WO2007095288A2 - Compositions protéiques ou peptidiques protéine contenant de la méthionine et leur procédé de fabrication et d'utilisation - Google Patents

Compositions protéiques ou peptidiques protéine contenant de la méthionine et leur procédé de fabrication et d'utilisation Download PDF

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Publication number
WO2007095288A2
WO2007095288A2 PCT/US2007/003905 US2007003905W WO2007095288A2 WO 2007095288 A2 WO2007095288 A2 WO 2007095288A2 US 2007003905 W US2007003905 W US 2007003905W WO 2007095288 A2 WO2007095288 A2 WO 2007095288A2
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Prior art keywords
methionine
protein
pth
containing peptide
composition
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PCT/US2007/003905
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English (en)
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WO2007095288A3 (fr
Inventor
Thomas E. Tarara
Cynthia Stevenson
Stewart Thompson
Reinhard Vehring
Negar Sadrzadeh
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Nektar Therapeutics
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Priority to EP07750726A priority Critical patent/EP1986674A4/fr
Publication of WO2007095288A2 publication Critical patent/WO2007095288A2/fr
Publication of WO2007095288A3 publication Critical patent/WO2007095288A3/fr

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    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/28—Insulins
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/1841—Transforming growth factor [TGF]
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/18—Growth factors; Growth regulators
    • A61K38/185—Nerve growth factor [NGF]; Brain derived neurotrophic factor [BDNF]; Ciliary neurotrophic factor [CNTF]; Glial derived neurotrophic factor [GDNF]; Neurotrophins, e.g. NT-3
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/29—Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0075—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a dry powder inhaler [DPI], e.g. comprising micronized drug mixed with lactose carrier particles
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/0078—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy for inhalation via a nebulizer such as a jet nebulizer, ultrasonic nebulizer, e.g. in the form of aqueous drug solutions or dispersions
    • 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
    • A61K9/007—Pulmonary tract; Aromatherapy
    • A61K9/0073—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy
    • A61K9/008—Sprays or powders for inhalation; Aerolised or nebulised preparations generated by other means than thermal energy comprising drug dissolved or suspended in liquid propellant for inhalation via a pressurized metered dose inhaler [MDI]

Definitions

  • Methionine-Containing Protein or Peptide Compositions and Methods of Making and Using
  • the present invention relates to formulations of methionine-containing peptides or proteins, such as parathyroid hormones, formulations comprising parathyroid hormones, unit doses of the same, and methods of making and methods of using the same. More particularly, the present invention relates to formulations of parathyroid hormones, such as cyclized parathyroid hormones, parathyroid hormone analogs, parathyroid hormone derivatives, parathyroid hormone fragments, formulations comprising them, unit doses of the same, and methods of making and using the same.
  • parathyroid hormones such as cyclized parathyroid hormones, parathyroid hormone analogs, parathyroid hormone derivatives, parathyroid hormone fragments
  • OSTABOLIN-CTM is a cyclized 31-amino acid analog of parathyroid hormone (PTH) with chemical and physical properties similar to other PTH analogs, such as PTH 1-34.
  • OSTABOLIN-CTM contains two methionine residues in the 8 and 18 positions, which can both undergo degradation. In some instances, this is via oxidation to form methionine sulfoxide.
  • the mechanisms of oxidation of methionine to methionine sulfoxide are thought to be either molecular oxygen-dependent, which is mediated through a transition metal, or peroxide-mediated oxidation with an alkyl peroxide as the oxidizer.
  • Another mode of degradation for these peptides is deamidation of either or both glutamine (positions 6 and 29) and asparagine (positions 10 and 16) residues fPharm Res 12, 2049-2052, 1995).
  • PTH analogs like OSTABOLIN-CTM may undergo undesirable degradation, such as oxidation, upon storage, there is a need for formulations of these agents having greater stability and shelf life, especially when in the solid, or dry, state.
  • one or more embodiments of the present invention satisfy one or more of these needs.
  • one or more embodiments of the present invention include compositions comprising methionine-containing peptides and proteins, methods of making and using methionine-containing peptides and proteins compositions, and systems for using methionine-containing peptides and proteins compositions.
  • the present invention provides inhalable methionine-containing peptides or protein compositions, comprising at least one methionine-containing peptide or protein, such as a parathyroid hormone, and at least one antioxidant.
  • one or more embodiments of the present invention include compositions comprising methionine-containing peptides and proteins, such as compositions with reduced amounts of degradants, such as oxidative degradants, methods of making and using methionine-containing peptide and protein compositions, and systems for using methionine-containing peptide and protein compositions.
  • one or more embodiments of the present invention include compositions comprising methionine-containing peptides and proteins comprising less than about 10 wt% of degradants thereof.
  • the methionine-containing peptides or protein comprises a cyclized parathyroid hormone, a parathyroid hormone derivative, a parathyroid hormone fragment, a parathyroid hormone analog, or combinations thereof.
  • the methionine-containing peptides or protein compositions, such as cyclized parathyroid hormone compositions are in particulate or powder form.
  • the methionine-containing peptides or protein compositions, such as cyclized parathyroid hormone compositions are in liquid form.
  • the antioxidant comprises at least one of thioethers, histidine, cysteine, tryptophan, tyrosine, ascorbic acid, vitamin E, and mixtures thereof.
  • Thioethers include, but are not limited to, methionine.
  • the methionine-containing peptides or protein compositions of the invention comprise, by weight: from about 1 % to about 25% of at least one methionine-containing peptide or protein, such as a cyclized parathyroid hormone analog; and from about 0.1% to about 10% of at least one antioxidant.
  • the inventive compositions may further comprise, by weight: from about 1% to about 10% of at least one buffering agent; from about 10% to about 60% of at least one dispersibility- enhancing excipient; and from about 20% to about 90% of at least one glass-stabilizing excipient.
  • compositions comprise, by weight: from about 3% to about 6% of at least one parathyroid hormone analog, derivative or fragment; from about 4% to about 6% of at least one buffering agent; from about 20% to about 50% of at least one dispersibility-enhancing excipient; from about 40% to about 80% of at least one glass-stabilizing excipient; and from about 0.2% to about 1 % of at least one antioxidant.
  • the parathyroid hormone comprises a cyclized parathyroid hormone analog
  • the buffering agent comprises sodium citrate, citric acid, and mixtures thereof
  • the dispersibility-enhancing excipient comprises an amino acid, such as leucine, dileucine, trileucine, norleucine, and mixtures thereof
  • the glass- stabilizing excipient comprises sucrose, rafflnose, trehalose, and mixtures thereof
  • the antioxidant comprises thioethers, and mixtures thereof.
  • compositions of the invention comprise, by weight: about 3-20% [LeU 27 JCyCIo(GIu 22 - Lys 26 )hPTH-(1 -3I)NH 2 ; about 0-6% sodium citrate; about 1-40% trileucine; about 1- 70% trehalose; and about 0-5% methionine.
  • the compositions of the invention comprise, by weight: about 10-18% [Leu 27 ]cyclo(Glu 22 -Lys 26 )hPTH-(1- 3I)NH 2 ; about 1-4% sodium citrate; about 10-30% trileucine; about 20-60% trehalose; and about 0.1-1% methionine.
  • One or more embodiments of the invention also provide methods of stabilizing formulations comprising at least one methionine-containing peptide or protein, such as at least one cyclized parathyroid hormone analog, the methods comprising formulating at least one methionine-containing peptide or protein, such as a cyclized parathyroid hormone analog with at least one antioxidant.
  • at least one cyclized parathyroid hormone analog may be combined with at least one antioxidant in a liquid, which may be aqueous.
  • the methods involve forming a liquid composition comprising at least one methionine-containing peptide or protein, such as at least one cyclized parathyroid hormone analog, and at least one antioxidant; and drying the liquid to form a powder comprising particles.
  • the liquid further comprises at least one surface excipient; wherein the particles comprise a core and a surface; and wherein a concentration of the surface excipient is greater on the surface of the particles than in the core. At least some of the surface excipient is exposed on the surface of the particle.
  • the particles may comprise a shell and a core.
  • At least one cyclized parathyroid hormone analog may comprise, for example, [Leu 27 ]cyclo(Glu 22 -Lys 26 )hPTH-( 1-31)NH 2 .
  • the liquid composition further comprises a pharmaceutically acceptable excipient or carrier.
  • the pharmaceutically acceptable excipient or carrier may comprise a carbohydrate such as a trehalose, a raffinose, and mixtures thereof.
  • the excipient or carrier may comprise a salt of an organic acid, such as sodium citrate.
  • the excipient or carrier may comprise an oligomeric or polymeric material, such as a cellulose or cellulosic material.
  • the liquid composition further comprises at least one antioxidant, such as at least one of thioethers, histidine, tyrosine, cysteine, tryptophan, and mixtures thereof. Thioethers include, but are not limited to, methionine.
  • the method of making the composition further comprises a solvent removal or drying step such as lyophilization, spray drying, freeze drying, or spray-freeze drying.
  • One or more embodiments of the invention also provide particles comprising a surface and a core (for example, a shell and a core), produced by the methods of the invention. Also provided are powders comprising at least one particle according to the invention.
  • One or more embodiments of the invention comprise a formulation comprising about 10-18% [Leu 27 ]cyclo(Glu 22 -Lys 26 )h PTH-(I -31)NH 2 ; about 1-4% sodium citrate; about 10-30% trileucine; about 20-60% trehalose; and about 0.1-1% methionine.
  • One or more embodiments of the invention comprise a formulation comprising about from about 3% to about 6% of at least one cyclized parathyroid hormone analog; from about 4% to about 7% of at least one buffering agent; from about
  • One or more embodiments of the invention comprise a formulation comprising about from about 1 % to about 25% of at least one parathyroid hormone, analog, fragment or derivative, from about 0% to about 10% of at least one buffering agent; from about 10% to about 60% of at least one dispersibility-enhancing excipient; and from about 10% to about 90% of at least one glass-stabilizing excipient.
  • One or more embodiments of the invention comprise a formulation comprising about from about about 10-18% [Leu 27 ]cyclo(Glu 22 -Lys 26 )hPTH-(1 -3I)NH 2 ; about 1-4% sodium citrate; about 10-30% trileucine;about 20-60% trehalose; and about 0.1-1% methionine.
  • One or more embodiments of the invention comprise a method of delivering a powder to the lungs of a mammalian patient, comprising administering by inhalation a composition, wherein the composition comprises particles comprising at least one methionine-containing peptide and at least one surface excipient wherein the particles comprise a core and a surface; and wherein the concentration of the surface excipient is greater on the surface of the particles than in the core.
  • a particulate composition comprises a methionine- containing peptide or protein comprising a cyclized parathyroid hormone, a parathyroid hormone derivative, a parathyroid hormone fragment, a parathyroid hormone analog, or combinations thereof, and trileucine, wherein the particulate is respirable.
  • On or more embodiments of the invention also provide particles comprising a surface enriched with a surface excipient having a glass transition temperature (T 9 ) generally above a T 9 of a material which is desired to be stabilized, such as a methionine-containing peptide or protein, and a core enriched with at least one methionine-containing peptide or protein, such as a cyclized parathyroid hormone analog.
  • the cyclized parathyroid hormone analog comprises [Leu 27 ]cyclo(Glu 22 -Lys 26 )hPTH-(1-31)NH 2 .
  • the glass transition temperature of the surface excipient is at least about 70 0 C, such as at least about 75°C, at least about 80 0 C, or at least about 85°C.
  • the surface excipient may comprise at least one of trileucine, leucine, isoleucine, norieucine, long-chain saturated phospholipids, e.g., distearoyl phosphatidylcholine (DSPC) and dipalmitoyl phosphatidylcholine (DPPC), and mixtures thereof.
  • DSPC distearoyl phosphatidylcholine
  • DPPC dipalmitoyl phosphatidylcholine
  • Further embodiments comprise a method for treating therapeutically or prophylatically a patient at risk of developing a condition or disease treatable by administering a methionine containing peptide or protein, such as a cyclized parathyroid hormone analog, and at least one antioxidant, the method comprising treating a patient prior to the onset of substantial symptoms, or prior to the expected occurrence of a disease or condition which may create the risk of such condition.
  • a methionine containing peptide or protein such as a cyclized parathyroid hormone analog
  • Further embodiments comprise a method for administering therapeutically or prophylatically to a patient at risk of developing a condition or disease treatable by administering a methionine containing peptide or protein, such as a cyclized parathyroid hormone analog, the method comprising treating a patient prior to the onset of symptoms, or prior to exposure to a disease, or prior to the expected development condition, any of which may be treatable by such administration.
  • a kit comprising a composition comprising at least one cyclized parathyroid hormone analog, and at least one antioxidant, and a delivery device.
  • kits comprising a composition and a delivery device, wherein the device comprises a metered dose inhaler having a HFA propella ⁇ t.
  • the particles of one or more embodiments of the invention may further comprise at least one additional active ingredient.
  • an additional active may be selected from vitamin D, estrogen, calcitonin, bisphosphonates, analogs thereof and mixtures thereof. If present, the additional active ingredient may be in the core or in the surface, or both.
  • the core is further enriched in at least one core excipient.
  • Core excipients comprise glass stabilizers, surface modifiers, dispersibility enhancers, and combinations thereof.
  • glass stabilizers may comprise sugars, such as trehalose and raffinose, organic acids (or salts) such as citrate, and mixtures thereof.
  • surface modifiers may comprise materials which are non-hygroscopic, such as being hydrophobic, and which impart a degree of non-hygroscopicity to the particle.
  • Surface modifiers may comprise, for example, surfactants.
  • Dispersibilty enhancers may also comprise surfactants.
  • particles according to the invention further comprise at least one antioxidant, which may be enriched in the core or surface.
  • Antioxidants comprise thioethers, which include, but are not limited to, methionine. Methionine may be present in an amount of from about 0.1% to about 10% by weight of the particle, or from about 0.3% to about 5% by weight of the particle, or about 0.5% by weight of the particle.
  • the particles according to one or more embodiments of the invention may be in a powder formulation.
  • the particles, when filled into capsules (such as HPMC) and stored at about 5°C exhibit a degradation of the cyclized parathyroid hormone analog of not more than about 10% after 24 months, or exhibit an oxidation of not more than about 2% after 24 months, or both.
  • the particles when filled into capsules (such as HPMC) and stored at room temperature and about 60% RH, exhibit a degradation of the cyclized parathyroid hormone analog of not more than about 10% after 19 months, or exhibit an oxidation of not more than about 2% after 19 months, or both.
  • the particles of the invention further comprise at least one amino acid
  • an amino acid comprises histidine, tryptophan, tyrosine, cysteine, and mixtures thereof.
  • One or more embodiments of the invention also provide inhalers containing the dry powder formulations according to the invention.
  • One or more embodiments of the invention also provide blisters or polymer capsules containing the dry powder formulation according to the invention.
  • the polymer may be hydroxypropylmethylcellulose (HPMC), or any other polymer used in pharmaceutical and/or inhalation grade capsules.
  • a dry powder formulation according to the invention may have particles having an MMD of less than about 20 microns ( ⁇ m,), or less than about 10, or 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 microns.
  • the dry powder formulation according to the invention may have particles having an MMAD of less than about 10 microns, or less than about 9 or 8 or 7 or 6 or 5 or 4 or 3 or 2 or 1 microns.
  • One or more embodiments of the invention also provide a unit dose of at least one methionine-containing peptide or protein, such as a cyclized parathyroid hormone analog, comprising a receptacle and particles contained within the receptacle, wherein the particles comprise a surface enriched with a surface excipient having a glass transition temperature above that of the methionine-contai ⁇ i ⁇ g peptide or protein, especially above that of a cyclized parathyroid hormone analog.
  • a unit dose of at least one methionine-containing peptide or protein such as a cyclized parathyroid hormone analog
  • One or more embodiments of the invention also provide a unit dose of at least one methionine-containing peptide or protein, such as a cyclized parathyroid hormone analog, and a delivery device, wherein the particles comprise a surface enriched with a surface excipient having a glass transition temperature above that of the methionine-containing peptide or protein, especially above that of a cyclized parathyroid hormone analog.
  • a methionine-containing peptide or protein such as a cyclized parathyroid hormone analog
  • One or more embodiments of the invention also provide a unit dose comprising a dispersible powder composition for delivery to the lungs of a patient by inhalation from a dry powder inhalation device, the composition including particles comprising a solid state matrix of a methionine containing peptide or protein, such as a cyclized parathyroid hormone analog, the particles having a MMAD of less than about
  • the particles comprise a core enriched with at least one methionine-containing peptide or protein, e.g., at least one cyclized parathyroid hormone analog, and a surface excipient with a glass transition temperature above at least about 50 0 C.
  • One or more embodiments of the invention comprise a particulate composition comprising at least one methionine-containing peptide or protein, and an oxygen scavenger, proximate to the particulate.
  • One or more embodiments of the invention comprises a particulate comprising at least one methionine-containing peptide or protein, and antioxidant, and including an oxygen scavenger, proximate to the particulate.
  • One or more embodiments of the invention comprise a particulate composition comprising a parathyroid homone, fragment thereof, analog thereof, derivative thereof, cyclized parathyroid hormone analog, or mixtures thereof, and an oxygen scavenger, proximate to the particulate.
  • One or more embodiments of the invention comprise a particulate composition comprising a parathyroid homone, fragment thereof, analog thereof, derivative thereof, cyclized parathyroid hormone analog, or mixtures thereof, and an antioxidant.
  • One or more embodiments of the invention comprise a particulate composition comprising a parathyroid homone, fragment thereof, analog thereof, derivative thereof, cyclized parathyroid hormone analog, or mixtures thereof, and wherein the particulate composition is chemically or physically stable, or both, at room temperature for at least about 19 months, or at 5°C for at least about 150 months, or both.
  • One or more embodiments of the invention comprise a particulate composition comprising a parathyroid homone, fragment thereof, analog thereof, derivative thereof, cyclized parathyroid hormone analog, or mixtures thereof, and at least one of an antioxidant or an oxygen scavenger, and wherein the particulate composition is chemically or physically stable, or both, at room temperature for at least about 22 months, or at 5°C for at least about 150 months, or both.
  • One or more embodiments of the invention comprise a unit dosage form wherein the unit dose comprises a particulate comprising at least one methionine- containing peptide or protein, such as a cyclized parathyroid hormone analog and an oxygen scavenger, proximate to the particulate.
  • the unit dose may be packaged in a capsule, blister or the like, or may be in bulk powder form.
  • One or more embodiments of the invention comprise a unit dosage form wherein the unit dose comprises a particulate comprising at least one methionine- containing peptide or protein, such as a cyclized parathyroid hormone analog, and antioxidant, and including an oxygen scavenger, proximate to the particulate.
  • the unit dose may be packaged in a capsule, blister or the like, or may be in bulk powder form.
  • Figure 1 shows the amino acid sequence of one embodiment of a cyclized parathyroid hormone analog marketed as OSTABOLIN-CTM.
  • Figure 2 shows representative RP-HPLC chromatograms of a 1 % methionine formulation at room temperature and 50 0 C.
  • Figure 3 shows percent peak area of oxidation peak (RRT 0.83 - 0.84) in one non-methionine and three methionine solution formulations at room temperature.
  • Figure 4 shows percent peak area of oxidation peak (RRT 0.83 - 0.84) in three methionine solution formulations at 50 0 C.
  • Figures 5A, 5B, and 5C show percent peak area of oxidation peak for methionine and non-methionine formulations as a function of time and temperature.
  • Figure 5A is at 25°C;
  • Figure 5B is 40 0 C; and
  • Figure 5C is 50 0 C.
  • Figure 6 shows an Arrhenius plot of OSTABOLIN-CTM oxidative degradation rate constants for methionine and non-methionine formulations.
  • Figure 7 shows values of T 9 versus weight fraction of water in accordance with the Gordon-Taylor equation, for a formulation according to Example 3.
  • Figure 8 is an HPLC stability analysis of two formulations (with and without an antioxidant) and stored at different temperatures, according to Example 3, showing the percent peak area of oxidation.
  • Figure 9 is an HPLC stability analysis for three different formulations and three different storage conditions, for formulations made according to Example 4, showing, stability (as percentage oxidation) over the time indicated.
  • Figure 10 is an HPLC chromatagram for a formulation according to
  • Example 6 with and without an oxygen scavenger.
  • Figure 11 is an HPLC stability analysis showing percent peak area of oxidative degradation peak in OCIP bulk powder (4% OCIP) and 5.0 mg fill weight capsules with and without an oxygen scavenger at 50°C as a function of storage duration.
  • Figure 12 is an HPLC stability analysis showing the purity of Ostabolin-
  • a reference to a compound or component includes the compound or component by itself, as well as in combination with other compounds or components, such as mixtures of compounds.
  • amino acid refers to any compound containing both an amino group and a carboxylic acid group. Although the amino group most commonly occurs at the position adjacent to the carboxy function, the amino group may be positioned at any location within the molecule.
  • the amino acid may also contain additional functional groups, such as amino, thio, carboxyl, carboxamide, imidazole, etc.
  • An amino acid may be synthetic or naturally occurring, and may be used in either its racemic or optically active (D-, or L-) form.
  • Leucine refers to the amino acid leucine, which may be a racemic mixture or in either its D- or L- form, as well as modified forms of leucine (i.e., where one or more atoms of leucine have been substituted with another atom or functional group) in which the dispersibility-enhancing effect of the modified amino acid or peptide is substantially unchanged or unimproved over that of the unmodified material.
  • Dipeptide also referred to herein as a dimer, refers to a peptide including two amino acids.
  • Trimer also referred to herein as a trimer, refers to a peptide including three amino acids.
  • a "surface active" material is one having surface activity (measured, e.g., by surface tensiometry), as characterized by its ability to reduce the surface tension of the liquid in which it is dissolved.
  • Surface tension which is associated with the interface between a liquid and another phase, is that property of a liquid by virtue of which the surface molecules exhibit an inward attraction.
  • a surface active dipeptide or tripeptide is identified by preparing solutions of varying concentrations (for example, from approximately 0.01% wt/vol (0.1 mgfml) to approximately 2% wt/vol (20 mg/ml)) of the subject peptide in water, and measuring the surface tension of each of the solutions.
  • a surface-active peptide is one that, when present at any concentration in solution, though typically present in an amount greater than 0.25 mg/ml, is effective to lower the surface tension of water.
  • a peptide that is more surface-active than another peptide is one that decreases the surface tension of water to a greater extent, when present in the liquid at the same concentration and measured under the same set of experimental conditions.
  • Dry powder refers to a powder composition that typically contains less than about 20 wt% moisture, or less than 10 wt% moisture, or contains less than about 5-6 wt% moisture, or contains less than about 3 wt% moisture, depending upon factors, such as the particular formulation.
  • a dry powder that is "suitable for pulmonary delivery” refers to a composition comprising solid (i.e., non-liquid) or partially solid particles that are capable of being (i) readily dispersed in/by an inhalation device and (ii) inhaled by a subject so that a portion of the particles reach the lungs to permit penetration into the alveoli. Such a powder is considered to be “respirable.”
  • "Aerosolized” or “aerosolizable” particles are particles which, when dispensed into a gas stream by either a passive or an active inhalation device, remain suspended in the gas for an amount of time sufficient for at least a portion of the particles to be inhaled by the patient, so that a portion of the particles reaches the lungs.
  • Emitted Dose provides an indication of the delivery of a drug formulation from a suitable inhaler device after a firing or dispersion event. More specifically, for dry powder formulations, the ED is a measure of the percentage of powder which is drawn out of a unit dose package and which exits the mouthpiece of an inhaler device. The ED is defined as the ratio of the dose delivered by an inhaler device to the nominal dose (i.e., the mass of powder per unit dose placed into a suitable inhaler device prior to firing). The ED is an experimentally-determined parameter, and is typically determined using an in-vitro device set up which mimics patient dosing.
  • a nominal dose of dry powder (as defined above) is placed into a Turbospin® DPI device (PH&T, Italy), described in U.S. Patent Nos. 4,069,819 and 4,995,385, which are incorporated herein by reference in their entireties.
  • the Turbospin® DPI is actuated, dispersing the powder.
  • the resulting aerosol cloud is then drawn from the device by vacuum (30 L/min) for 2.5 seconds after actuation, where it is captured on a tared glass fiber filter (Gelman, 47 mm diameter) attached to the device mouthpiece. The amount of powder that reaches the filter constitutes the delivered dose.
  • ED values provide an indication of the delivery of drug from an inhaler device after firing rather than of dry powder, and are based on amount of drug rather than on total powder weight.
  • the ED corresponds to the percentage of drug which is drawn from a dosage form and which exits the mouthpiece of an inhaler device.
  • FPD Fast particle dose
  • a "dispersible” or “dispersive” powder is one having an ED value of at least about 30%, such as at least about 40%, at least about 50%, at least about 55%, at least about 60%, at least about 65%, or more.
  • passive dry powder inhaler refers to an inhalation device that relies upon a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does not include inhaler devices which comprise a means for providing energy, such as pressurized gas and vibrating or rotating elements, to disperse and aerosolize the drug composition.
  • active dry powder inhaler refers to an inhalation device that does not rely solely on a patient's inspiratory effort to disperse and aerosolize a pharmaceutical composition contained within the device in a reservoir or in a unit dose form and does include inhaler devices that comprise a means for providing energy to disperse and aerosolize the drug composition, such as pressurized gas and vibrating or rotating elements.
  • mass median diameter or “MMD” refers to the median diameter of a plurality of particles, typically in a polydisperse particle population, i.e., consisting of a range of particle sizes.
  • MMD values as reported herein are determined by laser diffraction (Sympatec Helos, Clausthal-Zellerfeld, Germany), unless the context indicates otherwise.
  • powder samples are added directly to the feeder funnel of the Sympatec RODOS dry powder dispersion unit. This can be achieved manually or by agitating mechanically from the end of a VIBRI vibratory feeder element. Samples are dispersed to primary particles via application of pressurized air (2 to 3 bar), with vacuum depression (suction) maximized for a given dispersion pressure. Dispersed particles are probed with a 632.8 nm laser beam that intersects the dispersed particles' trajectory at right angles.
  • MMAD mass median aerodynamic diameter
  • the "aerodynamic diameter” is the diameter of a unit density sphere having the same settling velocity in air as a powder and is therefore a useful way to characterize an aerosolized powder or other dispersed particle in terms of its settling behavior.
  • the aerodynamic diameter encompasses particle or particulate shape, density, and physical size of the particle or particulate.
  • MMAD refers to the median of the aerodynamic particle or particulate size distribution of an aerosolized powder determined by cascade impaction, unless the context indicates otherwise.
  • “Pharmaceutically acceptable salt” includes, but is not limited to, salts prepared with inorganic acids, such as chloride, sulfate, phosphate, diphosphate, hydrobromide, and nitrate salts, or salts prepared with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, ethylsuccinate, citrate, acetate, lactate, methanesulfonate, benzoate, ascorbate, para-toluenesulfonate, palmoate, salicylate and stearate, as well as estolate, gluceptate and lactobionate salts.
  • salts containing pharmaceutically acceptable cations include, but are not limited to, sodium, ⁇ potassium, calcium, aluminum, lithium, and ammonium (including alkyl substituted ammonium).
  • “Pharmaceutically acceptable excipient or carrier” refers to an excipient that may optionally be included in the compositions of the invention, and taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject.
  • “Pharmacologically effective amount” or “physiologically effective amount of a bioactive agent” is the amount of an active agent present in an aerosolizable composition as described herein that is needed to provide a desired level of active agent in the bloodstream or at the site of action (e.g., the lungs) of a subject to be treated to give an anticipated physiological response when such composition is administered pulmonarily.
  • the precise amount will depend upon numerous factors, e.g., the active agent, the activity of the composition, the delivery device employed, the physical characteristics of the composition, intended patient use (i.e., the number of doses administered per day), patient considerations, and the like, and can readily be determined by one skilled in the art, based upon the information provided herein.
  • Polymer refers to a high molecular weight polymeric compound or macromolecule built by the repitition of small, simple chemical units.
  • a polymer may be a naturally occurring (e.g., proteins, carbohydrates, nucleic acids) or a non-naturally occurring polymer (e.g., polyethylene glycols, polyvinylpyrrolidones, Ficolls, and the like), as well known in the art.
  • therapeutically effective amount refers to an amount that is effective to achieve the desired therapeutic result.
  • a therapeutically effective amount of a given active agent will typically vary with respect to factors such as the type and severity of the disorder or disease being treated and the age, gender, and weight of the patient.
  • prophylactically effective amount refers to an amount that is effective to achieve the desired prophylactic result. Because a prophylactic dose is administered in patients prior to onset of disease (or prior to the onset of significant symptoms thereof) the prophylactically effective amount typically is less than the therapeutically effective amount.
  • the present invention is generally directed to compositions comprising cyclized parathyroid hormone (PTH) analogs, and methods of making the same.
  • the compositions of the present invention can be liquid or dry.
  • Liquid compositions include, but are not limited to, solutions, suspensions and dispersions.
  • Dry compositions include lyophillizates, powders, etc.
  • parathyroid hormone Unless otherwise noted or clear from the context, a parathyroid hormone, cyclized parathyroid hormone analog, parathyroid hormone fragment or parathyroid hormone derivative are deemed to be interchangeable for formulation purposes herein.
  • a methionine containing proteins or peptide is deemed to comprise each and all of the foregoing, individually or collectively.
  • methionine-containing proteins or peptides may be included in the compositions.
  • Methionine-containing proteins and peptides according to the present invention include, but are not limited to, parathyroid hormone, insulin-like growth factor, epidermal growth factor, nerve growth factor, transforming growth factor alpha precursor, transforming growth factor beta, transforming growth factor beta precursor, fibroblast growth factor, vaccinia growth factor, platelet derived growth factor, interleukins, e.g., IL-2, interferons, e.g., interferon beta-1b, tissue-factor-pathway inhibitor, factor VIII, growth hormone, prolactin, and granulocyte colony-stimulating factor, to name only a few.
  • Parathyroid hormones include, for example, parathyroid hormone analogs.
  • Exemplary PTH peptide analogs may be selected from the group consisting of PTH-(I -31 )NH2; PTH-(1-30)NH2; PTH-(I -29)NH2; PTH-(I -28)NH2; Leu27PTH-(1-31)NH2; Leu27PTH-(1-30)NH2; Leu27PTH-(1-29)NH2; Leu27cyclo(22- 26)PTH-(1-31 )NH2; Leu27cyclo(22-26)PTH-(1-34)NH2; Leu27cydo(Lys26-Asp30)PTH- (1-34)NH2; Cyclo(Lys27-Asp30)PTH-(1-34)NH2; Leu27cyclo(22-26)PTH-(1-31 )NH2; Ala27 or Nle27 orTyr27 or Ile27 cyclo(22-26)PTH-(1-31)NH2; Leu27cyclo(
  • the present invention may comprise the full length, 84 amino acid form of parathyroid hormone, particularly the human form, hPTH (1-84), obtained either recombinantly, by peptide synthesis or by extraction from human fluid. See, for example, U.S. Pat. No. 5,208,041 , incorporated herein by reference.
  • the amino acid sequence for hPTH (1-84) is reported by Kimura et al. in Biochem. Biophys. Res. Comm., 114(2):493.
  • composition of the present invention may also comprise fragments or variants of fragments of human PTH or of rat, porcine or bovine PTH that have human PTH activity as determined, for example, in the ovarectomized rat model of osteoporosis reported by Kimmel et al., Endocrinology, 1993, 32(4): 1577.
  • the parathyroid hormone fragments may in some embodiments incorporate at least the first 34 N-terminal residues, such as PTH(I -34), PTH(1-37), PTH(I -38) and PTH(I -41).
  • PTH variants incorporate from 1 to 5 amino acid substitutions that improve PTH stability and half-life, such as the replacement of methionine residues at positions 8 and/or 18 with leucine or other hydrophobic amino acid that improves PTH stability against oxidation and the replacement of amino acids in the 25-27 region with trypsin-insensitive amino acids such as histidine or other amino acid that improves PTH stability against protease.
  • the hormones may be obtained by known recombinant or synthetic methods, such as described in U.S. Pat. No. 4,086,196, incorporated herein by reference. [097] As noted, parathyroid hormone is an 84-amino acid peptide, but analogs
  • PTH analogs include, but are not limited to, PTH(1-11), PTH(1-14), PTH(1-34), and PTH(3-34).
  • PTH analogs within the scope of the invention comprise, for example, those disclosed in U.S. Patent Nos.
  • PTH analogs also include, but are not limited to, cyclized PTH analogs.
  • Cyclized PTH analogs falling within the scope of the invention include, but are not limited to, those described in, for example, U.S. Patent Nos.
  • compositions of the present invention may include one or more such cyclized PTH analogs.
  • the composition may include, but is not limited to, one, two, three, or more such analogs.
  • the amount of the methioni ⁇ e-containing protein or peptide in the composition is an amount that is sufficient to achieve a desired effect by administration of a desired dose. In practice, this will vary widely depending upon the particular agent, its activity, the severity of the condition to be treated, the patient population, dosing requirements, and the desired therapeutic effect. The amount may be such that two or more doses are needed to achieve the desired effect.
  • the compositions of the invention are particularly useful for active agents that are delivered in doses of from 0.001 mg/day to 100 mg/day, such as in doses from 0.01 mg/day to 75 mg/day, or in doses from 0.10 mg/day to 50 mg/day.
  • the methionine-containing protein or peptide in the composition will comprise from about 1% to about 50%, by weight of the composition. In some embodiments, the amount will range from about 2% to about 40%, or from about 3% to about 25%, or from about 4% to about 10%, by weight of the composition.
  • the amount can range from about 1 %, 2%, 3%, 4%, 5%, 6%, 7%, 8%, or 9%, to about 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 14%, 16%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%, or more, by weight of the composition.
  • Choices are not limited, but may be chosen for a desired combined therapeutic effect.
  • active ingredients that may be added for a complementary therapeutic effect include, but are not limited to, vitamin D and analogs, estrogen, calcitonin, bisphosphonates, and mixtures thereof. A particularly desirable choice is calcitonin.
  • Antioxidants include, but are not limited to, vitamin D and analogs, estrogen, calcitonin, bisphosphonates, and mixtures thereof. A particularly desirable choice is calcitonin.
  • compositions of the present invention may additionally include one or more antioxidants.
  • Antioxidants according to the invention prevent or reduce the oxidation of the methionine-containing protein or peptide of the compositions.
  • a suitable antioxidant is a pharmacetucially-acceptable antioxidant.
  • an antioxidant is a material which reduces the oxidation potential of the methionine-containing protein or peptide active material.
  • an antioxidant is any material that reduces the oxidation of the methionine-containing protein or peptide active agent, such as cyclized parathyroid hormone analog, by at least about 10% or 20% or 30% or 40% or 50% or 60% or 70% or 80% or 90% or 95% or 97% or 98% or 99%.
  • the antioxidants prevent or reduce the oxidation of amino acid residues in methionine-containing protein or peptide.
  • Amino acids that are particularly sensitive to oxidation include, but are not limited to, methionine.
  • agents that act to prevent or reduce oxidation of methionines are considered antioxidants within the scope of this invention.
  • OSTABOLIN-CTM a cyclized PTH analog
  • Figure 1 The mechanisms of oxidation of methionine to methionine sulfoxide are believed to be either molecular oxygen dependent mediated through a transition metal, or peroxide-mediated oxidation with an alkyl peroxide as the oxidizer.
  • antioxidants may be included in the inventive compositions to reduce or prevent oxidation, at either or both the methionine site(s), as well as that of any other any other oxidizable residue.
  • the antioxidant comprises at least one thioether.
  • thioether antioxidants include, but are not limited to, those disclosed in U.S. Patent No. 6,989,138, which is incorporated herein by reference in its entirety. While the particular choice of thioether is not limited, one example is methionine.
  • compositions of the invention include, but are not limited to other amino acids, such as histidine, cysteine, tryptophan, and tyrosine, vitamin E, and ascorbic acid.
  • the composition may comprise one or more antioxidants.
  • the amount of the antioxidant in the composition is an amount that is sufficient to achieve a desired antioxidant effect.
  • the amount may be such that oxidation of the methionine-containing protein or peptide is slightly reduced or an amount sufficient to essentially completely prevent oxidation.
  • the amount of antioxidant may be sufficient to provide a shelf life of a product, such as 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, or 24, 25, 50, 60, 70. 80, 90, 100, 120, 150, 160 or more months, whether measured at room temperature (such as about 25°C), elevated temperature (such as about 40 0 C) or low temperature (such as about 5°C).
  • the amount of antioxidant may be sufficient to extend shelf life of a product, such as by 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , or 12 weeks, or 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 or 50 or 100 or 150 or more months, whether measured at room temperature (such as about 25°C), elevated temperature (such as about 40 0 C) or low temperature (such as about 5°C).
  • shelf life it is meant in comparison to a shelf life of the same formulation without the anti-oxidant.
  • the antioxidant in the composition will comprise from about
  • the amount will range from about 0.2% to about 9%, or from about 0.3% to about 8%, or from about 0.4% to about 7%, or about 0.5% to about 5%, by weight of the composition.
  • the amount can be about 0.1 , 0.2, 0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1 , 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2.0, 2.1 , 2.2, 2.3, 2.4, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 7.5, 8.0, 8.5, 9.0, 9.5, or 10%, by weight of the composition.
  • the amount chosen will depend on its desired effect on the composition and can be varied as needed.
  • Other Excipients will depend on its desired effect on the composition and can be varied as needed.
  • compositions of the invention may further include one or more buffering, or pH-adjusting or -controlling, agents.
  • agents are generally a salt prepared from an organic acid or base.
  • Representative buffers include organic acid salts of citric acid, ascorbic acid, gluconic acid, carbonic acid, tartaric acid, succinic acid, acetic acid, or phthalic acid, Tris, tromethamine hydrochloride, betaine, or phosphate buffers.
  • Suitable amino acids which may also function in a buffering capacity, include alanine, glycine, arginine, histidine, glutamic acid, aspartic acid, cysteine, lysine, leucine, isoleucine, valine, methionine, phenylalanine, aspartame, tyrosine, tryptophan, and the like.
  • the amount ranges from about 2% to about 9%, or from about 3% to about 8%, or from about 4% to about 7%, or from about 5% to about 6%, or about 5%, by weight, of the composition.
  • the amount chosen will depend upon its desired effect on the composition and can be varied as needed.
  • compositions include excipients that are designed to impart desired physical characteristics to the end product, which may further impart desired or improved actions on the treated subject.
  • inventive compositions may comprise a pharmaceutically acceptable excipient or carrier, which may be taken into the lungs with no significant adverse toxicological effects to the subject, and particularly to the lungs of the subject.
  • excipients will, at least in part, serve to further improve the features of the active agent composition, for example by providing more efficient and/or reproducible delivery of the active agent, improve the handling characteristics of powders, such as flowability and consistency, and/or facilitate manufacturing and/or filling of unit dosage forms.
  • excipient materials can often function to further improve the physical and chemical stability of the active agent, minimize the residual moisture content and hinder moisture uptake, and to enhance particle size, degree of aggregation, particle surface properties, such as rugosity, ease of inhalation, and the targeting of particles to the lung.
  • One or more excipients may also be provided to serve as bulking agents when it is desired to reduce the concentration of active agent in the formulation.
  • Dispersibility-enhancing excipients One particular type of formulation-enhancing excipient that may be included in the formulation is dispersibility-enhancing excipients. These excipients generally provide more efficient and/or reproducible delivery of the methionine- containing protein or peptide, by improving the physical characteristics of the dry formulation.
  • Dispersibility-enhancing agents may comprise amino acids and polypeptides that function as dispersing agents. Amino acids falling into this category include, but are not limited to, hydrophobic amino acids such as leucine, norleucine, valine, isoleucine, tryptophan, alanine, methionine, phenylalanine, tyrosine, histidine, and proline.
  • Dispersibility-enhancing peptide excipients include dimers, trimers, tetramers, and pentamers comprising one or more hydrophobic amino acid components such as those described above. Examples include, but are not limited to, dimers, trimers, tetramers, and pentamers having at least two leucines in any position, such as dileucine and trileucine, as disclosed in U.S. Patent Nos. 6,518,239, and 6,835,372, both to Kuo et al, both of which are incorporated herein by reference their entireties.
  • excipients are generally present in the composition in amounts ranging from about 0.01% to about 95%, such as about 0.5% to about 80%, or about 1 % to about 60%, by weight.
  • the amount can be from about 10% to about 60%, or from about 20% to about 50%, or from about 30% to about 40%, or about 35%, by weight of the composition.
  • the amount chosen will depend on its desired effect on the composition and can be varied as needed.
  • the excipient may have a glass transition temperature (Tg) above about 35°C, such as above about 40 0 C, above about 45°C, above about 55°C, above about 60 0 C, above about 65°C, above about 70 0 C, above about 75°C, above about 80 0 C, above about 85°C, or above about 90 0 C, as measured by differential scanning calorimetry (DSC).
  • Tg glass transition temperature
  • Glass transition stabilizing excipients may comprise carbohydrates, excipients suitable for use in the invention include, for example, monosaccharides such as fructose, maltose, galactose, glucose, D-mannose, sorbose, and the like; disaccharides, such as lactose, sucrose, trehalose, cellobiose, and the like; polysaccharides, such as raffinose, melezitose, maltodextrins, dextrans, starches, and the like; and alditols, such as mannitol, xylitol, maltitol, lactitol, xylitol sorbitol (glucitol), pyranosyl sorbitol, myoinositol and the like, and combinations of any of the foregoing.
  • monosaccharides such as fructose, maltose, galactose, glucose, D-mannose,
  • stabilizing excipients comprise polyvinylpyrrolidone (PVP), polyvinyl acetate (PVA), vinylpyrrolidone/vinyl acetate copolymer (PVP-VA), poly ethylene oxide (PEO), cellulose, starch, polyethylene glycol (PEG), hydroxypropyl cellulose (HPC), hydroxyl propyl methyl cellulose (HPMC), and their copolymers and derivatives; carbohydrates; polyols; sugars; oligo saccharides such as cyclodextrins; proteins, peptides and amino acids', lipids and modified lipids such as lipid-PEG and lipid-sugar esters; salts; citric acid; citrates; known glass formers; and combinations thereof.
  • PVP polyvinylpyrrolidone
  • PVA polyvinyl acetate
  • PV-VA vinylpyrrolidone/vinyl acetate copolymer
  • PEO poly ethylene oxide
  • cellulose starch
  • the glass transition stabilizing excipients will generally be present in an amount by weight of from about 10% to about 90% of the composition. In some embodiments, they are present in an amount from about 20% to about 80%, or from about 30% to about 70%, or from about 40% to about 60%, or about 50%, by weight of the composition. The amount may be 10, 20, 30, 40, 50, 60, 70, 80, or 90% by weight of the composition. The amount chosen will depend upon its desired effect on the composition and can be varied as needed.
  • compositions and additives useful in the present pharmaceutical formulation include, but are not limited to, amino acids, peptides, proteins, non-biological polymers, biological polymers, carbohydrates, such as sugars, derivatized sugars such as alditols, aldonic acids, esterified sugars, and sugar polymers, which may be present singly or in combination.
  • Exemplary protein excipients include albumins such as human serum albumin (HSA), recombinant human albumin (rHA), gelatin, casein, hemoglobin, and the like. Suitable excipients are those provided in U.S. Patent No. 6,136,346 and WO 96/32096, which are incorporated herein by reference in their entireties.
  • inventive compositions may also include polymeric excipients/additives, e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxypropyl- ⁇ -cyclodextrin and sulfobutylether- ⁇ -cyclodextrin), polyethylene glycols, and pectin.
  • polymeric excipients/additives e.g., polyvinylpyrrolidones, derivatized celluloses such as hydroxymethylcellulose, hydroxyethylcellulose, and hydroxypropylmethylcellulose, Ficolls (a polymeric sugar), hydroxyethylstarch, dextrates (e.g., cyclodextrins, such as 2-hydroxyprop
  • inventive compositions may further include flavoring agents, taste- masking agents, inorganic salts (for example sodium chloride), antimicrobial agents (for example benzalko ⁇ ium chloride), sweeteners, antioxidants, antistatic agents, surfactants (for example polysorbates such as "TWEEN 20" and "TWEEN 80"), sorbitan esters, lipids (for example phospholipids such as lecithin and other phosphatidylcholines, phosphatidylethanolamines), fatty acids and fatty esters, steroids (for example cholesterol), and chelating agents (for example EDTA, zinc and other such suitable cations).
  • inorganic salts for example sodium chloride
  • antimicrobial agents for example benzalko ⁇ ium chloride
  • sweeteners for example polysorbates such as "TWEEN 20" and "TWEEN 80”
  • surfactants for example polysorbates such as "TWEEN 20" and "TWEEN 80”
  • sorbitan esters for example phospholipids
  • compositions described herein may be in powdered form (e.g., including particles of the invention) or may be liquids.
  • liquid formulations comprise solutions in which the active drug is dissolved in a solvent (e.g., water, ethanol, ethanol-water, saline).
  • solvent e.g., water, ethanol, ethanol-water, saline
  • liquid formulations comprise colloidal suspensions, or dispersions.
  • the liquid formulation may also be a solution, suspension or dispersion of the methionine-containing protein or peptide in a low boiling point propellant.
  • Liquid formulations containing the disclosed dileucyl-containing peptides are also highly dispersible, possessing high ED values.
  • a powdered or liquid formulation for use in the present invention includes an aerosol having a particle size selected to permit penetration into the alveoli of the lungs.
  • the size is typically less than about 10 ⁇ m mass median diameter (MMD), such as less than about 7.5 ⁇ m, or less than 5 ⁇ m, and may be in the range of about 0.1 ⁇ m to 5 ⁇ m, or about 0.5 ⁇ m to 4 ⁇ m in diameter, or any combination of the foregoing.
  • MMD mass median diameter
  • the pharmaceutical formulation When in a dry powder form, the pharmaceutical formulation may have a moisture content below about 10 wt%, such as below about 5 wt%, or below about 3 wt%.
  • the composition comprises particles having a mass median aerodynamic diameter from about 0.5 ⁇ m to about 10 ⁇ m, such as about 1 ⁇ m to about 9 ⁇ m, or about 1.5 ⁇ m to about 8 ⁇ m, or about 2 ⁇ m to about 6 ⁇ m or about 2.5 ⁇ m to about 5 ⁇ m, or any combination of the foregoing.
  • Some particles according to some aspects of the invention are formed in such a manner that the compositions are uniformly distributed throughout the particle. That is, the methionine-containing protein or peptide, as well as other elements of the composition, which may include antioxidant, buffer, dispersibility-enhancing agent, and glass-stabilizing agent, are uniformly distributed throughout the particle.
  • Other particles according to other aspects of the invention are formed in such a way as to enrich particular elements of the formulation in particular sections of the particle.
  • a particle may generally be described as including a core at its center and a surface around its periphery. With regard to the heterogeneity within the particle, the transition from core to surface may be gradual or abrupt, or any variation thereof.
  • Particles may be manufactured such that a core is enriched with one element and a surface is enriched with another.
  • This heterogeneity may be achieved by forming the core and surface in separate preparation steps, using different compositional elements during the different steps.
  • the heterogeneity may be achieved by introducing into a homogeneous mixture a component that has an affinity for a particular section of a particle or which migrates during a drying phase, for example. Examples of such methods are described in U.S. Patent No. 6,518,239, the entire disclosure of which is incorporated herein by reference.
  • heterogeneous particles are formed by forming a liquid composition comprising a methionine-containing protein or peptide and an antioxidant.
  • the liquid composition additionally includes at least one surface excipient, which is an agent that has a tendency to migrate to the surface of the particle.
  • surface excipients may be "surface active agents," as described in U.S. Patent No. 6,518,239. Examples of such agents include, but are not limited to, di-and tripeptides containing at least two leucines.
  • Unit dose pharmaceutical compositions may be contained in a container.
  • containers include, but are not limited to, capsules, blisters, vials, ampoules, or container closure systems made of metal, polymer (e.g., plastic, elastomer), glass, or the like.
  • the container may be inserted into an aerosolization device.
  • the container may be of a suitable shape, size, and material to contain the pharmaceutical composition and to provide the pharmaceutical composition in a usable condition.
  • the capsule or blister may comprise a wall which comprises a material that does not adversely react with the pharmaceutical composition.
  • the wall may comprise a material that allows the capsule to be opened to allow the pharmaceutical composition to be aerosolized.
  • the wall comprises one or more of gelatin, hydroxypropyl methylcellulose (HPMC), polyethyleneglycol-compounded HPMC, hydroxyproplycellulose, agar, aluminum foil, or the like.
  • the capsule may comprise telescopically adjoining sections, as described for example in U.S. Patent No.
  • the size of the capsule may be selected to adequately contain the dose of the pharmaceutical composition.
  • the sizes generally range from size 5 to size 000 with the outer diameters ranging from about 4.91 mm to 9.97 mm, the heights ranging from about 11.10 mm to about 26.14 mm, and the volumes ranging from about 0.13 ml_ to about 1.37 ml_, respectively.
  • Exemplary standard capsule sizes, and their corresponding volumes are shown in Table 1 below: Table 1
  • Suitable capsules are available commercially from, for example, Shionogi
  • a top portion may be placed over the bottom portion to form a capsule shape and to contain the powder within the capsule, as described in U.S. Patent Nos. 4,846,876 and 6,357,490, and in WO 00/07572, which are incorporated herein by reference in their entireties.
  • the capsule can optionally be banded.
  • compositions of one or more embodiments of the present invention may be made by any of the various methods and techniques known and available to those skilled in the art.
  • Dry powder formulations may be prepared by solvent removal processes appropriate to remove solvent from a liquid solution, suspension or dispersion.
  • suitable solvent removal processes comprise spray drying, freeze drying, and spray-freeze drying. Spray drying of the formulations is carried out, for example, as described generally in the "Spray Drying Handbook", 5 th ed., K. Masters, John Wiley & Sons, Inc., NY, N. Y. (1991), and in WO 97/41833, the contents of which are incorporated herein by reference.
  • the methionine-containing protein or peptides can be spray-dried from an aqueous solution.
  • the methionine-containing protein or peptide is first dissolved in water, optionally containing a physiologically acceptable buffer or other excipient as describe above.
  • the pH range of active agent-containing solutions is generally between about 2 and 11, with approximately neutral pHs being preferred, since such pHs may aid in maintaining the physiological compatibility of the powder after dissolution of powder within the lung.
  • the aqueous formulation may optionally contain additional water-miscible solvents, such as acetone, alcohols, and the like. Representative alcohols are lower alcohols such as methanol, ethanol, propanol, isbpropanol, and the like.
  • the pre-spray dried solutions will generally contain solids dissolved at a concentration from 0.01% (weight/volume) to about 20% (weight/volume), usually from 0.1% to 3% (weight/volume).
  • the solutions are then spray dried in a spray drier, such as those available from commercial suppliers such as Niro A/S (Denmark), Buchi (Switzerland) and the like, resulting in a dispersible, dry powder.
  • a spray drier such as those available from commercial suppliers such as Niro A/S (Denmark), Buchi (Switzerland) and the like.
  • Optimal conditions for spray drying the solutions will vary depending upon the formulation components, and are generally determined experimentally.
  • the gas used to spray dry the material is typically air, although inert gases such as nitrogen or argon are also suitable.
  • the temperature of both the inlet and outlet of the gas used to dry the sprayed material is such that it does not cause decomposition of the active agent in the sprayed material.
  • Such temperatures are typically determined experimentally, although generally, the inlet temperature will range from about 50 0 C to about 200 0 C while the outlet temperature will range from about 30 0 C to about 150 0 C.
  • the organic solvent is selected to provide a solubility for the hydrophilic component of at least 1 mg/ml, and preferably at least 5 mg/ml, and a solubility for the hydrophobic drug of at least 0.01 mg/ml, preferably at least 0.05 mg/ml.
  • the composition may be prepared by spray-drying a suspension, as described in U.S. Patent No. 5,976,574, assigned to Nektar Therapeutics, which document is incorporated herein by reference in its entirety.
  • the hydrophobic drug is dissolved in an organic solvent, e.g., methanol, ethanol, isopropanol, acetone, heptane, hexane chloroform, ether, followed by suspension of the hydrophilic excipient in the organic solvent to form a suspension.
  • the suspension is then spray-dried to form particles.
  • Preferred solvents, for both of the above spray-drying methods include alcohols, ethers, ketones, hydrocarbons, polar aprotic solvents, and mixtures thereof.
  • the dry powders of the invention may also be prepared by combining aqueous solutions or suspensions of the formulation components and spray-drying them simultaneously in a spray-dryer, as described in U.S. Patent No. 6,001 ,336, assigned to Nektar Therapeutics, which document is incorporated herein by reference in its entirety.
  • the dry powders may be prepared by preparing an aqueous solution of a hydrophilic excipient or additive, preparing an organic solution of a hydrophobic drug, and spray drying the aqueous solution and the organic solution simultaneously through a nozzle, e.g., a coaxial nozzle, to form a dry powder, as described in WO 98/29096, which is incorporated herein by reference in its entirety.
  • the particle completely solidifies with trileucine enriched on the surface or shell and the core components include Ostabolin-CTM, trehalose, citrate and methionine. All of which have a much greater solubility than trileucine.
  • methionine (i.e., the core) where methionine is present and affords unexpected stability. This could be due to interaction between methionine and Ostabolin-CTM.
  • powders may be prepared by lyophilization, vacuum drying, spray-freeze drying, super critical fluid processing, air drying, or other forms of evaporative drying.
  • dry powders may be prepared by agglomerating the powder components, sieving the materials to obtain agglomerates, spheronizing to provide a more spherical agglomerate, and sizing to obtain a uniformly-sized product, as described, e.g., in WO 95/09616, which is incorporated herein by reference in its entirety.
  • Dry powders may also be prepared by blending, grinding, sieving or jet milling formulation components in dry powder form.
  • the dry powder compositions are preferably maintained under dry (i.e., relatively low humidity) conditions during manufacture, processing, and storage. Irrespective of the drying process employed, the process will preferably result in respirable, highly dispersible particles comprising the methionine-containing protein or peptide, an antioxidant, and a dileucyl-containing dimer or trimer. Stability
  • the methionine-containing protein or peptide compositions according to the invention typically have improved shelf stability. For example, after storage at about 25°C and 60% RH for 38 months, one or more embodiments of the formulations of the invention (such as a bulk powder) may exhibit a degree of degradation and/or oxidation of the methionine-containing protein or peptide of less than about 10%, or 8%, or 5% or 4% or 3% or 2% or 1 %.
  • one or more embodiments of the formulations of the invention may exhibit a degree of degradation and/or oxidation of the methionine-containing protein or peptide of less than about 10%, or 8%, or 5% or 4% or 3% or 2% or 1 %.
  • one or more embodiments of the formulations of the invention may exhibit a degree of degradation and/or oxidation of the methionine-containing protein or peptide of less than about 10%, or 8%, or 5% or 4% or 3% or 2% or 1 %.
  • compositions of the present invention increase the shelf-life, depending upon storage temperature, by at least about 2, 4, 6, 8, 10, 12, or more months, as compared to methionine-containing protein or peptide compositions excluding an antioxidant and or other excipients of the inventive formulations.
  • shelf life is greater by at least 22 or 24 or 26 or 28 or 30 months at 25°C, or greater by at least 100, or 120, or 130, or 140, or 150 or 160 or 170 months at 5°C, or both.
  • the shelf life is of the product, either as bulk powder or in capsules is at least 20 or 25 or 30 or 35 or 40 or 45 or 50 or 60 or 70 or 80 months at 25°C, or greater by at least 120, or 130, or 140, or 150 or 160 or 170 or 180 or 190 or 200 months at 5°C, or both.
  • Administration of the Compositions is at least 20 or 25 or 30 or 35 or 40 or 45 or 50 or 60 or 70 or 80 months at 25°C, or greater by at least 120, or 130, or 140, or 150 or 160 or 170 or 180 or 190 or 200 months at 5°C, or both.
  • compositions of one or more embodiments of the present invention may be administered by any of the various methods and techniques known and available to those skilled in the art.
  • the compositions described herein may be delivered using any suitable dry powder inhaler (DPI), i.e., an inhaler device that utilizes the patient's inhaled breath as a vehicle to transport the dry powder drug to the lungs.
  • DPI dry powder inhaler
  • Such an inhaler device is described in US 4,069,819 and 4,995,385, the disclosures of which are incorporated herein by reference in their entireties.
  • DPI dry powder inhaler
  • the compositions described herein may be delivered using any suitable dry powder inhaler (DPI), i.e., an inhaler device that utilizes the patient's inhaled breath as a vehicle to transport the dry powder drug to the lungs.
  • the powdered medicament When administered using a device of this type, the powdered medicament is contained in a receptacle having a puncturable lid or other access surface, preferably a blister package or cartridge, where the receptacle may contain a single dosage unit or multiple dosage units.
  • a receptacle having a puncturable lid or other access surface preferably a blister package or cartridge
  • the receptacle may contain a single dosage unit or multiple dosage units.
  • Convenient methods for filling large numbers of cavities with metered doses of dry powder medicament are described in U.S. Pat. No. 5,826,633, incorporated herein by reference.
  • dry powder inhalers of the type described, for example, in U.S. Pat. Nos. 3,906,950 and 4,013,075, 4,069,819, and 4,995,385, incorporated herein by reference, wherein a premeasured dose of aminoglycoside dry powder for delivery to a subject is contained within a capsule such as a hard gelatin capsule or HPMC capsule.
  • HPMC capsules are preferred, sucha as size #2 capsules containing up to 50 mg powder, preferably 20-40 mg. It is to be understood that other sized capsules, such as 00, 0, No. 1, or No. 3 sized capsules are also suitable for use with the present invention and their suitability depends, among other factors, upon the inhalation device used to administer the powders
  • a preferred device is Nektar Therapeutics 1 dry powder inhalation devices as described in U.S. Patent Nos. 5,458,135; 5,740,794; and 5,785,049, the disclosures of which are incorporated herein by reference in their entireties.
  • Nektar Therapeutics' T-326 Dry Powder Inhaler (DPI) is a hand-held, manually operated, passive device. A single primary drug package (capsule) containing a dry powder for inhalation is Inserted into the DPI, and the DPI plunger is depressed, puncturing the capsule. When the subject inhales through the DPI, the airflow agitates the capsule and disperses the powder into an aerosol, which is carried into the respiratory tract. This device is described generally in the patents noted above.
  • Another preferred device is disclosed in USSN 60/854,601 , filed October
  • the powder When administered using a device of this type, the powder is contained in a receptacle having a puncturable lid or other access surface, preferably a blister package or cartridge, where the receptacle may contain a single dosage unit or multiple dosage units.
  • Convenient methods for filling large numbers of cavities (i.e., unit dose packages) with metered doses of dry powder medicament are described, e.g., in WO 97/41031 (1997), which is incorporated herein by reference in its entirety.
  • Also suitable for delivering the powders described herein are dry powder inhalers of the type described, for example, in U.S. Patent Nos. 3,906,950 and 4,013,075, which are incorporated herein by reference in their entireties, wherein a premeasured dose of dry powder for delivery to a subject is contained within a hard gelatin capsule.
  • dry powder dispersion devices for pulmonarily administering dry powders include those described, for example, in EP 129985; EP 472598; EP 467172; and U.S. Patent No. 5,522,385, which are incorporated herein by reference in their entireties.
  • inhalation devices such as the Astra-Draco "TURBUHALER”. This type of device is described in detail in U.S. Patent Nos. 4,668,281 ; 4,667,668; and 4,805,811, all of which are incorporated herein by reference in their entireties.
  • Suitable devices include dry powder inhalers such as the ROTAHALERTM (Glaxo), DiscusTM (Glaxo), SpirosTM inhaler (Dura Pharmaceuticals), and the SpinhalerTM (Fisons).
  • dry powder inhalers such as the ROTAHALERTM (Glaxo), DiscusTM (Glaxo), SpirosTM inhaler (Dura Pharmaceuticals), and the SpinhalerTM (Fisons).
  • devices which employ the use of a piston to provide air for either entraining powdered medicament, lifting medicament from a carrier screen by passing air through the screen, or mixing air with powder medicament in a mixing chamber with subsequent introduction of the powder to the patient through the mouthpiece of the device, such as described in U.S. Patent No. 5,388,572, which is incorporated herein by reference in its entirety.
  • Dry powders may also be delivered using a pressurized, metered dose inhaler (MDI), e.g., the VentolinTM metered dose inhaler, containing a solution or suspension of drug in a pharmaceutically inert liquid propellant, e.g., a chlorofluorocarbon or fluorocarbon, as described in U.S. Patent Nos. 5,320,094 and 5,672,581 , which are both incorporated herein by reference in their entireties.
  • MDI metered dose inhaler
  • the compositions of the present invention are suitable for use with metered-dose inhalers (MDIs).
  • the composition may comprise a suspension, made by using, for example, surface-active agents. See U.S. Patent No. 5,118,494, and WO 91/11173 and WO 92/00107.
  • a particularly useful class of MDIs are those which use hydrofluoroalkane
  • HFA hydrogen fluoride-containing propellants
  • the HFA propellants are further particularly well suited to be used with stabilized dispersions of an active agent such as formulations and composition of methionine-containing protein or peptide.
  • Suitable propellants, formulations, dispersions, methods, devices and systems comprise those disclosed in US 6,309,623, the disclosure of which is incorporated by reference in its entirety.
  • the various embodiments of the compositions, formulations, systems and methods of the present invention are suited to, and often optimal for, combination with such HFA-propellant based MDIs.
  • this is due to physical properties of the various embodiments of the particles and/or composition of methionine-containing protein or peptide, especially a cyclized PTH analog, such as the density, specific surface area, MMD and/or MMAD, as well as due in part to the methods of administration and methods of treatment herein.
  • a cyclized PTH analog such as the density, specific surface area, MMD and/or MMAD
  • dry powders Prior to use, dry powders may be stored under ambient conditions, and preferably are stored at temperatures at or below about 25°C, and relative humidities (RH) ranging from about 30 to 60%. More preferred relative humidity conditions, e.g., less than about 30%, may be achieved by the incorporation of a dessicating agent in the secondary packaging of the dosage form.
  • RH relative humidities
  • More preferred relative humidity conditions, e.g., less than about 30%, may be achieved by the incorporation of a dessicating agent in the secondary packaging of the dosage form.
  • the time for closing is typically short. For a single unit dose, or capsule
  • the total closing time is normally less than about 1 minute.
  • a 2 capsule dose e.g., 10 mg usually takes about 1 min.
  • a 5 capsule dose e.g., 25 mg may take about 3.5 min to administer.
  • the time for dosing may be less than about
  • Dosing may comprise administration of a single unit dose, or capsule, or multiple unit doses, or capsules.
  • compositions described herein may be administered by nebulization.
  • a dry powder may be dissolved or suspended in a solvent, e.g., water, ethanol, or saline, and delivered as an aerosolized solution using a nebulizer.
  • a solvent e.g., water, ethanol, or saline
  • Liquid formulations can be atomized by any of a variety of procedures, such as a two-fluid nozzle, a pressure nozzle, or a spinning disc, or atomized with an ultrasonic nebulizer or a vibrating orifice aerosol generator (VOAG), jet nebulizer, vibrating porous plate nebulizer, or a thermal vaporizing device.
  • a liquid formulation is atomized with a pressure nozzle, such as a BD
  • aerosolization apparatuses may be based on condensation aerosolization, an impinging jet technique, electrospray techniques, thermal vaporizing, or a Peltier device.
  • Vibrating porous plate nebulizers work by using a sonic vacuum produced by a rapidly vibrating porous plate to extrude a solvent droplet through a porous plate.
  • Jet nebulizers involve use of air pressure to break a liquid solution into aerosol droplets.
  • a jet nebulizer generates droplets as a mist by shattering a liquid stream with fast moving air supplied by tubing from an air pump. Droplets that are produced by this method typically have a diameter of about 2-5 ⁇ m.
  • an ultrasonic nebulizer that uses a piezoelectric transducer to transform electrical current into mechanical oscillations is used to produce aerosol droplets.
  • the resulting droplets typically have an MMAD in the range of about 1 to about 5 microns.
  • the aerosol generator is the commercially available Aerogen (available from Nektar Therapeutics, San Carlos, CA) aerosol generator which comprises a vibrational element and dome-shaped aperture plate with tapered holes. When the plate vibrates several thousand times per second, such as about 100 kHz to about 150 kHz, a micro-pumping action causes liquid to be drawn through the tapered holes, creating a low-velocity aerosol with a precisely defined range of droplet sizes.
  • the Aerogen aerosol generator does not require propellant.
  • the aerosol is formed by pumping drug formulation through a small, electrically heated capillary.
  • the formulation Upon exiting the capillary, the formulation is rapidly cooled by ambient air, and a gentle aerosol is produced that is relatively invariant to ambient conditions and the user inhalation rate.
  • the condensation aerosol generator comprises one disclosed by Alexza Molecular Delivery Corporation. See, e.g., U.S. Published Application No. 2004/0096402, which is incorporated herein by reference in its entirety.
  • WO 91/14468 and WO 97/12687 Another apparatus for delivery of a metered quantity of a liquid pharmaceutical composition for inhalation is described for example in WO 91/14468 and WO 97/12687, which are incorporated herein by reference in their entireties.
  • the nebulizers described therein are known by the name Respimat®.
  • One or more electrosprays may be used to nebulize liquid formulations.
  • electrostatic spray also known as electrohydrodynamic spray or electrospray
  • electrospray refers to systems in which the dispersion of the liquid relies on its electric charging, so that nebulization and gas flow processes are relatively uncoupled.
  • electrospray devices are disclosed in U.S. Patent Nos. 6,302,331; 6,583,408; and 6,803,565, which are incorporated herein by reference in their entireties. [0174] lExamples of foregoing devices are disclosed in U.S. Published
  • the aerosol generator comprises a thin film, high surface area boiler that relies on capillary force and phase transition. By inducing phase transition in a capillary environment, pressure is imparted onto the expanding gas, which is ejected.
  • This technology has been disclosed by Vapore, Inc., and is known as Vapore-Jet CFV technology. See, e.g., U.S. Patent Nos. 5,692,095; 5,870,525; 6,162,046; 6,347,936; 6,585,509; and 6,634,864, and U.S. Application No.
  • Active agents may be delivered simultaneously, some preferred order, and/or providing one agent in an aerosol of a certain size to target one region of the lung while providing another in another size to target another region.
  • purposeful variation of the aerosol size can cause some aerosol to deposit more proximally near the endotracheal tube to treat that area, while also sending in small aerosol to penetrate more deeply.
  • compositions of the invention are useful, when administered pulmonarily in a therapeutically effective amount to a mammalian subject, for treating or preventing any condition responsive to the administration of methionine-containing protein or peptide.
  • the compositions of the invention comprising a parthyroid homone analog, derivative or fragment, such as a cyclized parathyroid hormone, are useful, when administered pulmonarily in a therapeutically effective amount to prevent and/or treat osteoporosis.
  • Compositions of the invention may be used, for example, to stimulate new bone formation and significantly increase bone mineral density.
  • the methionine-containing peptide or protein composition such as cyclized parathyroid hormone analog
  • a di-mer or trimer containing one or two leucyl residues for good aerosol performance as taught, for example by the Kuo et al patents, supra.
  • the result is a particle with good aerosol characteristics and good dispersibility, suitable for respiration, as well as good physical and chemical stability.
  • Such a formulation is highly compatible with the Nektar Therapeutics T-326 Inhaler device.
  • a composition comprising trileucine or with a di-mer or trimer containing one or two leucyl residues desirably lowers the powder density, and/or increases drug loading and/or lowers fill mass, or combinations thereof.
  • This Example shows the impact of the addition of an antioxidant such as methionine, on the solution stability of OSTABOLIN-CTM.
  • an antioxidant such as methionine
  • this Example demonstrates the effect of varying levels of methionine (1 %, 5% and 10%) on the oxidative stability of OSTABOLIN-CTM in solution (4% OSTABOLIN-CTM, 20% trileucine, 71% trehalose, 5% citrate) as a function of storage temperature and duration.
  • OSTABOLIN-CTM purity was determined using reverse-phase high performance liquid chromatography (RP-HPLC)
  • OSTABOLIN-CTM 20% trileucine, 71% trehalose, 5% citrate
  • oxidation is a primary degradation product.
  • the basic formulation solution was found to be stable for approximately 24 hours at 2 — 8°C and approximately 8 hours at 15 C C and 25°C.
  • Methionine (Met) 8 and 18 of OSTABOLIN-CTM are the primary sites of oxidation (see Figure 1 ). Met residues are susceptible to oxidation, resulting in the formation of methionine sulfoxide.
  • Peroxides, such as hydrogen peroxide react with metal ions to form free radicals that can initiate oxidation of proteins and peptides. Met can also be photooxidized by a free radical pathway or via singlet oxygen intermediate formation.
  • the materials used in this Example include Ostabolin-C, L-trileucine, trehalose dehydrate, sodium citrate dehydrate, citric acid monohydrate, methionine, bottled water, HCI, NaOH, sodium perchlorate anhydrous and phosphoric acid.
  • the equipment used in this Example include a top loading balance, pH meter, pH buffer solutions at pH 4 and pH 7, a Mettler AT261 balance and a sterilizing low extractable membrane 0.2 ⁇ m nylon filter system.
  • trehalose 50 mg/ml trehalose, 1 mg/ml methionine and 3 mg/ml trileucine.
  • the trileucine solution was pH adjusted to pH 5.0 with 5 M HCI.
  • the sodium citrate solution was pH adjusted to pH 5.0 using the citric acid stock solution. All the stock solutions were filtered through a 0.2 ⁇ m nylon filter. Formulation components containing water content were corrected for weight. All formulations were prepared from common excipient stock solutions.
  • Methionine formulations containing 1 %, 5% and 10% were made, with the formulations shown in Table 2. Table 2. Methionine formulations
  • Mobile phase A contained 0.1 M sodium perchlorate. The solution was adjusted to pH 3.10 ⁇ 0.05 with phosphoric acid. The mobile phase was filtered through 0.2 ⁇ m nylon filter and stored at room temperature.
  • Mobile phase B contained acetonitrile.
  • the ratio of mobile phase A/B varied during the run according to the gradient specified below. The following conditions were used for the analysis:
  • OSTABOLIN-CTM purity are listed in Tables 3 and 4, with a representative chromatogram shown in Figure 2.
  • the other degradant peak area levels remained unchanged within the instrumental and method variability throughout the duration of the study.
  • Example 1 shows that the addition of methionine resulted in a reduction in oxidation in the solution state.
  • This Example shows the inhibitory effect of the addition of an antioxidant such as methionine, on oxidative degradation in the solid-state.
  • OSTABOLIN-CTM (OSTAB OL I N-C TM) formulations containing trileucine, trehalose, sodium citrate, citric acid, and methionine. Formulations were assessed for chemical stability using reverse-phase high performance liquid chromatography (RP-HPLC) after storage under accelerated conditions.
  • RP-HPLC reverse-phase high performance liquid chromatography
  • Example 1 with the addition of a Buchi mini spray dryer and an atomizer liquid nozzle.
  • Powders were weighed into 1.5 ml HPLC vials. Pouches and rayon balls were equilibrated for 24 hours at 11 % RH. Fifteen capped vials and one rayon ball were placed in a small inner foil pouch and sealed with a hand sealer inside a glovebox equilibrated to approximately 11% RH. This smaller pouch was then placed inside a larger foil pouch and sealed. The powders were stored under accelerated conditions and assayed by RP-HPLC for impurities at various times. [0199] Each sample preparation was analyzed using the HPLC method described in Example 1. The standard range for the samples was approximately between 80 to 120 ⁇ g/ml of OSTABOLIN-CTM in water. Mobile phase A contained 0.1 M sodium perchlorate.
  • the solution was adjusted to pH 3.10 ⁇ 0.05 with phosphoric acid.
  • the mobile phase was filtered through 0.2 ⁇ m nylon filter and stored at room temperature.
  • Mobile phase B contained acetonitrile.
  • the ratio of mobile phase A/B varied during the run according to the gradient specified in Example 1.
  • T 9 glass transition temperature of each powder was measured using a differential scanning calorimeter.
  • Sample preparation was using the test method DSC- 2920 Differential Scanning Calorimeter. Samples were pre-equilibrated at 11.3% RH using saturated salt solution of lithium chloride in a vacuum dessicator for a period of at least two days before sealing the pan. Each test run consisted of heating the sample from -60 0 C to 220 0 C at a heating rate of 2°C/min. The heating rate was modulated by superimposing a sinusoidal heating profile at ⁇ 0.318°C/min.
  • the moisture content was assessed by measuring the weight loss upon drying using a TGA-2950 instrument.
  • a disc of powder was prepared using a 5/32" diameter custom-made stainless steel press. Gentle pressure was applied to produce a 3 to 13 mg disc that fits inside a DSC pan.
  • the pan was hermetically sealed using a sample encapsulation press. In order to provide a vent, the lid of the sample pan was pierced just prior to starting the experiment. The samples were heated to 110 0 C at 2°C/min and held for 60 minutes to ensure that all the internal water molecules are dried out.
  • OSTABOLIN-CTM spray dried powder formulations were determined at 11.3% RH using
  • a rate of inhibition of powder (either bulk or in capsules) oxidation is reduced by about 10 times, or 12 times or 15 times or 20 times or 25 times or 30 times or more.
  • an initial amount of oxidation is decreased by about 10% or 20% or 30% or 40% or 50% or 60% or 70% or 80% or 90% or more, over a given time period.
  • a rate of degradant growth is decreased by about 10% or 20% or 30% or 40% or 50% or 60% or 70% or 80% or 90% or more, over a given time period.
  • Ostabolin-C inhalation powder (OCIP) formulations were investigated. Solutions with ("Formula A”) and without ("Formula B") methionine were prepared as shown in Table 8. The solutions were subsequently spray dried on a bench scale spray drier using spray drying conditions outlined in Example 2. The bulk powders were filled into size 2 HPMC capsules at a 5 mg fill weight. The capsules were subsequently placed into HDPE bottles and the bottles then placed into a labeled 6.25 in. x 7.25 in. pouch containing two conditioned rayon balls and sealed. This pouch was then placed into a labeled 7 in. x 7.25 in pouch containing a desiccant and sealed. The samples were then stored at either 5°C, 25°C/60% RH or 40°C/75% RH conditions for up to 24 months and tested periodically. Table 8 Formulation components used in Example 3
  • the initial median particle diameter (x50) was 1.81 ⁇ m and 1.95 ⁇ m for FORMULA B (Lot # 4792-04) and the 4% Ost-C with 0.5% methionine formulation (Lot # 4792-13), respectively.
  • the initial particle size distribution width (x84 — x16) was 2.29 ⁇ m and 2.68 ⁇ m for FORMULA B and 4% Ost-C with 0.5% methionine formulations, respectively. Inclusion of methionine in the 4% Ostabolin- C formulation had no significant effect on the particle size distribution.
  • %ED values of FORMULA B (Lot # 4792-04) for filled inhalation grade capsules at 2.5 mg, 5 mg and 15 mg packaged strength were found to be 87.8%, 91.8% and 92.0%, respectively. No differences were observed in the %ED as a function of fill weight indicating the powders were physically stable. Aerosol properties of the 4% Ost-C with 0.5% methionine formulation (Lot # 4792-13) were not determined but are expected to be similar to those observed for FORMULA B.
  • Oxidation levels in the capsules decreased from 0.84% to 0.61 % at 5°C but increased to 1.39% at 25°C and 2.65% at 4O 0 C after storage for 91 days.
  • Oxidative degradation levels for 4% Ost-C with 0.5% methionine formulation (Lot # 4792-13) capsules stored at 25°C and 40 0 C remained, for practical purposes, unchanged after 48 days of storage (See Figure 8, Table 11).
  • Ost-C with 0.5% methionine, and 25% Ost-C were manufactured using the same excipient ratios as in an Ost-C formulation designated ZL1-001. (ZL1-001 contained 4% Ost-C, 5% sodium citrate, 61% trehalose and 30% trileucine.)
  • the composition of the three high strength formulations is shown in Table 12. Table 12
  • Example 3 The formulations were then assessed for physical properties and chemical stability, as discussed in Example 3. No significant differences were observed in the physical properties of the three OCIP high strength formulation bulk powder.
  • the moisture content of the three lots decreased up to approximately 2% after storage in HPLC vials for 2 weeks. No further changes were observed in the moisture content after 4 weeks storage.
  • the oxidation levels of all three bulk powders ranged from 0.13% to 0.14%, similar to the levels obtained in the feedstock solutions.
  • the oxidation levels of all the formulations did not change upon spray drying, indicating that the spray drying process was not inducing oxidation.
  • OCIP formulation ZL1-002 contains 16% Ostabolin-C, 1.8% Citric Acid,
  • Example 2 Materials and equipment used in this Example as well as the solution preparation and spray dried procedures are those as outlined in Example 2. The objective of this Example is to demonstrate the bulk powder stability of the spray dried powder.
  • the spray-dried powder Lot #N020298 (ZL 1-002) was hand filled into 4 mL amber glass vials. The vials and packaging materials were equilibrated in ICS at 11 ⁇ 3%RH over 12 hours prior to filling. Two vials were filled for each stability condition.
  • One vial was filled for moisture testing and the other vial for determination of powder morphology, content and purity determination by HPLC (as described in Example 1) and particle size distribution by Sympatec.
  • Each vial and two rayon balls were sealed in a 6.25 in. x 7.25 in. foil pouch using a hand sealer.
  • the sealed pouch was subsequently sealed in a 7 in. x 7.25 in. secondary pouch with a 5g desiccant using a commercial sealer at ambient condition.
  • the stability pouches were packaged and stored in the stability chambers at either 5°C or 25°C/60% RH.
  • the powder was characterized at initial, 4 weeks, 3 months and 6 months.
  • Example 6 The effect of Oxygen Scavenger on the rate of Ostabolin-C oxidation in 4% Ostabolin-C lnahlation Powder (RD 938)
  • PharmaKeep® oxygen scavenger on the rate of oxidation of 4% Ostabolin-C Inhalation Powder (OCIP) (Formulation Code: ZL1-001).
  • OCIP Ostabolin-C Inhalation Powder
  • PharmaKeep® is a proprietary oxygen absorber marketed by Sud-Chemie Group/Mitsubishi Gas Chemical Company. The material, equipment, solution preparation and spray drying conditions used in this Example are the same as those cited in Example 2.
  • a 4% OCIP (Formulation Code ZL1-001 ) filled in HPLC vials at 2.5 mg fill weight and capsules at 5.0 mg fill weights were packaged in pouches.
  • the pouches were then packaged with and without oxygen scavenger and stored at 5O 0 C for up to 52 weeks.
  • the samples were analyzed by RP-HPLC to determine the Ostabolin-CTM content and purity, as described in Example 1.
  • comparison of the HPLC chromatograms of OCIP powders in capsules, packaged with and without oxygen scavenger demonstrates that all of the samples had approximately the same number of major degradant peaks. While the number of peaks was approximately unchanged, the results demonstrated that the amount of degradation was less in both the bulk powder and capsule samples packaged with an oxygen scavenger than without oxygen scavenger.
  • Suitable oxygen scavengers comprise any material which can reduce the amount of free or molecular oxygen to react with other species in a composition. In some embodiments, suitable oxygen scavengers are those that bind molecular oxygen.
  • An oxygen scavenger such as PharmaKeep®, can slow the rate of oxidation and/or degradation in a methionine-containing protein or peptide, such as OCIP, when stored in bulk and/or in capsules. In one or more embodiments, the rate of oxidatation and/or degradation is slowed by at least about 50% or 60% or 70% or 80% or 90% or 95% or 97% or 98% or 99% over 1 or 3 or 6 or 12 or 24 or 36 months or more.
  • the amount of impurities in the methionine- containing protein or peptide, such as OCIP is reduced by at least about 10% or 20% or 30% or 40% or 45% or 50% or more over 1 or 3 or 6 or 12 or 24 or 36 months or more.
  • Example 7 Stability results for 16% OCIP, 5.0 mg fill weight bulk capsules, lot #5244-13
  • OCIP 5.0 mg bulk capsules after storage at 5°C, 25°C/60% RH and 40 0 C.
  • the samples were evaluated for appearance, moisture content (as described in Example 2), identity, content and purity (as described in Example 1 ) and aerosol properties (as described in Example 3).
  • Ostabolin-C/mg capsule to 0.700 mg Ostabolin-C/capsule when the capsules were stored at 40 0 C for two months, 0.701 mg Ostabolin-C/capsule after storage for 3 months at 5°C and 0.706 mg Ostabolin-C/capsule after storage for 6 months at 25°C/60% RH (Table 20).
  • the total impurities increased from an initial value of 1.55% to 1.91% after storage for 3 months at 5 ⁇ C, 3.21% at 25°C/60% RH after storage for 6 months and 4.06% after storage for two months at 40 0 C.
  • the oxidation peak value at RRT 0.84 increased from an initial value of 0.31 % to 1.23% after storage for two months at 40 0 C, 0.34% after storage for 3 months at 5°C and 1.00% after storage for 6 months at 25°C/60% RH (Table 20).
  • Table 20 Identity, Content and Purity Results for 16% OCtP (Formulation Code ZH -002). Bulk Capsules. 5.0 mq Fill Weight
  • Test Article 5°C 25°C/60% RH 40 0 C
  • Example 8 Stability Results for 4% OCIP, bulk capsules at 2.5 mg and 5.0 mg fill weights, Lot #5244-05
  • Example 9 Pharmacokinetic analysis of a dry powder formulation of
  • a dry powder comprising 16% w/w Ostabolin-C, 0.5% w/w methionine,
  • OSTABOLIN-CTM Following 15-minute inhalation of 100 and 250 /yg/kg, absorption of OSTABOLIN-CTM was rapid with maximum plasma concentrations occurring between 15 and 35 minutes post-dose. OSTABOLIN-CTM was found to be subject to extensive distribution following both IV and inhaled administration. The clearance of OSTABOLIN-CTM was rapid following both inhaled and IV administration with mean terminal elimination half-lives of approximately 14 to 30 minutes. The inhaled absolute bioavailability of OSTABOLIN-
  • CTM was between 0.75 and 2.0 % for all animals. Exposure to OSTABOLIN-CTM increased in a greater than dose proportional manner over the 100 to 250//g/kg dose range with a 2.9-fold increase in dose resulting in an approximate 5 to 7-fold increase in exposure.
  • Ostabolin-C were determined, following one intravenous and two inhalation (oral/nasal) administrations to the monkey. Ostabolin-C was supplied in two physical forms,
  • Ostabolin-C for intravenous dosing, and a dry powder formulation for inhalation exposure.

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Abstract

La présente invention concerne des compositions protéiques ou peptidiques contenant de la méthionine pouvant comporter au moins une protéine ou un peptide contenant de la méthionine et au moins un antioxydant inhibiteur de l'oxydation dudit peptide ou de ladite protéine contenant de la méthionine, les compositions étant inhalables. Des particules peuvent présenter une surface enrichie d'un excipient de surface ayant une température de transition vitreuse et un noyau enrichi d'au moins une protéine ou un peptide contenant de la méthionine. L'invention concerne également des procédés de fabrication, des procédés de traitement et des formes posologiques.
PCT/US2007/003905 2006-02-13 2007-02-13 Compositions protéiques ou peptidiques protéine contenant de la méthionine et leur procédé de fabrication et d'utilisation WO2007095288A2 (fr)

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EP07750726A EP1986674A4 (fr) 2006-02-13 2007-02-13 Compositions protéiques ou peptidiques protéine contenant de la méthionine et leur procédé de fabrication et d'utilisation

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US60/773,384 2006-02-13

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Cited By (25)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1933863A2 (fr) * 2005-09-06 2008-06-25 Zelos Therapeutics, Inc. Analogues de l'hormone parathyroidienne et procedes les utilisant
WO2008145323A1 (fr) * 2007-05-31 2008-12-04 F. Hoffmann-La Roche Ag Formulation pharmaceutique comprenant des interférons
EP2299270A1 (fr) * 2008-07-14 2011-03-23 Alfresa Pharma Corporation Procédé pour stabiliser des microparticules comportant une substance réactive liée à celles-ci, et réactif comprenant les microparticules
FR2954325A1 (fr) * 2009-12-23 2011-06-24 Flamel Tech Sa Polymere amphiphile fonctionnalise par la methionine
WO2013016754A1 (fr) * 2011-08-01 2013-02-07 Monash University Procédé et formulation pour inhalation
JP2013519649A (ja) * 2010-02-12 2013-05-30 セントロ デ インヘニエリア ヘネティカ イ ビオテクノロヒア （セーイーヘベー） 上皮増殖因子の経口投与可能薬学的ペレット
EP2719393A1 (fr) * 2011-06-07 2014-04-16 Asahi Kasei Pharma Corporation Préparation pharmaceutique lyophilisée contenant du pth de pureté élevée et son procédé de production
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US9644017B2 (en) 2008-01-09 2017-05-09 Sanofi-Aventis Deutschland Gmbh Insulin derivatives having an extremely delayed time-action profile
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
US9839692B2 (en) 2014-01-09 2017-12-12 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US9839675B2 (en) 2013-02-04 2017-12-12 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US9895424B2 (en) 2014-01-09 2018-02-20 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US9895423B2 (en) 2014-01-09 2018-02-20 Sanofi Stabilized pharmaceutical formulations of insulin aspart
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients
CN110075293A (zh) * 2013-03-13 2019-08-02 霍夫曼-拉罗奇有限公司 氧化降低的配制剂
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation
US11596620B2 (en) 2013-03-13 2023-03-07 F. Hoffmann-La Roche Ag Formulations with reduced oxidation

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ATE461692T1 (de) * 1999-10-29 2010-04-15 Novartis Ag Trockenpulverzusammensetzungen mit verbesserter dispersität
AU2004251623B2 (en) * 2003-05-28 2010-03-18 Novartis Ag Spray drying of an alcoholic aqueous solution for the manufacture of a water-in-soluble active agentmicroparticle with a partial or complete amino acid and/or phospholipid coat

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Cited By (38)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1933863A4 (fr) * 2005-09-06 2010-06-09 Zelos Therapeutics Inc Analogues de l'hormone parathyroidienne et procedes les utilisant
EP1933863A2 (fr) * 2005-09-06 2008-06-25 Zelos Therapeutics, Inc. Analogues de l'hormone parathyroidienne et procedes les utilisant
WO2008145323A1 (fr) * 2007-05-31 2008-12-04 F. Hoffmann-La Roche Ag Formulation pharmaceutique comprenant des interférons
US9644017B2 (en) 2008-01-09 2017-05-09 Sanofi-Aventis Deutschland Gmbh Insulin derivatives having an extremely delayed time-action profile
EP2299270A1 (fr) * 2008-07-14 2011-03-23 Alfresa Pharma Corporation Procédé pour stabiliser des microparticules comportant une substance réactive liée à celles-ci, et réactif comprenant les microparticules
EP2299270A4 (fr) * 2008-07-14 2011-12-28 Alfresa Pharma Corp Procédé pour stabiliser des microparticules comportant une substance réactive liée à celles-ci, et réactif comprenant les microparticules
US10117909B2 (en) 2008-10-17 2018-11-06 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1 agonist
US9526764B2 (en) 2008-10-17 2016-12-27 Sanofi-Aventis Deutschland Gmbh Combination of an insulin and a GLP-1-agonist
US10029011B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist, an insulin and methionine
US9707176B2 (en) 2009-11-13 2017-07-18 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1 agonist and methionine
US10028910B2 (en) 2009-11-13 2018-07-24 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition comprising a GLP-1-agonist and methionine
FR2954325A1 (fr) * 2009-12-23 2011-06-24 Flamel Tech Sa Polymere amphiphile fonctionnalise par la methionine
WO2011077402A3 (fr) * 2009-12-23 2011-08-18 Flamel Technologies Polymere amphiphile fonctionnalise par la methionine
US9205130B2 (en) 2010-02-12 2015-12-08 Centro De Ingenieria Genetica Y Biotecnologia Orally administrable pharmaceutical pellet of epidermal growth factor
JP2013519649A (ja) * 2010-02-12 2013-05-30 セントロ デ インヘニエリア ヘネティカ イ ビオテクノロヒア （セーイーヘベー） 上皮増殖因子の経口投与可能薬学的ペレット
US9981013B2 (en) 2010-08-30 2018-05-29 Sanofi-Aventis Deutschland Gmbh Use of AVE0010 for the treatment of diabetes mellitus type 2
US9821032B2 (en) 2011-05-13 2017-11-21 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for improving glycemic control as add-on therapy to basal insulin
EP2719393A1 (fr) * 2011-06-07 2014-04-16 Asahi Kasei Pharma Corporation Préparation pharmaceutique lyophilisée contenant du pth de pureté élevée et son procédé de production
US10683335B2 (en) 2011-06-07 2020-06-16 Asahi Kasei Pharma Corporation Freeze-dried preparation containing high-purity PTH and method for producing same
US10011643B2 (en) 2011-06-07 2018-07-03 Asahi Kasei Pharma Corporation Freeze-dried preparation containing high-purity PTH and method for producing same
EP3020409A1 (fr) * 2011-06-07 2016-05-18 Asahi Kasei Pharma Corporation Préparation lyophilisée contenant de l'hormone parathyroïdienne (pth) de haute pureté et son procédé de production
EP2719393A4 (fr) * 2011-06-07 2015-04-08 Asahi Kasei Pharma Corp Préparation pharmaceutique lyophilisée contenant du pth de pureté élevée et son procédé de production
WO2013016754A1 (fr) * 2011-08-01 2013-02-07 Monash University Procédé et formulation pour inhalation
AU2011374218B2 (en) * 2011-08-01 2017-05-11 Monash University Method and formulation for inhalation
US9408893B2 (en) 2011-08-29 2016-08-09 Sanofi-Aventis Deutschland Gmbh Pharmaceutical combination for use in glycemic control in diabetes type 2 patients
US9364519B2 (en) 2011-09-01 2016-06-14 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9987332B2 (en) 2011-09-01 2018-06-05 Sanofi-Aventis Deutschland Gmbh Pharmaceutical composition for use in the treatment of a neurodegenerative disease
US9839675B2 (en) 2013-02-04 2017-12-12 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US11596620B2 (en) 2013-03-13 2023-03-07 F. Hoffmann-La Roche Ag Formulations with reduced oxidation
CN110075293A (zh) * 2013-03-13 2019-08-02 霍夫曼-拉罗奇有限公司 氧化降低的配制剂
US9895423B2 (en) 2014-01-09 2018-02-20 Sanofi Stabilized pharmaceutical formulations of insulin aspart
US10610595B2 (en) 2014-01-09 2020-04-07 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US9895424B2 (en) 2014-01-09 2018-02-20 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US9839692B2 (en) 2014-01-09 2017-12-12 Sanofi Stabilized pharmaceutical formulations of insulin analogues and/or insulin derivatives
US10806770B2 (en) 2014-10-31 2020-10-20 Monash University Powder formulation
US9950039B2 (en) 2014-12-12 2018-04-24 Sanofi-Aventis Deutschland Gmbh Insulin glargine/lixisenatide fixed ratio formulation
US10434147B2 (en) 2015-03-13 2019-10-08 Sanofi-Aventis Deutschland Gmbh Treatment type 2 diabetes mellitus patients
US10159713B2 (en) 2015-03-18 2018-12-25 Sanofi-Aventis Deutschland Gmbh Treatment of type 2 diabetes mellitus patients

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