EP-4740935-A1 - FORMULATION OF OLIGONUCLEOTIDE DRUGS FOR INHALATION

Abstract

The present invention relates to a formulation for inhalation comprising an active agent which is an oligonucleotide drug and further constituents. The formulation is stable when stored for extended time as well as during aerosolization and physiologically well tolerated.

Inventors

• Frischmuth, Thomas.
• Engelhardt, Stefan.
• Beck, Christina.
• Schmidt, Johannes.

Assignees

• RNATICS GmbH
• Technische Universität München, in Vertretung des Freistaats Bayern

Dates

Publication Date

20260513

Application Date

20241111

Claims (15)

1. A formulation for inhalation consisting of or comprising (i) an active agent which is an oligonucleotide drug; (ii) NaCl; (iii) water; and (iv) optionally a buffer.
2. The formulation of claim 1, which is a ready-to-use formulation.
3. The formulation of claim 1, which is a reconstitutable formulation.
4. The formulation of any one of claims 1-3, which is for oral inhalation.
5. The formulation of any one of claims 1-4, which is a single-dose formulation.
6. The formulation of any one of claims 1-3, wherein the oligonucleotide drug is present in an amount of about 1 mg/ml to about 100 mg/ml, about 5 mg/ml to about 50 mg/ml, about 5 mg/ml to about 20 mg/ml, about 13 mg/ml to about 15 mg/ml, or about 14 mg/ml based on the volume of liquid.
7. The formulation of any one of claims 1-5, wherein NaCl is present in an amount of about 7 mg/ml to about 11 mg/ml, about 8 mg/ml to about 10 mg/ml or particularly about 9 mg/ml based on the volume of liquid.
8. The formulation of any one of claims 1-7, wherein the pH is about 5.0 to about 8.0, particularly about 6.0.
9. The formulation of any one of claims 1-8, wherein the oligonucleotide drug is a miR-21 antagonist.
10. The formulation of any one of claims 1-9, wherein the oligonucleotide drug is RCS-21 or a physiologically acceptable salt thereof: wherein the capital letters T , C, A and G in the oligonucleotide moiety represent nucleotide building blocks comprising the nucleobases thymine, 5-methyl cytosine, adenine, and guanine, respectively, the lower-case letter s represents a phosphorothioate internucleosidic bond between two nucleotide building blocks, the lower-case letter b after a capital letter denotes a locked nucleotide building block having a 2'-O-CH 2 -4' bridge, and the lower-case letter d before a capital letter denotes a 2'-deoxyribonucleotide building block.
11. The formulation of any one of claims 1-10, wherein the buffer is a phosphate buffer, particularly a sodium phosphate buffer.
12. The formulation of any one of claims 1-11, which consists of components (i), (ii), and (iii) or which consists of components (i), (ii), (iii) and (iv).
13. The formulation of any one of claims 1-12 for use in human medicine.
14. The formulation of any one of claims 1-13 for use in the treatment of a disorder selected from pneumonia, COPD, a viral infection, cancer, and an inflammatory lung disease.
15. A method of treating a subject in need thereof, comprising administering to said subject a therapeutically effective amount of a formulation by inhalation, wherein the formulation comprises (i) an active agent which is an oligonucleotide; (ii) NaCl; (iii) water; and (iv) optionally a buffer.

Description

Field of the Invention The present invention relates to a formulation for inhalation comprising an active agent which is an oligonucleotide drug and further constituents. The formulation is stable when stored for extended time as well as during aerosolization and physiologically well tolerated. Background of the Invention In the treatment of respiratory tract disorders, drugs are frequently administered by inhalation. For this purpose, stable formulations having a long shelf-life are needed. On the other hand, the formulations should be physiologically tolerable. WO 2021/205032, the content of which is herein incorporated by reference, discloses inhibitors of miR-21 which may be administered by inhalation. These inhibitors may comprise an oligonucleotide drug, e.g., an antisense molecule directed against microRNA-21 (miR-21) conjugated to a targeting moiety for delivery to lung fibroblasts and/or lung macrophages. No specific formulations for inhalation are described. The publication by Beck et al. (Nature Communications 14 (2023): 4564; doi.org/10.1038/s41467-023-40185-1), the content of which is herein incorporated by reference, discloses a trimannose-conjugated antisense inhibitor of microRNA-21, designated RCS-21, as a therapeutic agent against hyperinflammation and fibrosis. No specific formulations for inhalation are described. It was an objective of the present invention to provide a stable and physiologically tolerable formulation for inhalation comprising as an active agent an oligonucleotide drug, particularly a conjugate of an oligonucleotide with a targeting moiety. Summary of the Invention A first aspect of the present invention is a formulation for inhalation comprising and particularly consisting of (i) an active agent which is an oligonucleotide drug;(ii) NaCl;(iii) water; and(iv) optionally a buffer. A further aspect of the present invention is a formulation for inhalation as described above for use in medicine, particularly in human medicine. Still a further aspect of the present invention is a method of treating a subject in need thereof, particularly a human subject, comprising administering to said subject a therapeutically effective amount of a formulation by inhalation, wherein the formulation consists of or comprises (i) an active agent which is an oligonucleotide drug;(ii) NaCl;(iii) water; and(iv) optionally a buffer. In certain embodiments, the oligonucleotide drug is a conjugate comprising an oligonucleotide moiety and a targeting moiety for delivering the oligonucleotide moiety to a predetermined target cell, e.g., a macrophage. In certain embodiments, the targeting moiety is a carbohydrate moiety, e.g., a trimannose moiety. In even more particular embodiments, the oligonucleotide drug is compound RCS-21 or a physiologically acceptable salt thereof: wherein the capital letters T, C, A and G in the oligonucleotide moiety represent nucleotide building blocks comprising the nucleobases thymine, 5-methyl cytosine, adenine, and guanine, respectively,the lower-case letter s represents a phosphorothioate internucleosidic bond between two nucleotide building blocks,the lower-case letter b after a capital letter denotes a locked nucleotide building block having a 2'-O-CH2-4' bridge, andthe lower-case letter d before a capital letter denotes a 2'-deoxyribonucleotide building block. Detailed description The present inventors have prepared aqueous liquid formulations comprising the oligonucleotide drug RCS-21 and tested their stability under different storage conditions. They found that the oligonucleotide drug remains stable after storage over an extended time period at -20°C, +5°C, +25°C and +40°C as determined by assessment of clarity and color of the solution as well as concentration, purity and impurity profile of the active agent. Further, the inventors found that the formulations are very well suited for aerosolization, e.g., using a mesh or a jet nebulizer, generating a wet aerosol without foam formation and allowing the administration of a high dose rate. In addition, the inventors found, that the drug substance in the aerosolized liquid formulations is stable during the aerosolization process and stays intact. Furthermore, the formulations have a high safety and tolerability in experimental animals. In certain embodiments, the formulation of the present invention is stable when stored for at least 3 months, for at least 6 months, for at least 9 months, for at least 12 months, or for at least 18 months at -20°C. In certain embodiments, the formulation of the present invention is stable when stored for at least 1 month, for at least 3 months, or for at least 12 months at +5°C. In certain embodiments, the formulation of the present invention is stable when stored for at least 1 month, for at least 3 months, for at least 6 months or for at least 12 months at +25°C. In certain embodiments, the formulation of the present invention is stable when stored for at least 1 month at +40°C. In