Pharmaceutical Compositions Containing Enterokine Releasing Substances In Multiple Dosage Forms In Combination With Gelling Agents

Abstract

The present invention relates to pharmaceutical compositions and pharmaceutical articles comprising such compositions wherein the compositions comprise multiple dosage forms each comprising a core and an enteric coating, wherein the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, wherein the size of the dosage forms, with respect to the largest dimension of the dosage forms, provides for entry of the dosage forms into the intestine of a subject independent of gastric emptying mechanisms, and wherein the composition further comprises one or more gelling agents. The invention also relates to the treatment and/or prevention of conditions amenable to stimulation of enterokine release by enteroendocrine cells.

Claims

1. A pharmaceutical composition comprising multiple dosage forms each comprising a core and an enteric coating, wherein the core comprises at least one compound stimulating enteroendocrine cells to release at least one enterokine, wherein the size of the dosage forms, with respect to the largest dimension of the dosage forms, provides for entry of the dosage forms into the intestine of a subject independent of gastric emptying mechanisms, and wherein the composition further comprises one or more gelling agents.

2. The composition according to claim 1 wherein the size of each of the dosage forms, with respect to the largest dimension of the dosage forms, is below 3 mm, preferably from 0.6 mm to 2.6 mm, more preferably from 0.6 mm to 1.7 mm, even more preferred from 0.8 mm to 1.2 mm.

3. The composition of claim 2 containing 10000 to 40000 dosage forms.

4. The composition of claim 3 containing 20000 to 30000 dosage forms.

5. The composition according to claim 1 wherein the enteric coating comprises a pH sensitive polymer selected such that the coating substantially dissolves and/or is substantially degraded in the, preferably terminal, jejunum of a subject such that the core is released into the jejunum, preferably the terminal jejunum, of the subject.

6. The composition of claim 5 wherein the pH sensitive polymer substantially degrades and/or dissolves at a pH value of about 5.5 to about 7.5, preferably about 7.2 to about 7.3.

7. The composition of claim 5 wherein the pH sensitive polymer is selected from the group consisting of hydroxypropylmethyl celluloses and anionic copolymers of methacrylic acid and methacrylmethacrylate.

8. The composition according to claim 1 wherein the at least one compound is selected from the group consisting of compounds stimulating the enteroendocrine cells by a mechanism selected from the group consisting of transport into enteroendocrine cells by a transporter expressed by said cells wherein the transporter is selected from the group consisting of GLUT2 and SGLT1, and binding to G protein-coupled receptors expressed by said cells.

9. The composition of claim 8 wherein the G-protein-coupled receptor is selected from bile acid receptors, amino acid receptors, peptide receptors and fatty acid receptors and taste receptors.

10. The composition of claim 8 wherein said compound(s) is/are selected from the group consisting of carbohydrates, fatty acids, bile acids, peptides, amino acids, alcohol amides, and anthocyanins.

11. The composition of claim 10 wherein the core contains glucose, and optionally one or more compounds selected from sucralose, fatty acids having 2 to 6 carbon atoms, oleic acid, bile acids, peptides, amino acids, ethanolamides and anthocyanins.

12. The composition of claim 11 wherein the multiple dosage forms each have a glucose content of form 5% (w/w) to 95% (w/w). (w/w), preferably from 25% (w/w) to 75% (w/w), more preferably from 40% (w/w) to 70% (w/w).

13. The composition of claim 11 containing 0.5 g to 30 g glucose, preferably 5 g to 20 g glucose, more preferably 7 g to 15 g glucose, per unit dose of the composition.

14. The composition according to claim 1 wherein the enteroendocrine cells are selected from the group consisting of I cells, K cells and L cells.

15. The composition according to claim 1 wherein the core further contains a substance enhancing enterokine release by the enteroendocrine cells effected by the compound stimulating enteroendocrine cells to release at least one enterokine,

16. The composition of claim 15 wherein the substance enhances release of GLP-1 and/or PYY by L cells.

17. The composition of claim 16 wherein the substance is caffeine.

18. The composition according to claim 1 wherein the core further contains an enteroendocrine cell maturation agent.

19. The composition of claim 18 wherein the maturation agent is a human milk oligosaccharide (HMO).

20. The composition according to claim 1 wherein the core contains at least one disintegrant providing a burst release of the ingredients of the core from the dosage form upon at least partial dissolving and/or degradation of the enteric coating.

21. The composition according to claim 1 wherein the multiple dosage forms and the one or more gelling agent are present in a liquid medium.

22. The composition of claim 21 wherein the liquid medium is water or an aqueous solution.

23. The composition according to claim 1 further comprising one or more pH modifiers.

24. The composition according to claim 1 wherein the one or more gelling agents is/are present in a gelling composition.

25. The composition of claim 24 wherein the gelling composition comprises one or more pH modifiers.

26. The composition of claim 24 the gelling composition and the multiple dosage forms form a heterogeneous mixture.

27. A pharmaceutical article comprising multiple dosage forms as defined according to claim 1 and at least one gelling agent wherein the multiple dosage forms and the at least one gelling agent are physically separated.

28. The article of claim 27 wherein the at least one gelling agent is present in a gelling composition.

29. The article of claim 28 wherein the gelling composition further contains one or more pH modifiers.

30. The article according to claim 27 further comprising a liquid medium physically separated from the multiple dosage forms and from the at least one gelling agent or gelling composition.

31. The article according to claim 27 wherein the multiple dosage forms and the at least one gelling agent and, optionally, the liquid medium, are provided in a single container comprising at least one compartment containing the multiple dosage form, at least one compartment containing the at least one gelling agent or gelling composition and, optionally, at least one compartment containing the water or aqueous solution, wherein said compartments are separated by a breakable physical separation.

32. A pharmaceutical article comprising the composition according to claim 24 comprising a liquid medium physically separated from said composition.

33. The article of claim 32 wherein the composition and the liquid medium are provided in a single container comprising at least one compartment containing the composition and at least one compartment containing the liquid medium, wherein said compartments are separated by a breakable physical separation.

34. The article according to claim 27 wherein the liquid medium is water or an aqueous solution.

35. The composition according to claim 1 for use in the prevention and/or treatment in a subject suffering from conditions and/or disorders and/or diseases associated with disturbed enterokine release by enteroendocrine cells and/or conditions and/or disorders and/or diseases amenable to increased enterokine release by enteroendocrine cells.

36. The composition of claim 35 wherein the condition, disorder or disease is selected from metabolic disorders, vascular disorders, neurodegenerative diseases, skeletal diseases and gastroenterologic disorders.

37. The composition of claim 36 wherein the metabolic disorder is selected from the group consisting of insulin resistance, type 2 diabetes mellitus, non-alcoholic fatty liver disease, non-alcoholic steatohepatosis, metabolic syndrome, hyperlipidemia and obesity.

38. The composition of claim 37 wherein the metabolic disorder, is associated with adipose tissue inflammation.

39. The composition of claim 36 wherein the vascular disorder is selected from microvascular dysfunction, cardiovascular diseases, cerebrovascular diseases and pulmonary vascular diseases.

40. The composition of claim 39 wherein the pulmonary disease is associated with pneumonia.

41. The composition of claim 40 wherein the pneumonia is caused by or associated with a viral infection.

42. The composition of claim 41 wherein the viral infection is an infection by a coronavirus causing a respiratory condition.

43. The composition of claim 41 wherein the viral infection is an infection by a coronavirus selected from the group consisting of SARS-COV-1, SARS-COV-2 and MERS.

44. The composition of claim 36 wherein the skeletal disease is osteoporosis.

45. The composition of claim 36 wherein the gastroenterological disorder is selected from the group consisting of impaired gastro-intestinal function and malabsorption conditions.

46. The composition of claim 35 wherein said condition, disorder or disease is accompanied by at least one condition selected from the group consisting of swallowing difficulty, impaired esophageal peristalsis, gastroparesis and impaired intestinal peristalsis.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0092] FIG. 1 shows a graphical representation of results of time-dependent GLP-1 blood level measurements (pmol/l) in subjects (n=20) from 1 hour before to 10 hours after oral administration of a composition according to the invention. Data shown are means+/−SEM.

DETAILED DESCRIPTION OF THE INVENTION

[0093] The following non-limiting example further illustrates the invention:

EXAMPLE

[0094] An exemplary pharmaceutical composition was prepared by mixing the following components (a) and (b): [0095] (a) Multiple dosage forms: Eudragit®-coated beads of ca. 1 mm diameter having a core containing 40 to 70% (w/w) glucose and a disintegrant in a carrier substance Total weight of glucose in a unit dose of the composition: 10 g. Number of coated beads ca. 20000 to 30000. [0096] (b) Gelling composition: [0097] Gelling agent mixture (Polysaccharide, modified cellulose, PEG) (84% (w/w) based on the total weight of the gelling composition) [0098] pH modifier [0099] Flavors [0100] Lubricant [0101] Pigments

[0102] Before oral administration, the pharmaceutical composition was mixed with 25 ml of water per unit dose.

[0103] The reconstituted composition was administered orally to 20 subjects. Blood GLP-1 values were measured at the following time points (in relation to time point of oral administration=0 h): −1.0 h, −0.5 h, 0 h, 0.5 h, 1.0 h, 1.5 h, 2.0 h, 2.5 h, 3.0 h, 3.5 h, 4.0 h, 4.5 h, 5.0 h, 5.5 h, 8.0 h, and 10.0 h.

[0104] The results are shown in FIG. 1. The pharmaceutical composition exerts a remarkably reproducible (low intra patient and inter-patient variability) and sharp rise in GLP-1 blood concentration (maximum at 2.88+/−0.46 fold increase with respect to base line GLP-1 blood level at 1.5 h post administration) as compared to prior art approaches, and the GLP-1 increase over base line value at 1.5 h lasts about 4 h. The sharp rise in GLP-1 blood level starting after 1.5 hours post administration is consistent with a burst release of the active compound (here: glucose) in the terminal jejunum of the subjects as demonstrated by the following data as obtained by Evans et al. (1988) Gut 29, 1035-1041).

TABLE-US-00001 TABLE 1 Localisation of pH sensitive telemetry capsule in the gastro- intestinal tract (GI) in dependency of time after intake GI region Time (hours) after intake Duodenum 0.75 to 1.8  Jejunum 1.8 to 3.8 Ileum 3.8 to 5.4 Colon ≥5.4

[0105] Applying the data of Evans et al. (1988), the burst release of the components of the multiple dosage forms contained in the composition of the invention occurred in the (terminal) jejunum of the subjects at a pH environment of >pH 7.0, and in particular ca. 7.3.