WO1998042382A1 - Pharmaceutical compositions containing propanamine derivatives and cyclodextrin - Google Patents

Pharmaceutical compositions containing propanamine derivatives and cyclodextrin 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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Prior art keywords
cyclodextrin
propanamine
methyl
formula
phenoxy
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PCT/HU1998/000028
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French (fr)
Inventor
Joseph Géczy
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Therabel Industries S.A.
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Publication date
Application filed by Therabel Industries S.A. filed Critical Therabel Industries S.A.
Priority to AU68481/98A priority Critical patent/AU6848198A/en
Priority to JP54325498A priority patent/JP2002514210A/en
Priority to EP98913968A priority patent/EP0969874A1/en
Publication of WO1998042382A1 publication Critical patent/WO1998042382A1/en
Priority to PL343568A priority patent/PL192179B1/en

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    • 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.

Abstract

A pharmaceutical composition, process for its preparation and method of antidepressive treatment with said composition containing a propanamine of general formula (I) - where 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. Said composition may optionally further contain auxiliary and additional materials acceptable in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical use. Cyclodextrins of preference are η-cyclodextrin, a methylated α-, β- or η-cyclodextrin, a hydroxypropylated α-, β- or η-cyclodextrin, an ionic watersoluble α-, β-, or η-cyclodextrin polymer, a maltosylated α-, β- or η-cyclodextrin. The invention also covers the inclusion complexes and their preparation. The most preferred inclusion complex is the one containing (±), (-) or (+) η-[4-(trifluoromethyl)-phenoxy]benzene-propanamine and η-cyclodextrin.

Description

Pharmaceutical Compositions Containing Propanamine Derivatives and Cyclodextrin
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.
More particularly 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.
In this patent specification the substituents, terms and abbreviations always represent the following and they are therefore not repeated: R = hydrogen or methyl fluoxetine = (±) -N-methyl-γ- [4- (trifluoro-methyl) - phenoxy] benzene-propanamine = FLU nor-fluoxetine = (±) -γ- [4- (trifluoromethyl) - phenoxy] - benzene-propanamine = N-FLU CD = cyclodextrin γ-cyclodextrin = cyclomaltooctaose = γCD β-cyclodextrin = cyclomaltoheptaose = βCD α-cyclodextrin = cyclomaltohexaose = αCD CDPSI = ionic watersoluble α, β or γ-cyclodextrin polymer
HPCD = hydroxypropylated α, β or γ-cyclodextrins
HPβCD = hydroxypropyl-β-cyclodextrin (2-8 hydroxypropyl groups per CD-unit) MECD = methylated α, β or γ-cyclodextrins DIMEB = heptakis-2, 6-di-0-methyl-β-cyclodextrin
(average) TRIMEB = heptakis 2, 3, 6-trι-O-methyl-β-cyclodextrιn RAMECD = randomly methylated α, β or γ-cyclodextπns RAMEB = randomly methylated-β-cyclodextπn comprising 12 methoxy groups per CD-unit (average) GBCD = maltosylated β-cyclodextrm .
More particularly 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 .
Compounds of the general formula I can appear in the form of the free base (these are the compounds named fluoxetine or nor-fluoxetine) and also in the form of their salts. In this specification the terms "fluoxetine" and "nor-fluoxetine" are always used for the free base and the salts are specifically indicated. The pharmaceutical compositions according to the present invention show valuable psychotropic activities l.a. antidepressant effects.
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®.
Cyclodextrins (CDs) are prepared from starches using a CD-glucosyl transferase enzyme. The CDs consist of glucopyranose units connected w th α-1,4 glucosidic bonds. Three different types of CDs are known which differ in their molecular weight, water-solubility and cavity- diameter: αCD containing 6, βCD containing 7, and γCD 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 succesfully formed with different kinds of CDs may have rather different properties.
There is a possibility to carry out further modifications in the α, β or γ CD molecules by way of substitutions e.g. methylation to give MECDs or hydroxypropylation to give HPCDs etc. For example in case of heptakιs-2, 6-dι-O-methyl-βCD (DIMEB) two hydroxyl groups in positions 2 and 6 respectively of every glucose unit are methylated, while in the case of randomly methylated βCD (RAMEB) the hydroxy groups are substituted randomly by methoxy groups, the average ratio of methylation being around 1,8. Both solubility and complex- forming capacity of such substituted CDs may differ from that of the corresponding unsubstituted CDs.
It is also known that due to the chiral character of the cavity of the CDs some of the CDs might be capable to be used for identification of the particular isomers in racemic mixtures of certain compounds. Thus β-CD has been used both m aqueous solution and bound to a solid phase for analytical identification of the + and - enantiomers of fluoxetine and nor-fluoxetine. (J. Chromatogr. A 700, 59-67. 1995.; 5-th Intl. Symp.on Chiral Discrimination, Stockholm, Sweden, Sept. 25-28 1994; Chirality 7 .257-266 1995) . The presence of two 98/42382
- h- lsomers was detected by UN in the chromatograms in the solutions that had been subjected to treatment with βCD. However none of the CD complexes of compounds of the formula I were isolated and used m pharmaceuticals so far nor were the specific isomers.
It was the aim of the present invention to improve the properties of the compounds of the formula I by combination of the same with cyclodextrins if possible.
Solubility isoterm experiments were carried out for this reason according to methods known per se (Adv. in Anal. Chem.and Instr. Ed.C.Ν. 1965, vol4.pp.117-212) . The present invention is based on the recognition that some of the CDs favourably influence the solubility behaviour of compounds of the general formula I. Tables I and Table II exemplify the change of solubilities of representatives of some compounds according to the invention.
Legends of the Tables: 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 )
Table I
CD% αCD βCD γCD HPβCD RAMEβ G2βCD
0 136 13 6 136 136 136 13 62
0 5 15 30 14 35 15 73 14 80 17 10 14 32
1 0 16 13 15 35 18 18 16 61 < 20 60 15 87
3 0 21 10 26 66 22 42 31 65 18 08
5 0 2460 33.82 26.11 4200 21 26
7 0 28 62 42 67 31 60 52 21 23 64
100 3498 55 00 38 20 65 10 27 63 Table I I
CD % β-CD γ-CD HPβCD θ 1.4-1.6 1.4-1.6 1.4-1.6
0.5 1.5 18 1.4
1.0 1.8 2.0 1.9
2.5 - 2.3 2.4
5.0 - 4.4 3.2
It can be concluded from the data of Tables I and II that among the studied unsubstituted CDs it was the γ- cyclodextrin which was found to improve the aqueous solubility of the investigated salts most remarkably and thus to have the highest affinity toward the drugs. Among the highly soluble βCD derivatives methylated-β-cyclodextrin appears as the most potent solubilizer of both the fluoxetine and the nor- fluoxetine salt while the hydroxypropylated derivative of βCD was found to be less effective.
Based on the above and further experiments one object of the present 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 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 γ-cyclodextrin, a methylated α-, β- or γ-cyclodextrin, a hydroxypropylated -, β- or γ- cyclodextrin, an ionic watersoluble α-, β- or γ-cyclodextrin polymer, β-cyclodextrin or α-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 preferably 1:1 and 1:2.
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.
Preferred 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 γ-cyclodextrin whereby the molar ratio of the propanamine of formula I to the γ-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 α, β or γ-cyclodextrin or a hydroxypropylated α, β or γ-cyclodextrm or a maltosylated α, β or γ-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-γ- [4- (trifluoromethyl) - -?- phenoxy] benzene-propanamine and its salts with γ cyclodextrin; inclusion complexes of (+) -N-methyl-γ- [ 4- ( trifluoromethyl ) - phenoxy] benzene-propanamine and its salts with γ cyclodextrin; inclusion complexes of (-) -N-methyl-γ- [ 4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts and γ cyclodextrin; inclusion complexes of (±) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts with γ cyclodextrin; inclusion complexes of (+) -N-methyl-γ- [ 4- ( trifluoromethyl) - phenoxy] benzene-propanamine and its salts and a methylated α, β or γ-cyclodextrin; inclusion complexes of (-) -N-methyl-γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts and a methylated α, β or γ-cyclodextrin; inclusion complexes of (+) -N-methyl-γ- [4- (trifluoromethyl ) - phenoxy] benzene-propanamine and its salts and a hydroxypropylated , β or γ-cyclodextrin; inclusion complexes of (-) -N-methyl-γ- [4- (trifluoromethyl ) - phenoxy] benzene-propanamine and its salts and a hydroxypropylated α, β or γ-cyclodextrin; inclusion complexes of (+) -γ- [4- (trifluoromethyl) - phenoxy] enzene-propanamine and its salts and a methylated α, β or γ-cyclodextrin; inclusion complexes of (-) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts and a methylated α, β or γ-cyclodextrin; inclusion complexes of (+) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and its salts and a hydroxypropylated α, β or γ-cyclodextrin; inclusion complexes of (-) -γ- [4- (trifluoromethyl) - phenoxy] enzene-propanamine and its salts and a hydroxypropylated α, β or γ-cyclodextrin.
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 γ- cyclodextπn, a methylated α, β or γ-cyclodextrin, an ionic watersoluble α-, β- or γ-cyclodextrin polymer, or hydroxypropylated α-, β- or γ-cyclodextrin or maltosylated α-, β- or γ-cyclodextrin or β-cyclodextrm or α-cyclodextrm b y reacting a propanamine of the general formula or any optical isomer or pharmaceutically acceptable salt thereof with γ- cyclodextnn, a methylated α, β or γ-cyclodextrin, an ionic watersoluble -, β- or γ-cyclodextrin polymer, a hydroxypropylated α-, β- or γ-cyclodextrin or maltosylated α, β or γ-cyclodextrin or β-cyclodextrin or α-cyclodextnn whereby the molar ratio of the applied propanamine to the applied cyclodextrin amounts to a value within the range of 1.1 to 1:6 preferably 1:1 or 1:2. 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.
When carrying out process variants a) , c) or d) according to the invention the compounds of formula I or their isomers or salts of these are reacted with the cyclodextrins and derivatives in aqueous medium. As a third component small amounts of suitable, pharmaceutically acceptable organic solvents or detergents can be used. When accomplishing the method b) according to the invention the best laboratory method seems to be kneading compounds according to the formula I and the applied cyclodextrins m presence of a small amount of water and some other solvent can be added preferably after some state of admixing had been reached already. Milling and grinding are the methods which are preferably used to prepare bigger quantities in production scale. The products thus obtained appear in the form of greasy materials which can be further treated to reach the stable solid isolated complexes.
Using 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.
It is preferable for the treatment of depression to administer to a patient an effective dose of 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. Specifically such cyclodextπne 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 γ-cyclodextrin is aαmimstered whereby the molar ratio of the propanamine of formula I to the γ-cyclodextrin is within the range of 1:1 to 1:6 or 1:1 and 1:2. Preferred compositions for such treatment are those containing an effective dose of inclusion complexes of (±) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine or ( + ) -γ- [ - (trifluoromethyl) - phenoxy] benzene-propanamine or (-) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine or (±) -N-methyl-γ- [4- (trifluoromethyl ) - phenoxy] benzene- propanamine or (+) -N-methyl-γ- [ 4- ( trifluoromethyl ) - phenoxy] enzene-propanamine or (-) -N-methyl-γ- [ - ( tri luoromethyl ) - phenoxy] enzene-propanamine with γ- cyclodextπne or with a methylated α, β or γ-cyclodextrin.
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 γ-[4-
( trifluoromethyl ) - phenoxy] enzene-propanamine or N-methyl-γ- [ 4- ( trifluoromethyl) - phenoxy] benzene-propanamine . For less severe cases daily doses of 5 mg or about 10 to 20 mg doses every two or three days are sufficient. Administration of the drugs can be accomplished by way of the oral, parenteral, transdermal, rectal or nasal route or by any other convenient medical route which can be used in antidepressant or antianxietic treatment both with hospitalization and in ambulant treatment. It is preferable to use 10 - 20 mg capsules or 20 mg/ 5 ml fluid dosage forms. - λl-
Details of the invention follow in the Examples for illustration and not for limitation purposes.
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
70.12 g (0.054 mol) of crystalline γ-CD is intensively stirred in 150 ml of water at room temperature for 30 minutes. Then 18.6 g (0.06 mol) of fluoxetine .HCl are added to the aqueous γCD solution, and the reaction mixture was further stirred for 8 hours at room temperature with 600 r.p.m. The resulting opalescent solution was freeze dried yielding 82.65 g (93.28%) of fluoxetine . HCl/γCD as a white, amorphous solid having a fluoxetine content of 21.5% by weight. Loss on drying of the product is 4.55%
Redissolution properties of the product: The solid formulation is easily dissolved in water at room temperature resulting in a stable, clear solution of 1.00 g/lOOml .
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 γ-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
product at the melting point range of fluoxetine .HCl is an evidence of the complex formation between γ-cyclodextrin and fluoxetine .HCl .
Example 1.2 120 g of γ-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 γ-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 γCD, 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) .
Table III
Figure imgf000014_0001
i -
Example I . 3
13.35 g (0.01 mole) of heptakιs-2, 6-dι-O-methyl-β- cyclodextnn is kneaded intensively with 2,5 ml of water and 3.1 g (0.01 mole) of fluoxetine . HCl for 30 minutes at room temperature in a tween-screw kneader. The wet solid formulation is dried on air to constant weight resulting in 16,47g of microcrystallme fluoxetm . HC1/DIMEB in solid form containing 18.23% of fluoxetine. Example 1.4.
15 g of maltosylated β-CD are dissolved in 100 ml of water. 3.1 g of fluoxetin . HCl are dissolved in 5 ml of 50 % aqueous ethanol and added dropwise into the solution of the CD. The slightly opalescent reaction mixture is stirred for additional 4 hours and the solvent is removed by lyophyli- zation. Yield: 17.78 g of a white, foam-like, amorphous solid having a fluoxetine content of 17.09% (b.w.). Example 1.5
15 g of 2-hydroxypropylated-β-cyclodextnn are dissolved in 50 ml of deiomzed water at ambient temperature. 3.0 g of fluoxetine hydrochloπde are added to the clear solution and the reaction mixture is stirred for 6 hours to obtain a slightly opalescent solution. On removing the solvent by spray-drying a white amorphous powder is obtained. Yield: 15.55g of fluoxetine . HCl/HPβCD. Fluoxetin content: 16,45 % b.w. Example I .6
18.54 g (0.06 mol) of fluoxetine is ground with 77.80 g (0.06 mol) of crystalline γ-cyclodextrin in a ceramic mortar for 5 minutes. Then 10 ml of deionised water are added to the mixture and the obtained slurry is thoroughly kneaded for 45 minutes. The wet paste is then passed through a sieve of 2.0 mm aperture and the wet granules are allowed to dry at 40 °C in air stream. The resulting dry granules can be ground ana sievea to desired particle size. Yield: 93.8 g white - IH- fluoxetme/γCD granules, with a fluoxetine content of 18.9% by weight. Molar ratio in the complex: 1:1. Example I .7 15,5 g of maltosylated β-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, . Molar ratio in the complex: 1:2. Example I .8 16.0 g (about 0.01 mole) of hydroxypropylated β-CD are dissolved in 40 ml of deionised water at 25°C by ultrasom- cation. To this clear solution 3.1 g (0.01 mol) of fluoxetine previously dissolved in 5 ml of 96% ethanol are added under intense agitation. The reaction mixture is further stirred for 4 hours at 25 °C and then chilled with a dry ice/ethanol mixture to -56 °C and liophylised. 18.8 g of fluoxetme/hydroxy-propylated-β-cyclodextnn complex are obtained as a white, amorphous powder having a fluoxetine content of 16.0% by weight. Molar ratio in the complex: about 1:1.
Example 1.9
1.2 g of crystalline γ-cyclodextrin (0.93 mM) are dissolved m 5.2 ml of deionised water at ambient temperature by ultrasonication for 5 minutes and then stirred with 600 r.p.m. The slightly hazy γ-CD solution has a pH of 5.3. To this solution 0.125 g (0.45 mM) of nor-fluoxetine previously dissolved in 2 ml of 96% ethanol are added dropwise. Upon addition the reaction mixture becomes turbid. The milky reaction mixture is further stirred for 8 hours with 600 r.p.m. and allowed to stand at 4 °C for 12 hours in a refrigerator. The white precipitate formed is filtered off - &- and dried in vacuum at 25 °C to constant weight. 1.28 g of a nor-fluoxetme/γ-cyclodextrin complex are obtained. Nor- fluoxetine content: 9.3% by weight (determined by UN spectrophotometry) . Molar ratio norfluoxetine :γCD ~ 1:2.
II. FORMULATIONS Example II.l
Effervescent sachets/ 20 mg fluoxetine are prepared from the product of Example 1.1 in a known manner. Composition:
- Fluoxetme/γCD (Example 1.1) 93 mg
- Citric acid 50 mg
- Sodium-bicarbonate 85 mg
- Saccharose 120 mg - Orange flavour 30 mg
- Mg-stearate 465 mg Example II.3 Tablets of 20 mg fluoxetine
Tablets are prepared from fluoxetine .HCl/γCD complexes of Example 1.2 in a known manner. Composition: -Fluoxetine. HCl/γCD (Example 1.2) 170 mg
-Magnesium stearate 13 mg
-Lactose 10 mg
-Esma Spreng 4 mg
III. BIOLOGICAL EXAMPLES
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/γCD on the electric activity of the serotonmergic cellules of the dorsal raphe.
The two active products and the control (saline) are aαministered orally to the live anesthestized rat (each group n=8). The administered dose corresponds to 10 mg/kg of fluoxetine base. -/6-
In the case of the control animals receiving drinking water the frequency of discharge of serotonmergic neurons decreases slightly with ongoing time. After 30 minutes a slight but significant decrease of around 7% (p=0,047) can be observed.
Oral administration of 10 m/kg of fluoxetine in the form of fluoxetine .HCl or fluoxetine . HCl/γCD 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.
The effect of both substances becomes significant as from the 10th minute after the oral administration. Between the 10th and the 15th minute the degree of significancy is more pronounced for the fluoxetine . HCl/γCD (p<0.005 and 0.0005) than for fluoxetine . HCl (p<0.05 and 0.005).
The variance analysis between the average ± the deviation (4.39-13.19 action potentials/10 sec) in view of maximum homogemsation of the groups during the control period shows that the fluoxetine . HCl/γCD is significantly different from the controls in the 25th minute (p=0.023) and in the 30th minute (p=0.004). Fig. 5 shows the change of the average action potentials/10 sec in function of the time measured every minute; and in function of the pharmacological treatment the ANOVA test (all groups n = 8) , standard deviations NS p>0.05, significant deviations *p<0.05, highly significant deviations **p<0.01 compared with the saline group. N=number of groups. The signs on the graph indicate the following groups:
-D- saline, -0- fluoxetine. HCl, fluoxetine. HCl/γCD.
Fluoxetine .HCl shows no significant difference to the control under these conditions (p = 0.16 and 0.06). Example III.2 Swimming test 8/42382
- ft-
Comparative study of fluoxetine. HCl and fluoxetine. HCl/γCD in the forced swimming test (Porsolt's model, 1977) in the mouse. The statistical comparison of the mean immobility times as a function of the drug and the dose was made using an analysis of variance followed by post hoc Newman-Keuls' test. The method is one way of determination of anitdepressant activity.
III.2.1. Comparison of saline groups with each other:
Groups N Mean SD Saline p o 10 1843 245
Thus a Student's test for independent groups revealed a non significant difference between the groups (t<l .00, p=0.946) .
III.2.2. Fluoxetine. HCl:
An analysis of variance with the factor dose as classification criterion revealed a significant difference among the groups (F=11.99, p<0.0001).
Post-hoc Newman-Keuls test reveal that some fluoxetine . HCl doses induce a significant decrease (p<0.05) in the immobility time.
Groups N Mean SD
Saline 10 184 3 24 51
16 mg/kg 10 152 0* 19 22
24 mg/ kg 10 96 . 1* 33 . 65
III.2.3. Fluoxetine. HCl/γCD:
Groups N Mean SD
Saline 10 1843 24 51
16 mg/kg 10 58.3* 29.81
24 mg/kg 10 97 2* 24 80 - δ- An analysis of variance with the factor dose as classification criterion shows a significant difference among the groups (F=55.58, p<0.0001). Post-hoc Newman-Keuls test reveals that fluoxetine .HCl/γCD doses induce a significant decrease (p<0.05) in the immobility time.
III.2. . Comparison between the two oral fluoxetine products :
Doses (mg/kg) Fluoxetine.HCI Fluoxetine.HCI/γCD
16 j 152.0 (19.2) j 58.3 (29.8)*
24 96.1 (33.6) i 97.2 (24.8)
Comparisons made by pairs for each administered dose, using the Student's t test for independent groups, reveal that at the dose of 16 mg/kg, the γCD compound is significantly more effective (p<0.0001).
III.2.5. Determination of oral ED50 and/or ED30
Fluoxetine.HCI Fluoxetine.HCI/γCD
ED30 = 15.69 mg/kg ED30 = 10.89 mg/kg
ED50 = 29.67 mg/kg ED50 = 18.67 mg/kg
III.2.6. Conclusions:
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/γCD . Fluoxetine.HCI decreases the immobility of 48% and fluoxetine .HCl/γCD 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/γCD. The ED50 and ED30 are decreased in the case of fluoxetine . HCl/γCD.
Example III.3. Bioavailability Study in Humans Materials : -^-
Fluoxetme.HCl [Prozac®] and fluoxetine . HCl/γCD - 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/γCD (FLU/γCD), nor-fluoxetme (NFLU) , nor-fluoxetme/γCD (NFLU/γCD)
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
A double blind, randomised parallel study was performed. According to the protocol, which was accepted by the Local Ethical Committee, the treatment was randomly assigned to the volunteers (Table V) . During the study six subjects received the treatment A (using FLU) and six the treatment B (using FLU/γCD) . The drug was administered with 200 ml of water. After administration, 10 ml heparmized blood samples were collected by means of a butterfly catheter at the following times: TO, lh, 2h, 3h, 4h, 5h, 6h, 7h, 8, 9, 24h, 36, 48h and 3, 4, 7, 9, 11, 14, 16, 18, 21, 23 and 25 days after αrug intake. The tubes were centrifuged during 5 minutes at 3000 rpm, the plasma was separated and refrigerated at -20 °C until the assay. Standard breakfast, lunch and dinner were allowed respectively at times 2, 5 and 8 hours after drug intake. c. Plasma level determination Fluoxetine and norfluoxetine plasma levels were measured by an LO-MΞ-MS method (high pressure liquid /42382
- 10- chromathography coupled with tandem mass spectrometer) after a solide phase extraction procedure. The accuracy of the method was evaluated each day of measurement, d. Pharmacokmetic parameters The relative bioavailability of the two active ingredients was compared using the following parameters obtained using a non compartmental analysis (TOPFIT 2.0 program) :
Cmax : 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'/∑β: 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/γCD.
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/γCD.
A Student's test was realised to compare the pharmacokmetic parameters of FLU and N-FLU, calculated with a non compartmental analysis, with treatment A or with treatment B. Table XIV and XV present the results obtained.
Legend of the Tables:
Table IV Physical data of the subjects Table V Randomisation schedule Table VI Plasma levels of FLU on treatment A with FLU
Table VII Plasma levels of FLU on treatment B with FLU/γCD -II-
Table VIII Plasma levels of N-FLU after treatment with FLU Table IX Plasma levels of N-FLU on treatment with FLU/γCD Table X Pharmacokmetic parameters of FLU after treatment
Figure imgf000023_0001
Table XI Pharmacokmetic parameters of FLU after treatment
Figure imgf000023_0002
Table XII Pharmacokmetic parameters of N-FLU after treatment with FLU Table XIII Pharmacokmetic parameters of N-FLU after treatment with FLU/γCD
Table XIV Summary of FLU and FLU/γCD pharmacokmetic parameters Table XV Summary of norfluoxetine and norfluoxetme/CD pharmacokmetic parameters.
Legend of the Figures:
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/γCD.
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/γCD.
-21- Table IV
Subj. Height Cm Weight Kg I Age Year i
1 LD 1 185 | 71 26 DCB 172 i 69 21
3GY 186 I 81 19
4DY 174 ! 71 22
5DB 175 I 62 19
6CA 185 | 80 25
7 CM 179 ! 70 25
8LG 181 73 ! 21
9TD 173 ! 73 22
1011 188 j 73 20 !
11 HV j 178 ! 62 22 2TJC 175 I 68 21 ean±SD I 179±5,6 | 71.1+5.8 | 22.9±2.3 |
Table V
Subj. | Date of Treatment administration
1 LD I 18.02.97 A I
2DCB I 18.02.97 B
3GY 18.02.97 B
4DY \ 18.02.97 A
5DB j 18.02.97 A
6CA ! 18.02.97 B
7 CM ; 25.02.97 A
8LG I 25.02.97 B
9TD | 25.02.97 A
1011 ! 25.02.97 A
11 HV \ 25.02.97 B I
12TJC | 25.02.97 | B cn c
□3 CΛ
-4
H
C H m n x 11) m σ m H
H (D
I
< C r m t
Figure imgf000025_0001
n c
CD cn
H
H
C H m 1-3 n cr x m (D m I
H < h
3 c r m ιo
0)
Figure imgf000026_0001
cn c
CD cn c
H m t-3 ω ID x cr l-1 m m (D
H <
7^ c r m
M
Figure imgf000027_0001
Figure imgf000028_0001
ω c
CO cn
C H m cn ι-3 x m cr m (D
H
3 c r 1 ro Ol
Figure imgf000028_0002
Table X
Figure imgf000029_0001
Table XI
] Subj. 2 j Subj. 3 j Subj. 6 j Subj. 8 | Subj. 11 ; Subj. 12 | Mean | SD j Cmax j 15.6 | 11.3 | 12 | 7.32 ! 15 | 14.5 [ 12.6 I 3.1 [ 1 ng/ml |
| tCmax2h | 3.08 I 6.95 | 8.92 \ 7.98 ! 8.05 | 3.98 | 6.6 ! 2.4 |
! AUC 0-48h ] 358.12 | 358.15 j 237.59 [ 214.76 | 471.62 ] 417.72 j 343.0 | 100.1 !
! AUC O-inf. ! 532.52 | 1122.5 ! 345.94 I 437.43 I 1211.74 1 872.72 | 753.8 ! 367.5 !
MRT | 26.3 ! 79.6 ! 25.6 \ 31 I 70.1 ! 56.7 I 48.2 I 23.8 I t ' 2 B I 27.2 ! 73 j 24.6 \ 42.4 | 52.3 I 49.1 ! 44.8 I 17.9 ! Vd ! 1470 I 1880 ! 2050 | 2800 | 1250 ] 1620 I 1845.0 ! 547.88 Cl tot 626 ! 297 I 964 I 762 I 275 I 382 I 551.0 ! 279.3 Table XII
Subj 1 Subj 4 Subj 5 Subj 7 Subj 9 Subj 10 Mean SD
Cmax 1 ng/ml 814 657 197 325 571 105 90 58 t Cmax2h 425 719 306 9 243 326 288 240
AUC0-48h 25062 1702 73758 13046 21294 40939 3185 2267
AUCO-mf 137679 146857 419246 74857 60474 203812 17382 13100
§ MRT 991 145 153 122 557 133 1180 359 cn t!/2B 154 101 117 145 781 101 1160 289
H C H Vd 3230 1980 802 5600 3730 1430 27953 17568 m cn Cltot 242 227 795 445 551 164 2848 1780 x m rπ
H 1 , Table Xlll c
Subj 2 Subj 3 Subj 6 Subj 8 ( Subj 11 Subj 12 Mean ( SD
^ Cmax1 ng&ml 128 689 821 484 971 913 86 27 t Cmax2h 721 797 . 892 487 144 146 713 ■ 621
AUC0-48h 46384 21964 21861 16988 21425 21279 2498 1065
AUCO-mf 359766 124375 198979 72582 257313 215034 20467 10086
MRT 180 122 218 926 204 191 1679 495 t'/2B 114 939 254 834 174 134 1422 635
Vd 918 2180 3680 3320 1950 1800 23080 10238
Cltot 927 268 168 459 130 155 2121 1344
-23-
Table XIV
Treatment A i Treatment B p I
Cmax (ng/ml) 8.9 12.6 0.134 t Cmax (hours) 4.9 6.5 0.233
AUC 0-48h (ng*h/ml) I 218.2 343.0 0.017
AUC O-∞ (ng*h/ml) 301.6 753.8 0.026
MRT (hours) 22.6 48.2 0.026 t ■/. B (hours) 25.6 44.8 0.034
Vd (1 ) 2955 1845 0.157
Cl Total (ml/min) 1432.5 \ 551.0 0.041
Table XV
Treatment A I Treatment B j P
C max (ng/ml) 9.0 8.6 0.886 t Cmax (hours) 28.8 71.3 0.149
AUC 0-48h (ng*h/ml) 318.5 249.8 I 0.517
AUC 0 - oo (ng*h/ml) j 1738.2 2046.7 j 0.657
MRT (hours) 118.0 167.9 | 0.073 t Vi B (hours) 1160 1422 | 0.379
Vd (1 ) 2795.3 2308.0 I 0.570
Cl Total (ml/min) 282.8 212.0 I 0.444

Claims

1. Pharmaceutical compositions 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 and said composition optionally in further containing auxiliary and additional materials acceptable in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.
2. Pharmaceutical compositions containing as an active ingredient a propanamine of the general formula I - m the formula
R stands for hydrogen or methyl - or any optical isomer and/or pharmaceutically acceptable salt thereof together with γ-cyclodextrin, a methylated α-, β- or γ-cyclodextrin, a hydroxypropylated a- , β- or γ- cyclodextrin, an ionic watersoluble α-, β- or γ-cyclo- dextrin polymer, a maltosylated α, β or γ-cyclodextrm, or β-cyclodextnn or α-cyclodextnn preferably m the form of an inclusion complex and said composition optionally further containing auxiliary and additional materials acceptable in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.
3. Pharmaceutical compositions according to any of claims 1 and 2 containing as an active ingredient inclusion complexes of a propanamine of the general formula I - in the formula
R stands for hydrogen or methyl - wnerem 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.
. Inclusion complexes of a propanamine of formula I - in the formula
R stands for hydrogen or methyl - and any optical isomer and salt of the same formed with γ- cyclodextrin whereby the molar ratio of the propanamine of formula I to the γ-cyclodextrin is within the range of 1:1 to 1:6 preferably 1:1 and 1:2.
5. Inclusion complexes of a propanamine of formula I - in the formula
R stands for hydrogen or methyl- and/or any of the optical isomers and/or salts of the same formed with a methylated α, β or γ-cyclodextrin or a hydroxypropylated α, β or γ-cyclodextrin whereby the molar ratio of the propanamine to the cyclodextrin is within the range of 1:1 to 1:6 or preferably 1:1 and 1:2.
6. Inclusion complexes of (±) -N-methyl-γ- [ 4-
( tri luoromethyl) - phenoxy] benzene-propanamine and γ- cyclodextrin.
7. Inclusion complexes of (±) -γ- [4- ( trifluoromethyl) - phenoxy] benzene-propanamine and γ cyclodextrin.
8. Inclusion complexes of (+) -N-methyl-γ- [4-
( trifluoromethyl) - phenoxy] benzene-propanamine and a methylated α, β or γ-cyclodextrm .
9. Inclusion complexes of (-) -N-methyl-γ- [ - ( trifluoromethyl ) - phenoxy] benzene-propanamine and a methylated α, β or γ-cyclodextnn.
10. Inclusion complexes of (+) -N-methyl-γ- [4-
(trifluoromethyl) - phenoxy] benzene-propanamine and a hydroxypropylated α, β or γ-cyclodextrin . -2,2.-
11. Inclusion complexes of (-) -N-methyl-γ- [ 4-
( trifluoromethyl) - phenoxy] benzene-propanamine and a hydroxypropylated α, β or γ-cyclodextrin
12. Inclusion complexes of ( + ) -γ- [ 4- (trifluoromethyl) - phenoxy] benzene-propanamine and a methylated α, β or γ- cyclodextnn .
13. Inclusion complexes of (-) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and a methylated oc, β or γ- cyclodextrin.
14. Inclusion complexes of (+) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and a hydroxypropylated , β or γ-cyclodextrin .
15. Inclusion complexes of (-) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine and a hydroxypropylated α, β or γ-cyclodextrin .
16. Process for the preparation of new inclusion complexes of a propanamine of the general formula I - in the formula
R stands for hydrogen or methyl - or any optical isomer or pharmaceutically acceptable salt thereof formed with γ-cyclodextrin, a methylated α, β or γ-cyclodextrin, an ionic watersoluble α-, β- or γ- cyclodextπn polymer, a hydroxypropylated α-, β- or γ- cyclodextnn, a maltosylated α, β or γ-cyclodextrin or β- cyclodextnn or α-cyclodextrin characterized by reacting a propanamine of the general formula I - m the formula
R stands for hydrogen or methyl - or any optical isomer or pharmaceutically acceptable salt thereof with γ-cyclodextrm, a methylated α, β or γ- cyclodextrin, an ionic watersoluble α-, β- or γ- cyclodextnn polymer, a hydroxypropylated - , β- or γ- cyclodextrm, a maltosylated , β or γ-cyclodextrm or β- cyclodextrm or α-cyclodextrm whereby the molar ratio of the applied propanamine to the applied cyclodextrin amounts to a value within the range of 1:1 to 1:6 preferably 1:1 or 1:2.
17. Process according to claim 16 characterized by reacting a propanamine of general formula I - in the formula R stands for hydrogen or methyl - or any optical isomer or pharmaceutically acceptable salt thereof with γ-cyclodextrin, a methylated α, β or γ- cyclodextnn, an ionic watersoluble α-, β- or γ- cyclodextnn polymer, a hydroxypropylated α-, β- or γ- cyclodextrin or β-cyclodextnn or α-cyclodextrin whereby the molar ratio of the applied propanamine to the applied cyclodextrin amounts to a value within the range of 1:1 to 1:6 preferably 1:1 or 1:2 using any of the following methods 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 m the presence or followed by addition of an organic solvent optionally followed by granulating and drying; c) reacting the propanamine with the cyclodextrin m solution of water or water and water-miscible organic solvents, cooling the solution 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. -ϊ -
18. Method of treatment of depression by administering to a patient an effective dose of 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 optionally in the form of an inclusion complex and said composition optionally further containing auxiliary and additional materials acceptable in pharmaceuticals for oral, parenteral, transdermal, rectal or other medical uses.
19. Method of treatment of depression by administering to a patient an effective dose of a pharmaceutical composition containing as an active ingredient inclusion complexes of a propanamine of the general formula I - in the formula
R stands for hydrogen or methyl - 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.
20. Method of treatment of depression by administering to a patient an effective dose of a pharmaceutical composition containing inclusion complexes of a propanamine of formula I - in the formula
R stands for hydrogen or methyl - and any optical isomer and salt of the same formed with γ- cyclodextnn whereby the molar ratio of the propanamine of formula I to the γ-cyclodextrin is within the range of 1:1 to 1:6 or 1:1 and 1:2.
21. Method of treatment of depression by administering to a patient an effective dose of inclusion complexes of
(x) -γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine or (+) -γ- [ - ( trifluoromethyl) - phenoxy] enzene-propanamine or
(-) -γ- [4- (trifluoromethyl) - phenoxy] enzene-propanamine or -S5-
(±) -N-methyl-γ- [4- (trifluoromethyl) - phenoxy] benzene- propanamine or (+) -N-methyl-γ- [4- (trifluoromethyl) - phenoxy] benzene-propanamine or (-) -N-methyl-γ- [4-
(trifluoromethyl) - phenoxy] benzene-propanamine with γ- cyclodextrine or with a methylated α, β or γ-cyclodextrin.
PCT/HU1998/000028 1997-03-24 1998-03-23 Pharmaceutical compositions containing propanamine derivatives and cyclodextrin WO1998042382A1 (en)

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EP98913968A EP0969874A1 (en) 1997-03-24 1998-03-23 Pharmaceutical compositions containing propanamine derivatives and cyclodextrin
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JP2003503493A (en) * 1999-07-01 2003-01-28 イタルファルマコ ソシエタ ペル アチオニ Complexes of paroxetine with cyclodextrin or cyclodextrin derivatives
US8580243B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8580244B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8389499B2 (en) 2002-09-06 2013-03-05 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8399431B2 (en) 2002-09-06 2013-03-19 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
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
US8580242B2 (en) 2002-09-06 2013-11-12 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8603454B2 (en) 2002-09-06 2013-12-10 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8609081B2 (en) 2002-09-06 2013-12-17 Cerulean Pharma Inc. Cyclodextrin-based polymers for therapeutics delivery
US8680202B2 (en) 2002-09-06 2014-03-25 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
US9610360B2 (en) 2007-01-24 2017-04-04 Ceruliean Pharma Inc. Polymer drug conjugates with tether groups for controlled drug 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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HUP9700632A2 (en) 1998-12-28
AU6848198A (en) 1998-10-20
ZA982457B (en) 1998-09-23
HUP9700632A3 (en) 1999-10-28
AR010910A1 (en) 2000-07-12
HU9700632D0 (en) 1997-05-28
JP2002514210A (en) 2002-05-14
HRP980155A2 (en) 1998-12-31

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