EP1524969A2 - Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung - Google Patents

Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung

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Publication number
EP1524969A2
EP1524969A2 EP03750853A EP03750853A EP1524969A2 EP 1524969 A2 EP1524969 A2 EP 1524969A2 EP 03750853 A EP03750853 A EP 03750853A EP 03750853 A EP03750853 A EP 03750853A EP 1524969 A2 EP1524969 A2 EP 1524969A2
Authority
EP
European Patent Office
Prior art keywords
coating
microcapsules
dry weight
total mass
following
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
EP03750853A
Other languages
English (en)
French (fr)
Inventor
Florence Guimberteau
Catherine Castan
Rémi Meyrueix
Gérard Soula
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Flamel Technologies SA
Original Assignee
Flamel Technologies SA
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Flamel Technologies SA filed Critical Flamel Technologies SA
Priority to EP10184459.5A priority Critical patent/EP2272506A3/de
Publication of EP1524969A2 publication Critical patent/EP1524969A2/de
Ceased legal-status Critical Current

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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
    • 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
    • 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

Definitions

  • the field of the present invention is that of systems for the modified release of medicinal and / or nutritional active principles (PA), intended for administration by the oral route.
  • PA nutritional active principles
  • the present invention thus relates to microcapsules for the administration / er ⁇ bone and containing at least one AP with low solubility.
  • the invention also relates to the drugs containing these microcapsules mentioned above and the use of the latter for the manufacture of drugs.
  • modified éer ⁇ tton indifferently designates a release of the active principle (s) starting as soon as the dosage form is brought into contact with its dissolution medium (in vivo or in in vitro) or even a release of the active principle (s) starting only after a predetermined duration ranging for example from 0.5 to several hours.
  • an extension of the release corresponds to a release time of 50% of the active principle (s) which is typically several hours and which can range from 0.25 to 20 hours, for example.
  • low solubility refers to active ingredients whose solubility in water is less than 10 g / 1 at 25 ° C.
  • the invention relates to pharmaceutical formulations for sustained release of active principles of low solubility, this formulation consisting of a plurality of microcapsules consisting of a core containing the active principle of low solubility and coated with a layer of polymer. who controls the release of the active principles of low solubility
  • the galenical modified-release systems consisting of a plurality of reservoir-type microcapsules with an average diameter of less than 1000 microns are particularly advantageous.
  • the dose of active principle (s) to be administered is distributed between a large number of microcapsules (typically 10,000 for a dose of 500 mg and a diameter of 400 microns) and this type of system presents , therefore, the following intrinsic advantages: •
  • the use of a mixture of microcapsules with different modified release profiles, makes it possible to produce release profiles having several release waves or ensuring by an adequate adjustment of the different fractions, a constant PA concentration level; • the sensitivity to the variability of gastric emptying is less, because emptying, which takes place here on a large number of particles is statistically more reproducible;
  • the residence time of the microcapsules in the upper parts of the tract can be extended, which ensures an increase in the duration of passage of the active principle (s) in front of the absorption windows and thus maximizes the bioavailability of the active ingredient (s).
  • the active principle is diffused through the coating film surrounding each microcapsule under the action of the concentration gradient in PA dissolved between the inside and the outside of the microcapsule. In other words, it is the difference in osmotic pressure of the AP between the inside and the outside of the microcapsule which is the engine of the release.
  • the internal PA concentration is the saturation concentration.
  • the external concentration of PA is negligible, under usual conditions (called "sink").
  • the engine of release is therefore directly linked to the saturation concentration of PA, that is to say its solubility.
  • the concentration at saturation in PA is low and the diffusion of PA towards the outside is therefore a priori very slow, even for thin coating films.
  • galenical, solid, multimicrocapsular systems those known are constituted by a multiplicity of particles or microcapsules each carrying the active principle (s) coated with a coating layer based on ethylcellulose, polyvinylpyrrolidone, magnesium stearate and castor oil, for example.
  • a galenical system is disclosed in PCT application WO-96/11675.
  • These reservoir microcapsules derive an advantage from their multiplicity, which is a more regular and reproducible gastric emptying time.
  • the multimicrocapsular galenic system according to WO-96/11675 can be improved with regard to poorly soluble PAs which can be administered orally, since it does not offer a solution to the problem of the diffusion of such a poorly soluble PA through a film of coating of a sufficiently large thickness, for example of several microns.
  • PCT patent application WO-00/18374 describes an invention of the same nature as the previous one: the active principle in the form of submicron particles ( ⁇ 1000 nm) is stabilized by a compound associated with the surface of the particles and mixed with a polymer. This mixture can then be put in the form of granules or pellets and possibly a tablet.
  • the active principle is quickly dissolved and it is the increase in bioavailability obtained thanks to the reduction in size which makes it possible to have an effective plasma concentration over a prolonged period.
  • Patent application GB-2 202 143 describes spheroids with a diameter greater than 0.5 mm and preferably greater than 0.8 mm, containing the poorly soluble active principle dispersed in 70 to 99.5% of microcrystalline cellulose. This matrix form does not require any coating controlling the release of the active ingredient.
  • Patent application JP-8073345 describes a controlled release system composed of a film granule.
  • the granule contains an active ingredient sparingly soluble at neutral pH and inorganic acids. This system therefore offers a solution suitable only for the case of poorly soluble basic active ingredients.
  • European patent EP-B-0 249 587 relates to a solid preparation allowing the slow release of an active substance, sparingly soluble ( ⁇ 0.1% by weight).
  • This controlled release preparation can be in the form of capsules comprising capsules consisting of coated granules.
  • the granules comprise the poorly soluble active principle and a solubilizer consisting of the commercial product Cremophor® RH 40 (polyoxyethylene hydrogenated castor oil: 40 ethylene oxide units), as well as other additives such as polyvinylpyrrolidone, cellulose, l starch and lactose.
  • Cremophor® RH 40 polyoxyethylene hydrogenated castor oil: 40 ethylene oxide units
  • other additives such as polyvinylpyrrolidone, cellulose, l starch and lactose.
  • the ingredients of the granules which are polyvinylpyrrolidone, cellulose, corn starch and lactose, seem to be the elements of the hydrophilic gel system specific to the galenic form according to EP-B-0 249 587.
  • These capsules therefore comprise a single constituent (ethylcellulose) in their coating layer, which limits its ability to modify the release of the active ingredient.
  • a coating layer composed solely of ethylcellulose (known to form impermeable films), will allow the release of a poorly soluble PA, in a controlled and industrially reproducible manner, over a period of a few hours , for example.
  • one of the essential objectives of the present invention is to provide a modified release form of poorly soluble AP (s) consisting of a plurality of microcapsules, each formed by a heart containing the AP and coated with a coating film.
  • Another object of the present invention is to provide a plurality of microcapsules of the AP reservoir type of low solubility, for oral administration of the latter (or these), the coating film of these microcapsules having a sufficient thickness for ensure controlled and industrially reproducible permeability.
  • Another essential objective of the present invention is to provide a plurality of microcapsules of poorly soluble AP (s), of size less than 1000 ⁇ m.
  • Another objective of the present invention is to provide an oral dosage form consisting of a large number (for example of the order of several thousand) of microcapsules, this multiplicity ensuring statistically good reproducibility of the transit kinetics of the PA throughout the gastrointestinal tract, so that it results in better control of bioavailability and therefore better efficiency.
  • Another essential objective of the present invention is to provide a plurality of microcapsules of poorly soluble AP (s), for oral administration of the latter (or these) according to a prolonged and / or possibly delayed release profile, so that the half-release time ⁇ ⁇ a is between 0.25 and 20 hours.
  • Another essential object of the present invention is to provide a modified release oral form in which the AP (s) is (are) in the form of a plurality of particles individually coated to form microcapsules and in which it is it is possible to mix several active ingredients in multimicrocapsular form, released according to different respective release times.
  • the subject of the present invention is a galenical system formed by microcapsules allowing the modified release of at least one PA poorly soluble in water, with the exclusion or not of anti-hyperglycemic agents, intended to be administered orally and of the type:
  • ⁇ - -I-- at least one film-forming polymer (PI) insoluble in liquids of the gastrointestinal tract;
  • TA lubricating surfactant
  • PI film-forming polymer insoluble in the fluids of the tract, present in an amount of 50 to 90, preferably 50 to 80% by dry weight relative to the total mass of the coating composition and consisting of at least one non-water-soluble derivative of cellulose, namely ethylcellulose and / or cellulose acetate;
  • N-vinyl-lactam namely polyacrylamide and / or polyvinylpyrrolidone
  • plasticizer present in an amount of 2 to 20, preferably from 4 to 15% by dry weight relative to the total mass of the coating composition and consisting of at least one of the following compounds: esters of glycerol, phthalates, citrates, sebacates, esters of cetyl alcohol, castor oil, salicylic acid and cutin;
  • surfactant and / or lubricant present in an amount of 2 to 20, preferably from 4 to 15% by dry weight relative to the total mass of the coating composition and chosen from anionic surfactants , namely the alkaline or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred, and / or among nonionic surfactants, namely polyoxyethylenated sorbitan esters and / or castor oil derivatives polyoxyethylenated, and / or among lubricating agents such as calcium, magnesium, aluminum or zinc stearates, or such as sodium stearyl fumarate and / or glycerol behenate; said agent possibly comprising a single or a mixture of the above products;
  • anionic surfactants namely the alkaline or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred
  • nonionic surfactants namely polyoxyethylenated sorbit
  • the coating film represents 3 to 40% w / w on dry weight of the total mass of the microcapsules.
  • PI is selected from the following group of products:
  • non-water-soluble cellulose derivatives preferably ethylcellulose and / or cellulose acetate, • acrylic derivatives,
  • P2 is selected from the following group of products: • water-soluble cellulose derivatives,
  • PNP Polyvinylpyrrolidones
  • PL is selected from the following group of products: • glycerol and its esters, preferably from the following subgroup: acetylated glycerides, glycerolmono-stearate, glyceryltriacetate, glyceroltributyrate, phthalates, preferably in the following subgroup: dibutylphthalate, dietliylphfhalate, dimethylphfhalate, dioctylphthalate, citrates, preferably in the following subgroup: acetyltributylcitrate, acetyltriethylcitrate, tributyl citrate, triethyl citrate, triethyl citrate, triethyl citrate following: diethylsébaçate, dibutylsébaçate, adipates, azelates, benzoates, vegetable oils, fumarates preferably diethylfumarate, malates, preferably
  • the coating film comprises component TA at a rate of 2 and 20% and preferably between 4 and 15% of the total mass of the dry coating.
  • TA is selected from the following group of products:
  • Anionic surfactants preferably in the subgroup of alkali or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred,
  • o polyoxyethylenated oils preferably polyoxyethylenated hydrogenated castor oil, o polyoxyethylene-polyoxypropylene copolymers, o polyoxyethylene sorbitan esters, o polyoxyethylenated castor oil derivatives, o stearates, preferably calcium, magnesium, aluminum or zinc, o stearyl fumarates, preferably sodium, o glycerol behenate, o and mixtures thereof.
  • the microcapsules are designed so as to be able to remain in the upper parts of the gastrointestinal tract for at least approximately 5 hours, preferably at least approximately 8 hours, and thus allow absorption of the AP for a prolonged period.
  • the coating film comprises from 35 to 75% of ethylcellulose PI, from 20 to 50% of polyvinylpyrrolidone P2 , from 5 to 15% of PL.
  • This preparation according to the invention makes it possible to produce a multimicrocapsular form with modified release of sparingly soluble PAs, the half-time of release of the PA being able to be adjusted between 0.25 and 20 hours in a reproducible manner by using a film coating which can be described as sufficiently thick diffusion coating film.
  • such a plurality of microcapsules typically 10,000 for a dose of 500 mg and an average diameter of 400 microns
  • each microcapsule indeed contains only a very reduced dose of AP. This eliminates the risk of tissue damage by local over-concentration of aggressive PA. • The residence time of the microcapsules in the upper parts of the tract can be extended, which ensures an increase in the duration of passage of the AP in front of the absorption windows and thus maximizes the bioavailability of the AP.
  • the sparingly soluble PAs used for the preparation of the modified-release, preferably controlled-release microcapsules according to the invention can be chosen from at least one of the following large varieties of active substances: antiulcer, antidiabetics, anticoagulants, antithrombics, lipid-lowering agents , antiarrhythmics, vasodilators, antiangina, antihypertensives, vasoprotectors, fertility promoters, inducers and inhibitors of uterine labor, contraceptives, antibiotics, antifungals, antivirals, anticancer drugs, anti-inflammatories, analgesics, anti-epileptics, antiparkinsonians, neuroleptics, hypnotics, hypnotics psychostimulants, anti-migraine, antidepressants, cough suppressants, antihista-minic or antiallergic.
  • the PA (s) is (are) chosen from the following compounds: prazosine, acyclovir, nifedipine, naproxen, ibuprofen, ketoprofen, fenoprofen, indomethacin, diclofenac, sulpiride, terfenadine, carbamazepine, fluoxetine, alprazolam ganciclovir, spironolactone, acetylsalycilic acid, quinidine, morphine, amoxicillin, paracetamol, metoclopramide, verapamil and their mixtures.
  • the AP consists of at least one nutritional and / or dietary supplement, preferably chosen from vitamins, amino acids, trace elements, antioxidants and their mixtures.
  • microencapsulation techniques accessible to those skilled in the art, the main ones of which are summarized in the article by C. DUNERNEY and JP BENOIT in "Chemical News ", December 1986. More specifically, the technique considered is microencapsulation by film coating, leading to individualized" reservoir “systems as opposed to matrix systems. For more details, reference is made to patent EP-B-0 953 359.
  • the particles of PA of desired particle size and necessary for the production of the microcapsules according to the invention can be crystals of pure PA and / or having undergone a pretreatment by one of the conventional techniques in the matter, such as for example granulation, in presence of at least one conventional binding agent and / or of an agent modifying the intrinsic solubility characteristics of the AP.
  • the present invention also relates to a medicament comprising the microcapsules as defined above.
  • This medicine can be in solid form: tablet, capsule, powder, etc. or in liquid form, for example aqueous suspension.
  • Their average diameter is less than 1000 microns, preferably between 800 and 50 microns and more preferably still between 600 and 100 microns,
  • their coating film contains the following components: -> -I-- at least one film-forming polymer (PI) insoluble in liquids of the gastrointestinal tract; - »-II— at least one water-soluble polymer (P2); - »-III- at least one plasticizer (PL);
  • PI film-forming polymer
  • P2 water-soluble polymer
  • PL plasticizer
  • TA lubricating surfactant
  • coating films constituted by enteric compositions and coating films of the following composition: 1 - at least one film-forming polymer (PI) insoluble in the fluids of the tract, present in an amount of 50 to 90, preferably 50 to 80% by dry weight relative to the total mass of the coating composition and consisting of at least one non-water-soluble derivative of cellulose, namely ethylcellulose and / or cellulose acetate;
  • PI film-forming polymer
  • plasticizer present in an amount of 2 to 20, preferably from 4 to 15% by dry weight relative to the total mass of the coating composition and consisting of at least one of the following compounds: esters of glycerol, phthalates, citrates, sebacates, esters of cetyl alcohol, castor oil, salicylic acid and cutin;
  • surfactant and / or lubricant present in an amount of 2 to 20, preferably from 4 to 15% by weight on a dry basis relative to the total mass of the coating composition and chosen from anionic surfactants , namely the alkaline or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred, and / or among nonionic surfactants, namely polyoxyethylenated sorbitan esters and / or castor oil derivatives polyoxyethylenated, and / or among lubricating agents such as calcium, magnesium, aluminum or zinc stearates, or such as sodium stearyl fumarate and / or glycerol behenate; said agent possibly comprising a single or a mixture of the above products;
  • anionic surfactants namely the alkaline or alkaline earth salts of fatty acids, stearic and / or oleic acid being preferred
  • nonionic surfactants namely polyoxyethylen
  • a medicament based on at least one sparingly soluble AP which can be administered orally, is easily swallowed and which is released in vivo in a controlled, prolonged and possibly delayed manner.
  • the present invention relates to a method of therapeutic treatment, in which a medicament as defined above is used as a product per se or as a product obtained by the process described above .
  • FIG. 1 shows the curve of the percentage of dissolution (% D) of the active ingredient PA, as a function of time (t) in hours (H), of the microcapsules of example 1, in the dissolution test described in the examples that follow.
  • FIG. 2 shows the curve of the percentage of dissolution (% D) of the active ingredient PA, as a function of time (t) in hours (H), of the microcapsules of Example 2, in the dissolution test described in the examples that follow.
  • Step 1 Granulated 970 g of Acyclovir and 30 g of Povidone (Plasdone® K29 / 32) are dry mixed beforehand in the tank of a high shear granulator (Lodige® M5MRK) for 5 minutes. This powder mixture is then granulated with water (200 g). The granules are dried at 40 ° C in a ventilated oven, then calibrated on a 500 ⁇ m grid. The fraction 200-500 ⁇ m is selected by sieving.
  • Step 2 Coating 700 g of granules obtained above are coated in a GLATT® GPCGl fluidized air bed apparatus with 50.65 g of ethylcellulose (Ethocel® 7 Premium), 50.65 g of povidone (Plasdone® K29 / 32), 12.35 g of magnesium stearate and 9.88 g of castor oil dissolved in an acetone / isopropanol mixture (60/40 m / m) ,.
  • composition of microcapsules is composition of microcapsules:
  • the release kinetics of Acyclovir are determined by a dissolution test (Type II device according to the European Pharmacopoeia 3rd edition, phosphate buffer medium pH 6.8, volume 900 ml, temperature 37 ° C, paddle shaking 100 rpm, detection UV 268 nm).
  • Figure 1 attached shows the dissolution profile obtained by these microcapsules.
  • composition of the microcapsules described above makes it possible to obtain a dissolution profile characterized by 80% of Acyclovir released at 3 hours.
  • Step 1 Granulated 970 g of amoxicillin trihydrate and 30 g of Povidone (Plasdone® K29 / 32)) are dry mixed beforehand in the tank of a high shear granulator (Lodige® M5MRK) for 5 minutes. This powder mixture is then granulated with water (200 g). The granules are dried at 40 ° C in a ventilated oven, then calibrated on a 500 ⁇ m grid. The fraction 200-500 ⁇ m is selected by sieving.
  • the kinetics of arnoxicillm release are determined by a dissolution test (Type II device according to the European Pharmacopoeia 3rd edition, phosphate buffer medium pH 6.8, volume 900 ml, temperature 37 ° C, paddle stirring 100 rpm, detection UN 240 nm).
  • Figure 2 attached shows the dissolution profile obtained for these microcapsules.
  • composition of the microcapsules described above makes it possible to obtain a dissolution profile characterized by 80% of amoxicillin released at 4 hours.

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  • Health & Medical Sciences (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Engineering & Computer Science (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
EP03750853A 2002-07-26 2003-07-28 Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung Ceased EP1524969A2 (de)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10184459.5A EP2272506A3 (de) 2002-07-26 2003-07-28 Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR0209530 2002-07-26
FR0209530A FR2842735B1 (fr) 2002-07-26 2002-07-26 Microcapsules a liberation modifiee de principes actifs peu solubles pour l'administration per os
PCT/FR2003/002384 WO2004010984A2 (fr) 2002-07-26 2003-07-28 Microcapsules a liberation modifiee de principes actifs peu solubles pour administration per os

Publications (1)

Publication Number Publication Date
EP1524969A2 true EP1524969A2 (de) 2005-04-27

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EP10184459.5A Withdrawn EP2272506A3 (de) 2002-07-26 2003-07-28 Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung
EP03750853A Ceased EP1524969A2 (de) 2002-07-26 2003-07-28 Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung

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EP10184459.5A Withdrawn EP2272506A3 (de) 2002-07-26 2003-07-28 Mikrokapseln mit gesteuerter verabreichung von schwerlöslichen wirkstoffen zur oralen anwendung

Country Status (13)

Country Link
US (2) US20060275376A1 (de)
EP (2) EP2272506A3 (de)
JP (1) JP2005535680A (de)
KR (1) KR20050026518A (de)
CN (1) CN1681483B (de)
AU (1) AU2003269068B2 (de)
BR (1) BR0312988A (de)
CA (1) CA2493464C (de)
FR (1) FR2842735B1 (de)
IL (1) IL166431A0 (de)
MX (1) MXPA05001076A (de)
WO (1) WO2004010984A2 (de)
ZA (1) ZA200500734B (de)

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WO2010136740A1 (fr) 2009-05-29 2010-12-02 Flamel Technologies Procede de preparation de particules creuses et leurs applications

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FR2885526B1 (fr) * 2005-05-13 2007-07-27 Flamel Technologies Sa Medicament oral a base d'inhibiteur de pompe a protons
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WO2004010984A2 (fr) 2004-02-05
CA2493464C (fr) 2012-07-03
WO2004010984A3 (fr) 2004-04-08
EP2272506A3 (de) 2013-07-10
EP2272506A2 (de) 2011-01-12
AU2003269068A1 (en) 2004-02-16
US20070160678A1 (en) 2007-07-12
AU2003269068B2 (en) 2009-01-22
IL166431A0 (en) 2006-01-15
BR0312988A (pt) 2005-06-21
US20060275376A1 (en) 2006-12-07
ZA200500734B (en) 2006-03-29
FR2842735B1 (fr) 2006-01-06
KR20050026518A (ko) 2005-03-15
CN1681483A (zh) 2005-10-12
FR2842735A1 (fr) 2004-01-30
CA2493464A1 (fr) 2004-02-05
JP2005535680A (ja) 2005-11-24
CN1681483B (zh) 2011-12-28
US8821935B2 (en) 2014-09-02
MXPA05001076A (es) 2005-06-06

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