US20090148531A1 - Rate-controlled particles - Google Patents

Rate-controlled particles Download PDF

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Publication number
US20090148531A1
US20090148531A1 US12/368,884 US36888409A US2009148531A1 US 20090148531 A1 US20090148531 A1 US 20090148531A1 US 36888409 A US36888409 A US 36888409A US 2009148531 A1 US2009148531 A1 US 2009148531A1
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US
United States
Prior art keywords
amino
alkyl
cyano
substituted
alkyloxy
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.)
Abandoned
Application number
US12/368,884
Other languages
English (en)
Inventor
Thomas Hantke
Bettina Rehbock
Joerg Rosenberg
Joerg Breitenbach
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.)
Janssen R&D Ireland ULC
Original Assignee
Tibotec Pharmaceuticals Ltd
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 Tibotec Pharmaceuticals Ltd filed Critical Tibotec Pharmaceuticals Ltd
Priority to US12/368,884 priority Critical patent/US20090148531A1/en
Publication of US20090148531A1 publication Critical patent/US20090148531A1/en
Priority to US13/420,013 priority patent/US9028876B2/en
Assigned to JANSSEN R&D IRELAND reassignment JANSSEN R&D IRELAND CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: TIBOTEC PHARMACEUTICALS
Assigned to TIBOTEC PHARMACEUTICALS reassignment TIBOTEC PHARMACEUTICALS CHANGE OF NAME (SEE DOCUMENT FOR DETAILS). Assignors: TIBOTEC PHARMACEUTICALS, LTD.
Abandoned legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/48—Two nitrogen atoms
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • 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
    • A61K31/53—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with three nitrogens as the only ring hetero atoms, e.g. chlorazanil, melamine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/46—Two or more oxygen, sulphur or nitrogen atoms
    • C07D239/50—Three nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D251/00—Heterocyclic compounds containing 1,3,5-triazine rings
    • C07D251/02—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings
    • C07D251/12—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members
    • C07D251/14—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom
    • C07D251/16—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom
    • C07D251/18—Heterocyclic compounds containing 1,3,5-triazine rings not condensed with other rings having three double bonds between ring members or between ring members and non-ring members with hydrogen or carbon atoms directly attached to at least one ring carbon atom to only one ring carbon atom with nitrogen atoms directly attached to the two other ring carbon atoms, e.g. guanamines
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • 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
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • the present invention concerns pharmaceutical compositions in the form of rate-controlled particles, comprising compounds of the formula (I) to (VI)
  • the compounds of formula (I) can be prepared according to the methods described in the patent applications with application number PCT/EP99/02043 and PCT/EP99/02044.
  • each A independently is N, CH or CR 6 ;
  • the compounds of formula (II) can be prepared according to the methods described in the U.S. patent applications with application No. 60/143,962 and 60/107,792.
  • each A independently is N, CH or CR 4 ;
  • the compounds of formula (III) can be prepared according to the methods described in the U.S. patent application with application No. 60/107,799.
  • Ar 1 is phenyl, or phenyl substituted with one, two or three substituents each independently selected from halo, C 1-6 alkyl, C 1-6 alkyloxy, cyano, nitro or trifluoromethyl; with the proviso that compounds (a) to (o)
  • the compounds of formula (IV) can be prepared according to the methods described in EP-A-0834507.
  • the compounds of formula (V) can be prepared according to the methods described in WO 99/02523.
  • (VI) is an apolipoprotein-B synthesis inhibitor of formula
  • the hydrogen atom in the bivalent radicals of formula (a) and (b) the hydrogen atom may be replaced by C 1-6 alkyl; in the bivalent radicals of formula (c), (d), (e), (f), one or two hydrogen atoms may be replaced by C 1-6 alkyl;
  • Het is bound to the sulfur atom via a carbon atom.
  • the compounds of formula (VI) can be prepared according to the methods described in WO 96/13499.
  • the particles comprise the compounds of formula (I) to (VI) as a solid dispersion in a polymeric matrix, wherein the polymeric matrix is consisting of a homo- or copolymer of N-vinyl-pyrrolidone. Furthermore, the invention concerns a process for manufacturing of such particles and pharmaceutical dosage forms comprising such particles.
  • the compounds of formula (I) to (VI) contained in the particles show poor bio-availability.
  • the compounds are dispersed in a polymeric matrix, preferably by using a melt-extrusion process.
  • EP-A 0 240 904 discloses a method for producing solid pharmaceutical forms by extrusion of polymer melts which contain active substances, using as polymers homo- or copolymers of N-vinyl-pyrrolidone.
  • EP-B 0 580 860 discloses a method for producing solid dispersions of drug substances in a polymeric matrix using a twin screw extruder.
  • Preferred compounds according to the invention are:
  • rate-controlled means that depending on the composition of the matrix the particles can show instant release of the active ingredient or modified release (sustained release).
  • the compounds according to the invention are homogeneously dispersed in a polymer matrix consisting of a homopolymer of N-vinylpyrrolidone or, preferably, a copolymer of N-vinyl-pyrrolidone.
  • a preferred copolymer is a copolymer of N-vinyl-pyrrolidone and vinyl acetate, especially a copolymer obtained from 60% b.w. of NVP and 40% b.w. of vinylacetate.
  • the polymers show Fikentscher K values of from 17 to 90, preferably a K value of 30 (for the definition of the K value see “H. Fikentscher, Cellulose-Chemie” (1932), 58-64 and 71-74).
  • the polymeric matrix component is used in amounts of from 40 to 70, preferably of from 50 to 65% b.w. of the total weight of the particles.
  • the polymeric matrix further comprises a surfactant, preferably a surfactant with a HLB-value of 10-18 (HLB: Hydrophilic Lipophilic Balance).
  • a surfactant preferably a surfactant with a HLB-value of 10-18 (HLB: Hydrophilic Lipophilic Balance).
  • HLB Hydrophilic Lipophilic Balance
  • Especially preferred surfactants are selected form the group consisting of low molecular weight polyoxyethylene polyoxy-propylene block copolymers with a mean molecular weight of 1000 to 6000 g/mol, and hydrogenated castor oil which can be modified with polyethylene glycol.
  • the amounts of surfactants used lies in the range of up to 20% b.w., preferably 5 to 15% b.w., of the particles.
  • the matrix further comprises an organic carboxylic acid in amounts of up to 5% b.w. of the particles.
  • the polymeric matrix further comprises hydroxypropyl methyl cellulose in amounts of up to 25% b.w., preferably from 5 to 10% b.w.
  • the particles of the present invention are prepared as solid dispersions of the active compounds in a polymeric matrix.
  • solid dispersion is well known in the art and means a dispersion consisting of solid components.
  • solid dispersions are in the form of solid solutions wherein the active ingredients are molecularly dispersed in the polymeric matrix.
  • Such solid dispersion is preferably obtained by forming a homogeneous mixture of the components in the form of a melt, extruding said melt and shaping of the extrudate.
  • the melting is effected by the input of thermal and/or mechanic energy.
  • the melting takes place in the range of from 40° C. to 190° C., preferably 50 to 150° C.
  • the suitable temperature range depends on the glass transition temperature of the polymer component, the properties of the active ingredients and further additives. The optimal temperature range can be established by a few simple tests.
  • the mixing of the active substances with the polymer and additional components of the matrix can take place before or after the melting of the polymer.
  • the process is solvent-free which means that no additional organic solvents or water are added.
  • the plastification and melting preferably can take place in an extruder, a kneader or a mixing reactor, preferably in an extruder having one or more screws which may rotate in the same direction or opposite directions, especially in a twin screw extruder.
  • the latter can be operated with or without kneading elements, but use of kneading elements is preferred because mixing is better.
  • the still plastic material is extruded through a die or a breaker plate and then shaped into particles. This may be effected by milling and subsequent sieving the cooled extrudate.
  • the preferred particle size for instant release forms lies in the range of from 0.5 to 1.5 mm.
  • the particles may be further processed to conventional pharmaceutical dosage forms such as tablets, pastilles, suppositories, or be packed in capsules.
  • Powder mixes of the components were melt kneaded at 145° C. for 5 min. After cooling the solidified melts were ground and sieved. The sieve fraction 0.5-1.5 mm was used for the dissolution tests.
  • composition of the individual powder mixes is listed in Table 1.
  • DSC-Measurements were performed with the formulations according to examples 1 to 6 in open pans (air) at temperatures of from 20 ⁇ 250° C., with a heating rate of 10° C. per minute. There is no indication of crystalline drug substance in the solid dispersions.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Virology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Glanulating (AREA)
  • Medicinal Preparation (AREA)
US12/368,884 1999-09-24 2009-02-10 Rate-controlled particles Abandoned US20090148531A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/368,884 US20090148531A1 (en) 1999-09-24 2009-02-10 Rate-controlled particles
US13/420,013 US9028876B2 (en) 1999-09-24 2012-03-14 Rate-controlled particles

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
DE19945982.7 1999-09-24
DE19945982A DE19945982A1 (de) 1999-09-24 1999-09-24 Geschwindigkeitsbestimmte Partikel
PCT/EP2000/009149 WO2001023362A2 (en) 1999-09-24 2000-09-19 Rate-controlled particles
US8840002A 2002-07-22 2002-07-22
US12/368,884 US20090148531A1 (en) 1999-09-24 2009-02-10 Rate-controlled particles

Related Parent Applications (3)

Application Number Title Priority Date Filing Date
US10088400 Division 2000-09-19
PCT/EP2000/009149 Division WO2001023362A2 (en) 1999-09-24 2000-09-19 Rate-controlled particles
US8840002A Division 1999-09-24 2002-07-22

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/420,013 Continuation US9028876B2 (en) 1999-09-24 2012-03-14 Rate-controlled particles

Publications (1)

Publication Number Publication Date
US20090148531A1 true US20090148531A1 (en) 2009-06-11

Family

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Family Applications (2)

Application Number Title Priority Date Filing Date
US12/368,884 Abandoned US20090148531A1 (en) 1999-09-24 2009-02-10 Rate-controlled particles
US13/420,013 Expired - Fee Related US9028876B2 (en) 1999-09-24 2012-03-14 Rate-controlled particles

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/420,013 Expired - Fee Related US9028876B2 (en) 1999-09-24 2012-03-14 Rate-controlled particles

Country Status (11)

Country Link
US (2) US20090148531A1 (ja)
EP (1) EP1214300B1 (ja)
JP (1) JP4996801B2 (ja)
CN (1) CN1376148A (ja)
AT (1) ATE248822T1 (ja)
AU (1) AU7520700A (ja)
CA (1) CA2387536C (ja)
DE (2) DE19945982A1 (ja)
ES (1) ES2206304T3 (ja)
NO (1) NO20021409L (ja)
WO (1) WO2001023362A2 (ja)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060252764A1 (en) * 2001-08-13 2006-11-09 Guillemont Jerome E G HIV inhibiting pyrimidines derivatives
US20080167464A1 (en) * 2002-08-09 2008-07-10 Didier Philippe Robert Schils Processes for the preparation of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
US20090012108A1 (en) * 2001-08-13 2009-01-08 Jerome Emile Guillemont Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile
US20110008434A1 (en) * 2001-08-13 2011-01-13 Guillemont Jerome Emile Georges Salt of 4-[[4-[[4-(2-cyanoethenyl)-2,6-dimethylphenyl]amino]-2-pyrimidinyl]amino]benzonitrile

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Publication number Priority date Publication date Assignee Title
ATE329579T1 (de) 1999-11-12 2006-07-15 Abbott Lab Feste dispersion mit ritonavir, fenofibrat oder griseofulvin
DE10026698A1 (de) 2000-05-30 2001-12-06 Basf Ag Selbstemulgierende Wirkstoffformulierung und Verwendung dieser Formulierung
TWI329105B (en) 2002-02-01 2010-08-21 Rigel Pharmaceuticals Inc 2,4-pyrimidinediamine compounds and their uses
AR039540A1 (es) * 2002-05-13 2005-02-23 Tibotec Pharm Ltd Compuestos microbicidas con contenido de pirimidina o triazina
CN1678321A (zh) 2002-07-29 2005-10-05 里格尔药品股份有限公司 用2,4－嘧啶二胺化合物治疗或者预防自体免疫性疾病的方法
WO2004050068A1 (en) * 2002-11-29 2004-06-17 Janssen Pharmaceutica N.V. Pharmaceutical compositions comprising a basic respectively acidic drug compound, a surfactant and a physiologically tolerable water-soluble acid respectively base
BRPI0413018B8 (pt) 2003-07-30 2021-05-25 Rigel Pharmaceuticals Inc composto, e, uso de um composto
US8025899B2 (en) 2003-08-28 2011-09-27 Abbott Laboratories Solid pharmaceutical dosage form
WO2006068770A1 (en) 2004-11-24 2006-06-29 Rigel Pharmaceuticals, Inc. Spiro-2, 4-pyrimidinediamine compounds and their uses
EP2161275A1 (en) 2005-01-19 2010-03-10 Rigel Pharmaceuticals, Inc. Prodrugs of 2,4-pyrimidinediamine compounds and their uses
EP2029110B1 (en) 2006-06-06 2011-08-31 Tibotec Pharmaceuticals Process for preparing spray dried formulations of tmc125
JP2010526848A (ja) * 2007-05-11 2010-08-05 エフ．ホフマン−ラ ロシュ アーゲー 難溶性薬物用の医薬組成物
CN101790371A (zh) * 2007-06-25 2010-07-28 泰博特克药品公司 包含达芦那韦和依曲韦林的组合制剂
AU2010230344B9 (en) 2009-03-30 2014-11-27 Janssen Sciences Ireland Uc Co-crystal of etravirine and nicotinamide

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WO2001023362A2 (en) 2001-04-05
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US20120172364A1 (en) 2012-07-05
EP1214300B1 (en) 2003-09-03
US9028876B2 (en) 2015-05-12
DE19945982A1 (de) 2001-03-29
CA2387536A1 (en) 2001-04-05
WO2001023362A3 (en) 2001-12-06
CN1376148A (zh) 2002-10-23
DE60005031T2 (de) 2004-07-08
JP4996801B2 (ja) 2012-08-08
NO20021409L (no) 2002-03-21
JP2003518012A (ja) 2003-06-03
AU7520700A (en) 2001-04-30

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