WO2016184577A2 - Composition de poudre sèche comprenant de l'arn à chaîne longu - Google Patents

Composition de poudre sèche comprenant de l'arn à chaîne longu Download PDF

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Publication number
WO2016184577A2
WO2016184577A2 PCT/EP2016/000846 EP2016000846W WO2016184577A2 WO 2016184577 A2 WO2016184577 A2 WO 2016184577A2 EP 2016000846 W EP2016000846 W EP 2016000846W WO 2016184577 A2 WO2016184577 A2 WO 2016184577A2
Authority
WO
WIPO (PCT)
Prior art keywords
dry powder
powder composition
long
rna molecule
diseases
Prior art date
Application number
PCT/EP2016/000846
Other languages
English (en)
Other versions
WO2016184577A3 (fr
Inventor
Benyamin YAZDAN PANAH
Fabian Johannes EBER
Stefanie SEWING
Thomas Ketterer
Thorsten Mutzke
Original Assignee
Curevac Ag
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.)
Filing date
Publication date
Application filed by Curevac Ag filed Critical Curevac Ag
Priority to EP16728216.9A priority Critical patent/EP3298143A2/fr
Publication of WO2016184577A2 publication Critical patent/WO2016184577A2/fr
Publication of WO2016184577A3 publication Critical patent/WO2016184577A3/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/005—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy characterised by an aspect of the 'active' part of the composition delivered, i.e. the nucleic acid delivered
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00—Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • A61K48/0091—Purification or manufacturing processes for gene therapy compositions

Definitions

  • RNA in solution
  • RNA is typically stored at -20° C or even -80° C and under RNAse free conditions to prevent degradation of the RNA.
  • Such storage conditions do not sufficiently prevent a loss of function over time. Additionally, applying such conditions is very cost-intensive, especially for shipping and storage, e.g. whenever such low temperatures have to be guaranteed.
  • Double-stranded short interfering RNAs for inhalation were dried by using a spray-drying technology.
  • PLGA poly(D,L-lactide-co-glycolide)
  • NPs nanoparticles
  • the inventive dry powder composition does not form agglomerates or aggregates that would inhibit packaging and/or dosage. Due to its flowability, the dry powder composition according to the invention can be readily further processed. For instance, the dry powder composition can be transferred, e.g. from one vessel to another or from a larger vessel into a plurality of smaller vessels, simply by pouring. The inventive dry powder composition can readily be packaged in a variety of packages and final dosage forms according to the actual requirements.
  • the dry powder composition according to the invention provides excellent storage stability.
  • the invention provides a dry powder composition comprising a long-chain RNA molecule, wherein the long-chain RNA molecule preferably comprises at least 30 nucleotides.
  • the long-chain RNA molecule is a molecule as defined herein. More preferably, the long-chain RNA molecule is not an RNA molecule selected from the group consisting of a small interfering RNA (siRNA), a microRNA, a small nuclear RNA (snRNA), a small-hairpin (sh) RNA, a riboswitch, a ribozyme or an aptamer.
  • the long-chain RNA is not an siRNA, most preferably not a double-stranded siRNA.
  • the residual moisture content of the dry powder composition as described herein is 5% (w/w) or less, more preferably 4% (w/w) or less, even more preferably 3% (w/w) or less, 2% (w/w) or less, or 1 % (w/w) or less.
  • the residual moisture content of the dry powder composition as described herein is preferably in the range from from 0% to 5% (w/w), from 0% to 4% (w/w), from 0% to 3% (w/w), from 0% to 2% (w/w) or from 0% to 1% (w/w).
  • the dry powder composition comprising a long-chain RNA molecule comprises a plurality of particles.
  • the term “particle” typically refers to an individual solid particle of the dry powder composition.
  • the individual particles of the dry powder composition according to the invention are preferably physically separated from each other, i.e. the individual particles that constitute the dry powder may be in lose and reversible contact with each other (as opposed to an irreversible link between individual particles).
  • the term “particle” refers to the smallest physical entity of the inventive dry powder composition.
  • the particles of the inventive dry powder composition do preferably not stick to each other.
  • the particulate nature of the formulation contributes to the superior characteristics of the inventive dry powder composition, e.g. its free flowability.
  • the parameter "Dv10" corresponds to the cut-off size (preferably in pm) of the particles in a volume weighted distribution, which represent 0% of the total volume of the sample, and which have a particle size equal to or smaller than the Dv 0 value.
  • the Dv10 of the dry powder composition according to the invention is at least 0.2, 0.3, 0.4, 0.5, 1 , 2, 3, 4, 5, 6, 7, 8, 9, or 10 pm. More preferably, the Dv10 of the dry powder composition is equal to or lower than 5, equal to or lower than 10, or equal to or lower than 20 pm. Most preferably, the Dv10 is in a range from 1 pm to 10 pm or from about 3 pm to about 5 pm.
  • the MMAD of the dry powder composition according to the invention is equal to or less than 1.500, 1.250, 1.000, 750, 600, 500, 400, 300, 200 or 100 pm. Further preferably, the MMAD may be in a range from 0.3 pm to 2.000 pm, from 1 pm to 1.000 pm, from 2 pm to 500 pm or from 2 pm to 200 pm. In a preferred embodiment, the MMAD of the dry powder composition is at least 1 pm or in the range from 1 to 200 pm. In a particularly preferred embodiment, the MMAD of the dry powder composition is at least 3 pm, at least 5 pm or at least 20 pm.
  • the inventive dry powder composition is characterized by a low span value, which indicates a narrow (or more homogeneous) particle size distribution. Typically, a narrow distribution enhances the flowability of the dry powder composition.
  • the span of the dry powder composition according to the present invention is equal to or less than 5, more preferably equal to or less than 4, and even more preferably equal to or less than 3.
  • the particle size distribution of the dry powder composition according to the invention is characterized by a span of equal to or less than about 2 or a span of equal to or less than about 1.5.
  • the dry powder composition according to the invention consists of particles, which are characterized by a sphericity of at least 0.7, preferably at least 0.75, at least 0.8, at least 0.85, at least 0.9, at least 0.95 or 1.
  • the dry powder composition consists of particles with a sphericity in the range from 0.7 to 1 , more preferably in the range from 0.8 to 1 , from 0.85 to 1 , or from 0.9 to 1.
  • the average sphericity of those particles of the dry powder composition that have a particle size equal to or lower than Dv90 as defined herein is at least 0.7, preferably of at least 0.75, at least 0.8, at least 0.85, at least 0.9, at least 0.95 or 1.
  • the average sphericity of those particles of the dry powder composition that have a particle size equal to or lower than Dv90 as defined herein is in the range from 0.7 to 1 , more preferably in the range from 0.8 to 1 , from 0.85 to 1 , or from 0.9 to 1.
  • the term "RNA" is used as abbreviation for ribonucleic acid.
  • the inventive dry powder composition comprises a solvent, preferably in the amounts as defined herein with respect to the residual moisture content of the dry powder composition.
  • the solvent is a residue of a solvent, which was used during preparation of the dry powder composition, a residue of which may be present in the inventive dry powder composition.
  • the solvent contained in the inventive dry powder composition is a residue of a solvent used during preparation of the dry powder composition by using the inventive method as described herein.
  • the solvent comprised in the dry powder composition according to the invention is suitable for use in spray drying and/or spray-freeze drying.
  • a solvent is comprised in the inventive composition, in which the long-chain RNA and any other component comprised in the composition, if present, are soluble.
  • a buffer as defined herein may also be a mannose containing buffer, an isotonic buffer or solution, preferably selected from isotonic saline, a lactate or ortho-lactate-containing isotonic solution, a isotonic buffer or solution selected from phosphate-buffered saline (PBS), TRIS-buffered saline (TBS), Hank's balanced salt solution (HBSS), Earle's balanced salt solution (EBSS), standard saline citrate (SSC), HEPES-buffered saline (HBS), Grey's balanced salt solution (GBSS), or normal saline (NaCI), hypotonic (saline) solutions with addition of glucose or dextrose, or any solution as defined herein, etc.
  • PBS phosphate-buffered saline
  • TRIS-buffered saline TRIS-buffered saline
  • HBSS Hank's balanced salt solution
  • EBSS Earle's balanced salt
  • a rotary atomizer is used as atomizer in the spray-drying or spray- freeze drying process.
  • Rotary atomizers exploit the energy of high-speed rotation to produce fine droplets.
  • the liquid feed is introduced into a reservoir, typically in the center of the rotary wheel.
  • the spray-drying or spray-freeze drying device preferably reduces the residual moisture content of the composition to the desired level, preferably as defined herein, in one pass through the system. If the moisture content of the product after one cycle is higher than desired, the moisture content of the powder may be further reduced by a second drying stage (or several of those) until the desired residual moisture content of the product is achieved.
  • the method comprises spray-freeze drying of the liquid comprising a long-chain RNA molecule.
  • the spray-freeze drying process may occur in bulk or as a continuous process, for example through a barrel lyophilizer.
  • the droplets formed by atomization are frozen immediately upon atomization.
  • the liquid feed is atomized, wherein the outlet of the atomizer is exposed to a coolant.
  • the atomizer is a rotary atomizer, a pressure nozzle, a vibrating orifice aerosol generator (VOAG), an ultrasonic nebulizer or a fountain nozzle.
  • the atomizer preferably sprays the droplets into the coolant.
  • inventive pharmaceutical composition may be administered orally, parenterally, by inhalation, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir.
  • parenteral as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional, intracranial, transdermal, intradermal, intrapulmonal, intraperitoneal, intracardial, intraarterial, and sublingual injection or infusion techniques.
  • Figure 2 Scheme of a continuous spray-freeze drying process line showing the three process compartments (A: droplet formation through nozzle; cooling and fast freezing of droplets to particles; B: continuous freeze-drying drum; C: flexible multi or single-dose packaging of bulk powder).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Veterinary Medicine (AREA)
  • Biotechnology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Manufacturing & Machinery (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)

Abstract

La présente invention concerne une formulation d'ARN à chaîne longue stable au stockage. En particulier, l'invention concerne une composition de poudre sèche comprenant une molécule d'ARN à chaîne longue. La présente invention concerne en outre des procédés de préparation d'une composition de poudre sèche comprenant une molécule d'ARN à chaîne longue par séchage par atomisation ou pulvérisation-cryodessiccation. L'invention concerne en outre l'utilisation de ladite composition de poudre sèche comprenant une molécule d'ARN à chaîne longue dans la préparation de compositions pharmaceutiques et de vaccins, un procédé de traitement ou de prévention d'un trouble ou d'une maladie, une première et une seconde utilisations médicales de ladite composition de poudre sèche comprenant une molécule d'ARN à chaîne longue et des kits, en particulier des kits de parties, comprenant ladite composition de poudre sèche comprenant une molécule d'ARN à chaîne longue.
PCT/EP2016/000846 2015-05-20 2016-05-20 Composition de poudre sèche comprenant de l'arn à chaîne longu WO2016184577A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP16728216.9A EP3298143A2 (fr) 2015-05-20 2016-05-20 Composition de poudre sèche comprenant de l'arn à chaîne longu

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP15001517 2015-05-20
EP15001517.0 2015-05-20

Publications (2)

Publication Number Publication Date
WO2016184577A2 true WO2016184577A2 (fr) 2016-11-24
WO2016184577A3 WO2016184577A3 (fr) 2017-01-12

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PCT/EP2016/000846 WO2016184577A2 (fr) 2015-05-20 2016-05-20 Composition de poudre sèche comprenant de l'arn à chaîne longu

Country Status (2)

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EP (1) EP3298143A2 (fr)
WO (1) WO2016184577A2 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10507183B2 (en) 2011-06-08 2019-12-17 Translate Bio, Inc. Cleavable lipids
US11865084B2 (en) 2016-12-23 2024-01-09 CureVac SE MERS coronavirus vaccine

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070172430A1 (en) * 2006-01-20 2007-07-26 Nastech Pharmaceutical Company Inc. Dry powder compositions for rna influenza therapeutics
WO2011069529A1 (fr) * 2009-12-09 2011-06-16 Curevac Gmbh Solution contenant du mannose pour la lyophilisation, la transfection et/ou l'injection d'acides nucléiques
WO2011069528A1 (fr) * 2009-12-09 2011-06-16 Curevac Gmbh Lyophilisation d'acides nucléiques dans des solutions contenant du lactate

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10507183B2 (en) 2011-06-08 2019-12-17 Translate Bio, Inc. Cleavable lipids
US10702478B2 (en) 2011-06-08 2020-07-07 Translate Bio, Inc. Cleavable lipids
US11234936B2 (en) 2011-06-08 2022-02-01 Translate Bio, Inc. Cleavable lipids
US11865084B2 (en) 2016-12-23 2024-01-09 CureVac SE MERS coronavirus vaccine

Also Published As

Publication number Publication date
EP3298143A2 (fr) 2018-03-28
WO2016184577A3 (fr) 2017-01-12

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