WO2024153784A1 - Use of butronics as small molecule solubilizers - Google Patents

Use of butronics as small molecule solubilizers Download PDF

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Publication number
WO2024153784A1
WO2024153784A1 PCT/EP2024/051237 EP2024051237W WO2024153784A1 WO 2024153784 A1 WO2024153784 A1 WO 2024153784A1 EP 2024051237 W EP2024051237 W EP 2024051237W WO 2024153784 A1 WO2024153784 A1 WO 2024153784A1
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small molecule
block copolymer
composition
butylene
anyone
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PCT/EP2024/051237
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French (fr)
Inventor
Meike Marie ROSKAMP
Sophia Ebert
Matthias KELLERMEIER
Felicitas Guth
Nadine LOEW
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Basf Se
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
    • C—CHEMISTRY; METALLURGY
    • C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
    • C08G—MACROMOLECULAR COMPOUNDS OBTAINED OTHERWISE THAN BY REACTIONS ONLY INVOLVING UNSATURATED CARBON-TO-CARBON BONDS
    • C08G65/00—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule
    • C08G65/02—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring
    • C08G65/26—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds
    • C08G65/2603—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen
    • C08G65/2606—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups
    • C08G65/2609—Macromolecular compounds obtained by reactions forming an ether link in the main chain of the macromolecule from cyclic ethers by opening of the heterocyclic ring from cyclic ethers and other compounds the other compounds containing oxygen containing hydroxyl groups containing aliphatic hydroxyl groups

Definitions

  • the present invention relates to the field liquid compositions, comprising a liquid, in particular aqueous mixture, more particularly aqueous solution, of at least one poorly water-soluble small molecule and at least one solubilizing surfactant,
  • Said surfactant is selected from a defined group of ethylene oxide/butylene oxide block copolymers (butronics).
  • Said ethylene oxide/butylene oxide block copolymers are capable to effectively solubilize poorly water-soluble small molecules while concomitantly conferring the composition superior properties in comparison to the presently known small molecule formulations, particularly with regard to water solubility, chemical stability and hemolytic activity.
  • Further embodiments of the invention relate to said group of block copolymers as well as to their use for solubilizing poorly water-soluble small molecules; methods for preparing said liquid compositions; the use of said compositions in medicine, in particular for diagnostic and/or therapeutic applications; essentially dry composition comprising said small molecule and said block copolymers; to method for preparing said dry compositions; the use of such dry compositions in medicine, in particular for diagnostic and/or therapeutic applications; pharmaceutical compositions comprising said liquid or dry compositions and optionally a pharmaceutically acceptable excipient; and to the use of said block copolymers for solubilizing said pharmaceutical formulation.
  • surfactants i.e. amphiphilic molecules bearing a polar head group and a non-polar tail part
  • amphiphilic molecules bearing a polar head group and a non-polar tail part are known for their capacity to influence the solubility of poorly water soluble drugs and thereby their bioavailability.
  • the effect is due to the formation of micelles in solution which reduce surface tension and improve the dissolution of lipophilic drugs.
  • Polysorbates and Poloxamers like Polysorbate 20 (POE sorbitan monolaurate, PS20) and Polysorbate 80 (POE sorbitan monooleate, PS80) and Poloxamer 188, are known which may enhance the solubility of lyophilic drugs.
  • Polysorbates are highly efficient, but difficult to manage due to their complex composition. Their multi-component nature makes them difficult to describe, control and it presents a particular challenge to monitor stability and degradation products.
  • hydrolytic degradation due presence of ester groups which themselves may react with the active ingredient is common, and poses major challenges in the widespread applicability of Polysorbates as excipient for pharmaceutical formulations.
  • the chemical stability of the surfactants used in the formulation is therefore a key aspect to be considered in the preparation of the specific excipient formulation of choice.
  • Poloxamer 188 a non-ionic surfactant with a more defined chemical structure and a better chemical stability (no ester-bonds), has been used as an alternative to Polysorbates. However, Poloxamer 188 is in general not as effective as a solubilizer.
  • Poloxamer 188 cannot match that of Polysorbates, for example in the presence of residual silicon oil traces in pre-filled syringes (Grapentin, C. et al., Protein-Polydimethylsiloxane Particles in Liquid Vial Monoclonal Antibody Formulations Containing Poloxamer 188. Journal of Pharmaceutical Sciences, 2020).
  • Poloxamers can be improved by adopting derivatives with higher molecular weight.
  • the latter solution is however less desirable due to otherwise poor clearance properties.
  • Block-copolymers characterized by the presence of short hydrophilic blocks relative to the length of the hydrophobic block are known for their capacity to form wormlike micelles with high solubilization capacity for poorly soluble aromatic drugs (Colloid Stability and Application in Pharmacy, edited by Tharwat F. Tadros, Weinheim 2007).
  • Solubilization of naphthalene in aqueous solution by a triblock copolymer of ethylene oxide and 1 ,2-butylene oxide of molecular weight 7100 g/mol and 80 wt.-% EO is described (C. Chaibundit, Journal of Science and Technology 2003, 25 (6), 783-790). Solubilization of benzene with a butronic of molecular weight of 2325 g/mol, and 70% EO was also shown (S. Xi, Langmuir 2019, 35, (14), 5081-5092).
  • butronic ethylene oxide and butylene oxide triblock copolymers with an inner butylene oxide block
  • Griseofulvin solubilization with one particular butronic having a molecular weight of 4790 g/mol and 80 wt.-% EO (EO43-BuO14-EO43) is described (D. Attwood, C. Booth: “Solubilization of a poorly soluble aromatic drug by micellar solutions of amphiphilic block copoly(oxyalkylene)s” Colloid Stability and Application in Pharmacy, edited by Tharwat F. Tadros, Weinheim 2007, and M. Crothers et al. International Journal of Pharmaceutics, 2005, 293 (1-2), 91-100).
  • Copolymer A and C are expected to be associated with a disadvantageously low solubilization performance, respectively, due to lower molecular weight or to lower surface activity resulting from high %EO.
  • Copolymer B is expected to be hemolytically too active due to the comparatively lower molecular weight.
  • Copolymer D does not result in clear solutions even at a content of 5wt% in water.
  • EP 3 378 493 relates to a nanoparticle compositions, comprising an active pharmaceutical ingredient and a polyethylene glycol-polybutylene glycol copolymer, which can be triblock copolymers ethylene oxide and butylene oxide with an inner butylene oxide block (cf. PEG-PBG copolymer of Formula III).
  • a polyethylene glycol-polybutylene glycol copolymer which can be triblock copolymers ethylene oxide and butylene oxide with an inner butylene oxide block (cf. PEG-PBG copolymer of Formula III).
  • PEG-PBG copolymer of Formula III inner butylene oxide block
  • a problem to be solved by the present invention is to provide a polymer surfactant which avoids the above problems as associated with the use of prior art butronics asa discussed in the prior art.
  • a further problem relates to the identification of polymer surfactants which besides the above mentioned higher solubilization properties are further characterized by a defined chemical structure and stability as compared to surfactants of the Kolliphor or Poloxamer type, and show good solubility in water combined with low to no hemolytic activity and surface tension comparable to that of Polysorbates and/or butronics described in the prior art.
  • butronics presenting a) a calculated molecular weight of 4.9kDa to 9.7kDa, particularly of 5kDa and 9kDa; more particularly 5.5kDa to 8.5kDa; and b) an EO% content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, especially 55 to 65 wt.-%, each based on the dry weight of said butronic.
  • butronics solubilize poorly water soluble small molecules at least as good as, and in some cases better, than the current best in class surfactants such as Kolliphor® EL or Kolliphor® ELP and Polysorbates while at the same time being less hemolytically active despite a similar surface activity.
  • API in the context of the present invention relates to “small molecule” based active pharmaceutical ingredients. They are thus readily distinguishable from biopolymer-based APIs, like for example proteins and nucleic acids, which are characterized by a much higher molecular weight.
  • the terms “about” or “approximately” indicate a potential variation of ⁇ 25% of the stated value, in particular ⁇ 15% or ⁇ 10 %, more particularly ⁇ 5%, ⁇ 2% or ⁇ 1 %.
  • the term “substantially” describes a range of values of from about 80 to 100%, such as, for example, 85-99.9%, in particular 90 to 99.9%, more particularly 95 to 99.9%, or 98 to 99.9% and especially 99 to 99.9%.
  • “Predominantly” refers to a proportion in the range of above 50%, as for example in the range of 51 to 100%, particularly in the range of 75 to 99,9%; more particularly 85 to 98,5%, like 95 to 99%.
  • halogen denotes in each case a fluorine, bromine, chlorine or iodine radical, in particular a fluorine radical.
  • Alkyl relates to a straight-chain or branched alkyl group having from 1 to 10, in particular 1 to 8, more particularly 1 to 4, 1 to 2 carbon atoms.
  • Example are methyl, ethyl, n-propyl, n-butyl, n-hexyl, n-heptyl or n-octyl.
  • Alkylene relates to a straight-chain or branched hydrocarbon bridging group having from 1 to 22, or 2 to 22, 1 to 6, 3 to 6, 2 or 4, carbon atoms.
  • Non limiting examples are -CH 2 -, -(CH 2 ) 2 -, -(CH 2 ) 3 -, -(CH 2 ) 4 -, -(CH 2 ) -, -(CH 2 )I 5 -, -(CH 2 ) 20 -, -(CH 2 ) 22 - and the respective branched analogues thereof.
  • alkylene groups may be interrupted by one or more heteroatoms, such as oxygen.
  • Alkyleneoxy relates to a radical of the formula -R-O-, wherein R is a straightchain or branched alkylene group having from 1 to 22, or 2 to 22, 1 to 6, 3 to 6, 2 or 4, carbon atoms as defined herein.
  • a “polyalkylene oxide” relates to a group in which at least two, identical or different repeating units of alkyleneoxy groups as defined above are covalently linked.
  • a “liquid composition” is to be interpreted broadly, and particularly refers to aqueous solutions of the block copolymer and small molecule as defined herein, wherein micellar structures of identical or different geometry as formed by the butronic molecules may be present.
  • a liquid composition of the invention encompasses aqueous solutions, in particular clear or transparent or slightly opalescent aqueous solutions of the block copolymer and small molecule at different viscosities. In that respect, nanoparticle solutions are not to be encompassed within the scope of the present disclosure.
  • “Block copolymer” defines a macromolecular entity characterized by at least two alternating structurally different polymer blocks; wherein each block consists essentially of structurally analogous, in particular identical repeating monomeric units. Within the structure of said block copolymer may optionally be present chemical moieties linking two or more alternating blocks, such as polyvalent, as for example di- or trivalent organic or inorganic moieties.
  • butronic is to be broadly interpreted and generally refers to block copolymers essentially consisting of alternating butylene oxide bocks and ethylene oxide bocks and presenting an molar ethylene oxide content (EO%) of about 10 to less than 100 mol%, as well as a molecular weight of 1.000 and 15.000 g/mol.
  • Particular butronics within the meaning of the invention present an EO% of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer in combination with a calculated molecular weight of 4kDa to 10kDa, particularly of 5kDa to 9kDa. More particular butronics within the meanings of the invention are exemplified in the general part and the experimental section below.
  • Relative solubilizing ability (RSA) is preferably to be interpreted as the ability of a butronic as defined herein above to solubilize a given small molecule within the meaning of the present invention at room temperature, and can be expressed as:
  • Cr is the saturation concentration of said small molecule in a 10% wt.-% buffered solution of a reference excipient being Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: Polyoxyl 35 Castor Oil).
  • the saturation concentrations Cs and Cr may be determined using any suitable quantitative analytical technique known in the art such as by RP-HPLC under standard conditions.
  • Example of said standard conditions which may be employed for the determination of the relative solubilizing ability are given in the experimental part (see A.3).
  • the pH of the buffered solution of the test sample is not critical and may vary depending on the specific small molecule-based API and/or reference excipient used.
  • Example of suitable pH values of said buffered solutions are pH comprised in the range of 5.7 to 9, particularly 6.8 to 8 and more particularly 7.0 to 7.6.
  • a “reference excipient” is preferably to be interpreted as a polyoxyethylene castor oil compound made by reacting castor oil with ethylene oxide in a molar ratio of 1 :35. Said compound is commonly designated as Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: “Polyoxyl 35 Castor Oil” or “Macrogolglycerol Ricinoleate” according to European pharmacopoe. Thus the terms’ “Polyoxyl 35 Castor Oil” or “Macrogolglycerol Ricinoleate” can be used interchangeably in the context of the present invention.
  • Polyoxyethylenglycerol triricinoleate 35 is a constituent of commercial product sold under the registered trademark Kolliphor® EL or Kolliphor® ELP.
  • Kolliphor® ELP is a purified version of Kolliphor® EL.
  • Kolliphor® ELP is particularly suited for use in parenteral applications.
  • As a non-ionic oil-in-water emulsifier and/or solubilizer is has found broad use with sensitive APIs, demonstrating very high solubilization capacity along with good compatibility with other ingredients.
  • a “small molecule” within the meaning of the present invention is to be interpreted broadly and refers to natural (i.e. biological) or artificial, inorganic, organic or organometallic small molecules which by virtue of their hydrophobicity or degree of crystallinity are characterized by a “low solubility” in water. Such small molecules may show pharmaceutical (i.e. prophylactic, therapeutic, diagnostic or even theranostic activity or even my even be pharmaceutically essentially or fully inactive.
  • acceptors of hydrogen bonds e.g. oxygen or nitrogen atoms
  • acceptors of hydrogen bonds e.g. oxygen or nitrogen atoms
  • Such “small molecule” are those classified according to the Biopharmaceutics Classification System (BCS) as having high permeability, low solubility (BCS class II) or low permeability, low solubility (BCS class IV).
  • BCS Biopharmaceutics Classification System
  • low solubility is to be interpreted broadly and preferably refers to a solubility of
  • “Static surface tension” within the meaning of the invention is to be preferably interpreted as the amount of energy per unit of surface area required to cause a deformation, such as a local increase, of the surface of a liquid sample presenting a given concentration of solute at the thermodynamic equilibrium at a predetermined temperature.
  • the “static surface tension” is measured in milliNewton per meter (mN/m) and is determined by means of the pendant drop technique.
  • “Ethylene oxide content” (EO%) and “butylene oxide content” (BuO%) within the meaning of the invention are stated herein as either mole % (mol%) or as weight percentage (wt.-%) of ethylene oxide and butylene oxide monomer units within a given block copolymer as herein defined. If not otherwise stated “%” refers to wt.-%.
  • EO% calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 refers to a wt.-% value obtained according to the following formula:
  • a calculated molecular weight of x to y g/mol encompasses the integers x, y and any integer between x and y.
  • a molecular weight of ”4.000 to 10.000 g/mol encompasses the integers:
  • Hemolysis within the meaning of the invention relates to the tendency of a given excipient to cause breakdown of cells, particularly of red blood cells with consequent release of intracellular components.
  • biopolymer encompasses molecules, selected from oligopeptides, polypeptides, proteins, any type of antibody molecule or fragment or derivative thereof as defined below, glycosylated proteins, proteoglycans, oligo- and polynucleotides, DNA and RNA molecules, oligosaccharides, polysaccharides, as well as adducts or conjugates of such biopolymers, in particular of antibodies, with a further constituent selected from payload molecules as further defined below.
  • the “logP” (synonym “Pow”) parameter is the decadal logarithm of the partition coefficient P.
  • the logP value can be determined mathematically (e.g. XLogP) and experimentally.
  • the P-value is usually determined as the ratio of the concentrations of a compound to be analysed in a phase with n-octanol and a phase with water.
  • Experimental details are described in OECD Guidelines for the Testing of Chemicals, 107, adopted 27.07.1995, Partition Coefficient (n-octanol/water): Shake Flask Method. C. Particular aspects and embodiments of the invention
  • the invention relates to a liquid composition, comprising a liquid, in particular aqueous mixture, more particularly aqueous solution, of at least one small molecule and at least one ethylene oxide/butylene oxide block copolymer of the general formula 1
  • X represents -O-; or a divalent organic moiety, in particular a moiety originating from an organic molecule comprising two active hydrogen atoms, such as -O-(C2 -C4-alkylene)-O-, ;
  • m independently represents an integer in the range of 4 to 25, like 10 to 22, 12 to 18 or an integer selected from 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18,19, 20, 21 , 22, 23, 24 or 25; and
  • n independently represents an integer in the range of 15 to 100, like 20 to 80 or 25 to 70, 30 to 60 or 35 to 65, or an integer selected from 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30; 31 , 32, 33, 34, 35, 36, 37,
  • said block copolymer shows a combination of the following features a) a calculated molecular weight of 4.000 to 10.000 g/mol, particularly 4.500 to 9.500 g/mol, more particularly 4.800 to 9.700 g/mol, especially 5.000 to 9.000 g/mol or 5.500 to 8.500 g/mol, in particular calculable from the sum of atomic masses of all atoms of the copolymer molecule of formula 1 ; and b) an EO content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer, in particular calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 .
  • Said ethylene oxide/butylene oxide block copolymer formally may also be designated as “triblock polymers”, as they contain
  • said block copolymer shows at least one of the following additional features: c) a water solubility of at least 5 wt.-%, or more particularly at least 10% based on the total weight of the aqueous solution of the block copolymer; d) an aqueous solution of said block copolymer (concentration 0.1 g/l) has a surface tension SFT of less than 60 mN/m to more than 25 mN/m, in particular of 53 to 30 mN/m, like, for example, of about 35, about 40, about 45 of about 50 mN/m; and e) lack of hemolytic activity, in particular less than 10% or more particularly less than 5%, or less than 1 , 2, 3 or 4% hemolysis, like 0 % or 0.1 to 0.9% hemolysis caused by a solution of 10Og/l block copolymer.
  • a particular subgroup of block-copolymers shows a combination of anyone of the above features a), b) and e).
  • a particular subgroup of blockcopolymers shows a combination of anyone of the above features a), b), c) and e).
  • a particular subgroup of blockcopolymers shows a combination of anyone of the above features a), b), c), d) and e).
  • said block copolymer may be characterized by a relative solubilizing ability (RSA) of a small molecule in the range of 5% to 200%, said relative solubilizing ability being expressed as:
  • Cs is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of said block copolymer
  • Cr is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of a reference excipient being a Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: Polyoxyl 35 Castor Oil); wherein
  • Cs and Cr are determined by HPLC method under standard conditions; and said block copolymer and reference excipient solution presents a pH comprised in the range of 5.7 to 9, particularly 6.8 to 8 and more particularly 7.0 to 7.6.
  • More particularly said relative solubilizing ability as defined above may be in the range of 5% to 200%, or 15% to 200% or 25% to 200%, or 35% to 200% or 50% to 200%, or 65% to 200%, 80% to 200, or 95 to 200%, and especially 100% to 200%, such as 120% to 200% or 140% to 200%, or 160% to 200%.
  • a liquid composition comprising an aqueous solution of at least one small molecule and at least one ethylene oxide/butylene oxide block copolymer of the general formula 1
  • X represents -O- or a divalent organic moiety
  • m independently of each other represent an integer in the range of 4 to 25
  • n independently of each other represent an integer in the range of 15 to 100
  • said small molecule has a molecular weight of 1.500g/mol or less
  • said block copolymer shows a combination of the following features: a) a molecular weight 4.900 to 9.700 g/mol, particularly 5.000 to 9.000 g/mol, more particularly 5.000 to 8.500 g/ml and especially 5.500 to 8.500; each calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ; b) an EO content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, and especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer; each calculable from the atomic
  • a liquid composition wherein X is selected from -O-; -O-alkylene-O-, in particular -O-(C2-C22-alkylene)-O-, more particularly -O-(Cs -Ce-alkylene)-O-, wherein the alkylene chain is straight-chained or branched, and is optionally interrupted by one or more heteroatoms, in particular oxygen atoms; more particularly -O-, -O-(n-butylene)-O-, -O-(1 ,2-butylene)-O-, a group of formula 2 below, and especially -O-(n-butylene)-O- or a group of the formula 2
  • Said block copolymer may be selected from the following compounds of the general formula 1 , wherein X, m and n have the following meanings:
  • a liquid composition wherein the block copolymer is selected from the following compounds of the general formula 1 , wherein X, m and n have the following meanings:
  • a liquid composition wherein said block copolymer of the general formula (I) is contained in a proportion of 0,001 to 20% or 0,001 to 15%, more particularly 0,001 to 10%, like 0,01 to 8%, 0,1 to 5% or 1 to 3%, each based on the total weight of the liquid composition.
  • a liquid composition said block copolymer it capable to solubilize the small molecule with an increase of 1000-fold compared water, particularly of 10000 fold, more particularly.
  • a liquid composition in which said small molecule is contained in a proportion of 0,0001 to 10wt%, particularly of 0,01 to 8%, more particularly about 0,03% to 6%, based on the total weight of the liquid composition.
  • a liquid composition is provided, which is optionally in buffered form, having a pH in the range of 5 to 9, particularly 6, 7 or 8.
  • said small molecule may be characterized by one or more of the following properties: a) solubility in water comprised in the range of 1 .0 *10 -6 to 20 mg/L, particularly of 2.0*1 O' 6 to 10 mg/L; more particularly 2.5*1 O' 6 to 9 mg/L, yet more particularly of less than 100 ng/L; and/or b) molecular weight comprised in the range of 100 to 1000 g/mol, particularly 200 to 950 g/mol, more particularly 250 to 880 g/mol.
  • said small molecule may be selected from: a) pharmaceutically active compounds (APIs), including prophylactically, therapeutically, diagnostically or even theranostically active compounds; examples of diagnostically active compounds are labelling agents as defined more detailed below; and b) artificial or synthetic inorganic, organic or organometallic small molecules, or natural or biological small molecules, such as lipids, phospholipids, glycolipids, sterols, vitamins, hormones, neurotransmitters, monosaccharides, which in turn may be either pharmaceutically active or essentially inactive.
  • APIs pharmaceutically active compounds
  • diagnostically active compounds are labelling agents as defined more detailed below
  • said artificial or synthetic small molecules are organic or organometallic small molecules.
  • Organic small molecules do not encompass oligo- or polypeptides and oligo- or polynucleotides.
  • Said particular small molecule may preferably be a diagnostically applicable or a therapeutically active small molecule.
  • the small molecule belongs to BCS class II and particularly is selected from the group Aceclofenac; Asciminib; Atorvastatin Calcium; Budesonide; Cefuroxime; Chlorzoxazone; Clonazepam; Clopidogrel; Clozapine; Daclatasvir; Danazol; Dexlansoprazole; Dextromethorphan hydrobromide: Diacerien; Diclofenac Sodium; Dolutegravir Sodium; Efavirenz; Enzalutamide; Eplerenone; Etoricoxib; Felodipine; Fenofibrate; Gefitinib; Ibrutinib; Ibuprofen; Indinavir Sulfate; Ketoprofen; Ivermectin; Lansoprazole; Mebendazole; Montelukast Na; Naproxen; Nicardipine; Nifedipine; Nitrofurantoin; Obeticholic acid; Olanzapine
  • the small molecule belongs to BCS class VI and particularly is selected from the group Abiraterone acetate; Acetazolamide; Albendazole; Aprepitant; Aripiprazole; Avacopan; Avapritinib; Ciprofloxacin HCI; Digoxin; Docetaxel; Erythromycin Succinate; Haloperidol; Hydrochlorothiazide; Mesalamine; Paclitaxel; Ponesimod; Relugolix; Ritonavir; Saquinavir; Sulfasalazine; Tivozanib; Verapamil HCI
  • the invention relates to an essentially dry small molecule composition, comprising at least one essentially dry small molecule as defined in the above-identified first aspect and at least one ethylene oxide/butylene oxide block copolymer of the general formula (1) as defined in the above-identified first aspect.
  • said essentially dry essentially dry small molecule composition has a liquid content of 0% to 5% wt.-%, as for example 0,1 to 4,5 wt.-%,, like 1 , 2, 3 or 4 wt.-%, based on the total weight of said composition.
  • said essentially dry essentially dry small molecule composition is characterized in that said block copolymer and said at least one essentially dry small molecule together are contained in a proportion of 1 to less than 100 wt.-%, in particular 5 to 60 wt.-%, more particular 10 to 50 wt.-%, or 20 to 40 wt.-% or even 20 to 25wt.-% based on the total weight of said essentially dry composition.
  • said essentially dry composition comprises at least one further excipient in a proportion of 0,1 to 99%, 40 to 95% and 50 to 90% wt.-% based on the total dry weight of said essentially dry composition.
  • said pharmaceutical composition is a parental formulation.
  • said pharmaceutical composition is an intravenous, intra-arterial, intracutaneous, intramuscular, intrathecal, intracardiac, intravitreal, intraosseous, intraperitoneal, subcutaneous, inhalation, urinary bladder, intranasal or topical formulation.
  • said pharmaceutical composition is in the form of a two-part-pharmaceutical composition comprising, separated from each other: a) at least a small molecule as defined in the first aspect; and b) at least one block copolymer as defined in the first aspect; and optionally c) at least one pharmaceutically acceptable excipient, optionally separated from a) and b) or in admixture with a) and/or b).
  • the invention relates to the use of a block copolymer as defined herein above in the first aspect for solubilizing at least one small molecule as defined in the first aspect.
  • the invention relates to the use of a block copolymer as defined herein above in the first aspect for solubilizing a pharmaceutical formulation of at least one small molecule as defined in the first aspect.
  • the invention relates to a composition as defined in the first or second aspect, or the pharmaceutical composition as defined in the third aspect for use in medicine, in particular for diagnostic and/or therapeutic applications.
  • the invention in a seventh aspect relates to a method of preparing a composition of as defined above in the first aspect, which method comprises a) preparing in any order an aqueous, optionally buffered solution of the of the block copolymer of general formula (1); and b) adding said small molecule as defined above in the first aspect.
  • the invention relates to a method of preparing a dry composition of as defined above in the second aspect, which method comprises a) preparing in any order an aqueous, optionally buffered solution of the of the block copolymer of general formula (1); and b) adding said small molecule as defined in the first aspect, thereby obtaining a block copolymer liquid preparation comprising the small molecule; c) optionally supplementing the aqueous, optionally buffered solutions prepared in step a) and/or the block copolymer liquid preparation comprising the small molecule prepared in step b), with at least one pharmaceutically acceptable excipient; d) drying the mixture obtained in step b) or c).
  • drying step d) is performed by conventional, well-known methods.
  • the drying step d) is performed by spray-drying or freeze-drying the mixture obtained in step b) or c).
  • a ninth aspect the invention relates to a block copolymer selected from the following compounds of the general formula (I), wherein X, m and n have the following meanings:
  • Particular polymer compounds of the general formula 1 are those, wherein X, m and n have the following meanings:
  • said block copolymers may, for example be prepared by a multistep protocol which foresees a first step in which an organic molecule comprising two active hydrogen atoms, like 1 ,4-butane diol or 1 ,3-butane diol, and butylene oxide are condensed to form a polyoxybutylene. Thereafter, ethylene oxide is added and the reaction is let to proceed until the desired oxyethylene content is reached.
  • butylene oxides examples include 1 ,2-butylene oxide and 2,3-butylene oxide.
  • the reaction is preferably carried out under moisture-free conditions at elevate temperature and in presence of a suitable catalyst such as an alkali metal hydroxide or alkoxide, like alkali metal tert, butoxide.
  • a suitable catalyst such as an alkali metal hydroxide or alkoxide, like alkali metal tert, butoxide.
  • the reaction can be carried out in presence of water, whereas reacting butylene oxide with water (in particular originating from an aqueous catalyst solution, or water contained in the starter or EO or BuO as added to the reaction (as further detailed in the experimental section below) forms in situ an organic molecule with two active hydrogen groups, e.g. 1 ,2-butane diol (in analogy to the disclosure in CA 698,568).
  • water in particular originating from an aqueous catalyst solution, or water contained in the starter or EO or BuO as added to the reaction (as further detailed in the experimental section below) forms in situ an organic molecule with two active hydrogen groups, e.g. 1 ,2-butane diol (in analogy to the disclosure in CA 698,568).
  • the amount of catalyst employed should be from 0.05 to 1 percent by weight based on the total reactants. Reaction temperatures are in the range of from 80° to 200° C., with a temperature of about 110°C or 170°C being preferred during most of the reaction.
  • the alkylene oxides employed are preferably substantially anhydrous, e.g. the moisture content of the oxides ordinarily should not exceed about 0.1 percent by weight.
  • the alkylene oxides are also preferably as free as practical from contaminants, such as aldehydes, which give rise to side reactions and by-product formation.
  • the reaction may be conducted either batch-wise or continuously as desired.
  • the commercially anhydrous organic molecule comprising two active hydrogen atoms, like 1 ,4-butane diol or butylene glycol is charged into a suitable dry reaction vessel, such as an autoclave, and mixed with an effective amount of catalyst, usually about 0.2 wt.-% of potassium hydroxide in terms of the total amount of reactants.
  • the reaction vessel Prior to the introduction of butylene oxide, the reaction vessel is advantageously flushed with a stream of dry inert gas, such as nitrogen, to remove any air or oxygen therefrom.
  • a stream of dry inert gas such as nitrogen
  • the mixture of -potassium hydroxide and said organic molecule comprising two active hydrogen atoms like 1 ,4-butane diol or butylene glycol, is heated to a reaction temperature of about 140°C and butylene oxide is added at a fairly rapid rate.
  • the rate of addition of butylene oxide is such as to maintain a pressure of about 3 bar in the reactor. Vigorous agitation is desirable to maintain a good dispersion of catalyst and uniform reaction rates throughout the mass.
  • reaction temperature By controlling the rate of addition of butylene oxide to maintain the pressure fairly constant, the reaction temperature may also be maintained constant.
  • butylene oxide is stopped upon obtaining the desired molecular weight of the polyoxybutylene glycol condensation product as determined by, for example, hydroxyl analysis or 1 H-NMR reckoning two free hydroxyl groups per molecule. Thereafter, ethylene oxide is condensed with the polyoxybutylene glycol condensation product to give a product in accordance with the invention. The addition of ethylene oxide is carried out in the same manner as the addition of butylene oxide already described.
  • Purification may be conducted by heating it at a reduced pressure under reflux or by stripping with inert gas to distill off any low boiling material.
  • Labeling agents which may be used as small molecule within the meanings of the present invention can comprise any type of label known in the art.
  • dyes e.g. fluorescent, luminescent, or phosphorescent dyes (e.g. fluorescent, luminescent, or phosphorescent dyes), such as dansyl, coumarin, fluorescein, acridine, rhodamine, silicon-rhodamine, BODIPY, or cyanine dyes), molecules able to emit fluorescence upon contact with a reagent, chromophores (e.g., phytochrome, phycobilin, bilirubin, etc.), radiolabels (e.g.
  • radioactive forms of hydrogen, fluorine, carbon, phosphorous, sulphur, or iodine such as tritium, fluorine-18, carbon-11 , carbon-14, phosphorous-32, phosphorous-33, sulphur-33, sulphur-35, indium-111 , iodine-123, or iodine-125), MRI-sensitive spin labels, affinity tags (e.g.
  • exemplary dyes can include an NIR contrast agent that fluoresces in the near infrared region of the spectrum.
  • exemplary near-infrared fluorophores can include dyes and other fluorophores with emission wavelengths (e.g., peak emission wavelengths) between about 630 and 1000 nm, e.g., between about 630 and 800 nm, between about 800 and 900 nm, between about 900 and 1000 nm, between about 680 and 750 nm, between about 750 and 800 nm, between about 800 and 850 nm, between about 850 and 900 nm, between about 900 and 950 nm, or between about 950 and 1000 nm.
  • Fluorophores with emission wavelengths (e.g., peak emission wavelengths) greater than 1000 nm can also be used in the methods described herein.
  • exemplary fluorophores include 7-amino-4- methylcoumarin-3 -acetic acid (AMCA), TEXAS REDTM (Molecular Probes, Inc., Eugene, Oreg.), 5-(and -6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and -6)- carboxyfluorescein, fluorescein-5-isothiocyanate (FITC), 7-diethylaminocoumarin-3- carboxylic acid, tetramethylrhodamine-5-(and -6)-isothiocyanate, 5 -(and -6)- carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5- (and -6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3- indacen
  • Further labelling agents are 111-lndium, 64-Copper, 67-Copper, 124-lodine, 227- Thorium, 188-Rhenium, 177-Lutetium, 89-Zirkonium, 131-lod, 68-Gallium, 99m- Technecium, 225-Actinium, 213-Bismut, 90-Ytrium and 212-Plumbum.
  • compositions comprising at least one small molecule as pharmaceutically active ingredient
  • pharmaceutical compositions comprised of a “therapeutically” and/or “prophylactically effective amount” or a “diagnostically” effective amount or theranostically” effective amount of at least one such active ingredient or its pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable excipient.
  • composition designates a liquid composition comprising or essentially consisting of at least one pharmaceutically active small molecule (i.e. the active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
  • a dried powder of such liquid preparation can be obtained by lyophilization or any other suitable drying method that is typically applied.
  • Non-limiting examples of such pharmaceutical compositions are:
  • compositions comprising or essentially consisting of at least one therapeutically active small molecule (i.e. the active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
  • Prophylactic compositions comprising or essentially consisting of at least one prophylactically active small molecule (i.e. the active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
  • at least one prophylactically active small molecule i.e. the active ingredient
  • at least one pharmaceutically inactive small molecule optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
  • Diagnostic compositions comprising or essentially consisting of at least one diagnostically active small molecule (i.e. the active ingredient, like for example at least one labelling agent), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
  • Theranostic compositions comprising or essentially consisting of at least one therapeutically active small molecule (i.e. a first active ingredient), and at least one diagnostically active small molecule (i.e. a second active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
  • Said pharmaceutical compositions may be delivered via suitable routes of administration such as via oral, rectal, transmucosal, topical, ophthalmic, otologic, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, as the case may be.
  • suitable routes of administration such as via oral, rectal, transmucosal, topical, ophthalmic, otologic, or intestinal administration
  • parenteral delivery including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, as the case may be.
  • said at least one additional pharmaceutical excipient may be different
  • excipient is a substance formulated alongside the active ingredient and is included for different purpose, as for example for long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred to as “bulking agents", “fillers”, or “diluents”), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as for example facilitating drug absorption, reducing viscosity, or enhancing solubility.
  • Excipients can also be useful in the manufacturing process of the pharmaceutical composition, to aid in the handling of the active substance concerns such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The selection of appropriate excipients not only depends upon the route of administration and the dosage form, but also on the particular active ingredient and other factors.
  • Excipients may be selected from the following classes: immunological adjuvants, antiadherents, binders, coatings, colours, disintegrant, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles
  • Non limiting examples of excipients comprise diluents, preserving agents, stabilizers, emulsifying agents, like emulsifying polymers, such as Polysorbates or Poloxamers, antioxidants, as for example chemical compounds, like epigallocatechin-3- O-gallate, lycopene, ellagic acid, coenzyme Q , indole-3-carbinol, genistein, quercetin, ascorbic acid, glutathione, melatonin, catechin, taurine, captopril, gallic acid, N-acetyl cysteine, a-lipoic acid, BHT, tocopherols and tocotrienols, or enzymes like superoxide dismutase and catalase; anti-irritants, chelating agents and stabililizing salts, such as chlorides, sulfates, phosphates, diphosphates, hydrobromides and nitrates, suspending agents, antibacterial agents or anti
  • buffering agents such as buffering systems of low molecular weight organic acids together with the respective salts, or inorganic buffering substances, such as phosphate buffers, can be used
  • suitable ingredients are also known from relevant pharmacological standard literature.
  • proportion of the various components will vary depending on the nature of the specific component used and is generally known to the person skilled in the art (Remington's Pharmaceutical science ("Handbook of Pharmaceutical Excipients", 2nd Edition, (1994), Edited by A Wade and PJ Weller or in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985).
  • a pharmaceutical composition as used herein may be presented in the form of a “dosage form” or “unit dose” and may comprise one or more liquid composition, or essentially dry composition comprising at least one pharmaceutically active small molecule compound and at least one EO/BuO block copolymer as described herein.
  • a pharmaceutical composition as used herein could, for example, provide two active agents admixed together in a unit dose or provide two active agents combined in a dosage form wherein the active agents are physically separated.
  • said pharmaceutical composition may also be in the form of a two forms composition, i.e. a composition in which the active ingredient (i.e. the small molecule), the EO/BuO block copolymer and/or optionally a pharmaceutically acceptable excipient are physically separated from one another.
  • a two forms composition i.e. a composition in which the active ingredient (i.e. the small molecule), the EO/BuO block copolymer and/or optionally a pharmaceutically acceptable excipient are physically separated from one another.
  • compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, emulsifying, encapsulating, entrapping or or combinations thereof. Proper formulation is dependent upon the route of administration chosen.
  • phrases "pharmaceutically acceptable” is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable risk/benefit ratio.
  • the invention includes all “pharmaceutically acceptable salt forms” of the active ingredient.
  • Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate.
  • Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
  • a “diagnostically effective amount” means an amount effective to allow obtaining from the patient a diagnostically valuable information on status or progression of a disease state.
  • a therapeutic benefit may be an amelioration of symptoms of a diseased patient, e.g., an amount effective to decrease the symptoms of a diseased patient.
  • a patient may not present symptoms of a condition for which the patient is being treated.
  • a prophylactically effective amount of a compound is also an amount sufficient to provide a significant positive effect on any indicia of a disease, disorder or condition e.g. an amount sufficient to significantly reduce the frequency and severity of disease symptoms to occur.
  • a therapeutically effective amount can also be an amount, which is prophylactically effective.
  • a “patient” as used herein means human or non-human, in particular human, animals.
  • a "dosage form” is any unit of administration (“unit dose”) of one or more active agents as described herein.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • treating refers to: (i) preventing a disease, disorder or condition from occurring in a patient which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition.
  • a prophylactic or therapeutic treatment or combinations thereof are examples thereof.
  • “Frequency” of dosage may vary depending on the compound used and the particular type of infection treated. A dosage regimen of once per day is possible. Dosage regimens in which the active agent is administered for several times daily, as for example 2 to 10 times, like 2, 3, 4, 5, 6, 7, 8, 9 or 10 times may occasionally be more helpful.
  • the specific dose level and frequency for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy. Patients may generally be monitored for therapeutic or prophylactic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
  • compositions according to the present invention are liquid form preparations such as solutions, suspensions, and emulsions and comprise, beside the block copolymer according to the present invention, a therapeutically effective amount of small molecule component as defined above, optionally together with at least one further pharmaceutically acceptable excipient as defined above and may be administered through any suitable route.
  • compositions according to the present invention are solid form preparations such as powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
  • XLogP3 Computed by XLogP3 3.0 (PubChem release 2021.05.07)
  • the HPLC measurement was done by gradient elusion using a RP-C18 column (Chromolith®, HighResolution, RP-18 endcapped, 100-4.6 mm, Merck KGaA) which was kept at 25°C.
  • the mobile phase composed of solvent A (water, 0.1% phosphoric acid) and solvent B (acetonitrile, 0.1% phosphoric acid) was at a flow rate of 1.5 ml/min.
  • the samples were detected and quantified using a DAD detector.
  • the herein used HPLC device was the 1260 Infinity II from Agilent Technologies.
  • the data were collected by HPLC measurement by gradient elusion using a RP- C18 column (Chromolith®, HighResolution, RP-18 endcapped, 100-4.6 mm, Merck KGaA) at a column temperature of 25°C.
  • the herein used HPLC device was the 1260 Infinity II from Agilent Technologies.
  • the mobile phase was composed of a mixture of solvent A (water, 0.1 % phosphoric acid) and solvent B (acetonitrile, 0.1 % phosphoric acid) and the flow rate was set to 1 .5 ml/min.
  • the solvent gradient for the measurement was as follows:
  • the samples were detected and quantified using a diode array detector (DAD).
  • the wavelength of the DAD detector that is used for the detection of the API depends of the properties of the API.
  • a wavelength is chosen that shows absorption in the UV/Vis spectrum of the API, ideally a wavelength at or close to the absorption maximum is chosen.
  • a UV/Vis spectrum of the API in the starting solvent mixture 80% A, 20% B is measured at an API concentration that results in an absorbance between 0.5 and 1.5 at the absorbance maximum.
  • Table 2B wavelengths used for the detection of each APIs
  • a stock solution (API dissolved in DMSO) is prepared.
  • the dilutions are made from this stock solution.
  • the saturation solubility of the pure API in water or buffer is used as a guide. Is the active substance detected? Based on these data, one decides how to prepare the stock solutions including the dilutions.
  • a stock solution active ingredient dissolved in DMSO
  • the dilutions are made in methanol.
  • the last dilution step is a 1 :2 dilution in 50mM phosphate buffer pH 7.4, as the solubilization test is also carried out in 50mM phosphate buffer.
  • the saturation solubility of the active substance in water is chosen as the lowest concentration as the first point in the calibration line. Then 10 times the saturation solubility is chosen as the highest calibration point. Therefore, one comes higher than the given saturation solubility in water, because we have dissolved API in DMSO. This step is necessary because the use of surfactants increases the solubility of API.
  • Each newly created calibration line must cover the range of the maximum solubility of the API with the addition of a surfactant.
  • the other calibration points are placed in between so that one has a good concentration distribution within the calibration line.
  • polymer solubility of a 10 wt.-% solution in a 100 ml glass flask 7 g polymer (100%) and 63 g distilled water are placed at room temperature. The mixture is stirred with a magnetic stirrer until polymer is completely dissolved. To determine solubility at other concentrations, polymer solutions with various polymer content are prepared in a similar way.
  • samples were dissolved in deionized water at a concentration of 1 g/L and subsequently diluted to 0.1 g/L.
  • the surfactant solutions were filled into a disposable syringe, which was then mounted on a Drop Shape Analyser (DSA) 100 drop shape tensiometer from Kruss (Hamburg, Germany).
  • DSA Drop Shape Analyser
  • Static surface tension was measured at 0.1 g/L by the pendant drop technique, where a free-hanging droplet of surfactant solution (typical volumes: 1-10 pL depending on surface tension) is generated at the outlet of the syringe. Then, a two-dimensional projection of the hanging droplet is acquired by an integrated camera system, from which the drop contour is determined via image analysis utilizing the instrument software Advance 1.9.2.
  • surfactant solution typically volumes: 1-10 pL depending on surface tension
  • the density of the solutions required for evaluation was assumed to be that of pure water.
  • RBC-test The principle of an RBC-test is described by Hoover (D.M: Hoover et al., Fundamental and Applied Toxicology 1990, 14, 589-597.) and Pape (W. J. W. Pape et al., Molecular Toxicology 1987 , 1 :525-536.).
  • the test is based on the integrity of the red blood cell (RBC) membrane and determines the degree of hemolysis after agitation of a cell suspension at different test compound concentrations.
  • RBC membrane damage due to the test substance hemoglobin is released via the disrupted cell membrane into the test solution. The free hemoglobin concentration in the test solution is measured as correlate for the RBC membrane damage caused by the test substance.
  • RBC red blood cell
  • Results were compared to totally lysed RBCs in distilled water (100% hemolysis) and to a fragility control with PBS/glucose (spontaneous, no substance related hemolysis). All samples were evaluated in triplicates.
  • Tested polymers were classified according to following scheme: low: ⁇ 10 % hemolysis at 100 mg/ml medium: ⁇ 10 % hemolysis at 10 mg/ml high: > hemolysis at 10 mg/ml
  • test substances butronics as well as reference excipient materials (Kolliphor® ELP and HS15) was prepared in 50mM phosphate buffer at pH 7.4.
  • the small molecule to be analysed is added in excess in each case (approximately 30mg - 500mg active substance per 5g 10% polymer solution or 5g buffer) to obtain a supersaturated solution.
  • approximately 500mg API per 5g of polymer solution is added, for diclofenac sodium only 100mg are used due to the lower solubility.
  • an amount between 100 to 200mg API was added.
  • the filtrate is diluted with a mixture of 50mM phosphate buffer/methanol 1 :1(V/V) until a concentration is reached that is in the concentration range of the calibration curve.
  • Table 2C shows the dilutions to be made for each API :
  • the saturation concentration of the API in each polymer solution is then detected by HPLC.
  • Item C.5 reports the experimental results of the tested compositions in terms of saturation concentration and solubility increase for each API.
  • Cs is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of said block copolymer
  • Cloud point is determined as the temperature, which induces a change from a clear to a turbid solution. Values of 20°C indicates the solution is turbid at room temperature. Cloud point of > 95°C means no turbidity is observed up to 95°C.
  • Exemplary butronics according to the invention (Test samples No. 4, 5, 6 and 9) as well as comparative butronics (CE1a to CE3a, CE7a, CE8a, CE10a, CE11a, CE1 to CE5) are characterized by the following general formula 1a
  • ethylene oxide content (wt.-% EO) was determined following the protocol described above (see item A.3).
  • Step a Synthesis of 1,4-butane diol, butoxylated with 20 mole 1,2-butylene oxide
  • Step b Synthesis of 1,4-butane diol, butoxylated with 20 mole 1,2-butylene oxide and ethoxylated with 34 mole ethylene oxide
  • Step a 1,4-butane diol, butoxylated with 8 mole 1,2-butylene oxide
  • Step b 1,4-butane diol, butoxylated with 42 mole 1,2-butylene oxide and ethoxylated with 108 mole ethylene oxide
  • Step a Synthesis of 1,4-butane diol, butoxylated with 10 mole 1,2-butylene oxide - in presence of waterin a 2 I autoclave 85.6 g 1 ,4-butane diol and 3.4 g potassium hydroxide (50% in water) were placed and the reactor heated to 100°C. The reactor was purged three times with nitrogen. The mixture was heated to 140°C. 771.0 g 1 ,2-butylene oxide was added within 6 hours. To complete the reaction, the mixture was allowed to post-react for additional 3 hours at 140°C. The reaction mixture was stripped with nitrogen and volatile compounds were removed in vacuo at 90°C for 2 hours. 852.0 g of a light orange oil was obtained.
  • Step b Synthesis of 1,4-butane diol, butoxylated with 24 mole 1,2-butylene oxide and ethoxylated with 96 mole ethylene oxide
  • Sample 5a was prepared according to Synthesis method B; all other samples were prepared according to Synthesis method A
  • the water solubility assay for the selected set of samples was performed as described above (see item A.5).
  • Table 5 Outcome of the water solubility test butronics according to the invention (Test samples No. 4, 5 and 6) and comparative butronics (CE1a to CE3a, CE7a, CE1 to CE5)
  • Kolliphor® EL is the registered trademark of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. Kolliphor EL is a synthetic, nonionic surfactant used to stabilize emulsions of nonpolar materials in water. Kolliphor® EL is an excipient or additive used in drugs.
  • Solutol® HS 15 is the registered trademark of a polyoxyethylated 12- hydroxystearic acid. It is another excipient or additive used in drugs.
  • the surface tension assay for the selected set of samples was performed as described above (see item A.6).
  • Table 6 Outcome of the surface tension assay test depicted in item A.6 for butronics according to the invention ((Test samples No. 4, 5, 6 and 9) and comparative butronics (CE1a to CE3a, CE7a, CE8a, CE10a, CE1 to CE5)
  • Hemolysis refers to a phenomenon leading to rupture and dissolution of red blood cells.
  • the assay for the selected set of samples was performed as described above (see item A.7).
  • Table 7 Outcome of the hemolysis test depicted in item A.7 for butronics according to the invention (Test samples No. 4, 5 and 6) and comparative butronics (CE1a to CE3a, CE7a, CE1 to CE5) to CE5)
  • CE1 to CE4 showed a high degree of hemolysis
  • samples CE1a to CE3a, CE7a and 4 to 6 and CE 5 showed a significantly lower hemolytic activity as compared to Polysorbate 80 which is indicative of their low toxicity and thus suitability as possible formulation additives.
  • Table 8 Outcome of the molecule solubilization ability test for Fenofibrate, Itraconazole and Nilotinb using samples CE1a, CE2a, CE3a, 5, CE7a and CE11a. The experimental results are reported in each case in terms of RSA using Kolliphor® ELP as standard.
  • Table 9 Outcome of the molecule solubilization ability test for test for a broader selection of APIs using test samples 4 and 6. For comparative purposes the outcome of the test using water, Kolliphor® HS 15 and Poloxamer P335 is reported. The experimental results are reported in each case in terms of RSA using Kolliphor® ELP as standard.
  • Table 10 Outcome of the molecule solubilization ability test for Fenofibrate, Itraconazole and Nilotinb using different Poloxamers as test samples. The experimental results are reported in each case in terms of RSA using Kolliphor®ELP as standard.
  • Test samples 4 and 6 displayed either a superior or at least a comparable small molecule solubilizing ability.
  • Table 11 shows how the saturation concentration of each of the selected API in water can be improved by addition of the surfactant.
  • test samples 4 and 6 showed, for the greatest majority of the selected APIs
  • test samples showed surface tension values in the range of 53 - 30 mN/m (0.1 g/l). All test samples with exception of test samples CE1a and CE5 showed a water solubility of more than 10%. Due to their poor water solubility CE5 is thus unsuitable as formulation excipient.
  • test samples having:
  • test samples 4 and 6 which additionally in comparison to Kolliphor ® ELP, for the greatest majority of the selected APIs, provided for:
  • polymeric surfactants of the present invention represent particularly advantageous small molecule solubilizes as compared to the currently most commonly employed surfactants such as Kolliphor® EL or ELP, or Poloxamers.

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Abstract

The present invention relates to the field of liquid compositions, comprising a liquid, in particular an aqueous mixture, more particularly an aqueous solution, of at least one poorly water- soluble small molecule and at least one solubilizing surfactant. Said surfactant is selected from a defined group of ethylene oxide/butylene oxide block copolymers (butronics). Said ethylene oxide/butylene oxide block copolymers are capable to effectively solubilize poorly water-soluble small molecules while concomitantly conferring the composition superior properties in comparison to the presently known small molecule formulations, particularly with regard to water solubility, chemical stability and hemolytic activity. Further embodiments of the invention relate to said group of block copolymers as well as to their use for solubilizing poorly water-soluble small molecules; methods for preparing said liquid compositions; the use of said compositions in medicine, in particular for diagnostic and/or therapeutic applications; essentially dry composition comprising said small molecule and said block copolymers; methods for preparing said dry compositions; the use of such dry compositions in medicine, in particular for diagnostic and/ or therapeutic applications; pharmaceutical compositions comprising said liquid or dry compositions and optionally a pharmaceutically acceptable excipient; and to the use of said block copolymers for solubilizing said pharmaceutical formulation.

Description

Use of butronics as small molecule solubilizers
Field of the Invention
The present invention relates to the field liquid compositions, comprising a liquid, in particular aqueous mixture, more particularly aqueous solution, of at least one poorly water-soluble small molecule and at least one solubilizing surfactant, Said surfactant is selected from a defined group of ethylene oxide/butylene oxide block copolymers (butronics). Said ethylene oxide/butylene oxide block copolymers are capable to effectively solubilize poorly water-soluble small molecules while concomitantly conferring the composition superior properties in comparison to the presently known small molecule formulations, particularly with regard to water solubility, chemical stability and hemolytic activity.
Further embodiments of the invention relate to said group of block copolymers as well as to their use for solubilizing poorly water-soluble small molecules; methods for preparing said liquid compositions; the use of said compositions in medicine, in particular for diagnostic and/or therapeutic applications; essentially dry composition comprising said small molecule and said block copolymers; to method for preparing said dry compositions; the use of such dry compositions in medicine, in particular for diagnostic and/or therapeutic applications; pharmaceutical compositions comprising said liquid or dry compositions and optionally a pharmaceutically acceptable excipient; and to the use of said block copolymers for solubilizing said pharmaceutical formulation.
Background of the Invention
A substantial proportion of small molecules nowadays applied as pharmaceutical drugs to be administered in liquid form suffers from poor solubility issues which limits their diagnostic or therapeutic applicability.
Thus, solubilization technologies which overcome this issue by increasing water solubility have become more prominent.
The use of surfactants, i.e. amphiphilic molecules bearing a polar head group and a non-polar tail part, are known for their capacity to influence the solubility of poorly water soluble drugs and thereby their bioavailability.
The effect is due to the formation of micelles in solution which reduce surface tension and improve the dissolution of lipophilic drugs.
In this regard certain Polysorbates and Poloxamers, like Polysorbate 20 (POE sorbitan monolaurate, PS20) and Polysorbate 80 (POE sorbitan monooleate, PS80) and Poloxamer 188, are known which may enhance the solubility of lyophilic drugs. Particularly, Polysorbates are highly efficient, but difficult to manage due to their complex composition. Their multi-component nature makes them difficult to describe, control and it presents a particular challenge to monitor stability and degradation products. In general, hydrolytic degradation due presence of ester groups which themselves may react with the active ingredient is common, and poses major challenges in the widespread applicability of Polysorbates as excipient for pharmaceutical formulations.
Furthermore, due to their similarity with the cell membrane lipids these surfactants may interact and disturb cellular equilibrium in erythrocytes, leading to membrane component reorganization and disturbance of the cell homeostasis which may eventually result in haemolysis. Polysorbates have also been described to cause immunogenic reactions, so a safer but equally effective stabilizer for parenteral formulations is highly desirable for the industry [Maggio, Edward. 2017. “Reducing or Eliminating Polysorbate Induced Anaphylaxis and Unwanted Immunogenicity in Biotherapeutics - Review Article.” Journal of Excipients and Food Chemicals 8 (3).]
The chemical stability of the surfactants used in the formulation is therefore a key aspect to be considered in the preparation of the specific excipient formulation of choice.
Poloxamer 188, a non-ionic surfactant with a more defined chemical structure and a better chemical stability (no ester-bonds), has been used as an alternative to Polysorbates. However, Poloxamer 188 is in general not as effective as a solubilizer.
In many cases, the performance of Poloxamer 188 cannot match that of Polysorbates, for example in the presence of residual silicon oil traces in pre-filled syringes (Grapentin, C. et al., Protein-Polydimethylsiloxane Particles in Liquid Vial Monoclonal Antibody Formulations Containing Poloxamer 188. Journal of Pharmaceutical Sciences, 2020).
The solubilization properties of Poloxamers can be improved by adopting derivatives with higher molecular weight. The latter solution is however less desirable due to otherwise poor clearance properties.
Block-copolymers characterized by the presence of short hydrophilic blocks relative to the length of the hydrophobic block are known for their capacity to form wormlike micelles with high solubilization capacity for poorly soluble aromatic drugs (Colloid Stability and Application in Pharmacy, edited by Tharwat F. Tadros, Weinheim 2007).
Their self-association and micellation behaviour in aqueous solution is intensively investigated (e.g. C. Booth et al., Phys. Chem. Chem. Phys., 2006, 8, 3612-3622 ; C. Booth et al.,. Block copolymers of ethylene oxide and 1 ,2-butylene oxide. In: Alexandridis, P., Lindman, B. (Eds.), Amphiphilic Block Copolymers: Self-assembly and Applications. Elsevier Science B.V., Amsterdam 2000).
Solubilization of naphthalene in aqueous solution by a triblock copolymer of ethylene oxide and 1 ,2-butylene oxide of molecular weight 7100 g/mol and 80 wt.-% EO is described (C. Chaibundit, Journal of Science and Technology 2003, 25 (6), 783-790). Solubilization of benzene with a butronic of molecular weight of 2325 g/mol, and 70% EO was also shown (S. Xi, Langmuir 2019, 35, (14), 5081-5092).
The use of ethylene oxide and butylene oxide triblock copolymers with an inner butylene oxide block (“butronic”) for solubilization of selected drugs is described in the literature:
Griseofulvin solubilization with one particular butronic having a molecular weight of 4790 g/mol and 80 wt.-% EO (EO43-BuO14-EO43) is described (D. Attwood, C. Booth: “Solubilization of a poorly soluble aromatic drug by micellar solutions of amphiphilic block copoly(oxyalkylene)s” Colloid Stability and Application in Pharmacy, edited by Tharwat F. Tadros, Weinheim 2007, and M. Crothers et al. International Journal of Pharmaceutics, 2005, 293 (1-2), 91-100). Said butronic is reported to have a low solubilization capacity for griseofulvin, most likely as consequence of lower surface activity resulting from higher wt.-% EO. No other butronics are investigated therein. For certain other di- or tri-block copolymers containing a hydrophobic polystyrene oxide block a four-fold higher solubilisation of said drug was observed.
D. Patel et al. J. Phys. Chem. B 2020, 124, 11750-11761 describes four butronics as drug delivery nanocarriers for Quercetin and Cucurmin as listed in Table 1 , below:
Table 1 :
Figure imgf000004_0001
Copolymer A and C are expected to be associated with a disadvantageously low solubilization performance, respectively, due to lower molecular weight or to lower surface activity resulting from high %EO.
Copolymer B is expected to be hemolytically too active due to the comparatively lower molecular weight.
Copolymer D does not result in clear solutions even at a content of 5wt% in water.
EP 3 378 493 relates to a nanoparticle compositions, comprising an active pharmaceutical ingredient and a polyethylene glycol-polybutylene glycol copolymer, which can be triblock copolymers ethylene oxide and butylene oxide with an inner butylene oxide block (cf. PEG-PBG copolymer of Formula III). However, the latter are only disclosed in general terms. EP 3 378 493 neither contains any specific example relating to the copolymers of Formula III nor any data for the assessment of the respective solubilization, hemolytic and/or surface tension properties.
A problem to be solved by the present invention is to provide a polymer surfactant which avoids the above problems as associated with the use of prior art butronics asa discussed in the prior art.
A further problem relates to the identification of polymer surfactants which besides the above mentioned higher solubilization properties are further characterized by a defined chemical structure and stability as compared to surfactants of the Kolliphor or Poloxamer type, and show good solubility in water combined with low to no hemolytic activity and surface tension comparable to that of Polysorbates and/or butronics described in the prior art.
Still further problems will become apparent to the skilled reader from a closer consideration of the present disclosure.
Summary of the Invention
The above mentioned objects could, surprisingly, be achieved by the provision of butronics (EO-BuO-EO block-copolymers) with a specific range of molecular weight and ethylene oxide content (EO%).
More particularly, the above mentioned problem could be solved by the provision of butronics presenting a) a calculated molecular weight of 4.9kDa to 9.7kDa, particularly of 5kDa and 9kDa; more particularly 5.5kDa to 8.5kDa; and b) an EO% content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, especially 55 to 65 wt.-%, each based on the dry weight of said butronic.
These butronics solubilize poorly water soluble small molecules at least as good as, and in some cases better, than the current best in class surfactants such as Kolliphor® EL or Kolliphor® ELP and Polysorbates while at the same time being less hemolytically active despite a similar surface activity.
Detailed Description of the Invention
A. Abbreviations
API active pharmaceutical ingredient BuO or OBu butylene oxide
CDC deuterated chloroform
EDTA Ethylenediaminetetraacetic acid
EO or OE ethylene oxide
HPLC high-performance liquid chromatography
PVDF polyvinylidene fluoride
PS20 Polysorbate 20
P188 Poloxamer 188
PS80 Polysorbate 80
PBS phosphate-buffered saline
RBC red blood cell
RSA relative solubilization ability
Unless otherwise stated the term “API” in the context of the present invention relates to “small molecule” based active pharmaceutical ingredients. They are thus readily distinguishable from biopolymer-based APIs, like for example proteins and nucleic acids, which are characterized by a much higher molecular weight.
B. Definitions
1. General
Unless otherwise defined herein, scientific and technical terms used in connection with the present invention shall have the meanings that are commonly understood by those of ordinary skill in the art. The meaning and scope of the terms should be clear, however, in the event of any latent ambiguity, definitions provided herein take precedent over any dictionary or extrinsic definition. Further, unless otherwise required by context, singular terms shall include pluralities and plural terms shall include the singular.
In the context of the descriptions provided herein and of the appended claims, the use of “or” means “and/or” unless stated otherwise. Similarly, “comprise,” “comprises”, “comprising”, “include”, “includes,” and “including” are interchangeable and not intended to be limiting.
It is to be further understood that where descriptions of various embodiments use the term "comprising," those skilled in the art would understand that in some specific instances, an embodiment can be alternatively described using language "consisting essentially of' or "consisting of.”
The terms “about” or “approximately” indicate a potential variation of ± 25% of the stated value, in particular ± 15% or ±10 %, more particularly ± 5%, ± 2% or ± 1 %. The term "substantially" describes a range of values of from about 80 to 100%, such as, for example, 85-99.9%, in particular 90 to 99.9%, more particularly 95 to 99.9%, or 98 to 99.9% and especially 99 to 99.9%.
“Predominantly” refers to a proportion in the range of above 50%, as for example in the range of 51 to 100%, particularly in the range of 75 to 99,9%; more particularly 85 to 98,5%, like 95 to 99%.
If the present disclosure refers to features, parameters and ranges thereof of different degree of preference (including general, not explicitly preferred features, parameters and ranges thereof) then, unless otherwise stated, any combination of two or more of such features, parameters and ranges thereof, irrespective of their respective degree of preference, is encompassed by the disclosure of the present description.
2. Chemical Terms
The term “halogen” denotes in each case a fluorine, bromine, chlorine or iodine radical, in particular a fluorine radical.
“Alkyl” relates to a straight-chain or branched alkyl group having from 1 to 10, in particular 1 to 8, more particularly 1 to 4, 1 to 2 carbon atoms. Example are methyl, ethyl, n-propyl, n-butyl, n-hexyl, n-heptyl or n-octyl.
“Alkylene” relates to a straight-chain or branched hydrocarbon bridging group having from 1 to 22, or 2 to 22, 1 to 6, 3 to 6, 2 or 4, carbon atoms. Non limiting examples are -CH2-, -(CH2)2-, -(CH2)3-, -(CH2)4-, -(CH2) -, -(CH2)I5-, -(CH2)20-, -(CH2)22- and the respective branched analogues thereof.
Optionally said alkylene groups may be interrupted by one or more heteroatoms, such as oxygen.
“Alkyleneoxy” relates to a radical of the formula -R-O-, wherein R is a straightchain or branched alkylene group having from 1 to 22, or 2 to 22, 1 to 6, 3 to 6, 2 or 4, carbon atoms as defined herein.
A “polyalkylene oxide” relates to a group in which at least two, identical or different repeating units of alkyleneoxy groups as defined above are covalently linked.
A “liquid composition” is to be interpreted broadly, and particularly refers to aqueous solutions of the block copolymer and small molecule as defined herein, wherein micellar structures of identical or different geometry as formed by the butronic molecules may be present. A liquid composition of the invention encompasses aqueous solutions, in particular clear or transparent or slightly opalescent aqueous solutions of the block copolymer and small molecule at different viscosities. In that respect, nanoparticle solutions are not to be encompassed within the scope of the present disclosure. “Block copolymer” defines a macromolecular entity characterized by at least two alternating structurally different polymer blocks; wherein each block consists essentially of structurally analogous, in particular identical repeating monomeric units. Within the structure of said block copolymer may optionally be present chemical moieties linking two or more alternating blocks, such as polyvalent, as for example di- or trivalent organic or inorganic moieties.
“Butronic” is to be broadly interpreted and generally refers to block copolymers essentially consisting of alternating butylene oxide bocks and ethylene oxide bocks and presenting an molar ethylene oxide content (EO%) of about 10 to less than 100 mol%, as well as a molecular weight of 1.000 and 15.000 g/mol. Particular butronics within the meaning of the invention present an EO% of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer in combination with a calculated molecular weight of 4kDa to 10kDa, particularly of 5kDa to 9kDa. More particular butronics within the meanings of the invention are exemplified in the general part and the experimental section below.
Relative solubilizing ability”(RSA) is preferably to be interpreted as the ability of a butronic as defined herein above to solubilize a given small molecule within the meaning of the present invention at room temperature, and can be expressed as:
RSA = (Cs/Cr) * 100 wherein:
Cs is the saturation concentration of said small molecule in a 10% wt.-% buffered solution of said block copolymer; and
Cr is the saturation concentration of said small molecule in a 10% wt.-% buffered solution of a reference excipient being Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: Polyoxyl 35 Castor Oil).
The saturation concentrations Cs and Cr may be determined using any suitable quantitative analytical technique known in the art such as by RP-HPLC under standard conditions. Example of said standard conditions which may be employed for the determination of the relative solubilizing ability are given in the experimental part (see A.3).
The pH of the buffered solution of the test sample is not critical and may vary depending on the specific small molecule-based API and/or reference excipient used. Example of suitable pH values of said buffered solutions are pH comprised in the range of 5.7 to 9, particularly 6.8 to 8 and more particularly 7.0 to 7.6.
A “reference excipient” is preferably to be interpreted as a polyoxyethylene castor oil compound made by reacting castor oil with ethylene oxide in a molar ratio of 1 :35. Said compound is commonly designated as Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: “Polyoxyl 35 Castor Oil" or “Macrogolglycerol Ricinoleate” according to European pharmacopoe. Thus the terms’ “Polyoxyl 35 Castor Oil” or “Macrogolglycerol Ricinoleate” can be used interchangeably in the context of the present invention. Polyoxyethylenglycerol triricinoleate 35 is a constituent of commercial product sold under the registered trademark Kolliphor® EL or Kolliphor® ELP. Kolliphor® ELP is a purified version of Kolliphor® EL. Kolliphor® ELP is particularly suited for use in parenteral applications. As a non-ionic oil-in-water emulsifier and/or solubilizer is has found broad use with sensitive APIs, demonstrating very high solubilization capacity along with good compatibility with other ingredients.
A “small molecule” within the meaning of the present invention is to be interpreted broadly and refers to natural (i.e. biological) or artificial, inorganic, organic or organometallic small molecules which by virtue of their hydrophobicity or degree of crystallinity are characterized by a “low solubility” in water. Such small molecules may show pharmaceutical (i.e. prophylactic, therapeutic, diagnostic or even theranostic activity or even my even be pharmaceutically essentially or fully inactive. More particularly such “small molecules” are readily distinguishable for biopolymers as herein defined above, as they have a relatively small molecular weight, typically of 1 .500 g/mol or less, like in the range of 100 to 1000 g/mol, particularly 200 to 950 g/mol, more particularly 250 to 880 g/mol. As a parameter suitable for identifying their high degree of hydrophobicity the logarithmic partition coefficient may be used, describing the molecules tendency to distribute between the two phase of an octanol/water two-phase system. Logarithmic partition coefficient may either be determined experimentally by measuring the respective concentration in said two phases and is then designated “logP”, or may be determined by calculation. Different methods of calculation are available. As example the distribution coefficient designated “XLogP3” is calculated by means of program “XLogP3 3.0” (PubChem release 2021.05.07). As different methods mostly result in very similar partition coefficients, reference can simply be made to “logP” values. A particular subgroup of “small molecules” of the present invention is characterized by the exclusion of those molecules meeting Lipinsiki’s “Rule of five” (Lipinski, C.A. et al, Adv. Drug Del. Rev. 2001 , 46, 3-26) or even the “Rule of tree” (Congreve M, Carr R, Murray C, Jhoti H. A 'rule of three' for fragment-based lead discovery? Drug Discov Today 2003, 8, 876-877). Each of the models are defining a framework for the development of orally bioavailable drug candidates or fragment-based lead structure discovery.
“Rule of five” Criteria:
- No more than five donors of hydrogen bonds (e.g. OH or NH groups)
- Not more than ten acceptors of hydrogen bonds (e.g. oxygen or nitrogen atoms)
- A molecular mass of not more than 500 daltons
- A partition coefficient (log P) between octanol and water (octanol-water partition coefficient) of not more than 5.
“Rule of 3” Criteria:
- A molecular mass of not more than 300 daltons
- No more than 3 donors of hydrogen bonds (e.g. OH or NH groups)
- Not more than 3 acceptors of hydrogen bonds (e.g. oxygen or nitrogen atoms)
- A partition coefficient ClogP (referring to a calculated logP) of no more than 3.
Small molecules which do not fulfil each of said two parameter combinations are expected to be poorly soluble in conventional solubilizing systems and, therefore, good candidates being formulated into compositions of the present invention.
The meaning of the term “small molecule” is understood to exclude “biopolymers” as defined herein below.
Particular examples of said “small molecule” are those classified according to the Biopharmaceutics Classification System (BCS) as having high permeability, low solubility (BCS class II) or low permeability, low solubility (BCS class IV).
The term “low solubility” is to be interpreted broadly and preferably refers to a solubility of
• less than 1 g/L, particularly of less than 500 mg/L, more particularly of less than 100 mg/L, yet more particularly of less than 10 mg/L and especially 100 ng/L; or
• in the range of 1.0 *10'8 to 100 mg/ L, particularly 1.0 *10'7 to 50 mg/L more particularly 1.0 *10'6 to 20 mg/L or 2.0*1 O'6 to 10 mg/L; yet more particularly 2.5*10' 6 to 9 mg/L.
“Static surface tension” within the meaning of the invention is to be preferably interpreted as the amount of energy per unit of surface area required to cause a deformation, such as a local increase, of the surface of a liquid sample presenting a given concentration of solute at the thermodynamic equilibrium at a predetermined temperature. The “static surface tension” is measured in milliNewton per meter (mN/m) and is determined by means of the pendant drop technique. “Ethylene oxide content” (EO%) and “butylene oxide content” (BuO%) within the meaning of the invention are stated herein as either mole % (mol%) or as weight percentage (wt.-%) of ethylene oxide and butylene oxide monomer units within a given block copolymer as herein defined. If not otherwise stated “%” refers to wt.-%.
The term “EO% calculable from the atomic masses of all atoms of the copolymer molecule of formula 1” refers to a wt.-% value obtained according to the following formula:
EO% = [^masses EO I (^masses EO + ^masses BuO + mass Starter X)] * 100
The term “a calculated molecular weight of x to y g/mol” encompasses the integers x, y and any integer between x and y. For example a molecular weight of ”4.000 to 10.000 g/mol” encompasses the integers:
4.000, 4.100, 4.200, 4.300, 4.400, 4.500. 4.600. 4.700. 4.800. 4.900;
5.000, 5.100, 5.200, 5.300, 5.400, 5.500. 5.600. 5.700. 5.800. 5.900;
6.000, 6.100, 6.200, 6.300, 6.400, 6.500. 6.600. 6.700. 6.800. 6.900;
7.000, 7.100, 7.200, 7.300, 7.400, 7.500. 7.600. 7.700. 7.800. 7.900;
8.000, 8.100, 8.200, 8.300, 8.400, 8.500. 8.600. 8.700. 8.800. 8.900;
9.000, 9.100, 9.200, 9.300, 9.400, 9.500. 9.600. 9.700. 9.800. 9.900; and
10.000.
“Hemolysis” within the meaning of the invention relates to the tendency of a given excipient to cause breakdown of cells, particularly of red blood cells with consequent release of intracellular components.
The term “biopolymer” as used herein encompasses molecules, selected from oligopeptides, polypeptides, proteins, any type of antibody molecule or fragment or derivative thereof as defined below, glycosylated proteins, proteoglycans, oligo- and polynucleotides, DNA and RNA molecules, oligosaccharides, polysaccharides, as well as adducts or conjugates of such biopolymers, in particular of antibodies, with a further constituent selected from payload molecules as further defined below.
The “logP” (synonym “Pow”) parameter is the decadal logarithm of the partition coefficient P. The logP value can be determined mathematically (e.g. XLogP) and experimentally. Experimentally, the P-value is usually determined as the ratio of the concentrations of a compound to be analysed in a phase with n-octanol and a phase with water. Experimental details are described in OECD Guidelines for the Testing of Chemicals, 107, adopted 27.07.1995, Partition Coefficient (n-octanol/water): Shake Flask Method. C. Particular aspects and embodiments of the invention
The present invention relates to the following aspects and particular embodiments thereof:
In a first aspect the invention relates to a liquid composition, comprising a liquid, in particular aqueous mixture, more particularly aqueous solution, of at least one small molecule and at least one ethylene oxide/butylene oxide block copolymer of the general formula 1
H-(-OE)n-(OBu)m-X-(BuO)m-(EO-)n-H (1 ) in which
X represents -O-; or a divalent organic moiety, in particular a moiety originating from an organic molecule comprising two active hydrogen atoms, such as -O-(C2 -C4-alkylene)-O-, ; m independently represents an integer in the range of 4 to 25, like 10 to 22, 12 to 18 or an integer selected from 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18,19, 20, 21 , 22, 23, 24 or 25; and n independently represents an integer in the range of 15 to 100, like 20 to 80 or 25 to 70, 30 to 60 or 35 to 65, or an integer selected from 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30; 31 , 32, 33, 34, 35, 36, 37,
38, 39, 40; 41 , 42, 43, 44, 45, 46, 47, 48, 49, 50; 51 , 52, 53, 54, 55, 56, 57,
58, 59, 60; 61 , 62, 63, 64, 65, 66, 67, 68, 69, 70, 71 , 72, 73, 74, 75, 76, 77,
78, 79, 80, 81 , 82, 83, 84, 85, 86, 87, 88, 89, 90, 91 , 92, 93, 94, 95, 96, 97,
98, 99 or 100; wherein said block copolymer shows a combination of the following features a) a calculated molecular weight of 4.000 to 10.000 g/mol, particularly 4.500 to 9.500 g/mol, more particularly 4.800 to 9.700 g/mol, especially 5.000 to 9.000 g/mol or 5.500 to 8.500 g/mol, in particular calculable from the sum of atomic masses of all atoms of the copolymer molecule of formula 1 ; and b) an EO content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer, in particular calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 . Said ethylene oxide/butylene oxide block copolymer formally may also be designated as “triblock polymers”, as they contain a central BuO block essentially consisting of BuO monomers, flanked by two EO blocks.
As particular combinations of features a) and b) there may be mentioned: a calculated molecular weight of 4.000 to 10.000 g/mol and an EO content of 45 to 77 wt.-% or 45 to 75 wt.-%; a calculated molecular weight of 4500 to 9.500 g/mol and an EO content of 50 to 75 wt.-%; a calculated molecular weight of 4.800 to 9.700 g/mol and an EO content of 52 to 70 wt.-%; a calculated molecular weight of 5.000 to 9.000 g/mol and an EO content of 55 to 65 wt.-%; a calculated molecular weight of 5.000 to 8.500 g/mol and an EO content of 55 to 65 wt.-%;and a calculated molecular weight of 5.500 to 8.500 g/mol and an EO content of 55 to 65 wt.-%; wherein, in particular, the molecular weight in each case being calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 and the EO content in each case calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 .
Particularly, said block copolymer shows at least one of the following additional features: c) a water solubility of at least 5 wt.-%, or more particularly at least 10% based on the total weight of the aqueous solution of the block copolymer; d) an aqueous solution of said block copolymer (concentration 0.1 g/l) has a surface tension SFT of less than 60 mN/m to more than 25 mN/m, in particular of 53 to 30 mN/m, like, for example, of about 35, about 40, about 45 of about 50 mN/m; and e) lack of hemolytic activity, in particular less than 10% or more particularly less than 5%, or less than 1 , 2, 3 or 4% hemolysis, like 0 % or 0.1 to 0.9% hemolysis caused by a solution of 10Og/l block copolymer.
According to a particular embodiment, a particular subgroup of block-copolymers shows a combination of anyone of the above features a), b) and e).
According to another particular embodiment, a particular subgroup of blockcopolymers shows a combination of anyone of the above features a), b), c) and e). According to still another particular embodiment, a particular subgroup of blockcopolymers shows a combination of anyone of the above features a), b), c), d) and e).
Particularly, said block copolymer may be characterized by a relative solubilizing ability (RSA) of a small molecule in the range of 5% to 200%, said relative solubilizing ability being expressed as:
RSA = (Cs/Cr) * 100 wherein:
Cs is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of said block copolymer; and
Cr is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of a reference excipient being a Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: Polyoxyl 35 Castor Oil); wherein
Cs and Cr are determined by HPLC method under standard conditions; and said block copolymer and reference excipient solution presents a pH comprised in the range of 5.7 to 9, particularly 6.8 to 8 and more particularly 7.0 to 7.6.
More particularly said relative solubilizing ability as defined above, may be in the range of 5% to 200%, or 15% to 200% or 25% to 200%, or 35% to 200% or 50% to 200%, or 65% to 200%, 80% to 200, or 95 to 200%, and especially 100% to 200%, such as 120% to 200% or 140% to 200%, or 160% to 200%.
In a particular embodiment of said first aspect a liquid composition is provided, comprising an aqueous solution of at least one small molecule and at least one ethylene oxide/butylene oxide block copolymer of the general formula 1
H-(-OE)n-(OBu)m-X-(BuO)m-(EO-)n-H (1 ) in which
X represents -O- or a divalent organic moiety; m independently of each other represent an integer in the range of 4 to 25; and n independently of each other represent an integer in the range of 15 to 100; wherein said small molecule has a molecular weight of 1.500g/mol or less; and said block copolymer shows a combination of the following features: a) a molecular weight 4.900 to 9.700 g/mol, particularly 5.000 to 9.000 g/mol, more particularly 5.000 to 8.500 g/ml and especially 5.500 to 8.500; each calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ; b) an EO content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, and especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer; each calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 ; c) a water solubility of at least 5 wt.-%, based on the total weight of the aqueous solution of the block copolymer; and d) a hemolytic activity of less than 10% hemolysis caused by a solution of 100g/l.
In a particular embodiment of said first aspect, a liquid composition is provided, wherein X is selected from -O-; -O-alkylene-O-, in particular -O-(C2-C22-alkylene)-O-, more particularly -O-(Cs -Ce-alkylene)-O-, wherein the alkylene chain is straight-chained or branched, and is optionally interrupted by one or more heteroatoms, in particular oxygen atoms; more particularly -O-, -O-(n-butylene)-O-, -O-(1 ,2-butylene)-O-, a group of formula 2 below, and especially -O-(n-butylene)-O- or a group of the formula 2
Figure imgf000015_0001
According to another particular embodiment of said first aspect, the invention relates to a liquid composition, wherein said block copolymer of general formula 1 shows a combination of the following features a) a molecular weight of 5.000 to 9.000 g/mole, particularly of 5.500 to 8.500 g/mole, in particular calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 , and b) an EO content of 55 to 65 wt.-%, based on the dry weight of said block copolymer, in particular calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 ; and c) X = -O-n-butylene-O-.
According to another particular embodiment of said first aspect, the invention relates to a liquid composition, wherein said block copolymer of general formula 1 shows a combination of the following features a) a molecular weight 5.500 to 8.500 calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ; b) an EO content of 55 to 65 wt.-%, based on the dry weight of said block copolymer, calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 ; and c) X = -O-n-butylene-O-.
Said block copolymer may be selected from the following compounds of the general formula 1 , wherein X, m and n have the following meanings:
X = -O-n-butylene-O-, m = 15, and n = 35;
X = -O-n-butylene-O-, m = 16, and n = 40;
X = -O-n-butylene-O-, m = 12, and n = 48;
X = -O-n-butylene-O-, m = 21 , and n = 54.
According to another more particular embodiment a liquid composition is provided, wherein the block copolymer is selected from the following compounds of the general formula 1 , wherein X, m and n have the following meanings:
X = -O-n-butylene-O -, m = 12, and n = 48 and a molecular weight of approximately 6.050, calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ;
X = -O-n-butylene-O-, m = 16, and n = 40 and a molecular weight of approximately 5.922, calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ; or
X = -O-n-butylene-O-, m = 21 , and n = 54 and a molecular weight of approximately 7.876, calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 .
In a particular embodiment of said first aspect, a liquid composition is provided, wherein said block copolymer of the general formula (I) is contained in a proportion of 0,001 to 20% or 0,001 to 15%, more particularly 0,001 to 10%, like 0,01 to 8%, 0,1 to 5% or 1 to 3%, each based on the total weight of the liquid composition.
In a further embodiment of said first aspect, a liquid composition said block copolymer it capable to solubilize the small molecule with an increase of 1000-fold compared water, particularly of 10000 fold, more particularly.
In a particular embodiment of said first aspect, a liquid composition is provided, in which said small molecule is contained in a proportion of 0,0001 to 10wt%, particularly of 0,01 to 8%, more particularly about 0,03% to 6%, based on the total weight of the liquid composition.
In a particular embodiment of said first aspect, a liquid composition is provided, which is optionally in buffered form, having a pH in the range of 5 to 9, particularly 6, 7 or 8.
Particularly, said small molecule may be characterized by one or more of the following properties: a) solubility in water comprised in the range of 1 .0 *10-6 to 20 mg/L, particularly of 2.0*1 O'6 to 10 mg/L; more particularly 2.5*1 O'6 to 9 mg/L, yet more particularly of less than 100 ng/L; and/or b) molecular weight comprised in the range of 100 to 1000 g/mol, particularly 200 to 950 g/mol, more particularly 250 to 880 g/mol.
Particularly, said small molecule may be selected from: a) pharmaceutically active compounds (APIs), including prophylactically, therapeutically, diagnostically or even theranostically active compounds; examples of diagnostically active compounds are labelling agents as defined more detailed below; and b) artificial or synthetic inorganic, organic or organometallic small molecules, or natural or biological small molecules, such as lipids, phospholipids, glycolipids, sterols, vitamins, hormones, neurotransmitters, monosaccharides, which in turn may be either pharmaceutically active or essentially inactive.
More particularly, said artificial or synthetic small molecules are organic or organometallic small molecules. Organic small molecules do not encompass oligo- or polypeptides and oligo- or polynucleotides.
Said particular small molecule may preferably be a diagnostically applicable or a therapeutically active small molecule.
In further particular embodiments the small molecule belongs to BCS class II and particularly is selected from the group Aceclofenac; Asciminib; Atorvastatin Calcium; Budesonide; Cefuroxime; Chlorzoxazone; Clonazepam; Clopidogrel; Clozapine; Daclatasvir; Danazol; Dexlansoprazole; Dextromethorphan hydrobromide: Diacerien; Diclofenac Sodium; Dolutegravir Sodium; Efavirenz; Enzalutamide; Eplerenone; Etoricoxib; Felodipine; Fenofibrate; Gefitinib; Ibrutinib; Ibuprofen; Indinavir Sulfate; Ketoprofen; Ivermectin; Lansoprazole; Mebendazole; Montelukast Na; Naproxen; Nicardipine; Nifedipine; Nitrofurantoin; Obeticholic acid; Olanzapine; Omeprazole; Oxcarbazepine; Ozanimod; Palbociclib Isethionat; Paliperidone palmitate; Pemigatinib; Phenytoin Sodium; Posaconazole; Pralsetinib; Rececadotril; Rifampicin; Risperidone; Rosuvastatin; Sertraline HOI; Sildenafil; Spironolactone; Sulfamethoxazole; Tamoxifen Citrate; Telmisartan; Terbinafine HCI; Trimethoprim; Valsartan; Venetoclax; Vericiguat
In particular embodiments the small molecule belongs to BCS class VI and particularly is selected from the group Abiraterone acetate; Acetazolamide; Albendazole; Aprepitant; Aripiprazole; Avacopan; Avapritinib; Ciprofloxacin HCI; Digoxin; Docetaxel; Erythromycin Succinate; Haloperidol; Hydrochlorothiazide; Mesalamine; Paclitaxel; Ponesimod; Relugolix; Ritonavir; Saquinavir; Sulfasalazine; Tivozanib; Verapamil HCI
According to a second aspect, the invention relates to an essentially dry small molecule composition, comprising at least one essentially dry small molecule as defined in the above-identified first aspect and at least one ethylene oxide/butylene oxide block copolymer of the general formula (1) as defined in the above-identified first aspect.
In particular embodiments said essentially dry essentially dry small molecule composition has a liquid content of 0% to 5% wt.-%, as for example 0,1 to 4,5 wt.-%,, like 1 , 2, 3 or 4 wt.-%, based on the total weight of said composition.
Optionally in said essentially dry essentially dry small molecule composition said at least one block copolymer of general formula 1 (=A) and said at least one small molecule (=B) are contained in a weight ratio (A) : (B) in the range of 1 : 20.000 to 10:1 , or 1 : 5.000 to 2: 1 or of 1 : 100 to 1 ,2 : 1 , particularly 1 : 50 to 5 : 1 , or 1 : 20 to 2: 1 , and more particularly 1 : 10 to 1 ,1 : 1.
In particular embodiments said essentially dry essentially dry small molecule composition is characterized in that said block copolymer and said at least one essentially dry small molecule together are contained in a proportion of 1 to less than 100 wt.-%, in particular 5 to 60 wt.-%, more particular 10 to 50 wt.-%, or 20 to 40 wt.-% or even 20 to 25wt.-% based on the total weight of said essentially dry composition.
Optionally said essentially dry composition comprises at least one further excipient in a proportion of 0,1 to 99%, 40 to 95% and 50 to 90% wt.-% based on the total dry weight of said essentially dry composition. In a third aspect the invention relates to a pharmaceutical composition comprising the composition as defined in the first aspect and optionally at least one further pharmaceutically acceptable excipient Optionally, said pharmaceutical composition is a parental formulation.
In particular embodiments, said pharmaceutical composition is an intravenous, intra-arterial, intracutaneous, intramuscular, intrathecal, intracardiac, intravitreal, intraosseous, intraperitoneal, subcutaneous, inhalation, urinary bladder, intranasal or topical formulation.
In particular embodiments, said pharmaceutical composition is in the form of a two-part-pharmaceutical composition comprising, separated from each other: a) at least a small molecule as defined in the first aspect; and b) at least one block copolymer as defined in the first aspect; and optionally c) at least one pharmaceutically acceptable excipient, optionally separated from a) and b) or in admixture with a) and/or b).
In a fourth aspect the invention relates to the use of a block copolymer as defined herein above in the first aspect for solubilizing at least one small molecule as defined in the first aspect.
In a fifth aspect the invention relates to the use of a block copolymer as defined herein above in the first aspect for solubilizing a pharmaceutical formulation of at least one small molecule as defined in the first aspect.
In a sixth aspect the invention relates to a composition as defined in the first or second aspect, or the pharmaceutical composition as defined in the third aspect for use in medicine, in particular for diagnostic and/or therapeutic applications.
In a seventh aspect the invention relates to a method of preparing a composition of as defined above in the first aspect, which method comprises a) preparing in any order an aqueous, optionally buffered solution of the of the block copolymer of general formula (1); and b) adding said small molecule as defined above in the first aspect.
In an eighth aspect the invention relates to a method of preparing a dry composition of as defined above in the second aspect, which method comprises a) preparing in any order an aqueous, optionally buffered solution of the of the block copolymer of general formula (1); and b) adding said small molecule as defined in the first aspect, thereby obtaining a block copolymer liquid preparation comprising the small molecule; c) optionally supplementing the aqueous, optionally buffered solutions prepared in step a) and/or the block copolymer liquid preparation comprising the small molecule prepared in step b), with at least one pharmaceutically acceptable excipient; d) drying the mixture obtained in step b) or c).
Said drying step d) is performed by conventional, well-known methods. For example the drying step d) is performed by spray-drying or freeze-drying the mixture obtained in step b) or c).
A ninth aspect the invention relates to a block copolymer selected from the following compounds of the general formula (I), wherein X, m and n have the following meanings:
X = -O-n-butylene-O-, m = 15, and n = 35;
X = -O-n-butylene-O-, m = 16, and n = 40;
X = -O-n-butylene-O-, m = 12, and n = 48;
X = -O-n-butylene-O-, m = 21 , and n = 54.
Particular polymer compounds of the general formula 1 are those, wherein X, m and n have the following meanings:
X = -O-n-butylene-O -, m = 12, and n = 48 and a molecular weight of approximately 6.050, calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1; or
X = -O-n-butylene-O-, m = 16, and n = 40 and a molecular weight of approximately 5.922, calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ; or
X = -O-n-butylene-O-, m = 21 , and n = 54 and a molecular weight of approximately 7.876, calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1.
D. Further embodiments
D.1. Synthesis of block copolymers of formula (1)
Methods for the preparation of ethylene oxide/butylene oxide block copolymers of the general formula 1 are generally known in the art.
Suitable methods for their preparation are reported, for example, in US 2,828,345.
Briefly, said block copolymers may, for example be prepared by a multistep protocol which foresees a first step in which an organic molecule comprising two active hydrogen atoms, like 1 ,4-butane diol or 1 ,3-butane diol, and butylene oxide are condensed to form a polyoxybutylene. Thereafter, ethylene oxide is added and the reaction is let to proceed until the desired oxyethylene content is reached.
Examples of suitable butylene oxides are 1 ,2-butylene oxide and 2,3-butylene oxide.
The reaction is preferably carried out under moisture-free conditions at elevate temperature and in presence of a suitable catalyst such as an alkali metal hydroxide or alkoxide, like alkali metal tert, butoxide.
The reaction can be carried out in presence of water, whereas reacting butylene oxide with water (in particular originating from an aqueous catalyst solution, or water contained in the starter or EO or BuO as added to the reaction (as further detailed in the experimental section below) forms in situ an organic molecule with two active hydrogen groups, e.g. 1 ,2-butane diol (in analogy to the disclosure in CA 698,568).
The amount of catalyst employed should be from 0.05 to 1 percent by weight based on the total reactants. Reaction temperatures are in the range of from 80° to 200° C., with a temperature of about 110°C or 170°C being preferred during most of the reaction.
Superatmospheric pressures in the range of from 0.5 to 15 bar are ordinarily employed, very good results being obtained at pressures of from about 1 to 5 bar. The alkylene oxides employed are preferably substantially anhydrous, e.g. the moisture content of the oxides ordinarily should not exceed about 0.1 percent by weight. The alkylene oxides are also preferably as free as practical from contaminants, such as aldehydes, which give rise to side reactions and by-product formation.
The reaction may be conducted either batch-wise or continuously as desired. In batchwise operation, the commercially anhydrous organic molecule comprising two active hydrogen atoms, like 1 ,4-butane diol or butylene glycol is charged into a suitable dry reaction vessel, such as an autoclave, and mixed with an effective amount of catalyst, usually about 0.2 wt.-% of potassium hydroxide in terms of the total amount of reactants.
Prior to the introduction of butylene oxide, the reaction vessel is advantageously flushed with a stream of dry inert gas, such as nitrogen, to remove any air or oxygen therefrom. The elimination of molecular oxygen from the reaction vessel is an important factor in obtaining colorless products and may, if desired, be carried out after adding the butylene glycol and catalyst to the reaction vessel.
After these preliminaries, the mixture of -potassium hydroxide and said organic molecule comprising two active hydrogen atoms, like 1 ,4-butane diol or butylene glycol, is heated to a reaction temperature of about 140°C and butylene oxide is added at a fairly rapid rate. Usually, the rate of addition of butylene oxide is such as to maintain a pressure of about 3 bar in the reactor. Vigorous agitation is desirable to maintain a good dispersion of catalyst and uniform reaction rates throughout the mass.
The reaction of butylene oxide with butylene glycol is exothermic and it is therefore necessary to provide adequate cooling means.
By controlling the rate of addition of butylene oxide to maintain the pressure fairly constant, the reaction temperature may also be maintained constant.
The addition of butylene oxide is stopped upon obtaining the desired molecular weight of the polyoxybutylene glycol condensation product as determined by, for example, hydroxyl analysis or 1H-NMR reckoning two free hydroxyl groups per molecule. Thereafter, ethylene oxide is condensed with the polyoxybutylene glycol condensation product to give a product in accordance with the invention. The addition of ethylene oxide is carried out in the same manner as the addition of butylene oxide already described.
Purification may be conducted by heating it at a reduced pressure under reflux or by stripping with inert gas to distill off any low boiling material.
D.2. Labelling Agents
Labeling agents which may be used as small molecule within the meanings of the present invention can comprise any type of label known in the art.
Examples are dyes (e.g. fluorescent, luminescent, or phosphorescent dyes (e.g. fluorescent, luminescent, or phosphorescent dyes), such as dansyl, coumarin, fluorescein, acridine, rhodamine, silicon-rhodamine, BODIPY, or cyanine dyes), molecules able to emit fluorescence upon contact with a reagent, chromophores (e.g., phytochrome, phycobilin, bilirubin, etc.), radiolabels (e.g. radioactive forms of hydrogen, fluorine, carbon, phosphorous, sulphur, or iodine, such as tritium, fluorine-18, carbon-11 , carbon-14, phosphorous-32, phosphorous-33, sulphur-33, sulphur-35, indium-111 , iodine-123, or iodine-125), MRI-sensitive spin labels, affinity tags (e.g. biotin, His-tag, Flag-tag, strep-tag, sugars, lipids, sterols, PEG-linkers, benzylguanines, benzylcytosines, or co-factors), polyethylene glycol groups (e.g., a branched PEG, a linear PEG, PEGs of different molecular weights, etc.), photocrosslinkers (such as p- azidoiodoacetanilide), NMR probes, X-ray probes, pH probes, IR probes, resins, solid supports and bioactive compounds as defied above.
In some embodiments, exemplary dyes can include an NIR contrast agent that fluoresces in the near infrared region of the spectrum. Exemplary near-infrared fluorophores can include dyes and other fluorophores with emission wavelengths (e.g., peak emission wavelengths) between about 630 and 1000 nm, e.g., between about 630 and 800 nm, between about 800 and 900 nm, between about 900 and 1000 nm, between about 680 and 750 nm, between about 750 and 800 nm, between about 800 and 850 nm, between about 850 and 900 nm, between about 900 and 950 nm, or between about 950 and 1000 nm. Fluorophores with emission wavelengths (e.g., peak emission wavelengths) greater than 1000 nm can also be used in the methods described herein.
In some embodiments, exemplary fluorophores include 7-amino-4- methylcoumarin-3 -acetic acid (AMCA), TEXAS RED™ (Molecular Probes, Inc., Eugene, Oreg.), 5-(and -6)-carboxy-X-rhodamine, lissamine rhodamine B, 5-(and -6)- carboxyfluorescein, fluorescein-5-isothiocyanate (FITC), 7-diethylaminocoumarin-3- carboxylic acid, tetramethylrhodamine-5-(and -6)-isothiocyanate, 5 -(and -6)- carboxytetramethylrhodamine, 7-hydroxycoumarin-3-carboxylic acid, 6-[fluorescein 5- (and -6)-carboxamido]hexanoic acid, N-(4,4-difluoro-5,7-dimethyl-4-bora-3a,4a diaza-3- indacenepropionic acid, eosin-5-isothiocyanate, erythrosin-5-isothiocyanate, and CASCADE™ blue acetylazide (Molecular Probes, Inc., Eugene, Oreg.) and ATTO dyes.
Further labelling agents are 111-lndium, 64-Copper, 67-Copper, 124-lodine, 227- Thorium, 188-Rhenium, 177-Lutetium, 89-Zirkonium, 131-lod, 68-Gallium, 99m- Technecium, 225-Actinium, 213-Bismut, 90-Ytrium and 212-Plumbum.
D.3. Pharmaceutical composition
The composition (i.e. compositions comprising at least one small molecule as pharmaceutically active ingredient) of this invention are generally given as “pharmaceutical compositions” comprised of a “therapeutically” and/or "prophylactically effective amount" or a “diagnostically” effective amount or theranostically” effective amount of at least one such active ingredient or its pharmaceutically acceptable salt and optionally at least one pharmaceutically acceptable excipient.
Thus the term "pharmaceutical composition" according to a particular embodiment of the present invention designates a liquid composition comprising or essentially consisting of at least one pharmaceutically active small molecule (i.e. the active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium. A dried powder of such liquid preparation can be obtained by lyophilization or any other suitable drying method that is typically applied. Non-limiting examples of such pharmaceutical compositions are:
Therapeutic compositions comprising or essentially consisting of at least one therapeutically active small molecule (i.e. the active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
Prophylactic compositions comprising or essentially consisting of at least one prophylactically active small molecule (i.e. the active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
Diagnostic compositions comprising or essentially consisting of at least one diagnostically active small molecule (i.e. the active ingredient, like for example at least one labelling agent), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium. Theranostic compositions comprising or essentially consisting of at least one therapeutically active small molecule (i.e. a first active ingredient), and at least one diagnostically active small molecule (i.e. a second active ingredient), optionally in combination with at least one pharmaceutically inactive small molecule and at least one EO/BuO block copolymer as described herein in a liquid, pharmaceutically acceptable medium.
Said pharmaceutical compositions may be delivered via suitable routes of administration such as via oral, rectal, transmucosal, topical, ophthalmic, otologic, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intramedullary injections, as well as intrathecal, direct intraventricular, intravenous, intraperitoneal, intranasal, or intraocular injections, as the case may be.
Depending on the nature or the mode of administration and dosage form said composition said at least one additional pharmaceutical excipient may be different
An “excipient” is a substance formulated alongside the active ingredient and is included for different purpose, as for example for long-term stabilization, bulking up solid formulations that contain potent active ingredients in small amounts (thus often referred to as "bulking agents", "fillers", or "diluents"), or to confer a therapeutic enhancement on the active ingredient in the final dosage form, such as for example facilitating drug absorption, reducing viscosity, or enhancing solubility. Excipients can also be useful in the manufacturing process of the pharmaceutical composition, to aid in the handling of the active substance concerns such as by facilitating powder flowability or non-stick properties, in addition to aiding in vitro stability such as prevention of denaturation or aggregation over the expected shelf life. The selection of appropriate excipients not only depends upon the route of administration and the dosage form, but also on the particular active ingredient and other factors.
Excipients may be selected from the following classes: immunological adjuvants, antiadherents, binders, coatings, colours, disintegrant, flavours, glidants, lubricants, preservatives, sorbents, sweeteners, and vehicles
Non limiting examples of excipients comprise diluents, preserving agents, stabilizers, emulsifying agents, like emulsifying polymers, such as Polysorbates or Poloxamers, antioxidants, as for example chemical compounds, like epigallocatechin-3- O-gallate, lycopene, ellagic acid, coenzyme Q , indole-3-carbinol, genistein, quercetin, ascorbic acid, glutathione, melatonin, catechin, taurine, captopril, gallic acid, N-acetyl cysteine, a-lipoic acid, BHT, tocopherols and tocotrienols, or enzymes like superoxide dismutase and catalase; anti-irritants, chelating agents and stabililizing salts, such as chlorides, sulfates, phosphates, diphosphates, hydrobromides and nitrates, suspending agents, antibacterial agents or antifungal agents. Further, buffering agents such as buffering systems of low molecular weight organic acids together with the respective salts, or inorganic buffering substances, such as phosphate buffers, can be used, Further suitable ingredients are also known from relevant pharmacological standard literature. Also the proportion of the various components will vary depending on the nature of the specific component used and is generally known to the person skilled in the art (Remington's Pharmaceutical science ("Handbook of Pharmaceutical Excipients", 2nd Edition, (1994), Edited by A Wade and PJ Weller or in Remington's Pharmaceutical Sciences, Mack Publishing Co. (A. R Gennaro edit. 1985).
A pharmaceutical composition as used herein may be presented in the form of a “dosage form” or “unit dose” and may comprise one or more liquid composition, or essentially dry composition comprising at least one pharmaceutically active small molecule compound and at least one EO/BuO block copolymer as described herein. Thus, a pharmaceutical composition as used herein could, for example, provide two active agents admixed together in a unit dose or provide two active agents combined in a dosage form wherein the active agents are physically separated.
As used herein said pharmaceutical composition may also be in the form of a two forms composition, i.e. a composition in which the active ingredient (i.e. the small molecule), the EO/BuO block copolymer and/or optionally a pharmaceutically acceptable excipient are physically separated from one another.
Furthermore, one may administer said pharmaceutical composition in a targeted drug delivery system, for example, in a liposome coated with endothelial cell-specific antibody.
The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, emulsifying, encapsulating, entrapping or or combinations thereof. Proper formulation is dependent upon the route of administration chosen.
The phrase "pharmaceutically acceptable" is employed herein to refer to those compounds, materials, compositions, and/or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of patients without excessive toxicity, irritation, allergic response, or other problem or complication commensurate with a reasonable risk/benefit ratio.
The invention includes all “pharmaceutically acceptable salt forms” of the active ingredient. Pharmaceutically acceptable salts are those in which the counter ions do not contribute significantly to the physiological activity or toxicity of the compounds and as such function as pharmacological equivalents. These salts can be made according to common organic techniques employing commercially available reagents. Some anionic salt forms include acetate, acistrate, besylate, bromide, chloride, citrate, fumarate, glucouronate, hydrobromide, hydrochloride, hydroiodide, iodide, lactate, maleate, mesylate, nitrate, pamoate, phosphate, succinate, sulfate, tartrate, tosylate, and xinofoate. Some cationic salt forms include ammonium, aluminum, benzathine, bismuth, calcium, choline, diethylamine, diethanolamine, lithium, magnesium, meglumine, 4-phenylcyclohexylamine, piperazine, potassium, sodium, tromethamine, and zinc.
A "therapeutically effective amount" and/or "prophylactically effective amount" means an amount effective, when administered to a human or non-human patient, to provide any therapeutic and/or prophylactic benefit. More particularly, a “therapeutically effective amount” is an amount of an active ingredient disclosed herein or a combination of two or more such active ingredients, which inhibits, totally or partially, the progression of the condition or alleviates, at least partially, one or more symptoms of the condition.
A "diagnostically effective amount" means an amount effective to allow obtaining from the patient a diagnostically valuable information on status or progression of a disease state.
A therapeutic benefit may be an amelioration of symptoms of a diseased patient, e.g., an amount effective to decrease the symptoms of a diseased patient. In certain circumstances a patient may not present symptoms of a condition for which the patient is being treated. Thus, a prophylactically effective amount of a compound is also an amount sufficient to provide a significant positive effect on any indicia of a disease, disorder or condition e.g. an amount sufficient to significantly reduce the frequency and severity of disease symptoms to occur.
A therapeutically effective amount can also be an amount, which is prophylactically effective.
A “patient” as used herein means human or non-human, in particular human, animals.
A "dosage form" is any unit of administration (“unit dose”) of one or more active agents as described herein.
The term "treating" or “treatment” refers to: (i) preventing a disease, disorder or condition from occurring in a patient which may be predisposed to the disease, disorder and/or condition but has not yet been diagnosed as having it; (ii) inhibiting the disease, disorder or condition, i.e., arresting its development; and (iii) relieving the disease, disorder or condition, i.e., causing regression of the disease, disorder and/or condition. In particular it encompasses a prophylactic or therapeutic treatment or combinations thereof.
“Frequency” of dosage may vary depending on the compound used and the particular type of infection treated. A dosage regimen of once per day is possible. Dosage regimens in which the active agent is administered for several times daily, as for example 2 to 10 times, like 2, 3, 4, 5, 6, 7, 8, 9 or 10 times may occasionally be more helpful.
It will be understood, however, that the specific dose level and frequency for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease in the patient undergoing therapy. Patients may generally be monitored for therapeutic or prophylactic effectiveness using assays suitable for the condition being treated or prevented, which will be familiar to those of ordinary skill in the art.
Particular examples of pharmaceutical composition according to the present invention are liquid form preparations such as solutions, suspensions, and emulsions and comprise, beside the block copolymer according to the present invention, a therapeutically effective amount of small molecule component as defined above, optionally together with at least one further pharmaceutically acceptable excipient as defined above and may be administered through any suitable route.
Further examples of pharmaceutical composition according to the present invention are solid form preparations such as powders, tablets, pills, capsules, cachets, suppositories, and dispersible granules.
The following example serve for a better understanding of the present invention without limiting its scope. Experimental Part
A. Material and Methods
A.1 Chemicals and Buffers
Unless stated otherwise all chemicals as applied were of analytical grade and obtained from commercial sources.
The following small molecule APIs as obtained from commercial sources were applied (Table 2, below):
Table 2: APIs, their respective molecular weights and logarithmic distribution coefficients (logP (measured) and XLog P3 (calculated) are shown
Figure imgf000028_0001
XLogP3 = Computed by XLogP3 3.0 (PubChem release 2021.05.07)
A.2 Analytical methods
The HPLC measurement was done by gradient elusion using a RP-C18 column (Chromolith®, HighResolution, RP-18 endcapped, 100-4.6 mm, Merck KGaA) which was kept at 25°C. The mobile phase composed of solvent A (water, 0.1% phosphoric acid) and solvent B (acetonitrile, 0.1% phosphoric acid) was at a flow rate of 1.5 ml/min. The samples were detected and quantified using a DAD detector. The herein used HPLC device was the 1260 Infinity II from Agilent Technologies.
1H-NMR spectra were measured in CDC with a Bruker AVANCE III 500 MHz spectrometer. A.3 HPLC analytics
A.3.1 Standard conditions for the HPLC determination of saturation concentrations, RSA and solubility increase compared to water
The following standard conditions were employed for the determination of relative solubilization ability of a solubilizing agent for APIs.
The data were collected by HPLC measurement by gradient elusion using a RP- C18 column (Chromolith®, HighResolution, RP-18 endcapped, 100-4.6 mm, Merck KGaA) at a column temperature of 25°C. The herein used HPLC device was the 1260 Infinity II from Agilent Technologies. The mobile phase was composed of a mixture of solvent A (water, 0.1 % phosphoric acid) and solvent B (acetonitrile, 0.1 % phosphoric acid) and the flow rate was set to 1 .5 ml/min. The solvent gradient for the measurement was as follows:
Table: 2A: solvent gradient for the measurements
Figure imgf000029_0001
The samples were detected and quantified using a diode array detector (DAD). The wavelength of the DAD detector that is used for the detection of the API depends of the properties of the API. A wavelength is chosen that shows absorption in the UV/Vis spectrum of the API, ideally a wavelength at or close to the absorption maximum is chosen. To determine the best wavelength, a UV/Vis spectrum of the API in the starting solvent mixture (80% A, 20% B) is measured at an API concentration that results in an absorbance between 0.5 and 1.5 at the absorbance maximum.
Depending on the absorbance of the respective API at the detection wavelength, different injection volumes are used. For each API a calibration curve with different concentrations of API needs to be prepared to determine in which concentration range the signal of the DAD detector is linear. The injection volume of the samples is then adjusted to a volume where the signal for the API remains in the linear range of the concentration range.
In the following table examples for the chosen wavelengths for the example APIs as well as the injection volume are listed: Table 2B: wavelengths used for the detection of each APIs
Figure imgf000030_0001
A.3.2 HPLC Calibration
First, a stock solution (API dissolved in DMSO) is prepared. The dilutions are made from this stock solution. The saturation solubility of the pure API in water or buffer is used as a guide. Is the active substance detected? Based on these data, one decides how to prepare the stock solutions including the dilutions.
As a rule, a stock solution (active ingredient dissolved in DMSO) is prepared. From this stock solution, the dilutions are made in methanol. The last dilution step is a 1 :2 dilution in 50mM phosphate buffer pH 7.4, as the solubilization test is also carried out in 50mM phosphate buffer.
The saturation solubility of the active substance in water is chosen as the lowest concentration as the first point in the calibration line. Then 10 times the saturation solubility is chosen as the highest calibration point. Therefore, one comes higher than the given saturation solubility in water, because we have dissolved API in DMSO. This step is necessary because the use of surfactants increases the solubility of API. Each newly created calibration line must cover the range of the maximum solubility of the API with the addition of a surfactant. The other calibration points are placed in between so that one has a good concentration distribution within the calibration line.
A.4 General protocol for determining of ethylene oxide content Weight percent of ethylene oxide (wt.-% EO) in the claimed polymers was determined by 1H-NMR spectroscopy. In 1H-NMR spectroscopy, the integral of each peak is proportional to the molar concentration of the protons being analysed.
For butylene oxide and ethylene oxide block copolymers (butronics), the CH3 groups from polymerized butylene oxide give a triplett signal at 5 = 0.95 ppm.
The ethylene oxide repeating group -O-CH2-CH2-O- and the butylene oxide repeating group -O-CH2-CH(Et)-O- give a broad multiplett from 5 = 3.0 to 4.2 ppm, whereas the contribution of each ethylene oxide repeating group is 4 protons (two CH2 groups), and each butylene oxide group contributes with 3 protons (one CH and one CH2 group) to the signal.
To determine the mol% of ethylene oxide and the wt.-% of ethylene oxide following calculations are done:
Integral at 5= 0.95 ppm is set as 3 protons is [Area BuO]
Integral at 5 = 3.0 to 4.2 ppm is [Area EO+BuO]
[Area EO] = [Area EO+BuO] - [Area BuO] mol% EO = ([Area EO]/4) I (([area EO]/4)+([Area BuO]/3)) *100 mol% BuO = ([Area BuO]/3) I (([area EO]/4)+([Area BuO]/3)) *100
From mol% EO and mol% BuO the weight percent of ethylene oxide wt.-% EO is calculated with molecular mass of ethylene oxide (44.05 g/mol) and molecular mass of butylene oxide (72.11 g/mol): wt.-% EO = mol% EO*44.05 /((mol% EO*44.05)+(mol% BuO*72.11))*100
A.5 General protocol for water solubility assay
To determine a polymer solubility of a 10 wt.-% solution in a 100 ml glass flask 7 g polymer (100%) and 63 g distilled water are placed at room temperature. The mixture is stirred with a magnetic stirrer until polymer is completely dissolved. To determine solubility at other concentrations, polymer solutions with various polymer content are prepared in a similar way.
A.6 General protocol for surface tension assay
For the characterization of the surface activity of synthesized polymers, samples were dissolved in deionized water at a concentration of 1 g/L and subsequently diluted to 0.1 g/L.
After stirring for 2 h and complete dissolution, the surfactant solutions were filled into a disposable syringe, which was then mounted on a Drop Shape Analyser (DSA) 100 drop shape tensiometer from Kruss (Hamburg, Germany).
Static surface tension was measured at 0.1 g/L by the pendant drop technique, where a free-hanging droplet of surfactant solution (typical volumes: 1-10 pL depending on surface tension) is generated at the outlet of the syringe. Then, a two-dimensional projection of the hanging droplet is acquired by an integrated camera system, from which the drop contour is determined via image analysis utilizing the instrument software Advance 1.9.2.
Fitting of the drop contour based on the Young-Laplace equation (C. Samuel et al., Polymer Testing, 2019, 78, 105995) yields the desired values for the surface tension.
The density of the solutions required for evaluation was assumed to be that of pure water.
Surface tension was monitored over a period of 5 minutes, and the measured values were averaged. All measurements were performed at 23 °C.
A.7 General protocol for haemolysis assay
The principle of an RBC-test is described by Hoover (D.M: Hoover et al., Fundamental and Applied Toxicology 1990, 14, 589-597.) and Pape (W. J. W. Pape et al., Molecular Toxicology 1987 , 1 :525-536.). The test is based on the integrity of the red blood cell (RBC) membrane and determines the degree of hemolysis after agitation of a cell suspension at different test compound concentrations. In case of RBC membrane damage due to the test substance, hemoglobin is released via the disrupted cell membrane into the test solution. The free hemoglobin concentration in the test solution is measured as correlate for the RBC membrane damage caused by the test substance.
Preparation of red blood cell (RBC) suspension: RBCs from EDTA blood of human blood donors were isolated by centrifugation and were washed three times with phosphate buffered saline plus glucose (PBS/glucose) to remove traces of plasma and the bulk of white blood cells. The washed RBCs were diluted with (PBS/glucose) and were adjusted to an approximate 2 % RBC suspension.
Test procedure: A test solution of the polymer of 1.33 % (=1 ,33g/10 ml, i.e. final concentration in test 100 mg/ml) was prepared in PBS/glucose and adjusted to pH 7.4. Further test solutions (final concentration of polymer of 10 and 1 mg/ml) were made by dilution with PBS/glucose. One volume of the RBC suspension was added to three volumes of test solutions, resulting in final test compound concentrations of 100, 10, and 1 mg/ml. The assay mixtures were incubated at room temperature with shaking by an Eppendorf mixer (Model 5432; at 1000 rpm) for 60 minutes.
After incubation the samples were centrifuged to sediment remaining intact RBCs and membrane fragments.
Released free haemoglobin in the supernatant as a degree of hemolysis was determined spectrophotometrical ly at 540 nm.
Results were compared to totally lysed RBCs in distilled water (100% hemolysis) and to a fragility control with PBS/glucose (spontaneous, no substance related hemolysis). All samples were evaluated in triplicates.
Tested polymers were classified according to following scheme: low: < 10 % hemolysis at 100 mg/ml medium: < 10 % hemolysis at 10 mg/ml high: > hemolysis at 10 mg/ml
A.8 General protocol for the determination of saturation concentration, RSA and solubility increase compared to water
A 10% (m/m) aqueous solution of the test substances (butronics as well as reference excipient materials (Kolliphor® ELP and HS15)) was prepared in 50mM phosphate buffer at pH 7.4.
Solutions of Poloxamers P335, P338, PE6400 and PE4300 were also prepared analogously.
For each test substance and reference three screw cap 5 ml brown glass ampoules were filled with 5g of the prepared aqueous solution. For the determination of the solubility of the respective API in water (without solubilizer) three screw cap 5 ml brown glass ampoules were filled with 5g of 50mM phosphate buffer at pH 7.4.
Then the small molecule to be analysed is added in excess in each case (approximately 30mg - 500mg active substance per 5g 10% polymer solution or 5g buffer) to obtain a supersaturated solution. In the case of Valsartan, Flurbiprofen, Tilmicosin, and Diclofenac Sodium, approximately 500mg API per 5g of polymer solution is added, for diclofenac sodium only 100mg are used due to the lower solubility. For all other example APIs, an amount between 100 to 200mg API was added.
After stirring for 72 h at room temperature, each sample is filtered through a 0.22 pm PVDF filter and the concentration of the respective API in the filtrate is quantified by HPLC using the standard conditions outlined in A.3.
The filtrate is diluted with a mixture of 50mM phosphate buffer/methanol 1 :1(V/V) until a concentration is reached that is in the concentration range of the calibration curve. The following table 2C shows the dilutions to be made for each API :
Table 2C:
Figure imgf000034_0001
The saturation concentration of the API in each polymer solution is then detected by HPLC. Item C.5, reports the experimental results of the tested compositions in terms of saturation concentration and solubility increase for each API.
The values relating to the saturation concentrations are used for the calculation of the RSA of each API in the test polymer solutions (Cs) and in Kolliphor® ELP as the reference excipient (Cr) according to the following equation:
RSA = (Cs/Cr) * 100 wherein:
Cs is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of said block copolymer; and
Cr is the saturation concentration of said small molecule in a 10 wt.-% buffered solution of Kolliphor ® ELP as reference excipient
The results relating to the RSA determined according to this method are reported in section C.5
The experimental results relating to the saturation concentration, solubility increase and RSA for each of the tested samples refer in each case to the average of three replicates.
A.9 General protocol for the determination of Cloud Point
Cloud points are determined according to DIN EN 1890, method A
In a 100 ml glass flask 0.4 g polymer (100 %) and 39.6 g dist. water are placed at room temperature. The mixture is stirred with a magnetic stirrer until polymer is completely dissolved. Ca. 30 ml of this solution are filled in a test glass. A thermometer is placed in the test glass to monitor the temperature. The test glass is heated slowly with a hot air dryer until a persistent turbidity is observed.
Cloud point is determined as the temperature, which induces a change from a clear to a turbid solution. Values of 20°C indicates the solution is turbid at room temperature. Cloud point of > 95°C means no turbidity is observed up to 95°C.
B. Synthesis examples
Exemplary butronics according to the invention (Test samples No. 4, 5, 6 and 9) as well as comparative butronics (CE1a to CE3a, CE7a, CE8a, CE10a, CE11a, CE1 to CE5) are characterized by the following general formula 1a
Figure imgf000035_0001
All polymers were synthetized by applying synthetic protocols similar to those described in synthesis example 1 (X derived from 1 ,4-butane diol) below.
Molecular weights given are calculated from the used molar ratio of starting materials. The ethylene oxide content (wt.-% EO) was determined following the protocol described above (see item A.3).
Synthesis Example 1 : 1,4-Butane diol, butoxylated with 20 mole 1,2- butylene oxide and ethoxylated with 34 mole ethylene oxide (“Comparative Example CE2a”) (Synthesis method A)
Step a: Synthesis of 1,4-butane diol, butoxylated with 20 mole 1,2-butylene oxide
In a 2I autoclave 90.12 g 1 ,4-butane diol and 3.1 g potassium tert, butoxide were placed and the reactor was purged three times with nitrogen. The mixture was heated to 140°C. 1440.0 g 1 ,2-butylene oxide was added within 20 hours. To complete the reaction, the mixture was allowed to post-react for additional 10 hours at 140°C. The reaction mixture was stripped with nitrogen and volatile compounds were removed in vacuo at 90°C for 2 hours. 1528.0 g of a light orange oil was obtained. 1H-NMR in CDCh confirmed the complete conversion to the expected polymer.
Step b: Synthesis of 1,4-butane diol, butoxylated with 20 mole 1,2-butylene oxide and ethoxylated with 34 mole ethylene oxide
In a 2 I autoclave 404.5 g 1 ,4-butane diol, butoxylated with 20 mole 1 ,2-butylene oxide (from step a) and 1.6 g potassium tert.-butoxide were placed and the reactor was purged three times with nitrogen. The mixture was heated to 110°C. 395.5 g ethylene oxide was added within 20 hours. To complete the reaction, the mixture was allowed to post-react for additional 10 hours at 140°C. The reaction mixture was stripped with nitrogen, and 1.3 g acetic acid was added for neutralization. Volatile compounds were removed in vacuo at 90°C for 2 hours. 800.0 g of a beige solid was obtained.
1H-NMR in CDCh confirmed the complete conversion to the expected polymer. Hydroxy value was measured to be 37.2 mg KOH/g, water was content 0.1 %.
Synthesis Example 2: 1,4-butane diol, butoxylated with 42 mole 1 ,2- butylene oxide and ethoxylated with 108 mole ethylene oxide (“Test Sample 6”)
Step a: 1,4-butane diol, butoxylated with 8 mole 1,2-butylene oxide
In a 2 I autoclave 117.2 g 1 ,4-butane diol and 1.7 g potassium tert, butoxide were placed and the reactor was purged three times with nitrogen. The mixture was heated to 140°C. 748.5 g 1 ,2-butylene oxide was added within 12 hours. To complete the reaction, the mixture was allowed to post-react for additional 10 hours at 140°C. The reaction mixture was stripped with nitrogen and volatile compounds were removed in vacuo at 90°C for 2 hours. 860.0 g of a orange oil was obtained. 1H-NMR in CDCh confirmed the complete conversion to the expected polymer.
Step b: 1,4-butane diol, butoxylated with 42 mole 1,2-butylene oxide and ethoxylated with 108 mole ethylene oxide
In a 2 I autoclave 79.9 g 1 ,4-butane diol, butoxylated with 8 mole 1 ,2-butylene oxide (from step a) and 1.9 g potassium tert, butoxide were placed and the reactor was purged three times with nitrogen. The mixture was heated to 140°C. 294.0 g 1 ,2-butylene oxide was added within 10 hours. The reaction mixture was stirred for additional 7 hours to complete the conversion. 570.3 g ethylene oxide was added within 8 hours. To complete the reaction, the mixture was allowed to post-react for additional 7 hours at 140°C. The reaction mixture was stripped with nitrogen, and 1.1 g acetic acid was added for neutralization. Volatile compounds were removed in vacuo at 90°C for 2 hours. 930.0 g of a beige solid was obtained. 1H-NMR in CDC confirmed the complete conversion to the expected polymer. Hydroxy value was measured to be 21.2 mgKOH/g.
Synthesis Example 3: 1,4-Butane diol, butoxylated with 24 mole 1,2- butylene oxide and ethoxylated with 96 mole ethylene oxide - synthesis step 1 in presence of water (Synthesis method B)
Step a: Synthesis of 1,4-butane diol, butoxylated with 10 mole 1,2-butylene oxide - in presence of waterin a 2 I autoclave 85.6 g 1 ,4-butane diol and 3.4 g potassium hydroxide (50% in water) were placed and the reactor heated to 100°C. The reactor was purged three times with nitrogen. The mixture was heated to 140°C. 771.0 g 1 ,2-butylene oxide was added within 6 hours. To complete the reaction, the mixture was allowed to post-react for additional 3 hours at 140°C. The reaction mixture was stripped with nitrogen and volatile compounds were removed in vacuo at 90°C for 2 hours. 852.0 g of a light orange oil was obtained.
1H-NMR in CDCh confirmed the complete conversion to the expected polymer. Hydroxy value was measured to be 130.0 mg KOH/g, water content was 0.13 wt%.
Step b: Synthesis of 1,4-butane diol, butoxylated with 24 mole 1,2-butylene oxide and ethoxylated with 96 mole ethylene oxide
In a 2 I autoclave 145.8 g 1 ,4-butane diol, butoxylated with 10 mole 1 ,2-butylene oxide (from step a) and 1 .6 g potassium hydroxide (50% in water) were placed. Vacuum was applied (< 25 mbar) and the mixture was heated to 125°C. The mixture was stirred for 2.5 hours at 125°C and < 25 mbar vacuum. Vacuum was broken with nitrogen. The mixture was heated to 140°C. 181.4 g butylene oxide was added within 2 hours. To complete the reaction, the mixture was allowed to post-react for 6 hours. 761.0 g ethylene oxide was added within 6 hours. To complete the reaction, the mixture was allowed to post-react for additional 2 hours at 140°C. The reaction mixture was stripped with nitrogen, and 2.5 g phosphoric acid (75% in water) was added for neutralization. Volatile compounds were removed in vacuo at 90°C for 2 hours. 0.10 g alpha-tocopherol was added and the mixture was stirred for 0.25 hours. After cooling, 1081 .0 g of a beige solid was obtained.
1H-NMR in CDCh confirmed the complete conversion to the expected polymer. Hydroxy value was measured to be 24.8 mg KOH/g, water was content 0.1 %. C. Experimental results
C.1 Exemplary block copolymers (butronics)
Table 3: Butronics according to the invention (Test samples No. 4, 5, 5a, 6 and 9) and comparative butronics CE1a to CE3a, CE7a, CE8a, CE10a, CE11a: all polymers do not show hemolysis (< 10% hemolysis at 100 g/l)
Figure imgf000038_0001
1 > calculated from the atomic masses of all atoms of the copolymer molecule of formula 1 :
[ Emasses EO / (Emasses EO + Emasses BuO + mass Starter X) ] * 100
Note: Sample 5a was prepared according to Synthesis method B; all other samples were prepared according to Synthesis method A
Table 4: Comparative examples; all polymers, except of CE5, show hemolysis (>10% hemolysis at 10 g/l)
Figure imgf000039_0001
Note: All samples were prepared according to Synthesis method A
C.2 Results of the water solubility assay
The water solubility assay for the selected set of samples was performed as described above (see item A.5).
The results are summarized in Table 5:
Table 5: Outcome of the water solubility test butronics according to the invention (Test samples No. 4, 5 and 6) and comparative butronics (CE1a to CE3a, CE7a, CE1 to CE5)
Figure imgf000039_0002
Kolliphor® EL is the registered trademark of polyethoxylated castor oil. It is prepared by reacting 35 moles of ethylene oxide with each mole of castor oil. Kolliphor EL is a synthetic, nonionic surfactant used to stabilize emulsions of nonpolar materials in water. Kolliphor® EL is an excipient or additive used in drugs.
Solutol® HS 15 is the registered trademark of a polyoxyethylated 12- hydroxystearic acid. It is another excipient or additive used in drugs.
As it can be observed, all samples tested with exception of CE1a and CE5 showed a water solubility of more than 10%. Due to their poor water solubility CE5 is thus unsuitable as formulation excipient.
C.3 Results of the surface tension assay
The surface tension assay for the selected set of samples was performed as described above (see item A.6).
The results are summarized in Table 6.
Table 6: Outcome of the surface tension assay test depicted in item A.6 for butronics according to the invention ((Test samples No. 4, 5, 6 and 9) and comparative butronics (CE1a to CE3a, CE7a, CE8a, CE10a, CE1 to CE5)
Figure imgf000040_0001
As it can be observed, all samples tested showed surface tension values comprised between 53 - 30 mN/m (0.1 g/l). C.4 Results of the hemolysis assay
Hemolysis refers to a phenomenon leading to rupture and dissolution of red blood cells. The assay for the selected set of samples was performed as described above (see item A.7).
The results are summarized in Table 7:
Table 7: Outcome of the hemolysis test depicted in item A.7 for butronics according to the invention (Test samples No. 4, 5 and 6) and comparative butronics (CE1a to CE3a, CE7a, CE1 to CE5) to CE5)
Figure imgf000041_0001
While CE1 to CE4 showed a high degree of hemolysis, samples CE1a to CE3a, CE7a and 4 to 6 and CE 5 showed a significantly lower hemolytic activity as compared to Polysorbate 80 which is indicative of their low toxicity and thus suitability as possible formulation additives.
C.5 Small molecule relative solubilizing ability (RSA)
The suitability of the butronics according to the present invention for the solubilization of model small molecules was tested as described above (see item 0). The results are summarized in the following tables.
Table 8: Outcome of the molecule solubilization ability test for Fenofibrate, Itraconazole and Nilotinb using samples CE1a, CE2a, CE3a, 5, CE7a and CE11a. The experimental results are reported in each case in terms of RSA using Kolliphor® ELP as standard.
Figure imgf000042_0004
Figure imgf000042_0001
Table 9: Outcome of the molecule solubilization ability test for test for a broader selection of APIs using test samples 4 and 6. For comparative purposes the outcome of the test using water, Kolliphor® HS 15 and Poloxamer P335 is reported. The experimental results are reported in each case in terms of RSA using Kolliphor® ELP as standard.
Figure imgf000042_0002
Table 10: Outcome of the molecule solubilization ability test for Fenofibrate, Itraconazole and Nilotinb using different Poloxamers as test samples. The experimental results are reported in each case in terms of RSA using Kolliphor®ELP as standard.
Figure imgf000042_0003
In comparison with the reference Kolliphor® ELP, while Poloxamers proved to be quite inefficient in the solubilization of the selected APIs, Test samples 4 and 6 displayed either a superior or at least a comparable small molecule solubilizing ability.
C.6 Saturation concentration and solubility increase
The following Table 11 outlines:
1) On the left: the saturation concentration of selected APIs in a 10% (w/w) aqueous solution of test samples 4 and 6. For comparative purposes the saturation concentrations of the same APIs in a 10 % (w/w) aqueous solution of Kolliphor® ELP and in water are reported.
The data relating to the saturation concentration were collected using the protocol described in above section A.8
2) On the right: the solubility increase compared to water of selected APIs in a 10% (w/w) aqueous solution of test samples 4 and 6. For comparative purposes the solubility increase compared to water of the same APIs in a 10% (w/w) aqueous solution of Kolliphor® ELP are reported.
The data relating to the solubility increase compared to water were collected using the protocol described in above section A.8
Table 11 : Saturation concentrations and solubility increase compared to water of selected APIs for samples 4 and 6, water and Kolliphor ® ELP
Figure imgf000043_0001
(below limit of detection, value retrieved from the internet: https ://pubchem.ncbi.nlm.nih.gov/source/hsdb/7736#section=Color-Form-(Complete))
**(below limit of detection)
Table 11 (left) shows how the saturation concentration of each of the selected API in water can be improved by addition of the surfactant.
However, in comparison to Kolliphor ® ELP, test samples 4 and 6 showed, for the greatest majority of the selected APIs
• a higher saturation concentration (Table 11 left); and
• an higher a solubility increase compared to water (Table 11 right).
C.7 Summary
Summarizing, the inventors' attempts to provide polymeric solubilizers as better alternative to presently known surfactants for small molecules formulations allows the following conclusions:
All test samples showed surface tension values in the range of 53 - 30 mN/m (0.1 g/l). All test samples with exception of test samples CE1a and CE5 showed a water solubility of more than 10%. Due to their poor water solubility CE5 is thus unsuitable as formulation excipient.
While CE1 to CE4 showed a high degree of hemolysis, samples CE1a to CE3a, 4 to 6 and CE7a, and CE5 showed a significantly lower hemolytic activity as compared to Polysorbate 80 which is indicative of their low toxicity.
In comparison with the reference Kolliphor® ELP, while Poloxamers proved to be quite inefficient in the solubilization of the selected APIs, test samples having:
• a calculated molecular weight of 4kDa to 10kDa, particularly of 5kDa to 9kDa; and
• an EO% content of 45 to 77 wt.-%, particularly of 55 to 65 wt.-% displayed either a superior or at least a comparable small molecule solubilisation ability (Table 8 and 9).
This applies all the more for test samples 4 and 6 which additionally in comparison to Kolliphor ® ELP, for the greatest majority of the selected APIs, provided for:
• a higher saturation concentration (Table 11 , left); and
• a higher solubility increase compared to water (Table 11 , right).
Thus taken all together the polymeric surfactants of the present invention, particularly test samples according to the invention 4 and 6, represent particularly advantageous small molecule solubilizes as compared to the currently most commonly employed surfactants such as Kolliphor® EL or ELP, or Poloxamers.
The content of all documents referred to herein above is incorporated by reference.

Claims

Claims
1. A liquid composition, comprising an aqueous solution of at least one small molecule and at least one ethylene oxide/butylene oxide block copolymer of the general formula 1
H-(-OE)n-(OBu)m-X-(BuO)m-(EO-)n-H (1 ) in which
X represents -O- or a divalent organic moiety; m independently of each other represent an integer in the range of 4 to 25; and n independently of each other represent an integer in the range of 15 to 100; wherein said small molecule has a molecular weight of 1.500g/mol or less; and said block copolymer shows a combination of the following features a) a molecular weight 4.900 to 9.700 g/mol, particularly 5.000 to 9.000 g/mol,, more particularly 5.000 to 8.500 g/mol, and especially 5.500 to 8.500; each calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 ; b) an EO content of 45 to 77 wt.-%, particularly 45 to 75 wt.-%, more particularly 50 to 75 wt.-% or 52 to 70 wt.-%, and especially 55 to 65 wt.-%, each based on the dry weight of said block copolymer; each calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 ; c) a water solubility of at least 5 wt.-%, based on the total weight of the aqueous solution of the block copolymer; and d) a hemolytic activity of less than 10% hemolysis caused by a solution of 100g/l.
2. The composition of claim 1 , wherein said block copolymer further shows at least one of the following additional features a) a water solubility of at least 8%, more particularly at least 10% based on the total weight of the aqueous solution of the block copolymer; b) a surface tension SFT of 53 to 30m N/m based on a 0.1 g/l solution of said block copolymer; and c) a lack of hemolytic activity.
3. The composition of claim 1 or 2, wherein said block copolymer is characterized by a relative solubilizing ability of a small molecule in the range of 5% to 200%, said relative solubilizing ability being expressed as:
RSA = (Cs/Cr) * 100 wherein:
Cs is the saturation concentration of said small molecule in a 10wt% buffered solution of said block copolymer; and
Cr is the saturation concentration of said small molecule in a 10 wt% buffered solution of a reference excipient being a Polyoxyethylenglycerol triricinoleate 35 (US pharmacopoe: Polyoxyl 35 Castor Oil); wherein
Cs and Cr are determined by HPLC method under standard conditions; and said block copolymer and reference excipient solution presents a pH comprised in the range of 5.7 to 9, particularly 6.8 to 8 and more particularly 7.0 to 7.6.
4. The composition of anyone of the preceding claims, wherein the butylene oxide block is composed of monomer units derived from 1,2-butylene oxide, 2,3- butylene oxide, isobutylene oxide, or mixtures thereof, in particular essentially form 1,2-butylene oxide, and more particularly from 1,2-butylene oxide.
5. The composition of anyone of the preceding claims, wherein
X is selected from -O-; -O-alkylene-O-, in particular -O-(C2 -C22-alkylene)-O-, more particularly -O-(C2 -Ce-alkylene)-O-, or even more particularly -O-(C2 -C4- alkylene)-O-, wherein the alkylene chain is straight-chained or branched, and is optionally interrupted by one or more heteroatoms; in particular oxygen or -O-(n- butylene)-O-; or X is a group of the formula 2
Figure imgf000047_0001
6. The composition of anyone of the preceding claims, wherein said block copolymer of general formula 1 shows a combination of the following features a) a molecular weight 5.500 to 8.500 calculable from the sum of atomic masses of all atoms of the copolymer molecule of general formula 1 and b) an EO content of 55 to 65 wt.-%, based on the dry weight of said block copolymer, calculable from the atomic masses of all atoms of the copolymer molecule of formula 1 ; and c) X = -O-n-butylene-O-.
7. The composition of anyone of the preceding claims, wherein the block copolymer is selected from the following compounds of the general formula 1 , wherein X, m and n have the following meanings:
X = -O-n-butylene-O-, m = 5, and n = 35;
X = -O-n-butylene-O-, m = 16, and n = 40;
X = -O-n-butylene-O-, m = 12, and n = 48;
X = -O-n-butylene-O-, m = 21, and n = 54.
8. The composition of anyone of the preceding claims, wherein said block copolymer of the general formula (1) is contained in a proportion of 0,001 to 20%, particularly 0,001 to 15%, more particularly 0,001 to 10%, based on the total weight of the liquid composition; and/or wherein said block copolymer is capable to solubilize the small molecule with an increase of 1.000-fold compared to water, particularly of 10000 fold; and/or said small molecule is contained in a proportion of 0,0001 to 10%, particularly 0,01 to 8 %, more particularly about 0,03 to 6 %, based on the total weight of the liquid composition; and/or wherein said composition is in optionally buffered form, having a pH in the range of 5 to 9, particularly 6 to 8.
9. The composition of anyone of the preceding claims, wherein said small molecule is characterized by one or more of the following properties: a) solubility in water comprised in the range of 1 .0 *10-6 to 20 mg/L, particularly of 2.0*1 O'6 to 10 mg/L; more particularly 2.5*1 O'6 to 9 mg/L, yet more particularly of less than 100 ng/L; and/or b) molecular weight comprised in the range of 100 to 1000 g/mol, particularly 200 to 950 g/mol, more particularly 250 to 880 g/mol.
10. The composition of anyone of the preceding claims, wherein said small molecule is selected from: a) pharmaceutically active compounds (APIs), including prophylactically, therapeutically, diagnostically or even theranostically active compounds; b) artificial, or synthetic inorganic, organic or organometallic, small molecules, or natural or biological small molecules, such as lipids, phospholipids, glycolipids, sterols, vitamins, hormones, neurotransmitters, monosaccharides, which in turn may be either pharmaceutically active or essentially inactive; and in particular c) a small molecule belonging to BCS class II or IV.
11. An essentially dry composition, comprising at least one small molecule as defined in anyone of the claims 9 and 10 and at least one stabilizing ethylene oxide/butylene oxide block copolymer of the general formula (1) as defined in anyone of claims 1 to 7; which a) has a liquid content of 0% to 5% wt% based on the total weight of said composition; and optionally b) wherein said at least one block copolymer (A) and said at least one small molecule (B) are contained in a weight ratio (A) : (B) in the range of 1 : 20.000 to 10:1 , or 1 : 5.000 to 2:1 , 1 : 100 to 1 ,2 : 1 : particularly 1 : 10 to 1 ,1 : 1 ; and/or c) wherein said at least one block copolymer and said at least one small molecule together are contained in a proportion of 1 to less than 100 wt%, in particular 5 to 60 wt%, more particular 10 to 50 wt%, or 20 to 40 wt.% or 20 to 25 wt.-% based on the total weight of said essentially dry composition, and/or d) further comprising at least one further excipient in a proportion of 0,1 to 99%, 40 to 95% and 50 to 90% wt.-% based on the total dry weight of said essentially dry composition.
12. A pharmaceutical composition comprising the composition as defined in anyone of the preceding claims and optionally at least one further pharmaceutically acceptable excipient; in particular a parental formulation and more particularly an intravenous, intra-arterial, intracutaneous, intramuscular, intrathecal, intracardiac, intravitreal, intraosseous, intraperitoneal, subcutaneous, inhalation, urinary bladder, intranasal or topical formulation.
13. Use of a block copolymer of anyone the claims 1 to 7 for solubilizing at least one small molecule as defined in anyone of the claims 9 and 10 or for solubilizing a pharmaceutical formulation of at least one small molecule as defined in anyone of the claims 9 and 10.
14. The composition of anyone of claims 1 to 11, or the pharmaceutical composition of anyone of claims 12 and 13 for use in medicine, in particular for diagnostic and/or therapeutic applications.
15. A block copolymer selected from the following compounds of the general formula 1 , wherein X, m and n have the following meanings:
X = -O-n-butylene-O-, m = 5, and n = 35;
X = -O-n-butylene-O-, m = 16, and n = 40;
X = -O-n-butylene-O-, m = 12, and n = 48;
X = -O-n-butylene-O-, m = 21 , and n = 54.
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