WO1998000116A1 - Oral composition comprising a triazole antifungal compound - Google Patents

Oral composition comprising a triazole antifungal compound Download PDF

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Publication number
WO1998000116A1
WO1998000116A1 PCT/US1997/010122 US9710122W WO9800116A1 WO 1998000116 A1 WO1998000116 A1 WO 1998000116A1 US 9710122 W US9710122 W US 9710122W WO 9800116 A1 WO9800116 A1 WO 9800116A1
Authority
WO
WIPO (PCT)
Prior art keywords
composition
beads
antifungal compound
surfactant
weight
Prior art date
Application number
PCT/US1997/010122
Other languages
English (en)
French (fr)
Inventor
Surendra A. Sangekar
Winston A. Vadino
Ping I. Lee
Original Assignee
Schering Corporation
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 Schering Corporation filed Critical Schering Corporation
Priority to HU9903869A priority Critical patent/HUP9903869A3/hu
Priority to CA002258683A priority patent/CA2258683C/en
Priority to IL12778097A priority patent/IL127780A0/xx
Priority to AU33874/97A priority patent/AU731704B2/en
Priority to NZ333514A priority patent/NZ333514A/xx
Priority to SK1775-98A priority patent/SK177598A3/sk
Priority to EP97929927A priority patent/EP0914100A1/en
Priority to BR9710069A priority patent/BR9710069A/pt
Priority to JP10504148A priority patent/JP2000514059A/ja
Publication of WO1998000116A1 publication Critical patent/WO1998000116A1/en
Priority to NO986087A priority patent/NO986087L/no

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • 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
    • A61P31/10—Antimycotics

Definitions

  • the present invention relates to compositions having enhanced or improved bioavailability for a novel triazole antifungal compound.
  • compositions such as powders or granules, were found to have reduced anti-fungal activity and/or bioavailability, presumably due to this compound's extremely low water solubility. It would be desirable to provide this antifungal compound in a pharmaceutical composition whose antifungal and/or bioavailabilty would be enhanced or improved.
  • the present invention is directed to a pharmaceutical composition
  • a pharmaceutical composition comprising: i) a plurality of beads; wherein said beads are coated with ii) an antifungal agent of the formula:
  • the pharmaceutical composition may also contain other excipients such as iv) surfactants, v) plasticizers, vi) defoaming agents and coloring agents.
  • the pharmaceutical composition can also be formulated into any other suitable delivery system or dosage form, such as capsules, tablets, or beads for reconstitution.
  • the present invention has the advantage of being able to provide the antifungal compound in a pharmaceutical composition that can conveniently be formulated into solid or "dry" delivery systems or dosage forms such as capsules, tablets or loose beads having effective antifungal activity and/or bioavailabilty.
  • R 1 is a straight or branch chain (C3 to C8) alkyl group substituted by one or two hydroxy moieties; esters and ethers thereof or a pharmaceutically acceptable salt thereof.
  • An especially preferred compound of the above group taught in Examples 24 and 32 of WO 95/17407 is the antifungal compound, (-)- (2R-cis)-4-[4-[4-[4-[[-5-(2,4-difluorophenyl)-tetrahydro-5- ⁇ 1 H-1 ,2,4-triazol-1 - ylmethyl)furan-3-yl]methoxy]phenyl]-1-piperazinyl]phenyl]-2,-4-dihydro-2-[(S)-1- ethyl-2(S)-hydroxypropyl]-3H-1 ,2,4-triazol-3-one ("the antifungal compound”); Formula: C37H42F2N8O4; Molecular weight: 700.8; m.p. 164-165°C
  • Micron-sized particles of the antifungal compound can be obtained either by the final step during the manufacture of the antifungal compound or by the use of conventional micronizing techniques after the conventional crystallization procedure(s).
  • the antifungal compound may be micronized to the desired particle size range by conventional techniques, for example, using a ball mill, ultrasonic means, or preferably using fluid energy attrition mills such as the trost fluid energy mill from Plastomer Products, Newton, Pennsylvania 18940.
  • the desired particle size can be obtained by varying the feed rate of the antifungal into the mill.
  • About 99% of the of the micronized antifungal particle are less than or equal to 100 microns in length, of which 95% are less than or equal to 90 microns.
  • about 99% of the micronized particles are less than or equal to 50 microns, of which 95% are less than or equal to 40 microns. More preferably, 99% of the micronized particles are less than or equal to 20 microns, of which 95% are less than or equal to 10 microns.
  • the antifungal compound is employed in the composition in amounts effective to control the organism or fungi of interest. Such amounts can range from about 2% to about 50% by weight of the composition, more preferably from 6% to about 40%, most preferably from about 5 to about 33% by weight.
  • the amount of composition in the particular dosage form, e.g. capsule, tablet, etc. can range from about 10 to about 300 mg antifungal compound per dosage form, preferably from about 50 to about 200 mg.
  • compositions of the present invention can be prepared by dissolving or suspending the antifungal compound in an a suitable solvent system containing a binder, and optionally with one or more ingredients such as a surfactant, plasticizer, defoaming agent and/or coloring agent and coating the solution or suspension on the inert beads.
  • the pharmaceutical composition of the present invention can be formulated into any suitable dosage form, such as capsules, tablets or loose beads for constitution.
  • a suitable cushioning agent such as microcrystalline cellulose, and optionally, a disintegrant, lubricant, glident, and the like.
  • compositions ingredients which can be employed in its formulation and methods for assessing its bioactivity or bioavailability.
  • the beads or seeds are discrete particles, preferably spherical particles or spheres, which serve as the solid substrate upon which the antifungal compound is coated, and make up the major portion of the composition or dosage form.
  • Beads can be made of sugars such as lactose, sucrose, mannitol and sorbitol; other beads can be derived from starches derived from wheat, corn rice and potato; and celluloses such as microcrystalline cellulose.
  • a source of sugar beads (non-pareil seeds) is known as Nu-pareil PG, tradename of Crompton and Knowles Ingredient Technology Corporation, of Mahawah, New Jersey.
  • a source of microcrystalline cellulose beads is known as Celphere, tradename of the FMC Corporation, Philadelphia, Pennsylvania.
  • Beads of differing mesh sizes can be employed, such as 18/20 mesh, 25/30 mesh and 40/50 mesh.
  • Such mesh sizes refer to particle or bead sizes whose diameters can ranges from about 1.0 millimeters (mm) to about 0.297 mm.
  • the bead sizes or diameters are within a relative narrow range such as, for example, between about 1.0-0.84 mm (18/20 mesh), or between about 0.71- 0.59 mm (25/30 mesh), or between about 0.42-0.297 mm (40/50 mesh).
  • the beads should be "inert" meaning that the beads themselves have little or no antifungal effectiveness.
  • the amount of beads in the composition can range from about 50 to about 90% by weight of the total composition, preferably from about 60 to about 80%, more preferably from about 65 to about 75% by weight.
  • Binders - refers to substances that bind or "glue" the antifungal compound and other ingredients onto the beads, enabling the beads to be coated.
  • Suitable binders include sugars such as sucrose; starches derived from wheat, corn rice and potato; natural gums such as acacia, gelatin and tragacanth; derivatives of seaweed such as alginic acid, sodium alginate and ammonium calcium alginate; cellulosic materials such as methylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose and sodium carboxymethylcellulose; polyvinylpyrrolidone (Povidones); protein hydrolysates; methacrylic acid and salts thereof; and inorganic compounds such as magnesium aluminum silicate.
  • Opadry powders tradename of the Coloron Corporation, West Point, Pennsylvania.
  • Opadry powders may contain hydroxypropylmethylcellulose, along with a plasticizer such as polyethylene glycol and a surfactant such as polysorbate-80.
  • the amount of binder in the composition can range from about 1 to about 10% by weight of the composition, preferably from about 2 to about 8% by weight, more preferably from about 3 to about 6%.
  • Disintegrants refers to materials added to the composition to help it break apart (disintegrate) and release the medicaments.
  • Suitable disintegrants include starches; "cold water soluble" modified starches such as sodium carboxymethyl starch; natural and synthetic gums such as locust bean, karaya, guar, tragacanth and agar; cellulose derivatives such as methylcellulose and sodium carboxymethylcellulose; microcrystalline celluloses and cross-linked microcrystalline celluloses such as sodium croscarmellose; alginates such as alginic acid and sodium alginate; clays such as bentonites; and effervescent mixtures.
  • the amount of disintegrant in the composition can range from about 2 to about 15% by weight of the composition, more preferably from about 4 to about 10% by weight.
  • Surfactant - refers to a compound that can reduce the interracial tension between two immiscible phases and this is due to the molecule containing two localized regions, one being hydrophilic in nature and the other- hydrophobic.
  • Non-ionic surfactant - refers to a surfactant which lacks a net ionic charge and do not dissociate to an appreciable extent in aqueous media.
  • the properties of non-ionic surfactants are largely dependent upon the proportions of the hydrophilic and hydrophobic groups in the molecule.
  • Hydrophilic groups include the oxyethylene group (-OCH2CH2-) and the hydroxy group. By varying the number of these groups in a hydrophobic molecule, such as a fatty acid, substances are obtained which range from strongly hydrophobic and water insoluble compounds, such as glyceryl monostearate, to strongly hydrophilic and water-soluble compounds, such as the macrogols.
  • hydrophilic and hydrophobic groups are more evenly balanced, such as the macrogol esters and ethers and sorbitan derivatives.
  • Suitable non-ionic surfactants may be found in Martindale, The Extra Pharmacopoeia, 28th Edition, 1982, The Pharmaceutical Press, London, Great Britain, pp. 370 to 379.
  • non-ionic surfactants include block copolymers of ethylene oxide and propylene oxide, glycol and glyceryl esters of fatty acids and their derivatives, polyoxyethylene esters of fatty acids (macrogol esters), polyoxyethylene ethers of fatty acids and their derivatives (macrogol ethers), polyvinyl alcohols, and sorbitan esters.
  • the non-ionic surfactant is a block copolymer of ethylene oxide and propylene oxide.
  • Suitable block copolymers of ethylene oxide and propylene oxide generically called “Poloxamers” and include those represented by the following chemical structure:
  • a is an integer ranging from about 10 to about 110, preferably from about 12 to 101 ; more preferably from about 12 to 80; and b is an integer ranging from about 20 to about 60, more preferably from about 20 to about 56; also from about 20 to 27.
  • a is 80 and b is 27, otherwise known as Pluronic®F68 surfactant, trademark of the BASF Corporation, Mount Olive, New Jersey, USA.
  • Pluronic®F68 surfactant is also known as Poloxamer 188. This surfactant has an average molecular weight of 8400, is a solid at 20°C, has a viscosity (Brookfield) of 1000 cps at 77°C.
  • Suitable block copolymers of ethylene oxide and propylene oxide include Pluronic F87, also known as Poloxamer 237 wherein a is 64 and b is 37; and Pluronic F127, also known as Poloxamer 407 wherein a is 101 and b is 56.
  • Pluronic F87 also known as Poloxamer 237 wherein a is 64 and b is 37
  • Pluronic F127 also known as Poloxamer 407 wherein a is 101 and b is 56.
  • Suitable glycol and glyceryl esters of fatty acids and their derivatives include glyceryl monooleate and similar water soluble derivatives
  • Suitable polyoxyethylene esters of fatty acids (macrogol esters) include polyoxyethylene castor oil and hydrogenated castor oil derivatives;
  • Suitable polyoxyethylene ethers of fatty, acids and their derivatives include Cetomacrogel 1000, Lauromacrogols (a series of lauryl ethers of macrogols of differing chain lengths) e.g. Laureth 4, Laureth 9 and Lauromacrogol 400.
  • Suitable Sorbitan esters include, e.g. Polysorbate 20, Polysorbate 40, Polysorbate 60, Polysorbate 65, Polysorbate 80, Polysorbate 85, Sorbitan Monolaurate, Sorbitan Mono-oleate, Sorbitan Monopalmitate, Sorbitan Monostearate, Sorbitan Sesquioleate, Sorbitan Trioleate and Sorbitan Tristearate.
  • the amount of surfactant in the composition can range from about 0.5 to about 25% by weight of the total composition, more preferably from about 5 to about 15% by weight.
  • Anionic surfactant - refers to a surfactant which has a net negative ionic charge and dissociates to an appreciable extent in aqueous media.
  • the present composition may also contain an anionic surfactant, e.g. sodium lauryl sulfate, the amount of which can range from about 1 to about 10% by weight of the total composition, more preferably from about 3 to about 8% by weight.
  • Plasticizers refer to substances which make the binder flexible. Suitable plasticizers include propylene glycol, glycerin, diethylphthalate, dibutyl sebacate, triethyl citrate, hydrogenated glycerides, polyethylene glycols, polyethylene oxides, triacetin and the like.
  • the amount of plasticizer in the composition can be in the range of about 1 -2 to about 5% by weight.
  • Defoaming agents also known as antifoaming agents, are substances used to reduce foaming due to mechanical agitation or to gases, nitrogenous materials or other substances which may interfere during processing. Examples include metallic salts such as sodium chloride; C6 to C12 alcohols such as octanol; sulfonated oils; silicone ethers such as simethicone; organic phosphates and the like.
  • the amount of defoaming agent in the composition can range from about 0.05 to 5%, preferably from about 0.1 to 2%.
  • Suitable glidents include silicon dioxide and talc.
  • the amount of glident in the composition can range from about 0.1% to about 5% by weight of the total composition, preferably from about 0.5 to about 2% by weight.
  • Lubricant - refers to a substance added to the dosage form to enable the tablet, granules, etc. after it has been compressed, to release from the mold or die by reducing friction or wear.
  • Suitable lubricants include metallic stearates such as magnesium, calcium or potassium stearate; stearic acid; high melting point waxes; and water soluble lubricants such as sodium chloride, sodium benzoate, sodium acetate, sodium oleate, polyethylene glycols and d'l-leucine.
  • Lubricants are usually added at the very last step before compression, since they must be present on the surfaces of the granules and in between them and the parts of the tablet press.
  • the amount of lubricant in the composition can range from about 0.2 to about 5% by weight of the composition, preferably from about 0.5 to about 2%.
  • Coloring agents - excipients that provide coloration to the composition or the dosage form.
  • excipients can include food grade dyes and food grade dyes adsorbed onto a suitable adsorbent such as clay or aluminum oxide.
  • the amount of the coloring agent can vary from about 0.1 to about 5% by weight of the composition, preferably from about 0.1 to about 1%.
  • Dosage form - composition containing the antifungal compound formulated into a delivery system i.e., tablet, capsule, oral gel, powder for constitution or suspension in association with inactive ingredients.
  • Capsule - refers to a special container or enclosure made of methyl cellulose, polyvinyl alcohols, or denatured gelatins or starch for holding or containing compositions comprising the active antifungal compound.
  • Hard shell capsules are typically made of blends of relatively high gel strength bone and pork skin gelatins. The capsule itself may contain small amounts of dyes, opaquing agents, plasticizers and preservatives.
  • Tablet- refers to a compressed or molded solid dosage form containing the active ingredient (antifungal compound) with suitable diluents.
  • the tablet can be prepared by compression of mixtures or granulations obtained by wet granulation, dry granulation, compaction or compression of mixtures containing coated active beads.
  • Beads for constitution refers to the loose, coated beads which can be suspended in water, juices or sauces such as applesauce.
  • Bioavailability - refers to the rate and extent to which the active drug ingredient or theraputic moiety is absorbed into the systemic circulation from an administered dosage form as compared to a standard or control.
  • Cmax values refers to the maximum concentration of the antifungal compound measured (i.e. "peak") in the plasma serum.
  • AUC (0-72 hr) values refer to the area under the plasma/serum concentration-time curve for the antifungal over a designated time.
  • compositions of the present invention containing the antifungal compound are not to be interpreted as limiting the scope of the claims.
  • Antifungal compound 135 20.3 micronized
  • Non-Pareil Seeds (25/30 mesh) 5QQ 75
  • Antifungal compound 75 11.0 micronized
  • Non-Pareil Seeds (25/30 mesh) 500 73.5
  • Antifungal compound 100.0 28.6 micronized
  • Dogs are administered a 200 mg dose of the antifungal compound using two capsules or in suspension.
  • Samples of serum are collected at selected times and analyzed by an HPLC/UV detection procedure using a high pressure liquid chromatograph equipped with an ultra-violet detector.
  • the Cmax and AUC (0-72 hr) values are indicators of the antifungal compound's bioavailability. The larger the AUC value, the greater the total amount of antifungal compound that accumulated in the plasma serum over the 72 hour period.
  • Antifungal compound 75.0 1 1.80 micronized
  • Non-Pareil Seeds (25/30 mesh) 500-0 78,60

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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  • Chemical Kinetics & Catalysis (AREA)
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PCT/US1997/010122 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound WO1998000116A1 (en)

Priority Applications (10)

Application Number Priority Date Filing Date Title
HU9903869A HUP9903869A3 (en) 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound
CA002258683A CA2258683C (en) 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound
IL12778097A IL127780A0 (en) 1996-06-28 1997-06-25 Oral compositions comprising a triazole antifungal compound
AU33874/97A AU731704B2 (en) 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound
NZ333514A NZ333514A (en) 1996-06-28 1997-06-25 Oral pharmaceutical composition comprising a triazole antifungal compound
SK1775-98A SK177598A3 (en) 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound
EP97929927A EP0914100A1 (en) 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound
BR9710069A BR9710069A (pt) 1996-06-28 1997-06-25 Composição oral compreendendo um composto antifúngico triazol
JP10504148A JP2000514059A (ja) 1996-06-28 1997-06-25 トリアゾール抗真菌化合物を含む経口組成物
NO986087A NO986087L (no) 1996-06-28 1998-12-23 Oralt preparat omfattende en antifungal triazolforbindelse

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US67243296A 1996-06-28 1996-06-28
US08/672,432 1996-06-28

Publications (1)

Publication Number Publication Date
WO1998000116A1 true WO1998000116A1 (en) 1998-01-08

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PCT/US1997/010122 WO1998000116A1 (en) 1996-06-28 1997-06-25 Oral composition comprising a triazole antifungal compound

Country Status (16)

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EP (1) EP0914100A1 (no)
JP (1) JP2000514059A (no)
KR (1) KR20000022294A (no)
CN (1) CN1228693A (no)
AU (1) AU731704B2 (no)
BR (1) BR9710069A (no)
CA (1) CA2258683C (no)
CZ (1) CZ421498A3 (no)
HU (1) HUP9903869A3 (no)
IL (1) IL127780A0 (no)
NO (1) NO986087L (no)
NZ (1) NZ333514A (no)
PL (1) PL330864A1 (no)
SK (1) SK177598A3 (no)
TR (1) TR199802718T2 (no)
WO (1) WO1998000116A1 (no)

Cited By (21)

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WO1998042318A1 (en) * 1997-03-26 1998-10-01 Janssen Pharmaceutica N.V. Pellets having a core coated with an antifungal and a polymer
WO1999063971A1 (en) * 1998-06-11 1999-12-16 Em Industries, Inc. Micro-osmotic controlled drug delivery systems
WO2000003697A1 (en) * 1998-07-17 2000-01-27 Janssen Pharmaceutica N.V. Pellets having a core coated with an antifungal and a polymer
WO2000004881A1 (es) * 1998-07-21 2000-02-03 Liconsa, Liberacion Controlada De Sustancias Activas, S.A. Preparacion farmaceutica oral de un compuesto de actividad antifungica y procedimiento para su preparacion
FR2795961A1 (fr) * 1999-07-09 2001-01-12 Ethypharm Lab Prod Ethiques Composition pharmaceutique contenant du fenofibrate micronise, un tensioactif et un derive cellulosique liant et procede de preparation
WO2002062318A2 (en) * 2001-02-06 2002-08-15 Dsm Ip Assets B.V. Oral itraconazole formulations and methods of making the same
EP1233756A1 (en) * 1999-11-23 2002-08-28 Lipocine, Inc. Solid carriers for improved delivery of active ingredients in pharmaceutical compositions
WO2004105725A2 (en) * 2003-05-30 2004-12-09 Eurand S.P.A. Microcapsules by coacervation containing a pharmaceutical incorporated in the coating polymer
KR100694667B1 (ko) * 1999-12-08 2007-03-14 동아제약주식회사 생체내이용률 향상과 개인간 및 개인내 흡수 편차를감소시킨 이트라코나졸 함유 항진균성 제제
EP1842532A2 (en) * 2001-02-06 2007-10-10 Stiefel Laboratories, Inc. Oral sparingly water-soluble antifungal formulations and methods of making the same
US7863331B2 (en) 1999-07-09 2011-01-04 Ethypharm Pharmaceutical composition containing fenofibrate and method for the preparation thereof
US8652523B2 (en) 2002-07-26 2014-02-18 Flamel Technologies Oral pharmaceutical formulation in the form of a plurality of microcapsules for prolonged release of active principle(s) with slow solubility
US8865695B2 (en) 2009-01-08 2014-10-21 Lipocine Inc. Steroidal compositions
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US9358241B2 (en) 2010-11-30 2016-06-07 Lipocine Inc. High-strength testosterone undecanoate compositions
US9402851B2 (en) 2003-11-27 2016-08-02 Bayer Intellectual Property Gmbh Process for the preparation of a solid, orally administrable pharmaceutical composition
US9498485B2 (en) 2014-08-28 2016-11-22 Lipocine Inc. Bioavailable solid state (17-β)-hydroxy-4-androsten-3-one esters
US10561615B2 (en) 2010-12-10 2020-02-18 Lipocine Inc. Testosterone undecanoate compositions
US11433083B2 (en) 2010-11-30 2022-09-06 Lipocine Inc. High-strength testosterone undecanoate compositions
US11559530B2 (en) 2016-11-28 2023-01-24 Lipocine Inc. Oral testosterone undecanoate therapy
US11707467B2 (en) 2014-08-28 2023-07-25 Lipocine Inc. (17-ß)-3-oxoandrost-4-en-17YL tridecanoate compositions and methods of their preparation and use

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CN105949278B (zh) * 2016-03-30 2019-12-06 南京曼杰生物科技有限公司 一种取代的四氢呋喃水溶性衍生物及其应用

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WO1994005263A1 (en) * 1992-09-03 1994-03-17 Janssen Pharmaceutica N.V. Beads having a core coated with an antifungal and a polymer
EP0636366A2 (en) * 1993-07-27 1995-02-01 Euroceltique S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
WO1995017407A1 (en) * 1993-12-21 1995-06-29 Schering Corporation Tetrahydrofuran antifungals

Patent Citations (3)

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Publication number Priority date Publication date Assignee Title
WO1994005263A1 (en) * 1992-09-03 1994-03-17 Janssen Pharmaceutica N.V. Beads having a core coated with an antifungal and a polymer
EP0636366A2 (en) * 1993-07-27 1995-02-01 Euroceltique S.A. Controlled release formulations coated with aqueous dispersions of acrylic polymers
WO1995017407A1 (en) * 1993-12-21 1995-06-29 Schering Corporation Tetrahydrofuran antifungals

Cited By (55)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
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IL127780A0 (en) 1999-10-28
PL330864A1 (en) 1999-06-07
NO986087D0 (no) 1998-12-23
NO986087L (no) 1999-02-26
SK177598A3 (en) 1999-07-12
AU731704B2 (en) 2001-04-05
KR20000022294A (ko) 2000-04-25
HUP9903869A3 (en) 2000-07-28
NZ333514A (en) 2000-05-26
CA2258683C (en) 2007-07-31
CA2258683A1 (en) 1998-01-08
TR199802718T2 (xx) 1999-03-22
EP0914100A1 (en) 1999-05-12
HUP9903869A2 (hu) 2000-06-28
CN1228693A (zh) 1999-09-15
AU3387497A (en) 1998-01-21
JP2000514059A (ja) 2000-10-24
CZ421498A3 (cs) 1999-06-16
BR9710069A (pt) 1999-08-10

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