Novel formulations for oral administration of oligonucleotides

Abstract

The present invention provides novel pharmaceutical compositions for oral delivery of an oligonucleotide to a patient, as well as uses of those compositions.

Description

[0001] Applicant’s Ref.: P39435-WO-1 Novel formulations for oral administration of oligonucleotides FIELD OF THE INVENTION The present invention relates to the field of solid oral dosage forms, and in particular to tablet formulations for oral administration of oligonucleotides. BACKGROUND OF THE INVENTION To date, there is no marketed orally administered oligonucleotide therapeutics and only a few orally administered oligonucleotides are in clinical development showing minimal systemic absorption. The oral delivery of an oligonucleotide presents several challenges such as the molecule being susceptible to degradation by the acidic environment in the stomach and proteolytic enzymes throughout the gastrointestinal (GI) tract (Liu et al., Scientific Reports 5, Article number: 11936 (2015)). Furthermore, oligonucleotide therapeutics generally have large molecular weight and are hydrophilic, which hinders the molecule to permeate across the lipophilic cell membranes of the GI tract. Pharmaceutical formulations comprising an absorption enhancer (or permeation enhancer) such as Sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) or sodium caprate (C10) for the oral delivery of peptides or proteins have been described in several patent documents (WO2011 / 094531, WO2012 / 080471, WO2013 / 139694, WO2016 / 120378, WO2016 / 120380, WO2022 / 058465 and US2022 / 184112). However, peptide molecules are considerably smaller in molecular size compared to oligonucleotide, so despite the progress in preclinical and clinical evaluations of oral delivery of macromolecules, a drug product for oral delivery of an oligonucleotide has yet to reach the market. In particular, WO2022 / 058465 discloses compositions which require a coating to make them gastro-resistant when formulated as solid oral dosage forms. Therefore, pharmaceutical formulations providing increased oral bioavailability of oligonucleotide therapeutics by means of higher stability in the gastrointestinal tract and enhanced permeability are highly desirable and offer a painless and convenient route of administration. BRIEF DESCRIPTION OF THE FIGURES Fig.1: Stability of GalNAc-conjugated oligonucleotide (HBV-LNA) in simulated gastric fluid (SGF) at pH 2 and 37 °C. Fig. 2: The dissolution rates (Release %) of oligonucleotide from tablets with different C10 : sorbitol ratios and HBV-LNA load (GalNAc-conjugated). The designation A1 / A2 (A); and A5 / A6 / A7 (B) corresponds to the respective compositions in Table 1. Fig.3: The dissolution rates (Release %) of oligonucleotide from tablets with different HIF1a load (non GalNAc-conjugated): The designation B1 / B2 (A); B3 / B4 (B) and B5 / B6 / B7 (C) corresponds to the respective compositions in Table 1. Fig.4: The buffering effect of the tablets as determined in 110 ml SGF at pH 2 at 37 °C using a heated magnetic stirrer operating at 150 rpm. The designation A1 to A7 corresponds to the respective compositions in Table 1. Fig.5: The dissolution rates (Release %) of oligonucleotide C (ASO factor B) from tablets with different C10 : sorbitol ratios: The designation C5 / C6 / C7 corresponds to the respective compositions in Table 1. Fig.6: The dissolution rates (Release %) of oligonucleotide D (PDL1-LNA) from tablets with different C10 : sorbitol ratios: The designation D5 / D6 / D7 corresponds to the respective compositions in Table 1. SEQUENCE LISTINGS SEQ ID NO.1: Sequence of oligonucleotide A SEQ ID NO.2: Sequence of oligonucleotide B SEQ ID NO.3: Sequence of oligonucleotide C SEQ ID NO.4: Sequence of oligonucleotide D DETAILED DESCRIPTION OF THE INVENTION The present invention provides a pharmaceutical composition for oral delivery of an oligonucleotide to a patient. In accordance with the present invention said composition comprises an oligonucleotide, an absorption enhancer and solubilizer (such as e.g. sorbitol). The present compositions have useful pharmacological properties in the sense that they improve the release of an oligonucleotide drug from the tablets into the gastric fluids. The improved release of said oligonucleotide and its subsequent stability in acidic fluids, which are typically found in the human stomach, is achieved by an effective buffering of the pH in the environment of release, e.g. in a patient’s gastric fluids, by the present compositions. More particularly, the present compositions have demonstrated the ability to effectively increase the pH in simulated gastric fluids. This effect contributes to the stability and improved release profile of the oligonucleotides from the tablets in accordance with the present invention. In accordance with the present invention, it has been found that no coating (enteric coating) is required to provide sufficient protection to oligonucleotides against degradation acidic conditions such as the gastric media. That means the combination of permeation enhancer and soluble filler according to the present invention enables a fast dissolution of both permeation enhancer and oligonucleotide resulting in a fast buffering (increase in pH). Therefore, a simpler and cheaper manufacturing process can be enabled still allowing for adequate protection in gastric media. In addition, the oral dosage forms, such as e.g. tablets, prepared from compositions in accordance with the present invention can be manufactured by standard dry manufacturing processes, such as direct compression or roller compaction, which not only enables a simpler manufacturing process but is also of advantage in case of moisture sensitive Active Pharmaceutical Ingredients, (APIs) such as e.g. certain oligonucleotide drugs. The term “oligonucleotide”, or “oligonucleotide drug”, has the meaning generally understood by a skilled person. In one embodiment said term means a molecule comprising two or more covalently linked nucleotides, and having therapeutic activity. In one embodiment oligonucleotides of the present invention comprise from 10 to 40 nucleotides, preferably 10 to 25 nucleotides in length. The oligonucleotides may consist of optionally modified DNA, RNA or LNA nucleoside monomers or combinations thereof. The LNA nucleoside monomers are modified nucleosides which comprise a linker group or a bridge between C2’ and C4’ of the ribose sugar ring of a nucleotide. These nucleosides are also termed bridged nucleic acid or bicyclic nucleic acid (BNA) in the literature. In one preferred embodiment, an oligonucleotide in accordance with the present invention is selected from oligonucleotide A, B, C and / or D as defined in the accompanying working examples. In another preferred embodiment, an oligonucleotide in accordance with the present invention is an oligonucleotide independently selected from SEQ ID NOs 1, 2, 3 and 4 as defined herein. In another preferred embodiment an oligonucleotide in accordance with the present invention is the oligonucleotide with the INN sefaxersen. Sefaxersen is available from Ionis Pharmaceuticals, Inc. (Carlsbad, CA). The term “optionally modified” as used herein refers to nucleosides modified as compared to the equivalent DNA, RNA or LNA nucleoside by the introduction of one or more modifications of the sugar moiety or the nucleobase moiety. In a preferred embodiment the modified nucleoside comprises a modified sugar moiety, and may for example comprise one or more 2’ substituted nucleosides and / or one or more LNA nucleosides. The term modified nucleoside may also be used herein interchangeably with the term “nucleoside analogue” or modified “units” or modified “monomers”. In one embodiment, the DNA, RNA or LNA nucleosides are linked by a phosphodiester (P=O) and / or a phosphorothioate (P=S) internucleoside linkage which covalently couples two nucleosides together. Accordingly, in some oligonucleotides all internucleoside linkages may consist of a phosphodiester (P=O), in other oligonucleotides all internucleoside linkages may consist of a phosphorothioate (P=S) or in still other oligonucleotides the sequence of internucleoside linkages vary and comprise both phosphodiester (P=O) and phosphorothioate (P=S) internucleoside. The nucleobase moieties may be indicated by the letter code for each corresponding nucleobase, e.g. A, T, G, C or U, wherein each letter may optionally include modified nucleobases of equivalent function. For example, in the exemplified oligonucleotides, the nucleobase moieties are described with capital letters A, T, G and MeC (5-methyl cytosine) for LNA nucleoside and with small letters a, t, g, c and Mec for DNA nucleosides. Modified nucleobases include but are not limited to nucleobases carrying protecting groups such as tert-butylphenoxyacetyl, phenoxyacetyl, benzoyl, acetyl, isobutyryl or dimethylformamidino. Preferably the oligonucleotide consists of optionally modified DNA, RNA or LNA nucleoside monomers or combinations thereof and is 10 to 40, preferably 10 to 25 nucleotides in length. The oligonucleotide can be 5’ amino modified which signifies that an amino linker is attached to the 5’ terminal group of the oligonucleotide. The linker preferably is an aliphatic alkyl group of 2 to 12 carbon atoms or an ethylene glycol linker containing 1 to 10 ethylene glycol units. The preferred 5’ amino-modifier is selected from an optionally amino group protected amino C2-12- alkyl linker or an amino ethylene glycol linker containing 1 to 10 ethylene glycol units. Suitable amino protecting groups for the 5’ amino modified oligonucleotide are trifluoroacetyl (TFA) or monomethoxytrityl (MMT). In one embodiment, the amino linker is introduced via a commercially available amino linker phosphoroamidite such as for instance via the TFA- or MMT-C6-linker phosphoroamidites e.g. from Sigma Aldrich or via the 5’ amino modifier TEG (tri ethyleneglycol) CE phosphoroamidite from Glen Research. The described principles of the oligonucleotide synthesis are well known in the art (see Wikipedia contributors. "Oligonucleotide synthesis" Wikipedia, The Free Encyclopedia., 19 Jan.2021. Web.16 Feb.2021). Larger scale oligonucleotide synthesis can be carried out automatically using computer controlled synthesizers. In one embodiment, oligonucleotide synthesis is a solid-phase synthesis, wherein the oligonucleotide being assembled is covalently bound, via its 3'-terminal hydroxy group, to a solid support material and remains attached to it over the entire course of the chain assembly. Suitable supports are the commercially available macroporous polystyrene supports like the Primer support 5G from GE Healthcare or the NittoPhase®HL support from Kinovate, or controlled pore glass supports like the nucleobase pre-loaded support from LGC. The oligonucleotide synthesis in principle is a stepwise addition of nucleotide residues to the 5'-terminus of the growing chain until the desired sequence is assembled. As a rule, each addition is referred to as a synthetic cycle and in principle consists of the chemical reactions al) de-blocking the protected hydroxyl group on the solid support, a2) coupling the first nucleoside as activated phosphoramidite with the free hydroxyl group on the solid support, a3) oxidizing or sulfurizing the respective P-linked nucleoside to form the respective phosphodiester (P=0) or the respective phosphorothioate (P=S); a4) optionally, capping any unreacted hydroxyl groups on the solid support; a5) de-blocking the 5’ hydroxyl group of the first nucleoside attached to the solid support; a6) coupling the second nucleoside as activated phosphoramidite to form the respective P-linked dimer; a7) oxidizing or sulfurizing the respective P-linked dinucleoside to form the respective phosphodiester (P=0) or the respective phosphorothioate (P=S); a8) optionally, capping any unreacted 5’ hydroxyl groups; a9) repeating the previous steps a5 to a8 until the desired sequence is assembled. The subsequent cleavage from the resin can be performed with concentrated aqueous ammonia. The protecting groups on the phosphate and the nucleotide base are also removed within this cleavage procedure. In a further embodiment the oligonucleotide may comprise cell targeting moieties for targeting the oligonucleotide to a given receptor, such as for instance the asialoglycoprotein receptor (c.f. X.Huang et al, Bioconjugate. Chem.2017, 28, 283-295). In a preferred embodiment the cell targeting moiety comprises 1 to 3 N-acetyl galactosamine (GalNAc) ligands. GalNAc comprising cell targeting moieties are known to a person of skill in the art. In one embodiment, GalNAc comprising cell targeting moieties can be selected from formulas (I), (II), (III) or (IV) 5

[0002] (IV); or from moieties of the formula (V) wherein R2is hydrogen or a hydroxy protecting group and n is an integer from 0 to 10, preferably an integer from 0 to 5, more preferably from 1 to 3, but most preferred is 2, enantiomers and / or a stereoisomer thereof. Suitable hydroxy protecting groups are acyl, particularly the C1-12-alkylcarbonyl group, more particularly the C1-6-alkylcarbonyl group which is optionally substituted by C1-6-alkyl or phenyl. More preferred is acetyl, pivaloyl or benzoyl, whereby acetyl is the most preferred hydroxy protecting group. In a more preferred embodiment the GalNAc comprising cell targeting moieties can be selected from the moiety of formula V. In a further preferred embodiment the oligonucleotide is a GalNAc oligonucleotide conjugate comprising a 5’ amino modified oligonucleotide as described above. Absorption enhancers In one embodiment the composition of the invention comprises one absorption enhancer, wherein the enhancer is selected from a salt of N-(8-(2-hydroxybenzoyl) amino) caprylic acid, preferably the sodium salt, or a fatty acid consisting of 6-14 carbon atoms or a salt hereof. Salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid The structural formula of the sodium salt of N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC) is shown in formula (VI) While the sodium cation is the preferred counter ion, the absorption enhancers used in the present invention can be any salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC). In some embodiments the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid comprises one monovalent cation, two monovalent cations or one divalent cation. In one embodiment the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt, potassium salt and / or the ammonium salt. In one embodiment the salt of N-(8-(2- hydroxybenzoyl)amino)caprylic acid is the sodium salt or the potassium salt. In one embodiment the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is selected from the group consisting of the sodium salt and the ammonium salt. Salts of N-(8-(2- hydroxybenzoyl)amino)caprylic acid may be prepared using the method described in e.g. WO96 / 030036, WO00 / 046182, WO01 / 092206, WO2008 / 028859. The salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid may be crystalline and / or amorphous. In some embodiments the absorption enhancer comprises the anhydrate, monohydrate, dihydrate, trihydrate, a solvate or one third of a hydrate of the salt of N-(8-(2- hydroxybenzoyl)amino)caprylic acid as well as combinations thereof. In some embodiments one absorption enhancer is the sodium salt of N-(8-(2- hydroxybenzoyl)amino)caprylic acid sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (referred to as “SNAC” herein), also known as sodium 8-(salicyloylamino)octanoate. Fatty acid or salt hereof In one embodiment, the compositions according to the invention comprises a second absorption enhancer which is a medium chain fatty acid consisting of 6-14 carbon atoms or a salt hereof. In one embodiment the fatty acid consists of 8-12 carbon atoms, such as 8, 10 or 12 carbon atoms. In one embodiment the fatty acid is a saturated fatty acid. In one embodiment the absorption enhancer is capric acid or a salt hereof. Capric acid may also be referred to as decanoic acid (CH3(CH2)8COOH). In one embodiment the salt of capric acid is sodium caprate (i.e. CH3(CH2)8COONa). Composition The composition or pharmaceutical composition of the present invention is a solid or dry composition suited for administration by the oral route as described further herein below. In some embodiments the composition comprises at least one pharmaceutically acceptable excipient. The term "excipient" as used herein broadly refers to any component other than the active therapeutic ingredient(s) or active pharmaceutical ingredient(s) (API(s)) which in the present application is referred to as oligonucleotide. The excipient may be a pharmaceutically inert substance, an inactive substance, and / or a therapeutically or medicinally non-active substance. The excipient may serve various purposes, e.g. as a carrier, vehicle, filler, binder, lubricant, glidant, disintegrant, flow control agent, crystallization inhibitors, solubilizer, stabilizer, coloring agent, flavoring agent, surfactant, emulsifier or combinations of thereof and / or to improve administration, and / or absorption of the therapeutically active substance(s) or active pharmaceutical ingredient(s). The amount of each excipient used may vary within ranges conventional in the art. Techniques and excipients which may be used to formulate oral dosage forms are described in Handbook of Pharmaceutical Excipients, 8th edition, Sheskey et al., Eds., American Pharmaceuticals Association and the Pharmaceutical Press, publications department of the Royal Pharmaceutical Society of Great Britain (2017); and Remington: the Science and Practice of Pharmacy, 22nd edition, Remington and Allen, Eds., Pharmaceutical Press (2013). In one embodiment, excipients are selected from binders, such as polyvinyl pyrrolidone (povidone), hydroxypropyl cellulose and hydroxypropyl methylcellulose, etc.; fillers such as cellulose powder, microcrystalline cellulose, cellulose derivatives like hydroxy methylcellulose, hydroxyethylcellulose, hydroxypropyl cellulose and hydroxypropyl methylcellulose, dibasic calcium phosphate, corn starch, pregelatinized starch, isomalt, mannitol, sorbitol, lactose etc.; disintegrants such as crospovidone, sodium starch glycolate, sodium croscarmellose; lubricants and / or glidants such as stearic acid, magnesium stearate, sodium stearyl fumarate, glycerol tribehenate, etc.; flow control agents such as colloidal silica, talc, etc.; crystallization inhibitors such as Povidone, etc.; solubilizers such as poloxamer, Povidone, etc.; coloring agents, including dyes and pigments such as iron oxide red or yellow, titanium dioxide, talc, etc.; pH control agents such as citric acid, tartaric acid, fumaric acid, sodium citrate, dibasic calcium phosphate, dibasic sodium phosphate, magnesium oxide, sodium bicarbonate, meglumine, etc.; surfactants and emulsifiers such as poloxamer, polyethylene glycols, sodium carboxymethyl cellulose, polyethoxylated and hydrogenated castor oil, etc.; and mixtures of two or more of these excipients and / or adjuvants. In some embodiments the composition comprises a binder, such as povidone, starches, celluloses and derivatives thereof, such as microcrystalline cellulose, e.g., Avicel PH from International Flavors & Fragrances Inc. (IFF), hydroxypropyl cellulose, hydroxyethyl cellulose and hydroxypropyl methylcellulose (METHOCEL) from IFF; sucrose; dextrose; corn syrup; polysaccharides; and gelatin. The binder may be selected from the group consisting of dry binders and / or wet granulation binders. Suitable dry binders are, e.g., cellulose powder and microcrystalline cellulose, such as Avicel PH 102 and Avicel PH 200. In some embodiments the composition comprises Avicel, such as Avicel PH 102. Suitable binders for wet granulation or dry granulation are corn starch, polyvinyl pyrrolidone (povidone), vinylpyrrolidone-vinyl acetate copolymer (co-povidone) and cellulose derivatives like hydroxyethyl cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose and hydroxyl- propylmethyl cellulose. In some embodiments the composition comprises povidone. In some embodiments the composition comprises a filler which may be selected from lactose, mannitol, erythritol, sucrose, sorbitol, calcium phosphate, such as calcium hydrogen phosphate, microcrystalline cellulose, powdered cellulose, confectioner's sugar, compressible sugar, dextrates, dextrin and dextrose. In some embodiments the composition comprises microcrystalline cellulose, such as Avicel PH 102 or Avicel PH 200. In one embodiment, the filler is sorbitol. In some embodiments the composition comprises a lubricant and / or a glidant. In some embodiments the composition comprises a lubricant and / or a glidant, such as talc, magnesium stearate, calcium stearate, zinc stearate, glyceryl behenate, glyceryl dibehenate, behenoyl polyoxyl-8 glycerides, polyethylene oxide polymers, sodium lauryl sulfate, magnesium lauryl sulfate, sodium oleate, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oils, silicon dioxide and / or polyethylene glycol etc. In some embodiments the composition comprises sodium stearyl fumarate, magnesium stearate or glyceryl dibehenate (such as the product Compritol® 888 ATO). In one embodiment the composition comprises sodium stearyl fumarate. In some embodiments the composition comprises a disintegrant, such as sodium starch glycolate, polacrilin potassium, sodium starch glycolate, crospovidone, croscarmellose, sodium carboxymethylcellulose or dried corn starch. The composition may comprise one or more surfactants, for example a surfactant, at least one surfactant, or two different surfactants. The term “surfactant” refers to any molecules or ions that are comprised of a water-soluble (hydrophilic) part, and a fat-soluble (lipophilic) part. The surfactant may e.g. be selected from the group consisting of anionic surfactants, cationic surfactants, nonionic surfactants, and / or zwitterionic surfactants. In some embodiments, the present composition comprises a polyol. The function of said polyol is to increase the dissolution rate of the formulation and / or to improve the release of the oligonucleotide from the formulation or dosage form (e.g. a tablet). The term “polyol” refers to a compound containing multiple hydroxyl groups and, in some cases, may also be referred to as a “sugar alcohol.” Non-limiting examples of polyols include mannitol, maltitol, sorbitol, xylitol, erythritol, isomalt, and the like. In some embodiments, a polyol is included in an oral dosage form, such as a tablet, as described herein. In one embodiment, the polyol is sorbitol, preferably in the amounts and / or ratios used in the accompanying working examples. Dosage form The composition may be administered in several dosage forms, for example as a tablet, a coated tablet, a sachet or a capsule, such as hard or soft shell capsules, and all such compositions are considered solid oral dosage forms. A dose unit refers to a single entity to be administered such as a tablet or a capsule, and the amounts of each ingredient comprised by a dose unit thus refers to the content of a single entity, such as one tablet. The composition may be in the form of a dose unit, such as a tablet. In a preferred embodiment, the present invention provides an oral dosage form prepared from the present compositions without any functional coating. The term “functional coating” means any coating which protects the components comprised in said dosage forms, including any oligonucleotide, from degradation by gastric fluids such as, for example, enteric coatings. Preferably, said oral dosage form is prepared using dry manufacturing. The term “dry manufacturing” as used herein is known to a person of skill in the field of solid pharmaceutical dosage forms for oral delivery of drugs such as, for example, tablets. In one embodiment, dry manufacturing means direct compression or roller compaction. In some embodiments, the weight of the unit dose is in the range of 50 to 2000 mg, such as 50 mg to 1200 mg, such as in the range of 50-1000 mg, or such as in the range of 100-800 mg. In some embodiments the weight of the unit dose is in the range of 50 mg to 1000 mg, such as in the range of 50-750 mg, or such as in the range of 100-600 mg. In some embodiments the weight of the dose unit is in the range of 75 mg to 400 mg. In an embodiment the weight of the unit dose is in the range of 100-400 mg, such as in the range of 100-300 mg or such as in the range of 150-350 mg. In an embodiment the weight of the dose unit is in the range of 300 mg to 800 mg, such as in the range of 400-700 mg. In another embodiment, the unit dose comprises the amounts of oligonucleotide and excipients as shown in Table 1 (Example 1) herein. The preferred embodiments of the present invention can be expressed by the following clauses: 1. A pharmaceutical composition comprising an oligonucleotide, an absorption enhancer and a polyol, wherein the absorption enhancer is selected from N-(8-(2-hydroxybenzoyl) amino) caprylate or sodium caprate, and wherein the weight ratio (w / w) of absorption enhancer to polyol is within the range from 90:10 to 10:90. 2. The pharmaceutical composition according to clause 1, wherein the weight ratio (w / w) of absorption enhancer to polyol is within the range from 70:30 to 30:70. 3. The pharmaceutical composition according to clause 1, wherein the weight ratio (w / w) of absorption enhancer to polyol is about 70:30, 50:50 or 30:70. 4. The pharmaceutical composition according to any one of clauses 1 to 3, wherein the absorption enhancer is N-(8-(2-hydroxybenzoyl) amino) caprylate, preferably Sodium N-(8- (2-hydroxybenzoyl) amino) caprylate (SNAC). 5. The pharmaceutical composition according to any one of clauses 1 to 3, wherein the absorption enhancer is sodium caprate (C10). 6. The pharmaceutical composition according to any one of clauses 1 to 5, wherein the polyol is sorbitol. 7. A dosage form consisting of the pharmaceutical composition of any one of clauses 1 to 6, optionally together with additional pharmaceutically acceptable excipients. 8. The dosage form of clause 7 for use as in oral administration, preferably for use as a tablet. 9. The pharmaceutical composition of any one of clauses 1 to 6, or the dosage form of clauses 7 or 8, for use as a medicament. 10. The pharmaceutical composition of any one of clauses 1 to 6, or the dosage form of clauses 7 or 8, for use as a medicament for the oral delivery of said oligonucleotide. 11. The pharmaceutical composition of any one of clauses 1 to 6, or the dosage form of clauses 7 or 8, for use as a medicament for the improved release and stability of said oligonucleotide in an acidic environment, for example, the human stomach. 12. The pharmaceutical composition of any one of clauses 1 to 6, or the dosage form of clauses 7 or 8, for use as a medicament for improving the bioavailability, or blood plasma - or target tissue levels, of a pharmaceutically active ingredient, which is an oligonucleotide. 13. The use of a pharmaceutical composition of any one of clauses 1 to 6 for the manufacture of a medicament. 14. The use of a pharmaceutical composition according to clause 13, wherein the medicament is characterized by an improved release and stability of said oligonucleotide in an acidic environment such as gastric fluids, or the human stomach. 15. The use of a pharmaceutical composition according to clause 13, wherein the medicament is characterized by improving the bioavailability, or blood plasma - or target tissue levels, of a pharmaceutically active ingredient, which is an oligonucleotide. 16. A method of improving the oral bioavailability, or blood plasma - or target tissue level of an oligonucleotide drug, wherein said method comprises oral administration of the composition of any one of clauses 1 to 6, or the dosage form of clause 7 or 8, to a patient in need of such treatment. 17. A method for making the dosage forms of clause 7 or 8, wherein said method is a dry manufacturing method, preferably a method selected from direct compression and roller compaction. 18. The method of clause 17, which does not involve any coating or functional coating. 19. The compositions, methods and uses substantially as disclosed herein. 20. The embodiment according to any one of the preceding clauses, wherein the oligonucleotide is independently selected from oligonucleotides A to D as described herein; or from SEQ ID Nos 1 to 4, as described herein. The invention will now be further illustrated by the following, non-limiting working examples EXAMPLES Materials and Methods Materials The “HBV-LNA” (Oligonucleotide A) used herein is a GalNAc-conjugated oligonucleotide of the formula GN2-AM-C6-5'-caG*MeC*G*t*a*a*a*g*a*g*a*G*G-3' The “HIF1a” (Oligonucleotide B) used herein is a non GalNAc-conjugated oligonucleotide of the formula 5'-T*G*G*c*a*a*g*c*a*t*c*c*T*G*T*a-3' wherein AM-C6 means a C6 amino linker; * stands for phosphorothioate bridges; A,G,T and MeC (5-methyl cytosine) are LNA nucleoside monomers and a,t,c,g are DNA nucleoside monomers; and GN2 is the GalNAc cluster moiety of the formula (V) herein (n = 2; R2 = acetyl). The “ASO Factor B” (Oligonucleotide C, sefaxersen) used herein is a GalNAc conjugated oligonucleotide of the formula: TGN.Lo.eAs.eTs.eEs.eEs.eEs.dAs.dEs.dGs.dEs.dEs.dEs.dEs.dTs.dGs.dTs.eEs.eEs.eAs.eGs.e E wherein each nucleotide is described by three-letters, wherein First letter: Sugar (d = DNA, e = MOE) Second letter: Nucleobase (A = adenine, E = 5-methylcytosine, G = guanine, T = thymine) Third letter: Backbone (o = phosphate, s = thiophosphate) L = C6-hexylaminolinker, TGN is a triantennary GalNAc cluster based on a TRIS core The "PD-L1 LNA” (Oligonucleotide D) as used herein is a GalNAc conjugated oligonucleotide of the formula GN2-AM-C6-5`-caC*C*t*a*t*t*t*a*a*c*a*t*c*A*G*A*C-3` wherein AM-C6 means a C6 amino linker; * stands for phosphorothioate bridges; A,G,T andMeC (5-methyl cytosine) are LNA nucleoside monomers and a,t,c,g are DNA nucleoside monomers; and GN2 is the GalNAc cluster moiety of the formula (V) herein (n = 2; R2= acetyl). The Sequence information is provided from 5'-end (left) to 3'-end (right) according to MSC- 0106143. The “HBV-LNA”, “HIF1a” and “PD-L1 LNA” oligonucleotides as well as methods for making them are, for example, specifically disclosed in WO2021 / 001329. “ASO Factor B” (Oligonucleotide C, sefaxersen) is available from Ionis Pharmaceuticals, Inc. (Carlsbad, CA) Methods The Methods used to generate the present data are described in the Examples. Example 1: Preparation of solid compositions comprising oligonucleotides GalNAc-conjugated and unconjugated oligonucleotides have been formulated as 14 mg, 63 and 112 mg immediate release tablets for oral administration. The present pharmaceutical formulations comprise 2% w / w sodium stearyl fumarate that leads to a satisfactory lubrication level. The present pharmaceutical formulations also comprise sorbitol and either N-(8-(2- hydroxybenzoyl)amino)caprylate or sodium caprate in a ratio of 100:0, 70:30, 50:50, 30:70 or 0:100 w / w to obtain a satisfactory dissolution rate of the tablets and satisfactory level of stability of the oligonucleotide in an acidic environment such as the human stomach in the fasted state. Table 1: Compositions of formulations containing GalNAc-conjugated and non-conjugated oligonucleotide Formulati Formulati Formulati Formulati Oligonucl Sodium Sorbitol Sodium on on on on eotide (m caprate stearyl g) (mg) (mg) fumarate oligonucl oligonucle oligonucle oligonucle (mg) eotide A otide B otide C otide D A1 B1 - - 14 470 202 14 A2 B2 - - 14 202 470 14 A3 B3 - - 112 402 172 14 A4 B4 - - 112 172 402 14 A5 B5 C5 D5 63 312 312 14 A6 B6 C6 D6 63 623 0 14 A7 B7 C7 C6 63 0 623 14 The lubricant and the API were delumped using a 0.5 mm sieve, the absorption enhancer and the soluble filler were delumped using a 0.8 mm sieve. The API together with the absorption enhancer and / or soluble filler were mixed volumetrically by hand and transferred to a container before blending in a TURBULA mixer for 3 min at 32 rpm. The blend was delumped using a 0.8 mm sieve. The lubricant was mixed volumetrically with the blend and transferred to the same container before blendingin a TURBULA mixer for 3 min at 32 rpm. The tablets were manufactured by direct compression using a STYL’ONE EVO (Medelpharm, Beynost, France) equipped with a 21x9.72 mm oblong punch (Adamus, Warszawa, Poland). A punch displacement profile simulating a Korsch XL100 rotary press with a turret speed of 20 rpm was applied and the tablets were compressed to a solid fraction of 0.8. Example 2: The chemical stability of the oligonucleotide drug The chemical stability of the oligonucleotide drug was determined in 110 ml simulated gastric fluid (SGF) pH 2 at 37 °C using a heated magnetic stirrer. A 1 mg / ml solution of the oligonucleotide drug was incubated for 120 min. Samples were taken at 3, 6, 9, 12, 15, 20, 30, 45, 60, 90 and 120 min, pH adjusted to 8 and analyzed by HPLC-UV. Samples were analyzed for determining dissolved amount of active ingredient using an Agilent 1290 series UPLC systems (Santa Clara, California, US), equipped with a binary pump, autosampler, temperature-controlled column compartment and PDA detector. Column used was a Thermo Scientific DNAPac PA200 RS, 4.6 x 150 mm (4µm). Eluent A: 40mM Tris-Buffer pH 8.5 / Acetonitrile 80 / 20 (v / v) and eluent B: 40mM Tris-Buffer pH 8.5 / Acetonitrile 80 / 20 (v / v) + 1.25M NH4Cl. The elution gradient can be found in the table below (Table 2). Flow rate was 1.2 mL / min, injection volume 10 µL and run time 8 min. Column temperature was 80 °C and detection at wavelength of 260 nm. Autosampler temperature was set to 20 °C throughout the experiment. Table 2: Time (min.) A (%) B (%) Flow (ml / min) 0 95 5 1.2 2.0 90 10 1.2 12.0 10 90 1.2 17.0 10 90 1.2 17.2 95 5 1.2 22.0 95 5 1.2 It was shown that the GalNAc-conjugated oligonucleotide drugs are chemically unstable in simulated gastric fluid (SGF) pH 2 at 37 °C as the content was decreasing over time (see Fig. 1) and additional peaks were observed in the chromatogram. Similar results will be obtained with the gradient disclosed in Table 3 (Example 3). Example 3: Dissolution / Release of the oligonucleotide drug The dissolution rate of the oligonucleotides from the tablets was determined in 110 mL simulated gastric fluid (SGF) pH 2 at 37 °C using an USP II dissolution apparatus (Sotax, Aesch, Switzerland) equipped with mini paddles operating at 75 rpm. Samples were withdrawn at 3, 6, 9, 12, 15, 20 and 30 min, filtered and analyzed by a 1290 Infinity II HPLC- UV system (Agilent, California, USA). The same working conditions than those described in Example 2 were applied. The gradient program used here is according to Table 3 (below): Table 3 Time (min.) A (%) B (%) Flow (ml / min) 0 95 5 1.2 1 90 10 1.2 4.5 10 90 1.2 5 95 5 1.2 8 95 5 1.2 The buffering effect of the tablets were determined in 110 ml SGF at pH 2 at 37 °C using a heated magnetic stirrer operating at 150 rpm. The tablet was placed in a basket and monitored using a pH meter until the tablet was completely dissolved. As observed in the Figure 2, complete release of the oligonucleotide is seen for the formulation comprising C10:sorbitol 70:30 w / w (A1). In contrast, the formulation comprising C10:sorbitol 30:70 w / w (A2) shows a decline in oligonucleotide dissolved after 10 minutes indicating chemical degradation of the oligonucleotide. Furthermore, it is observed that the formulation comprising C10:sorbitol 50:50 w / w (A5) shows complete release, whereas the formulation comprising C10:sorbitol 100:0 w / w (A6) does not reach complete release within 30 min (Figure 2B). Similarly, the formulation comprising C10:sorbitol 0:100 w / w (A7) does not show full release, however a decline from dissolved oligonucleotide is also observed which can be attributed to the chemical degradation of the oligonucleotide throughout the dissolution process. A similar trend is seen for a non-conjugated oligonucleotide drug (see Fig.3). Example 4: Buffering effect of the tablet formulations To further study the tablet formulations, the buffering effect was determined in the same dissolution medium i.e.110 ml SGF pH 2.0. As observed in Figure 4, the formulations containing C10 : sorbitol 70:30 w / w showed a fast buffering of the pH from 2 to 6. Additionally, a similar but also slower effect was seen for the formulation containing C10 : sorbitol 100:0 w / w. Furthermore, the formulations containing C10 : sorbitol 30:70 w / w only will buffer up the pH to approx.3 during the dissolution. Finally, the formulation containing C10 : sorbitol 0:100 w / w did not show any influence on the pH during dissolution.

Claims

Claims 1. A pharmaceutical composition comprising an oligonucleotide, an absorption enhancer and a polyol, wherein the absorption enhancer is selected from N-(8-(2-hydroxybenzoyl) amino) caprylate or sodium caprate, and wherein the weight ratio (w / w) of absorption enhancer to polyol is within the range from 90:10 to 10:

90.

2. The pharmaceutical composition according to claim 1, wherein the weight ratio (w / w) of absorption enhancer to polyol is within the range from 70:30 to 30:

70.

3. The pharmaceutical composition according to claim 1, wherein the weight ratio (w / w) of absorption enhancer to polyol is about 70:30, 50:50 or 30:

70.

4. The pharmaceutical composition according to any one of claims 1 to 3, wherein the absorption enhancer is N-(8-(2-hydroxybenzoyl) amino) caprylate, preferably Sodium N-(8- (2-hydroxybenzoyl) amino) caprylate (SNAC).

5. The pharmaceutical composition according to any one of claims 1 to 3, wherein the absorption enhancer is sodium caprate (C10).

6. The pharmaceutical composition according to any one of claims 1 to 5, wherein the polyol is sorbitol.

7. A dosage form consisting of the pharmaceutical composition of any one of claims 1 to 6, optionally together with additional pharmaceutically acceptable excipients.

8. The dosage form of claim 7 for use as in oral administration, preferably for use as a tablet.

9. The pharmaceutical composition of any one of claims 1 to 6, or the dosage form of claims 7 or 8, for use as a medicament.

10. The pharmaceutical composition of any one of claims 1 to 6, or the dosage form of claims 7 or 8, for use as a medicament for the oral delivery of said oligonucleotide.

11. The pharmaceutical composition of any one of claims 1 to 6, or the dosage form of claims 7 or 8, for use as a medicament for the improved release and stability of said oligonucleotide in an acidic environment, for example, the human stomach.

12. The pharmaceutical composition of any one of claims 1 to 6, or the dosage form of claims 7 or 8, for use as a medicament for improving the bioavailability, or blood plasma - or target tissue levels, of a pharmaceutically active ingredient, which is an oligonucleotide.

13. The use of a pharmaceutical composition of any one of claims 1 to 6 for the manufacture of a medicament.

14. The use of a pharmaceutical composition according to claim 13, wherein the medicament is characterized by an improved release and stability of said oligonucleotide in an acidic environment such as gastric fluids, or the human stomach.

15. The use of a pharmaceutical composition according to claim 13, wherein the medicament is characterized by improving the bioavailability, or blood plasma - or target tissue levels, of a pharmaceutically active ingredient, which is an oligonucleotide.

16. A method of improving the oral bioavailability, or blood plasma - or target tissue level of an oligonucleotide drug, wherein said method comprises oral administration of the composition of any one of claims 1 to 6, or the dosage form of claims 7 or 8, to a patient in need of such treatment.

17. The compositions, methods and uses substantially as disclosed herein. ***

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