WO2007103425A2 - Kits et procedes destines a la preparation de compositions pharmaceutiques comprenant un inhibiteur de la voie du facteur tissulaire (tfpi) - Google Patents

Kits et procedes destines a la preparation de compositions pharmaceutiques comprenant un inhibiteur de la voie du facteur tissulaire (tfpi) Download PDF

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WO2007103425A2
WO2007103425A2 PCT/US2007/005814 US2007005814W WO2007103425A2 WO 2007103425 A2 WO2007103425 A2 WO 2007103425A2 US 2007005814 W US2007005814 W US 2007005814W WO 2007103425 A2 WO2007103425 A2 WO 2007103425A2
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tfpi
diluent
aqueous solution
pharmaceutical composition
variant
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WO2007103425A3 (fr
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Augustus Okhamafe
Chin-Yi Huang
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Novartis AG
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Novartis AG
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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
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/55—Protease inhibitors
    • A61K38/57—Protease inhibitors from animals; from humans
    • 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
    • A61K47/12—Carboxylic acids; Salts or anhydrides thereof
    • 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
    • A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
    • A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
    • A61K47/183—Amino acids, e.g. glycine, EDTA or aspartame
    • 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
    • A61K47/20—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
    • 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
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system

Definitions

  • the present invention relates to the packaging and storage of components used to prepare pharmaceutical compositions comprising Tissue Factor Pathway Inhibitor (TFPI) or variants thereof.
  • TFPI Tissue Factor Pathway Inhibitor
  • the pharmaceutical compositions are therapeutically beneficial (e.g., for the treatment of severe Community Acquired Pneumonia).
  • Drug products are in many cases packaged and/or stored in forms that differ significantly from those employed when the drug is ultimately administered to a patient.
  • Drug storage forms may vary in terms of physical state, composition (e.g., concentration), or conditions (e.g., temperature) relative to their corresponding administration forms.
  • a drug may be administered in a solution form that is relatively unstable and therefore not suitable for extended storage periods.
  • the drug can be stored for an extended period (which may include packaging and shipping time) in a powdered or lyophilized form that is considerably more stable than its administration form.
  • Other drugs although they may be effectively stored in solution form, require dilution prior to administration.
  • the storage form of the drug must be diluted or reconstituted with a diluent (e.g., an aqueous solution containing any of a number of solubilizers, stabilizers such as antioxidants, buffers, or other agents compatible with the drug) to obtain the administration form.
  • a diluent e.g., an aqueous solution containing any of a number of solubilizers, stabilizers such as antioxidants, buffers, or other agents compatible with the drug
  • an overriding consideration especially in the case of drugs administered parenterally (e.g. , intravenously) is the maintenance of these components in a sterile environment.
  • maintaining sterility and stability often present conflicting challenges.
  • the "terminal sterilization" i.e., after packaging and sealing
  • heating to about 120 0 C (248°F) can destabilize them to the point where their biological activity is wholly or partly lost.
  • overcoming stability problems may require manufacturing a drug in high volumes and at a low concentration, whereby the correspondingly large manufacturing scale poses a significant barrier to maintaining aseptic conditions.
  • Manufacturing and shipping costs which are often related to the ability of a particular drug formulation to be made in relatively low volumes and without significant modifications to existing,, standard facilities, represent other major considerations. For all of these reasons, appropriate storage and administration forms are highly drug-specific and require extensive investigation into the properties and requirements of the particular drug at issue.
  • TFPI tissue factor pathway inhibitor
  • LACI lipoprotein associated coagulation inhibitor
  • TFI tissue factor inhibitor
  • EPI extrinsic pathway inhibitor
  • TFPI cDNA have been isolated from placental and endothelial cDNA libraries (Wun et al. (1988) J. BIOL. CHEM. 263:6001-6004); Girard et al. (1989) THROMB. RES. 55:37-50).
  • the cloning of the TFPI cDNA. which encodes TFPI, is further described in U.S. Patent No. 4,966,852; see also U.S. Patent Nos. 5,773,251 and 5,849,875.
  • TFPI variants which differs from TFPI by the addition of an alanine residue at the amino terminus (“ala-TFPI"), has been shown to be efficacious in animal models for the treatment of sepsis.
  • ala-TFPI a TFPI variant, which differs from TFPI by the addition of an alanine residue at the amino terminus
  • TFPI Use of TFPI has been proposed for the treatment of various indications, including severe pneumonia (U.S. Published Application No. 2003/0139339), sepsis (U.S. Patent No. 6,063,764 and WO 93/24143), deep vein thrombosis (U.S. Patent Nos. 5,563,123 and 5,589,359, and WO 96/04378), ischemia (U.S. Patent No. 5,885,781 and U.S. Patent No- 6,242,414, and WO 96/40224), restenosis (U.S. Patent No. 5,824,644 and WO 96/01649), and cancer (U.S. Patent No. 5,902,582 and WO 97/09063).
  • severe pneumonia U.S. Published Application No. 2003/0139339
  • sepsis U.S. Patent No. 6,063,764 and WO 93/24143
  • deep vein thrombosis U.S. Patent Nos. 5,563,
  • TFPI Despite the above-noted characteristics of TFPI, methods and kits for effectively storing TFPI and thereafter using it in pharmaceutical compositions, suitable for parenteral administration to patients, have been now been discovered. These methods and kits effectively take advantage of a combination of properties of TFPI, thereby allowing the cost effective provision of sterile TFPI pharmaceutical compositions with essentially complete maintenance of biological activity.
  • these properties of TFPI include its ability to be concentrated in solutions comprising some of the agents used in a TFPI pharmaceutical composition, the ability of other agents to undergo sterilization by heating and/or irradiation, and the directionally increasing stability of TFPI against oxidation at increasing concentrations.
  • the present invention is a method for preparing a pharmaceutical composition for parenteral administration to a patient.
  • the method comprises aseptically packaging an aqueous solution comprising from about 1 mg/ml , to about 20 mg/ml of TFPI or a TFPI variant having about 70% or greater amino acid sequence identity to SEQ ID NO:1.
  • the method further comprises combining the aqueous solution with a diluent, packaged in a second container, to provide the pharmaceutical composition.
  • the first container and second container are selected from the group consisting of a vial, a flexible bag, an ampule, and a cartridge.
  • the TFPI variant is selected from the group consisting of (i) Tissue Factor Pathway Inhibitor (TFPI), (ii) ala-TFPI, and (iii) analogs of (i) or (ii) having from 1 to 5 amino acid substitutions.
  • the TFPI variant is ala-TFPI.
  • the pharmaceutical composition has a pH from about 4 to about 8 and comprises from about 0.10 mg/ml to about 0.50 mg/ml of ala- TFPI, from about 100 mM to about 400 mM of arginine, from about 2 mM to about 10 mM methionine, and from about 10 mM to about 50 mM of citric acid/sodium citrate.
  • the method further comprises, prior to combining the aqueous solution with the diluent, terminally sterilizing the diluent.
  • the aqueous solution is maintained at a temperature from about 2°C (36°F) to about 8°C (46°F) prior to combining the aqueous solution with the diluent.
  • the aqueous solution has a volume of less than about 100 ml.
  • the present invention is a method for preparing a pharmaceutical composition for parenteral administration to a patient.
  • the method comprises providing a first container comprising an aseptically packaged aqueous solution comprising from about 1 mg/ml to about 20 mg/ml of TFPI or a TFPI variant having about 70% or greater amino acid sequence identity to SEQ ID NO:1.
  • the method further comprises providing a second container comprising a terminally sterilized diluent.
  • the method further comprises exposing the aseptically packaged aqueous solution to the diluent under aseptic conditions to provide the pharmaceutical composition.
  • the present invention is a method for stabilizing a an aqueous solution prior to its use in the preparation of a pharmaceutical composition.
  • the method comprises aseptically packaging an aqueous solution comprising TFPI or a TFPI variant having about 70% or greater amino acid sequence identity to SEQ ID NO:1.
  • the method further comprises storing the aqueous solution under conditions whereby the aqueous solution has half-life with respect to both aggregation and oxidation from about 25 months to about 200 months and thereafter exposing the aseptically packaged aqueous solution to the diluent to provide the pharmaceutical composition.
  • the conditions include a concentration of the TFPI or TFPI variant in the aqueous solution from about 1 mg/ml to about 20 mg/ml and a temperature of the aqueous solution from about 2°C (36°F) to about 8°C (46°F).
  • the aqueous solution is stored for a period from about 6 months to about 24 months.
  • the present invention is a method for providing a pharmaceutical composition to a remote location.
  • the method comprises aseptically packaging, at a first location, an aqueous solution comprising from about 1 mg/ml to about 20 mg/ml of TFPI or a TFPI variant having about 70% or greater amino acid sequence identity to SEQ ID NO:1.
  • the method further comprises diluting, at a second location, the aqueous solution with a diluent to provide the pharmaceutical composition.
  • the present invention is a pharmaceutical composition prepared according to any of the above methods.
  • the present invention is a kit for preparing a pharmaceutical composition for parenteral administration to a patient.
  • the kit comprises an aqueous solution, packaged under aseptic conditions and comprising from about 1 mg/ml to about 20 mg/ml of TFPI or a TFPI variant having about 70% or greater amino acid sequence identity to SEQ ED NO:1.
  • the kit further comprises a diluent, wherein the aqueous solution and the diluent are packaged in separate containers.
  • the separate containers are connected to allow the aqueous solution and the diluent to be aseptically combined upon establishing flow communication between the separate containers.
  • the aqueous solution is packaged in a vial container and the diluent is packaged in a flexible bag container.
  • the diluent comprises a buffer.
  • the aqueous solution further comprises a solubilizer and an antioxidant.
  • the resulting pharmaceutical composition has a pH from about 4 to about 8 and comprises from about 0.10 mg/ml to about 0.50 mg/ml of ala-TFPI, from about 100 mM to about 400 mM of arginine, from about 2 mM to about 10 mM methionine, and from about 10 mM to about 50 mM of citric acid/sodium citrate.
  • the present invention is based on the finding that TFPI and TFPI variants can be advantageously stored in a form (e.g., a concentrated aqueous solution) that exhibits high stability and thereafter converted (e.g., by mixing with a diluent) into a form that is therapeutically effective when administered parenterally (e.g., intravenously) to patients.
  • a form e.g., a concentrated aqueous solution
  • a diluent e.g., by mixing with a diluent
  • the components (i.e., the aqueous solution and the diluent) of the TFPI pharmaceutical composition can be prepared in a sterile environment or otherwise sterilized and thereafter aseptically combined prior to use.
  • Tissue Factor Pathway Inhibitor is a polypeptide having the amino acid sequence shown in SEQ DD NO: 1.
  • TFPI may be recombinant human protein generated in a microbial host.
  • TFPI is further characterized and described with respect to its biological activity in WO 01/24814.
  • TFPI variants and the production of TFPI variants are described in detail in U.S. Patent Application Publication No. 2004/0224886 and include polypeptide analogs, fragments, and derivatives of TFPI.
  • Analogs are TFPI molecules with one or more amino acid substitutions, insertions, deletions, and/or additions. Typical variants which are analogs include those having from 1 to 5 amino acid substitutions. In the case of TFPI analogs having one or more amino acid additions, these additional amino acids can be added at any position in the molecule, for example at the amino or carboxy terminus.
  • One TFPI analog, N-L-alanyl-TFPI (“ala-TFPI”) has an additional alanine residue at the amino terminal end.
  • Ala-TFPI may be produced recombinantly (r- ala-TFPI) according to procedures described in U.S. Patent Application Publication No. 2004/0224886.
  • Fragments are portions of TFPI, TFPI analogs, or TFPI derivatives and include Kunitz domains 1 ; 2; 3; 1 and 2; or 2 and 3, or deletions of the N-terminus, C-terminus, or both. Fragments of TFPI comprise at least 20 consecutive amino acids of SEQ ID NO: 1. Derivatives are defined as TFPI, TFPI analogs, or TFPI fragments having additional moieties. Examples of such additions include those generated by glycosylation, phosphorylation, acetylation, or amidation.
  • TFPI variants Percent homology or identity between a TFPI variant and SEQ ID NO: 1 is determined using the Blast2 alignment program (Blosum62, Expect 10, standard genetic codes, open gap 11, extension gap 1, gap x_dropoff 50, and low complexity filter off).
  • Blast2 alignment program Bosum62, Expect 10, standard genetic codes, open gap 11, extension gap 1, gap x_dropoff 50, and low complexity filter off.
  • TFPI variants will generally have about 70% or greater, typically about 80% or greater, usually about 90% to about 95% ⁇ e.g., 90, 91, 92, 93, 94, or 95%) or greater, and often about 98% or 99% amino acid sequence identity to SEQ ID NO: 1.
  • the TFPI or TFPI variant in pharmaceutical compositions of the present invention for parenteral administration is present in concentrations generally ranging from about 0.05 to about 5 mg/ml, more typically from about 0.05 to about 1 mg/ml, often from about 0.1 to about 1 mg/ml, and usually from about 0.10 to about 0.50 mg/ml.
  • concentrations of ala-TFPI ranging from about 0.15 to about 0.45 mg/ml have been found to be therapeutically effective in the treatment of indications such as severe Community Acquired Pneumonia (CAP).
  • CAP severe Community Acquired Pneumonia
  • the TFPI or TFPI variant pharmaceutical compositions are administered parenterally.
  • Parenteral administration refers to administration routes other than through the gastrointestinal tract, including intravenous, intramuscular, intradermal, subcutaneous, intrathecal, intraarterial, intracardiac, transdermal, transmucosal, etc. Intravenous administration is often employed.
  • representative parenteral administrations to patients include continuous intravenous infusions of about 10 ⁇ g/hr/kg to about 100 ⁇ g/hr/kg for a period from about 24 hours to about 168 hours.
  • Pharmaceutical compositions comprising TFPI or a TFPI variant may generally comprise any of a number of solubilizers, antioxidants, and/or buffers.
  • Suitable solubilizers include amino acids such as arginine or lysine, which may be present in either a free base or a salt form, for example the hydrochloric acid salt form.
  • Arginine and lysine analogs and the L-stereoisomers of arginine and lysine, any of which may also be in their free base or salt forms, are described in U.S. Patent Application Publication No. 2004/0224886 and may also be used as solubilizers.
  • Arginine is beneficial not only for increasing the solubility of the TFPI or TFPI variant in aqueous solutions, but also for increasing, in a concentration dependent manner, the stability of the polypeptide against aggregation/precipitation (i.e., aggregation stability).
  • concentration of solubilizer in the pharmaceutical composition generally ranges from about 50 to about 600 mM, typically from about 100 to about 400 raM, and is often about 300 mM.
  • Suitable antioxidants for use in TFPI or TFPI variant compositions of the present invention are described in U.S. Patent Application Publication No. 2004/0224886 and include oxygen displacement gases (e.g., nitrogen), scavengers of oxygen or free radicals (e.g., methionine), and chelating agents (e.g., EDTA).
  • oxygen displacement gases e.g., nitrogen
  • scavengers of oxygen or free radicals e.g., methionine
  • chelating agents e.g., EDTA
  • Methionine is particularly effective, and is believed to function as a "sacrificial" scavenger of oxygen molecules that could otherwise oxidize the methionine residues which are part of the TFPI or TFPI variant polypeptide.
  • Native TFPI for example, has 5 methionine residues per polypeptide molecule.
  • methionine when used in the TFPI or TFPI variant compositions of the present invention, it is present in an amount such that the molar ratio of non-TFPI or non- TFPI variant methionine to TFPI or TFPI variant methionine is generally at least about 1:1, typically at least about 10:1, usually at least about 25:1, and often at least about 100:1.
  • the upper bound of this molar ratio may generally be up to 10,000:1, typically up to 5,000:1, and usually up to 1,000:1.
  • TFPI or TFPI variant methionine is used to indicate methionine that is part of the TFPI or TFPI variant polypeptide, in contrast to "non-TFPI or non-TFPI variant methionine," which is methionine added to the composition as an antioxidant and which is not part of the TFPI or TFPI variant polypeptide. It is possible that the "non-TFPI or non-TFPI variant methionine” may itself be bound methionine, such as when methionine is added in the form of a polypeptide. For example, a polypeptide comprising poly(methionine) may be added to the composition as an antioxidant and function in a manner similar to free methionine.
  • an antioxidant such as methionine
  • it is present in the pharmaceutical composition in a concentration generally from about 1 mM to about 10 mM and typically from about 2 mM to about 10 mM.
  • free methionine is introduced at a concentration of about 5 mM.
  • Buffers which may be used in the TFPI or TFPI variant compositions of the present invention are described in U.S. Patent Application Publication No. 2004/0224886.
  • a buffer comprising an acid is used in an aqueous composition, it is prepared using a salt form of the acid or a combination of the acid and a salt form of the conjugate base of the acid.
  • the buffer may be prepared using an acid in combination with the sodium, potassium, ammonium, calcium, and/or magnesium salt of its conjugate base.
  • Typical acids employed in such combinations include citric acid, succinic acid, phosphoric acid, glutamic acid, maleic acid, malic acid, acetic acid, tartaric acid, and aspartic acid.
  • Citric acid or succinic acid may be used in the composition together with their respective conjugate bases.
  • the combination citric acid/sodium citrate represents one such buffer system.
  • the buffer may be present in the composition in a concentration from about 5 mM to about 50 mM, and is often present in a concentration from about 10 mM to about 30 mM. A typical buffer concentration is about 20 mM.
  • the amounts of acid and salt form of its conjugate base to buffer a solution at a given buffer strength (i.e., concentration) and pH may be readily determined.
  • the pH of TFPI or TFPI variant compositions of the present invention significantly affects the polypeptide solubility and hence its stability. Normally, the TFPI or TFPI variant composition will therefore be buffered at a pH from about 4 to about 8, and often from about 5 to about 6.5. A pH of about 5.5, for example, can provide good stability of the TFPI or TFPI variant.
  • a suitable TFPI pharmaceutical composition therefore comprises, in addition to TFPI or a TFPI variant, from about 100 mM to about 400 mM of arginine, from about 2 to about 10 mM methionine, and from about 10 to about 50 mM of citric acid/sodium citrate, at a pH from about 4 to about 8.
  • the above pharmaceutical compositions comprising TFPI or a TFPI variant are generally prepared from an aqueous solution having a higher concentration of polypeptide, which is stored and later diluted, prior to use of the pharmaceutical composition.
  • the “solution” or “aqueous solution” of TFPI or TFPI variant therefore refers to the generally more concentrated form used to store the polypeptide (i.e., the storage form), which is diluted with a diluent, prior to use, to provide the pharmaceutical composition containing this polypeptide (i.e., the administration form).
  • the term “storage” refers to all time periods during which the polypeptide is maintained in its storage form, including packaging (e.g., under aseptic conditions), labeling, shelving, shipping, etc. Typical storage periods for the TFPI or TFPI variant containing aqueous solution generally range from about 1 to about 60 months, typically from about 5 to about 36 months, and often from about 6 to about 24 months.
  • the TFPI or variant concentration in the aqueous solution therefore, is typically in the range from about 1 mg/ml to about 20 mg/ml, and often from about 5 mg/ml to about 10 mg/ml. These concentrations of the polypeptide in solution are achieved using a suitable solubilizer described above. Normally, solutions having relatively high TFPI or TFPI variant concentrations in the above ranges are susceptible to loss of soluble protein due to aggregation/precipitation. This phenomenon represents a major degradation pathway for TFPI and it can adversely impact biological activity and therapeutic efficacy of the polypeptide.
  • the solubilizer arginine can significantly improve the aggregation stability of TFPI and TFPI variants. Arginine is therefore generally present in the TFPI or TFPI variant solution in an amount that brings about the desired effect of stabilizing the polypeptide during storage, such that, relative to a similar solution but without added arginine, the solution exhibits improved resistance to aggregation (i.e., aggregation stability) during storage.
  • the solubilizer e.g., arginine
  • the solubilizer that is present in the pharmaceutical compositions described above is stored with the TFPI or TFPI variant solution to allow the polypeptide to be effectively concentrated and stabilized against aggregation/precipitation.
  • solubilizer is also normally present in the diluent. This allows the solubilizer concentrations in the solution, diluent, and pharmaceutical composition to be maintained essentially constant (e.g., the solubilizer concentration in solution maintained within about +/- 20% of the solubilizer concentration in the pharmaceutical composition, after combining the diluent and solution to provide the pharmaceutical composition).
  • Aggregation stability is expressed in terms of the polypeptide (i.e., TFPI or TFPI variant) solution half-life with respect to aggregation.
  • the loss of soluble polypeptide due to aggregation/precipitation is monitored over time, by maintaining one or more stability samples and, at various time intervals, separating soluble protein from aggregated/precipitated protein in a given volume (e.g., through centrifugation in a microcentrifuge tube).
  • the concentration of soluble protein is determined based on the decrease in total polypeptide peak area, as measured using ion-exchange high pressure liquid chromatography (EEX-HPLC) (Chen et al., J. PHARM. SCI.
  • the solution comprising TFPI or a TFPI variant has a half-life with respect to aggregation generally of at least about 15 days, and typically from about 20 days to about 70 days, at 50 0 C.
  • TFPI or TFPI variant solutions stored at a sufficiently high polypeptide concentration and/or at a sufficiently low temperature may have adequate oxidation stability for commercial use, even without the need for (i.e. t in the absence of) an antioxidant such as the oxygen free radical scavenger methionine, discussed above.
  • an antioxidant e.g., methionine
  • the antioxidant e.g., methionine
  • a significant portion, typically at least about 70% and usually at least about 80%, of the antioxidant is also normally present in the diluent. This allows the antioxidant concentrations in the solution, diluent, and pharmaceutical composition to be maintained essentially constant (e.g., the antioxidant concentration in solution maintained within about +/- 20% of the antioxidant concentration in the pharmaceutical composition, after combining the diluent and aqueous solution to provide the pharmaceutical composition).
  • solubilizer and antioxidant with the diluent, as they can generally undergo terminal sterilization by heat without suffering from a loss of functionality (i.e., the ability to soiubilize the polypeptide or hinder its oxidation) in the pharmaceutical composition.
  • Storage of significant portions of the solubilizer and antioxidant with the diluent reduces the amount of material that must be prepared and introduced into a storage container with the TFPI or TFPI variant solution under aseptic conditions.
  • Oxidation stability is expressed in terms of the polypeptide (i.e., TFPI or TFPI variant) solution half-life with respect to oxidation.
  • Degradation by the oxidation of TFPI or TFPI variant methionine can be measured in stability samples over time, based on the decrease in the polypeptide peak area(s) corresponding to non-oxidized species (i.e., species not having one or more oxidized methionine residues, such as methionine sulfoxide), as measured using RP-EDPLC.
  • the loss in the concentration of non-oxidized polypeptide (Y nO n-ox) from its initial concentration (Y 0 ,non-ox) over storage time (t) can then be fitted to a first-order exponential decay model (Y non - to determine the deactivation rate constant (IC 0X ) and half-life (ti/2 )O ⁇ ) with respect to oxidation.
  • Y non - the deactivation rate constant
  • ti/2 )O ⁇ half-life with respect to oxidation.
  • the estimated half-life with respect to oxidation is 0.693/ko ⁇ -
  • the solution half-life with respect to oxidation is dependent on solution temperature, requiring the stability sample(s) to be maintained at constant temperature.
  • the solution comprising TFPI or a TFPI variant has a half-life with respect to oxidation generally of at least about 5 months, typically from about 10 months to about 100 months, and often from about 25 months to about 50 months, at 30 0 C.
  • the solution may be stored under refrigerated conditions.
  • the solution may be maintained at a temperature from about 2°C (36°F) to about 8 0 C (46°F) at polypeptide concentrations given above, prior to dilution to provide the pharmaceutical composition.
  • the solution half-life with respect to both aggregation and oxidation is generally at least about 10 months, typically at least about 20 months, and often in the range from about 25 months to about 200 months.
  • a half-life from about 75 months to about 200 months with respect to both aggregation and oxidation is representative of the polypeptide solution stability according to the present invention.
  • the solution composition e.g., the amounts of TFPI or TFPI variant, solubilizer, and/or antioxidant
  • solution temperature essentially no degradation of the polypeptide with respect to either aggregation or oxidation may be detectible for at three months of storage, and often for at least six months of storage.
  • TFPI or TFPI variant solutions may generally be stored for periods of up to about 36 months without suffering a significant loss of biological activity. Typical storage periods can range from about 6 months to about 24 months.
  • the oxidation stability of TFPI or variant may also be directionally improved as the solution polypeptide concentration is increased.
  • This characteristic provides important advantages in the kits and methods of the present invention where a TFPI or a TFPI variant solution is stored in a relatively concentrated aqueous solution (i.e., in a state less susceptible to degradation by oxidation) and then diluted to provide drug concentrations for parenteral administration at practical therapeutic administration rates.
  • a 100 ml vial of concentrated TFPI or TFPI variant may be stored with sufficient polypeptide for polypeptide administration at a representative rate from about 10 to about 100 ⁇ g/hr/kg body weight, and usually from about 25 to about 15 ⁇ g/hr/kg body weight, for a time from about 96 to about 120 hours.
  • Typical concentrated TFPI or TFPI variant solution vials will contain from about 5 mg to about 450 mg, and often from about 20 to about 150 mg, of polypeptide.
  • TFPI or TFPI variant will generally necessitate the use of multiple vials over the course of administration (e.g., by intravenous infusion), which typically requires a total dosage from about 48 mg to about 2160 mg, and often from about 48 mg to about 1080 mg.
  • TFPI or a TFPI variant in concentrated aqueous solutions is also important in terms of providing manufacturing flexibility.
  • the availability of manufacturing facilities having the capacity to produce a commercial batch of TFPI or TFPI variant at the relatively low concentrations used for administration e.g., from about 0.15 mg/ml to about 0.45 mg/ml
  • concentrations used for administration e.g., from about 0.15 mg/ml to about 0.45 mg/ml
  • a typical production run at these concentrations would likely involve the manufacture of approximately 25,000 to 50,000 type I glass vials.
  • This scale of production typically requires the use of tanks having a capacity on the order of 5,000 liters as well as other large-scale equipment.
  • the buffer e.g., citric acid/sodium citrate
  • the buffer can generally be terminally stabilized by heat without suffering from a loss of functionality (i.e., the ability to maintain pH) in the pharmaceutical composition.
  • Storage of a significant portion of the buffer with the diluent also reduces the amount of material that must be prepared and introduced into a storage container with the TFPI or TFPI variant under aseptic conditions.
  • Storing at least some portion of the buffer with the TFPI or TFPI variant solution allows for the maintenance of a desired solution pH and can therefore improve TFPI or TFPI variant solubility and stability in the solution.
  • storing a significant portion of the buffer with the diluent allows the buffer concentrations in the solution, diluent, and pharmaceutical composition to be maintained essentially constant (e.g., the buffer concentration in solution maintained within about +/- 20% of the antioxidant concentration in the pharmaceutical composition, after combining the diluent and solution to provide the pharmaceutical composition).
  • both the TFPI or TFPI variant solution and the diluent have a pH from about 4 to about 8 and comprise from about 100 mM to about 400 mM arginine, from about 2 to about 10 mM methionine, and from about 10 mM to about 50 mM of citric acid/sodium citrate buffer.
  • the amount of diluent used will generally be from about 50 ml to about 1000 ml, typically from about 50 ml to about 500 ml, and often from about 100 ml to about 250 ml:
  • the pharmaceutical composition resulting from the combination of these components will generally comprise from about 0.10 mg/ml to about 10 mg/ml of the polypeptide, from about 50 mM to about 600 mM solubilizer, from about 1 mM to about 10 mM antioxidant, and from about 5 mM to about 50 mM buffer.
  • TFPI or TFPI variant solutions of the present invention are aseptically packaged and maintained in a sterile environment prior to (as well as after) their subsequent dilution to provide the pharmaceutical compositions described above. The presence of harmful bacteria in the polypeptide solution is therefore avoided.
  • TFPI and TFPI variants are heat-sensitive and cannot be exposed to the elevated temperatures and/or radiation doses commonly used for sterilization, without suffering from a loss in biological activity. For these reasons, the TFPI or TFPI variant solutions must be manufactured and introduced into a container in a sterile mode.
  • a number of medical containers such as molded plastic containers may be used for aseptically packaging and containing TFPI or TFPI variant solutions for parenteral administration.
  • containers having a closure system that provides a sterile barrier or seal are described in U.S. Patent No. 6,371,319.
  • Flexible bags that may be filled and maintained under aseptic conditions are described, for example, in U.S. Patent No. 4,840,017.
  • Other methods for aseptically packaging solutions into containers are described, for example, in U.S. Patent No. 6,769,231.
  • Medical containers used for aseptic packaging are normally sterilized (prior to the aseptic introduction of the TFPI or TFPI variant solution into this container), by a sterilization process such as autoclaving. Autoclaving subjects the container to temperatures typically in the range of about 115°C (240 0 F) to about 125°C (260 0 F).
  • So-called "form, fill, and seal” machines can be used for packaging or introducing the TFPI or TFPI variant solution into a container under aseptic conditions. These machines typically form a bag from a web of flexible material and pass the bag directly to a filling station where a solution may be fed by gravity or otherwise introduced into the bag through an opening in the bag. The same machine then seals the bag opening to enclose the product.
  • a solution may be fed by gravity or otherwise introduced into the bag through an opening in the bag.
  • the same machine then seals the bag opening to enclose the product.
  • the diluent (which is later combined with this solution to provide the pharmaceutical composition) may advantageously be sterilized (e.g., in a second container that is separate from a first container into which the TFPI or TFPI variant solution is introduced) by heating and/or irradiation, without adverse effects on the ability of the diluent to solubilize, stabilize, and/or buffer the pharmaceutical composition.
  • terminal sterilization may be employed subsequent to packaging.
  • Terminal sterilization refers to the process of sterilizing the packaged material (e.g., the diluent, packaged in a flexible, collapsible "bag” container) and often involves heating the diluent to a temperature from about 80 0 C (175°F) to about 150 0 C (300°F), and typically from about 105°C (220 0 F) to about 130 0 C (265°F), for a time from about 5 minutes to about 1 hour, and typically from about 10 minutes to about 30 minutes.
  • the ability to terminally sterilize a component of pharmaceutical composition i.e., the diluent
  • aseptic packaging and storage of the component of the pharmaceutical comprising the TFPI or TFPI variant combined with terminal sterilization of another component of the pharmaceutical composition prior to dilution, reduces overall production costs, relative to the situation where the entire pharmaceutical composition requires aseptic packaging and storage.
  • terminal sterilization of the diluent prior to dilution i.e., combining the TFPI or TFPI variant solution with the diluent to provide the pharmaceutical composition
  • Sterile filtration may be employed in either the aseptic packaging of the TFPI or TFPI variant solution or in the terminal sterilization of the diluent.
  • the subsequent mixing of these components, to reduce the polypeptide concentration of the solution and to provide the pharmaceutical composition may be accompanied by sterile filtration.
  • sterility concerns arise especially in cases where the components to be mixed, although stored in a sterile environment, are susceptible to contact with bacteria during or after mixing (e.g., into a third, separate container).
  • a process employing a sterilizing-grade filter or other known sterilization processes may be used to maintain a sterile mixing environment.
  • the TFPI or TFPI variant solution may be diluted with the diluent in a completely enclosed system, including those described below, such that aseptic conditions can be maintained without additional sterilization steps.
  • compositions comprising TFPI or a TFPI variant may be conveniently prepared in remote locations (i.e., away from the manufacturing site, such as in a hospital), whereby the components of such compositions are maintained under both sterile and stable conditions.
  • a concentrated TFPI or TFPI variant solution as a first component, may be manufactured in commercially practical volumes per manufacturing batch.
  • concentrating the TFPI or TFPI variant directionally improves its stability with respect to oxidation.
  • the avoidance of large manufacturing capacity requirements provides flexibility in the choice of manufacturing site and/or allows for minimal modification of existing commercial drug manufacturing facilities (e.g., to provide sterile manufacturing in large-scale operations).
  • limiting the number of vials or other containers to be stored, especially under refrigerated conditions reduces overall costs.
  • a diluent may contain one or more solubilizers, antioxidants, and/or buffers which are capable of undergoing sterilization by heat and/or irradiation without a loss of functionality.
  • the TFPI or TFPI variant solution and diluent may be provided to the remote location in a ready-to-use format (e.g., in a kit) which does not necessarily require special handling, for example in a hospital pharmacy, to generate the pharmaceutical composition.
  • the kits of the present invention, for preparing the pharmaceutical compositions described herein may therefore comprise separate containers in which the aqueous solution comprising TFPI or a TFPI variant and the diluent are packaged, respectively.
  • the aqueous solution is packaged under aseptic conditions and the diluent is terminally sterilized as described above or otherwise aseptically packaged as well.
  • the aseptically packaged aqueous solution is then exposed to the diluent (e.g., by opening vials, breaking seals, etc.) under aseptic conditions to provide the pharmaceutical composition.
  • aqueous solution comprising TFPI or a TFPI variant may be packaged in a glass vial container and the diluent packaged in a flexible bag container that is attached to the glass vial via an umbilical transfer tube.
  • the combination of the vial and diluent bag therefore represents a kit of the present invention, where the components are provided in a format that allows for their mixing (and consequently the provision of the pharmaceutical composition) under aseptic conditions.
  • Packaging the diluent in a flexible bag allows for its terminal sterilization by heating or irradiation.
  • the TFPI or TFPI variant solution vial may be screwed or "docked" onto a flexible bag containing the diluent.
  • a threaded slot can provide an air-tight connection, allowing the components to mix aseptically when a stopper or cap on the solution vial is removed.
  • the ADD- VANTAGE ® system Hospira, Inc., Lake Forest, IL, USA) exemplifies such as system.
  • the containers used for the TFPI or TFPI variant solution and the diluent may be made from conventional materials such as glass or plastics which are used to package pharmaceuticals in a sterile environment. Kits of the present invention may therefore utilize vials, ampules, cartridges, bags or other large-volume containers, etc.
  • the container used for the diluent is preferably capable of undergoing terminal sterilization, without adverse effects (e.g., thermal degradation of the container).
  • Representative containers for the diluent include vials and flexible plastic bags.
  • diluent in an amount generally ranging from about 10 ml to about 500 ml, typically from about 50 ml to about 200 ml, may be contained in flexible bags which allow terminal sterilization of the bag contents.
  • bags include those which are made from polyolefin (e.g., polypropylene or polyethylene), polyvinyl chloride (PVC), ethylene vinyl acetate (EVA), and other thermally stable materials.
  • the aqueous solution component comprises TFPI or TFPI variant at a relatively high concentration, a solubilizer, an antioxidant, and a buffer.
  • the diluent component comprises additional amounts of the solubilizer, antioxidant, and buffer.
  • the TFPI or TFPI variant solution and the diluent when combined (e.g., by establishing flow communication between these components) results in a pharmaceutical composition having a pH from about 4 to about 8 and comprising from about 0.10 mg/ml to about 0.50 ala-TFPI, from about 100 mM to about 400 mM arginine, from about 2 to about 10 mM methionine, and from about 10 mM to about 50 mM of citric acid/sodium citrate buffer.
  • aqueous solution of the TFPI variant ala-TFPI is prepared and purified in a manufacturing facility according to procedures outlined in U.S. Published Application No. 2005/0037475.
  • a flexible diluent bag also part of this system, is filled with 328 ml of aqueous diluent containing arginine, methionine, and buffer in the same concentrations as in the ala-TFPI solution.
  • the contents of this bag are terminally sterilized by subjecting the filled bag to a temperature of 120 0 C (248°F) for about 15 minutes.
  • the contents of the vial are stored at about 5°C (41 0 F) 5 allowing the aqueous solution to be stored for at least a 24 months.
  • the sterile ala-TFPI solution and diluent described above are combined aseptically at the hospital where the pharmaceutical composition resulting from this combination is ultimately administered intravenously to a patient.
  • Protective covers on both the ala- TFPI solution vial and the vial port of the diluent bag are removed, according to instructions supplied with the vial/bag kit.
  • the vial is screwed onto to the vial port of the diluent bag until an air-tight seal is achieved.
  • the inner cap of the vial is then pulled into the interior of the diluent container, allowing the ala-TFPI solution and diluent to mix aseptically within the diluent bag.
  • ala-TFPI pharmaceutical composition in 300 mM arginine, 5 mM methionine, and 20 mM of citric acid/sodium citrate buffer at a pH of 5.5.
  • This resulting pharmaceutical composition is administered to a patient by continuous intravenous infusion of the polypeptide at a rate of 25 ⁇ g/kg/hr. The administration period begins within 48 hours of mixing the concentrated ala-TFPI aqueous solution and diluent.
  • a 10 ml portion of the concentrated ala-TFPI aqueous solution (10 mg/ml) and 212 ml of the aqueous diluent described in Example 1 are aseptically packaged in a vial portion and a bag portion, respectively, of a pre-attached vial and bag assembly (or kit).
  • the vial and bag are physically attached through a tubing connection, but fluid communication between the vial and bag is prevented by a partition.
  • ala-TFPI pharmaceutical composition Following a storage period and within 48 hours prior to intravenous administration of the ala-TFPI pharmaceutical composition to a patient, removal of this partition allows the aqueous solution and diluent to mix aseptically and provide an ala-TFPI pharmaceutical composition comprising 0.45 mg/ml ala-TFPI pharmaceutical composition in 300 mM arginine, 5 mM methionine, and 20 mM of citric acid/sodium citrate buffer at a pH of 5.5.
  • the ala-TFPI solution described in Example 1 After manufacture of the ala-TFPI solution described in Example 1 , it is packaged aseptically in a container that has been sterilized by autoclaving.
  • the aqueous diluent described in Example 1 is packaged in a flexible bag which is then terminally sterilized at 120 0 C (248°F) for about 15 minutes.
  • a kit comprising the separate containers is prepared (with instructions for combining the contents of the containers prior to administration) and transferred to a hospital where the kit is stored for up to 24 months under refrigerated conditions.
  • the ala-TFPI solution and aqueous diluent are ultimately mixed under aseptic conditions to provide a pharmaceutical composition that is administered intravenously to a patient.

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Abstract

La présente invention concerne un inhibiteur de la voie du facteur tissulaire (TFPI) polypeptidique et ses variantes qui peuvent être stockés de façon avantageuse sous une forme (par ex., une solution aqueuse concentrée) qui présente une stabilité élevée et qui est ensuite convertie (par ex., par mélange avec un diluant) sous une forme qui est thérapeutiquement efficace (par ex., dans le traitement de la pneumonie extrahospitalière grave) quand elle est administrée par voie parentérale (par ex., par voie intraveineuse) à des patients. Le stockage séparé des composants de compositions pharmaceutiques comprenant le TFPI et des variantes du TFPI présente plusieurs avantages importants. Les composants sont généralement une solution de polypeptides concentrée et un diluant.
PCT/US2007/005814 2006-03-06 2007-03-06 Kits et procedes destines a la preparation de compositions pharmaceutiques comprenant un inhibiteur de la voie du facteur tissulaire (tfpi) Ceased WO2007103425A2 (fr)

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WO2007103425A3 WO2007103425A3 (fr) 2008-01-31

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DE60031999T2 (de) * 1999-10-04 2007-06-06 Novartis Vaccines and Diagnostics, Inc., Emeryville Stabilisierte flüssige polypeptid-haltige pharmazeutische zusammensetzungen
CA2512680A1 (fr) * 2003-01-08 2004-07-29 Chiron Corporation Compositions lyophilisees stabilisees renfermant un inhibiteur de la voie du facteur tissulaire ou des variantes d'un inhibiteur de la voie du facteur tissulaire
DE602004019761D1 (de) * 2003-01-08 2009-04-16 Novartis Vaccines & Diagnostic Stabilisierte wässrige zusammensetzungen mit gewebefaktorinhibitor (tfpi) oder gewebefaktorinhibitor-variante

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