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WO1998042382A1 - Compositions pharmaceutiques contenant des derives de propanamine et de la cyclodextrine - Google Patents

Compositions pharmaceutiques contenant des derives de propanamine et de la cyclodextrine Download PDF

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Publication number
WO1998042382A1
WO1998042382A1 PCT/HU1998/000028 HU9800028W WO9842382A1 WO 1998042382 A1 WO1998042382 A1 WO 1998042382A1 HU 9800028 W HU9800028 W HU 9800028W WO 9842382 A1 WO9842382 A1 WO 9842382A1
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WIPO (PCT)
Prior art keywords
cyclodextrin
propanamine
methyl
formula
phenoxy
Prior art date
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Ceased
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PCT/HU1998/000028
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English (en)
Inventor
Joseph Géczy
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Therabel Industries SA
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Therabel Industries SA
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Publication date
Application filed by Therabel Industries SA filed Critical Therabel Industries SA
Priority to EP98913968A priority Critical patent/EP0969874A1/fr
Priority to AU68481/98A priority patent/AU6848198A/en
Priority to JP54325498A priority patent/JP2002514210A/ja
Publication of WO1998042382A1 publication Critical patent/WO1998042382A1/fr
Priority to PL343568A priority patent/PL192179B1/pl
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

Definitions

  • the present invention relates to pharmaceutical compositions containing as an active ingredient a propanamine-derivative together with a cyclodextrin preferably in the form of an inclusion complex.
  • the objects of the invention are a pharmaceutical composition containing as an active ingredient a propanamine of the general formula I - in the formula R stands for hydrogen or methyl - or any optical isomer and/or pharmaceutically acceptable salt thereof together with a cyclodextrin preferably in the form of an inclusion complex, as well as the new inclusion complexes, processes for the preparation of the complexes, processes for the preparation of the pharmaceutical composition and use of the products.
  • a propanamine of the general formula I - in the formula R stands for hydrogen or methyl - or any optical isomer and/or pharmaceutically acceptable salt thereof together with a cyclodextrin preferably in the form of an inclusion complex, as well as the new inclusion complexes, processes for the preparation of the complexes, processes for the preparation of the pharmaceutical composition and use of the products.
  • HPCD hydroxypropylated ⁇ , ⁇ or ⁇ -cyclodextrins
  • HP ⁇ CD hydroxypropyl- ⁇ -cyclodextrin (2-8 hydroxypropyl groups per CD-unit)
  • MECD methylated ⁇ , ⁇ or ⁇ -cyclodextrins
  • DIMEB heptakis-2, 6-di-0-methyl- ⁇ -cyclodextrin
  • TRIMEB heptakis 2, 3, 6-tr ⁇ -O-methyl- ⁇ -cyclodextr ⁇ n
  • RAMECD randomly methylated ⁇ , ⁇ or ⁇ -cyclodext ⁇ ns
  • RAMEB randomly methylated- ⁇ -cyclodext ⁇ n comprising 12 methoxy groups per CD-unit (average)
  • GBCD maltosylated ⁇ -cyclodextrm .
  • one object of the present invention is a pharmaceutical composition containing as an active ingredient a propanamine of the general formula I or any optical lsomer and/or pharmaceutically acceptable salt thereof together with a cyclodextrin preferably m the form of an inclusion complex and optionally in further admixture with usual auxiliary and additional materials used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.
  • Compounds of the formula I include the active ingredient known under the name fluoxetine and its active metabolite known as nor-fluoxetine . Both compounds contain a chiral carbon atom so that they can appear in the forms of two different stereoisomers depending on the position of the substitutents on the chiral carbon atom.
  • the present invention is related to either of the pure isomer forms as well as to any mixture of such pure isomers including the race ates .
  • Fluoxetine is known as a highly selective, serotonine ( 5-hydroxy-tryptamme) re-uptake inhibitor useful in the treatment of depression (Curr. Ther . Res. 37. 115. 1985) and its preparation is known (USP 4314081, DBP 2500110) .
  • the commercially available fluoxetine is a racemate marketed under the trademarks Prozac®, Potac®' Fontex®.
  • CDs Cyclodextrins
  • the CDs consist of glucopyranose units connected w th ⁇ -1,4 glucosidic bonds.
  • Three different types of CDs are known which differ in their molecular weight, water-solubility and cavity- diameter: ⁇ CD containing 6, ⁇ CD containing 7, and ⁇ CD containing 8 glucopyranose units.
  • CDs may or may not be able to form inclusion complexes with different kinds of compounds under appropriate conditions by including the whole or parts of the guest molecules into their cavities.
  • the inclusion complexes of the same compound successivefully formed with different kinds of CDs may have rather different properties.
  • Table I Solubility of fluoxetine . HC1 with cyclodextrins as a function of cyclodextrin concentration in water (mg/ml )
  • Table II Solubility of nor-fluoxetine . oxalate with cyclodextrins as a function of CD concentration in water (mg/ml )
  • compositions containing as an active ingredient a propanamine of the general formula I or any optical isomer and/or pharmaceutically acceptable salt thereof together with a cyclodextrin preferably in the form of an inclusion complex and optionally in further admixture with usual auxiliary and additional materials used in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.
  • Preferred embodiments of the invention are pharmaceutical compositions containing as an active ingredient a propanamine of the general formula I or any optical isomer and/or pharmaceutically acceptable salt thereof together with ⁇ -cyclodextrin, a methylated ⁇ -, ⁇ - or ⁇ -cyclodextrin, a hydroxypropylated -, ⁇ - or ⁇ - cyclodextrin, an ionic watersoluble ⁇ -, ⁇ - or ⁇ -cyclodextrin polymer, ⁇ -cyclodextrin or ⁇ -cyclodextrin preferably in the form of an inclusion complex and optionally in further admixture with usual auxiliary and additional materials used in pharmaceuticals for - ⁇ a ⁇ oral, parenteral, transdermal, rectal or other medical uses. It has been found that in the compositions according to the invention it is preferable to use a molar ratio of the propanamine of formula I to the cyclodextrin which is within the range of 1:1 to 1:6
  • the compounds of formula I can appear as the "free base" in the inclusion complex or they can form e.g. the following salts with the corresponding acids: chloride, bromide, methane sulfonate, tosylate, besylate, pivalate, caproate etc.
  • auxiliary materials to be used m the compositions include carriers, diluting agents, surface active agents, colorants, aromatizers and the like which are acceptable in the pharmaceutical art and which are compatible with the active ingredient.
  • the further objects of the present invention are the new inclusion complexes of a propanamine of formula I and any optical isomer and salt of the same formed with ⁇ -cyclodextrin whereby the molar ratio of the propanamine of formula I to the ⁇ -cyclodextrin is within the range of 1:1 to 1:6 preferably 1:1 and 1:2.
  • Such complexes can be prepared and isolated in the solid state and are readily handled for laboratory or production use in pharmaceutical industry.
  • the further objects of the present invention are the new inclusion complexes of a propanamine of formula I and/or any of the optical isomers and/or salts of the same formed with a methylated ⁇ , ⁇ or ⁇ -cyclodextrin or a hydroxypropylated ⁇ , ⁇ or ⁇ -cyclodextrm or a maltosylated ⁇ , ⁇ or ⁇ -cyclodextrin whereby the molar ratio of the propanamine to the cyclodextrin within the range of 1:1 to 1:6 preferably 1:1 and 1:2.
  • Such complexes can be prepared and isolated in the solid state and are readily handled for laboratory or production use in pharmaceutical industry.
  • Preferred new complexes according to the invention include the following: inclusion complexes of ( ⁇ ) -N-methyl- ⁇ - [4- (trifluoromethyl) - -?- phenoxy] benzene-propanamine and its salts with ⁇ cyclodextrin; inclusion complexes of (+) -N-methyl- ⁇ - [ 4- ( trifluoromethyl ) - phenoxy] benzene-propanamine and its salts with ⁇ cyclodextrin; inclusion complexes of (-) -N-methyl- ⁇ - [ 4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts and ⁇ cyclodextrin; inclusion complexes of ( ⁇ ) - ⁇ - [4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts with ⁇ cyclodextrin; inclusion complexes of (+) -N-methyl- ⁇ - [ 4- ( trifluoro
  • a further object of the present invention are the processes for the preparation of new inclusion complexes of a propanamine of the general formula I or any optical isomer or pharmaceutically acceptable salt thereof formed with ⁇ - cyclodext ⁇ n, a methylated ⁇ , ⁇ or ⁇ -cyclodextrin, an ionic watersoluble ⁇ -, ⁇ - or ⁇ -cyclodextrin polymer, or hydroxypropylated ⁇ -, ⁇ - or ⁇ -cyclodextrin or maltosylated ⁇ -, ⁇ - or ⁇ -cyclodextrin or ⁇ -cyclodextrm or ⁇ -cyclodextrm b y reacting a propanamine of the general formula or any optical isomer or pharmaceutically acceptable salt thereof with ⁇ - cyclodextnn, a methylated ⁇ , ⁇ or ⁇ -cyclodextrin, an ionic watersoluble -, ⁇ - or ⁇ -cyclodextrin polymer
  • the following methods might be used to carry our the above process alone or in combination : a) reacting the propanamine with the cyclodextrin in solution of water or water and water-miscible organic solvents, cooling the solution and isolating the complex by freeze drying; b) intimately admixing (grinding, milling, kneading) in solid state the propanamine with the cyclodextrin optionally in the presence or followed by addition of an organic solvent or water or an aqueous organic solvent optionally followed by granulating and drying; c) reacting the propanamine with the cyclodextrin in solution of water or water and water-miscible organic solvents and isolating the complex by spray drying; d) reacting the propanamine with the cyclodextrin in solution of water or water and water-miscible organic solvents while heating to about 60°C, cooling the solution and isolating the complex by way of crystallization.
  • methylated- and hydroxypropylated- cyclodextrins for the formulation of compounds of the formula I or any isomer of the same or their salts solid, powder-like products can be isolated. Isolation from the reaction mixtures can be accomplished by known methods, like evaporation, spray-drying, freeze- drying .
  • a further object of the invention is a method of treatment of depression by administering to a patient in need of such treatment an effective dose of a pharmaceutical composition containing as an active ingredient a propanamine of the general formula I or any optical isomer and/or pharmaceutically acceptable salt thereof together with a cyclodextrin optionally in the form of an inclusion complex and said composition optionally n further containing auxiliary and additional materials acceptable in pnarmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.
  • a pharmaceutical composition containing as an active ingredient inclusion complexes of a propanamine of the general formula I and a cyclodextrin, wherein the molar ratio of the propanamine of formula I to the cyclodextrin is within the range of 1:1 to 1:6 preferably 1:1 and 1:2.
  • cyclodext ⁇ ne compositions or complexes show good results where an effective -nodose of a pharmaceutical composition containing inclusion complexes of a propanamine of formula I or any optical isomer and salt of the same formed with ⁇ -cyclodextrin is a ⁇ mimstered whereby the molar ratio of the propanamine of formula I to the ⁇ -cyclodextrin is within the range of 1:1 to 1:6 or 1:1 and 1:2.
  • compositions for such treatment are those containing an effective dose of inclusion complexes of ( ⁇ ) - ⁇ - [4- (trifluoromethyl) - phenoxy] benzene-propanamine or ( + ) - ⁇ - [ - (trifluoromethyl) - phenoxy] benzene-propanamine or (-) - ⁇ - [4- (trifluoromethyl) - phenoxy] benzene-propanamine or ( ⁇ ) -N-methyl- ⁇ - [4- (trifluoromethyl ) - phenoxy] benzene- propanamine or (+) -N-methyl- ⁇ - [ 4- ( trifluoromethyl ) - phenoxy] enzene-propanamine or (-) -N-methyl- ⁇ - [ - ( tri luoromethyl ) - phenoxy] enzene-propanamine with ⁇ - cyclodext ⁇ ne or with a methylated ⁇ , ⁇ or ⁇ -
  • the effective doses of the compounds according to the invention depend very much on the treated patient and on the severity of the case. Doses are within the range corresponding to about 10 to 20 mg/kg bodyweight daily of ⁇ -[4-
  • Examples I Complexation
  • the interaction between the propanamines and cyclodextrin was studied by registration of phase solubility diagrams in distilled water at 25 °C after a 48-hour equilibration while stirring (admixing the 2 ingredients).
  • the quantitative determination of dissolved amount of the propanamine molecule was carried out by UV-spectrophotometry, on a Hewlett Packard 8452A diode-array spectrophotometer . Calibration was taken on the substance in 50% (v/v) aqueous ethanol at the analytical wavelength of 264-266 nm in the concentration range of 0.05-0.5 mg/ml of the drug. None of the applied cyclodextrins were found to affect the UV absorption of the drug, thus the method could be used reliably.
  • Example. 1.1 The interaction between the propanamines and cyclodextrin was studied by registration of phase solubility diagrams in distilled water at 25 °C after a 48-hour equilibration while
  • Solid state characteristics of the product X-ray powder diffraction; a new solid phase of amorphous character is formed as compared with the crystalline structure of starting ⁇ -CD hydrate ( Figure 1.) DSC comparison of the product with fluoxetine . HCl ( Figures 2 and 3.): The absence of the endothermic heat flow m the graph of the 98/42382
  • Example 1.2 120 g of ⁇ -Cyclodextrin are stirred with 500 ml of water at room temperature for 10 minutes resulting in a slightly opalescent solution. 15.6 g of fluoxetine (free base, an oily substance) are dissolved in 25 ml of 96% ethanol and added dropwise to the ⁇ -CD solution. The reaction mixture is stirred at room temperature with 600 r.p.m. for 8 hours. A white precipitate is formed which is filtered off and dried on air to constant weight. Yield: 114.9 g of fluoxetine/CD as a white, microcrystalline, odourless solid. Fluoxetine content: 12.7 % by weight. Loss on drying: 13.35 % by weight. X-ray powder diffraction:.
  • the diffraction pattern of the complex differs significantly from that of ⁇ CD, and possesses a high degree of crystallinity (See Figure 4.)
  • the oily, non-crystalline base forms a well defined crystalline complex.
  • Dissolution characteristics Improved wettability and rate of dissolution is found compared with free fluoxetine (Table III) .
  • Example I 15 g of maltosylated ⁇ -CD (approx. 0.01 mol) is ground with 1.54 g (0.005 mol) of fluoxetine in a ceramic mortar for 5 minutes. The homogeneous mixture is wetted with 2.5 ml of 50% (vol/vol) aqueous ethanol. The wet slurry is kneaded for 30 minutes at room temperature to obtain a sticky wet material. This paste is allowed to dry in a drying cabinet at 40°C to constant weight. The dry formulation is ground in a ball mill resulting in a white, amorphous solid. Yield: 16.78 g of a white powder with a fluoxetine content of 9.0, .
  • Effervescent sachets/ 20 mg fluoxetine are prepared from the product of Example 1.1 in a known manner.
  • Tablets are prepared from fluoxetine .HCl/ ⁇ CD complexes of Example 1.2 in a known manner.
  • Composition -Fluoxetine.
  • HCl/ ⁇ CD Example 1.2 170 mg
  • Example III.l Influence of oral administration on the eiectroactivity of serotonmergic neurons of the dorsal raphe in vivo.
  • the aim of the study is to compare the influence of fluoxetine. HCl and of fluoxetine .HCl/ ⁇ CD on the electric activity of the serotonmergic cellules of the dorsal raphe.
  • the administered dose corresponds to 10 mg/kg of fluoxetine base. -/6-
  • Oral administration of 10 m/kg of fluoxetine in the form of fluoxetine .HCl or fluoxetine . HCl/ ⁇ CD causes a progressive diminution of the discharge frequency of serotonmergic neurons of the RD. This diminution is of the order of 45% after 30 minutes.
  • -D- saline -0- fluoxetine. HCl, fluoxetine. HCl/ ⁇ CD.
  • the maximal decrease of immobility was observed at the dose of 24 mg/kg for fluoxetine .HCl and at the dose of 16 mg/kg for fluoxetine . HCl/ ⁇ CD .
  • Fluoxetine.HCI decreases the immobility of 48% and fluoxetine .HCl/ ⁇ CD of 68%.
  • No clear dose-effect relationship is observed in the case of fluoxetine .HCl while a U-shape dose-effect relation is measured for fluoxetine . HCl/ ⁇ CD.
  • the ED50 and ED30 are decreased in the case of fluoxetine . HCl/ ⁇ CD.
  • Fluoxetme.HCl [Prozac ® ] and fluoxetine . HCl/ ⁇ CD - prepared according to Example 1 - respectively were given in a single dose [each containing 20 mg of fluoxetine] to healthy male subjects (Subj.)
  • the aim of the study was to compare the bioavailability of fluoxetine . HCl (FLU), fluoxetine . HCl/ ⁇ CD (FLU/ ⁇ CD), nor-fluoxetme (NFLU) , nor-fluoxetme/ ⁇ CD (NFLU/ ⁇ CD)
  • Methods a. Patient selection Twelve healthy male persons (of Caucasian origin, between 18 and 45 years) participated after giving written informed consent. They were within ⁇ 10 ?, of their ideal body weight for their age and height calculated with the index of Broca. They were judged to be in good health on basis of their previous medical history, physical examination, haematology and blood chemistry profiles, blood pressure and electrocardiogram. Table I presents their physical data. b. Trial design
  • Plasma level determination Fluoxetine and norfluoxetine plasma levels were measured by an LO-M ⁇ -MS method (high pressure liquid /42382
  • C max maximal plasma level (ng/ml); ⁇ rnax • time of C max (h) ;
  • AUC (0-48h) area under the curve calculated by the trapezoidal rule between T Oh and T 48h (ng*h/ml); AUC (O-oo) . area under the curve extrapolated until ⁇ (ng*h/ml); MRT: mean residence time of drug (h) ; t'/ ⁇ : terminal half time (h) ; volume of distribution (1); C1T: Total clearance (ml/mm) .
  • Tables X and XI present the pharmacokmetic parameters (individual values, mean, SD an SE) of FLU respectively after treatment A with FLU and treatment B with FLU/ ⁇ CD.
  • Tables XII and XIII present the pharmacokmetic parameters (individual values, mean, SD and SE) of N-FLU respectively after treatment A with FLU and treatment B with FLU/ ⁇ CD.
  • Table XIV Summary of FLU and FLU/ ⁇ CD pharmacokmetic parameters
  • Table XV Summary of norfluoxetine and norfluoxetme/CD pharmacokmetic parameters.
  • Figure 6 Curves of plasma levels of FLU (Mean ⁇ SE); time in hours after administration as a function of concentration. Round spots FLU, square spots FLU/ ⁇ CD.
  • Figure 7 Curves of plasma levels of N-FLU (Mean ⁇ SE) time in hours after administration as a function of concentration. Round spots N-FLU, square spots N-FLU/ ⁇ CD.

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Abstract

L'invention concerne une composition pharmaceutique, un procédé de préparation de cette composition pharmaceutique, et une méthode de traitement antidépresseur au moyen de cette composition qui contient une propanamine de la formule générale (I) - dans laquelle R représente un hydrogène ou un méthyle - ou n'importe quel isomère optique et/ou un sel de ce dernier acceptable du point de vue pharmaceutique, ainsi que de la cyclodextrine, de préférence sous la forme d'un composé d'inclusion. Ladite composition peut aussi comprendre éventuellement des matières auxiliaires et supplémentaires acceptables dans des produits pharmaceutiques destinés à un usage oral, parentéral, transdermique, rectal ou tout autre usage médical. Les cyclodextrines sont de préférence une η-cyclodextrine, une α-, β- ou η-cyclodextrine méthylée, une α-, β- ou η-cyclodextrine hydroxypropylée, un polymère de α-, β- ou η-cyclodextrine ionique soluble dans l'eau, ou une α-, β- ou η-cyclodextrine maltosylée. L'invention concerne également les composés d'inclusion et leur préparation. Le composé d'inclusion idéal est celui contenant (±), (-) ou (+) η-[4-(trifluorométhyl)-phénoxy]benzène-propanamine et η-cyclodextrine.
PCT/HU1998/000028 1997-03-24 1998-03-23 Compositions pharmaceutiques contenant des derives de propanamine et de la cyclodextrine Ceased WO1998042382A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
EP98913968A EP0969874A1 (fr) 1997-03-24 1998-03-23 Compositions pharmaceutiques contenant des derives de propanamine et de la cyclodextrine
AU68481/98A AU6848198A (en) 1997-03-24 1998-03-23 Pharmaceutical compositions containing propanamine derivatives and cyclodextrin
JP54325498A JP2002514210A (ja) 1997-03-24 1998-03-23 プロパンアミン誘導体およびシクロデキストリンを含有する医薬組成物
PL343568A PL192179B1 (pl) 1998-03-23 1999-04-16 Reaktor ceramiczny do procesów spalania

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
HU9700632A HUP9700632A3 (en) 1997-03-24 1997-03-24 Pharmaceutical compositions containing propylamine derivative and cyclodextrine and process for producing the same
HUP9700632 1997-03-24

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WO1998042382A1 true WO1998042382A1 (fr) 1998-10-01

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EP (1) EP0969874A1 (fr)
JP (1) JP2002514210A (fr)
AR (1) AR010910A1 (fr)
AU (1) AU6848198A (fr)
HR (1) HRP980155A2 (fr)
HU (1) HUP9700632A3 (fr)
WO (1) WO1998042382A1 (fr)
ZA (1) ZA982457B (fr)

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JP2003503493A (ja) * 1999-07-01 2003-01-28 イタルファルマコ ソシエタ ペル アチオニ パロキセチンとシクロデキストリンまたはシクロデキストリン誘導体との錯体
US7091192B1 (en) * 1998-07-01 2006-08-15 California Institute Of Technology Linear cyclodextrin copolymers
US8252276B2 (en) 2002-09-06 2012-08-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8497365B2 (en) 2007-01-24 2013-07-30 Mark E. Davis Cyclodextrin-based polymers for therapeutics delivery
US11464871B2 (en) 2012-10-02 2022-10-11 Novartis Ag Methods and systems for polymer precipitation and generation of particles
US11464866B2 (en) 2016-05-06 2022-10-11 Biodynamic Research Foundation Pharmaceutical composition containing macromolecular drug

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WO2004069187A2 (fr) * 2003-02-03 2004-08-19 Shire Laboratories, Inc. Formulation et administration d'un medicament a l'aide de cyclodextrines cristallines methylees

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STRAVOULA PIPERAKI; SHARRON G. PENN ET AL.: "Systematic approach to treatment of enantiomeric separations in capillary electrophoresis and liquid chromatography. A study of the enantiomeric separation of fluoxetine and norfluoxetine.", J. OF CHROMATOGRAPHY A, vol. 700, 1995, pages 59 - 67, XP002076045 *

Cited By (20)

* Cited by examiner, † Cited by third party
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US7091192B1 (en) * 1998-07-01 2006-08-15 California Institute Of Technology Linear cyclodextrin copolymers
JP2003503493A (ja) * 1999-07-01 2003-01-28 イタルファルマコ ソシエタ ペル アチオニ パロキセチンとシクロデキストリンまたはシクロデキストリン誘導体との錯体
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US8580243B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
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US8404662B2 (en) 2002-09-06 2013-03-26 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8475781B2 (en) 2002-09-06 2013-07-02 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US9550860B2 (en) 2002-09-06 2017-01-24 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8518388B2 (en) 2002-09-06 2013-08-27 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8252276B2 (en) 2002-09-06 2012-08-28 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8314230B2 (en) 2002-09-06 2012-11-20 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
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HRP980155A2 (en) 1998-12-31
HUP9700632A2 (hu) 1998-12-28
HUP9700632A3 (en) 1999-10-28
JP2002514210A (ja) 2002-05-14
HU9700632D0 (en) 1997-05-28
ZA982457B (en) 1998-09-23
AR010910A1 (es) 2000-07-12
AU6848198A (en) 1998-10-20

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