EP1517676A1 - Oral dosage forms comprising fenofibrate - Google Patents

Oral dosage forms comprising fenofibrate

Info

Publication number
EP1517676A1
EP1517676A1 EP03722005A EP03722005A EP1517676A1 EP 1517676 A1 EP1517676 A1 EP 1517676A1 EP 03722005 A EP03722005 A EP 03722005A EP 03722005 A EP03722005 A EP 03722005A EP 1517676 A1 EP1517676 A1 EP 1517676A1
Authority
EP
European Patent Office
Prior art keywords
dosage form
fenofibrate
amount
present
phosphohpid
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
EP03722005A
Other languages
German (de)
English (en)
French (fr)
Inventor
Michael Vachon
Mishra K. Awedesh
Robert A. Snow
Pol-Henri Guivarc'h
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.)
Skyepharma Canada Inc
Original Assignee
Skyepharma Canada Inc
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 Skyepharma Canada Inc filed Critical Skyepharma Canada Inc
Priority to EP10000401A priority Critical patent/EP2228060A1/en
Publication of EP1517676A1 publication Critical patent/EP1517676A1/en
Ceased legal-status Critical Current

Links

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
    • A61K9/20—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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/282—Organic compounds, e.g. 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806—Coating materials
    • A61K9/2833—Organic macromolecular compounds
    • A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • 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
    • A61P19/06—Antigout agents, e.g. antihyperuricemic or uricosuric agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/06—Antihyperlipidemics
    • 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

  • fenofibric acid a fibrate active species which has an elimination half-life of approximately twenty hours.
  • Fenofibric acid lowers plasma triglycerides by potentially inhibiting triglyceride synthesis leading to a reduciton of VLDL released into the circulation.
  • Fenofibric acid also stimulates the catabolism of triglyceride-rich lipoprotein (VLDL).
  • Ben-Armor solubilized fenofibrate in nonaqueous dimethyl isosorbide with a miscible wetting agent to improve its bioavailability Colloidal silicon oxide was added to mcrease the viscosity, and the liquid so obtained was placed in hard gelatin capsules and sealed. In vivo studies with this formulation indicated no statistically significant difference in bioavailability between the liquid formulation and a conventional form when the product was given with food.
  • compositions and methods to enhance the bioavailabilty of fibrates such as fenofibrate from various dosage forms none sufficiently address the need to substantially reduce or eliminate the difference between the amount of the drug taken up in patients who are fasting versus the otherwise enhanced uptake of the drug in patients who are fed or take food with or proximal to the taking of a dosage form of a fibrate.
  • a fibrate such as fenofibrate
  • the first homogenization step is done on a heated suspension having the poorly water soluble drug in a molten phase in the presence of one or more than one surface active substance to provide a heated homogenate containing the drug.
  • the heated homogenate is usually in the form of a microemulsion comprising small molten particles or droplets of drug stabilized by one or more than one surface active substance.
  • the heated homogenate containing the drug is then cooled to provide a transiently stable cooled homogenate containing the drug.
  • the aqueous carrier can be maintained at the first temperature range generally without the need of pressurization to maintain the aqueous carrier as a liquid during the heated homogenization process, hi another aspect of this invention, preferred suitable drugs melt without decomposition in the range from at the boiling point of the aqueous carrier under ambient pressure, i.e., from 100 °C up to 275 °C.
  • the aqueous carrier can be maintained at the first temperature range generally by using a pressurized apparatus to maintain the aqueous carrier as a liquid during the heated homogenization process.
  • Lipoid E80 is from about 1% to 15%, more preferably from about 2% to about 10%, and most preferably from 3 to 5%.
  • the admixture of the drag, for example fenofibrate, and a surface active substance such as a phosphohpid substance in an aqueous carrier is heated to a first temperature range during the application of a high shear mixing to produce a heated suspension containing the drug.
  • Method 6 slow stepwise cooling from above the melting point of the drug to about 40 °C below the melting point of the drug which for fenofibrate is from about 85 °C to about 40 °C at the rate of 1 Centigrade degree per minute.
  • Bulking agents are useful as protectants in a drying process such as cryoprotectants in a lyophilization process or as additives in a spray drying process or an evaporation process, preventing or substantially reducing particle fusion, combination, suspension degradation and agglomeration during drying, and assisting in the resuspension of particles from a dried state.
  • Dry small particles containing a poorly water soluble drug can be produced for example as a lyophilizate which is a solid produced from a cooled dispersion of particles by the process of freezing the aqueous carrier to a solid comprising a dispersion in ice and then removing the water by subliming the ice under reduced pressure.
  • Bulking agents can also reduce or depress the freezing point of aqueous compositions in which they are dissolved or partially dissolved.
  • Phosphatidyl choline can be present in an amount up to 20% of the total weight of phosphohpid in the suspension, preferably in a range from about 0.1 %> to about 15% of the total weight of phosphohpid in the suspension, and more preferably from about 1% to about 10% of the total weight of phosphohpid in the suspension.
  • egg phosphohpid useful in the pre-mix to form a suspension of phosphohpid comprises sphingomyelin.
  • a preferred bulking agent that is added to the suspension is maltodextrin such as, for example, commercially available maltodextrin known as Maltrin Ml 80, Maltrin Ml 00, Maltrin M040, and the like.
  • the composition produced comprises granules of lactose beads coated with bulking agent in the form of a matrix in which is embedded phosphohpid not associated with the fenofibrate microparticles, phospholipid-stabilized fenofibrate microparticles, and phosphate buffer salt.
  • the granules can be separate or can be agglomerated.
  • the support, e.g., beads can be of any suitable size; for example, lactose beads, in an embodiment, can have a diameter of from 0.2 mm to 2 mm.
  • Such exposed surface of a water soluble support such as lactose will be readily hydrated and dissolve when exposed to an aqueous medium together with the matrix bulking agent and buffer salt and liberate the phospholipid-coated microparticles at a rate that is 1.1 to 10 times, or even to 100 times, or even to 1000 times faster than the rate of release from a granule comprising a support that is completely coated with the fluid bed dried composition comprising bulking agent as a matrix in which is embedded phosphohpid, phospholipid-stabilized microparticles of fenofibrate, and phosphate buffer salt at 20 °C or at 37 °C.
  • the aqueous carrier of the cooled dispersion is frozen and lyophilized under reduced pressure and application of heat to the frozen suspension to provide a lyophilizate comprising small particles containing poorly soluble drug.
  • Freezing and lyophilization are preferably done in a conventional freeze dryer, for example, in a Virtis Corporation Unitop freeze dryer using conventional techniques. Lyophilization can be done on cooled dispersions added to trays or on cooled dispersions added to vials, for example in 2 mL or 10 mL vials. Bulking agents can be added to the formulation to facilitate reconstitution of the lyophilizate.
  • small particles containing a poorly water soluble drag particles in the range of 0.1 micron to 20 micrometers in average diameter containing a poorly water soluble drug, preferably in the range of 0.1 to 5 micrometers containing a poorly water soluble drag, and most preferably in the range of 0.1 to 2 micron containing a poorly water soluble drug.
  • Additional currently preferred dosage levels contain 50 mg, 67 mg, 100 mg, 134 mg, 150 mg, 160 mg, 200 mg and 213 mg of fenofibrate as microparticles stabilized with phosphohpid.
  • Capsules and tablets for oral administration provide fenofibrate to a human patient in need of treatment by fenofibrate that is relatively independent of food effect.
  • a patient in a fasted state will receive at least 80 % of the dose of the drag that a patient in a fed state will receive by taking the same capsule or tablet dosage form (at the same level of drug per unit dosage form, i.e., at the same number of mg of drag per tablet or capsule given to the same patient when fasted as when fed).
  • This invention also discloses the above process comprising a first temperature range, wherem the first temperature range is at or above the melting point of fenofibrate or in the range of about 82 °C to about 100 °C.
  • This invention also discloses the above process comprising an aqueous carrier, wherem the aqueous carrier is phosphate buffered water having a pH from 7 to 9.
  • the cellulosic additive is present in an amount of from about 3% w/w to about 8% w/w of the dosage form.
  • the phosphohpid is an egg lecithin.
  • the present invention further provides a pharmaceutically acceptable tablet dosage form of fenofibrate comprising fenofibrate present in an amount of from about 15% w/w to about 20 % w/w of the dosage form; phosphohpid present in an amount of from about 1% w/w to about 8% w/w of the dosage form; a buffer salt present in an amount of from about 0.1% w/w to about 0.5% w/w of the dosage form; a water-soluble bulking agent selected from maltodextrin, mannitol, and a combination thereof present in an amount of from about 7% w/w to about 20%> w/w of the dosage form; a cellulosic additive present in an amount of from about 3%> w/w to about 8% w/w of the dosage form; beads or crystals of a pharmaceutically acceptable water-soluble excipient support material present in an amount of from about 12% w/w to 16%> w/w of the dosage form; a polyviny
  • the fenofibrate is present in an amount of from 45 to 51 mg per dosage form.
  • a two-treatment, two-period, two-sequence crossover clinical study was performed to evaluate the relative bioavailability of fenofibric acid in blood in 24 healthy volunteers after single dose oral administration of a tablet formulation of this invention comprising phosphohpid stabilized microparticles of fenofibrate.

Landscapes

  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Epidemiology (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Hematology (AREA)
  • Diabetes (AREA)
  • Obesity (AREA)
  • Emergency Medicine (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Physical Education & Sports Medicine (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
EP03722005A 2002-05-03 2003-05-02 Oral dosage forms comprising fenofibrate Ceased EP1517676A1 (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP10000401A EP2228060A1 (en) 2002-05-03 2003-05-02 Oral dosage forms comprising fenofibrate

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US37723702P 2002-05-03 2002-05-03
US377237P 2002-05-03
PCT/US2003/013865 WO2003092659A1 (en) 2002-05-03 2003-05-02 Oral dosage forms comprising fenofibrate

Publications (1)

Publication Number Publication Date
EP1517676A1 true EP1517676A1 (en) 2005-03-30

Family

ID=29401461

Family Applications (2)

Application Number Title Priority Date Filing Date
EP03722005A Ceased EP1517676A1 (en) 2002-05-03 2003-05-02 Oral dosage forms comprising fenofibrate
EP10000401A Withdrawn EP2228060A1 (en) 2002-05-03 2003-05-02 Oral dosage forms comprising fenofibrate

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP10000401A Withdrawn EP2228060A1 (en) 2002-05-03 2003-05-02 Oral dosage forms comprising fenofibrate

Country Status (5)

Country Link
EP (2) EP1517676A1 (enExample)
JP (1) JP2005535582A (enExample)
AU (1) AU2003225285A1 (enExample)
CA (1) CA2484375C (enExample)
WO (1) WO2003092659A1 (enExample)

Families Citing this family (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
TWI347942B (en) * 2005-06-22 2011-09-01 Lundbeck & Co As H Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
US7834201B2 (en) 2005-06-22 2010-11-16 H. Lundbeck A/S Crystalline base of escitalopram and orodispersible tablets comprising escitalopram base
MX2009000035A (es) * 2006-06-26 2009-05-28 Mutual Pharmaceutical Co Formulaciones de agente activo, procedimientos de preparacion y procedimientos de uso.
FR2940118B1 (fr) * 2008-12-24 2013-08-09 Ethypharm Sa Formulation pharmaceutique de fenofibrate nanonise
US8685458B2 (en) 2009-03-05 2014-04-01 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives
WO2010111132A2 (en) 2009-03-27 2010-09-30 Bend Research, Inc. Spray-drying process
US9084976B2 (en) 2010-09-03 2015-07-21 Bend Research, Inc. Spray-drying apparatus and methods of using the same
PT2611530T (pt) 2010-09-03 2019-05-09 Bend Res Inc Aparelho de secagem por pulverização e métodos de utilização do mesmo
US8815294B2 (en) 2010-09-03 2014-08-26 Bend Research, Inc. Pharmaceutical compositions of dextran polymer derivatives and a carrier material
EP2618924A1 (en) 2010-09-24 2013-07-31 Bend Research, Inc. High-temperature spray drying process and apparatus
US9060938B2 (en) 2011-05-10 2015-06-23 Bend Research, Inc. Pharmaceutical compositions of active agents and cationic dextran polymer derivatives
CA2962719A1 (en) 2014-10-31 2016-05-06 Bend Research Inc. Process for forming active domains dispersed in a matrix
WO2016196648A1 (en) * 2015-06-01 2016-12-08 Autotelic Llc Phospholipid-coated therapeutic agent nanoparticles and related methods
CN106552266A (zh) * 2015-09-25 2017-04-05 英创远达制药公司 一种美法仑口服制剂

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2758459B1 (fr) * 1997-01-17 1999-05-07 Pharma Pass Composition pharmaceutique de fenofibrate presentant une biodisponibilite elevee et son procede de preparation
EP1320362B1 (en) * 2000-09-20 2011-08-31 Jagotec AG Stabilised fibrate microparticles
FR2819720B1 (fr) * 2001-01-22 2004-03-12 Fournier Lab Sa Nouveaux comprimes de fenofibrate

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO03092659A1 *

Also Published As

Publication number Publication date
CA2484375C (en) 2012-04-10
AU2003225285A1 (en) 2003-11-17
EP2228060A1 (en) 2010-09-15
JP2005535582A (ja) 2005-11-24
CA2484375A1 (en) 2003-11-13
WO2003092659A1 (en) 2003-11-13

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