BASF
• 5 g of dibutylsebacate are dispersed in a mixture of 70% ethanol and 30% water. This solution is sprayed on 950 g of acyclovir tablets (prepared in step 1). These coated tablets are the final form of the drug.
• Step 1
• Plasdone K29 / 32® Plasdone K29 / 32® (Povidone / ISP) are premixed dry in the tank of a high shear granulator (Aeromatic PMAl) for 5 minutes. This powder mixture is then granulated with water (200 g). The The granules are dried at 40 ° C. in a ventilated oven and then calibrated on a 500 ⁇ m grid. The 200-500 ⁇ m fraction is sieved.
• the granulate obtained has an acyclovir concentration of 97%.
• ethylcellulose Ethocel 20 Premium / Dow
• Plasdone K29 / 32® Plasdone / ISP
• 6 g of Lutrol F-68 Polyxamer 188 / BASF
• 6 g of castor oil are dispersed. in a mixture of 70% ethanol and 30% water.
• This solution is sprayed on 920 g of acyclovir granulate (prepared in step 1) in a Glatt GPCG1.
• the microparticles obtained are then placed in a size 1 gelatin capsule.
• the dose of acyclovir per capsule was fixed in this test at 200 mg (302 mg of microparticles). This capsule is the final form of the drug.
• Ml Microcapsule capsule according to Example 6, containing 600 mg of acyclovir
• 3 Cl tablets and 1 M1 capsule are administered after dinner to 48 healthy volunteers in a crossover study.
• Plasma concentrations of acyclovir are measured at time: 0 - 0.5 - 1 - 2 - 3 - 4 - 6 - 8 - 10 - 12 - 16 - 20 - 24 - 36 - 48 hours post administration.
• the M1 form according to the invention makes it possible to reduce by a factor of 1.65 the Cmax / C24h ratio with respect to the Cl form. At the same time, the variability of the Cmax is decreased by a factor of 1.12. .

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