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WO2000030615A1 - Procede de preparation de suspensions stables de microparticules insolubles - Google Patents

Procede de preparation de suspensions stables de microparticules insolubles Download PDF

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Publication number
WO2000030615A1
WO2000030615A1 PCT/US1999/027435 US9927435W WO0030615A1 WO 2000030615 A1 WO2000030615 A1 WO 2000030615A1 US 9927435 W US9927435 W US 9927435W WO 0030615 A1 WO0030615 A1 WO 0030615A1
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WO
WIPO (PCT)
Prior art keywords
agent
surfactant
phospholipid
hlb
micron
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
PCT/US1999/027435
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English (en)
Inventor
Sheema Khan
Indu Parikh
Helen C. Loughrey
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.)
RTP PHARMA Inc
RTP Pharma Corp
Original Assignee
RTP PHARMA Inc
RTP Pharma Corp
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 RTP PHARMA Inc, RTP Pharma Corp filed Critical RTP PHARMA Inc
Priority to JP2000583499A priority Critical patent/JP5296954B2/ja
Priority to AU17374/00A priority patent/AU767737B2/en
Priority to IL14319699A priority patent/IL143196A0/xx
Priority to EP99960497A priority patent/EP1133280A1/fr
Priority to KR1020017006123A priority patent/KR20010075713A/ko
Priority to CA2349202A priority patent/CA2349202C/fr
Publication of WO2000030615A1 publication Critical patent/WO2000030615A1/fr
Priority to IL143196A priority patent/IL143196A/en
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular 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
    • A61K9/10—Dispersions; Emulsions
    • 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
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A61P21/02—Muscle relaxants, e.g. for tetanus or cramps
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P23/00—Anaesthetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/08—Antiepileptics; Anticonvulsants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants
    • 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]
    • 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
    • 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
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • This invention relates to compositions and procedures that yield sub-micron and micron-size stable particles of water-insoluble or poorly soluble drugs or other industrially useful insoluble compounds.
  • This invention provides for the first time a reliable HLB-based selection criteria for selecting the type and amount of surface modifiers used to obtain sub-micron stable suspensions.
  • cloud-point modifiers are described in US 5,298,262, 5,326,552, 5,336,507, 5,340,564 and 5,470,583 in which a poorly-soluble drug or diagnostic agent has adsorbed on its surface both a cloud-point modifier and a non-crosslinked ionic surfactant.
  • the cloud point modifier is said to increase the cloud point of the surfactant such that the resulting nanoparticles are resistant to particle size growth upon heat sterilization at 121° C.
  • WO 98/07414 describes a poorly soluble drug having two surface modifiers adsorbed on its surface; the addition of the second surface modifier provides approximately a 50% reduction in particle size as compared to the use of only one modifier.
  • EP 0580690B1 describes solubilizing water-insoluble peptides by coating them with a charged phospholipid such that the weight ratio of drug to phospholipid is above a critical number.
  • Poloxamer 188 is also used to prepare the drug particles at concentration from 0.01% - 0.5%. A reduction in the magnitude of the zeta potential is observed as the poloxamer 188 concentration is increased.
  • US 5,091 ,187 renders water-insoluble drugs injectable by formulating them as aqueous suspensions of phospholipid-coated microcrystals. The crystalline drug is reduced to 50nm - 10 ⁇ m by sonication or other processes inducing high shear in the presence of phospholipid.
  • Phospholipid is described as the sole surface modifier.
  • US 5,858,410 solubilizes water-insoluble drugs by the addition of a surfactant (synthetic or natural) using a piston-gap homogenizer.
  • the resulting particles are determined by photon correlation microscopy to be in the range of 10nm - 1 ,000 nm, with less than 0.1% of the population above 5 microns.
  • the surface modifiers are arbitrarily selected.
  • compositions prepared according to the method of this invention include, in addition to particles of a water-insoluble ore poorly soluble drug or other industrially useful compound, natural or synthetic phospholipids or surfactant alone, or in combination with each other.
  • the type and amount of surface modifiers is chosen relative to the drug, such that the system
  • HLB Hydrophile-Lipophile Balance
  • System HLB Y - 2 — — — x (HLB value of surfactant j) j weight of drug) is within the range of 4 to 9. When the system HLB is within this range, the resulting formulation has a volume-weighted average particle size that is less than about 1 micron, and exhibits good stability at different temperatures, and stress tests.
  • system means the entire composition including drug(s), surface modifiers, carriers, vehicles, diluents and other components customarily present is such compositions.
  • the Hydrophile-Lipophile Balance is a scale that balances between two opposing tendencies present in a surfactants: hydrophilic (that portion which has an affinity towards water) versus lipophilic (that portion which has an affinity towards oil).
  • hydrophilic that portion which has an affinity towards water
  • lipophilic that portion which has an affinity towards oil
  • HLB value of the surface modifier or modifiers is between 5 and 35.
  • the water insoluble or poorly water soluble compound may be selected from various therapeutic agents, including an antifungal agent, immunosuppressive or immunoactive agent, antiviral agent, antineoplastic agent, analgesic or anti- inflammatory agent, antibiotic, antiepileptic, anesthetic, hypnotic, sedative, antipsychotic agent, neuroleptic agent, antidepressant, anxiolytic, anticonvulsant agent, antagonist, neuron blocking agent, anticholinergic or cholinomimetic agent, antimuscarinic or muscarinic agent, antiadrenergic, or an antarrhythmic, antihypertensive agent, hormone or a nutrient.
  • an antifungal agent including an antifungal agent, immunosuppressive or immunoactive agent, antiviral agent, antineoplastic agent, analgesic or anti- inflammatory agent, antibiotic, antiepileptic, anesthetic, hypnotic, sedative, antipsychotic agent, neuroleptic agent, antidepressant, anxi
  • the phospholipid may be any naturally occurring phospholipid or mixtures of phospholipids, sometimes referred to herein as "commercial" phospholipids, such as egg or soybean phospholipid or a combination thereof.
  • the phospholipid may be desalted, hydrogenated or partially hydrogenated or natural, semi-synthetic or synthetic.
  • Examples of commercially available phospholipids include but are not limited to egg phospholipids P123 (Pfanstiehl), Lipoid E80 (Lipoid); and hydrogenated soy phospholipids Phospholipon 90H and 100H (Natterman) and 99% pure egg and soy phosphatidyl choline (Avanti Polar Lipids).
  • the amount of phospholipid present in the composition ranges from 0.01% to 50%, preferably from 0.05% to 20%.
  • the surfactant sometimes referred to as a second surface modifier, includes: (a) natural surfactants such as casein, gelatin, tragacanth, waxes, enteric resins, paraffin, acacia, gelatin cholesterol esters and triglycerides (b) nonionic surfactants such as polyoxyethylene fatty alcohol ethers, sorbitan fatty acid esters, polyoxyethylene fatty acid esters, sorbitan esters glycerol monostearate, polyethylene glycols, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, poloxamers, poloxamines, methylcellulose, hydroxycelllulose, hydroxy propylcellulose, hydroxy propylmethylcellulose, noncrystalline cellulose; polyvinyl alcohol, polyvinylpyrrolidone, and synthetic phospholipids, and (c) colloidal clays such as bentonite, veegum and colloidal silica. A detailed description of these surfactants may be found in Remington's
  • suitable second surface modifiers include the following: poloxamers, such as Pluronic TM F68, F108, and F127, which are block copolymers of ethylene oxide and propylene oxide available from BASF, and poloxamines, such as Tetronic TM 908, which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF, Triton TM X-100, which is an alkyl aryl polyether sulfonate, available from Rohm and Haas.
  • poloxamers such as Pluronic TM F68, F108, and F127
  • poloxamines such as Tetronic TM 908, which is a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylene-diamine available from BASF
  • Triton TM X-100 which is an alkyl aryl polyether sulfonate, available from Rohm and
  • Tween 20, 40, 60 and 80 which are polyoxyethylene sorbitan fatty acid esters available from ICI Specialty Chemicals, CarbowaxTM 3550 and 934, which are polyethylene glycols available from Union Carbide, hydroxy propyimethylcellulose and polyvinylpyrrolidone.
  • the surface modifier is a polyoxyethylene sorbitan fatty acid ester, a block copolymer of ethylene oxide and propylene oxide, polyoxyethylene stearate a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, hydroxy propyimethylcellulose, and polyvinylpyrrolidone.
  • a polyoxyethylene sorbitan fatty acid ester a block copolymer of ethylene oxide and propylene oxide, polyoxyethylene stearate a tetrafunctional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, hydroxy propyimethylcellulose, and polyvinylpyrrolidone.
  • the surfactant desirably is a polyoxyethylene sorbitan fatty acid ester polyoxyethylene stearate, a block copolymer of ethylene oxide, and propylene oxide, a tetra functional block copolymer derived from sequential addition of ethylene oxide and propylene oxide to ethylenediamine, an alkyl aryl polyether sulfonate, polyethylene glycol, hydroxy propyimethylcellulose, and polyvinylpyrrolidone.
  • the phospholipid may be desalted, hydrogenated or partially hydrogenated or natural, semisynthetic or synthetic and preferably is phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine, phosphatidylinoistol, phosphatidylglycerol or phosphatidic acid.
  • a “pass” is defined as one cycle of the formulation through the different elements of the processing machine.
  • the “pass” or cycle for each machine is as follows: Avestin C-50 and C-5: Formulation is placed in inlet reservoir then passes to the homogenization valve, next a heat exchanger then back to the inlet reservoir. It is the homogenization valve that subjects the formulation to the forces of shear, cavitation, impact and attrition.
  • M110 EH The formulation is first put through 20 passes of the bypass loop, defined as follows: inlet reservoir to auxiliary processing module to heat exchanger then back to inlet reservoir. The resulting formulation is then put through the interaction chamber loop, defined as follows: inlet reservoir to auxiliary processing module to interaction chamber to heat exchanger then back to inlet reservoir.
  • each formulation was collected and placed in vials, capped with rubber stoppers and sealed with an aluminum cap, for stability testing.
  • Acceptable particles are those microparticles falling within the range of 0.05 to 10 microns.
  • a formulation is regarded as being stable if at least two of the following conditions are satisfied:
  • the average particle size is less than 1.5 ⁇ m at 4°C over a period of four weeks.
  • the average particle size is less than 1.5 ⁇ m at 25°C over a period of four weeks.
  • the average particle size is less than 2.5 ⁇ m at 40°C over a period of one week.
  • the average particle size is less than 1.5 ⁇ m following 7-day shaking.
  • the average particle size is less than 1.5 ⁇ m following 3 cycles of thermal cycling.
  • the above formulations were prepared in 200 gram batches on the Avestin C- 50 at an operating pressure of 18,000 psi. Prior to homogenization, 5.5% w/w mannitol was added along with 1N NaOH to adjust the pH in the range 7-8. Particle size is a volume-weighted average, measured on the Malvern Mastersizer. Example 1 exhibited an average particle size in the range of 7 ⁇ m - 9 ⁇ m during homogenization. The extrapolation of data indicates that the particle remains in this range even after 180 passes.
  • Example 4 illustrates the effect of reducing the system HLB value to 8.4 using a suitable combination of phospholipid and surface modifier, which leads to a micron-sized, stable formulation.
  • Examples 1 ,2 and 3 in Table 2.1 illustrate the effect of increasing the phospholipid concentration from 0%, 2.4% w/w and 6% w/w such that the system HLB values are 0, 1.7, and 4.2 respectively.
  • the formulation with the system HLB above 4 is sub-micron size and stable, whereas the others are not.
  • Examples 3 and 4 illustrate the effect of increasing the PF 68 concentration from 0% to 2%, at a fixed phospholipid concentration of 6%, such that the system HLB values are 4.2 and 10 respectively.
  • the formulation with the system HLB between 4 - 9 is sub-micron size and stable, whereas the other formulation is not.
  • Examples 4 and 5 illustrate the effect of decreasing the phospholipid concentration from 6% to 3.8%, at a fixed PF 68 concentration of 2%, such that the system HLB values are 10 and 8.5 respectively.
  • the formulation with the system HLB between 4 - 9 is sub-micron size and stable, whereas the other formulation is not.
  • Examples 6 and 7 illustrate the effect of the system HLB value outside the range of 3.9 - 9: particle size greater than 1 micron, and unstable formulations.
  • example 5 has an system HLB of less than 3.9
  • example 6 has an system HLB value of greater than 9.
  • the formulations given in Table 3.1 were prepared in 200 gram batches on the M110 EH at an operating pressure of 18,000 psi. Prior to homogenization, 1 N NaOH was added to adjust the pH in the range 6-8. Particle size is a volume-weighted average, measured on the Malvern Mastersizer.
  • the above examples 2 and 4 in Table 3.1 illustrate the effect of increasing the PF 127 concentration from 0% to 1% w/w such that the system HLB values are 2.1 and 5, respectively.
  • the formulation with the system HLB above 4 is sub-micron size and stable, whereas the other formulation is not.
  • Examples 3 and 4 illustrate the effect of changing the relative amounts of Lip E80 and PF 127 such that the total surface modifier concentration is 4% w/w.
  • the formulation with a system HLB value > 4 (example 4) is stable, whereas the formulation with a system HLB value of ⁇ 4 (example 3) is not stable.
  • Examples 5 and 6 illustrate the effect of changing the relative amounts of Phospholipon 100H and PF 108; the formulation with a system HLB value > 4 (example 5) is stable, whereas the formulation with a system HLB value of ⁇ 4 (example 6) is not stable.
  • Examples 7 and 8 are stable, sub-micron size formulations with total surface modifier concentration of 2.5% w/w, such that the system HLB value of each formulation is between 4 and 9. In both formulations, different combinations of Lipoid E80 and PF 127 are used.
  • Examples 3 and 7 illustrate the effect of increasing the PF 127 weight ratio relative to the drug from 0 to 1 , while maintaining the Lip E80 weight ratio at 4.
  • the system HLB values are 2.8 and 5.7, respectively.
  • the formulation with the system HLB above 4 is sub-micron size and stable, whereas the other formulation is not stable.
  • the particle size is 0.34 microns, identical to the starting size, hence the particles were stable.

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Abstract

Selon cette invention, on prépare des particules stables microniques et sub-microniques de médicaments ou d'autres produits d'utilité industrielle, qui sont insolubles ou faiblement solubles dans l'eau et suspendus dans un milieu liquide comprenant au moins un modificateur de surface, en sélectionnant le ou les modificateur(s) de surface de manière à ce que le rapport hydrophile-lipophile (HLB) de la composition, qui est défini comme formule (I) doit être compris entre 4 et 9. Ce procédé permet d'obtenir un critère de sélection fiable sur la base du HLB, qui permet de sélectionner le type et la quantité des modificateurs de surface utilisés pour obtenir des suspensions stables de taille sub-micronique.
PCT/US1999/027435 1998-11-20 1999-11-19 Procede de preparation de suspensions stables de microparticules insolubles Ceased WO2000030615A1 (fr)

Priority Applications (7)

Application Number Priority Date Filing Date Title
JP2000583499A JP5296954B2 (ja) 1998-11-20 1999-11-19 不溶性微粒子の安定なサスペンションを製造する方法
AU17374/00A AU767737B2 (en) 1998-11-20 1999-11-19 Method of preparing stable suspensions of insoluble microparticles
IL14319699A IL143196A0 (en) 1998-11-20 1999-11-19 Method of preparing stable suspensions of insoluble microparticles
EP99960497A EP1133280A1 (fr) 1998-11-20 1999-11-19 Procede de preparation de suspensions stables de microparticules insolubles
KR1020017006123A KR20010075713A (ko) 1998-11-20 1999-11-19 불용성 마이크로입자의 안정된 현탁액의 제조방법
CA2349202A CA2349202C (fr) 1998-11-20 1999-11-19 Procede de preparation de suspensions stables de microparticules insolubles
IL143196A IL143196A (en) 1998-11-20 2001-05-17 Stable suspensions of insoluble microparticles

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US10920398P 1998-11-20 1998-11-20
US60/109,203 1998-11-20

Publications (1)

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WO2000030615A1 true WO2000030615A1 (fr) 2000-06-02

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PCT/US1999/027435 Ceased WO2000030615A1 (fr) 1998-11-20 1999-11-19 Procede de preparation de suspensions stables de microparticules insolubles

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EP (1) EP1133280A1 (fr)
JP (1) JP5296954B2 (fr)
KR (1) KR20010075713A (fr)
CN (1) CN1213733C (fr)
AU (1) AU767737B2 (fr)
CA (1) CA2349202C (fr)
IL (2) IL143196A0 (fr)
WO (1) WO2000030615A1 (fr)

Cited By (19)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6579895B2 (en) 2000-05-26 2003-06-17 Pharmacia Corporation Use of a celecoxib composition for fast pain relief
US6835396B2 (en) 2001-09-26 2004-12-28 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US6869617B2 (en) 2000-12-22 2005-03-22 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US6884436B2 (en) 2000-12-22 2005-04-26 Baxter International Inc. Method for preparing submicron particle suspensions
US6951656B2 (en) 2000-12-22 2005-10-04 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US6977085B2 (en) 2000-12-22 2005-12-20 Baxter International Inc. Method for preparing submicron suspensions with polymorph control
US7026290B1 (en) 1998-12-30 2006-04-11 Dexcel Ltd. Dispersible concentrate for the delivery of cyclosprin
US7112340B2 (en) 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix
US7172769B2 (en) 1999-12-08 2007-02-06 Pharmacia Corporation Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect
US7193084B2 (en) 2000-12-22 2007-03-20 Baxter International Inc. Polymorphic form of itraconazole
US7255877B2 (en) 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
EP1878725A2 (fr) 2002-08-21 2008-01-16 Glaxo Group Limited Dérivés de la pyrimidine et leur utilisation comme modulateurs de CB2
EP1267946A4 (fr) * 2000-02-28 2008-07-02 Genesegues Inc Systeme et procede d'encapsulation de nanocapsules
US7828996B1 (en) 2009-03-27 2010-11-09 Abbott Cardiovascular Systems Inc. Method for the manufacture of stable, nano-sized particles
US7976869B2 (en) 2001-01-22 2011-07-12 Laboratoires Fournier S.A. Fenofibrate tablets
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US8663693B2 (en) 2001-08-09 2014-03-04 Jagotec Ag Nanoparticulate formulations of fenofibrate
US8722091B2 (en) 2001-09-26 2014-05-13 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds

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WO2013081554A1 (fr) * 2011-11-30 2013-06-06 Agency For Science, Technology And Research Rapport d'un polypeptide de microparticule à ganglioside gm1 à un polypeptide de microparticule à annexine v pour une surveillance biologique
CN114367383B (zh) * 2022-01-13 2024-01-09 苏州丰倍生物科技股份有限公司 一种脂肪酸酯纳米悬浮液、其制备方法和应用

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Cited By (21)

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US7255877B2 (en) 1996-08-22 2007-08-14 Jagotec Ag Fenofibrate microparticles
US7026290B1 (en) 1998-12-30 2006-04-11 Dexcel Ltd. Dispersible concentrate for the delivery of cyclosprin
US7172769B2 (en) 1999-12-08 2007-02-06 Pharmacia Corporation Cyclooxygenase-2 inhibitor compositions having rapid onset of therapeutic effect
EP1267946A4 (fr) * 2000-02-28 2008-07-02 Genesegues Inc Systeme et procede d'encapsulation de nanocapsules
US6579895B2 (en) 2000-05-26 2003-06-17 Pharmacia Corporation Use of a celecoxib composition for fast pain relief
US7193084B2 (en) 2000-12-22 2007-03-20 Baxter International Inc. Polymorphic form of itraconazole
US6977085B2 (en) 2000-12-22 2005-12-20 Baxter International Inc. Method for preparing submicron suspensions with polymorph control
US7037528B2 (en) 2000-12-22 2006-05-02 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US9700866B2 (en) 2000-12-22 2017-07-11 Baxter International Inc. Surfactant systems for delivery of organic compounds
US6951656B2 (en) 2000-12-22 2005-10-04 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US6884436B2 (en) 2000-12-22 2005-04-26 Baxter International Inc. Method for preparing submicron particle suspensions
US6869617B2 (en) 2000-12-22 2005-03-22 Baxter International Inc. Microprecipitation method for preparing submicron suspensions
US8067032B2 (en) 2000-12-22 2011-11-29 Baxter International Inc. Method for preparing submicron particles of antineoplastic agents
US7976869B2 (en) 2001-01-22 2011-07-12 Laboratoires Fournier S.A. Fenofibrate tablets
US8663693B2 (en) 2001-08-09 2014-03-04 Jagotec Ag Nanoparticulate formulations of fenofibrate
US6835396B2 (en) 2001-09-26 2004-12-28 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US8722091B2 (en) 2001-09-26 2014-05-13 Baxter International Inc. Preparation of submicron sized nanoparticles via dispersion lyophilization
US7112340B2 (en) 2001-10-19 2006-09-26 Baxter International Inc. Compositions of and method for preparing stable particles in a frozen aqueous matrix
EP1878725A2 (fr) 2002-08-21 2008-01-16 Glaxo Group Limited Dérivés de la pyrimidine et leur utilisation comme modulateurs de CB2
US7828996B1 (en) 2009-03-27 2010-11-09 Abbott Cardiovascular Systems Inc. Method for the manufacture of stable, nano-sized particles
US8273274B2 (en) 2009-03-27 2012-09-25 Abbott Cardiovascular Systems Inc. Method for the manufacture of stable, nano-sized particles

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IL143196A (en) 2012-01-31
AU767737B2 (en) 2003-11-20
JP5296954B2 (ja) 2013-09-25
CN1337877A (zh) 2002-02-27
CN1213733C (zh) 2005-08-10
JP2002530320A (ja) 2002-09-17
KR20010075713A (ko) 2001-08-09
CA2349202A1 (fr) 2000-06-02
EP1133280A1 (fr) 2001-09-19
IL143196A0 (en) 2002-04-21
CA2349202C (fr) 2012-06-19
AU1737400A (en) 2000-06-13

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