WO1998031360A1 - Composition pharmaceutique presentant une biodisponibilite elevee et son procede de preparation - Google Patents

Composition pharmaceutique presentant une biodisponibilite elevee et son procede de preparation Download PDF

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Publication number
WO1998031360A1
WO1998031360A1 PCT/IB1998/000066 IB9800066W WO9831360A1 WO 1998031360 A1 WO1998031360 A1 WO 1998031360A1 IB 9800066 W IB9800066 W IB 9800066W WO 9831360 A1 WO9831360 A1 WO 9831360A1
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WIPO (PCT)
Prior art keywords
weight
active ingredient
composition according
surfactant
fenofibrate
Prior art date
Application number
PCT/IB1998/000066
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English (en)
Inventor
André Stamm
Pawan Seth
Original Assignee
Pharma Pass
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.)
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Publication date
Application filed by Pharma Pass filed Critical Pharma Pass
Priority to AU53368/98A priority Critical patent/AU5336898A/en
Publication of WO1998031360A1 publication Critical patent/WO1998031360A1/fr

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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
    • A61K9/20—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
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug

Definitions

  • the present invention relates to a novel pharmaceutical composition having high bioavailability through improved dissolution, and a method for preparing it.
  • the invention more particularly relates to a pharmaceutical composition for administration by oral route, containing an active ingredient of poor aqueous solubility.
  • Fenofibrate is a well-known hypolipemiant from the family of fibrates, which is commercially available in various doses (100 and 300 mg for example Secalip®) but in a form leading to poor bioavailability of the active ingredient. Indeed, due to it poor hydrosolubility, fenofibrate is poorly absorbed in the digestive tract and consequently its bioavailability is incomplete, irregular and often varies from one person to another.
  • EP-A-0330532 discloses a method for improving bioavailability of fenofibrate. This patent describes the effect of co-micronizing fenofibrate with a surfactant, for example sodium laurylsulfate in order to improve fenofibrate solubility and thereby increase its bioavailability.
  • a surfactant for example sodium laurylsulfate
  • This patent teaches that co-micronizing fenofibrate with a solid surfactant improves fenofibrate bioavailability to a much greater extent than the improvement that would be obtained either by adding a surfactant, or through solely micronizing the fenofibrate, or, yet again, through intimately mixing the fenofibrate and surfactant, micronized separately.
  • the dissolution method employed is the conventional rotating blade technique (European Pharmacopoeia) : product dissolution kinetics are measured in a fixed volume of the dissolution medium, agitated by means of a standardized device; a test was also carried out with an alternative technique to the European Pharmacopoeia, using the continuous-flow cell method.
  • EP-A-0330532 leads to a new dosage form in which the active ingredient, co-micronized with a solid surfactant, has improved fenofibrate dissolution, and thus increased bioavailability, which makes it possible, for a given level of effectiveness, to decrease the daily dose of the medicament: respective 67 mg and 200 mg instead of 100 mg and 300 mg.
  • Such substances are those of the fenofibrate family, such as for example gemfibrosil, cipofibrate, beclobrate, clinofibrate, simfibrate and bezafibrate, along with other substances such as glipizide, nifedipine, spironolactone, griseofulvine, acetazolamide, pipemidic acid, alprazolam, amphotericin B, atenolol, azathioprine, zidovudine, cortisone, econazole, itraconazole, furosemide, ketoconazole, loperamide, lovastatine, mesalazine, sucralfate, tolbutamide, papaverine, piroxicam, verapamil, etc., this list not being limiting.
  • Applicant has found that, surprisingly, it is possible to resolve this problem by a new method for preparing a pharmaceutical composition by spraying a suspension of the active ingredient onto an inert hydrosoluble carrier.
  • the present invention also relates to pharmaceutical compositions thus prepared.
  • polyvinylpyrrolidone for producing tablets, in concentrations of the order of 0.5 to 5% by weight, at a maximum 10% by weight.
  • the polyvinylpyrrolidone is used as a binder.
  • a polymer such as hydroxymethylpropylmethyl cellulose as a granulation binder is known.
  • European patent application 0,519,144 discloses pellets of a poorly soluble substance, omeprazole, obtained by spraying a dispersion or suspension of the active ingredient in a solution containing said polymer onto inert pellets in a fluidized-bed granulator.
  • the polymer HPMC and HPC
  • HPMC and HPC is only used as a granulation binder, in an amount of about 50% by weight, based on the weight of the active ingredient, which, bearing in mind the presence of the inert pellets of a large size (about 700 ⁇ m) and the overall final weight leads to final active ingredient and polymer contents which are very low, of the order of barely a few percent based on the weight of the final covered pellet.
  • the size of the inert pellets in this documents is fairly large, which, in the case of fenofibrate, would lead to a final formulation having a volume which is much too large for ready oral administration.
  • polymer such as polyvinylpyrrolidone for manufacturing "solid dispersions”
  • solid dispersions obtained in general by co-precipitation, co-fusion or liquid-phase mixing followed by drying. What we have here is fixation of the active ingredient in isolated microparticles on the polyvinylpyrrolidone, which avoids problems of poor wetting of the solid and re-agglomeration of the particles.
  • WO-A-96 01621 further discloses a sustained release composition, comprising an inert core (silica in all examples) coated with a layer -which contains the active ingredient in admixture with a hydrophilic polymer, the weight ratio active ingredient/polymer being comprised between 10/1 and 1/2 and the weight ratio active ingredient/inert core being comprised between 5/1 and 1/2, with an outer layer to impart the sustained release property.
  • the hydrophilic polymer can be polyvinylpyrrolidone.
  • This document also discloses a process for preparing said composition; for example in a fluidized-bed granulator one will spray a " dispersion of active ingredient in a polymer solution onto the inert cores.
  • This document solely relates to sustained release compositions, the technical problem to be solved being the compression, without damages, of the outer layer imparting the sustained release property. Nevertheless, nothing in the state of the art teaches nor suggest the present invention.
  • the present invention provides an immediate- release composition
  • an immediate- release composition comprising: (a) an inert hydrosoluble carrier covered with at least one layer containing active ingredient except fenofibrate in a micronized form having a size less than 20 ⁇ m, a hydrophilic polymer and, optionally, a surfactant; said hydrophilic polymer making up at least 10% by weight of (a) ; and
  • a surfactant is present with the active ingredient and the hydrophilic polymer.
  • the active ingredient is selected from the group consisting of gemfibrosil, cipofibrate, beclobrate, clinofibrate, simfibrate and bezafibrate .
  • the active ingredient is selected from the group consisting of acetazolamide, pipemidic acid, alprazolam, amphotericin B, atenolol, azathioprine, .zidovudine, cortisone, econazole, itraconazole, furosemide, glipizide, nifedipine, spironolactone, griseofulvine, ketoconazole, loperamide, lovastatine, mesalazine, sucralfate, tolbutamide, papaverine, piroxicam and verapamil .
  • the invention also provides a composition comprising a glipizide active ingredient having a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured using the rotating blade method at 75 rpm according to the European Pharmacopoeia, in a dissolution medium constituted by water with 2% by weight polysorbate 80.
  • the invention also provides a composition comprising a nifedipine active ingredient having a dissolution of at least 10% in 5 minutes, 20% in 10 minutes, 50% in 20 minutes and 75% in 30 minutes, as measured using the rotating blade method at 75 rpm according to the European Pharmacopoeia, in a dissolution medium constituted by water with 2% by weight polysorbate 80.
  • a method for preparing a pharmaceutical composition comprising the steps of: (a) preparing a suspension of active ingredient except fenofibrate in micronized form with a particle size below 20 ⁇ m, in a solution of hydrophilic polymer and, optionally surfactant;
  • step (b) applying the suspension from step (a) to an inert hydrosoluble carrier;
  • Step (b) is preferably carried out in a fluidized-bed granulator .
  • the method can comprise a step in which products obtained from step (b) or (c) are compressed, with or without additional excipients.
  • the invention also provides a suspension of active ingredient except fenofibrate in micronized form having a size less than 20 ⁇ m, in a solution of hydrophilic polymer and, optionally, surfactant.
  • FIG. 1 is a graph of a comparative study of the dissolution profile of a composition according to the invention, compared to that of Lipanthyl® 200M;
  • FIG. 2 is a graph illustrating a comparative study of the dissolution profile of a composition according to the invention and that of pharmaceutical products commercially available on the German market;
  • FIG. 3 shows the dissolution profile of a composition according to the invention containing glipizide.
  • FIG. 4 shows the dissolution profile of the composition according to the invention containing nifedipine.
  • compositions according to this invention are particularly suitable, in view of their improved dissolution profile, for administration of an active ingredient having poor solubility. This last term can be understood, in the framework of the invention, as an active ingredient having a solubility that is less than 1% by weight in pure water (or a solubility less than 10% in a dissolution medium constituted of water to which 2%
  • Polysorbate 80 has been added (The solubility test is carried out using the rotating blade method as described in the European Pharmacopoeia. Mixtures of active ingredients are also suitable.
  • in micronized form in this invention means a substance in a particulate form, the dimensions of the particles being less than or equal to about 20 ⁇ m.
  • this dimension is less than or equal to 10 ⁇ m.
  • inert hydrosoluble carrier means any excipient, generally hydrophilic, pharmaceutically inert, crystalline or amorphous, in a particulate form, not leading to a chemical reaction under the operating conditions employed, and which is soluble in an aqueous medium, notably in a gastric acid medium.
  • excipients are derivatives of sugars, such as lactose, saccharose, hydrolyzed starch (malto-dextrine) , etc. Mixture are also suitable.
  • the individual particle size of the inert hydrosoluble carrier can be, for example, between 50 and 500 micron.
  • hydrophilic polymer in the invention should be taken to mean any high molecular weight substance (greater, for example, than 300) having sufficient affinity towards water to dissolve therein and form a gel .
  • examples of such polymers are polyvinylpyrrolidone, poly(vinyl alcohol), hydroxypropylcellulose, hydroxymethylcellulose, hydroxypropylmethylcellulose , gelatin, etc. Polymer blends are also suitable.
  • the preferred hydrophylic polymer is polyvinylpyrrolidone (PVP) .
  • PVP polyvinylpyrrolidone
  • the PVP used in this invention has, for example, a molecular weight comprised between 10,000 and 100,000, preferably for example between 20,000 and 55,000.
  • surfactant is used in its conventional sense in this invention. Any surfactant is suitable, whether it be amphoteric, non-ionic, cationic or anionic. Examples of such surfactants are: sodium lauryl sulfate, monooleate, monolaurate, monopalmitate , monostearate or another ester of polyoxyethylene sorbitane, sodium dioctylsulfosuccinate (DOSS) , lecithin, stearylic alcohol, cetostearylic alcohol, cholesterol, polyoxyethylene ricin oil, polyoxyethylene fatty acid glycerides, poloxamer®, etc. Mixtures of surfactants are also suitable.
  • the preferred surfactant is sodium laurylsulfate, which can be co-micronized with the active ingredient.
  • compositions according to the invention can additionally contain any excipient conventionally used in the pharmaceutical and chemical fields which is compatible with the active ingredient, such as binders, fillers, pigments, disintegrating agents, lubricants, wetting agents, buffers, etc.
  • excipients able to be used in this invention we can cite: microcrystalline cellulose, lactose, starch, colloidal silica, talc, glycerol esters, sodium stearyl fumarate, titanium dioxide, magnesium stearate, stearic acid, cross-linked polyvinyl pyrrolidone (AC DI SOL®) , carboxymethyl starch (Explotab®, Primojel®) , hydroxypropylcellulose , hydroxymethylcellulose , hydroxypropylmethylcellulose, gelatin, etc.
  • the expression "outer phase or layer” should be taken to mean any coating on the element (a) with the active ingredient (forming a “core”) . Indeed, it can be useful to have available one or several phase (s) or layer (s) on top of the coated core.
  • the invention thus covers a single core with one layer, but also several cores in a phase, as is the case of tablets which are formed from “cores” mixed with a phase.
  • This outer layer comprises conventional excipients.
  • an outer layer will comprise alkali reaction agents when the active ingredient is, for example, acido-labile . It is also possible to provide a layer comprising additives, for the manufacture of tablets.
  • the outer layer comprises a disintegration agent and, for example, a lubricant; the thus covered and mixed granules can then be readily compressed and easily disintegrate in water.
  • the hydrophilic polymer represents preferably more than 20% by weight, based on the weigt of (a) , especially more than 25% by weight.
  • compositions according to the invention comprise, in general, based on the total composition weight excluding the outer phase or layer, an inert hydrosoluble carrier making up from 10 to 90% by weight, preferably 25 to 80% by weight, the active ingredient representing from 5 to 40% by weight, preferably from 10 to 40% by weight, the hydrophilic polymer representing from 10 to 60% by weight, preferably 10 to 50% by weight, the surfactant making up from 0 to 10% by weight, preferably 0.1 to 3% by weight .
  • the outer layer or phase if present, can make up to 80% by weight of the total weight, preferably up to 50% by weight .
  • the weight ratio active ingredient/hydrophilic polymer can for example be comprised between 1/10 and 4/1, preferably, for example, between 1/2 and 2/1.
  • the weight ratio surfactant/hydrophilic polymer can be comprised for example between 1/500 and 1/10, preferably, for example, between 1/100 and 5/100.
  • the composition according to the invention takes the form of tablets.
  • This tablet preferably results from the compression of elements (a) (under the form of granules) together with an outer phase.
  • composition of the invention takes the form of granules enclosed inside a capsule, for example in gelatin, or inside a bag.
  • compositions of the invention are particularly suitable for administering active ingredients by oral route .
  • composition according to the invention is prepared by a novel process comprising spraying a suspension of the active ingredient in a micronized form in a solution of a hydrophilic polymer and, optionally, a surfactant, onto the inert cores.
  • the active ingredient can be co-micronized with the surfactant.
  • the method according to the invention consists in using the fluidized bed granulation principle, but with specific starting materials, in order to arrive at an improved dissolution profile and thus, at elevated bioavailability.
  • the invention employs a suspension of the micronized active ingredient in a solution of a hydrophylic polymer and, optionally, a surfactant .
  • the fluidized-bed granulation technique is widely used in the pharmaceutical industry for preparing capsules or tablets.
  • a powder or a mixture of powders (active ingredient + excipients) is put into suspension in the fluidized bed in a granulator, and a solution containing a binder and, optionally, a surfactant, is sprayed onto this bed to form granules.
  • the fluidized-bed granulation technique is well known to those skilled in the art and reference should be made to standard works such as for example "Die Tablette", by Ritschel, Ed. Cantor Aulendorf, pages 211-212.
  • the invention comprises spraying a suspension of an active ingredient micronized with a hydrophilic polymer onto an inert carrier.
  • the granulate formed consists of crystals of, for example, lactose, which are isolated (or possibly agglomerated together by the spaying solution) and particles of active ingredient and PVP adhering to the crystal surface.
  • the granulate could similarly be constituted of coated crystals which are agglomerated, or even of such an agglomerate having received a coating.
  • compositions according to the invention can also be prepared by other methods, for example by spraying a solution of the micronized active ingredient onto the hydrosoluble inert carrier.
  • the granulates thus obtained can, if desired, be provided with an outer coating or compressed into tablets, or form agglomerates.
  • the outer layer or layer is/are applied using conventional coating techniques such as coating in a pan or fluidized bed coater.
  • the significant starting product is the suspension of the active ingredient.
  • This suspension is prepared by putting the micronized active ingredient into suspension in a solution comprising the hydrophylic polymer and, optionally, a surfactant, in solution in a solvent. If a surfactant is employed, it is put into solution in the solvent (beaker + magnetic or vane stirrer) .
  • the hydrophylic polymer (PVP) is dispersed, while stirring, in the solution previously obtained.
  • the micronized active ingredient is dispersed in the form of a fine shower into the above solution or suspension, to form a homogeneous suspension.
  • the order of these steps can be reversed.
  • the solvent employed can be aqueous or organic (for example ethanol) .
  • demineralized water can be used.
  • the active ingredient concentration in the suspension is from 1 to 40% by weight, preferably from 10 to 25%.
  • the hydrophylic polymer concentration in the suspension is from 5 to 40% by weight, preferably 10 to 25%.
  • the surfactant concentration in the suspension is from 0 to 10% by weight, preferably below 5%.
  • the invention also covers this novel suspension. Without wishing to be tied down to a specific theory, applicant believes that this novel method, through the use of a micronized active ingredient suspension in a hydrophilic polymer solution, enabled a novel composition to be obtained in which the active ingredient is in a non-re-agglomerated form.
  • Example 1 Preparation of a pharmaceutical composition of fenofibrate .
  • a composition containing, as the element a) , micronized fenofibrate, Plasdone®, Capsulac® and sodium lauryl sulfate was prepared.
  • the micronized fenofibrate had a particle size of about 5 ⁇ m, as measured using a Coulter counter.
  • the Plasdone K25® corresponds to a polyvinylpyrrolidone PVP ISP and the Capsulac 60® corresponds to a coarse crystal lactose monohydrate (particle size between 100 and 400 ⁇ m) (Meggle) .
  • the sodium laurylsulfate (7g) is dissolved in water (demineralized water, 1750 g) and the micronized fenofibrate (350 g) is put into suspension in the mixture obtained (for example using a helix stirrer at 300 rpm for 10 minutes, then using an Ultra Turrax agitator at 10,000 rpm, for 10 minutes). Following this, the PVP (350 g) is added while still agitating, stirring (helix stirrer) being continued until the latter had dissolved (30 minutes) . It is all passed through a sieve (350 ⁇ m) to eliminate possible agglomerates.
  • the lactose (400 g) is put into suspension in a fluidized air bed granulator (of the Glatt® GPCG1 - Top Spray type or equivalent) and heated to a temperature of 40°C.
  • the fenofibrate suspension is sprayed onto the lactose. This step is carried out under the following conditions: spraying pressure : 2.1 bar, air throughput 70 m-Vh, air inlet temperature: 45°C; air outlet temperature: 33°C; product temperature 34°C; duration of spraying: 3 h.
  • the granulate thus obtained can be put inside capsules or transformed into tablets. Any suitable conventional technique for preparing such dosage forms can be used.
  • transformation to tablet form one will mix 191 g of the granulate obtained (using for example a mixer- grinder type mixing apparatus, a planetary mixer or turnover mixer) , with the outer phase having the following composition:
  • Polyplasdone XL® cross-linked polyvinylpyrrolidone ISP, as described in the USA Pharmacopoeia "USP - NF" under the name of crospovidone, mean molecular weight > 1,000,000); - 88 g Avicel® PH200 (microcrystalline cellulose) ;
  • Aerosil® 200 (colloidal silica) .
  • cross- linked polyvinylpyrrolidone, the microcrystalline cellulose, the sodium stearyl fumarate and the colloidal silica are respectively, disintegration agents, binders, lubricating and flow enhancing agents.
  • the tablet can be obtained on an alternating compression machine (for example Korsch EKO) or a rotary machine (for example Fette Perfecta 2) .
  • Example 2 Dissolution of a composition according to the invention and a composition according to the prior art. a) dissolution medium and procedure for measuring dissolution. A dissolution medium which is discriminating, in other words one in which two products having very different dissolution profiles in gastric juices will have very different dissolution curves is looked for.
  • an aqueous medium containing a surfactant this being Polysorbate 80 (polyoxyethylene sorbitane mono-oleate) is used.
  • This surfactant is readily available from various suppliers, is the object of a monograph in the Pharmacopoeias, and is thus easy to implement (being also a water-soluble liquid product) .
  • Other surfactants can also be used, such as sodium lauryl sulfate .
  • the rotating blade method (European Pharmacopoeia) is used under the following conditions: volume of medium: 1200 ml; medium temperature: 37°C; blade rotation speed: 75 rpm; samples taken: every 2.5 minutes. Determination of the amount dissolved is carried out by spectrophotometry . Test are repeated 6 times over. b) Results
  • composition according to the invention consisted of two tablets containing about 100 mg fenofibrate prepared according to example 1.
  • the prior art composition was Lipanthyl® 200M from Laboratoires Fournier, containing 200 mg fenofibrate (corresponding to capsules of 200 mg fenofibrate co- micronized with sodium laurylsulfate, and containing lactose, pre-gelatinized starch, cross-linked polyvinylpyrrolidone and magnesium stearate, in line with the teachings of EP-A-0330532) .
  • Example 3 Study of bioavailability of compositions according to the invention and prior art compositions.
  • composition according to the invention capsules containing granules prepared according to example 1, containing 200 mg fenofibrate.
  • first composition according to the prior art Lipanthyl® M from Fournier, containing 200 mg fenofibrate, identical to that in the previous example.
  • second prior art composition Secalip® in capsule form (300 mg fenofibrate in the form of three 100 mg capsules) .
  • the samples for pharmaco-kinetic analysis were collected after each administration at the following .times : 0.5 h; 1 h; 2 h; 3 h; 4 h; 5 h; 6 h; 8 h; 10 h; 12 h; 24 h; 36 h; 48 h; 72 h; and 96 hours following administration of the medicament.
  • Fenofibric acid content in plasma was measured for each sample .
  • AUC 0 - t area under the curve from 0 to t
  • AUC 0 -co area under the curve from 0 toco .
  • compositions of the present invention have a dissolution profile that is an improvement over compositions of the prior art, leading to a considerably enhanced bioavailability of the active ingredient compared to that obtained with compositions of the prior art .
  • Example 4 Comparison of the dissolution profile of compositions according to the invention and that of products currently on the German market.
  • Composition 100 mg fenofibrate
  • Excipients lactose, corn starch, magnesium stearate,
  • Composition 100 mg fenofibrate
  • Excipients lactose, corn starch, magnesium stearate, E 171 colorant, gelatine.
  • Composition 200 mg Fenofibrate;
  • FIG. 2 summarizes the results .
  • compositions of the invention have a distinctly improved dissolution compared to prior art compositions.
  • Example 5 Preparation of compositions according to the invention containing other fibrate derivatives.
  • compositions according to the invention in which fenofibrate was replaced by gemfibrosil, ciprofibrate or bezafibrate were prepared according to the method of example 1.
  • the compositions were identical to that given in example 1, except for the active ingredient, which varied.
  • compositions thus obtained was compared to the one obtained for pharmaceutical preparations that were commercially available, as follows : Gemfibrosil (450 mg) , Lipur® tablets, - Parke Davis; Ciprofibrate (500 mg) , capsules, Lipanor® - Sanofi Winthrop;
  • Example 6 Study of dissolution profile of a composition according to the present invention containing other classes of active ingredient.
  • Other active ingredients known for their poor solubility, were tested in this example, these being: glipizide and nifedipine.
  • compositions according to the invention were the following (suspension of the active ingredient being carried out in 50.00 mg demineralized water) : Composition 1 :
  • Nifedipine (5 ⁇ m) 10.00 mg Plasdone K29-32® 15.00 mg Lactose EP D20® 80.00 mg
  • the compositions according to the invention that were tested were prepared according to example 1, the various compounds being present in amounts calculated for 10 mg of glipizide or nifedipine active ingredient.
  • compositions were compared to untreated active ingredients.
  • the results of dissolution tests (carried out according to the method of example 2) are illustrated graphically in FIGS. 3 and 4 respectively, for glipizide or nifedipine active ingredients. These results clearly show that the compositions according to the present invention have a dissolution profile which is improved compared to the untreated starting active ingredients. Similar tests carried out on other poorly-soluble active ingredients, such as griseofulvine and spironolactone lead to similar results .

Abstract

L'invention concerne une composition comprenant: (a) un excipient hydrosoluble inerte recouvert d'au moins une couche contenant un ingrédient actif à l'exception du fénofibrate en une forme micronisée ayant une grosseur inférieure à 20 νm, un polymère hydrophile et, facultativement, un tensioactif, le polymère constituant au moins 10 % en poids de (a); et (b) facultativement une ou plusieurs phases ou couches extérieures. L'invention concerne également un procédé de préparation de ladite composition.
PCT/IB1998/000066 1997-01-17 1998-01-16 Composition pharmaceutique presentant une biodisponibilite elevee et son procede de preparation WO1998031360A1 (fr)

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FR9700480A FR2758461A1 (fr) 1997-01-17 1997-01-17 Composition pharmaceutique presentant une biodisponibilite elevee et son procede de preparation

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DE10117049A1 (de) * 2001-04-05 2002-10-17 Novartis Ag Zusammensetzung
US6627757B2 (en) 2001-03-28 2003-09-30 Schering Corporation Enantioselective synthesis of azetidinone intermediate compounds
US6663897B2 (en) 2001-02-06 2003-12-16 Dsm Ip Assets B.V. Oral itraconazole formulations and methods of making the same
US7037529B2 (en) 1997-01-17 2006-05-02 Laboratoires Fournier Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US7101574B1 (en) 1999-07-09 2006-09-05 Laboratoires Des Produits Ethiques Ethypharm Pharmaceutical composition containing fenofibrate and the preparation method
JP2006520770A (ja) * 2003-02-28 2006-09-14 ソシエテ ア レスポンサビリテ リミテ ガルニクス イノヴァシオン フィブレートを含有する錠剤の形の製薬組成物の製造方法、および該方法に従って得られた錠剤
US7144585B1 (en) 1999-03-25 2006-12-05 Otsuka Pharmaceutical Co., Ltd. Cilostazol preparation
US7700128B2 (en) 2003-10-31 2010-04-20 Takeda Pharmaceutical Company Limited Solid preparation comprising an insulin sensitizer, an insulin secretagogue and a polyoxyethylene sorbitan fatty acid ester
US7850995B2 (en) 1999-10-08 2010-12-14 Elan Pharma International, Ltd. Bioadhesive nanoparticulate compositions having cationic surface stabilizers
US7863331B2 (en) 1999-07-09 2011-01-04 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
US8003690B2 (en) 2002-12-13 2011-08-23 Jagotec Ag Topical nanoparticulate spironolactone formulation
US8124057B2 (en) 1998-11-12 2012-02-28 Alkermes Pharma Ireland Limited Propellant-based nanoparticulate dry powder aerosols and method of making
US8236352B2 (en) * 1998-10-01 2012-08-07 Alkermes Pharma Ireland Limited Glipizide compositions
EP1438960B2 (fr) † 2003-01-14 2012-12-19 Acino Pharma AG Composition sous la forme d'une dispersion solide comprenant de l'itraconazole et un polymer hydrophilique dont la biodisponibilité est améliorée
US8663693B2 (en) 2001-08-09 2014-03-04 Jagotec Ag Nanoparticulate formulations of fenofibrate
EP1438961B2 (fr) † 2003-01-14 2014-08-20 Acino Pharma AG Composition bioéquivalente sous la forme d'une dispersion solide comprenant de l'itraconazole et un polymer hydrophile
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials

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US8329214B2 (en) 1997-01-17 2012-12-11 Laboratoires Fournier S.A. Process for producing fenofibrate tablets
US7037529B2 (en) 1997-01-17 2006-05-02 Laboratoires Fournier Fenofibrate pharmaceutical composition having high bioavailability and method for preparing it
US7041319B2 (en) 1997-01-17 2006-05-09 Laboratoires Fournier Fenofibrate pharmaceutical composition having high bioavailabilty
US8236352B2 (en) * 1998-10-01 2012-08-07 Alkermes Pharma Ireland Limited Glipizide compositions
US8124057B2 (en) 1998-11-12 2012-02-28 Alkermes Pharma Ireland Limited Propellant-based nanoparticulate dry powder aerosols and method of making
US7144585B1 (en) 1999-03-25 2006-12-05 Otsuka Pharmaceutical Co., Ltd. Cilostazol preparation
US8529952B2 (en) 1999-07-09 2013-09-10 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
US8658212B2 (en) 1999-07-09 2014-02-25 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
US7863331B2 (en) 1999-07-09 2011-01-04 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
US7101574B1 (en) 1999-07-09 2006-09-05 Laboratoires Des Produits Ethiques Ethypharm Pharmaceutical composition containing fenofibrate and the preparation method
US8563042B2 (en) 1999-07-09 2013-10-22 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
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US6663897B2 (en) 2001-02-06 2003-12-16 Dsm Ip Assets B.V. Oral itraconazole formulations and methods of making the same
US6627757B2 (en) 2001-03-28 2003-09-30 Schering Corporation Enantioselective synthesis of azetidinone intermediate compounds
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US8663693B2 (en) 2001-08-09 2014-03-04 Jagotec Ag Nanoparticulate formulations of fenofibrate
US10357455B2 (en) 2002-02-01 2019-07-23 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US9486410B2 (en) 2002-02-01 2016-11-08 Bend Research, Inc. Pharmaceutical compositions of amorphous dispersions of drugs and lipophilic microphase-forming materials
US8003690B2 (en) 2002-12-13 2011-08-23 Jagotec Ag Topical nanoparticulate spironolactone formulation
EP1438960B2 (fr) † 2003-01-14 2012-12-19 Acino Pharma AG Composition sous la forme d'une dispersion solide comprenant de l'itraconazole et un polymer hydrophilique dont la biodisponibilité est améliorée
EP1438961B2 (fr) † 2003-01-14 2014-08-20 Acino Pharma AG Composition bioéquivalente sous la forme d'une dispersion solide comprenant de l'itraconazole et un polymer hydrophile
JP2006520770A (ja) * 2003-02-28 2006-09-14 ソシエテ ア レスポンサビリテ リミテ ガルニクス イノヴァシオン フィブレートを含有する錠剤の形の製薬組成物の製造方法、および該方法に従って得られた錠剤
US9023393B2 (en) 2003-08-04 2015-05-05 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
USRE47033E1 (en) 2003-08-04 2018-09-11 Bend Research, Inc. Pharmaceutical compositions of adsorbates of amorphous drugs and lipophilic microphase-forming materials
US7700128B2 (en) 2003-10-31 2010-04-20 Takeda Pharmaceutical Company Limited Solid preparation comprising an insulin sensitizer, an insulin secretagogue and a polyoxyethylene sorbitan fatty acid ester

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