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US-12616738-B2 - Solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid

US12616738B2US 12616738 B2US12616738 B2US 12616738B2US-12616738-B2

Abstract

The invention relates to pharmaceutical compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid. The invention further relates to processes for the preparation of such compositions, and their use in medicine.

Inventors

  • Simon Bjerregaard
  • ULRIK LYTT RAHBEK
  • PHILIP JONAS SASSENE
  • Jorrit Jeroen Water
  • Andreas Vegge

Assignees

  • NOVO NORDISK A/S

Dates

Publication Date
20260505
Application Date
20221116
Priority Date
20180507

Claims (20)

  1. 1 . A composition comprising i) a GLP-1 agonist, ii) a sodium salt of N-(8-(2-hydroxybenzoyl) amino) caprylic acid (SNAC) and iii) a hydrotrope, wherein the hydrotrope increases the solubility of SNAC at least 2-fold when the solubility is measured at a concentration of 200 mg/ml of the hydrotrope at a pH of 6.
  2. 2 . The composition according to claim 1 , wherein the hydrotrope is selected from the group consisting of nipecotamide, nicotinamide, p-hydroxybenzoic acid sodium, N,N dimethyl urea, N,N dimethyl benzamide, N,N diethyl nicotinamide, sodium salicylate, resorcinol, sodium benzoate, sodium xylenesulfonate, sodium p-toluenesulfonate, 1-methylnicotinamide, pyrogallol, pyrocathecol, epigallocatechin gallate, tannic acid and gentisic acid sodium salt hydrate.
  3. 3 . The composition according to claim 2 , wherein the composition further comprises a lubricant.
  4. 4 . The composition according to claim 3 , wherein the lubricant is selected from the group consisting of magnesium stearate and glyceryl dibehenate.
  5. 5 . The composition according to claim 3 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-10.
  6. 6 . The composition according to claim 5 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-8.
  7. 7 . The composition according to claim 6 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-5.
  8. 8 . The composition according to claim 2 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-10.
  9. 9 . The composition according to claim 8 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-8.
  10. 10 . The composition according to claim 9 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-5.
  11. 11 . The composition according to claim 1 , wherein the GLP-1 agonist comprises at least one albumin binding substituent.
  12. 12 . The composition according to claim 1 , wherein the composition further comprises a lubricant.
  13. 13 . The composition according to claim 1 , wherein the lubricant is selected from the group consisting of magnesium stearate and glyceryl dibehenate.
  14. 14 . The composition according to claim 1 , wherein the composition is a solid composition.
  15. 15 . The composition according to claim 14 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-10.
  16. 16 . The composition according to claim 15 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-8.
  17. 17 . The composition according to claim 16 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-5.
  18. 18 . The composition according to claim 14 , wherein the hydrotrope is selected from the group consisting of nipecotamide, nicotinamide, p-hydroxybenzoic acid sodium, N,N dimethyl urea, N,N dimethyl benzamide, N,N diethyl nicotinamide, sodium salicylate, resorcinol, sodium benzoate, sodium xylenesulfonate, sodium p-toluenesulfonate, 1-methylnicotinamide, pyrogallol, pyrocathecol, epigallocatechin gallate, tannic acid and gentisic acid sodium salt hydrate.
  19. 19 . The composition according to claim 18 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-10.
  20. 20 . The composition according to claim 19 , wherein the ratio of SNAC/hydrotrope (w/w) is 0.5-8.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS This application is a continuation of U.S. application Ser. No. 17/053,511, filed Nov. 6, 2020 which is a 35 U.S.C. § 371 National Stage application of International Application PCT/EP2019/061502 (WO 2019/215063), filed May 6, 2019, which claims priority to European Patent Application 18171046.8, filed May 7, 2018; the contents of which are incorporated herein by reference TECHNICAL FIELD OF THE INVENTION The present invention relates to solid compositions comprising a GLP-1 agonist and a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, their method of preparation and their use in medicine. INCORPORATION-BY-REFERENCE OF THE SEQUENCE LISTING The instant application contains a Sequence Listing which has been submitted in XML format via the USPTO patent electronic filing system and is hereby incorporated by reference in its entirety. Said XML file, created on Nov. 9, 2022, is named 180033US02.xml and is 11 kilobytes in size. BACKGROUND Human GLP-1 and analogues thereof have a low oral bioavailability. Exposure and bioavailability of human GLP-1 and analogues thereof is very low following oral administration. Human GLP-1 and analogues thereof can only reach therapeutically relevant plasma concentration after oral administration if formulated with certain absorption enhancers in a specific amount. Steinert et al. (Am J Clin Nutr, October 2010; 92: 810-817) discloses oral administration of a tablet comprising GLP-1(7-36)amide and 150 mg sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC). WO 2010/020978 discloses an oral pharmaceutical composition comprising a protein and N-(8-[2-hydroxybenzoyl) amino)caprylate (SNAC). Patent applications disclosing oral dosage forms of GLP-1 analogues containing a salt of N-(8-(2-hydroxybenzoyl)amino)caprylate include WO2012/080471, WO2013/189988, WO2013/139694, WO2013/139695 and WO2014/177683. Despite these findings there is still room for a further optimized pharmaceutical composition for oral administration of a GLP-1 agonist such as a GLP-1 analogue comprising a substituent. SUMMARY The present invention in an aspect relates to a composition comprising a GLP-1 agonist, an absorption enhancer or delivery agent and a hydrotrope. The composition according to the invention comprises balanced amounts of the delivery agent and the hydrotrope. The provided compositions display an accelerated absorption, enabling fast and efficient uptake of the active pharmaceutical ingredient. Oral administration of therapeutic peptides is challenging, due to the rapid degradation of such peptides in the gastrointestinal system. Described herein are pharmaceutical compositions providing accelerate absorption of the GLP-1 agonist within 15-30 minutes after administration and thereby improved exposure of the GLP-1 agonist by oral administration. The inventors have surprisingly found that an increased exposure of GLP-1 agonists is observed when compositions are prepared with a hydrotrope. An aspect of the invention relates to a composition comprising i) a GLP-1 agonist,ii) a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC) andiii) a hydrotrope, wherein the hydrotrope is capable of increasing the solubility of SNAC at least 2-fold, such as 5-fold or such as at least 10-fold. In one embodiment the composition comprises: i) 0.1-50 mg GLP-1 agonist, such as Semaglutide, GLP-1 agonist B or GLP-1 agonist C.ii) 50-600 mg salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid (NAC), such as the sodium salt of NAC (SNAC) andiii) 20-200 mg nicotinamide or resorcinol andiv) 0-10 mg lubricant. A further aspect relates to a method for producing a solid pharmaceutical composition comprising the steps of; i) obtaining a blend comprising a salt of NAC and a hydrotrope,ii) co-processing the blend of i) andiii) preparing said solid pharmaceutical composition using the product of ii). A further aspect relates to the medical use of compositions described herein. An embodiment relates to pharmaceutical use of compositions described herein, such as compositions for oral administration. In a further embodiment the composition is a pharmaceutical composition for use in a method of treating diabetes and/or obesity. In a further aspect the invention relates to a method of treating diabetes or obesity comprising administering the composition as defined herein to a patient in need thereof. BRIEF DESCRIPTION OF DRAWINGS FIG. 1 shows dose dependent effect of nicotinamide (A) and resorcinol (B) on SNAC solubility at pH 6. FIG. 2 shows the dose corrected exposure during the first 30 minutes observed in dogs after dosing of formulations with two different GLP-1 agonists, GLP-1 agonist A and B, respectively. Compositions according to the invention all demonstrate an increased dose-corrected exposure relative to the reference compositions. DESCRIPTION Aspects of the invention described herein relate to a composition comprising a GLP-1 agonist and an absorption enhancer or delivery agent