US20070077297A1 - Modified release ibuprofen dosage form - Google Patents

Modified release ibuprofen dosage form Download PDF

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Publication number
US20070077297A1
US20070077297A1 US11/633,322 US63332206A US2007077297A1 US 20070077297 A1 US20070077297 A1 US 20070077297A1 US 63332206 A US63332206 A US 63332206A US 2007077297 A1 US2007077297 A1 US 2007077297A1
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Prior art keywords
ibuprofen
weight
concentration
dosage form
hpmc
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Abandoned
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US11/633,322
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English (en)
Inventor
Michael Hite
Cathy Federici
Alan Brunelle
Stephen Turner
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Scolr Pharma Inc
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Scolr Pharma Inc
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Priority claimed from US11/238,802 external-priority patent/US20060068009A1/en
Application filed by Scolr Pharma Inc filed Critical Scolr Pharma Inc
Priority to US11/633,322 priority Critical patent/US20070077297A1/en
Assigned to SCOLR PHARMA, INC. reassignment SCOLR PHARMA, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRUNELLE, ALAN, FEDERICI, CATHY, HITE, MICHAEL, TURNER, STEPHEN
Publication of US20070077297A1 publication Critical patent/US20070077297A1/en
Priority to US11/906,303 priority patent/US7749537B2/en
Priority to CA 2670887 priority patent/CA2670887A1/en
Priority to EP07862281A priority patent/EP2099432B1/en
Priority to AU2007328390A priority patent/AU2007328390B2/en
Priority to JP2009539301A priority patent/JP2010511613A/ja
Priority to BRPI0717916A priority patent/BRPI0717916A8/pt
Priority to JP2009539304A priority patent/JP2010511614A/ja
Priority to KR1020097014021A priority patent/KR20090090369A/ko
Priority to CN2007800505822A priority patent/CN101588793B/zh
Priority to CA002671420A priority patent/CA2671420A1/en
Priority to EP20070862287 priority patent/EP2099433A2/en
Priority to KR20097014019A priority patent/KR20090086468A/ko
Priority to MX2009005958A priority patent/MX2009005958A/es
Priority to PCT/US2007/024489 priority patent/WO2008069938A2/en
Priority to AU2007328393A priority patent/AU2007328393A1/en
Priority to CNA2007800505381A priority patent/CN101594853A/zh
Priority to BRPI0717914-6A priority patent/BRPI0717914A2/pt
Priority to PCT/US2007/024496 priority patent/WO2008069941A2/en
Priority to MX2009005959A priority patent/MX2009005959A/es
Priority to PL07862281T priority patent/PL2099432T3/pl
Priority to TW096146118A priority patent/TW200831136A/zh
Priority to TW96146116A priority patent/TW200831135A/zh
Priority to IL199191A priority patent/IL199191A0/en
Priority to ZA200904436A priority patent/ZA200904436B/xx
Priority to CO09068963A priority patent/CO6190599A2/es
Priority to CO09068966A priority patent/CO6190600A2/es
Priority to US12/706,429 priority patent/US9028869B2/en
Priority to US14/611,372 priority patent/US9730895B2/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
    • A61K9/20—Pills, tablets, discs, rods
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/02—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic 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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • Ibuprofen is 2-(4-isobutylphenyl)propionic acid and is a non-steroidal anti-inflammatory compound (NSAID), which exhibits high levels of anti-inflammatory, analgesic and antipyretic activities necessary for the effective treatment of rheumatoid arthritis and osteo-arthritis and other inflammatory conditions.
  • NSAID non-steroidal anti-inflammatory compound
  • Most dosage forms of ibuprofen are immediate release dosage forms that provide rapid onset of therapeutic action, then rapidly declining levels of active ingredient, necessitating repeated dosing. They do not maintain therapeutic levels from one treatment over an extended period of time. Repeat dosing is thus required at intervals of four to six hours.
  • Formulations that claim extended release fail to have an initial burst of the drug and thus exhibit substantial delay between administration and the achievement of an effective therapeutic blood level. Therefore, a need exists for a solid dosage form, for example a compressed tablet, which provides an initial burst of released ibuprofen, leading to prompt onset of action, then thereafter provides a sustained release of sufficient ibuprofen to maintain beneficial blood levels of ibuprofen over an extended period of 8 or more hours.
  • ibuprofen is not directly compressible, and attempts to directly manufacture ibuprofen results in tablets which stick to the faces of the tableting press, are too friable for storage or transport, or split into two or more segments when expelled from the tableting press.
  • those skilled in the art carry out a preliminary step prior to tableting, in which ibuprofen is wet granulated with a microcrystalline cellulose additive to form a granular composition comprising ibuprofen and microcrystalline cellulose, which is then capable of blending with further excipients and/or is directly compressible for the manufacture of a suitable solid dosage form. Therefore, a need exists for a dry blend of ibuprofen which is suitable for manufacture of a satisfactory tableted dosage form, obviating the need for a pre-granulation step.
  • a solid dosage form for oral administration of ibuprofen comprising a modified release formulation of ibuprofen which provides an immediate burst effect and thereafter a sustained release of sufficient ibuprofen to maintain blood levels at least 6.4 ⁇ g/ml over an extended period of at least 8 hours following administration of a single dose.
  • the invention comprises a solid dosage form for oral administration comprising a hydrophilic polymer, a pharmaceutically effective amount of ibuprofen in the range of 300 mg to 800 mg uniformly dispersed in the polymer, a dissolution additive dispersed in the polymer in an amount in the range of 10% to 35% by weight of the ibuprofen, and a formulation additive dispersed in the polymer in an amount of 15% to 75% by weight of the ibuprofen.
  • the dosage form releases ibuprofen at a rate sufficient to initially deliver an effective amount of ibuprofen within about 2.0 hours following administration.
  • the dosage form then subsequently delivers the remaining amount of ibuprofen at a relatively constant rate sufficient to maintain a level of ibuprofen over a predetermined delivery period of for at least 8 hours.
  • a relative constant rate refers to a substantially linear relationship shown in the examples following the initial burst (up to about 2 hours) between percentage released and elapsed time.
  • FIG. 1 In-vitro dissolution of Example 1
  • FIG. 2 In-vitro dissolution of Example 2
  • FIG. 3 In-vitro dissolution of Example 3
  • FIG. 4 In-vitro dissolution of Example 4
  • FIG. 5 In-vitro dissolution of Example 5
  • FIG. 6 In-vitro dissolution of Example 6
  • FIG. 7 In-vitro dissolution of Example 7
  • FIG. 8 In-vitro dissolution of Example 8
  • FIG. 9 In-vitro dissolution of Example 9
  • FIG. 10 In-vitro dissolution of Example 10
  • FIG. 11 In-vitro dissolution of Example 11
  • FIG. 12 In-vitro dissolution of Example 12
  • FIG. 13 In-vitro dissolution of Example 13
  • FIG. 14 In-vitro dissolution of Example 14
  • FIG. 15 In-vitro dissolution of Example 15
  • FIG. 16 In-vitro dissolution of Example 16
  • FIG. 17 In-vitro dissolution of BRUFEN RETARD, an extended release form of Ibuprofen available for sale in Europe.
  • FIG. 18 In-vivo data from comparison of present invention versus Motrin®
  • FIG. 19 In-vitro dissolution of Example 21
  • the ibuprofen content of the dosage form may be between in the range about 300 mg and about 800 mg per dosage unit, for example about 300, 400 or 600 mg per unit dosage form. Also contemplated is using prodrugs of ibuprofen such as ibuprofen-lysine and ibuprofen-arginine. If a smaller dosage form is desired, a single dose of ibuprofen may be divided between multiple, for example two to three, dosage units, such as tablets, which may be administered at substantially the same time.
  • the dosage form may comprise from about 25% to about 75% by weight ibuprofen.
  • hydrophilic polymer used in the dosage form may be selected from a wide variety of hydrophilic polymers.
  • Hydrophilic polymers suitable for use in the sustained release formulation include: one or more natural or partially or totally synthetic hydrophilic gums such as acacia, gum tragacanth, locust bean gum, guar gum, or karaya gum; modified cellulosic substances such as methylcellulose, hydroxy methylcellulose, hydroxypropyl methylcellulose, hydroxypropyl cellulose, hydroxyethylcellulose, or carboxyethylcellulose; proteinaceous substances such as agar, pectin, carrageenan, gelatin, casein, zein and alginates; and other hydrophilic polymers such as carboxypolymethylene, bentonite, magnesium aluminum silicate, polysaccharides, modified starch derivatives, and other hydrophilic polymers known to those of skill in the art, or a combination of such polymers.
  • hydrophilic polymers gel and dissolve slowly in aqueous acidic media thereby allowing the ibuprofen to diffuse from the gel in the stomach and gastrointestinal tract.
  • Hydroxypropyl methylcellulose (HPMC) and other hydrophilic polymers mentioned above may be available in forms that have varying viscosity ratings. In general these polymers, or the combination of them, may be present in the dosage form alone or in combination in an amount or at a concentration in the range of about 10% to about 70% by weight of the ibuprofen present in the formulation, for example about 10% to about 50% or about 10% to about 35%, depending on the release pattern which is sought to be achieved with the particular dosage form.
  • HPMC K4M hydrophilic polymer useful in the present invention.
  • HPMC K4M is a nonionic swellable hydrophilic polymer manufactured by The Dow Chemical Company under the tradename “Methocel.”
  • HPMC K4M is also referred to as HPMC K4 MP, in which the “P” refers to premium cellulose ether designed for pharmaceutical formulations.
  • the “4” in the abbreviation suggests that the polymer has a nominal viscosity (2% in water) of 4000.
  • the percent of methoxyl and hydroxypropyl groups are 19-24 and 7-12, respectively.
  • HPMC K4M is a free-flowing, off-white powder with a particle size limitation of 90% ⁇ 100 mesh screen.
  • a more complete list of HPMC includes K100LVP, K15 MP, K100MP, E4MP and E10MP CR with nominal viscosities of 100, 15000, 100000, 4000, and 10000 respectively.
  • a formulation in which the hydrophilic polymer comprises two viscosities of HPMC employed at the same or different percentages relative to the amount of ibuprofen present in the formulation.
  • a low viscosity HPMC such as HPMC 100LV may be used at a concentration in the range of about 10% to about 20% in combination with a higher viscosity HPMC, for example HPMC, such as HPMC K4M, HPMC K15M or HPMC K100M, at a concentration which may be substantially the same or a different viscosity in the range of about 10-30%, in which the combined amounts of HPMC employed in the formulation is in the range of about 30% to about 40% relative to the amount of ibuprofen present in the formulation.
  • HPMC K100LV in combination with about 21% of HPMC K4M, a total of about 32% HPMC based on the amount of ibuprofen present in the formulation, in which the weight ratio of the higher viscosity to the lower viscosity HPMC is about 2:1.
  • the solid dosage form also includes at least one formulation additive such as one or more of a filler, a diluent or a compression aid.
  • a tableting aid such as microcrystalline cellulose (MCC), such as MCC 105 (particle size of about 20 ⁇ m), MCC 200 (particle size of about 180 ⁇ m) and MCC 302 (particle size of about 90 ⁇ m), which as used herein includes silicified microcrystalline cellulose (MCC bonded to SiO 2 ), such as Prosolv 90 (particle size of about 110 ⁇ m) and Prosolv 50 (particle size of about 60 ⁇ m); lactose, such as spray dried lactose (Lactopress®); dicalcium phosphate; silica; pregelatinized starch; and combinations thereof may be incorporated into the formulation in an amount or at a concentration in the range of about 15% to about 75% by weight of the i
  • a formulation in which the formulation additive comprises silicified microcrystalline cellulose present at two different particle sizes ranging from 60 ⁇ m to 110 ⁇ m.
  • a formulation additive may comprise two different particle sizes of ProsolvTM microcrystalline cellulose, wherein for example Prosolv50 (particle size 60 ⁇ m) is present in combination with a Prosolv90 (particle size 110 ⁇ m), suitably at a weight ratio in the range of about 1:1 to about 2:1, with the combination being present at a concentration of about 40% to about 60% by weight of the ibuprofen present in the formulation.
  • This embodiment may suitably be used in combination with a hydrophilic polymer having two different particle sizes as exemplified and described above, for example HPMC K100LV and HPMC K4M.
  • the dosage form also contains at least one dissolution additive.
  • Such additives which generally comprise a pore-forming, wetting or disintegration agent which facilitates dissolution of the dosage form.
  • Such dissolution additives may be present in the dosage form at an amount or concentration in the range of about 10% to about 35% by weight of the ibuprofen, for example, at 10-20%.
  • the additive may suitably be selected from alkali metal salts, such as sodium and potassium carbonate; sodium carbonate, monohydrate; sodium bicarbonate; amino acids with neutral-to-basic side chains, such as glycine, alanine, valine, leucine, iso-leucine, cysteine, methionine, phenylalanine, proline, lysine, arginine, histidine, serine, threonine, asparagine, tryptophan, tyrosine and glutamine; conventional pharmaceutical disintegrants and combinations or mixtures thereof.
  • alkali metal salts such as sodium and potassium carbonate; sodium carbonate, monohydrate; sodium bicarbonate
  • amino acids with neutral-to-basic side chains such as glycine, alanine, valine, leucine, iso-leucine, cysteine, methionine, phenylalanine, proline, lysine, arginine, histidine, serine, threonine,
  • a formulation in which the dissolution additive comprises two different additives wherein the dissolution additive is present in a combined range of about 10-20% by weight of ibuprofen.
  • a croscarmellose sodium may be present in combination with a second dissolution additive glycine wherein the combined range of the croscarmellose sodium and gycline is about 10-20% by weight of ibuprofen.
  • manufacture of ibuprofen tablets improved by pre-blending ibuprofen with silica or a combination of silica and microcrystalline cellulose. form improved by pre-blending ibuprofen with silica or a combination of silica and microcrystalline cellulose. form.
  • the process of pre-blending ibuprofen with silica, or a combination of silica and microcrystalline cellulose improves manufacturability of the dosage form and reduces the tendency of the dosage form to fracture, or stick to the faces of the compression machine.
  • the pre-blending duration can range from about 15 minutes to about 60 minutes with significant improvement as blending time is increased to at least 30-40 minutes. Blending can be performed in several different sizes of V-blenders and at several different speeds.
  • blending can be performed in a 16 qt V-blender ( ⁇ 1 ft 3 ) at 36 rpm while in another embodiment blending can be performed in a 40 ft 3 V-blender at 10 rpm.
  • the resulting dry pre-blend suitably in the form of a finely divided powder, may then blended with the remaining excipients and the resulting composition directly compressed into a satisfactory tableted dosage form.
  • ibuprofen In addition to ibuprofen, multiple active ingredients are contemplated and may be present in the present dosage form. Combinations of ibuprofen with actives such as caffeine, aspirin, pseudoephedrine, phenylephrine and/or other sympathomimetics, analgesics, such as hydrocodone, and antihistamines are within the scope of the invention.
  • in vitro characteristics that lead to an acceptable in vivo efficacy are contemplated as 20% or greater release within 2.0 hours after oral administration or contact with an aqueous environment, followed by more gradual release over several hours, leading to release of at least 70% release in 8 to 12 hours following administration or contact with an aqueous environment.
  • the method of determining in vitro release is using an agitated aqueous medium, such as stirring at 50 rpm in pH 7.2 KH 2 PO 4 media; or surrogate methods using alternate pH media, such as 0.1N HCl or SGF @ pH 1.2 for an initial (30 min-2 hr period or using alternate hydrodynamic conditions such as 100 to 150 rpm for a period of 1-2 hrs).
  • the accepted range for minimal efficacy in vivo is from about 6.4 ⁇ g/ml to about 10 ⁇ g/ml mean ibuprofen blood concentration.
  • the present invention is capable of quickly achieving these levels within 2 hours of oral administration, and maintaining such levels for a period of 8 to 12 hours depending on the amount of ibuprofen administered and the dosing regimen.
  • formulations of the invention are illustrated by the following examples.
  • the use of particular polymers, electrolytes, additives, fillers and compression aids are not intended to limit the scope of this invention but are exemplary only.
  • the solid dosage comprising a modified release formulation of the present invention was prepared and tested for both in vitro release and in vivo blood levels as described in Examples 1-20 below. In the in vivo testing, the dissolution rates of the subject dosage forms were compared against two commercially available tablets, one being an immediate release formulation of 200 mg of ibuprofen and the other being an immediate release 600 mg ibuprofen formulation.
  • the solid dosage forms comprising the modified release formulation of the present invention demonstrated an initial burst similar to an immediate release tablet and a slower, more controlled release of ibuprofen over a eight hour period, as best seen in FIG. 19 .
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M and HPMC K100LV), glycine and sodium carbonate, in which HPMC K15M was present at a concentration of 18% by weight of ibuprofen, Ex. 1a, and at a concentration of 21% by weight of ibuprofen, Ex. 1b, HPMC K100LV was present at a concentration of 17% by weight of ibuprofen, glycine was present at a concentration of 2.5% by weight of ibuprofen, and sodium carbonate was present at a concentration of 17% by weight of ibuprofen within a monolithic compressed tablet.
  • HPMC K15M hydroxypropyl methylcellulose
  • HPMC K100LV glycine
  • sodium carbonate was present at a concentration of 17% by weight of ibuprofen within a monolithic compressed tablet.
  • the specific formulations are as follows: Ex. 1a mg Ex.
  • the results of this Example demonstrate that the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material, leading to in excess of 90% release in approximately 12 hours.
  • This formulation thus overcomes one of the principle problems with many ibuprofen formulations which exhibit substantially less than complete release over an extended period of time.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K100M and HPMC K100LV), sodium carbonate, flow agents and tableting aids, in which HPMC K100M was present at a concentration of 17% by weight of ibuprofen, HPMC K100LV was present at a concentration of 17% by weight of ibuprofen, and sodium carbonate was present at a concentration of 25% by weight of ibuprofen within a compressed monolithic tablet.
  • the specific formula is as follows: Ex. 2 mg Ibuprofen 600 HPMC K100M 100 HPMC K100LV 100 Na 2 CO 3 , anhydrous 150 MCC PH102 150 Silica, Syloid 244 20 Mg Stearate 10 Total: 1130
  • the formulation components were mixed in a V-blender.
  • the resulting powder was compressed into tablets using conventional technologies.
  • a combination of a medium to high viscosity HPMC and a low viscosity HPMC were used.
  • the results of this Example demonstrate an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the burst effect provides release of 20% of ibuprofen within 2 hours, and the release of approximately 90% of the available ibuprofen over a period of 12 to 14 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M and HPMC K100LV), sodium carbonate, glycine, flow agents and tableting aids, in which HPMC K15M was present at a concentration of 17% by weight of ibuprofen, HPMC K100LV was present at a concentration of 17% by weight of ibuprofen and sodium carbonate was present at a concentration of 25% by weight of ibuprofen within a compressed monolithic tablet.
  • HPMC K15M hydroxypropyl methylcellulose
  • HPMC K100LV was present at a concentration of 17% by weight of ibuprofen
  • sodium carbonate was present at a concentration of 25% by weight of ibuprofen within a compressed monolithic tablet.
  • Ibuprofen 600 HPMC K15M 100 HPMC K100LV 100 MCC PH102 100 Na 2 CO 3
  • the formulation components were mixed in a V-blender.
  • the resulting powder was compressed into tablets using conventional compression technology.
  • a combination of a medium to high viscosity HPMC and a low viscosity HPMC was used.
  • the results of this Example demonstrate an in vitro release profile comprising a burst effect providing release of 20% of ibuprofen within 2 hours, followed by the sustained release of the remaining material evidencing release of 100% of the ibuprofen present in about 11 hours and greater than 90% in approximately 8 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K100M and HPMC K100LV), sodium carbonate, flow agents and tableting aids, in which HPMC K100M was present at a concentration of 17% by weight of ibuprofen, HPMC K100LV was present at a concentration of 17% by weight of ibuprofen, and sodium carbonate was present at a concentration of 25% by weight of ibuprofen within a compressed monolithic tablet.
  • the specific formulation is as follows: Ex. 4 mg Ibuprofen 600 HPMC K100M 100 HPMC K100LV 100 MCC PH102 100 Na 2 CO 3 , anhydrous 150 Silica, Syloid 244 20 Mg Stearate 10 Total: 1080
  • the formulation components were mixed in a V-blender.
  • the resulting powder was compressed into tablets using conventional technologies.
  • a combination of a medium to high viscosity HPMC and a low viscosity HPMC was used.
  • the results of this Example demonstrate an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material. 20% of ibuprofen was released within 2 hours, followed by gradual sustained release, resulting in approximately 95% release after 12 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K100M), polyethylene oxide (PEO WSRN 301), sodium carbonate, glycine, flow agents and tableting aids, in which HPMC was present at a concentration of 17% by weight of ibuprofen, PEO was present at a concentration of 8.3% by weight of ibuprofen, glycine was present at a concentration of 3% by weight of ibuprofen and sodium carbonate was present at a concentration of 25% by weight of ibuprofen within a compressed monolithic tablet.
  • HPMC hydroxypropyl methylcellulose
  • PEO polyethylene oxide
  • sodium carbonate glycine
  • flow agents and tableting aids in which HPMC was present at a concentration of 17% by weight of ibuprofen
  • PEO was present at a concentration of 8.3% by weight of ibuprofen
  • glycine was present at a concentration of 3% by weight of ibupro
  • the formulation components were mixed in a V-blender.
  • the resulting powder was compressed into tablets using conventional compression technology.
  • the results of this Example demonstrate an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • 20% of ibuprofen was released within 2 hours, but incomplete release was evidenced after 12 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M), potassium carbonate, microcrystalline cellulose (PH105 and PH 200), flow agents and tableting aids, in which HPMC was present at a concentration of 32% by weight of ibuprofen, and potassium carbonate was present at a concentration of 17% by weight of ibuprofen within a compressed monolithic tablet.
  • HPMC hydroxypropyl methylcellulose
  • PH105 and PH 200 microcrystalline cellulose
  • flow agents and tableting aids in which HPMC was present at a concentration of 32% by weight of ibuprofen, and potassium carbonate was present at a concentration of 17% by weight of ibuprofen within a compressed monolithic tablet.
  • Ibuprofen 90 grade 600 MCC PH 105 210 HPMC K15M
  • Prem 190 MCC PH 200 100 K 2 CO 3 anhydrous 100 1200
  • the formulation components were mixed in a V-blender.
  • the resulting powder was compressed into tablets using conventional compression technology.
  • the results of this Example demonstrate an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material. 20% of ibuprofen was released in under 2 hours, and release was thereafter sustained over a period of 15 hours. However, incomplete release was exhibited by the dosage form.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M), sodium carbonate, microcrystalline cellulose (MCC PH105 and MCC PH200), in which HPMC was present at a concentration of 32% by weight of ibuprofen, sodium carbonate was present at a concentration of 17% by weight of ibuprofen, MCC PH105 was present at a concentration of 35%, and MCC PH200 was present at a concentration of 17% within a compressed monolithic tablet.
  • HPMC K15M hydroxypropyl methylcellulose
  • MCC PH105 and MCC PH200 microcrystalline cellulose
  • Ibuprofen 90 grade 600 HPMC K15M Prem 190 MCC PH 105 210 MCC PH 200 100 Na 2 CO 3 anhydrous 100 1200
  • this Example demonstrates an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the burst effect releases 20% of ibuprofen in under 2 hour, followed by relatively constant release over the next 10-12 hours and resulting in approximately 90% release after 12 hours.
  • Example 1a the tablet resulting from the formulation was split into two equal parts, and both sections were placed into a dissolution vessel.
  • the results of this Example demonstrates an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material, even when split into sections after tableting.
  • 20% of ibuprofen was released in less than one hour and substantially all the ibuprofen had been released at about 12 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K15M), sodium carbonate, microcrystalline cellulose (MCC PH 302), glycine and silica in which HPMC was present at a concentration of 33% by weight of ibuprofen, sodium carbonate was present at a concentration of 17% by weight of ibuprofen, and MCC PH 302 was present at a concentration of 33% within a compressed monolithic tablet.
  • the specific formulation is as follows: Ex. 9 mg Ibuprofen 90 grade 300 HPMC K15M Prem 100 MCC PH 302 100 Na 2 CO 3 anhydrous 50 Glycine 7.5 Silica 5.5 Total: 563
  • the results of this Example demonstrate an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material. 20% of ibuprofen was released within 2 hours, about 90% release was obtained in about 9 hours followed by 100% release in under 16 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), arginine, flow agents and tableting aids, in which HPMC K4M was present at a concentration of 32% by weight of ibuprofen, and arginine was present at a concentration of 17% by weight of ibuprofen within a compressed monolithic tablet.
  • HPMC K4M hydroxypropyl methylcellulose
  • arginine was present at a concentration of 17% by weight of ibuprofen within a compressed monolithic tablet.
  • microcrystalline cellulose, MCC PH 105, and 5.5 mg of silica were pre-blended in a V-blender with ibuprofen. The remaining excipients were then blended with the dry pre-blended powder. The resulting tableting formulation was compressed into tablets using conventional technologies.
  • the results of this Example demonstrate an in vitro release profile comprising a slight burst effect, followed by the sustained release of the remaining material. While the burst effect in this formulation produces somewhat delayed achievement of the percentage released, this formulation demonstrates in excess of 90% release over a period of 8 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), sodium carbonate, arginine, flow agents and tableting aids, in which HPMC K4M was present at a concentration of 32% by weight of ibuprofen, sodium carbonate was present at concentration of 17% by weight of the ibuprofen, and arginine was present at a concentration of 17% by weight of ibuprofen within a compressed monolithic tablet.
  • HPMC K4M hydroxypropyl methylcellulose
  • sodium carbonate was present at concentration of 17% by weight of the ibuprofen
  • arginine was present at a concentration of 17% by weight of ibuprofen within a compressed monolithic tablet.
  • microcrystalline cellulose PH 105 and 5.5 mg of silica were pre-blended in a V-blender with ibuprofen to form a pre-blended powder.
  • the remaining excipients were blended with the resulting pre-blended powder.
  • the resulting tableting formulation was compressed into tablets using conventional technologies.
  • the results of this Example demonstrate the in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the initial release is greater than 20% of ibuprofen in less than two hours, and approximately 90% release over a period of 14 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), microcrystalline cellulose (MCC 105), sodium carbonate, flow agents and various tableting aids, in which HPMC K4M was present at a concentration of 32% by weight of ibuprofen, sodium carbonate was present at concentration of 17% by weight of the ibuprofen, and tableting aid, either Lactopress (12a), dicalcium phosphate (12b), or pregelatinized starch (12c), was present at a concentration of 17% by weight of ibuprofen within a monolithic tablet. mg Ex.
  • the results of this Example demonstrate the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material, with little or no alteration in release profile when the tableting aid selection is varied.
  • the in vitro profile shows greater than 20% release before 2.0 hours with a constant rate release and at least 70% release by 14 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), microcrystalline cellulose (MCC 105), sodium carbonate, flow agents and various tableting aids, in which HPMC K4M was present at a concentration of 32% by weight of ibuprofen, sodium carbonate was present at concentration of 17% by weight of the ibuprofen, and croscarmellose sodium was present at a concentration of 3% by weight of ibuprofen within a monolithic tablet.
  • HPMC K4M hydroxypropyl methylcellulose
  • MCC 105 microcrystalline cellulose
  • sodium carbonate was present at concentration of 17% by weight of the ibuprofen
  • croscarmellose sodium was present at a concentration of 3% by weight of ibuprofen within a monolithic tablet.
  • the results of this Example demonstrates an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the in vitro profile shows greater than 20% release before 2.0 hours followed by a relatively constant rate release and at least 80% release by 14 hours.
  • the formulation comprised ibuprofen, hydroxypropyl methylcellulose (HPMC K4M), microcrystalline cellulose (MCC PH 105 and PH 200), glycine, croscarmellose sodium, flow agents and various tableting aids, in which HPMC K4M was present at a concentration of 32% by weight of ibuprofen, glycine was present at a concentration of 8% by weight of ibuprofen and croscarmellose sodium was present at a concentration of 6% by weight of ibuprofen within a monolithic tablet.
  • HPMC K4M hydroxypropyl methylcellulose
  • MCC PH 105 and PH 200 microcrystalline cellulose
  • glycine croscarmellose sodium
  • flow agents and various tableting aids in which HPMC K4M was present at a concentration of 32% by weight of ibuprofen, glycine was present at a concentration of 8% by weight of ibuprofen and croscarmel
  • the results of this Example demonstrate the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the in vitro profile shows greater than 20% release before 2.0 hours with a constant rate release and at least 70% release by 14 hours.
  • the formulation comprised ibuprofen, polyethylene oxide (PEO 301 and PEO 60K), glycine, sodium carbonate, flow agents and various tableting aids, in which PEO was present at a concentration of 31% by weight of ibuprofen, sodium carbonate was present at concentration of 25% by weight of the ibuprofen, and glycine was present at a concentration of 38% by weight of ibuprofen within a monolithic tablet.
  • PEO polyethylene oxide
  • PEO 60K polyethylene oxide
  • sodium carbonate was present at concentration of 25% by weight of the ibuprofen
  • glycine was present at a concentration of 38% by weight of ibuprofen within a monolithic tablet.
  • the results of this Example demonstrate the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the in vitro profile shows greater than 20% release before 2.0 hours with a constant rate release and at least 80% release by 8 hours.
  • the formulation comprised ibuprofen, polyethylene oxide (PEO 301, PEO 60K), glycine, sodium carbonate, flow agents and various tableting aids, in which PEO was present at a concentration of 25% by weight of ibuprofen, sodium carbonate was present at concentration of 25% by weight of the ibuprofen, and glycine was present at a concentration of 25% by weight of ibuprofen within a monolithic tablet.
  • PEO polyethylene oxide
  • PEO 60K polyethylene oxide
  • Na2CO3 100
  • Glycine 100
  • Maltodextrin M-580 100 Stearic acid 10 Silica 10 Total: 820
  • the results of this Example demonstrate the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the in vitro profile shows greater than 20% release before 2.0 hours with a constant rate release and at least 90% release by 8 hours.
  • the formulation comprised ibuprofen, polyethylene oxide (PEO 301), glycine, sodium carbonate, and a stearic acid lubricant, in which PEO was present at a concentration of 25% by weight of ibuprofen, sodium carbonate was present at concentration of 25% by weight of the ibuprofen, and glycine was present at a concentration of 25% by weight of ibuprofen within a monolithic tablet.
  • PEO polyethylene oxide
  • glycine sodium carbonate
  • glycine was present at a concentration of 25% by weight of ibuprofen within a monolithic tablet.
  • the results of this Example demonstrate the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the in vitro profile shows greater than 20% release before 2.0 hours with a constant rate release and at least 80% release.
  • the formulation comprised ibuprofen, polyethylene oxide (PEO 301), glycine, sodium carbonate, croscarmellose sodium, flow agents and various tableting aids, in which PEO was present at a concentration of 25% by weight of ibuprofen, sodium carbonate was present at concentration of 25% by weight of the ibuprofen, and glycine was present at a concentration of 25% by weight of ibuprofen within a monolithic tablet.
  • the specific formulation was as follows: Ex. 18 Mg Ibuprofen 400 PEO 301 100 Na2CO3 100 Glycine 100 Croscarmellose 50 Sodium DCP 150 Stearic acid 10 Total: 910
  • the results of this Example demonstrate the invention is capable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material.
  • the in vitro profile shows greater than 20% release before 2.0 hours with a constant rate release and at least 90% release.
  • BRUFEN RETARD is a commercially available in Europe as a sustained release formulation of ibuprofen.
  • BRUFEN RETARD tablets are specially formulated to allow the gradual release of active substance giving stable levels and a prolonged duration of effect over the dosage interval.
  • BRUFEN RETARD is a film coated tablet with 800 mg of ibuprofen.
  • BRUFEN RETARD is indicated for its analgesic and anti-inflammatory effect in the treatment of rheumatoid arthritis (including juvenile rheumatoid arthritis or Still's disease), ankylosing spondylitis, and osteo-arthritis.
  • BRUFEN RETARD is indicated in the treatment of non-articular rheumatism including fibrositis.
  • BRUFEN RETARD is indicated in periarticular conditions such as frozen shoulder (capsulitis), bursitis, tendinitis, tenosynovitis and low-back pain. BRUFEN RETARD can also be used in soft-tissue injuries such as sprains and strains. BRUFEN RETARD is also indicated for its analgesic effect in the relief of mild to moderate pain such as dysmenorrhea, dental, post-episiotomy pain and post-partum pain.
  • BRUFEN RETARD tablet in vitro release performance was evaluated in a type II dissolution apparatus in 900 mL KH 2 PO 4 buffer, pH 7.2, at 50 rpm paddle speed. As shown in FIG. 17 , the results of this Example demonstrate the in vitro data results of BRUFEN RETARD. The figure shows that BRUFEN RETARD is incapable of an in vitro release profile comprising a burst effect, followed by the sustained release of the remaining material. BRUFEN RETARD fails to deliver to release at least 20% of ibuprofen by 2.0 hours with a constant rate of release with at least 70% release at 14 hours.
  • modified release solid dosages of 1a and 1b from Example 1 were compared to the in vivo behavior of an immediate release formulation (MOTRIN®).
  • the open-label study involved 10 healthy male volunteers over the age of 18. Following an overnight fast of at least ten hours, each subject received either one 600 mg dose of one of the two above described modified release tablets or 200 mg every four hours for 3 doses of the immediate release formulation of MOTRIN® IB or one 600 mg tablet of MOTRIN®. 88 blood samples were taken prior to dosing and at specific intervals up to 12 hours after dosing.
  • the blood samples were kept in ice bath prior to centrifugation and were centrifuge as soon as possible under refrigerated condition at 35000 rpm for seven minutes.
  • the collected plasma from each blood collection tube was aliquotted into pre-cooled labeled polypropylene tubes.
  • the samples were kept in an ice bath, then stored frozen at minus 25° C. ⁇ 10° C. until assayed.
  • the plasma samples were analyzed by a fully validated HPLC method.
  • the analytes were separated by reverse phase chromatography.
  • Evaluation of the assay was carried out by the construction of an eight point calibration curve (excluding zero concentration) covering the range of 0.400 ⁇ g/ml to 51.200 ⁇ g/ml (in human plasma) for ibuprofen.
  • the slope and intercept of the calibration curves were determined through weighted linear regression analysis (1/conc. 2 ). The results are depicted in FIG. 18 .
  • the systematic exposure to ibuprofen after the administration of the one 600 mg ibuprofen tablet 1a or 1b was similar to that obtained when compared to the administration of one MOTRIN® 600 mg tablet.
  • the peak exposure to ibuprofen from one 600 mg ibuprofen tablet 1a or 1b was significantly lower than that from the MOTRIN® 600 mg tablet.
  • the absorption time was modified comparing one 600 mg ibuprofen tablet 1a or 1b (Treatments B & C) with median T max value of 5.0 h to a 1.5 h T max of one MOTRIN® 600 mg tablet.
  • the systematic exposure to ibuprofen after the administration of the one 600 mg ibuprofen tablet 1a or 1b was similar to that obtained when compared to the administration of three MOTRIN® IB 200 mg tablets.
  • the peak exposure to ibuprofen from one 600 mg ibuprofen tablet 1a or 1b was significantly lower than that from three MOTRIN® IB 200 mg tablets.
  • the absorption time was modified comparing one 600 mg ibuprofen tablet 1a or 1b (Treatments B & C) with median T max value of 5.0 h to a 1.0 h T max of three MOTRIN® IB 200 mg tablet.
  • FIG. 18 depicts the results discussed above.
  • Treatment D shows an initial burst that falls to a valley at four hours and the second tablet is administered. This valley again happens at the eighth hour. This valley constitutes the minimum plasma concentration for ibuprofen to be considered therapeutic.
  • a mean ibuprofen plasma concentration of about 6.4-10 ⁇ g/ml is considered the concentration of ibuprofen needed in the blood to be considered clinically effective.
  • Treatment E shows an extreme initial burst of ibuprofen followed by a steady decline that falls below therapeutic threshold at about 6 hours.
  • Treatments B and C have an initial burst of ibuprofen that reaches the level of 6.4 ⁇ g/ml at about 0.5 to 1 hour and maintains the level until about hour 12.
  • the present invention provides for a single dosage of ibuprofen that provides an initial burst similar to an immediate release formulation of ibuprofen and then provides a mean ibuprofen plasma concentration of above 6.4 ⁇ g/ml for about 12 hours.
  • the formulation comprised two viscosities of HPMC, two particle sizes of silicified MCC, in combination with croscarmellose and glycine, and a stearic acid lubricant, in which the combined HPMC was present at about 32% based on the ibuprofen present in the formulation in HPMC K100LV and HPMC K4M were present in a weight ratio of about 2:1 respectively, and silicified MCC was present as Prosolv50 and Prosolv90 in a weight ratio of about 2:1 at a combined concentration of about 50% based on the ibuprofen present in the formulation within a monolithic tablet.
  • the formulation comprised two viscosities of HPMC, two particle sizes of silicified MCC, in combination with croscarmellose and glycine, and a stearic acid lubricant.
  • This formulation is similar in its proportions to the formulation of example 21, except that the resulting monolithic tablets contained approximately half of the quantities of example 21.
  • this formulation comprised a two-tablet dosage unit having essentially the same ingredients as example 21.
  • This formulation comprised two different viscosities of HPMC and two different particle sizes of silicified MCC, together with croscarmellose and glycine, as also exemplified in Example 21.
  • silicified MCC was present at a concentration of about 42% based on the ibuprofen present, and the weight ratio of Prosolv 50 to Prosolve 90 was about 1:1.5.
  • the ibuprofen was pre-blended with 6 mg silica in a V-blender at about a 1:100 ratio.
  • the dry pre-blended ibuprofen powder was then blended with the remaining excipients.
  • the resulting powder was compressed into tablets using conventional technologies.

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US11/633,322 US20070077297A1 (en) 2004-09-30 2006-12-04 Modified release ibuprofen dosage form
US11/906,303 US7749537B2 (en) 2006-12-04 2007-10-01 Method of forming a tablet
PCT/US2007/024496 WO2008069941A2 (en) 2006-12-04 2007-11-28 Modified release ibuprofen solid oral dosage form
MX2009005959A MX2009005959A (es) 2006-12-04 2007-11-28 Metodo para formar una tableta que comprende el premezclado de ibuprofeno y silice.
PL07862281T PL2099432T3 (pl) 2006-12-04 2007-11-28 Sposób wytwarzania tabletki zawierającej wstępną mieszankę ibuprofenu i dwutlenku krzemu
KR20097014019A KR20090086468A (ko) 2006-12-04 2007-11-28 개질된 방출 이부프로펜 투여 형태
AU2007328393A AU2007328393A1 (en) 2006-12-04 2007-11-28 Modified release ibuprofen solid oral dosage form
AU2007328390A AU2007328390B2 (en) 2006-12-04 2007-11-28 Method of forming a tablet comprising pre-blend of ibupropen and silicon dioxide
JP2009539301A JP2010511613A (ja) 2006-12-04 2007-11-28 錠剤を形成する方法
BRPI0717916A BRPI0717916A8 (pt) 2006-12-04 2007-11-28 forma de dosagem sólida para liberação modificada e método para a liberação modificada de ibuprofeno
JP2009539304A JP2010511614A (ja) 2006-12-04 2007-11-28 改変放出イブプロフェン剤形
KR1020097014021A KR20090090369A (ko) 2006-12-04 2007-11-28 정제의 형성 방법
CN2007800505822A CN101588793B (zh) 2006-12-04 2007-11-28 包括预混合布洛芬和二氧化硅的形成片剂的方法
CA002671420A CA2671420A1 (en) 2006-12-04 2007-11-28 Method of forming a tablet
EP20070862287 EP2099433A2 (en) 2006-12-04 2007-11-28 Modified release ibuprofen solid oral dosage form
CA 2670887 CA2670887A1 (en) 2006-12-04 2007-11-28 Modified release ibuprofen solid oral dosage form
MX2009005958A MX2009005958A (es) 2006-12-04 2007-11-28 Forma de dosis oral de ibuprofeno solido de liberacion modificada.
PCT/US2007/024489 WO2008069938A2 (en) 2006-12-04 2007-11-28 Method of forming a tablet comprising pre-blend of ibupropen and silicon dioxide
EP07862281A EP2099432B1 (en) 2006-12-04 2007-11-28 Method of forming a tablet comprising pre-blend of ibuprofen and silicon dioxide
CNA2007800505381A CN101594853A (zh) 2006-12-04 2007-11-28 调释布洛芬固体口服剂型
BRPI0717914-6A BRPI0717914A2 (pt) 2006-12-04 2007-11-28 "metodo de formação de um comprimido"
TW96146116A TW200831135A (en) 2006-12-04 2007-12-04 Modified release ibuprofen dosage form
TW096146118A TW200831136A (en) 2006-12-04 2007-12-04 Method of forming a tablet
IL199191A IL199191A0 (en) 2006-12-04 2009-06-04 Modified release ibuprofen solid oral dosage form
ZA200904436A ZA200904436B (en) 2006-12-04 2009-06-25 Modified release ibuprofen solid oral dosage form
CO09068963A CO6190599A2 (es) 2006-12-04 2009-07-03 Forma de dosis de ibuprofeno modificada
CO09068966A CO6190600A2 (es) 2006-12-04 2009-07-03 Metodo para formar una tableta que comprende el premezclado de ibuprofeno y silice
US12/706,429 US9028869B2 (en) 2004-09-30 2010-02-16 Modified release ibuprofen dosage form
US14/611,372 US9730895B2 (en) 2004-09-30 2015-02-02 Method for providing modified release of ibuprofen

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US68963105P 2005-06-10 2005-06-10
US11/238,802 US20060068009A1 (en) 2004-09-30 2005-09-29 Modified release ibuprofen dosage form
US11/633,322 US20070077297A1 (en) 2004-09-30 2006-12-04 Modified release ibuprofen dosage form

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US14/611,372 Active US9730895B2 (en) 2004-09-30 2015-02-02 Method for providing modified release of ibuprofen

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AU (1) AU2007328393A1 (zh)
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US20100143466A1 (en) * 2004-09-30 2010-06-10 Scolr Pharma, Inc. Modified release ibuprofen dosage form
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