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US20040022849A1 - Oral pharmaceutical composition with controlled release and prolonged absorption - Google Patents

Oral pharmaceutical composition with controlled release and prolonged absorption Download PDF

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Publication number
US20040022849A1
US20040022849A1 US10/332,463 US33246303A US2004022849A1 US 20040022849 A1 US20040022849 A1 US 20040022849A1 US 33246303 A US33246303 A US 33246303A US 2004022849 A1 US2004022849 A1 US 2004022849A1
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weight
composition
individual
polymer
excipients
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Catherine Castan
Valerie Legrand
Remi Meyrueix
Gerard Soula
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Flamel Technologies SA
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Flamel Technologies SA
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Assigned to FLAMEL TECHNOLOGIES reassignment FLAMEL TECHNOLOGIES ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: CASTAN, CATHERINE, LEGRAND, VALERIE, MEYRUEIX, REMI, SOULA, GERARD
Publication of US20040022849A1 publication Critical patent/US20040022849A1/en
Priority to US11/723,553 priority Critical patent/US7879362B2/en
Abandoned legal-status Critical Current

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    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • the present invention relates to the technical field of pharmaceutical dosage systems with prolonged and controlled release of medicinal and/or nutritional active principles (AP), intended for oral administration.
  • AP nutritional active principles
  • the invention is targeted at a pulverulent pharmaceutical composition which can be administered per os and which comprises at least one active principle AP absorbed in particular in the upper parts of the gastrointestinal tract and excipients capable of conferring thereon properties of prolonged absorption of the AP.
  • the oral route is the most convenient and the most widely used administration route for medicinal and/or dietary active principles. These systems have obvious advantages in terms of ease of administration and of tolerance for the patients.
  • An additional condition to that of increasing the bioabsorption time, which is the first objective of the pharmaceutical dosage system of the present invention, is that of maintaining the bioavailability of the AP at a satisfactory and sufficient level.
  • the bioabsorption time (Tabs) is deduced from the plasma concentration profile (PCP) of the AP: this is the time at the end of which the PCP enters a situation of pure elimination.
  • the bioavailability is, for its part, evalued conventionally by the ratio of the area under the curve of the PCP to the area under the curve of the PCP of a reference immediate release form.
  • bioadhesive systems which adhere to the gastric and/or intestinal mucous membranes
  • Patent application PCT WO-99/47128 provides a review of the prior art relating to these three types of approach for the development of gastroretentive pharmaceutical dosage forms having properties of prolonged and controlled release of the AP.
  • This pharmaceutical dosage system with controlled release of AP has two phases. It comprises:
  • the distinctive feature of these granules is that of being uncoated and of comprising one or more excipients which can be:
  • a hydrophobic polymer copolymer of (meth)acrylic acid (Eudragit®), ethylcellulose,
  • hydrophilic polymer sodium carboxymethylcellulose or sodium alginate
  • hydrophobic compounds waxes, fatty alcohols, fatty acid esters,
  • this solid continuous external phase comprising:
  • one or more hydrophilic polymers [hydroxypropylmethylcellulose (HPMC) (with a viscosity of 5 cPs and 1 ⁇ 10 5 cps), microcrystalline cellulose),
  • HPMC hydroxypropylmethylcellulose
  • hydrophobic compounds waxes, fatty alcohols, fatty acid esters.
  • This pharmaceutical dosage system is preferably in the tablet form. It is presented as having an increased residence time in the upper part of the gastrointestinal tract (stomach/small intestine) by an effect of increase in size, without, however, reaching an upper limit leading to blockage.
  • This pharmaceutical dosage form exhibits a variable gastric residence time, unlike a microparticulate pharmaceutical dosage form, the residence time of which is kept in balance by the large number of particles.
  • this pharmaceutical dosage system according to WO-99/47128 (preferably a tablet) has a low mechanical strength in a gastric medium. Under such an assumption, the release of the AP would no longer be controlled.
  • Patent application PCT WO-99/47125 provides a pharmaceutical dosage form, the application of which is limited to antihyperglycemics of very high solubility and more particularly metformin.
  • This form makes it possible to obtain therapeutic cover over 24 hours after oral administration in the nourished state. It is composed of a macroscopic tablet surrounded by a membrane which is permeable to water but not to the AP.
  • the core of the invention is the development of a tablet which releases the AP by an osmotic effect.
  • the release of the AP is controlled by adjusting the osmotic pressure by addition of a polymer which increases the inflow of water and by adjusting the rate for departure of the AP by inserting an orifice in the semipermeable membrane.
  • the bioavailability is maintained by adding an absorption promoter, such as a bile salt, to the tablet.
  • this “tablet” form exhibits a variable gastric residence time, unlike a microparticulate pharmaceutical dosage form, the residence time of which is kept in balance by the large number of particles.
  • U.S. Pat. No. 5,472,704 provides a controlled release system which maintains the bioavailability of the AP by increasing the residence time of the pharmaceutical dosage form passing through the window of absorption of the AP in the (GIT).
  • This bioadhesive pharmaceutical dosage system is composed of a plurality of individual particles, the largest dimension of which is at most 2 500 microns, in practice 300-600 microns.
  • Each particle can comprise a bioadhesive part formed of an acrylate copolymer and of hydroxypropylmethylcellulose (HPMC) and a noncontinuous part comprising coated AP granules (125-600 ⁇ m) in which the AP is combined with an excipient which is active with regard to the prolonged and controlled release of said AP, this excipient not having bioadhesive properties (castor oil and/or lactose and/or polyvinyl alcohol and/or a vegetable oil and/or a calcium hydrogenphosphate, and the like).
  • HPMC hydroxypropylmethylcellulose
  • the bioadhesive part comprises, for example:
  • hydrophobic agents such as stearic acid salts, hydrogenated vegetable oils, polyethylene glycols, talc, and the like,
  • disintegrating agents of the following types polyvinylpyrrolidone, starch functionalized by methyl and sodium carboxylate groups, starch, alginic acid, calcium carboxymethylcellulose, guar gum, silica, sodium alginate, gelatin, pectin, and the like.
  • coated AP granules with a diameter of 125-600 ⁇ m are mixed with the excipients intended to form the bioadhesive part. This mixture is subsequently formed into tablets, which are subsequently milled and sieved, so as to obtain a powder comprising granules with a size of 300-600 ⁇ m.
  • Another type of pharmaceutical dosage system is also known, composed of a multiplicity of particles or microcapsules each carrying AP coated with a layer of film coating based on ethylcellulose, on polyvinylpyrrolidone, on magnesium stearate and on castor oil, for example.
  • a pharmaceutical dosage system is disclosed in application PCT WO-96/11675.
  • These reservoir microcapsules benefit from their multiplicity, which benefit is a more uniform and reproducible gastric emptying time.
  • the multiparticulate pharmaceutical dosage system according to WO 96/11675 can be improved as regards the absorption time and the bioavailability of active principles having a high solubility in water and absorbed in the upper part of the GIT, such as, for example, metformin.
  • one of the essential objectives of the present invention is to provide a novel improved pharmaceutical dosage system for the oral administration of active principles APs, in particular of APs having a high solubility in water and absorbed in the upper part of the GIT, this system having to make it possible to obtain effective therapeutic cover over 24 hours.
  • Another essential objective of the invention is to provide a gastroretentive pharmaceutical dosage system for the oral administration of an AP having a high solubility in water and absorbed in the upper part of the GIT, this system exhibiting an increased bioabsorption time, while maintaining the bioavailability of the AP at a sufficient and satisfactory level.
  • Another essential objective of the invention is to provide an oral pharmaceutical dosage composition for the administration of an AP having a high solubility in water, the in vitro release profile for the AP of which has a sigmoidal shape.
  • Another essential objective of the invention is to provide an oral pharmaceutical dosage composition of one dose per 24 hours type which is effective therapeutically, which can be tolerated by the patient, which is economic, which is easy to manufacture and in which recourse has been had to a combination of conventional and harmless pharmaceutical excipients.
  • Another essential objective of the invention is to provide a pharmaceutical dosage system of the type of that mentioned above which is provided in the form of gelatin capsules.
  • Another essential objective of the invention is to provide for the use of the abovementioned oral pharmaceutical dosage system or composition for the preparation of a medicament, in particular of a medicament with an active principle which is very soluble in water and more particularly still with an AP which is an antidiabetic, such as metformin.
  • the present invention which relates, first of all, to the oral pharmaceutical composition comprising at least one active principle (AP) and excipients capable of conferring, on this composition, properties of controlled release and of prolonged absorption of the AP in the gastrointestinal tract, this composition being of the type of those comprising:
  • AP active principle
  • phase is dispersed this plurality of individual and coated particles, characterized in that:
  • [0052] -a- it comprises two systems for the controlled release of the AP combined in series, namely: individual and coated particles, first, and the continuous external phase, secondly;
  • microcapsules having the following characteristics:
  • [0055] 1 at least one film-forming polymer (P1) which is insoluble in the fluids of the tract, present in a proportion of 50 to 90% by weight, preferably 50 to 80% by weight, on a dry basis with respect to the total mass of the coating composition and composed of at least one water-insoluble cellulose derivative, ethylcellulose and/or cellulose acetate being particularly preferred;
  • At least one nitrogenous polymer (P2) present in a proportion of 2 to 25% by weight, preferably of 5 to 15% by weight, on a dry basis with respect to the total mass of the coating composition and composed of at least one polyacrylamide and/or one poly-N-vinylamide and/or one poly-N-vinyllactam, polyacrylamide and/or polyvinylpyrrolidone being particularly preferred;
  • At least one plasticizer present in a proportion of 2 to 20% by weight, preferably of 4 to 15% by weight, on a dry basis with respect to the total mass of the coating composition and composed of at least one of the following compounds: glycerol esters, phthalates, citrates, sebacates, esters of cetyl alcohol, castor oil, salicylic acid and cutin, castor oil being particularly preferred;
  • anionic surfactants preferably alkali metal or alkaline earth
  • PEP polyelectrolytic hydrophilic polymer
  • NP neutral hydrophilic polymer
  • a gelling/crosslinking additive for the PEP polymer, preferably a compound based on a cation with a valency ⁇ 2, preferably a calcium-based compound and more preferably still calcium acetate;
  • the microcapsules make possible the controlled release of the AP and its absorption in the upper part of the gastrointestinal tract.
  • this pharmaceutical dosage system makes possible gradual release of the microparticles (microcapsules) of internal phase into the stomach, as the gelled matrix is eroded by the gastric fluids.
  • this composition exhibits an in vitro dissolution curve in a test D having a sigmoidal appearance defined in the following way:
  • test D This in vitro dissolution curve is given by a test D which is defined as follows:
  • a gelatin capsule comprising the oral pharmaceutical dosage composition in the powder form is stirred using a paddle at 100 revolutions/min in a simulated gastric medium at a temperature of 37° C.
  • This medium comprises 0.034 mol/l of NaCl, 0.063 mol/l of HCl and 3.2 g/l of pepsin.
  • the dissolution curves for the AP present in the pharmaceutical dosage systems according to the invention comprise a point T, the tangent to which passes through the origin and the abscissa t T of which is ⁇ 1 H, preferably t T ⁇ 1.5 H and more preferably still is: 1 ⁇ t T ⁇ 3 H.
  • the pharmaceutical dosage composition according to the invention makes it possible to increase the therapeutic cover of the AP by an increase in the t max , while maintaining the bioavailability at a sufficient and satisfactory level.
  • the curves giving the plasma concentrations of AP as a function of the time following ingestion of the composition, respectively for an immediate release AP (metformin) and for this same AP in a pharmaceutical dosage composition according to the invention, are shown in FIG. 3.
  • the increase in the t max obtained by virtue of the formulation according to the invention is obvious.
  • composition As regards the continuous external phase or matrix, it is preferable for its composition to be as follows:
  • PEP gelling/crosslinking polyelectrolytic hydrophilic polymer
  • NP neutral hydrophilic cellulose polymer
  • ADD gelling/crosslinking additive
  • the viscosity ⁇ may possibly be a criterion for selection of the PEP and NP polymers.
  • This viscosity ⁇ is conventionally a viscosity measured at 25° C. for a polymer solution with an assay which can vary, for example: 1.25 or 2%.
  • the methodology used is that set by the US pharmacopeia, namely USP 2208.
  • the products are selected which have a viscosity ⁇ of:
  • [0087] preferably: 50 000 mPa ⁇ s ⁇ 150 000 mPa ⁇ s,
  • PEP gelling polyers
  • HPMC is not the only neutral hydrophilic polymer (NP) capable of being suitable in the context of the invention.
  • NP neutral hydrophilic polymer
  • HPPC hydroxypropylcellulose
  • the gelling additives are specific to the polymers on which they exert their action.
  • barium, strontium, copper, nickel, zinc or manganese salts crosslink the alginate, resulting in the formation of a gel.
  • composition according to the invention has the advantageous characteristic of comprising:
  • the oral composition according to the invention is preferably pulverulent.
  • the oral composition according to the invention is a pulverulent form present in a gelatin capsule which, in an in vitro dissolution test D, spontaneously forms, in the presence of water, a cohesive solid formed from a gel matrix based on the continuous external phase and including the individual particles of AP coated with excipients.
  • This cohesive solid is formed in less than 30 minutes and preferably between 1 and 20 minutes. It maintains its cohesion in the test D for at least 3 hours, thus providing, first, for the formation of an object with a size such that it cannot be expelled from the stomach during the time of the digestion during which the pylorus is in the closed position.
  • the AP is released into the system by virtue of the osmotic pressure exerted by the active principle.
  • the object disintegrates, thus releasing the microparticles, which can then migrate toward the small intestine, where they will continue to release the AP, thus increasing the absorption time for the AP in the body.
  • this pulverulent mixture could be formed into tablets capable of being converted in the gastrointestinal tract into a system comprising a gelled matrix based on the continuous external phase including the individual and coated particles of AP and of excipients.
  • the excipients selected and the way in which they are arranged in the pharmaceutical dosage system are essential characteristics of the invention.
  • the functionalities of these excipients will be all the better expressed if the AP belongs to at least one of the following families of active substances:
  • antiulcer drugs antidiabetics, anticoagulants, antithrombics, hypolipemics, antiarrhythmics, vasodilators, antianginals, antihypertensives, vasoprotectants, fertility promoters, uterine labor inducers and inhibitors, contraceptives, antibiotics, antifungals, antivirals, antineoplastics, antiinflammatories, analgesics, antiepileptics, antiparkinsonians, neuroleptics, hypnotics, anxiolytics, psychostimulants, antimigraines, antidepressants, antitussives, antihistaminics or antiallergics;
  • this AP preferably being chosen from the following compounds:
  • metformin pentoxyfylline, prazosin, diltiazem, ketoprofen, metoprolol, captopril, atenolol, salbutamol, ranitidine, quinidine, perindopril, morphine, verapamil and their mixtures.
  • the active principles to which the invention also relates could be nutritional and/or dietary supplements or their mixtures, such as, for example, vitamins, amino acids, antioxidants or trace elements, or their mixtures.
  • Vaccines can optionally constitute other medicinal APs.
  • the AP is present in a proportion of at least 10% by weight, preferably in a proportion of 15 to 50% by weight and more preferably still in a proportion of 20 to 40% by weight.
  • the pharmaceutical dosage system to which it relates comprises the composition as defined above, this composition being present, preferably, in a gelatin capsule, for example made of gelatin, preferably in an amount of between 300 and 1 000 mg, and more preferably still between 400 and 700 mg.
  • the invention relates to the use of the composition as defined above in the preparation of pharmaceutical or dietary forms which are preferably pulverulent and are present in gelatin capsules.
  • the pharmaceutical dosage system according to the invention could comprise other nontoxic excipients used by a person skilled in the art in gelatin capsule and tablet forms.
  • Preservatives, stabilizers, agents for combating adhesion and taste-masking agents can also be employed.
  • the coating of AP particle is carried out by spraying the coating composition onto the AP particles brought into motion, preferably by mechanical stirring or by fluidization.
  • FIGS. 1 and 2 represent the dissolution profile for an AP (metformin), expressed by the % by weight of AP dissolved in the in vitro test D as a function of the time in hours, for the compositions of examples 2 and 3 respectively.
  • FIG. 2 a represents the dissolution profile for an AP (metformin), expressed by the % by weight of AP dissolved in the in vitro test D as a function of the time in hours, for the microparticles according to WO 96/11675, taken by themselves alone and prepared according to the methodology described in point 1.2 of example 1.
  • AP metalformin
  • FIG. 3 represents the plasma concentration profiles of metformin after administration per os as a single dose to the subject:
  • metformin/HCl sold by Interchemical.
  • Ethylcellulose characterized by an ethoxyl level of between 48 and 49.5% and a viscosity of between 6 and 8 cP, manufactured by Dow and sold under the name Ethocel 7
  • Hydroxypropylmethylcellulose characterized by a viscosity of between 80 000 and 120 000 cP, sold by Colorcon under the name Methocel K 100 M Premium EP
  • metformin.HCl 1 kg was film-coated in a fluidized air bed device (Niro, precision coater) with an 8% (w/w) acetone/isopropanol (60/40 (%) (w/w) solution composed of a mixture of ethocel 7, of plasdone K29/32, of castor oil and of magnesium stearate (example of composition and of amount of coating deposited in tables 1 and 2).
  • These film-coated metformin particles were subsequently dry blended in a cube mixer with a mixture of sodium alginate powder, hydroxypropylmethylcellulose powder and calcium acetate powder. This mixture was finally introduced into gelatin capsules with a size of 00.
  • the release of metformin.HCl was tested in vitro by the test D.
  • a gelatin capsule comprising 142.9 mg of metformin HCl is prepared; the level of coating deposited on the metformin.HCl microparticles is 26%.
  • TABLE 1 percentage composition of example 2 Percentage Unit composition composition Components % (w/w) (mg) Metformin ⁇ HCl 25.47 142.9 mg Ethocel 7 6.60 37.1 mg Magnesium stearate 0.89 5.0 mg Castor oil 0.72 4.0 mg Plasdone K 29/32 0.72 4.0 mg Kelton HVCR 50.91 285.6 mg Methocel premium K 100M 13.12 73.6 mg Calcium acetate 1.57 8.8 mg
  • FIG. 1 shows the dissolution profile obtained. It is observed, with regard to this FIG. 1, that it comprises a point T, the tangent to which passes through the origin and the abscissa T of which is 5 H 20. Such a dissolution profile reveals a prolonged and controlled release of the AP. This also shows that the pharmaceutical dosage form according to the invention retains mechanical integrity (weight ⁇ dimension ⁇ cohesion) for a relatively long time (at least 4 h). The concavity of the first part of the curve (0-4 H) is directed upward: the release kinetics are slow and controlled.
  • FIG. 1 also reveals the dissolution profile for the pharmaceutical dosage system according to application PCT WO-99/47128.
  • a gelatin capsule comprising 166.7 mg of metformin.HCl is prepared; the level of coating deposited on the metformin.HCl microparticles is 12%.
  • FIG. 2 shows the dissolution profile obtained. Each point on this curve corresponds to a mean obtained with respect to 16 gelatin capsules.
  • the curve in FIG. 2, corresponding to the composition according to the invention, comprises a point T, the tangent to which passes through the origin and the abscissa t T of which is 4 H.
  • the profile in FIG. 2 is of sigmoidal shape. It is clearly distinguished from the dissolution profile obtained with the coated microparticles alone (FIG. 2 a ) as obtained according to the methodology described in point 1.2 above of example 1.
  • FIGS. 2 and 2 a show that the pharmaceutical dosage form according to the invention retains mechanical integrity (weight ⁇ dimension ⁇ cohesion) for a relatively long time (at least 4 H).
  • the concavity of the first part of the curve (0-4 H) is directed upward.
  • gelatin capsules tested have the composition described in example 2 and are prepared according to the process described example 1.
  • metformin 1 000 mg of metformin, distributed in 7 gelatin capsules with a size of 00 each comprising 561 mg of the pharmaceutical form according to the present invention, were administered to 6 healthy subjects after taking a meal.
  • the plasma concentration of metformin is recorded as a function of the time between 0 and 36 hours after administration.
  • the metformin granules represent a fraction by weight of 25.5%, the coating of the granules a fraction by weight of 8.9% and, finally, the continuous external phase a fraction by weight of 65.6%.
  • compositions are as follows: For the metformin granule: Metformin 100% 142.9 mg For the coating: Ethocel 7 74% 37.1 mg Magnesium stearate 10% 5 mg Plasdone K 29/32 8% 4 mg Castor oil 8% 4 mg For the continuous phase: Keltone HVCR 77.6% 285.6 mg Methocel K 100M 20.0% 73.6 mg Calcium acetate 2.4% 8.8 mg
  • the mean plasma concentration profile with regard to 6 healthy subjects is represented in FIG. 3.
  • the mean plasma concentration profile resulting from the administration to 24 healthy subjects, after a meal, of a single dose of 850 mg of the immediate release form of metformin, Glucophage® is also displayed.
  • the pharmaceutical form according to the invention spectacularly increases the bioabsorption time, also increases the Tmax and maintains the AUC at more than 50% of the value corresponding to an immediate release oral form.

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US10/332,463 2000-07-11 2001-07-10 Oral pharmaceutical composition with controlled release and prolonged absorption Abandoned US20040022849A1 (en)

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Applications Claiming Priority (3)

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FR0009047 2000-07-11
FR0009047A FR2811571B1 (fr) 2000-07-11 2000-07-11 Composition pharmaceutique orale, permettant la liberation controlee et l'absorption prolongee d'un principe actif
PCT/FR2001/002224 WO2002003964A1 (fr) 2000-07-11 2001-07-10 Composition pharmaceutique orale a liberation controlee et a absorption prolongee

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EP (1) EP1299090B1 (de)
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AU (1) AU2001277570A1 (de)
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Cited By (18)

* Cited by examiner, † Cited by third party
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US20030224056A1 (en) * 2002-05-31 2003-12-04 Sanjay Kotha Hemostatic composition
US20040096501A1 (en) * 2002-08-05 2004-05-20 Navin Vaya Novel drug delivery system
US20040105980A1 (en) * 2002-11-25 2004-06-03 Sudarshan Tirumalai S. Multifunctional particulate material, fluid, and composition
US20040234601A1 (en) * 2001-10-09 2004-11-25 Valerie Legrand Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
US20050037077A1 (en) * 2001-10-09 2005-02-17 Valerie Legrand Galenic microparticulate oral formulation for delayed and controlled release of pharmaceutical active principles
US20060018934A1 (en) * 2002-08-05 2006-01-26 Navin Vaya Novel drug delivery system
US20060110463A1 (en) * 2002-04-09 2006-05-25 Catherine Castan Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin
WO2006084547A1 (de) * 2005-02-11 2006-08-17 Merck Patent Gmbh Biguanid enthaltende zusammensetzungen
US20070207191A1 (en) * 2006-01-10 2007-09-06 Kanzer Steve H Pharmaceutical compositions and methods to achieve and maintain a targeted and stable copper status and prevent and treat copper-related central nervous system diseases
US20070224129A1 (en) * 2005-11-10 2007-09-27 Flamel Technologies, Inc. Anti-misuse microparticulate oral pharmaceutical form
US20070264326A1 (en) * 2005-05-24 2007-11-15 Flamel Technologies Anti-misuse oral microparticle medicinal formulation
US20080008659A1 (en) * 2005-06-13 2008-01-10 Flamel Technologies Oral dosage form comprising an antimisuse system
US20080063725A1 (en) * 2006-05-24 2008-03-13 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
US7448389B1 (en) 2003-10-10 2008-11-11 Materials Modification, Inc. Method and kit for inducing hypoxia in tumors through the use of a magnetic fluid
US7811604B1 (en) 2005-11-14 2010-10-12 Barr Laboratories, Inc. Non-effervescent, orally disintegrating solid pharmaceutical dosage forms comprising clozapine and methods of making and using the same
US7906145B2 (en) 2002-04-09 2011-03-15 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US8911781B2 (en) 2002-06-17 2014-12-16 Inventia Healthcare Private Limited Process of manufacture of novel drug delivery system: multilayer tablet composition of thiazolidinedione and biguanides
US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

Families Citing this family (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2816840B1 (fr) * 2000-11-17 2004-04-09 Flamel Tech Sa Medicament a base de microcapsules d'anti-hyperclycemiant a liberation prolongee et son procede de preparation
JP3834215B2 (ja) 2001-09-07 2006-10-18 アグリテクノ矢崎株式会社 ゲル被覆種子
US7985422B2 (en) 2002-08-05 2011-07-26 Torrent Pharmaceuticals Limited Dosage form
US20040265372A1 (en) * 2003-06-27 2004-12-30 David Wynn Soft tablet containing high molecular weight cellulosics
WO2005065639A2 (en) * 2003-11-21 2005-07-21 Torrent Pharmaceuticals Limited Novel pharmaceutical compositions
MXPA06011871A (es) * 2004-04-15 2007-10-08 Chiasma Inc Composiciones capaces de facilitar la penetracion a traves de una barrera biologica.
US20070219131A1 (en) * 2004-04-15 2007-09-20 Ben-Sasson Shmuel A Compositions capable of facilitating penetration across a biological barrier
FR2891459B1 (fr) * 2005-09-30 2007-12-28 Flamel Technologies Sa Microparticules a liberation modifiee d'au moins un principe actif et forme galenique orale en comprenant
FR2892937B1 (fr) * 2005-11-10 2013-04-05 Flamel Tech Sa Forme pharmaceutique orale microparticulaire anti-mesusage
US20070264346A1 (en) * 2006-02-16 2007-11-15 Flamel Technologies Multimicroparticulate pharmaceutical forms for oral administration
JP4741991B2 (ja) 2006-07-14 2011-08-10 株式会社日立製作所 シリアアライザ／デシリアライザ方式の転送装置
GB2482810A (en) 2008-09-17 2012-02-15 Chiasma Inc Enhanced delivery of exenatide using a medium chain fatty acid and salt thereof
JP2013515783A (ja) * 2009-12-29 2013-05-09 インパックス ラボラトリーズ，インコーポレーテッド 膨潤性親水性ポリマーを用いた胃滞留型固体経口投与剤形
EP2568989B1 (de) 2010-05-12 2021-03-24 Spectrum Pharmaceuticals, Inc. Lanthan-carbonat-hydroxid, lanthan-oxycarbonat und verfahren zu deren herstellung und verwendung
BR112015000320B1 (pt) 2012-07-12 2023-03-07 SpecGx LLC Composições farmacêuticas dissuasivas de abuso e seu processo de preparação
US9132096B1 (en) 2014-09-12 2015-09-15 Alkermes Pharma Ireland Limited Abuse resistant pharmaceutical compositions
EP4527456A3 (de) 2015-02-03 2025-05-21 Amryt Endo, Inc. Verfahren zur behandlung von krankheiten
US12186296B1 (en) 2016-07-22 2025-01-07 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11504347B1 (en) 2016-07-22 2022-11-22 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11986451B1 (en) 2016-07-22 2024-05-21 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US11602512B1 (en) 2016-07-22 2023-03-14 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
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EP3930702A1 (de) 2019-03-01 2022-01-05 Flamel Ireland Limited Gamma-hydroxybutyratzusammensetzungen mit verbesserter pharmakokinetik im zugeführten zustand
CN110354090B (zh) * 2019-07-29 2021-10-01 石药集团欧意药业有限公司 一种盐酸二甲双胍缓释片及其制备方法
CN111202718A (zh) * 2020-02-25 2020-05-29 北京鑫开元医药科技有限公司 一种盐酸雷尼替丁胶囊及其制备方法
US11141457B1 (en) 2020-12-28 2021-10-12 Amryt Endo, Inc. Oral octreotide therapy and contraceptive methods
US11583510B1 (en) 2022-02-07 2023-02-21 Flamel Ireland Limited Methods of administering gamma hydroxybutyrate formulations after a high-fat meal
US11779557B1 (en) 2022-02-07 2023-10-10 Flamel Ireland Limited Modified release gamma-hydroxybutyrate formulations having improved pharmacokinetics
US12303604B1 (en) 2024-10-16 2025-05-20 Currax Pharmaceuticals Llc Pharmaceutical formulations comprising naltrexone and/or bupropion

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5945123A (en) * 1998-04-02 1999-08-31 K-V Pharmaceutical Company Maximizing effectiveness of substances used to improve health and well being
US6068859A (en) * 1994-05-06 2000-05-30 Pfizer Inc. Controlled-release dosage forms of Azithromycin

Family Cites Families (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS6248618A (ja) * 1985-08-27 1987-03-03 Zeria Shinyaku Kogyo Kk 徐放性製剤およびその製造法
US5268182A (en) * 1988-06-24 1993-12-07 Abbott Laboratories Sustained-release drug dosage units of terazosin
CA2007181C (en) 1989-01-06 1998-11-24 Angelo Mario Morella Sustained release pharmaceutical composition
IT1250421B (it) 1991-05-30 1995-04-07 Recordati Chem Pharm Composizione farmaceutica a rilascio controllato con proprieta' bio-adesive.
FR2704146B1 (fr) 1993-04-19 1995-07-13 Cripdom Microcapsules d'acide acétylsalicylique à libération contrôlée.
DE4432757A1 (de) 1994-09-14 1996-03-21 Boehringer Mannheim Gmbh Pharmazeutische Zubereitung enthaltend Metformin und Verfahren zu deren Herstellung
FR2725623A1 (fr) * 1994-10-18 1996-04-19 Flamel Tech Sa Microcapsules medicamenteuses et/ou nutritionnelles pour administration per os
US5858398A (en) 1994-11-03 1999-01-12 Isomed Inc. Microparticular pharmaceutical compositions
NZ506202A (en) * 1998-03-19 2003-10-31 Bristol Myers Squibb Co Biphasic controlled release delivery system for high solubility pharmaceuticals and method
US6099859A (en) 1998-03-20 2000-08-08 Andrx Pharmaceuticals, Inc. Controlled release oral tablet having a unitary core
US6499158B1 (en) 2000-10-30 2002-12-31 Steris, Inc. Surgical table top and accessory clamp used thereon

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6068859A (en) * 1994-05-06 2000-05-30 Pfizer Inc. Controlled-release dosage forms of Azithromycin
US5945123A (en) * 1998-04-02 1999-08-31 K-V Pharmaceutical Company Maximizing effectiveness of substances used to improve health and well being

Cited By (32)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20040234601A1 (en) * 2001-10-09 2004-11-25 Valerie Legrand Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
US20050037077A1 (en) * 2001-10-09 2005-02-17 Valerie Legrand Galenic microparticulate oral formulation for delayed and controlled release of pharmaceutical active principles
US8101209B2 (en) 2001-10-09 2012-01-24 Flamel Technologies Microparticulate oral galenical form for the delayed and controlled release of pharmaceutical active principles
US7910133B2 (en) 2002-04-09 2011-03-22 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin
US7906145B2 (en) 2002-04-09 2011-03-15 Flamel Technologies Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US20060110463A1 (en) * 2002-04-09 2006-05-25 Catherine Castan Oral pharmaceutical formulation in the form of aqueous suspension of microcapsules for modified release of amoxicillin
US10004693B2 (en) 2002-04-09 2018-06-26 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US9814684B2 (en) 2002-04-09 2017-11-14 Flamel Ireland Limited Oral pharmaceutical formulation in the form of aqueous suspension for modified release of active principle(s)
US7670623B2 (en) 2002-05-31 2010-03-02 Materials Modification, Inc. Hemostatic composition
US20030224056A1 (en) * 2002-05-31 2003-12-04 Sanjay Kotha Hemostatic composition
US8911781B2 (en) 2002-06-17 2014-12-16 Inventia Healthcare Private Limited Process of manufacture of novel drug delivery system: multilayer tablet composition of thiazolidinedione and biguanides
US20060018933A1 (en) * 2002-08-05 2006-01-26 Navin Vaya Novel drug delivery system
US8268352B2 (en) 2002-08-05 2012-09-18 Torrent Pharmaceuticals Limited Modified release composition for highly soluble drugs
US8216609B2 (en) 2002-08-05 2012-07-10 Torrent Pharmaceuticals Limited Modified release composition of highly soluble drugs
US20060018934A1 (en) * 2002-08-05 2006-01-26 Navin Vaya Novel drug delivery system
US7976871B2 (en) 2002-08-05 2011-07-12 Torrent Pharmaceuticals Limited Modified release composition of highly soluble drugs
US20040096501A1 (en) * 2002-08-05 2004-05-20 Navin Vaya Novel drug delivery system
US7560160B2 (en) * 2002-11-25 2009-07-14 Materials Modification, Inc. Multifunctional particulate material, fluid, and composition
US20040105980A1 (en) * 2002-11-25 2004-06-03 Sudarshan Tirumalai S. Multifunctional particulate material, fluid, and composition
US7448389B1 (en) 2003-10-10 2008-11-11 Materials Modification, Inc. Method and kit for inducing hypoxia in tumors through the use of a magnetic fluid
WO2006084547A1 (de) * 2005-02-11 2006-08-17 Merck Patent Gmbh Biguanid enthaltende zusammensetzungen
US20070264326A1 (en) * 2005-05-24 2007-11-15 Flamel Technologies Anti-misuse oral microparticle medicinal formulation
US20080008659A1 (en) * 2005-06-13 2008-01-10 Flamel Technologies Oral dosage form comprising an antimisuse system
US8895063B2 (en) 2005-06-13 2014-11-25 Flamel Technologies Oral dosage form comprising an antimisuse system
US8445023B2 (en) 2005-11-10 2013-05-21 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
US8652529B2 (en) 2005-11-10 2014-02-18 Flamel Technologies Anti-misuse microparticulate oral pharmaceutical form
US20070224129A1 (en) * 2005-11-10 2007-09-27 Flamel Technologies, Inc. Anti-misuse microparticulate oral pharmaceutical form
US7811604B1 (en) 2005-11-14 2010-10-12 Barr Laboratories, Inc. Non-effervescent, orally disintegrating solid pharmaceutical dosage forms comprising clozapine and methods of making and using the same
US20070207191A1 (en) * 2006-01-10 2007-09-06 Kanzer Steve H Pharmaceutical compositions and methods to achieve and maintain a targeted and stable copper status and prevent and treat copper-related central nervous system diseases
US20080063725A1 (en) * 2006-05-24 2008-03-13 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
US9023400B2 (en) * 2006-05-24 2015-05-05 Flamel Technologies Prolonged-release multimicroparticulate oral pharmaceutical form
US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

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US7879362B2 (en) 2011-02-01
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CA2415378C (fr) 2010-03-16
WO2002003964A1 (fr) 2002-01-17
EP1299090A1 (de) 2003-04-09
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AU2001277570A1 (en) 2002-01-21
ATE319431T1 (de) 2006-03-15
DE60117801D1 (de) 2006-05-04
US20070207214A1 (en) 2007-09-06
FR2811571A1 (fr) 2002-01-18
ZA200209525B (en) 2003-11-24
IL153086A0 (en) 2003-06-24
CA2415378A1 (fr) 2002-01-17
EP1299090B1 (de) 2006-03-08
JP2004502723A (ja) 2004-01-29
BR0112532A (pt) 2003-07-29

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