Classifications

• • B—PERFORMING OPERATIONS; TRANSPORTING
  • B82—NANOTECHNOLOGY
  • B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
  • B82Y5/00—Nanobiotechnology or nanomedicine, e.g. protein engineering or drug delivery
• • 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
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
  • A61K31/5375—1,4-Oxazines, e.g. morpholine
  • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
• • 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
  • A61K47/50—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
  • A61K47/69—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
  • A61K47/6949—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
  • A61K47/6951—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 the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
• • 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
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
  • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P17/00—Drugs for dermatological disorders
  • A61P17/06—Antipsoriatics
• • 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

• the present invention relates to unique oral dosage formulations of l-(5-
• urea a pharmacological agent exhibiting novel anti-inflammatory activity. More
• the present invention relates to oral dosage formulations of l-(5-tert-butyl-2-
• BIRB 796 l-(5-tert-butyl-2-p-tolyl-2H-pyrazol-3-yl)-3-[4-(2-morpholin-4-yl-ethoxy)- naphthalen-l-yl]-urea
• cytokines such as tumor necrosis factor (TNF) and interleukin-1 (IL-1).
• TNF tumor necrosis factor
• IL-1 interleukin-1
• the polymorphs generally exist in the form of elongated needles.
• BIRB 796 is relatively poorly soluble in physiological
• polymorphic BIRB 796 drug substance (Form IV) has been determined to be about 0.5 ug/ml at pH 7.4 and about 10 mg/ml at pH 2.0.
• BIRB 796 may be administered by the many routes of administration
• preferred route of administration is oral administration by way of, for example, tablets,
• tablets may be prepared by addition of excipient, binder, disintegrant, lubricant and so on,
• a main coating agent such as, but not limited to, hydroxypropylmethylcellulose, hydroxymethylcellulose, hydroxypropyl cellulose and
• Formulations have been prepared which deliver doses from 0.5 mg to 300 mg.
• ionic strength may have significant adverse impacts on the overall bioavailability of BIRB
• the present invention discloses formulations of BIRB 796, and processes
• BIRB 796 drug substance may be significantly improved (adherence to surfaces reduced),
• Such granular compositions of BIRB 796 have
• solubility is peculiarly affected by the ionicity of its attendant milieu.
• aqueous solubility of BIRB 796 has been found to significantly decrease as the ionic strength of its milieu increases. Decreased dissolution has been found to affect overall » bioavailability of drugs.
• Such improved formulation includes a
• inclusion compound it is meant a compound capable of forming a cage structure with an unrelated molecule so as to form a well-defined addition structure (the
• preferred inclusion compound of the present invention contains amylose moieties.
• particularly preferred inclusion compound is cyclodextrin.
• cyclodextrin is ⁇ -cyclodextrin.
• beta-cyclodextrin:BIRB 796 weight ratio be at least about 1, more preferably to be at
• compression i.e. tablets and the like
• core tablet contains substantial amounts bf cyclodextrin (> about 40%), In particular,
• coatings applied to compressions (such as core tablets) containing beta-cyclodextrin need to be applied at temperatures below 40°C, more preferably below 39°C, temperatures
• T max concentration
• One aspect of the present invention consists of a pharmaceutical oral
• dosage form comprsing (a) a pharmaceutically effective dose of BIRB 796; and (b) a
• an aqueous soluble inclusion compound that is capable of forming a complex with BIRB 796 in its aqueous state so as to substantially
• composition comprising: (a) a homogenous core comprising granulated BIRB
• composition comprising: (a) between about 0.1 to about 35% by weight granulated BIRB 796; (b) between about 25 to about 50% by weight binding agent; (c)
• Fig. 1 is a graph of the solubility ( ⁇ g/ml) of BIRB 796 versus ionic strength
• Fig. 2 is a graph of the solubility ( ⁇ g/ml) of BIRB 796 versus ionic strength
• f Fig. 3 ⁇ is a graph of the percentage of 100 mg of BIRB 796 dissolved in an
• Fig. 3 b is a graph of the percentage of 100 mg of BIRB 796 dissolved in an
• Fig. 4 ⁇ is a graph of the percentage of 100 mg of BIRB 796 dissolved in an
• Fig. 4b is a graph of the percentage of 100 mg of BIRB 796 dissolved in an
• t Fig. 5 is a graph of mean BIRB 796 plasma concentration after oral
• the present invention overcomes many of the problems associated with the
• invention provides novel formulations of BIRB 796 that improve the solubility and bioavailabilty of BIRB 796 in oral dosage forms, as well as its powder flow properties
• BIRB 796 is a fine powder with poor flow characteristics
• BIRB 796 is also a poorly soluble
• the present invention provides for the economical production and processing of physiochemically stable oral dosage forms of BIRB 796 with improved
• the portion of granules that do not pass through a 1000 micron sieve should not account for more than about 5 percent by weight of the total granules, the amount that do not pass through a 250 micron sieve should not account for
• milling methods known in the art may also be used to produce such a granule distribution.
• solubility of BIRB 796 decreases. Similarly, as shown in Fig. 2, the solubility of BIRB
• the decrease in aqueous solubility of the drug may have
• aqueous-soluble inclusion compound preferably polymeric in
• solubility of BIRB 796 can be significantly
• amylose moieties are unexpectedly useful in aiding dissolution of BIRB 796.
• a particularly preferred inclusion compound is cyclodextrin.
• cyclodextrins are particularly preferred.
• ⁇ -cyclodextrin has been found to be particularly advantageous.
• beta-cyclodextrin be incorporated into
• BIRB formulation in an amount (weight basis) at least about that of BIRB 796, more
• beta-cyclodextrin is used with BIRB 796 to form
• Figs. 3a and 3b illustrate in graphic form the effect of beta-cyclodextrin on
• BIRB 796 solubility (as a percent of 100 mg of BIRB 796 dissolved) in an aqueous
• BCD beta-cyclodextrin
• beta-cyclodextrin reduces the impact of
• Figs. 4a and 4b illustrate in graphic form the effect of beta-cyclodextrin on
• beta-cyclodextrin to one part BIRB 796 (middle curve) > 3.7 parts lactose to one part
• beta-cyclodextrin on BIRB 796 solubility (as a percent of 100
• test tablets were dosed in a crossover fashion with 100 mg test tablets containing either lactose or beta-cyclodextrin.
• the composition of the tablets used in the study are set forth below in
• Fig. 5 sets for in graphical form mean BIRB 796 plasma concentration after
• the blend may be used to make a number of
• oral dosage forms including tablets, filled hard gelatin capsules (of different sizes and/or
• net fills caplets, powder papers, cachets, granules, etc.
• a light/heat absorbing coating preferably a water dispersible
• Tablet coatings preferably comprise 2 - 3%, more preferably about
• BIRB 796 has been found to be pharmaceutically compatible with a
• a preferred tablet formulation of BIRB BIRB
• soluble granulation aid such as lactose monohydrate
• binding agent such as lactose monohydrate
• a granulating binding agent such as povidone
• dry binding agent such as povidone
• microcrystalline cellulose such as microcrystalline cellulose
• disintegrants such as pre-gelatinized starch and
• sodium starch glycolate sodium starch glycolate
• a flow aid such as colloidal silicon dioxide
• a lubricant such as colloidal silicon dioxide
• BIRB 796 tablet (such as magnesium stearate). It is preferred in order to produce a BIRB 796 tablet with a
• granulation aid(s) comprise between 40 to 50% of the tablet weight
• the dry binding agent(s) comprise between 30 to 50% of the tablet weight
• the disintegrant(s) comprise
• the flow aid(s) comprise between 0.25 to 1 % of the
• the lubricant(s) comprise between 0.5 to 1% of the tablet weight.
• Buffering agents may also be added (typically comprising less than 1% of the total tablet
• the wet granulation was then spread onto stainless steel trays and dried in an oven at 40 - 50°C to an LOD of 2%. The dried granules were then milled through an 18 mesh
• tabletted using tablet tooling and adjusting the tablet weight for the appropriate potency.
• BIRB 796 was solubilized in a pH 2, phosphate buffer to prepare a spray
• Lactose monohydrate and povidone K30 were mixed and heated with low
• Microcrystalline cellulose, pre-gelatinized starch, sodium starch glycolate, and colloidal silicon dioxide were then screened through an 18 mesh screen into
• Tablets may be prepared from the respective
• the tablets may be film coated.
• Tablets may be coated to a weight increase of about 2 to about 3%, preferably about 2.5%.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• General Health & Medical Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Engineering & Computer Science (AREA)
• Veterinary Medicine (AREA)
• Public Health (AREA)
• Animal Behavior & Ethology (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Epidemiology (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Organic Chemistry (AREA)
• Nanotechnology (AREA)
• Molecular Biology (AREA)
• Biophysics (AREA)
• General Engineering & Computer Science (AREA)
• Rheumatology (AREA)
• Crystallography & Structural Chemistry (AREA)
• Medical Informatics (AREA)
• Biotechnology (AREA)
• Pain & Pain Management (AREA)
• Dermatology (AREA)
• Physical Education & Sports Medicine (AREA)
• Orthopedic Medicine & Surgery (AREA)
• Immunology (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (2)

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Cited By (18)

Families Citing this family (11)

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• 2001
  • 2001-07-11 US US09/902,822 patent/US6565880B2/en not_active Expired - Lifetime
  • 2001-07-11 JP JP2002513505A patent/JP2004504360A/ja active Pending
  • 2001-07-11 CA CA002415131A patent/CA2415131A1/en not_active Abandoned
  • 2001-07-11 MX MXPA02012909A patent/MXPA02012909A/es active IP Right Grant
  • 2001-07-11 EP EP01984305A patent/EP1305050A2/en not_active Withdrawn
  • 2001-07-11 WO PCT/US2001/021860 patent/WO2002007772A2/en not_active Ceased

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