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US-20260124281-A1 - FORMULATIONS COMPRISING ACID-NEUTRALIZING POLYMER FOR ORAL ADMINISTRATION OF PARATHYROID HORMONE

US20260124281A1US 20260124281 A1US20260124281 A1US 20260124281A1US-20260124281-A1

Abstract

A pharmaceutical composition is described herein, which comprises a therapeutically active agent, an absorption enhancer, and a polymer comprising a plurality of alkaline groups. The therapeutically active agent is a parathyroid hormone. A concentration of the polymer in the composition is at least 10 weight percent of the total weight of the composition. The absorption enhancer is preferably a substituted or non-substituted fatty acid or a salt thereof. Further described herein are methods of treating a condition treatable by the therapeutically active agent, comprising orally administering the pharmaceutical composition.

Inventors

  • Gregory Burshtein
  • Constantin ITIN
  • Hillel GALITZER
  • Phillip M. SCHWARTZ

Assignees

  • ENTERA BIO LTD.

Dates

Publication Date
20260507
Application Date
20260105

Claims (20)

  1. 1 . A pharmaceutical composition comprising, (i) PTH(1-34); (ii) an absorption enhancer comprising a substituted or non-substituted fatty acid or a salt thereof, and (iii) a polymer comprising a plurality of alkaline groups, wherein the polymer is at least 10 weight percent of the total weight of the composition.
  2. 2 . (canceled)
  3. 3 . The composition of claim 1 , wherein at least a portion of the alkaline groups are carboxylate groups.
  4. 4 . The composition of claim 3 , wherein at least a portion of the carboxylate groups is in a form of a pharmaceutically acceptable salt.
  5. 5 . The composition of claim 4 , wherein at least a portion of the carboxylate groups are in a form of a sodium salt.
  6. 6 . (canceled)
  7. 7 . The composition of claim 1 , wherein the absorption enhancer comprises 8-N-(2-hydroxybenzoyl)aminocaprylic acid (NAC) or a salt thereof.
  8. 8 . The composition of claim 1 , wherein the absorption enhancer is at least 50 weight percent of the total weight of the composition.
  9. 9 . (canceled)
  10. 10 . The composition of claim 1 concentration of the absorption enhancer and the polymer is at least 80 weight percent of the total weight of the composition.
  11. 11 . The composition of claim 1 concentration of the alkaline groups in the composition is at least 0.1 millimoles per gram.
  12. 12 . The composition of claim 1 , wherein the polymer is a crosslinked polymer.
  13. 13 . The composition of claim 1 , wherein the polymer comprises a polysaccharide.
  14. 14 . The composition of claim 13 , wherein the polysaccharide comprises a starch derivative, a cellulose derivative, or combinations thereof.
  15. 15 . (canceled)
  16. 16 . The composition of claim 1 , wherein the polymer is characterized by a pKa from 3 to 5.5.
  17. 17 . The composition of claim 1 , wherein the polymer is sodium starch glycolate and/or croscarmellose sodium.
  18. 18 . (canceled)
  19. 19 . (canceled)
  20. 20 . (canceled)

Description

RELATED APPLICATION/S This application claims the benefit of priority under 35 USC § 119 (e) of U.S. Provisional Patent Application No. 63/313,367 filed on Feb. 24, 2022, the contents of which are incorporated herein by reference in their entirety. This application is also related to co-filed PCT International Patent Application having Attorney's Docket No. 95409, entitled “FORMULATIONS COMPRISING ACID-NEUTRALIZING POLYMER FOR ORAL ADMINISTRATION OF ACTIVE AGENTS”, which claims the benefit of priority under 35 USC § 119 (e) of U.S. Provisional Patent Application No. 63/313,363 filed on Feb. 24, 2022, the contents of which are incorporated herein by reference in their entirety. FIELD AND BACKGROUND OF THE INVENTION The present invention, in some embodiments thereof, relates to drug delivery, and more particularly, but not exclusively, to formulations and/or systems for oral administration of therapeutically active agents, such as, but not limited to, a parathyroid hormone. Human parathyroid hormone (PTH) is secreted by the parathyroid gland as a polypeptide containing 84 amino acids. PTH regulates serum calcium levels by enhancing release of calcium from bones (bone resorption), and by enhancing intestinal absorption and renal reabsorption of calcium. Teriparatide is a recombinant form of the first 34 amino acids of human PTH(hPTH(1-34)), and is used for treatment of osteoporosis. Administration of teriparatide is by subcutaneous injection once per day at a dose of 20 μg [Rick & Towler, Mo Med 2011, 108:118-123]. PTH(including PTH(1-34)) has been reported to enhance bone formation provided that it is administered intermittently, with circulating levels returning to control levels within 3 hours [Martin, J Bone Metab 2014, 21:8-20]. In contrast, prolonged elevated PTH levels deplete bones by enhancing bone resorption. Oral administration of peptide and/or protein pharmaceuticals is problematic due to degradation of peptides and/or proteins in the digestive system and poor absorption of large molecules. Qi & Ping [J Microencapsulation 2004, 21:37-45] describe administration of enteric microspheres containing insulin with SNAC (sodium 8-N-(2-hydroxybenzoyl)aminocaprylate). The enteric microspheres are for protecting the insulin from digestive enzymes of the stomach and small intestine, and the SNAC is for enhancing absorption. U.S. Patent Application Publication No. 2011/0142800 describes compositions for oral administration of a protein, comprising a protein having a molecular weight of up to 100,000 Da, a protease inhibitor, and an absorption enhancer, such as SNAC, N-(10-[2-hydroxybenzoyl]amino) decanoic acid (SNAD), 8-[N-(2-hydroxy-4-methoxybenzoyl)amino]caprylic acid (4-MOAC), 8-[N-(2-hydroxy-5-chlorobenzoyl)amino]caprylic acid (5-CNAC) and 4-[(4-chloro-2-hydroxy-benzoyl)amino]butanoic acid (4-CNAB) and sodium salts thereof. International Patent Application Publication No. WO 00/48589 describes solid oral dosage forms comprising a heparin drug in admixture with SNAC or SNAD for facilitating absorption and/or enhancing bioavailability of the heparin drug, wherein the heparin drug is reported to protect the SNAC or SNAD from precipitation during transit through acidic regions of the gastrointestinal (GI) tract. International Patent Application Publication No. WO 2016/128974 describes a pharmaceutical composition for oral administration comprising a therapeutically active agent, SNAC and at least one antacid compound; as well as a pharmaceutical composition unit dosage form for oral administration which comprises a core comprising a therapeutically active agent and SNAC, and an external layer comprising at least one of an antacid compound and a protease inhibitor. Buckley et al. [Sci Transl Med 2018, 10: eaar7047] reports that upon oral administration of a tablet comprising the peptide agent semaglutide and SNAC, absorption of the semaglutide takes place in the stomach and is confined to an area in close proximity to the tablet surface, and that the SNAC protects against enzymatic degradation via local buffering actions and only transiently enhances absorption. Sodium carboxymethylcellulose (CMC) is prepared by modifying cellulose with chloroacetic acid, and may be crosslinked or non-crosslinked. In its crosslinked form, wherein crosslinking is effected by formation of ester bonds between carboxymethyl groups and cellulose, it is commonly referred to as croscarmellose sodium (CCS) or sodium croscarmellose, and is used as a superdisintegrant in pharmaceutical formulations. Similarly, sodium starch glycolate (SSG) can be prepared by modifying starch with chloroacetic acid to form carboxymethyl groups. The sodium starch glycolate may be further crosslinked by phosphate groups (—O—P(═O)(—O)—O—) between starch backbones, and used as a superdisintegrant. Additional background art includes Qi et al. [Acta Pharm Sinica 2004, 39:844-848]; International Patent Application Publication Nos. WO 00/50386, WO 01/32130, WO 0