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• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
  • A61K39/39591—Stabilisation, fragmentation
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
  • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
  • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
  • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/08—Solutions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K39/00—Medicinal preparations containing antigens or antibodies
  • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

• the present invention relates to compositions comprising a protein and a polyoxyalkyl fatty acyl surfactant.
• protein drugs are delivered in the clinic through IV infusion, particularly for oncology drugs.
• protein drugs are developed for other diseases, such as rheumatoid arthritis or other autoimmune disorders, patients prefer self-administration at home. With the move from the clinic to the home, liquid formulations, where feasible, are the preferred delivery form.
• Surfactants in particular stabilize proteins by blocking the proteins’ access to hydrophobic surfaces (e.g. vial walls or air interfaces) on which they can adsorb, denature, and ultimately aggregate.
• hydrophobic surfaces e.g. vial walls or air interfaces
• surfactants have also been proposed to stabilize certain protein sub-regions or block protein-protein interactions that could also lead to denaturation, though this is not believed to be the dominant mechanism of action.
• the vast majority of products formulated with surfactants contain either a polysorbate (Polysorbate 80 or Polysorbate 20) or Poloxamer 188, as they have well-established safety profiles. While polysorbates and Poloxamer 188 have been utilized because of their safety in injectable formulations, they still have significant drawbacks, especially due to surfactant degradation.
• a series of surfactants that are built on common, inert building blocks for use in protein formulations has recently been developed as disclosed in WO 2017/044366.
• These novel surfactants comprise a fully-saturated alkyl chain, commonly found in natural lipids, an amino acid residue that could fine-tune the functionality of the surfactant, and a polyether non-ionic hydrophilic head group.
• These building blocks were combined through amide bonds to resist hydrolysis of the hydrophobe (compared to an ester bond), which has been implicated in polysorbate degradation.
• the use of these surfactants to stabilize proteins in aqueous solution is disclosed in WO 2017/044367.
• the concentration of the surfactant relative to the protein reported in the formulations of WO 2017/044367 is 1:200 or less and preferably 1 : 100 or less.
• the present invention relates to a composition
• a composition comprising a protein and a polyalkoxy fatty acyl surfactant compound of general formula I
• R 2 is H or a substituted or unsubstituted hydrocarbyl group
• X 1 is O or NH
• X 2 is O or NH
• n is 0 or an integer of 1-5
• R 3 is a polymeric group comprising polymerized units of general formula II and III
• weight ratio of said protein to said polyalkoxy fatty acyl surfactant is in the range of 200: 1 to 1000: 1.
• Surfactants of formula (I) have been found to exhibit a critical micelle concentration (the concentration above which a surfactant spontaneously assembles into micelles) that is lower than that of conventional surfactants such as polysorbates or Poloxamer 188.
• a lower critical micelle concentration is indicative of a stronger drive to assemble which may translate into a faster stabilization of an interface.
• a lower critical micelle concentration may explain the finding that surfactants of formual (I) approach surface equilibrium 1 to 2 orders of magnitude faster than the conventional surfactants and outcompete a protein at an interface, thus reducing the likelihood of protein aggregation.
• a polyalkoxy compound is a compound that contains one or more group having the structure -(-A-0) m - , where m is three or more, and A is an unsubstituted alkyl group.
• the group A may be linear, branched, cyclic, or a combination thereof.
• the various A groups among the various -(-A-O)- groups may be the same as each other or different.
• a fatty compound is a compound that contains one or more fatty group.
• a fatty group is a group that contains 8 or more carbon atoms, each of which is bonded to one or more of the other carbon atoms in the group.
• a polyalkoxy fatty compound is a compound that is both a polyalkoxy compound and a fatty compound.
• Number-average molecular weight is defined as the total weight of a sample divided by the number of molecules in the sample.
• a protein is a polymer in which the polymerized units are polymerized units of amino acids. The amino acids are bonded together by peptide bonds.
• a protein contains 20 or more polymerized units of one or more amino acid residues.
• the term protein includes linear polypeptide chains as well as more complex structures that contain polypeptide chains.
• a protein is considered to be in solution in a liquid medium (or, synonymously, dissolved in the liquid medium) if the molecules of the protein are distributed throughout the continuous liquid medium in the form of dissolved individual molecules.
• the protein is considered to be dissolved in water if the continuous liquid medium contains water in the amount of 60% or more by weight based on the weight of the continuous liquid medium.
• a chemical group is an ionic group if there is a pH value between 4.5 and 8.5 such that, when the chemical group is in contact with water at that pH value, 50 mole% or more of those chemical groups present are in ionic form.
• a buffer is either (i) a compound that has the ability to accept a proton to form the conjugate acid of that compound, and the conjugate acid of that compound has pKa of less than 10, or (ii) a compound that has the ability to release a proton, and the compound has pKa of greater than 4.
• R 1 is preferably a substituted or
• R 1 is an unsubstituted aliphatic group; more preferably, R 1 is an unsubstituted alkyl group.
• R 1 is a linear alkyl group with 9-22 carbon atoms, preferably 10-18 carbon atoms, more preferably 10-16 carbon atoms.
• R 2 has 20 or fewer atoms; more preferably 15 or fewer.
• R 2 contains one or more carbon atom.
• R 2 is either hydrogen or an unsubstituted hydrocarbon group; more preferably, R 2 is either hydrogen, an unsubstituted alkyl group, or an alkyl group whose only substituent is an unsubstituted aromatic hydrocarbon group.
• unsubstituted alkyl groups preferred is methyl.
• alkyl groups whose only substituent is an unsubstituted aromatic hydrocarbon group preferred is -CH 2 -(C 6 H 5 ), where -(C 6 H 5 ) is a benzene ring.
• R 2 represents a side chain of a naturally occurring amino acid.
• R 3 has a number-average molecular weight of 600-5000 Daltons, more preferably 800-3000 Daltons.
• the group R 3 is either a statistical copolymer of (II) and (III) or a block copolymer of (II) and (III); more preferably the group R 3 is a statistical copolymer of (II) and (III).
• -R 3 has the structure -R 4 -CH 3 , where R 4 is a polymeric group comprising polymerized units of structure (II) and structure (III).
• R 4 has no other polymerized units in addition to structure (II) and (III).
• R 1 is CH 3 -(CH 2 )n- CH 2 -, n is 1, X 1 and X 2 are both NH, R 2 is -CH 2 (C 6 H 5 ), and R 3 is a copolymer of PO and EO units capped with CH with an approximate number-average molecular weight of 1000 and ratio of PO to EO of 3: 19.
• This surfactant has been found to stabilize an interface 1 to 2 orders of magnitude faster than polysorbates or Poloxamer 188 which are the standard surfactants used to stabilize aqueous protein solutions. The faster dynamics have been found to lead to improved stabilization of model protein drugs against agitation induced aggregation.
• R 1 is CH 3 -(CH 2 )n-CH 2 -, n is 0, X 2 is NH, and R 3 is a copolymer of PO and EO units capped with CH 3 with an approximate number-average molecular weight of 1000 and ratio of PO to EO of 3: 19.
• the compound of formula (I) has no ionic groups.
• each X 3 is independently O or NH.
• the terminal X 3 is preferably O.
• Preferences for R 1 , X 2 , R 2 , R 3 , and n are the same as those described above.
• Preferably, X 3 is O.
• Another preferred method of making some embodiments of the compound of formula (I) is as follows.
• an acyl chloride is reacted with an amino acid to form a carboxyl- functional fatty amide as follows:
• PO is structure (II) and EO is structure (III).
• R 3 is shown as (PO) x and (EO) y in the structures above, it should not be taken as an indication that the PO and EO units invariably are present as blocks; indeed, they may also be randomly distributed throughout R 3 .
• Preferred proteins to be included in the present composition are selected from monoclonal antibodies, growth factors, insulins, immunoglobulins, polyclonal antibodies, antibody-drug conjugates, hormones, enzymes, polypeptides, fusions of peptides, glycosylated proteins, antigens, antigen subunits, or combinations thereof. Preferred proteins have therapeutic efficacy to treat a disease or medical condition or to function as vaccines.
• therapeutic proteins are immunoglobulin-g, adalimumab, interferon alfa, bevacizumab, human growth hormone, rituximab, human serum albumin, insulin, erythropoietin alpha, pembrolizumab, etanercept, filgrastim, nivolumab, trastuzumab, durvalumab, interleukin-2, infliximab, chorionic gonadotropin, avelumab, denosumab, ranibizumab, aflibercept, tremelimumab, factor viii, interferon beta, ipilimumab, atezolizumab, abatacept, tocilizumab, ustekinumab, pegfilgrastim, secukinumab, streptokinase, cetuximab, omalizumab, ramucirumab, urokinase
• the weight ratio of protein to compound of formula (I) is in the range of 250: 1 to 900:1, more preferably in the range of 300: 1 to 800: 1, in particular in the range of 400: 1 to 700:1.
• the weight ratio of protein to compound of formula (I) is in the range of 201 : 1 to 250: 1, preferably in the range of 205: lto 245: 1, more preferably in the range of 210:1 to 240: 1.
• the present invention relates to a composition as described above wherein the monoclonal antibody is cetuximab and wherein the ratio of cetuximab to polyalkoxy fatty acyl surfactant of formula (I) is from 300: 1 to 750: 1.
• the polyalkoxy fatty acyl surfactant is preferably a compound of formula (I) wherein R 1 is CH 3 -(CH 2 ) II -CH2-, n is 1, X 1 and X 2 are both NH, R 2 is -CH 2 (C 6 H 5 ), and R 3 is a copolymer of PO and EO units capped with CH 3 with an approximate number-average molecular weight of 1000 and ratio of PO to EO of 3: 19.
• a preferred method of making a composition that contains both a protein and a compound of formula (I) is to mix together water, one or more proteins, one or more compounds of formula (I), and optional additional ingredients to provide a composition in which the protein is dissolved in water.
• the protein molecules are not aggregated into large particles, even if the aggregated particles are dispersed in the liquid medium.
• the volume-average hydrodynamic radius of such particles is 10 nm or smaller; more preferably 6 nm or smaller.
• the present composition optionally contains one or more additional ingredients.
• Additional ingredients are compounds other than water, proteins, and compounds of formula (I).
• Preferred additional ingredients are sugars, sugar alcohols, salts, buffers, amino acids, salts of amino acids, and mixtures thereof.
• the total amount of all additional ingredients is 300 mg/mL or less.
• preferred amino acids and salts thereof are selected from lysine, glycine, arginine, histidine, and mixtures thereof.
• FM1000 is a surfactant compound of formula (I), wherein R 1 is CH 3 -(CH 2 )n-CH 2 -, n is 1, X 1 and X 2 are both NH, R 2 is -CH 2 (C 6 H 5 ), and R 3 is a copolymer of PO and EO units capped with CH 3 with an approximate molecular weight of 1000 and ratio of PO to EO of 3 : 19.
• FM1000 was prepared as reported in WO 2017/044366. Briefly, myristoyl chloride was amidated with phenylalanine in water in the presence of sodium hydroxide and triethylamine. The resulting suspension was acidified to pH 2 with concentrated HC1 and filtered.
• DLS Dynamic Light Scattering
• concentration of IgG was 20 mg/mL; the surfactant concentration was 0.05 mg/mL (ratio of protein to surfactant was 400:1).
• Polysorbate 20 was also studied as a control. 500 pL samples were shaken as in the other examples for 18 hrs. The data are as follows:
• the experiment was set up as in Example 3, but the solution contained 25 mM citrate (pH 6) rather than 0.9% sodium chloride.
• the concentration of IgG was 20 mg/mL; the surfactant concentration was 0.05 mg/mL (ratio of protein to surfactant was 400:1). Clarity was not measured for these samples.
• the data are as follows:
• Cetuximab is commercially available under the trade name Erbitux ® and was acquired from a pharmacy. It is formulated as a 2 mg/mL solution in 10 mM phosphate buffer and 145 mM sodium chloride, pH 7.2.
• the 7.5 mg/mL samples were concentrated via centrifugal filtration to 10 mg/mL and then diluted to 7.5 mg/mL.
• Surfactant stock solutions were prepared in 10 mM phosphate, 145 mM NaCl, pH 7.2. Each shaken sample was 3.0 mL in a 5 mL serum vial from Wheaton. Pre-shaken samples were aliquots removed to bring the shaken sample volume to 3 mL. Shaken samples were shaken overnight at 150 strokes/min on a reciprocal shaker.

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• 2019
  • 2019-09-06 CN CN201980059505.6A patent/CN112672734B/zh active Active
  • 2019-09-06 WO PCT/US2019/049904 patent/WO2020055679A2/en not_active Ceased
  • 2019-09-06 KR KR1020217007252A patent/KR20210056349A/ko not_active Withdrawn
  • 2019-09-06 JP JP2021513234A patent/JP2022500376A/ja active Pending
  • 2019-09-06 EP EP19773254.8A patent/EP3849519B1/en active Active
• 2024
  • 2024-09-12 US US18/883,173 patent/US20260115292A1/en active Pending

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