WO2024100130A1 - Formulations vaccinales thermostables et leur procédé de préparation - Google Patents

Formulations vaccinales thermostables et leur procédé de préparation Download PDF

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Publication number
WO2024100130A1
WO2024100130A1 PCT/EP2023/081175 EP2023081175W WO2024100130A1 WO 2024100130 A1 WO2024100130 A1 WO 2024100130A1 EP 2023081175 W EP2023081175 W EP 2023081175W WO 2024100130 A1 WO2024100130 A1 WO 2024100130A1
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WO
WIPO (PCT)
Prior art keywords
vaccine
melezitose
protein
thermostability
dry
Prior art date
Application number
PCT/EP2023/081175
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English (en)
Inventor
Tobias Rosenkranz
Janet SCHACHE
Original Assignee
Merck Patent Gmbh
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
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Publication of WO2024100130A1 publication Critical patent/WO2024100130A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1617—Organic compounds, e.g. phospholipids, fats
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1682—Processes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/04—Immunostimulants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to the use of melezitose to improve thermostability of a dry protein formulation, a process for increasing the thermostability and thermally stabilized dry protein formulations. More specifically, the present disclosure relates to the use of melezitose for increasing thermostability of a dry vaccine formulation.
  • Thermostability and cold-chain interruptions are major obstacles in assuring delivery of stable vaccine doses especially to remote areas in poverty-stricken countries.
  • vaccines are refrigerated during shipping, however 25% of all liquid and 50% of all lyophilized vaccine doses shipped to developing countries are lost because continuous refrigeration cannot be guaranteed.
  • excipients and techniques for protein formulations, in particular vaccine formulations that increase thermostability of the formulations and that can withstand cold-chain interruptions without significant reduction in vaccine activity.
  • excipients that are capable of stabilizing protein formulations, in particular vaccine formulations, at temperatures of 50°C or higher.
  • melezitose can be used for increasing thermostability of a dry protein formulation at a temperature of 55°C or higher, in particular between 55°C and 80°C. It was further found that melezitose is particularly suitable to improve thermostability of a dry vaccine formulation.
  • the invention provides a process for increasing the thermostability of a dry protein formulation comprising the steps of (a) providing a liquid composition comprising a protein and melezitose, and (b) spray-drying or lyophilizing the liquid composition to yield a dry protein formulation, whereas the thermostability of the dry protein formulation is increased at a temperature of 55°C or higher.
  • the protein is a vaccine.
  • a further aspect of the invention concerns the thermally stabilized dry protein formulation, obtainable by a process for increasing the thermostability as described above.
  • An embodiment of the invention is the use of melezitose for increasing thermostability of a dry protein formulation at a temperature of 55°C or higher, preferably a dry vaccine formulation.
  • Melezitose also spelled melicitose, is a nonreducing trisaccharide sugar that is produced by many plant sap eating insects, including aphids such as Cinana pilicornis by an enzymatic reaction.
  • the IIIPAC name is (2R,3R,4S,SS,6R)-2- [[(2S,3S,4R, SR)-4-hydroxy-2,5-bis(hydroxymethyl)-3-[[(2R, 3R,4S,SS,6R)-3,4,5- trihydroxy-6-(hydroxylmethyl)-2-tetrahydropyranyl]oxy]-2-tetrahydrofuranyl]oxy]-6- (hydroxylmethyl)- tetrahydropyran-3,4,5-triol.
  • Melezitose has a molecular weight of 504.44 g/mol.
  • the respective structure is represented by the formula (I):
  • a “protein” is herein defined as a polymer of amino acids linked to each other by peptide bonds to form a polypeptide. Proteins can be naturally occurring or non- naturally occurring, synthetic, or semisynthetic. The term “protein” is understood to also cover peptides, oligopeptides, polypeptides and any therapeutic protein as defined below. Preferably the “protein” has a length sufficient to form a detectable tertiary structure.
  • the protein contained in the dry or liquid formulations according to the invention is a therapeutic protein.
  • therapeutic proteins refers to any protein or polypeptide that is administered to a subject with the aim of treating or preventing a disease or medical condition.
  • the subject may be a mammal or a human.
  • Therapeutic proteins can be administered for different purposes, such as replacing a protein that is deficient or abnormal, augmenting an existing pathway, providing a novel function or activity, interfering with a molecule or organism and delivering other compounds or proteins, such as a radionuclide, cytotoxic drug, or effector proteins.
  • Therapeutic proteins encompass antibody-based drugs, Fc fusion proteins, anticoagulants, blood factors, bone morphogenetic proteins, engineered protein scaffolds, enzymes, growth factors, hormones, interferons, interleukins, antibody drug conjugates (ADCs), thrombolytics and vaccines.
  • Therapeutic proteins can be naturally occurring proteins or recombinant proteins. Their sequence can be natural or engineered.
  • the protein dry and liquid formulations according to the invention is a vaccine.
  • a “vaccine” is herein defined as a pharmaceutical formulation designed to create an immune response. Said immune response can be directed against a current illness.
  • the vaccine would be curative. In other cases, the immune response would be directed to prevent future infectious disease.
  • Such a vaccine would be prophylactic.
  • prophylactic vaccines are protein-based vaccines such as protein or conjugate vaccines.
  • vaccines comprised of a protein to which other components for example polysaccharides can be fused to.
  • Other examples of vaccines were a subunit of a protein or virus is used.
  • viruses can be used as vaccines.
  • live and inactivated virus vaccines meaning the virus is either alive and no longer dangerous or has been inactivated.
  • Typical examples for protein-based vaccines are the tetanus toxoid or the toxoid of diphtheria.
  • the tetanus toxoid comprises of the Titanic toxin which has been inactivated by formaldehyde crosslinking.
  • the diphtheria toxoid is a protein carrying a mutation which renders it unfunctional but does not affect its three-dimensional structure. Through this mutation the protein becomes non-toxic and yet can still elicit an immune response.
  • Another example for protein-based vaccines is lactate dehydrogenase or ovalbumin.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation, wherein the vaccine is a virus vaccine or a protein-based vaccine, preferably a protein-based vaccine.
  • thermodynamics the probability that a protein may unfold spontaneously, or a larger structure may disassemble at any point in time, is increased at temperatures above the desired storage temperature. Rather than an assessment of thermostability such a study is a mere simulation of a long-term storage in an experimental setting.
  • thermostability is used in the context that a vaccine mostly stays in its native, form during storage at certain temperatures.
  • the present analytical efforts are directed to thermostability by determining the thermodynamic transition mid-points of thermally stressed proteins.
  • the effect of model molecules or of selected excipients is examined for their stabilizing effect on the structure of model proteins at a certain temperature.
  • the experiments analyze in which concentration ranges the thermostabilizing excipients are effective.
  • the biological activity of the immunogen is determined before and after exposure to high temperatures.
  • the transition mid-point T m is determined by fluorescence spectroscopy, this means by Nano-Differential Scanning Fluorimetry (nanoDSF) using a protein solution comprising the protein in a concentration of 0.05 to 1.8 mg/ml.
  • the prepared protein solution is heated with a heating rate of 1°C/minute and the ratio of the fluorescence emission at 350/330 nm is recorded and plotted vs. temperature.
  • the resulting curve resembles a Boltzmann function and the inflection point of this curve represents the mean unfolding temperature T m . From this curve the change in T m determined by subtracting T m native from T m excipient formulation, which yields to dT m .
  • thermo denaturation midpoint is also used in connection with stability of a protein, and it is defined, that a deviation of 10% in either direction as acceptable. It is important to note that any change in transition mid-point, also to higher temperatures, is a result of either a change of the protein conformation or of the data quality. The latter can for example be affected by aggregation of proteins or by numerous of other effects. Therefore, transition temperatures are required that deviate less than 10% from the initially measured value.
  • the term “increasing thermostability of a dry protein formulation” means that the formulation maintains the biological structure and or activity or pharmaceutical efficacy of a vaccine. Maintenance of biological structure can be assessed by methods like fluorescence spectroscopy and can for example be proven by verifying an unchanged transition midpoint. The biological activity can be measured via an activity essay commonly used for enzymes or an enzyme- linked immunosorbent assay (ELISA) which verifies that specific antibodies can still bind to the protein.
  • ELISA enzyme- linked immunosorbent assay
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation at a temperature of 55°C or higher, preferably at a temperature of 55°C or higher for 72 hours.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation at a temperature of 60°C or higher, preferably at a temperature of 60°C or higher for 72 hours.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation at a temperature of 70°C or higher, preferably at a temperature of 70°C or higher for 72 hours.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation at a temperature of 80°C or higher, preferably at a temperature of 80°C or higher for 72 hours.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation between 60°C or higher and 80°C or higher, preferably between 60°C or higher and 80°C or higher for 72 hours.
  • the thermostability of a dry vaccine formulation is increased at the aforementioned temperatures for the duration of 1 week.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation between 55°C and 80°C, preferably between 55°C and 80°C for 72 hours.
  • a further embodiment of the invention is the use of melezitose for increasing thermostability of a dry vaccine formulation between 60°C and 80°C, preferably between 60°C and 80°C for 72 hours.
  • a further embodiment of the invention is the above-mentioned use, wherein the dry vaccine formulation is a spray-dried or lyophilized dry vaccine formulation of a liquid composition comprising a vaccine and melezitose.
  • liquid formulation refers to an aqueous protein or vaccine composition comprising melezitose.
  • melezitose is present in an amount of up to about 4-9 % in the solution prior drying.
  • the lower limit depends on the amount of melezitose resulting in a sufficient stabilizing effect on the protein of interest.
  • the suitable amount can be readily determined by the skilled person employing the methodology of the examples and his or her general knowledge.
  • a feasible range is for example 1% to about 25% or from about 2% to about 15% related to the final formulation.
  • Preferably the melizitose concentration is higher than 3% or higher than 8%.
  • the concentration of the protein or vaccine in the liquid composition is 0.01 mg/ml to up to 5 mg/ml.
  • the mass concentration of melezitose in the liquid composition is in a 50-fold to 100-fold excess based on the mass concentration of the vaccine.
  • Liquid protein or vaccine formulations of the present invention are adjusted to a specific pH.
  • suitable buffers are added to the formulations.
  • the buffers can be added in form of a carrier fluid suitable for dissolving and/or dispersing the protein to be solved.
  • the buffer is usually selected from a pharmaceutically accepted buffer system.
  • the preferred buffer is a pharmaceutically accepted buffer system with the ability to resist a change in pH upon addition of acid, base, inorganic compound, organic compound or solvent or diluent.
  • Buffering components such as phosphate or citrate are included to control the pH of the vaccine containing solution, as well as to adjust the solution osmolarity.
  • the buffer concentration may range from 5 mM to 2 M, with the pH of the solution adjusted to a range from about pH 4 to about pH 10, preferably to a range from about pH 6 to about pH 8.
  • There are other typical buffer components such as Tris or carbonate.
  • the liquid composition additionally comprises a buffer and the pH value of the liquid composition is between 7 and 7.8, preferably between 7.4 and 7.7.
  • a pharmaceutically acceptable buffer may be selected from the group consisting of potassium phosphate, sodium phosphate, sodium acetate, histidine, imidazole, sodium citrate, sodium succinate, HEPES, Tris, Bis-Tris, ammonium bicarbonate, and other carbonates.
  • the buffer may comprise a pH ranging from about pH 4 to about pH 10, preferably from about pH 6 to pH 8, but also from about pH 6 to about pH 7.
  • the liquid formulation can contain further excipients, such as amino acids, proteins, chelating agent, salts, preservatives, stabilizers, antioxidants, emulsifiers, surfactants or polymers.
  • Polymers can be included to stabilize the protein. These polymers can be added in amounts of 0.1 % w/v and more.
  • Surfactants can be added to decrease surface tension and to displace protein molecules from the surface. Surfactants may also increase the solubility of other formulation components. Surfactants may be comprised in amounts of 0.005 % and more by weight of said protein containing formulation.
  • Divalent cations and amino acids can be included to stabilize the protein and to adjust the pH and osmolarity of the solution.
  • concentration of the divalent cation may range from 0.1 mM to about 100 mM and the amino acid may be contained in a concentration in the range from about 0.1 % to about 1% (w/v).
  • thermostability is increased, wherein the thermodynamic transition mid-point of the spray-dried vaccine remains unaffected after storing at 60°C, preferably at 60°C for 72 hours.
  • thermodynamic transition mid-point of the spray-dried vaccine remains unaffected means that any detected change between an untreated sample and a thermally stressed sample is smaller than 10%, preferably smaller than 5%.
  • thermostability is increased, wherein the vaccine activity of the spray-dried vaccine remains unaffected after storing at 60°C, preferably at 60°C for 72 hours.
  • the term “the vaccine activity of the spray-dried vaccine remains unaffected” means that any detected change in activity between an untreated and a thermally stressed sample is smaller than 10%, preferably smaller than 5%.
  • the dry protein or vaccine formulation can be prepared by various processes known to the skilled person.
  • the dry protein or vaccine formulation is prepared by spray-drying or lyophilization of a liquid composition.
  • Another aspect of the invention is a process for increasing the thermostability of a dry vaccine formulation comprising the steps of, (a) providing a liquid composition comprising a vaccine and melezitose, and (b) spray-drying or lyophilizing the liquid composition to yield a dry vaccine formulation, whereas the thermostability of the dry vaccine formulation is increased at a temperature of 55°C or higher. Additionally, a secondary drying step may be included into the process.
  • the process for increasing stability according to the invention includes all embodiments referring to the liquid composition, the concentration of melezitose, the concentration of the protein or vaccine and the increase of thermostability as mentioned above.
  • Another aspect of the invention is a thermally stabilized dry vaccine formulation, obtainable by a process as mentioned above.
  • Another aspect of the invention is a lyophilized or spray-dried dry vaccine formulation containing a vaccine and melezitose, wherein the thermostability of the dry vaccine formulation is increased at a temperature of 55°C or higher, preferably at a temperature of 55°C or higher for 72 hours.
  • the lyophilized or spray-dried dry vaccine formulation according to the invention includes all embodiments referring to the concentration of melezitose, the concentration of the protein or vaccine and the increase of thermostability as mentioned above.
  • LDH proteins (suspension in 3.2 M ammoniumsulfate, pH 7) were buffer exchanged into a 50 mM Na2HPO4, pH 7.6 without excipient in Amicon ® Ultra Centrifugal Filters - 15 mL - 30 K. The protein concentration after buffer exchange was measured.
  • Step 5 - 7 Five times until the fivefold of the buffer volume is exchanged (the volume of the LDH-solution is reduced to approximately 2 -3 mL at the end)
  • the buffer exchanged and concentrated LDH proteins were accordingly diluted with the certain excipient stock (20 %) and filled up to 20 mL with the buffer solution (50 mM Na2HPO4, pH 7.6) to obtain a 1 mg/mL protein solution w 10% excipient for spray drying.
  • the feed tube (outlet) shall not be connected to the system, otherwise disconnect the outlet tube - put the inlet tube of the pump into a milli-Q water then switch on the pump and position the lever of the pump
  • the timer can be started after the sugar solution enters the system • After half of the excipient amount is spray dried, write down the outlet temperature and the exhaust air pressure
  • Fig. 1 compares the final product yield of each run for sucrose and melezitose stabilized samples under the respective conditions. It is found that when using melezitose a higher product yield could be obtained under all conditions (Fig. 1).
  • the stressed dried samples were set back to room temperature and reconstituted into 250 pL MQ water (final 1 mg/mL protein). These samples were further analytically analyzed.
  • the melting temperature (Tm) and emission ratio 350 nm and 330 nm were determined by measuring the samples with the NT48 NanoDSF device.
  • Fig. 2 shows the thermodynamic transition mid-point of LDH stabilized with of sucrose (S) and melezitose (M) for two different conditions (4°C and 60°C, 72h) of each run.
  • thermodynamic transition mid-point remained constant for LDH under all conditions indicating the absence of major structural changes of the protein (Fig. 2).
  • Spray dried samples and the thermal stressed spray dried samples were measured at 350 nm using the Multiskan Spectrum to evaluate the turbidity of the reconstitute samples (1 mg/mL).
  • the blanking of the instrument was done using LDH which was buffer exchanged. 70 pL of the sample was pipetted into a disposable UV cuvette and measured against the reference.
  • Fig. 3 shows the turbidity of the liquid LDH formulation stabilized with of sucrose (S) and melezitose (M) for two different conditions (4°C and 60°C, 72h) of each run.
  • the final measurement [(A450)final] for calculating the enzyme activity would be penultimate reading or the value before the most active sample is near or exceeds the end of the linear range of the standard curve, see step 5.
  • Fig. 4 shows the LDH activity in formulations stabilized with of sucrose (S) and melezitose (M) for two different conditions (4°C and 60°C, 72h) of each run.

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Abstract

La présente invention concerne l'utilisation de mélézitose pour améliorer la thermostabilité d'une formulation protéique sèche, un procédé pour augmenter la thermostabilité et des formulations protéiques sèches stabilisées thermiquement. Plus spécifiquement, la présente invention concerne l'utilisation de mélézitose pour augmenter la thermostabilité d'une formulation vaccinale sèche.
PCT/EP2023/081175 2022-11-11 2023-11-08 Formulations vaccinales thermostables et leur procédé de préparation WO2024100130A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP22207039 2022-11-11
EP22207039.3 2022-11-11

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219475A1 (en) * 2002-04-11 2003-11-27 Medlmmune Vaccines, Inc. Preservation of bioactive materials by freeze dried foam
WO2008029908A1 (fr) * 2006-09-07 2008-03-13 Kyowa Hakko Kirin Co., Ltd. Préparation pharmaceutique lyophilisée stable comprenant un anticorps
US20080152673A1 (en) * 2005-02-09 2008-06-26 Stabilitech Ltd. Desiccated Product
US20110236412A1 (en) * 2008-09-24 2011-09-29 Stabilitech Ltd. Method for Preserving Polypeptides Using a Sugar and Polyethyleneimine

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20030219475A1 (en) * 2002-04-11 2003-11-27 Medlmmune Vaccines, Inc. Preservation of bioactive materials by freeze dried foam
US20080152673A1 (en) * 2005-02-09 2008-06-26 Stabilitech Ltd. Desiccated Product
WO2008029908A1 (fr) * 2006-09-07 2008-03-13 Kyowa Hakko Kirin Co., Ltd. Préparation pharmaceutique lyophilisée stable comprenant un anticorps
US20110236412A1 (en) * 2008-09-24 2011-09-29 Stabilitech Ltd. Method for Preserving Polypeptides Using a Sugar and Polyethyleneimine

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