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
  • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
  • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
  • A61K9/5047—Cellulose ethers containing no ester groups, e.g. hydroxypropyl methylcellulose
• • 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
• • 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
  • A61K31/4184—1,3-Diazoles condensed with carbocyclic rings, e.g. benzimidazoles
• • 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
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
  • A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • 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
  • A61K9/5015—Organic compounds, e.g. fats, sugars
• • 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

Definitions

• the field of the invention is that of the medicaments more particularly useful for the prevention and treatment of gastrointestinal disorders.
• the present invention relates to an oral medicament based on at least one proton pump inhibitor (PPI) and allowing the modified release of I 1 IPP.
• PPI proton pump inhibitor
• IPP insulin receptor protein
• the oral medicament according to the invention preferably comprises a plurality of microcapsules of IPP in each of which 1 IPP is contained in a microparticle itself coated with a coating allowing the modified release of NPP in the gastrointestinal tract. -intestinal or under corresponding in vitro conditions.
• the invention also relates to the microcapsules of IPP taken as such.
• the active ingredient "IPP” denotes indifferently one or more PPI per se and / or one or more IPP metabolites and / or one or more PPI derivatives and / or any mixture of these assets.
• PPIs are inhibitors of acidic gastric secretions, by specific inhibition of the H + , K + -ATPase (proton pump) enzymatic system of the secretory surface of parietal gastric cells.
• PPIs are advantageous substitutes for histamine H2 blockers (blocking gastric acid secretion) or antacids, which are not fully effective in the treatment of ulcers, whether or not associated with Helicobacter pylori or other infections. gastric disorders and which, in addition, lead to many side effects.
• the PPIs more particularly concerned by the present invention are benzimidazole derivatives.
• benzimidazole derivative denotes, without distinction, any benzimidazole-substituted PPI, with or without the exception of lansoprazole per se, one or more salts of these benzimidazole PPIs, any enantiomer of these benzimidazole PPIs, one or more salts.
• enantiomer (s) any isomer of these PPIs benzimidazoles, any benzimidazole derivative, any benzimidazole free base of IPP or any mixture thereof.
• IPP indifferently to one or more PPIs.
• the active principles concerned by the present invention are, in particular, the PPIs described on pages 7 to 11 of WO-A-97/25066, this passage being incorporated by reference in the present disclosure.
• WO-A-2004/035020 gives a general formula of IPP of the class of benzimidazoles: pages 35-48, formula I 1 .
• This passage of WO-A-2004/035020 is incorporated by reference in the present disclosure.
• PPIs PPIs
• examples of PPIs mention may be made of the following products: esomeprazole, leminoprazole, omeprazole, pantoprazole, pariprazole, rabeprazole. Examples of these are timoprazole, picoprazole, tenatoprazole and ilaprazole.
• PPIs are weak lipophilic bases that undergo rapid degradation under acidic conditions but, on the other hand, are relatively stable at neutral or basic pH.
• an oral PPI-based medicinal product should, on the one hand, sufficiently protect NPP from acidic stomach conditions, before it is absorbed downstream of the stomach and, on the other hand, make it possible to obtain a plasmatic profile which is maintain the effective therapeutic concentration for as long as possible to maximize the duration of action of NPP, and therefore its therapeutic efficacy.
• This goal runs up against the limited residence time of NPP in the blood compartment.
• the plasma half-life time of omeprazole is 0.5-1H.
• enteric coatings ie enteric.
• enteric release forms known quickly I 1 PPI when they enter the intestine and does not ensure a satisfactory elevated gastric pH for 24 hours or more, especially at night.
• enteric forms do not allow to quickly relieve the patient.
• I 1 PPI with buffers to protect against acid.
• these formulations protect I 1 IPP, they do not allow to maintain the high gastric pH for a very long time.
• a first class of PPI-based pharmaceutical preparations concerns solid monolithic forms in which the active ingredient is coated with an enteric layer which protects it from degradation under the acidic pH conditions of the stomach.
• WO-A-97/25066 proposes a tablet containing micro-granules of omeprazole (sprayed on a sugar-neutral core), each of which is coated successively with at least one separation layer.
• enteric layer methacrylic acid / mono and diglyceride / triethylcitrate / polysorbate copolymer
• upper layer methacrylic acid / mono and diglyceride / triethylcitrate / polysorbate copolymer
• these microgranules are compressed after mixing with an antacid (aluminum hydroxide / magnesium carbonate) or an alginate.
• This type of enteric formulation has several flaws:
• This variability is further enhanced by the inter- and intra-individual variability in gastric residence time of monolithic oral forms.
• enteric coatings can delay the absorption and therefore the beginning of the therapeutic activity of NPP.
• a second class of PPI-based pharmaceutical preparations concerns non-enteric forms in which the degradation of I 1 IPP in acid medium is inhibited by the addition of another active compound acting as a buffer.
• PCT patent application WO-A-02/053097 proposes to reduce the inter and intra-individual variability, by removing the enteric coating and by associating NPP immediate release with a buffer agent combining a metal bicarbonate salt of the group IA and a carbonate salt of a group metal
• This PCT application aims to provide a stable and non-enteric formulation of lansoprazole allowing faster action than enteric formulations. This formulation does not make it possible to increase the action time of lansoprazole.
• a third class of proton pump inhibitor formulations concerns non-enteric osmotic systems.
• PCT application WO-A-00/78293 discloses oral pharmaceutical forms comprising microgranules each containing omeprazole mixed with an alkaline agent and one or more blowing agents (crosslinked polyvinylpyrrolidone), filmed by a semi-permeable membrane composed solely of ethylcellulose and talc. Under the effect of swelling of the crosslinked polyvinylpyrrolidone, the ethyl cellulose membrane breaks and omeprazole can be released.
• the application WO-A-00/78293 describes a release of 60% of the active ingredient in 2 hours, after exposure for 2 hours in acidic medium, which simulates the residence time in the gastric medium. This PCT application does not disclose release that starts in the stomach but rather a non-enteric release, triggered by a mechanism depending on the swelling time of the blowing agent.
• a fourth class of PPI formulations is for sustained release preparations.
• PCT application WO-A-2004/035020 proposes a formulation, in particular of IPP, in which the release of the active principle is controlled and which contains, in addition, a gelling polymer.
• the release control is obtained by coating the core containing the active ingredient with an enteric layer or with a polymer layer controlling the diffusion kinetics of the active principle towards the outside or else by dispersion of the active ingredient in an insoluble polymer matrix at through which the active ingredient diffuses.
• the gelling polymer contained in the formulation according to WO-A-2004/035020 serves to increase the residence time of the particles containing the active principle in the gastrointestinal tract and thus to allow it to be released longer in front of its windows. 'absorption.
• the granulate is coated with an enteric film composed of a methacrylic copolymer EUDRAGITOLD (enteric) / talc / TiO 2 / polysorbate / macrogol.
• EUDRAGITOLD enteric copolymer
• talc talc / TiO 2 / polysorbate / macrogol.
• This enteric coating deposited on microparticles of IPP may itself be covered with a layer based on EUDRAGIT®S (gelling polymer) / EUDRAGIT®L (gelling polymer) / talc / triethylcitrate.
• the delayed release pantoprazole galenic, tableted or granular forms comprise a pantoprazole, sodium carbonate, mannitol, HPMC 2910-3, HPMC 2910-15 core, and calcium stearate, a an insoluble sustained release intermediate layer based on ethylcellulose, lactose, propylene glycol and ammonia, and an enteric topcoat based on EUDRAGIT®L and triethylcitrate.
• This patent also discloses microcapsules consisting of a core based on sugar particles coated with HPMC, propylene glycol and sodium hydroxide. This heart is then coated in an active layer comprising pantoprazole, HPMC, propylene glycol and sodium hydroxide.
• An enteric coating based on EUDRAGIT®L and triethylcitrate is applied to the active layer to form microcapsules or "pellets" then packaged in capsules.
• a sustained release layer may be interposed between the active layer and the enteric layer.
• the examples are for pantoprazole, but the claims in this patent exclude pantoprazole and are directed to PPIs, particularly omeprazole or lansoprazole.
• a delayed release controlled release form of PPI other than pantoprazole associated with an immediate release form of said PPI.
• the galenic forms disclosed in this patent are all controlled release and delayed release forms comprising an enteric layer and which do not allow the release of NPP in the stomach.
• WO-A-99/32091 discloses oral pharmaceutical forms, particularly sustained-release tablets of IPP, films by an enteric membrane.
• WO-A-99/32091 discloses inter alia in vitro release rates such that 70% omeprazole is released in 10 hours.
• the prolonged release of NPP is a matrix release, provided by the dispersion of the active ingredient in a polymer matrix, hydrophilic and / or hydrophobic.
• This polymer matrix may also contain an antacid agent which maintains the NPP environment at a pH of at least 7.
• the matrix core containing omeprazole and antacid, is film-coated with an enteric film, which protects the active ingredient of the acidic gastric medium, and optionally by a water-soluble polymer-based interlayer, such as hydroxypropylmethylcellulose, which separates the matrix core from the enteric layer.
• enteric film which protects the active ingredient of the acidic gastric medium
• a water-soluble polymer-based interlayer such as hydroxypropylmethylcellulose
• WO-A-2004/035090 discloses: a compressed pharmaceutical formulation comprising:
• IPP in the form of modified release microgranules, in particular lansoprazole or omeprazole (as described in PCT application WO-A-97/25066 referred to above) coated with an enteric layer, an intermediate layer of separation between the enteric film and the core of IPP (composed for example of hydroxypropyl methylcellulose / talc / magnesium stearate) and optionally of a water-soluble upper layer
• An H2 receptor antagonist (cimetidine or famotidine), said antagonist being immediate release; a compressed pharmaceutical formulation comprising:
• IPP in the form of modified release microgranules, in particular lansoprazole or omeprazole (as described in patent US-B-6,274,173 above mentioned) coated with an insoluble polymer coating layer, based on ethylcellulose or polyvinyl acetate, which slows the release of the active ingredient, and an enteric outer layer, and
• H2 receptor antagonist cimetidine or famotidine
• said antagonist being immediate release.
• EP-A-1,086,694 proposes microgranules of IPP films by at least one coating layer composed of a mixture of soluble polymers.
• This film coating allows a slowdown in speed omeprazole release, said release can not begin until the exit of the stomach due to the presence of the enteric layer.
• European patent EP-BO 709 087 discloses microcapsules whose core comprises an active ingredient such as an IPP used as an antiulcer (eg omeprazole), wherein the composition of the coating film of the heart comprises from 60 to 80% ethylcellulose, 5 to 10% polyvinylpyrrolidone, 5 to 10% castor oil and 2 to 8% magnesium stearate. These microcapsules have a particle size of between 50 and 1000 microns and are designed so as to be able to stay in the small intestine for a period of 5 and 24 hours, ie from 2 to 12 times greater than the natural transit time. This result is particularly interesting.
• an active ingredient such as an IPP used as an antiulcer (eg omeprazole)
• the composition of the coating film of the heart comprises from 60 to 80% ethylcellulose, 5 to 10% polyvinylpyrrolidone, 5 to 10% castor oil and 2 to 8% magnesium stearate.
• These microcapsules have a particle size of
• one of the objectives of the invention is to provide an improved oral medicament for the treatment of gastric ulcers and pains and related disorders, more specifically an oral medicament with modified release of PPI.
• Another object of the invention is to provide a modified oral release medicament of IPP extending the duration of bioabsorption compared to a traditional enteric form, so as to maintain the gastric pH at a high value for at least 24 hours and in particular the night.
• Another object of the invention is to provide an oral modified-release medicament of IPP for rapidly and lastingly relieving patients of gastric (burns) or epigastric (reflux) pain, and related disorders (bleeding), and this in satisfying in particular the following characteristics: a) Quickly relieve the patient by a rise in gastric pH, after oral intake of the drug. b) Accelerate patient healing by maintaining this elevation of gastric pH for as long as possible after oral administration of the drug, especially at night. c) Improve treatment compliance and patient comfort with a single daily intake.
• Another object of the invention is to provide a non-enteric, IPP-modified, oral release drug leading in the patient to sufficient elevation of pH over a longer period than that achieved with known PPI-based formulations. .
• Another object of the invention is to provide a non-enteric, IPP-modified oral release drug of the matrix system or reservoir type and leading in the patient to a sufficient rise in pH and over a longer duration than that obtained with formulations based on known PPIs.
• Another object of the invention is to provide a multimicrocapsular oral medicament containing a plurality of non-enteric, modified release IPP microcapsules, said formulation having an in vitro release profile independent of the administered dose.
• Another object of the invention is to provide a multimicrocapsular oral medicament containing a plurality of non-enteric, modified release IPP microcapsules, which microcapsules can be administered in admixture with excipients and / or a buffer agent.
• the invention which relates to an oral medicament based on IPP allowing the modified release of this PPI, characterized in that it is designed so that after ingestion into a daily intake, it allows to maintain, from the first day of treatment, an average gastric pH between 0 and 24h, greater than or equal to the average gastric pH between 0 and 24h obtained with an oral enteric drug immediate release reference *, administered under the same conditions.
• the medicament according to the invention is designed such that after its ingestion, the release of NPP begins in the stomach and that, when administered in a single daily dose the morning, it allows to maintain, from the fifth day of the treatment, the average gastric pH between 16 hours and 20 hours after the higher setting, preferably higher by at least 0.5 pH unit, and, better still, higher than at least 1 pH unit, at average gastric pH between 16 hours and 20 hours hours after taking, obtained with an oral enteric reference immediate-release medication * administered under the same conditions.
• This medicine which may or may not meet the definition given in the preceding paragraphs, may also be designed so that after ingestion in a single daily dose, it allows to maintain, from the first day of treatment, a higher gastric pH or equal to the gastric pH obtained with an oral enteric reference immediate-release medication *, administered under the same conditions, for at least 16 hours, preferably at least 20 hours, and more preferably still at least 22 hours, in the dosing interval. (ie 24 hours for a single daily medication). This period during which the gastric pH verifies the previous condition can be continuous or discontinuous. The cumulative duration is considered during the dosing interval.
• This medicine which may or may not meet the definition given in the preceding paragraphs, may also be designed so that after ingestion in a single daily dose, it allows to maintain, from the fifth day of treatment, a higher gastric pH or equal to the gastric pH obtained with an enteric oral immediate-release reference drug *, administered under the same conditions, for at least 13 h, preferably at least 16 h, and more preferably still at least 20 h, in the dosing interval. (ie 24 hours for a single daily medication). This period during which the gastric pH verifies the previous condition can be continuous or discontinuous. The cumulative duration is considered during the dosing interval.
• oral enteric drug immediate reference release is meant in the present disclosure, an enteric drug releasing the same PPI as the drug according to the invention, at pH 6.8 and SINK conditions in a dissolution test in in vitro, most of the amount of I 1 IPP it contains, in a relatively short time; for example, at least 70% are released in 45 minutes, preferably in thirty minutes.
• the comparison between the drug according to the invention and the oral enteric reference immediate-release medication *, with regard to the elevation of the gastric pH can be done by means of a clinical reference T1 test.
• the experimental conditions of the T1 test may be, for example, the following: once-daily administration for five days to 30 healthy human volunteers in a crossover study. Gastric pH is measured by a Digitrapper® pH100 probe every 4 seconds after 24 hours. administration on days 1 and 5. Non-physiological aberrant pH points are considered unmeasured. The average gastric pH is then calculated from the values collected.
• the gastric pH profiles measured in the T1 test for the drug according to the invention and for the reference formulation are first smoothed by replacing the pH value at each instant t by its average taken over the time interval t -15 minutes ; t + 15 minutes.
• the smoothed profiles are then measured the time during which the formulation according to the present invention gives a pH greater than the pH given by the reference formulation.
• This clinical test defines the invention by the pharmacodynamic properties obtained specifically under the conditions of the T1 test.
• the invention is not limited to an implementation under the conditions of this T1 test.
• modified release medicaments according to the invention are, for example, reservoir or matrix type systems.
• the term "reservoir-type system” is intended to mean a system in which the volume of material containing I 1 IPP is entirely coated with at least one film which controls the rate of release of I 1 IPP by diffusion of I 1 IPP through the film and which does not include PPI. This release occurs as a result of contacting the system with the liquids of the gastrointestinal tract.
• Containing material I 1 IPP is for example I 1 IPP itself or a mixture of pharmaceutical excipients and IPP.
• the reservoir system comprises, for example, a plurality of individually coated microcapsules or a monolithic system such as a coated tablet (s) or a tablet or other pharmaceutical form containing a plurality of coated microcapsules.
• matrix system is meant within the meaning of the present invention, a system wherein I 1 IPP is dispersed in a polymeric phase called matrix, which controls the I 1 IPP release rate. This matrix can be non-erodible or erodible.
• the matrix is composed of pharmaceutical excipients known to those skilled in the art.
• the matrix system comprises, for example, a plurality of matrix microparticles (matrix elements) containing I 1 IPP, uncoated or not fully coated, with at least one film.
• the matrix system may be, for example, also a monolithic system (matrix element) such as a (or tablet (s) not fully coated with at least one continuous film, not containing a reservoir system.
• the matrix system can thus be eg a tablet comprising IPP granules with immediate and extended release, dispersed in a polymeric matrix.
• the IPP-based oral medicament according to the invention is a reservoir-type system, comprising a plurality of microcapsules (reservoir elements) with modified release of IPP, these microcapsules individually comprising at least one microparticle containing I 1 PPI and coated with at least one coating allowing the modified release of I 1 IPP.
• oral enteric drug immediate reference reference in the present description, a drug releasing the same IPP as the drug according to the invention and whose microcapsules, or the dosage form, comprise an enteric coating releasing at pH 6.8 and under SINK conditions in an in vitro dissolution test, most of the amount of PPI contained in the microcapsules, in a relatively short time; for example, at least 70% of 1 IPP is released in 45 minutes, preferably in thirty minutes.
• microcapsules refers to microparticles comprising 1 IPP and film coated with at least one coating for the modified release of IPP.
• the microparticles PPI non film-coated can be, for example, neutral cores covered with at least one layer containing I 1 IPP, or of pure PPI microparticles or granules formed by a matrix including excipients media of I 1 IPP.
• the coating (s) of coating has sufficient mechanical strength to prevent its / their tearing and / or bursting in the body until the end of the release. active ingredient.
• the drug is designed so that after ingestion, release of I 1 PPI begins in the stomach and in that, when administered in a single daily dose, it allows to maintain, from the fifth day of the treatment, even from the first day of the treatment, the gastric pH to a value greater than or equal to 4.0, for a duration D greater than or equal to the duration D * during which the pH is maintained at a value greater than or equal to 4.0 with an oral enteric drug with reference immediate release *, administered under the same conditions, D being preferably greater than or equal to D * of at least 5% (% relative to D), more preferably at least 10%, and more preferably still at least 20%.
• this medicament is characterized in that it is non-enteric.
• the medicament is characterized in that it comprises microcapsules with modified release of PPI and in that the coating of the microcapsules of PPI is not enteric.
• enteric drug or coating in the sense of the invention, a drug or an enteric coating, which does not release in gastric conditions and which releases in the small intestine.
• enteric drugs or coatings Many published patent applications, including those mentioned above, describe enteric drugs or coatings.
• US Pharmacopoeia: "USP 28 NF 23 EDITION 2005” also provides a definition of an enteric drug or coating,
• a non-enteric drug or coating within the meaning of the invention may be, for example, a medicament or coating which does not contain enteric polymer in a significant amount, that is to say in an amount sufficient to be effective in particular on a physicochemical level.
• Enteric polymer means an insoluble polymer with a lower or equal pH at 5, 5.5, 6 or 7, respectively, depending on the nature of the polymer, and soluble above this pH.
• the administration of the drug, preferably multimicrocapsular, according to the invention to patients or subjects leads to an increase in their gastric pH, for at least 24 hours, and in particular at night.
• This elevation of gastric pH can be followed by in situ measurement of gastric pH, using a gastric tube.
• the medicament according to the invention may also be characterized by the plasma concentration profile obtained in a standard T2 clinical test according to which the drug is administered orally to a sample of N human subjects, preferably N ⁇ 20 or 30 subjects.
• the individual plasma concentration profile of each patient is then measured, 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 plasma are determined. maximum concentration Cmax. 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 T2 clinical test may be, for example, the following: administration of the form (capsule, tablet, sachet or suspension) once a day, before breakfast, to 20 healthy human volunteers during a study in cross tests. Plasma levels of PPI are 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 T2 clinical test defines the invention by the pharmacokinetic properties obtained specifically under the conditions of the test.
• the drug according to the invention is characterized in that it is designed such that so that, when administered in a single daily dose, it allows to obtain, after taking, a plasma profile defined as follows:
• - Cmax representing the maximum mean plasma concentration of IPP after taking
• - Cmax * representing the maximum mean plasma concentration of the same IPP obtained under the same conditions as Cmax, with a reference oral immediate-release enteric drug *, containing the same dose of the same IPP.
• modified release is meant herein a release of IPP by an oral drug in which 70% of 1 IPP is released, in an in vitro dissolution test, at pH 6.8, in a time greater than or equal to 45 minutes.
• a modified release drug may, for example, include an immediate release phase and a slow release phase.
• Modified-release drugs are well known in this field; see for example Remington: The Science and Practice of Pharmacy, 19 th Edition, Mack Publishing Co. Pennsylvania, USA.
• the modified release can be in particular a prolonged and / or delayed release.
• the multimicrocapsular drug according to the invention can also be characterized in that the microcapsules of IPP have an in vitro release profile in 0.05M potassium dihydrogenphosphate buffer medium at pH 6.8:
• 70% of the IPP are released in a time of between 1 and 10 hours, preferably between 2 and 8 hours, and still more preferably between 2 and 6 hours, and 40% of 1 IPP are released in one time between 0.5 and 5 hours, preferably between 1 and 4 hours, and more preferably between 1 and 3 hours.
• the omeprazole microcapsules have an in vitro release profile in 0.05M potassium dihydrogenphosphate buffer medium at pH 6.8, such as:
• - 70% of omeprazole are released in a time between 2h and 8h, preferably between 2h and 5h,
• omeprazole 40% of the omeprazole are released in a time of between 1h and 4h, preferably between 1h and 3h,
• the microcapsules of IPP have an in vitro release profile in 0.05M potassium dihydrogenphosphate buffer medium at pH 6.8, such that for any value of time t between 2h and t (70%), preferably for any value of time t between 1 h and t (70%), the% of dissolved (released) IPP is greater than or equal to 35 t / t (70%). That is to say, the profile according to the invention releasing 70% of the IPP at the time called t (70%) remains above a linear profile releasing half of the IPP (ie 35%) in the same time t (70%), and this at any time between 2h and t (70%), preferably at any time between 1 h and t (70%).
• the medicament comprises at least one external buffering agent.
• external buffering agent denotes, in the plural as in the singular, a single compound or a mixture of compounds.
• This external buffering agent formulated and / or administered with the matrix elements or reservoir (eg microcapsules) with modified release of IPP, has the effect of preventing the acid degradation of I 1 IPP and to preserve its bioavailability.
• the term "external" indicates that the buffering agent is outside the matrix elements or reservoir (e.g. microcapsules).
• a buffering agent contained in the matrix or reservoir elements e.g. microcapsules
• the external buffering agent is present in the medicament according to the invention in the form of one or more individualized structures distinct from the matrix elements or reservoir (e.g. microcapsules).
• the drug according to the invention is constituted by one or more same galenic units (eg tablet, capsule or sachet) each containing, on the one hand, the matrix elements or reservoir (eg microcapsules), and on the other hand , the external buffering agent.
• the matrix elements or reservoir eg microcapsules
• the drug according to the invention is constituted, on the one hand, by one or more galenic units (eg tablet, capsule or sachet) each containing the matrix or reservoir elements (eg microcapsules), and, on the other hand, by one or more dosage units (eg tablet, capsule or sachet) each containing the external buffering agent.
• galenic units eg tablet, capsule or sachet
• dosage units eg tablet, capsule or sachet
• the medicinal product according to the invention comprises:
• one or more same galenic units e.g. tablet, capsule or sachet
• the matrix or reservoir elements e.g., microcapsules
• one or more pharmaceutical units e.g. tablet, capsule or sachet
• the matrix or reservoir elements e.g., microcapsules
• dosage units e.g., tablet, capsule or sachet
• the medicament comprises at least one matrix element without an external buffer.
• the drug according to the invention may also be in the form of a multidose oral suspension, reconstituted from powder and water, before administration.
• the external buffering agent advantageously comprises at least one pharmaceutically acceptable compound, weakly or strongly basic.
• the external buffering agent may be chosen from the following list, without being limited thereto: the amino acids and their salts, the sodium, potassium, calcium, magnesium and aluminum salts, these salts being preferably selected from the following salts: hydroxides, oxides, lactates, gluconates, sesquicarbonates carbonates, bicarbonates, silicates, phosphates, glycerophosphates, pyrophosphates, polyphosphates or chlorides.
• the buffering agent can of course be a mixture of all or part of these compounds.
• the external buffering agent or part of the external buffering agent preferably has a high buffering capacity, for example greater than or equal to 10 mEq / g
• the external buffering agent is preferably calcium carbonate optionally combined with the oxide or magnesium hydroxide.
• the medicament contains between 0 and 10OmEq, preferably between 2 and 40mEq of external buffer agent.
• the external buffering agent comprises calcium carbonate.
• the calcium carbonate is present in a proportion of 2 to 15mEq, preferably 5 to 10mEq.
• the external buffering agent comprises magnesium oxide.
• the external buffering agent comprises between 5 and 35 mEq, preferably between 5 and 25 mEq of magnesium oxide.
• the external buffering agent comprises from 3 to 7 mEq of calcium carbonate and a quantity of magnesium oxide such that the ratio magnesium oxide / calcium carbonate, in milliequivalents, is between 1.5 and 5.
• the external buffering agent comprises approximately 5 mEq of calcium carbonate and approximately 12.5 mEq of magnesium oxide.
• the external buffering agent chosen comprises magnesium hydroxide.
• the external buffer agent chosen comprises between 5mEq and 30mEq, preferably between 5mEq and 20mEq of magnesium hydroxide.
• the external buffer agent chosen comprises from 3 to 7 mEq of calcium carbonate and an amount of magnesium hydroxide such that the magnesium hydroxide / calcium carbonate ratio, in milliequivalents, is between 1, 5 and 5.
• the external buffering agent chosen comprises about 5mEq of calcium carbonate and about 8.5mEq of magnesium hydroxide.
• the buffering agent is, for example, immediate release.
• the matrix elements or reservoir (e.g. microcapsules) of IPP may contain at least one internal buffer agent.
• the internal buffer agent is an integral part of the matrix elements or reservoir (e.g. microcapsules).
• Said internal buffering agent is selected from pharmaceutically acceptable compounds, weakly or strongly basic, and selected for example from the list of buffering agents mentioned below: amino acids and their salts, sodium, potassium, calcium salts, magnesium, aluminum, these salts being preferably selected from the following salts: hydroxides, oxides, lactates, gluconates, sesquicarbonates carbonates, bicarbonates, silicates, phosphates, glycerophosphates, pyrophosphates, polyphosphates or chlorides.
• the buffering agent can of course be a mixture of all or part of these compounds.
• This internal buffering agent preferably comprises magnesium hydroxide.
• This internal buffering agent in direct contact with IPP I 1 has the effect to prevent acid degradation of I 1 IPP, which may occur within the matrix or reservoir elements (eg microcapsules).
• the coating of the reservoir elements comprises at least one layer that governs the modified release of IPP whose composition is as follows:
• D at least one plasticizer (D);
• E optionally at least one surfactant and / or lubricant (E).
• (A) is selected from the following product group:
• non-water-soluble derivatives of cellulose preferably ethylcellulose and / or cellulose acetate, polyvinylacetates,
• (B) is selected from non-water soluble filled acrylic polymers, preferably from acrylic and / or methacrylic acid ester (co) polymers bearing at least one quaternary ammonium group; (B) more preferably comprising at least one copolymer of alkyl (meth) acrylate and trimethylammonioethylmethacrylate chloride and more specifically the products marketed under the tradenames EUDRAGIT ® RS and / or EUDRAGIT ® RL [ester copolymers d acrylic acid (ethyl acrylate) and (meth) acrylic acid ester (methyl (meth) acrylate) and trimethylammonioethylmethacrylate chloride, eg EUDRAGIT ® RL PO and / or I 1 EUDRAGIT ® RS powders PO and / or EUDRAGIT ® RL 100 and / or EUDRAGIT ® RS 100 granules and / or suspensions and / or solutions of these EUDR
• the nitrogenous (co) polymers preferably in the group comprising polyacrylamides, poly-N-vinylamides, polyvinylpyrrolidones (PVP) and poly-N-vinyl-lactams;
• PVA polyvinyl alcohols
• PEG polyethylene glycols
• hydrocolloids such as xanthan gums, guar gums, pectins, locust bean gum, carrageenans, gelatin, agar agar, modified or unmodified starches, dextrins, alginates.
• polyvinylpyrrolidone polyoxyethylenes, polyethylene glycols and hydroxypropylcellulose being particularly preferred;
• (D) is selected from the group consisting of:
• esters of cetyl alcohol - glycerol and its esters preferably in the following subgroup: acetylated glycerides, glycerolmonostearate, glyceryltriacetate (triacetin), glycerol tributet,
• phthalates preferably in the following subgroup: dibutylphthalate, diethylphthalate, dimethylphthalate, dioctylphthalate,
• 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
• (E) is selected from the group consisting of:
• anionic surfactants preferably in the subgroup of alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred,
• nonionic surfactants preferably in the following subgroup:
• Polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil
• Stearates preferably calcium, magnesium, aluminum or zinc, Stearyl fumarates, preferably sodium,
• composition of the modified-release layer is as follows:
• the film-forming polymer (s) (A) is (are) present in a proportion of 10 to 90%, preferably 20 to 40% by weight, on a dry basis with respect to the total mass; the coating composition;
• the water-insoluble hydrophilic polymeric (s) (s) (B) is (are) present in a proportion of 10 to 90%, preferably 20 to 40% by weight. dry weight relative to the total mass of the coating composition;
• the soluble polymer (s) (C) in the fluids of the gastrointestinal tract (s) is (are) present in a proportion of 2 to 25, preferably 5 to 15% by weight. dry weight relative to the total mass of the coating composition;
• the plasticizer (s) (D) is (are) present in a proportion of 2 to 20, preferably 4 to 15% by weight on a dry basis with respect to the total weight of the composition of coating;
• the (or any) surfactant (s) and / or lubricant (s) (E) is (are) present in a proportion of 2 to 20, preferably 4 to 15% by weight. on a dry basis with respect to the total mass of the coating composition.
• the modified release layer may preferably have the following mass composition: A. (or) polymer (s) fémmo misleading (s) (A) is (are) present (s) at a rate of 40 to 55%, preferably 45 to 55% by weight on a dry basis relative to the total weight of the coating composition;
• the (or) soluble polymer (s) (C) is (are) present (s) at a rate of 15 to 30%, preferably 20 to 30% by weight on a dry basis with respect to the total mass the coating composition,
• At least one plasticizer (D) is (are) present (s) in a proportion of 3 to 10%, preferably 3 to 7% by weight on a dry basis relative to the total mass of the coating composition,
• the (or any) surfactant (s) and / or lubricant (s) (E) is (are) present in a proportion of 10 to 30%, preferably 15 to 25% by weight. dry weight relative to the total mass of the coating composition.
• the coating the reservoir elements comprises at least one layer that regulates the modified release of omeprazole.
• the composition of this layer is as follows:
• (A) is selected from the group of products: non-water soluble derivatives of cellulose, preferably ethylcellulose and / or cellulose acetate;
• C is selected from polyvinylpyrrolidones (PVP) and water-soluble cellulose derivatives such as hydroxypropylcellulose; PVPs being preferred;
• (D) is castor oil;
• (E) is chosen from: polyoxyethylene-polyoxypropylene copolymers, preferably polyoxyethylene-polyoxypropylene block terpolymers.
• the monolayer or multilayer coating may comprise various other additional adjuvants conventionally used in the field of coating. It may be, for example, pigments, dyes, fillers, defoamers, etc.
• the coating of microcapsules governing the modified release of IPP consists of a single layer or a single coating film. This simplifies their preparation and limits the rate of coating. Furthermore, the drug according to the invention has the particularity that the coating of each element "reservoir (eg microcapsule) is non-enteric and does not disintegrate regardless of the pH and in particular at pH greater than or equal to 5.0 .
• the array of matrix elements may comprise all the pharmaceutically acceptable excipients and in particular those defined above for the composition of the reservoir elements.
• the main functional materials used to prepare these matrix systems correspond to the following families: hydrophilic polymers soluble in the liquids of the gastrointestinal tract such as povidone, the water-soluble derivatives of cellulose, xanthan gum, polyethylene glycols, alcohols polyvinyl ... hydrophobic polymers insoluble in the liquids of the gastrointestinal tract, such as non-water-soluble derivatives of cellulose, non-water-soluble (meth) acrylic polymers, polyvinylacetates, etc.
• excipients may also be included in the formulation of the matrix compounds such as, for example, disintegrants, lubricants, waxy compounds, dyes, plasticizers, bulking agents, pH modifiers, pH-sensitive compounds. , surfactants, flavors, ...
• the diameter of the microcapsules is less than or equal to 1,000 ⁇ m, preferably between 5 and 800 ⁇ m, and even more preferably between 100 and 600 ⁇ m.
• the diameter of the microcapsules may be between 100 and 500 ⁇ m, preferably between 100 and 400 ⁇ m, and more preferably between 100 and 300 ⁇ m.
• the diameters of microparticles and microcapsules referred to herein are, unless otherwise indicated, mean diameters by volume.
• the proportion of PPI in the microcapsules is between 5 and 95, preferably between 10 and 85. and more preferably between 20 and 70.
• the monolayer or multilayer coating (or film) governing the modified release of I 1 IPP represents, for example, at most 40%, preferably at most 15% by weight of the microcapsules.
• the modified-release layer represents from 2 to 25% by weight, preferably from 5 to 20% by weight, and more preferably from 5 to 15% by weight. weight, based on total weight of omeprazole microcapsules.
• Such limited coating rates make it possible to produce pharmaceutical units each containing a high dose of IPP, without exceeding a prohibitive size with regard to swallowing. The observance and therefore the success of the treatment can only be improved.
• the invention is described below, without limitation, two preferred embodiments of the structure of the microcapsules.
• the microcapsules with modified release of IPP each comprise: a microparticle of PPI, coated with
• At least one coating allowing the modified release of IPP.
• the microparticle of IPP is constituted by 1 IPP crude (pure) or a matrix granule of IPP with one or more other pharmaceutically acceptable ingredients.
• At least a portion of the microcapsules with modified release of IPP each comprise:
• At least one active layer comprising 1 IPP and coating the neutral core, and at least one coating governing the modified release of IPP.
• the neutral heart contains sucrose and / or dextrose and / or lactose.
• the neutral core is a cellulose microsphere.
• the neutral core has a mean diameter less than or equal to
• the active layer may optionally contain, in addition NPP, at least one internal buffering agent and / or at least one active ingredient other than I 1 IPP and / or one or more pharmaceutically acceptable excipients.
• the optional internal buffer agent is for example included inside the microparticles of IPP (granule or coated neutral core), from which the microcapsules are made, in direct contact with I 1 IPP.
• the internal buffer agent may for example be:
• the coating deposition techniques allowing the modified release of IPP or deposition of the active layer based on IPP, are techniques known to those skilled in the art, for example the technique of spray coating in bed fluidized air, wet granulation, compaction, extrusion-spheronization ...
• microcapsules of IPP are all the more interesting that they are also perfectly tolerated by the body, especially at the gastric level and also can be obtained easily and economically.
• the medicament according to the invention may comprise, in addition to a PPI, one or more other active ingredients.
• This (or these) other principle (s) active (s) can to be included in matrix elements or reservoir (eg microcapsules) with modified release of active principle (s) with or without a PPI.
• the IPP-based oral medicament also comprises at least one H 2 -receptor antagonist, preferably selected from the group comprising the following active ingredients: cimetidine, ranitidine, nizatidine, famotidine, and their pharmaceutically acceptable salts. areomers and their isomer salts, as well as any mixture of these different active ingredients.
• the medicament according to the invention may comprise micro-units consisting of microcapsules with modified release of IPP and / or microunits of IPP, other than microcapsules, such as matrix (micro) granules. It could be, for example, microparticles for immediate release of PPIs and / or other active principle (s). These immediate release microparticles may be of the same type as those used in the preparation of the above-mentioned microcapsules.
• all the micro-units (microparticles and / or microcapsules) constituting the drug according to the invention can be formed by different populations of micro-units, these populations differing from each other at least by the nature of (or) active principle (s) other than the PPI contained in these micro-units and / or by the quantity in PPI or other possible active principle (s) (s) ) they contain and / or by the composition of the coating and / or by the fact that they are modified release or immediate release.
• microcapsules described above can be used for the manufacture of new pharmaceutical preparations or PPI-based medicaments, having optimized therapeutic performances, especially with respect to gastric disorders, and preferably occurring in various galenic forms: deltable tablets or orodispersibles, capsules, tablets or matrix granules, multi-dose sachets or suspensions to be reconstituted without modifying the release profile of the microcapsules of PPI.
• the medicament containing the modified release microcapsules of IPP also comprises pharmaceutically acceptable excipients, conventional and known to those skilled in the art, useful for example to present the microcapsules in tablet form.
• these excipients may be especially: - Compression agents such as microcrystalline cellulose or mannitol - dyes disintegrators such as crospovidone or crosslinked polyvinylpolypyrrolidone or crosslinked povidone; croscarmellose sodium or crosslinked sodium carboxymethylcellulose; sodium starch glycolate; pregelatinized corn starch
• - Compression agents such as microcrystalline cellulose or mannitol - dyes disintegrators such as crospovidone or crosslinked polyvinylpolypyrrolidone or crosslinked povidone
• croscarmellose sodium or crosslinked sodium carboxymethylcellulose sodium starch glycolate
• pregelatinized corn starch pregelatinized corn starch
• flow agents such as talc, lubricants such as, for example, glycerol behenate
• the drug When the drug is presented in tablet form, it can be coated according to the techniques and formulas known to those skilled in the art to improve its presentation: color, appearance, taste masking, etc.
• the drug when it is in tablet form, it comprises a plurality of modified release microcapsules of IPP as described above.
• the tablet has an in vitro release profile in 0.05M potassium dihydrogenphosphate buffer medium at pH 6.8, similar to that of the microcapsules of said tablet, according to the similarity factor f2.
• the similarity test is defined as follows: the similarity between two dissolution profiles is evaluated using the similarity factor f 2 as defined in the document "Quality of the modified-release products" of the European Agency for the Evaluation of Medicinal Products, document referenced CPMP / QWP / 604/96 (Annex 3). A value of f 2 between 50 and 100 indicates that the two dissolution profiles are similar.
• the tablet contains, in addition to a plurality of microcapsules with modified release of IPP, from 5 to 25 mEq of external buffer agent, preferably from 10 to 20 mEq of external buffer agent,
• the external buffering agent is selected from calcium carbonate, magnesium oxide and mixtures thereof.
• the tablet has a higher hardness, in increasing order preferably, at 8ON, 100N, 120N.
• the hardness is less than 300N, more preferably less than 200N.
• the hardness of the tablet is between 100N and 150N.
• the medicament according to the invention may advantageously exist in the form of a single daily oral dose comprising from 1 mg to 500 mg of IPP, without this being limiting.
• the new PPI-based medicaments according to the invention are original in their structure, their presentation and their composition and are administrable per os, especially in single daily doses.
• a daily oral single dose comprising from 100 to 500,000 micro-units, some of which contain 1 IPP;
• a daily oral single dose comprising from 100 to 500,000 microcapsules with modified release of I 1 IPP and possibly at least one other active ingredient.
• the invention relates to the use of the microparticles as defined above, for the preparation of pharmaceutical microparticulate oral dosage forms, preferably in the form of tablets, powders for oral suspension or capsules.
• the invention also provides a method of therapeutic treatment characterized in that it consists essentially of ingestion, in a given posology, of a drug as defined above and comprising the microcapsules also defined above. According to another of its aspects, the invention also relates to microcapsules per se as defined above.
• Figure 9 shows the change in concentration (ng / mL) in omeprazole in plasma over time after taking day 1 after administration of P1 (full triangle) and F1 (full rhombus) once daily .
• Figure 10 shows the change in concentration (ng / mL) in omeprazole in plasma over time after day 5 taken after administration of P1 (empty triangle) and F1 (empty diamond) once daily .
• the abscissa represents the time expressed in hours.
• Example 1 omeprazole granule 700 g omeprazole and 100 g hydroxypropyl cellulose (Klucel EF ® /
• Aqualon are dispersed in 3000 g of isopropanol. The suspension is sprayed on 200 g of neutral microspheres (Asahi-Kasei) in a spray-coater Glatt GPCG 1.
• the granulate obtained has an omeprazole concentration of 70%.
• microcapsules obtained are then placed in a size 3 gelatin capsule.
• the dose of omeprazole per capsule was fixed in this test at 80 mg, ie 127 mg of microcapsules). This capsule is the final form of the drug.
• the capsule containing the microcapsules was tested in a Type II dissolutest according to the Pharmacopoeia at 37 ° C. and with stirring at 100 rpm at pH 6.8 (KH 2 PO 4 0.05M / NaOH). See Figure 1.
• ethyl cellulose Ethocel 20 Premium ® / Dow
• povidone Plasdone K29 / 32 ® / ISP
• poloxamer 188 20 g of oil castor oil
• microcapsules obtained are then placed in a size 3 gelatin capsule.
• the dose of omeprazole per capsule was fixed in this test at 40 mg, ie 71.4 mg of microcapsules). This capsule is the final form of the drug.
• the capsule containing the microcapsules was tested in a Type II dissolutest according to the Pharmacopoeia at 37 ° C. and with stirring at 100 rpm at pH 6.8 (KH 2 PO 4 0.05M / NaOH). See Figure 2.
• omeprazole and 100 g of hydroxypropyl cellulose are dispersed in 2333 g of water.
• the suspension is sprayed on 250 g of neutral microspheres (Celphere SCP100F / Asahi-Kasei) in a spray coater Glatt GPCGL
• the granulate obtained has an omeprazole concentration of 72%.
• microcapsules ie 10 mg of omeprazole
• omeprazole 1355.2 g of omeprazole, 140.8 g of hydroxypropyl cellulose (Klucel EF ® / Aqualon), 88.0 g of poloxamer 188 (Lutrol F68 ® / BASF) and 176.0 g of hydroxide magnesium (Magnesia ® 725 / Magnesia) incorporated as internal buffering agent are dispersed in 4107.0 g of water. The suspension is sprayed on 440.0 g of neutral microspheres (Asahi-Kasei) in a Glatt GPCG 1 coater spray. The granule obtained has an omeprazole concentration of 61.6%.
• microcapsules obtained are then placed in a gelatin capsule, with 138.9 g of DESTAB Ultra ® 250S (Particle Dynamic Inc.) corresponding to 125.0 mg of calcium carbonate and 13.9 g of pregelatinized starch, 125, 0 mg of magnesium oxide, 3.4 mg of anhydrous colloidal silica (Aerosil 200® / Degussa) and 1.7 mg of magnesium stearate.
• the dose of omeprazole per capsule was fixed in this test at 840 mg or 12472.2 mg of microcapsules. This capsule is the final form of the drug.
• Example 8 Omeprazole sustained-release tablets 144.1 g of sustained-release microcapsules prepared according to the example
• P1 Capsules containing microcapsules of S (-) - omeprazole film-coated with an enteric membrane - Inexium® - dose 40 mg
• the enteric reference drug * P1 or the non-enteral oral antidepressant modified omeprazole according to the invention F1 are administered once a day, after 10 hours of fasting and before breakfast, for five days at 28 days. healthy volunteers during a crossover trial.
• Plasma omeprazole concentrations are measured at time: 0-0.5-0.75-1-1, 5-2-3-4-6- 8-10-12-14-16-20-24 h post -administration on days No. 1 and No. 5 by an LC-MS method.
• Gastric pH is measured by a Digitrapper® pH100 probe every 4 seconds after 24 hours post-administration.
• the drug F1 according to the invention improves the parameter Cmax / C12h by a factor of about 12 for days No. 1 and No. 5 relative to the reference form * P1.
• the F1 drug according to the invention significantly increases the average pH over 24 hours compared to the oral enteric reference drug * P1.
• the average pH during the night is significantly increased by the formulation F1 according to the invention relative to the reference enteric form * P1.
• Formulation F1 according to the invention thus makes it possible to obtain a gastric pH during the night (between 16 and 20 h) of day n ° 1 equal to 2.49, whereas the average pH overnight is 1.68 with the form reference * P1.
• the drug F1 according to the invention significantly increases the average pH over 24 hours and the time during which the gastric pH is greater than 4 (T> pH 4) relative to the oral enteric drug of reference * P1.
• the average pH during the night is significantly increased by the formulation F1 according to the invention relative to the reference enteric form * P1.
• Formulation F1 according to the invention thus makes it possible to obtain a gastric pH during the night (between 16 and 20 h) of day 5, equal to 3.44, while the average pH overnight is 1.93 with the form reference * P1.

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