US20140005123A1 - Pharmaceutical compositions - Google Patents

Pharmaceutical compositions Download PDF

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Publication number
US20140005123A1
US20140005123A1 US13/992,948 US201113992948A US2014005123A1 US 20140005123 A1 US20140005123 A1 US 20140005123A1 US 201113992948 A US201113992948 A US 201113992948A US 2014005123 A1 US2014005123 A1 US 2014005123A1
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weight
composition
amount
surfactant
fatty acid
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Inventor
Elisabete Goncalves
Karin Rapp
Bertrand Sutter
Frank Stowasser
Bjoern Trupp
Sebastian Chabaut
Julien Thorens
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Debiopharm SA
Novartis AG
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Debiopharm SA
Novartis AG
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Application filed by Debiopharm SA, Novartis AG filed Critical Debiopharm SA
Priority to US13/992,948 priority Critical patent/US20140005123A1/en
Assigned to DEBIOPHARM S.A. reassignment DEBIOPHARM S.A. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: THORENS, JULIEN, CHABAUD, SEBASTIEN
Assigned to NOVARTIS PHARMA AG reassignment NOVARTIS PHARMA AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: STOWASSER, FRANK, SUTTER, BERTRAND, TRUPP, BJOERN, GONCALVES, ELISABETE, RAPP, KARIN
Assigned to NOVARTIS AG reassignment NOVARTIS AG ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: NOVARTIS PHARMA AG
Publication of US20140005123A1 publication Critical patent/US20140005123A1/en
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/12—Cyclic peptides, e.g. bacitracins; Polymyxins; Gramicidins S, C; Tyrocidins A, B or C
    • A61K38/13—Cyclosporins
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention relates to lipid-based compositions, specifically to lipid-/surfactant-based compositions for oral administration of cyclophilin binding non-immunosuppressive cyclosporins, in particular, compositions having alisporivir as an active agent.
  • PCT/EP 2004/009804, WO 2005/021028, or WO 2006/071619 disclose non-immunosuppressive cyclosporins which bind to cyclophilin and which have also been found to have an inhibitory effect on Hepatitis C virus (HCV).
  • Alisporivir (Debio-025) is a cyclophilin (Cyp) inhibitor and its mode of action as an anti-HCV agent is via inhibition of host proteins, in particular of cyclophilin A, that are directly involved in HCV replication.
  • Cyclosporins are sparingly soluble in water and, therefore, are difficult to formulate into commercially acceptable formulations.
  • Microemulsion preconcentrates as lipid-/surfactant-based formulations consisting of a hydrophilic phase, a lipophilic phase and poorly-water soluble drugs, such as cyclosporin A have been described, for example, in the UK patent application No 2 222 770 A (equivalent to DE-A-39 30 928).
  • lipid-/surfactant-based pharmaceutical compositions with poorly-water soluble drugs such as alisporivir, having a high drug load of about 15 to about 20% by weight of the composition, are obtained using water content from about 2% to about 15% by weight of the composition.
  • such compositions can, in practice, be prepared comprising water as an essential component.
  • the present invention provides a lipid-/surfactant-based pharmaceutical composition
  • a lipid-/surfactant-based pharmaceutical composition comprising alisporivir, a carrier medium comprising a lipophilic component, a surfactant, a hydrophilic component and water.
  • Alisporivir may be in amorphous or crystalline form and can include any pharmaceutically acceptable salts or esters thereof.
  • compositions of the present invention are preferably for oral administration but may be suitable for buccal, pulmonal, topical, rectal or vaginal administration.
  • a pre-concentrate such as lipid-/surfactant-based formulation comprises alisporivir, a lipophilic component, a surfactant, a hydrophilic component and water is disclosed.
  • the pharmaceutical composition in the form of a pre-concentrate such as lipid-/surfactant-based formulation contains the active agent, as herein defined and is capable of producing colloidal structures when diluted with an aqueous medium, for example water, or gastric juices.
  • the colloidal structures are preferably liquid droplets wherein the liquid droplets are in the emulsion size range or in the microemulsion size range.
  • the present invention provides a pharmaceutical composition comprising alisporivir for administration to a subject in need thereof, wherein the pharmaceutical composition is in the form of a pre-concentrate, such as lipid-/surfactant-based formulation.
  • the present invention provides an emulsion or a microemulsion comprising alisporivir as the active agent, a carrier medium that comprises a lipophilic component, a surfactant, a hydrophilic component and water.
  • the colloidal structures of the microemulsion or emulsion form spontaneously or substantially spontaneously when the components of the composition of the invention are brought into contact with an aqueous medium, e.g. by simple shaking by hand for a short period of time, for example for 10 seconds.
  • the compositions of the invention are kinetically stable, e.g. for at least 15 minutes or up to 4 hours, or even to 24 hours or longer.
  • FIGS. 1 , 2 and 3 are graphs which illustrate the impact of water in the equilibrium solubility of various formulations comprising alisporivir according to the Examples.
  • FIG. 4 shows the impact of water, ethanol, and glycerol and their interactions in the equilibrium solubility of DEB025 Ethanol solvate in formulation according to Example A1.
  • the lipophilic component comprises one or more lipophilic substances.
  • the hydrophilic component comprises one or more hydrophilic substances.
  • the surfactant comprises one or more surfactants.
  • compositions of the invention may include a variety of additives including antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavours, sweeteners and further components such as those described in Fiedler, H. P. “Lexikon der Hilfsstoffe für Pharmazie, Kosmetik and angrenzende füre”, Editio Cantor, D-7960 Aulendorf, 5 th revised and expanded edition (2002).
  • additives will conveniently be dissolved in the carrier medium.
  • the present invention provides a pharmaceutical composition, preferably in form of a pre-concentrate, such as lipid-/surfactant-based formulation for oral administration, comprising:
  • the lipophilic component is selected from the group consisting of glyceryl mono-C6-C14-fatty acid esters, mixtures of mono- and di-glycerides of C6-C18 fatty acids, glyceryl di-C6-C18-fatty acid esters, medium chain fatty acid triglyceride, glyceryl mono-C16-C18-fatty acid esters, mixed mono-, di-, tri-glycerides, acetylated monoglycerides (C18), propylene glycol monofatty acid esters, propylene glycol mono- and di-fatty acid esters, propylene glycol diesters, propylene glycol monoacetate and propylene glycol diacetate, transesterified ethoxylated vegetable oils, sorbitan fatty acid esters, esterified compounds of fatty acid and primary alcohols, glycerol triacetate or (1,2,3)-triacetin, acetyl triethyl citrate, tribut
  • the surfactant is selected from the group consisting of reaction products of a natural or hydrogenated castor oil and ethylene oxide, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene co-polymers and block co-polymers or poloxamers, polyoxyethylene mono esters of a saturated C10 to C22, polyoxyethylene alkyl ethers, sodium alkyl sulfates and sulfonates, and sodium alkyl aryl sulfonates, water soluble tocopheryl polyethylene glycol succinic acid esters (TPGS), polyglycerol fatty acid esters, alkylene polyol ethers or esters, polyethylene glycol glyceryl fatty acid esters, sterols and derivatives thereof, transesterified, polyoxyethylated caprylic-capric acid glycerides, sugar fatty acid esters, PEG sterol ethers, dioctyls
  • the hydrophilic component is selected from the group consisting of polyethylene glycol glyceryl C 6 -C 10 fatty acid esters, N-alkylpyrrolidone, benzyl alcohol, triethyl citrate, polyethylene glycols, ethanol, 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 (Arlasolve), triethylenglycol, ethylacetate, glycerol, sorbitol and ethyl lactate.
  • polyethylene glycol glyceryl C 6 -C 10 fatty acid esters N-alkylpyrrolidone
  • benzyl alcohol triethyl citrate
  • polyethylene glycols ethanol
  • transcutol C 2 H 5 —[O—(CH 2 ) 2
  • hydrophilic component can also be but does not have to be a solvent for the drug substance.
  • Hydrophilic components with an amphiphilic nature can function as co-surfactants, although they are not usually regarded as surfactants, due to their ability to further reduce the surface tension below the level achieved with the surfactants.
  • hydrophilic components which are also co-surfactants for alisporivir include for instance ethanol, glycerol or sorbitol, preferably ethanol or glycerol.
  • the present invention provides a pharmaceutical composition as defined above and wherein the water in an amount of about 4 to about 5% by weight of the composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising alisporivir in an amount of about 19% to about 20% by weight of the composition and the water is in an amount of about 4% to about 5% by weight of the composition.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising alisporivir in an amount of about 19% to about 20% by weight of the composition, water in an amount of about 2% to about 15%, preferably of about 2% to about 5%, by weight of the composition and a hydrophilic component in an amount of about 5% to about 25%, preferably suitable hydrophilic components include for instance ethanol and/or polyethylene glycol.
  • the present invention provides a pharmaceutical composition, preferably in form of a pre-concentrate such as lipid-/surfactant-based formulation, for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a pre-concentrate, such as lipid-/surfactant-based formulation, for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a pre-concentrate, such as lipid-/surfactant-based formulation, for oral administration comprising:
  • compositions of the present invention include a hydrophilic component or phase.
  • Suitable hydrophilic compounds or components include:
  • 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 (Arlasolve), triethylenglycol, ethylacetate, and ethyllactate.
  • the hydrophilic component may comprise 5 to 60% by weight of the composition of the invention, e.g. 10 to 50%; preferably 10 to 40% by weight, more preferably about 10 to about 30% by weight, most preferred about 20% by weight.
  • the hydrophilic component may comprise one component or a mixture of two or more hydrophilic components.
  • the ratio of main hydrophilic component to hydrophilic co-component is typically from about 0.5:1 to about 2:1.
  • compositions of the invention include a lipophilic component or phase.
  • the lipophilic component is preferably characterized by a low HLB value of less than 10, e.g. up to 8.
  • Suitable lipophilic components include:
  • Neobee® M 5 F is a fractionated caprylic-capric acid triglyceride available from coconut oil; acid value max. 0.2; saponification value about 335 to 360; iodine value max 0.5, water content max. 0.15%, D. 20 0.930-0.960, n D 20 1,448-1,451 (manufacturer information).
  • Neobee® M 5 F is available from Stepan Europe.
  • a further example is Miglyol 829 containing additionally esters with succinic acid.
  • Such esters may include e.g. sorbitan mono C 12-18 fatty acid esters, or sorbitan tri C 12-18 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., 2, p. 1571; Handbook of Pharmaceutical Excipients, loc. cit., page 511).
  • lipophilic components e.g. (1-3,5-6, 8-9, 12-13, 19)
  • the lipophilic component preferably comprises 5 to 85% by weight of the composition of the invention, e.g. 10 to 85%; preferably 15 to 60% by weight, more preferably about 15 to about 40% by weight.
  • compositions of the present invention preferably contain one or more surfactants to reduce the interfacial tension thereby providing thermodynamic stability.
  • 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.
  • the complex mixtures or each surfactant preferably has a hydrophilic-lipophilic balance (HLB) value of 8 to 17, especially 10 to 17.
  • the HLB value is preferably the mean HLB value.
  • Suitable surfactants include:
  • C 3-5 alkylene triols in particular glycerol, ethers or esters.
  • Suitable C 3-5 alkylene triol ethers or esters include mixed ethers or esters, i.e. components including other ether or ester ingredients, for example transesterification products of C 3-5 alkylene triol esters with other mono-, di- or poly-ols.
  • Particularly suitable alkylene polyol ethers or esters are mixed C 3-8 alkylene triol/poly-(C 2-4 alkylene) glycol fatty acid esters, especially mixed glycerol/polyethylene- or polypropylene-glycol fatty acid esters.
  • Preferred glycerides are fatty acid triglycerides, e.g. (C 10-22 fatty acid) triglycerides, including natural and hydrogenated oils, in particular vegetable oils.
  • Suitable vegetable oils include, for example, olive, almond, peanut, coconut, palm, soybean and wheat germ oils and, in particular, natural or hydrogenated oils rich in (C 12-18 fatty acid) ester residues.
  • the surfactant may comprise 5 to 90% by weight of the composition of the invention; preferably 10 to 85% by weight, more preferably 15 to 60% by weight.
  • surfactants may also act as hydrophilic component and some hydrophilic components may also act as surfactants.
  • compositions of the invention include additives for example antioxidants, antimicrobial agents, enzyme inhibitors, stabilizers, preservatives, flavours, sweeteners and other components such as those described in Fiedler, H. P., loc. cit.
  • additives or ingredients may comprise about 0.05 to 5% by weight of the total weight of the composition.
  • Antimicrobial agents, enzyme inhibitors, stabilizers or preservatives typically provide up to about 0.05 to 1% by weight based on the total weight of the composition.
  • Sweetening or flavouring agents typically provide up to about 2.5 or 5% by weight based on the total weight of the composition.
  • the invention provides a process for preparing a dispersible, preferably spontaneously dispersible, pharmaceutical composition containing alisporivir, which process comprises bringing alisporivir and a carrier medium comprising (1) a lipophilic component, (2) a surfactant, (3) a hydrophilic component, and (4) water into intimate admixture.
  • the carrier medium can be prepared separately before bringing the active agent into intimate admixture with the carrier medium.
  • the two or more of the components of the carrier medium can be mixed together with the active agent.
  • the spontaneously dispersible or dispersible pharmaceutical composition is preferably a preconcentrate, such as lipid-/surfactant-based formulation as herein defined.
  • the spontaneously dispersible or dispersible pharmaceutical compositions preferably spontaneously or substantially spontaneously form an o/w (oil-in-water) micro-/emulsion, when diluted with an aqueous medium such as water to a dilution of 1:1 to 1:300, e.g. 1:1 to 1:70, especially 1:10 to 1:70, more especially e.g. 1:10, or in the gastric juices of a patient after oral administration/application.
  • the invention provides a process for preparing a pharmaceutical composition containing alisporivir, which process comprises:
  • the active agent in particular, alisporivir, may be present in an amount by weight of up to about 30% by weight of the composition, e.g. about 20% by weight.
  • the active agent is preferably present in an amount of about 15 to about 25% by weight of the composition, more preferably, in an amount of about 15% to about 20% by weight of the composition.
  • the hydrophilic component may comprise about 5% to about 45% by weight of the composition of the invention, e.g. about 5% to about 40%; preferably about 5% to about 30% by weight, more preferably about 10% to about 25% by weight.
  • composition of the invention preferably contains from about 5% to about 45% of a hydrophilic component by weight.
  • a particularly suitable composition contains hydrophilic component from about 5% to about 45% by weight of e.g. ethanol, polyethyleneglycol 400, or triethylcitrate diethylene glycol monoethyl ether or propylene glycol.
  • the lipophilic component preferably comprises about 5% to about 45% by weight of the composition of the invention, e.g. about 10% to about 35%; preferably about 15% to about 20% by weight.
  • composition of the invention preferably contains from about 5% to about 45% of a lipophilic component by weight.
  • a particularly suitable composition contains as lipophilic component from about 5% to about 45% by weight of e.g. medium chain triglycerides, corn oil mono-di-triglycerides, sorbitan monooleate, linoleoyl macrogolglycerides or oleic acid.
  • the surfactant may comprise about 5% to about 70% by weight of the composition of the invention; preferably about 20% to about 45% by weight, more preferably about 20% to about 40% by weight.
  • composition of the invention preferably contains from about 5% to about 70% of a surfactant by weight.
  • a particularly suitable composition contains as surfactant from about 5% to about 45% by weight.
  • Suitable surfactants include, for instance, Macrogolglycerol hydroxystearate, Caprylocaproyl Macrogol-8 glycerides, Vitamin E Polyethylene Glycol Succinate or Glyceryl caprylate.
  • the water may be present in an amount of about 2% to about 15% by weight of the composition of the invention, preferably about 3% to about 10% by weight, more preferably about 4% to about 5% by weight, e.g. about 5% by weight.
  • the relative proportion of the active agent(s), the lipophilic component(s), the surfactant(s) the hydrophilic component(s), and water preferably may result in a colloidal system that lies within the “emulsion” region on a standard three way plot graph.
  • the compositions will therefore be of high stability and are capable, on addition to an aqueous medium, of becoming emulsions.
  • the present invention provides a pharmaceutical composition, preferably in the form of a lipid-/surfactant-based formulation for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising:
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising:
  • the active ingredient may be present in an amount by weight of the composition of about 15% to about 30%; for example, in an amount by weight of about 15% to about 20%, 19% to about 20%, for example 15%, 16%, 17%, 18%, 19%, or 20%.
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising alisporivir in an amount of about 5% to about 15% by weight of the composition for example, in an amount by weight of about 5% to about 10%, for example about 5%, about 6%, about 7%, about 8%, about 9%, or about 10%.
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising alisporivir in an amount of about 5% to about 15% by weight of the composition; and a hydrophilic component wherein the hydrophilic component is in an amount from about 5 to about 45% by weight, about 5% to about 30% by weight, more preferably about 10% to about 25% by weight and wherein the hydrophilic component is selected from the group consisting of ethanol, polyethyleneglycol, triethylcitrate, diethylene glycol monoethyl ether and propylene glycol; and wherein when alisporivir is in an amount of 10% and the hydrophilic component is ethanol or propylene glycol, the composition does not contain 41% of polyethyleneglycol-hydrogenated castor oil.
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration comprising:
  • composition of the invention as defined above is a microemulsion preconcentrate it may be combined with water or an aqueous solvent medium to form a micro-/emulsion.
  • the emulsion or microemulsion may be administered enterally, for example orally, for example in the form of a capsule or a drinkable solution which can be taken orally and swallowed.
  • a unit dosage of the preconcentrate formulation is preferably used to fill orally administrable capsule shells.
  • the capsule shells may be soft or hard capsule shells, for example made of gelatine.
  • Each unit dosage will suitably contain from about 0.1 to about 200 mg active agent, for example about 0.1 mg, about 0.25 mg, about 0.5 mg, about 1 mg, about 2 mg, about 10 mg, about 15 mg, about 25 mg, about 50 mg, about 75 mg, about 100 mg, about 150 mg or about 200 mg of the active agent.
  • Such unit dosage forms are suitable for administration 1 to 5 times daily depending upon the particular purpose of therapy, the phase of therapy and the like.
  • compositions may be in drink solution form and may include water or any other aqueous system, e.g. fruit juice, milk, and the like, to provide e.g. colloidal systems, suitable for drinking, e.g. with a dilution of from about 1:10 to about 1:100.
  • aqueous system e.g. fruit juice, milk, and the like
  • compositions of the invention may exhibit especially advantageous properties when administered orally; for example, in terms of consistency and high level of bioavailability obtained in standard bioavailability trials.
  • Such trials are performed in animals, e.g. rats or dogs or healthy volunteers using chromatographic methods, e.g. HPLC.
  • compositions of the invention may show good stability characteristics as indicated by standard stability trials, for example having a shelf life stability of up to one, two or three years, and even longer.
  • One group of compositions of the invention may be of high stability that are capable, on addition to water, of providing aqueous emulsions.
  • compositions of the invention exhibit especially advantageous properties when administered orally; for example, in terms of consistency and high levels of bioavailability obtained in standard bioavailability trials.
  • compositions of the present invention are effective with biosurfactants or tenside materials, for example bile salts, being present in the gastro-intestinal tract. That is, the pharmaceutical compositions of the present invention are fully dispersible in aqueous systems comprising such natural tensides and thus capable of providing emulsion or microemulsion systems and/or particulate systems in situ which are stable.
  • the function of the pharmaceutical compositions upon oral administration remain substantially independent of and/or unimpaired by the relative presence or absence of bile salts at any particular time or for any given individual.
  • the compositions of this invention may also reduce variability in inter- and intra-patient dose response.
  • the optimal dosage of active agent to be administered to a particular patient must be considered carefully. It may be advisable to monitor the blood serum levels of the active agent by radioimmunoassay, monoclonal antibody assay, or other appropriate conventional means. Dosages of alisporivir will generally range from about 100 to about 1600 mg per day, e.g. about 200 mg to about 1200 mg per day for a 75 kilogram adult, preferably about 400 mg to about 1200 mg, with the optimal dosage being approximately about 800 to about 1200 mg per day.
  • compositions as defined herein are preferably compounded in unit dosage form, for example by filling them into orally administrable capsule shells.
  • the capsule shells may be soft or hard gelatin or HPMC-based (Hydroxypropylmethyl cellulose) capsule shells or Vegicaps.
  • each unit dosage will suitably contain between about 50 and about 400 mg of the active agent; for example about 50 mg, about 100 mg, about 200 mg, about 300 mg, about 400 mg.
  • Such unit dosage forms are suitable for administration once or more times daily depending upon the particular purpose of therapy, the phase of therapy and the like.
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration as defined above, for use as a medicament, preferably in treatment of a Hepatitis C virus infected patient and wherein alisporivir is to be administered in an amount of about 400 to about 600 mg twice per day.
  • the present invention provides a pharmaceutical composition, preferably in form of a lipid-/surfactant-based formulation for oral administration as defined above, for use as a medicament, preferably in treatment of a Hepatitis C virus infected patient and wherein (i) alisporivir is administered during an initial phase in an amount of about 600 mg, twice per day; (ii) followed by administering alisporivir during the second phase in an amount of 600 mg or about 800 mg once per day.
  • the term “by weight”, unless the context dictates otherwise, is used to mean by weight of the composition, e.g. percentage by weight of the composition.
  • the term “by weight” in the context of mixtures such as mixtures of hydrophilic components, of lipophilic components, or of surfactants, unless the context dictates otherwise, is used to mean the sum of the weights of the respective components of the mixture by weight of the composition.
  • the present invention provides a method of treatment of a subject suffering from a disorder treatable with alisporivir comprising administering a therapeutically effective amount of a pharmaceutical composition of the invention to a subject in need of such treatment.
  • the present invention provides the use of alisporivir for the manufacture of a pharmaceutical composition for the treatment of a subject suffering from a disorder treatable with alisporivir.
  • compositions of the present invention may be observed in standard clinical tests in, for example, known indications of active agent dosages giving equivalent blood levels of active agent; for example using dosages in the range of 100 mg to 1200 mg of active agent per day for a 75 kilogram mammal, e.g. adult and in standard animal models.
  • the increased bioavailability of the active agent provided by the compositions may be observed in standard animal tests and in clinical trials, e.g. as described above.
  • compositions of the present invention are particularly useful for treatment and prevention Hepatitis C virus infections or HCV induced disorders in a patient, multiple sclerosis, muscular dystrophy, Ullrich congenital muscular dystrophy and ischemia.
  • This Example (and Examples 2 through 3) describes means to prepare high drug load alisporivir (DEB025) 19 wt %) lipid-based formulations and illustrates means to increase the equilibrium solubility of DEB025 ethanol solvate above the target drug load of such formulations through the addition of water.
  • a stock solution of the DEB025 formulations shown in Table 1 (Formulations A1 to A3) and Table 2 (Formulations A through C) was prepared as follows. Solid or semi-solid excipients were heated in a water bath at 50° C. and well stirred prior dispensing step. A quantity of each excipient was weighted into a glass bottle, followed by addition of ethanol. The excipients were stirred at room temperature until a homogeneous solution was obtained. Then, an adequate amount of DEB025 amorphous form was added to the glass bottle containing the prepared vehicle and stirred with magnetic bar at room temperature until complete dissolution of drug substance (clear light yellow solution with no visible drug particles).
  • the stock solution was then aliquoted into small glass vials (2 g) followed by the addition of a small amount of DEB025 ethanol solvate (60 to 120 mg).
  • DEB025 ethanol solvate 60 to 120 mg
  • the amorphous form of DEB025 was added to the vials. Vials were placed at 25° C. and stirred with magnetic bar until an excess of solid drug identified as DEB025 ethanol solvate or DEB025 amorphous form (for ethanol-free compositions) was obtained (at least 24 h). An additional amount of DEB025 ethanol solvate or DEB025 amorphous form (60 to 120 mg) was added to those vials showing a clear solution upon equilibration. These vials were re-equilibrated until an excess of drug was observed. Finally, the supernatant from these suspensions was filtrated and analyzed for DEB025 using HPLC.
  • DEB025 (amorphous form) was formulated with the compositions listed in Table 3 (formulations D1, D and E), and the equilibrium solubility of DEB025 ethanol solvate was measured at 25° C. as a function of water ( FIG. 2 ). The formulations and solubility measurements were done as described in Example 1.
  • DEB025 (amorphous form) was formulated with the compositions listed in Table 4 (formulations F through H), and the equilibrium solubility of DEB025 ethanol solvate was measured at 25° C. as a function of water ( FIG. 3 ). The formulations and solubility measurements were done as described in Example 1.
  • Example 5 illustrates formulations of DEB025 intended for encapsulation in 200 mg soft-gelatin capsules.
  • Fill solution formulations were prepared as described in Example 1. Equilibrium solubility of DEB025 ethanol solvate in fill solution mimicking the final capsule was measured at 20° C. in the presence of water and glycerol (common plasticizer used in manufacture of soft-gelatin capsules) at the final concentrations (wt %) listed in Table 5.
  • This Example illustrates high drug load formulations of DEB025 (19 wt %) containing PEG400 intended for encapsulation in 200 mg soft-gelatin capsules.
  • Fill solution formulations were prepared as described in Example 1. Equilibrium solubility of DEB025 ethanol solvate in fill solution mimicking the final capsule was measured at 20° C. as described in Example 4.
  • This Example illustrates formulations of DEB025 with reduced ethanol content (55%) intended for either encapsulation in soft gelatin capsules or filling into bottles (Tables 6 through 8).
  • Fill solution formulations were prepared as described in Example 1.
  • Equilibrium solubility of DEB025 ethanol solvate or amorphous DEB025 (for ethanol-free formulations) were measured in the formulation at 21 ⁇ 2° C. as described in Example 1.
  • This Example presents formulations comprising about 20% DEB025 and which are intended as solution (Formulation O), as intermediate for encapsulation in soft gelatin capsules (Formulation P), as final composition in soft gelatin capsules (Formulation Q).
  • DoE A 2 3 full factorial Design of Experiments (DoE) was performed consisting of 3 variables (Water, Glycerol, and Ethanol), tested at 2 levels each (high and low), with 4 points used as center points, in a total of 12 runs. Table 9 lists the levels for each parameter tested in the DoE and FIG. 4 shows the corresponding Pareto chart of effects for mean solubility.

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JO3337B1 (ar) 2010-12-13 2019-03-13 Debiopharm Sa تركيبات صيدلية تشمل أليسبوريفير
WO2015008223A1 (en) 2013-07-17 2015-01-22 Novartis Ag Treatment of hepatitis c virus infection with alisporivir and ribavirin
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