EP1915132A1 - Mikropartikelzusammensetzungen des topoisomerase-i-inhibitors 7-tert-butoxyiminomethylcamptothecin - Google Patents

Mikropartikelzusammensetzungen des topoisomerase-i-inhibitors 7-tert-butoxyiminomethylcamptothecin

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Publication number
EP1915132A1
EP1915132A1 EP06792739A EP06792739A EP1915132A1 EP 1915132 A1 EP1915132 A1 EP 1915132A1 EP 06792739 A EP06792739 A EP 06792739A EP 06792739 A EP06792739 A EP 06792739A EP 1915132 A1 EP1915132 A1 EP 1915132A1
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EP
European Patent Office
Prior art keywords
pharmaceutical composition
cancer
fatty acid
oil
composition according
Prior art date
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Application number
EP06792739A
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English (en)
French (fr)
Inventor
Isabel Ottinger
Oskar Kalb
Walter Stebler
Agnes Taillardat
Wolfgang Wirth
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Novartis AG
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Novartis AG
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Application filed by Novartis AG filed Critical Novartis AG
Publication of EP1915132A1 publication Critical patent/EP1915132A1/de
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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
    • A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00

Definitions

  • the present invention relates to microparticle compositions in which the active agent is a topoisomerase I inhibitor and pharmaceutical compositions comprising the microparticle compositions that are useful for the treatment and prevention of proliferative diseases including cancer.
  • Camptothecin derivatives are a class of compounds described in U.S. Patent No. 6,242,457. Camptothecin derivatives, such as those disclosed in U.S. Patent No. 6,242,457, present highly specific difficulties in relation to administration generally and galenic compositions in particular, including in particular problems of drug bioavailability because these derivatives have very poor solubility.
  • Figure 1 illustrates in vitro dissolution rate profiles.
  • Figure 2 illustrates in vivo dog bioavailability.
  • Figure 3 illustrates in vivo dog bioavailability.
  • Figure 4 illustrates in vitro dissolution rate profiles.
  • the present invention relates to microparticle compositions comprising a topoisomerase I inhibitor, in particular, 7-f-butoxyiminomethylcamptothecin, as the active agent in a vehicle.
  • the present invention also relates to microparticle compositions comprising a topoisomerase I inhibitor, in particular, 7-f-butoxyiminomethylcamptothecin, as the active agent, and optionally at least one surface stabilizer in a vehicle.
  • the vehicle is selected from an oily vehicle, a hydrophilic non-aqueous vehicle or a self micro-emulsifying vehicle.
  • the self micro-emulsifying vehicle further comprises excipients.
  • the microparticle compositions may further comprise a sedimentation inhibitor and also further comprises excipients.
  • the present invention also relates to pharmaceutical compositions comprising the microparticle compositions of the invention and a pharmaceutically acceptable carrier, as well as any desired excipients.
  • the unit dose forms of the present invention are, for example, capsules, coated and uncoated tablets, ampoules, vials or bottles.
  • Examples are capsules containing from about 0.1 g to about 5 mg of 7-£-butoxyiminomethylcamptothecin.
  • the present invention provides a method of treatment of a subject suffering from a disorder treatable with 7-f-butoxyiminomethylcamptothecin comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention to a subject in need of such treatment.
  • an effective amount or “pharmaceutically effective amount” of a microparticle formulation refer to a non-toxic but sufficient amount of the microparticle formulation to provide the desired response and the corresponding therapeutic effect, in an amount sufficient to effect treatment of the subject, as defined below.
  • the exact amount required may vary from subject to subject, depending on the species, age and general condition of the subject, the severity of the condition being treated, the mode of administration.
  • An appropriate "effective" amount in any individual case may be determined by one of ordinary skill in the art using routine experimentation.
  • phrases "pharmaceutically acceptable” or “pharmacologically acceptable” means a material which is not biologically or otherwise undesirable, i.e., the material may be administered to an individual along with the microparticle formulation without causing any undesirable biological effects or interacting in a deleterious manner with any of the components of the composition in which it is contained.
  • Active agent means 7-f-butoxyiminomethylcamptothecin which has the following structure known as Compound A:
  • the preferred active agent can be in free or pharmaceutically acceptable salt form, in the form of their possible enantiomers, diastereoisomers and relative mixtures, polymorphs, amorphous, partially amorphous forms, solvates, their active metabolites and prodrugs.
  • the active agent may be present in an amount by weight from about 0.1 % to about 30% by weight of the composition of the invention.
  • the active agent is preferably present in an amount of about 1-10%, most preferably in an amount of about 1 % to about 5 % by weight of the composition.
  • microparticle refers to a particle of the active ingredient that is up to about 15 microns in diameter, more preferably about 0.5 microns to about 5 microns in diameter, most preferably about 1 micron to about 3 microns in diameter. Microparticle size is readily determined by techniques well-known in the art, laser diffractometry and/or scanning electron microscopy.
  • microsuspension refers to microparticle compositions comprising a topoisomerase I inhibitor, in particular, 7-f-butoxyiminomethylcamptothecin, as the active agent, and optionally at least one surface stabilizer in a vehicle.
  • the microparticle compositions may further comprise a sedimentation inhibitor and also further comprises excipients.
  • the surface stabilizer enhances the physical stability of the suspension and improves the dispersibility of the suspensions in contact with aqueous, e.g., gastrointestinal fluids.
  • the surface stabilizer also helps to inhibit crystal growth of the active agent in the microsuspension.
  • Preferred surface stabilizers of the present invention include, but are not limited to, cellulose derivatives, polyvinylpyrrolidone, random copolymers of vinyl pyrrolidone and vinyl acetate, sodium lauryl sulfate, sodium dioctylsulfosuccinate, colloidal or precipitated silicas (e.g., Aerosil ® from Degussa or Zeopharm ® from Huber) poloxamers (e.g., Pluronics F68 ® and F108 ® , which are block copolymers of ethylene oxide and propylene oxide); or a combination thereof.
  • cellulose derivatives include, but are not limited to, hydroxypropyl methylcellulose, hydroxypropylcellulose.
  • surface stabilizers which can be employed in the invention include, but are not limited to, known organic and inorganic pharmaceutical excipients. Such excipients include various polymers, low molecular weight oligomers, natural products and surfactants. Surface stabilizers also include nonionic, cationic, ionic and zwitterionic surfactants.
  • surface stabilizers include gelatin, casein, lecithin (phosphatides), dextran, gum acacia, cholesterol, tragacanth, stearic acid, benzalkonium chloride, calcium stearate, glycerol monostearate, cetostearyl alcohol, cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers (e.g., macrogol ethers, such as cetomacrogol 1000), polyoxyethylene castor oil derivatives, polyoxyethylene sorbitan fatty acid esters (e.g., the commercially-available Tweens ® , such as, e.g., Tween 20 ® and Tween 80 ® (ICI Specialty Chemicals)); polyethylene glycols (e.g., Carbowaxs 3550 ® and 934 ® (Union Carbide)), polyoxyethylene stearates, phosphates, carboxymethylcellulose calcium, carboxymethylcellulose
  • Exemplary cationic surface stabilizers are described in Cross and Singer, Cationic Surfactants: Analytical and Biological Evaluation, Marcel Dekker (1994); Rubingh, Editor, Cationic Surfactants: Physical Chemistry, Marcel Dekker (1991); and Richmond, Cationic Surfactants: Organic Chemistry, Marcel Dekker (1990).
  • the surface stabilizer is present in an amount by weight from about 0.1 % to about 30% by weight of the composition of the invention.
  • the surface stabilizer is preferably present in an amount of about 1% to about 15% by weight of the composition.
  • the vehicles of the present invention may be an oily vehicle; hydrophilic, nonaqueous vehicle; or self micro-emulsifying vehicle.
  • the vehicle is present in an amount by weight from about 70% to about 99% by weight of the composition of the invention.
  • the vehicle is preferably present in an amount of about 80% to about 98% by weight of the composition, most preferably in an amount of about 90-98%.
  • Oily vehicles of the present invention include alone or in combination corn oil, sesame oil, olive oil, paraffin oil, soy bean oil, cottonseed oil, long chain, medium and short chain mono-, di-, trigylcerides and other suitable lipophilic components.
  • Suitable lipophilic components include:
  • Monoglycerides suitable for use in the compositions of the invention include both symmetric (i.e., ⁇ -monoglycerides), as well as asymmetric monoglycerides ( ⁇ -monoglycerides). They also include both uniform glycerides (in which the fatty acid constituent is composed primarily of a single fatty acid), as well as mixed glycerides (i.e., in which the fatty acid constituent is composed of various fatty acids).
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Ci 4 .
  • caprylic or lauric acid monoglycerides which are commercially available, e.g., under the trade names Imwitor ® 308 or Imwitor ® 312, respectively, from, e.g., sasol.
  • Imwitor ® 308 comprises at least 80% monoglycerides and exhibits the following additional characterizing data: free glycerol max. 6%, acid value max. 3, saponification value 245-265, iodine value max. 1 , water content max. 1%.
  • it comprises 1% free glycerol, 90% monoglycerides, 7% diglycerides, 1% triglycerides (H. Fiedler, loc. cit, Vol. 1 , p. 798).
  • a further example is Capmul MCM C8 from Abitec Corporation.
  • ⁇ -monoglycerides and ⁇ , ⁇ 1 -diglycerides include both symmetric (i.e., ⁇ -monoglycerides and ⁇ , ⁇ 1 -diglycerides), as well as asymmetric mono- and diglycerides (i.e., ⁇ -monoglycerides and ⁇ , ⁇ -diglycerides) and acetylated derivatives thereof.
  • symmetric i.e., ⁇ -monoglycerides and ⁇ , ⁇ 1 -diglycerides
  • asymmetric mono- and diglycerides i.e., ⁇ -monoglycerides and ⁇ , ⁇ -diglycerides
  • acetylated derivatives thereof include both uniform glycerides (in which the fatty acid constituent is composed primarily of a single fatty acid), as well as mixed glycerides (i.e., in which the fatty acid constituent is composed of various fatty acids) and any derivatives thereof with lactic or citric acid.
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Ci 0 .
  • Particularly suitable are mixed caprylic and capric acid mono- and diglycerides as commercially-available, e.g., under the trade name Imwitor ® 742 or Imwitor 928 from, e.g., sasol.
  • Imwitor ® 742 comprises at least 45% monoglycerides and exhibits the following additional characterizing data: free glycerol max. 2%, acid value max. 2, saponification value 250-280, iodine value max. 1 , water max. 2% (H. Fiedler, loc. cit, VoI 1 , p.
  • Capmul ® MCM mono/diglycerides of caprylic/capric acid in glycerol as known and commercially- available under, e.g., the trade name Capmul ® MCM from, e.g., Abitec Corporation.
  • Capmul ® MCM exhibits the following additional characterizing data: acid value 2.5 max., ⁇ -mono (as oleate) 80% min., free glycerol 2.5% max., iodine value 1 max., chain length distribution: caproic acid (C6) 3% max., caprylic acid (C8) 75% min., capric acid (C10) 10% min., lauric acid (C12) 1.5% max., moisture (by Karl Fisher) 0.5% max.
  • Suitable examples of mono-/di-glcyerides with additional derivatization with lactic or citric acid are those marketed under the brand names of Imwitor 375, 377 or 380 by sasol.
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., C 16 -C 18 .
  • a suitable example is Tegin ® O (glyceryl oleate) exhibiting the following additional characterizing data: monoglyceride content 55-65%, peroxide value max. 10, water content max. 1%, acid value max. 2, iodine value 70-76, saponification value 158-175, free glycerol max. 2%, (manufacturer information). 3) Glyceryl di-C 6 -Ci 8 -fatty acid esters
  • symmetric i.e., ⁇ , ⁇ 1 -diglycerides
  • asymmetric diglycerides i.e., ⁇ , ⁇ -diglycerides
  • acetylated derivatives thereof include both uniform glycerides (in which the fatty acid constituent is composed primarily of a single fatty acid), as well as mixed glycerides (i.e., in which the fatty acid constituent is composed of various fatty acids) and any acetylated derivatives thereof.
  • the fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length of from C 6 -Ci 8 , e.g., C 6 -Ci 6 , e.g., C 8 -Ci 0 , e.g., C 8 .
  • Particularly suitable is caprylic diglycerides, which is commercially-available, e.g., under the trade name Sunfat ® GDC-S, e.g., from Taiyo Kagaku Co., Ltd.
  • Sunfat ® GDC-S has an acid value of about 0.3, a diglyceride content of about 78.8%, and a monoester content of about 8.9.
  • triglycerides of saturated fatty acid having 6-12, e.g., 8-10, carbon atoms include triglycerides of saturated fatty acid having 6-12, e.g., 8-10, carbon atoms.
  • Suitable medium chain fatty acid triglycerides are those known and commercially-available under the trade names Acomed ® , Myritol ® , Captex ® , Neobee ® M 5 F, Miglyol ® 810, Miglyol ® 812, Miglyol ® 818, Mazol ® , Sefsol ® 860, Sefsol ® 870; Miglyol ® 812 being the most preferred.
  • Neobee ® M 5 F is available from Stepan Europe.
  • a further example is Miglyol 829 containing additionally esters with succinic acid.
  • Monoglycerides suitable for use in the compositions of the invention include both symmetric (i.e., ⁇ -monoglycerides), as well as asymmetric monoglycerides ( ⁇ -monoglycerides). They also include both uniform glycerides (in which the fatty acid constituent is composed primarily of a single fatty acid), as well as mixed glycerides (i.e., in which the fatty acid constituent is composed of various fatty acids).
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., Ci 6 -Ci 8 .
  • GMOrphic ® -80 glyceryl monooleate
  • monoglyceride content min. 94% Ci 8 :1 content 75% min.
  • peroxide value max. 2.5 Ci 8 :2 + Ci 8 :3 max. 15%
  • Ci 6 :0 + Ci 8 :0 + C 2 o:O max. 10% water max. 2%
  • acid value max. 3 iodine value 65-75, saponification value 155-165, free glycerine max. 1%, hydroxyl number 300-330 (manufacturer information).
  • the fatty acid content for Maisine ® is typically: palmitic acid ca. 11%, stearic acid ca. 2.5%, oleic acid ca. 29%, linoleic acid ca. 56% and others ca. 1.5% (H. Fiedler, loc. cit., Vol. 2, p. 958; manufacturer information).
  • Mixed mono-, di-, triglycerides preferably comprise mixtures of C 8 -Ci 0 - or Ci 2 -C 2 o-fatty acid mono-, di- and triglycerides, especially mixed Ci 6 -Ci 8 -fatty acid mono-, di- and triglycerides.
  • the fatty acid component of the mixed mono-, di- and triglycerides may comprise both saturated and unsaturated fatty acid residues. Preferably, however, they are predominantly comprised of unsaturated fatty acid residues, in particular, Ci 8 unsaturated fatty acid residues.
  • the mixed mono-, di-, triglycerides comprise at least 60%, preferably at least 75%, more preferably at least 85% by weight of a Ci 8 unsaturated fatty acid (e.g., linolenic, linoleic and oleic acid) mono-, di- and triglycerides.
  • a Ci 8 unsaturated fatty acid e.g., linolenic, linoleic and oleic acid
  • the mixed mono-, di-, triglycerides comprise less than 20%, e.g., about 15% or 10% by weight or less, saturated fatty acid (e.g., palmitic and stearic acid) mono-, di- and triglycerides.
  • Mixed mono-, di-, triglycerides are preferably predominantly comprised of mono- and diglycerides; e.g., mono- and diglycerides comprise at least 50%, more preferably at least 70% based on the total weight of the lipophilic phase or component. More preferably, the mono- and diglycerides comprise at least 75% (e.g., about 80% or 85% by weight of the lipophilic component. Preferably, monoglycerides comprise from about 25% to about 50%, based on the total weight of the lipophilic component, of the mixed mono-, di-, triglycerides. More preferably from about 30% to about 40% (e.g., 35-40%) monoglycerides are present.
  • diglycerides comprise from about 30% to about 60%, based on the total weight of the lipophilic component, of the mixed mono-, di-, triglycerides. More preferably from about 40% to about 55% (e.g., 48-50%) diglycerides are present. Triglycerides suitably comprise at least 5% but less than about 25%, based on the total weight of the lipophilic component, of the mixed mono-, di-, triglycerides. More preferably from about 7.5% to about 15% (e.g., from about 9-12%) triglycerides are present.
  • Mixed mono-, di-, triglycerides may be prepared by admixture of individual mono-, di- or triglycerides in appropriate relative proportion.
  • transesterification products of vegetable oils e.g., almond oil, ground nut oil, olive oil, peach oil, palm oil; or, preferably, corn oil, sunflower oil or safflower oil; and most preferably corn oil, with glycerol.
  • vegetable oils e.g., almond oil, ground nut oil, olive oil, peach oil, palm oil; or, preferably, corn oil, sunflower oil or safflower oil; and most preferably corn oil, with glycerol.
  • Such transesterification products are generally obtained as described in GB 2 257 359 or WO 94/09211.
  • some of the glycerol is first removed to give a "substantially glycerol free batch" when soft gelatine capsules are to be made.
  • Purified transesterification products of corn oil and glycerol provide particularly suitable mixed mono-, di- and triglycerides hereinafter referred to as "refined oil” and produced according to procedures described in United Kingdom patent specification GB 2,257,359 or international patent publication WO 94/09211.
  • Acetylated monoglycerides (Ci 8 ) These include Myvacet 9-45. 8) Propylene glycol monofatty acid esters
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Ci 2 .
  • Particularly suitable are propylene glycol mono ester of caprylic and lauric acid as commercially-available, e.g., under the trade names Sefsol ® 218, Capryol ® 90 or Lauroglycol ® 90, from, e.g., Nikko Chemicals Co., Ltd. or Gattefosse or Capmul PG-8 from Abitec Corporation.
  • Lauroglycol ® 90 exhibits the following additional characterizing data: acid value max. 8, saponification value 200-220, iodine value max. 5, free propylene glycol content max. 5%, monoester content min. 90%; Sefsol ® 218 exhibits the following additional characterizing data: acid value max. 5, hydroxy value 220-280 (H. Fiedler, loc. cit, VoI 2, p. 906, manufacturer information).
  • Propylene glycol mono- and di-fatty acid esters include Lauroglycol FCC and Capryol PGMC.
  • Propylene glycol di-fatty acid esters such as propylene glycol dicaprylate (which is commercially-available under the trade name Miglyol ® 840 from, e.g., sasol; H. Fiedler, loc. cit, Vol. 2, p. 1008) or Captex 200 from Abitec Corporation.
  • propylene glycol dicaprylate which is commercially-available under the trade name Miglyol ® 840 from, e.g., sasol; H. Fiedler, loc. cit, Vol. 2, p. 1008
  • Captex 200 from Abitec Corporation.
  • transesterified ethoxylated vegetable oils such as those obtained by reacting various natural vegetable oils (e.g., corn oil, maize oil, castor oil, kernel oil, almond oil, ground nut oil, olive oil, soybean oil, sunflower oil, safflower oil and palm oil or mixtures thereof) with polyethylene glycols that have an average molecular weight of from 200-800, in the presence of an appropriate catalyst.
  • various natural vegetable oils e.g., corn oil, maize oil, castor oil, kernel oil, almond oil, ground nut oil, olive oil, soybean oil, sunflower oil, safflower oil and palm oil or mixtures thereof
  • polyethylene glycols that have an average molecular weight of from 200-800
  • Transesterified ethoxylated vegetable oils are known and are commercially-available under the trade name Labrafil ® (H. Fiedler, loc. cit., Vol. 2, p. 880).
  • Labrafil ® M 2125 CS obtained from corn oil and having an acid value of less than about 2, a saponification value of 155-175, an HLB value of 3-4, and an iodine value of 90-110) and Labrafil ® M 1944 CS (obtained from kernel oil and having an acid value of about 2, a saponification value of 145-175 and an iodine value of 60-90).
  • Labrafil ® M 2130 CS (which is a transesterification product of a Ci 2 -Ci 8 glyceride and polyethylene glycol and which has a melting point (m.p.) of about 35-40 0 C, an acid value of less than about 2, a saponification value of 185-200 and an iodine value of less than about 3) may also be used.
  • the preferred transesterified ethoxylated vegetable oil is Labrafil ® M 2125 CS which can be obtained, e.g., from Gattefosse, Saint-Priest Cedex, France.
  • esters include, e.g., sorbitan mono-Ci2-Ci 8 -fatty acid esters, or sorbitan tri- Ci 2 -Ci 8 -fatty acid esters are commercially-available under the trade mark Span ® from, e.g., Uniqema.
  • An especially preferred product of this class is, e.g., Span ® 20 (sorbitan monolaurate) or Span ® 80 (sorbitan monooleate) (Fiedler, loc. cit, Vol. 2, p. 1430; Handbook of Pharmaceutical Excipients, loc. cit., p. 473).
  • esterified compounds of fatty acid having 8-20 carbon atoms and primary alcohol having 2-3 carbon atoms e.g., isopropyl myristate, isopropyl palmitate, ethyl linoleate, ethyl oleate, ethylmyristate etc.
  • esterified compound of linoleic acid and ethanol being particularly preferable, also isopropylmyristat and isopropylpalmitat.
  • Glycerol triacetate is commercially-available as, e.g., Priacetin ® 1580 from Uniqema International, or as EastmanTM Triacetin from Eastman, or from Courtaulds Chemicals Ltd. Glycerol triacetate exhibits the following additional characterizing data: molecular weight 218,03, D. 20 3 1,159-1 ,163, n D 20 1 ,430-1 ,434, water content max. 0.2%, viscosity (25°) 17.4 mPa s, acid value max. 0.1 , saponification value of about 766-774, triacetin content 97% min. (H. Fiedler, loc. cit., Vol. 2, p. 1580; Handbook of Pharmaceutical Excipients, loc. cit, p. 534, manufacturer information). 16) Acetyl triethyl citrate
  • Acetyl triethyl citrate is commercially-available, e.g., under the trade name Citroflex ® A-2 from, e.g., Morflex Inc.
  • the fatty acid constituent can include both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Ci 8 .
  • Particularly suitable is, e.g., Plurol Oleique CC497 from Gattefosse, having a saponification value of 133-155 and a saponification value of 196-244.
  • Further suitable polyglycerol fatty acid esters include diglyceryl monooleate (DGMO) and Hexaglyn-5-O, as known and commercially-available from, e.g., Nikko Chemicals Co., Ltd.
  • Fatty acids can be obtained by hydrolyzing various animal and vegetable fats or oils, such as olive oil, followed by separation of the liquid acids.
  • the fatty acid/alcohol constituent can include both saturated and mono- or di-unsaturated fatty acids/alcohols having a chain length of from, e.g., C 6 -C 2 o- Particularly suitable are, e.g., oleic acid, oleyl alcohol, linoleic acid, capric acid, caprylic acid, caproic acid, tetradecanol, dodecanol or decanol.
  • Oleyl alcohol is commercially-available under the trade mark HD-Eutanol ® V from, e.g., Henkel KGaA.
  • Oleyl alcohol exhibits the following additional characterizing data: acid value max. 0.1 , hydroxy value of about 210, iodine value of about 95, saponification value max 1 , D. 20 about 0,849, n D 20 1 ,462, molecular weight 268, viscosity (20°) about 35 mPa s (manufacturer information).
  • Oleic acid exhibits the following additional characterizing data: molecular weight 282,47, D. 20 0,895, n D 20 1 ,45823, acid value 195-202, iodine value 85-95, viscosity (25°) 26 mPa s [H. Fiedler, loc. cit, Vol. 2, p. 1112; Handbook of Pharmaceutical Excipients, 2 nd Edition, Wade and Weller, Eds. (1994), Joint publication of American Pharmaceutical Assoc, Washington, USA and The Pharmaceutical Press, London, England, p. 325].
  • Coviox T-70 Coviox T-70, Copherol 1250, Copherol F-1300, Covitol 1360 and Covitol 1100.
  • the lipophilic component comprises, e.g., a pharmaceutically acceptable oil, preferably with an unsaturated component, such as a vegetable oil.
  • C 3 -C 5 -alkylene triols include C 3 -C 5 -alkylene triols, in particular, glycerol, ethers or esters.
  • Suitable C 3 -C 5 -alkylene triol ethers or esters include mixed ethers or esters, i.e., components including other ether or ester ingredients, e.g., transesterification products of C 3 -C 5 - alkylene triol esters with other mono-, di- or poly-ols.
  • alkylene polyol ethers or esters are mixed C 3 -C 5 -alkylene triol/poly-(C 2 -C 4 -alkylene) glycol fatty acid esters, especially mixed glycerol/polyethylene- or polypropylene-glycol fatty acid esters.
  • alkylene polyol ethers or esters include products obtainable by transesterification of glycerides, e.g., triglycerides, with poly-(C 2 -C 4 -alkylene) glycols, e.g., poly-ethylene glycols and, optionally, glycerol.
  • glycerides e.g., triglycerides
  • poly-(C 2 -C 4 -alkylene) glycols e.g., poly-ethylene glycols and, optionally, glycerol.
  • Such transesterification products are generally obtained by alcoholysis of glycerides, e.g., triglycerides, in the presence of a poly-(C- 2 -C 4 -alkylene) glycol, e.g., polyethylene glycol and, optionally, glycerol (i.e., to effect transesterification from the glyceride to the poly-alkylene glycol/glycerol component, i.e., via poly-alkylene glycolysis/glycerolysis).
  • glycerides e.g., triglycerides
  • a poly-(C- 2 -C 4 -alkylene) glycol e.g., polyethylene glycol
  • glycerol i.e., to effect transesterification from the glyceride to the poly-alkylene glycol/glycerol component, i.e., via poly-alkylene glycolysis/glycerolysis.
  • reaction is effected by reacting the indicated components (glyceride, polyalkylene glycol and, optionally, glycerol) at elevated temperature under an inert atmosphere with continuous agitation.
  • Preferred glycerides are fatty acid triglycerides, e.g., (Ci O -C 22 -fatty acid) triglycerides, including natural and hydrogenated oils, in particular, vegetable oils.
  • Suitable vegetable oils include, e.g., olive, almond, peanut, coconut, palm, soybean and wheat germ oils and, in particular, natural or hydrogenated oils rich in (Ci 2 -Ci 8 -fatty acid) ester residues.
  • Preferred polyalkylene glycol materials are polyethylene glycols, in particular, polyethylene glycols having a molecular weight of from ca. 500-4,000, e.g., from ca. 1 ,000-2,000.
  • Suitable alkylene polyol ethers or esters include mixtures of C 3 -C 5 -alkylene triol esters, e.g., mono-, di- and tri-esters in variable relative amount, and poly (C 2 -C 4 - alkylene) glycol mono- and di-esters, together with minor amounts of free C 3 -C 5 - alkylene triol and free poly-(C 2 -C 5 -alkylene) glycol.
  • the preferred alkylene triol moiety is glyceryl; preferred polyalkylene glycol moieties include polyethylene glycol, in particular, having a molecular weight of from ca. 500- 4,000; and preferred fatty acid moieties will be Ci O -C 22 -fatty acid ester residues, in particular, saturated Ci O -C 22 -fatty acid ester residues.
  • Particularly suitable alkylene polyol ethers or esters include transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and, optionally, glycerol; or compositions comprising or consisting of glyceryl mono-, di- and tri-C 10 -C 22 -fatty acid esters and polyethylene glycol mono- and di-Ci O -C 22 -fatty esters (optionally together with, e.g., minor amounts of free glycerol and free polyethylene glycol).
  • Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties in relation to the above definitions are as hereinbefore set forth.
  • the compositions of the invention may include mixtures of such ethers or esters.
  • Ethylene glycol esters These include Monthyle ® (ethylene glycol monostearate) available from, e.g., Gattefosse.
  • pentaerythrite-dioleate examples include, e.g., pentaerythrite-dioleate, -distearate, -monolaurate, -polyglycol ether, and -monostearate, as well as pentaerythrite-fatty acid esters (Fiedler, loc. cit., Vol. 2, pp. 1158-1160, incorporated herein by reference).
  • hydrophilic, non-aqueous vehicles include, but are not limited to, the following excipients alone or in combination:
  • the fatty acid ester may include mono- and/or di- and/or tri-fatty acid esters. It optionally includes both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Ci 0 .
  • the polyethylene glycols may have, e.g., from 5-10 [CH 2 -CH 2 - O] units, e.g., 7 units.
  • a particularly suitable fatty acid ester is polyethylene glycol (7) glyceryl monococoate, which is commercially-available, e.g., under the trade name Cetiol ® HE, e.g., from Henkel KGaA. Cetiol ® HE has a D.
  • ⁇ /-methyl-2-pyrrolidone e.g., as commercially-available under the trade name PharmasolveTM, from e.g. International Specialty Products (ISP).
  • ⁇ /-Methylpyrrolidone exhibits the following additional characterizing data: molecular weight 99,1 , D.25 1 ,027-1 ,028, purity (as area % by GC) (including methyl isomers) 99.85% min. (H. Fiedler, loc. cit., Vol. 2, p. 1004, manufacturer information).
  • Benzyl alcohol This is commercially-available from, e.g., Merck or may be obtained by distillation of benzyl chloride with potassium or sodium carbonate. Benzyl alcohol exhibits the following additional characterizing data: molecular weight 108,14, D. 1 ,043-1 ,049, nD 1 ,538-1 ,541. (H. Fiedler, loc. cit., Vol. 1 , p. 238; Handbook of Pharmaceutical Excipients, loc. cit, p. 35).
  • Triethyl citrate is commercially- available, e.g., under the trade names Citroflex ® 2, or in a pharmaceutical grade under the name TEC-PG/N from, e.g., Morflex Inc. Particularly suitable is triethyl citrate which has molecular weight of 276,3, a specific gravity of 1 ,135-1 ,139, a refractive index of 1 ,439-1 ,441 , a viscosity (25°) of 35,2 mPa s, assay (anhydrous basis) 99,0-100,5%, water max. 0,25% (H. Fiedler, loc. cit., Vol. 1 , p. 371 ; Handbook of Pharmaceutical Excipients, loc. cit., p. 540).
  • hydrophilic compounds include transcutol (C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH); glycofurol (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether); 1 ,2-propylene glycol; dimethylisosorbide, e.g., Arlasolve from Uniqema; polyethylene glycol, such as 200, 300, 400, 600, etc.; triethylenglycol; ethylacetate; and ethyllactate.
  • transcutol C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH
  • glycofurol also known as tetrahydrofurfuryl alcohol polyethylene glycol ether
  • dimethylisosorbide e.g., Arlasolve from Uniqema
  • polyethylene glycol such as 200, 300, 400, 600, etc.
  • triethylenglycol ethy
  • Microemulsion preconcentrate means a composition which spontaneously forms a microemulsion in an aqueous medium, e.g., in water, e.g., on dilution of 1 :1 to 1 :300, preferably 1 :1 to 1 :70, but especially 1 :1 to 1 :10 or in the gastric juices after oral application.
  • the self micro-emulsifying vehicle comprises one or more of the following lipophilic component and one or more of the following surfactant described below. In other embodiments the self micro-emulsifying vehicle comprises one or more of the following lipophilic component, one or more of the following one or more of the following hydrophilic component and one or more of the following surfactant described below.
  • Surfactants may be complex mixtures containing side products or unreacted starting products involved in the preparation thereof, e.g., surfactants made by polyoxyethylation may contain another side product, e.g., polyethylene glycol.
  • Each surfactant preferably has a hydrophilic-lipophilic balance (HLB) value of 8-17, especially 10-17.
  • the HLB value is preferably the mean HLB value.
  • Suitable surfactants include:
  • the natural or hydrogenated castor oil may be reacted with ethylene oxide in a molar ratio of from about 1 :35 to about 1 :60, with optional removal of the polyethylene-glycol component from the products.
  • ethylene oxide in a molar ratio of from about 1 :35 to about 1 :60, with optional removal of the polyethylene-glycol component from the products.
  • surfactants are commercially-available.
  • Particularly suitable surfactants include polyethyleneglycol-hydrogenated castor oils available under the trade name Cremophor ® ; Cremophor ® RH 40, which has a saponification value of about 50-60, an acid value less than about 1 , a water content (Fischer) less than about 2%, an n D 60 of about 1.453-1.457 and an HLB of about 14-16; and Cremophor ® RH 60, which has a saponification value of about 40-50, an acid value less than about 1 , an iodine value of less than about 1 , a water content (Fischer) of about 4.5-5.5%, an n D 60 of about 1.453-1.457 and an HLB of about 15-17.
  • Cremophor ® RH40 An especially preferred product of this class is Cremophor ® RH40.
  • Other useful products of this class are available under the trade names Nikkol ® (e.g., Nikkol ® HCO-40 and HCO-60), Mapeg ® (e.g., Mapeg ® CO-40h), Incrocas ® (e.g., Incrocas ® 40), Tagat ® (e.g., polyoxyethylene-glycerol-fatty acid esters, e.g., Tagat ® RH 40) and Simulsol OL-50 (PEG-40 castor oil, which has a saponification value of about 55-65, an acid value of max. 2, an iodine value of 25-35, a water content of max. 8%, and an HLB of about 13, available from Seppic).
  • These surfactants are further described in H. Fiedler, loc. cit.
  • Suitable surfactants of this class include polyethyleneglycol castor oils, such as that available under the trade name Cremophor ® EL, which has a molecular weight (by steam osmometry) of about 1630, a saponification value of about 65-70, an acid value of about 2, an iodine value of about 28-32 and an n D 25 of about 1.471.
  • Tween ® 20 and Tween ® 80 are especially preferred products of this class.
  • Myrj ® 52 having a D25 of about 1.1., a m.p. of about 40-44 0 C, an HLB value of about 16.9, an acid value of about 0-1 and a saponification value of about 25-35.
  • Pluronic ® and Emkalyx ® include the type known and commercially-available under the trade names Pluronic ® and Emkalyx ® (H. Fiedler, loc. cit., Vol. 2, p. 1203).
  • An especially preferred product of this class is Pluronic ® F68 (poloxamer 188) from BASF, having a m.p. of about 52°C and a molecular weight of about 6,800-8,975.
  • a further preferred product of this class is Synperonic ® PE L44 (poloxamer 124) from Uniqema.
  • Polyoxyethylene mono esters of a saturated C1 0 -C22 include Ci 8 -substituted, e.g., hydroxy fatty acid, e.g., 12 hydroxy stearic acid PEG ester, e.g., of PEG about, e.g., 600-900, e.g., 660 Daltons MW, e.g., Solutol ® HS 15 from BASF, Ludwigshafen, Germany.
  • MEF 151 E (1986) comprises about 70% polyethoxylated 12-hydroxystearate by weight and about 30% by weight unesterified polyethylene glycol component.
  • Solutol HS 15 has a hydrogenation value of 90-110, a saponification value of 53-63, an acid number of max. 1 , and a max. water content of 0.5% by weight.
  • polyoxyethylene glycol ethers of C 12 -Ci 8 -alcohols e.g. Polyoxyl 2-, 10- or 20-cetyl ether or Polyoxyl 23-lauryl ether, or polyoxyl 20-oleyl ether, or Polyoxyl 2-, 10-, 20- or 100-stearyl ether, as known and commercially-available, e.g., under the trade mark Brij ® from Uniqema.
  • An especially preferred product of this class is, e.g., Brij ® 35 (Polyoxyl 23 lauryl ether) or Brij ® 98 (Polyoxyl 20 oleyl ether) (H. Fiedler, loc. cit, Vol. 1 , p.
  • suitable products include polyoxyethylene-polyoxypropylene-alkyl ethers, e.g., polyoxyethylene-polyoxypropylene-ethers of Ci 2 -Ci 8 -alcohols, e.g., polyoxyethylen- 20-polyoxypropy-lene-4-cetylether which is known and commercially-available under the trade mark Nikkol PBC ® 34 from, e.g., Nikko Chemicals Co., Ltd. (H. Fiedler, loc. cit, Vol. 2, p. 1239).
  • Polyoxypropylene fatty acid ethers e.g., Acconon ® E are also suitable.
  • sodium lauryl sulfate which is also known as sodium dodecyl sulfate and commercially-available, e.g., under the trade name Texapon K12 ® from Henkel KGaA.
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Ci 8 .
  • Particularly suitable is, e.g., decaglycerylmonolaurat or decaglycerylmonomyristat, as known and commercially-available under the trade mark Decaglyn ® 1-L or Decaglyn ® 1-M or Decaglyn 1-0, respectively, from, e.g., Nikko Chemicals Co., Ltd (H. Fiedler, loc. cit, Vol. 2, p. 1228).
  • C 3 -C 5 -alkylene triols include C 3 -C 5 -alkylene triols, in particular, glycerol, ethers or esters.
  • Suitable C 3 -C 5 -alkylene triol ethers or esters include mixed ethers or esters, i.e., components including other ether or ester ingredients, e.g., transesterification products of C 3 -C 5 - alkylene triol esters with other mono-, di- or poly-ols.
  • alkylene polyol ethers or esters are mixed C 3 -C 5 -alkylene triol/poly-(C 2 -C 4 -alkylene) glycol fatty acid esters, especially mixed glycerol/polyethylene- or polypropylene-glycol fatty acid esters.
  • alkylene polyol ethers or esters include products obtainable by transesterification of glycerides, e.g., triglycerides, with poly-(C 2 -C 4 -alkylene) glycols, e.g., poly-ethylene glycols and, optionally, glycerol.
  • glycerides e.g., triglycerides
  • poly-(C 2 -C 4 -alkylene) glycols e.g., poly-ethylene glycols and, optionally, glycerol.
  • Such transesterification products are generally obtained by alcoholysis of glycerides, e.g., triglycerides, in the presence of a poly-(C 2 -C 4 -alkylene) glycol, e.g., polyethylene glycol and, optionally, glycerol (i.e., to effect transesterification from the glyceride to the poly-alkylene glycol/glycerol component, i.e., via poly-alkylene glycolysis/glycerolysis).
  • glycerides e.g., triglycerides
  • a poly-(C 2 -C 4 -alkylene) glycol e.g., polyethylene glycol and, optionally, glycerol
  • glycerol i.e., to effect transesterification from the glyceride to the poly-alkylene glycol/glycerol component, i.e., via poly-alkylene glycolysis/glycer
  • Preferred glycerides are fatty acid triglycerides, e.g., Ci O -C 22 -fatty acid triglycerides, including natural and hydrogenated oils, in particular, vegetable oils.
  • Suitable vegetable oils include, e.g., olive, almond, peanut, coconut, palm, soybean and wheat germ oils and, in particular, natural or hydrogenated oils rich in Ci 2 -Ci 8 -fatty acid ester residues.
  • Preferred polyalkylene glycol materials are polyethylene glycols, in particular, polyethylene glycols having a molecular weight of from ca. 500-4,000, e.g., from ca. 1 ,000-2,000.
  • Suitable alkylene polyol ethers or esters include mixtures of C 3 -C 5 -alkylene triol esters, e.g., mono-, di- and tri-esters in variable relative amount, and poly-(C 2 -C 4 - alkylene) glycol mono- and di-esters, together with minor amounts of free C 3 -C 5 - alkylene triol and free poly-(C 2 -C 5 -alkylene) glycol.
  • the preferred alkylene triol moiety is glyceryl; preferred polyalkylene glycol moieties include polyethylene glycol, in particular, having a molecular weight of from ca. 500- 4,000; and preferred fatty acid moieties will be Ci O -C 22 -fatty acid ester residues, in particular, saturated Ci O -C 22 -fatty acid ester residues.
  • Particularly suitable alkylene polyol ethers or esters include transesterification products of a natural or hydrogenated vegetable oil and a polyethylene glycol and, optionally, glycerol; or compositions comprising or consisting of glyceryl mono-, di- and tri-Cio-C 22 -fatty acid esters and polyethylene glycol mono- and di-Ci O -C 22 -fatty esters (optionally together with, e.g., minor amounts of free glycerol and free polyethylene glycol).
  • Preferred vegetable oils, polyethylene glycols or polyethylene glycol moieties and fatty acid moieties in relation to the above definitions are as hereinbefore set forth.
  • the fatty acid ester may include mono- and/or di- and/or tri-fatty acid ester.
  • the fatty acid constituent may include both saturated and unsaturated fatty acids having a chain length of from, e.g., Ci 2 -Ci 8 .
  • the polyethylene glycols may have, e.g., from 10-40 [CH 2 -CH 2 -O] units, e.g., 15 or 30 units. Particularly suitable is polyethylene glycol (15) glyceryl monostearat which is commercially-available, e.g., under the trade name TGMS ® -15, e.g., from Nikko Chemicals Co., Ltd.
  • glyceryl fatty acid esters include polyethylene glycol (30) glyceryl monooleate which is commercially-available, e.g., under the trade name Tagat ® O, e.g., from Goldschmidt (H. Fiedler, loc. cit., Vol. 2, pp. 1502-1503), and Tagat 02 (polytheylene glycol (20) glycerol monooleate, as well as Tagat L (polytheylene glycol (30) glycerol monolaurate) and Tagat L2 (polytheylene glycol (20) glycerol monolaurate), all, e.g., from Goldschmidt (H. Fiedler, loc. cit, Vol. 2, pp. 1502-1503).
  • a further suitable polyethylene glycol glyceryl fatty acid ester is Tagat TO.
  • Sterols and derivatives thereof include cholesterols and derivatives thereof, in particular, phytosterols, e.g., products comprising sitosterol, campesterol or stigmasterol, and ethylene oxide adducts thereof, e.g., soya sterols and derivatives thereof, e.g., polyethylene glycol sterols, e.g., polyethylene glycol phytosterols or polyethylene glycol soya sterols.
  • the polyethylene glycols may have, e.g., from 10-40 [CH 2 -CH 2 -O] units, e.g., 25 or 30 units.
  • polyethylene glycol (30) phytosterol which is commercially-available, e.g., under the trade name Nikkol BPS ® -30, e.g., from Nikko Chemicals Co., Ltd.
  • polyethylene glycol (25) soya sterol which is commercially-available, e.g., under the trade name Generol ® 122 E 25, e.g., from Henkel (H. Fiedler, loc. cit, Vol. 1, p. 680).
  • Labrasol ® has an acid value of max. 1 , a saponification value of 90-110, and an iodine value of max. 1 (H. Fiedler, loc. cit, Vol. 2, p. 880).
  • Ci 2 -Ci 8 -fatty acids e.g., sucrose monolaurate, e.g., Ryoto L-1695 ® , which is commercially-available from, e.g., Mitsubishi-Kasei Food Corp., Tokyo, Japan.
  • Aerosol OT ® This is commercially-available under the trade mark Aerosol OT ® from, e.g., American Cyanamid Co. (H. Fiedler, loc. cit., Vol. 1 , p. 118), or di-[2-ethylhexyl]-succinate (H. Fiedler, loc. cit, Vol. 1 , p. 487).
  • lecithins H. Fiedler, loc. cit, Vol. 2, p. 910, 1184.
  • Suitable lecithins include, in particular, soya bean lecithins. 18) Salts of fatty acids, fatty acid sulfates and sulfonates
  • C 6 -Ci 8 -acylated amino acids e.g., sodium lauroyl sarcosinate, which is commercially-available from, e.g., Fluka.
  • C 6 -Ci 8 -acylated amino acids e.g., cetyl trimethyl ammonium bromide, which is commercially-available from, e.g., E. Merck AG.
  • hydrophilic components of the present invention include, but are not limited to:
  • the fatty acid ester may include mono- and/or di- and/or tri-fatty acid esters. It optionally includes both saturated and unsaturated fatty acids having a chain length of from, e.g., C 8 -Cio-
  • the polyethylene glycols may have, e.g., from 5-10 [CH 2 -CH 2 - O] units, e.g., 7 units.
  • a particularly suitable fatty acid ester is polyethylene glycol (7) glyceryl monococoate, which is commercially-available, e.g., under the trade name Cetiol ® HE, e.g., from Henkel KGaA. Cetiol ® HE has a D.
  • ⁇ /-methyl-2-pyrrolidone e.g., as commercially-available under the trade name PharmasolveTM from, e.g., International Specialty Products (ISP).
  • ⁇ /-Methylpyrrolidone exhibits the following additional characterizing data: molecular weight 99,1 , D.25 1 ,027-1 ,028, purity (as area % by GC) (including methyl isomers) 99.85% min. (H. Fiedler, loc. cit., Vol. 2, p. 1004, manufacturer information).
  • Triethyl citrate is commercially- available, e.g., under the trade names Citroflex ® 2, or in a pharmaceutical grade under the name TEC-PG/N from, e.g., Morflex Inc. Particularly suitable is triethyl citrate which has molecular weight of 276,3, a specific gravity of 1 ,135-1 ,139, a refractive index of 1 ,439-1 ,441 , a viscosity (25°) of 35,2 mPa s, assay (anhydrous basis) 99,0-100,5%, water max. 0,25% (H. Fiedler, loc. cit, Vol. 1 , p. 371 ; Handbook of Pharmaceutical Excipients, loc. cit., p. 540).
  • hydrophilic compounds include transcutol (C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH); glycofurol (also known as tetrahydrofurfuryl alcohol polyethylene glycol ether); 1 ,2-propylene glycol, dimethylisosorbide, e.g., Arlasolve from Uniqema; polyethylene glycol, such as 200, 300, 400, 600, etc.; triethylenglycol; ethylacetate; and ethyllactate.
  • transcutol C 2 H 5 -[O-(CH 2 ) 2 ] 2 -OH
  • glycofurol also known as tetrahydrofurfuryl alcohol polyethylene glycol ether
  • 1 ,2-propylene glycol, dimethylisosorbide e.g., Arlasolve from Uniqema
  • polyethylene glycol such as 200, 300, 400, 600, etc.
  • triethylenglycol ethy
  • An example of the self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, corn oil, mono-, di-, triglycerides, propyleneglycol 1 ,2 and ethanol.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, corn oil, mono-, di-, triglycerides and propyleneglycol 1 ,2.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, corn oil, mono-, di and triglycerides, polyethylene glycol 400 and ethanol.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, corn oil, mono-, di and triglycerides and polyethylene glycol 400.
  • Another example of the self-micro-emulsifying media includes vitamin E TPGS, dimethyl isosorbide, triethylcitrate and ethanol.
  • Another example of the self-micro-emulsifying media includes vitamin E TPGS, dimethyl isosorbide and triethylcitrate.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, C 8 /Ci 0 -mono-/diglycerides, triethylcitrate and ethanol.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, C 8 /Ci 0 -mono-/diglycerides and triethylcitrate.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, lineoyl macrogol-6 glycerides, propyleneglycol and ethanol.
  • self-micro-emulsifying media includes hydrogenated polyoxyl castor oil, lineoyl macrogol-6 glycerides and propyleneglycol.
  • the microparticle compositions of the present invention may further comprise a sedimentation inhibitor which significantly enhances the viscosity.
  • a sedimentation inhibitor which significantly enhances the viscosity.
  • the sedimentation inhibitor are oleogel formers which include, but are not limited to, precipitated or colloidal silica (e.g., Aerosil 200 ® or 300 ® ), Bentonit, zinc/aluminium stearate and certain copolymers, such as ethylene/propylene/styrene copolymer, butylene/ethylene/styrene copolymer (e.g., Versagel ® MP), hydrogenated styrene/isoprene copolymer and hydrogenated styrene/butadiene copolymer).
  • oleogel formers which include, but are not limited to, precipitated or colloidal silica (e.g., Aerosil 200 ® or 300 ® ), Bentonit, zinc/aluminium
  • sedimentation inhibitors are waxes and solid excipients, e.g., surfactants, lipophilic or hydrophilic excipients, e.g., polyethylene glycol of higher molecular weight (2,000, 4,000, ...) or alkylene polyol ethers or esters, e.g., Gelucire 44/14.
  • solid excipients e.g., surfactants, lipophilic or hydrophilic excipients, e.g., polyethylene glycol of higher molecular weight (2,000, 4,000, ...) or alkylene polyol ethers or esters, e.g., Gelucire 44/14.
  • the sedimentation inhibitor can be either added during milling or after the milling procedure.
  • compositions of the present invention comprising the microparticle compositions of the present invention can be administered as oral suspensions in multidose or single dose containers or filled in hard or soft gelatin capsules.
  • the microparticles of the present invention may also be absorbed on a carrier and compressed into hard tablets.
  • suitable carriers are precipitated and colloidal silicas (e.g., Zeopharm 80 ® , 600 ® or 5170 ® from Huber Corp., Aerosil 200 ® or 300 ® , Aeroperl 300 ® from Degussa), as well as sugar spheres or cellulose derivative spheres (e.g., Celphere ® from Asahi-Kasei or Cellets ® from Syntapharm).
  • compositions of the present invention include additives, e.g., antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavors, sweeteners and other components, such as those described in H. Fiedler, loc. cit.
  • additives e.g., antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavors, sweeteners and other components, such as those described in H. Fiedler, loc. cit.
  • Preferred antioxidants include ascorbyl palmitate, butyl hydroxy anisole (BHA), butyl hydroxy toluene (BHT), alpha-tocopherol.
  • Preferred stabilizers include an organic acid, e.g., citric acid, fumaric acid, maleic acid, tartaric acid, ascorbic acid and phosphoric acid.
  • organic acid e.g., citric acid, fumaric acid, maleic acid, tartaric acid, ascorbic acid and phosphoric acid.
  • the dose of the active agent in the compositions of the invention is of the same order as, or up to half, that used in known compositions containing the active agent.
  • the compositions of the invention show activity at concentrations from about 0.1 mg to about 40 mg/day of active agent, preferably from about 0.1 mg to about 20 mg/day, e.g., most preferably from about 0.1 to about 5 mg/day of active agent.
  • a typical dose for the active agent is from 0.1-5 mg/day for treating proliferative diseases or diseases that are associated with or triggered by persistent angiogenesis.
  • a proliferative disease is mainly driven by tumor(s) disease (or cancer) (and/or any metastases).
  • the inventive compositions are particularly useful for treating a tumor which is a breast cancer, lung cancer, gastrointestinal cancer, including esophageal, gastric, small bowel, large bowel and colorectal cancer, glioma, sarcoma, such as those involving bone, cartilage, soft tissue, muscle, blood and lymph vessels, ovarian cancer, myeloma, female cervical cancer, endometrial cancer, head and neck cancer, mesothelioma, renal cancer, ureter, bladder and urethral cancers, prostate cancer, skin cancers and melanoma.
  • inventive compositions are particularly useful for treating: (i) a breast tumor; a lung tumor, e.g., non-small cell and small cell lung cancer; a gastrointestinal tumor, e.g., a colorectal tumor; or a genitourinary tumor, e.g., a prostate tumor;
  • a proliferative disease may furthermore be a hyperproliferative condition, such as a leukemia, lymphoma and multiple myeloma.
  • additives or ingredients may comprise about 0.05-5% by weight of the total weight of the composition.
  • Antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers or preservatives typically provide up to about 0.05-2% by weight based on the total weight of the composition.
  • Sweetening or flavouring agents typically provide up to about 0.5% or 1% by weight based on the total weight of the composition.
  • microparticle compositions of the present invention can be prepared by milling techniques including, but not limited to, wet-milling including wet ball milling, high pressure homogenization, microfluidization or precipitation techniques.
  • microsuspensions can be prepared using other mills and/or milling conditions (rotation speed, concentration of ingredients, time, beads - material and size).
  • Self-micro-emulsifying system 1 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% ethanol abs.
  • Self-micro-emulsifying system 2 40% corn oil mono-, di- and triglycerides, 49% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 10% propylene glycol.
  • the larger irregular shaped particles could be identified as excipient particles, while the small particles are drug substance particles.
  • Figure 1 of the present invention describes the in vitro dissolution rate profiles (USP2, 1 ,000 ml_, 0.3% SDS, 50 rpm, 37°C). It can be seen that all microparticle formulations show improved dissolution and resuspendability behavior compared to the crystalline drug substance. Especially significant increase in dissolution rate was observed for Trials 4 and 5 containing corn oil and Pluronic F68 ® as surface stabilizer and Trials 8, 9, 11 and 13 using self-microemulsifiying vehicles as milling media.
  • bioavailability of 7-£-butoxyiminomethylcamptothecin is compared as it is determinable after administration of unmilled drug substance in a dry powder formulation (hard capsule) and of a composition according to the present invention.
  • Administered form 0.5 mg 7-£-butoxyiminomethylcamptothecin per capsule and dog.
  • composition according to the present invention corresponds to Trials 4 and 8 in Example 1.
  • Figures 2 and 3 of the present invention describes the in vivo dog bioavailability (0.5 mg 7-f-butoxyiminomethylcamptothecin/dog, beagle dogs, 6 dogs).
  • a significant increase in bioavailability was observed for the two microparticle formulations ( Figure 2) compared to the one observed for a dry mixture containing crystalline compound A ( Figure 3).
  • the microparticle suspension compositions tested correspond to Trials 4 and 8 in Table 1.
  • microparticle formulation can be prepared using other mills and/or milling conditions (rotation speed, concentration of ingredients, time, beads - material and size).
  • Self-micro-emulsifying system 1 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% ethanol abs.
  • Self-micro-emulsifying system 2 40% corn oil mono-, di- and triglycerides, 49% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 10% propylene glycol.
  • Figure 4 of the present invention describes the in vitro dissolution rate profiles (USP2, 1 ,000 ml_, 0.3% SDS, 50rpm, 37°C) of the scale-up trial batches 15 compared to the small scale batch 14. Dissolution rate profiles were comparable.
  • Microparticle formulation 16 and 17 were diluted with the self-micro emulsifying system used also to prepare the milled product. In some cases Aerosil 200 was added. The resulting diluted microparticle formulation were either filled in soft gelatin capsules (18, 19) or in hard gelatin capsules (20, 21). The composition of these dosage forms is summarized in Table 5.
  • Self-micro-emulsifying system 1 36% corn oil mono-, di- and triglycerides, 45% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 9% propylene glycol, 10% ethanol abs.
  • Self-micro-emulsifying system 2 40% corn oil mono-, di- and triglycerides, 49% polyethylene glycol 40 hydrogenated castor oil (Cremophor RH40), 10% propylene glycol.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Dispersion Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
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  • Molecular Biology (AREA)
  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
EP06792739A 2005-08-10 2006-08-08 Mikropartikelzusammensetzungen des topoisomerase-i-inhibitors 7-tert-butoxyiminomethylcamptothecin Withdrawn EP1915132A1 (de)

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US70713905P 2005-08-10 2005-08-10
PCT/EP2006/065160 WO2007017514A1 (en) 2005-08-10 2006-08-08 Microparticle compositions of the topoisomerase i inhibitor 7-tert-butoxyiminomethylcamptothecin

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US5145684A (en) * 1991-01-25 1992-09-08 Sterling Drug Inc. Surface modified drug nanoparticles
US5726181A (en) * 1995-06-05 1998-03-10 Bionumerik Pharmaceuticals, Inc. Formulations and compositions of poorly water soluble camptothecin derivatives
US7374779B2 (en) * 1999-02-26 2008-05-20 Lipocine, Inc. Pharmaceutical formulations and systems for improved absorption and multistage release of active agents
IT1306129B1 (it) * 1999-04-13 2001-05-30 Sigma Tau Ind Farmaceuti Esteri della l-carnitina o di alcanoil l-carnitine utilizzabili comelipidi cationici per l'immissione intracellulare di composti
EP1269994A3 (de) * 2001-06-22 2003-02-12 Pfizer Products Inc. Pharmazeutische Zusammensetzungen die ein Arzneimittel und die Konzentration verbesserende Polymere enthalten
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KR20080034989A (ko) 2008-04-22
CN101287448A (zh) 2008-10-15
PE20070232A1 (es) 2007-04-09
ECSP088166A (es) 2008-03-26
BRPI0614757A2 (pt) 2011-04-12
WO2007017514A1 (en) 2007-02-15
MA29735B1 (fr) 2008-09-01
AU2006277879A1 (en) 2007-02-15
IL189076A0 (en) 2008-08-07
TNSN08062A1 (en) 2009-07-14
JP2009504616A (ja) 2009-02-05
MX2008001965A (es) 2008-03-26
CA2618084A1 (en) 2007-02-15
RU2008108885A (ru) 2009-09-20

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