Methods and compositions for improving digestion and absorption in the small intestine

• US 5,977,175 A
• Filed: 04/03/1997
• Issued: 11/02/1999
• Est. Priority Date: 05/17/1995
• Status: Expired due to Term

• Current Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Original Assignee: Cedars-Sinai Medical Center (Cedars Sinai Health System)
• Inventors: Lin, Henry C.
• Primary Examiner(s): Raymond, Richard L.
• Application Number:
  US08/832,307
• Time in Patent Office: 943 Days
• Field of Search: 514/549, 514/552, 514/558, 514/560, 514/784, 514/785, 514/786, 424/457, 424/458, 424/489, 424/498
• US Class Current: 514/558
• CPC Class Codes: A23L 33/115 Fatty acids or derivatives thereof; Fats or oils
• CPC Class Codes: A23L 33/12 Fatty acids or derivatives thereof
• CPC Class Codes: A23V 2002/00 Food compositions, function of food ingredients or processes for food or foodstuffs
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/19 Carboxylic acids, e.g. valproic acid salicylic acid A61K31/60
• CPC Class Codes: A61K 31/20 having a carboxyl group bound to a chain of seven or more carbon atoms, e.g. stearic, palmitic, arachidic acids
• CPC Class Codes: A61K 31/201 having one or two double bonds, e.g. oleic, linoleic acids
• CPC Class Codes: A61K 31/202 having three or more double bonds, e.g. linolenic eicosanoids, e.g. leukotrienes A61K31/557
• CPC Class Codes: A61K 31/22 of acyclic acids, e.g. pravastatin
• CPC Class Codes: A61K 31/23 of acids having a carboxyl group bound to a chain of seven or more carbon atoms
• CPC Class Codes: A61K 47/14 Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
• CPC Class Codes: A61K 9/08 Solutions composition of solutions A61K47/00
• CPC Class Codes: A61K 9/48 Preparations in capsules, e.g. of gelatin, of chocolate A61K9/0004 takes precedence; bite capsules A61K9/0056
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention provides methods and compositions for slowing gastrointestinal transit and prolonging residence time to optimize presentation and absorption of ingested nutrients and/or pharmacologically active agents in the small intestine to prevent and/or reduce ineffectiveness thereof due to malabsorption.

The present invention further provides methods and compositions for enhancing the bioavailability and therapeutic effectiveness of pharmacologically active agents.

Claims

1. A method for prolonging the residence time of an orally or enterally administered substance by promoting its dissolution, bioavailability and/or absorption in the small intestine, comprising administering to a subject in need of the treatment an anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition comprising a carrier and a dispersion consisting essentially of an active lipid in the carriers, the active lipid being selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats and mixtures thereof, in an amount and a form effective to promote contact of the lipid with the subject'"'"'s small intestine and, thereby, prolong the residence time of an orally or enterally administered substance dissolution, bioavailability and/or through the small intestine for a period of time effective to increase substance absorption there through.

2. The method of claim 1, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition is administered orally.

3. The method of claim 2, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition is administered up to about 24 hours prior to the administration of the substance.

4. The method of claim 1, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition is administered concurrently with the substance.

5. The method of claim 1, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition is a liquid or a solid.

6. The method of claim 1, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition is tube-delivered.

7. The method of claim 1, wherein the active lipid comprises fully hydrolyzed fats.

8. The method of claim 1, wherein the active lipid comprises a fatty acid.

9. The method of claim 8, wherein the fatty acid is selected from the group of (C₄ -C₂₄) saturated and unsaturated fatty acids and mixtures thereof.

10. The method of claim 9, wherein the fatty acids are selected from the group consisting of caprolic acid, caprulic acid, capric acid, lauric acid, myristic acid, oleic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, trans-hexadecanoic acid, elaidic acid, columbinic acid, arachidic acid, behenic acid eicosenoic acid, erucic acid, bressidic acid, cetoleic acid, nervonic acid, Mead acid, arachidonic acid, timnodonic acid, clupanodonic acid, docosahexaenoic acid and mixtures thereof.

11. The method of claim 10, wherein the fatty acid comprises oleic acid or mixtures thereof with other fatty acids.

54. The method of claim 1, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

12. A method of treating a gastrointestinal disorder by slowing the gastrointestinal transit of an orally or enterally administered substance in a subject, comprising administering to a subject in need of the treatment a composition comprising a carrier and a dispersion consisting essentially of an active lipid in the carrier, the active lipid being selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats and mixtures thereof, in an amount and in a form effective to promote contact of the lipid with the subject'"'"'s small intestine and, thereby, slow the gastrointestinal transit of an orally or enterally administered substance through the small intestine.

13. The method of claim 12, wherein the gastrointestinal transit of the substance through the small intestine is slowed for a period of time effective for absorption of the substance to occur.

14. The method of claim 13, wherein the increased absorption of the substance is associated with the slowing of the gastrointestinal transit of the substance through the small intestine.

55. The method of claim 12, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

15. A method of enhancing the digestion and absorption of orally or enterally administered nutrients and/or pharmacological agents, comprising administering to a subject in need of the treatment a composition comprising a carrier and a dispersion consisting essentially of an active lipid in the carrier, the active lipid being selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats and mixtures thereof, in an amount and in a form effective to promote the contact of the active lipid with the small intestine and, thereby, prolong the residence time and enhance the digestion and absorption of orally or enterally administered nutrients and/or pharmacological agents in the small intestine.

56. The method of claim 15, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

16. A method for reducing diarrhea, comprising

administering to a subject in need of the treatment a composition comprising an active lipid selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats, and mixtures thereof, in an amount, and in a form effective to promote contact of the active lipid with the small intestine, and prolong the residence time of the luminal contents of the small intestine and, thereby, reduce diarrhea.

57. The method of claim 16, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

17. A method of reducing the serum level of atherogenic lipids derived from an ingested substance, comprising

administering to a subject in need of the treatment a composition comprising an active lipid selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats, and mixtures thereof, in an amount and in a form effective for promoting contact of the active lipid with small intestine, prolong the residence time in the small intestine of the ingested substance, and thereby, reduce atherogenic lipid serum levels.

18. The method of claim 17, wherein the composition is administered in an amount and in a form effective for limiting the spread and increasing the contact of the ingested substance with the proximal segment of the small intestine.

58. The method of claim 17, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

19. A method of enhancing the bioavailability of an orally ingested pharmacological agent by promoting a digestive, dissolving, absorptive, anti-atherogenic, anti-diarrheal and/or gastrointestinal transit slowing effect, comprising administering to a subject in need of the treatment an anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition comprising a carrier and a dispersion consisting essentially of an active lipid in the carrier, the active lipid being selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed lipid and mixtures thereof, in an amount and in a form effective for promoting the contact of the lipid with the subject'"'"'s small intestine, promoting an anti-atherogenic, anti-diarrheal, digestive, dissolving and/or absorptive effect and, thereby, prolonging residence time, enhancing the dissolution, bioavailability and/or absorption of an ingested pharmacological agent in the small intestine.

20. The method of claim 19, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition is administered prior to administration of the pharmacological agent.

21. The method of claim 20, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition is administered about 5 to about 60 minutes prior to administration of the pharmacological agent.

22. The method of claim 19, wherein the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition is administered concurrently with the agent.

59. The method of claim 19, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

23. An anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing controlled release oral composition, comprising

a dispersion in a carrier of a plurality of particles which comprise an active lipid selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats and mixtures thereof;

and

a controlled release coating thereon, which coating upon ingestion releases the active lipid and the particles and promotes their absorption, into the proximal segment of the small intestine by effecting and sustaining gastrointestinal transit slowing, dissolution, bioavailability and/or absorption promotion and/or an anti-diarrheal and/or anti-atherogenic effect.

24. An anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing liquid enteral composition, comprising a liquid carrier and a dispersion in the carrier consisting essentially of a substance and an active lipid selected from the group consisting of saturated and unsaturated fatty acids, fully hydrolyzed fats, and mixtures thereof;

which composition upon ingestion releases the active lipid into the proximal segment of the small intestine, so as to prolong the residence time of the substance in the small intestine and, thereby, increase substance digestion, dissolution, bioavailability and/or absorption and/or anti-diarrheal and/or anti-atherogenic effect.

25. A method of enhancing the absorption of a substance in the small intestine and promoting anti-atherogenes, anti-diarrheal, digestion, and/or dissolution, and/or slowing gastrointestinal transit, comprising

administering to a subject in need of the treatment the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing liquid enteral composition of claim 24, in an amount and for a period of time effective for the active lipid to contact and be absorbed through the small intestine and, thereby, prolong the residence time, promote digestion, bioavailability and/or absorption of the substance in the small intestine and/or have an anti-diarrheal and/or anti-atherogenic effect.

60. The method of claim 25, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

26. A method of enhancing the absorption of an orally administered substance and promoting an anti-atherogenic and/or anti-diarrheal effect, and promoting digestion and dissolution, and slowing gastrointestinal transit, comprising administering to a subject in need of treatment an anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing oral composition, comprising a core comprising a substance selected from the group consisting of nutrients and pharmacological agents and a coating thereon comprising an active lipid selected from the group consisting of saturated and unsaturated fatty acids and mixtures thereof, in an amount effective for promoting contact of the active lipid with, and its absorption from, the proximal segment of the small intestine, thereby prolonging the residence time and increasing the digestion and absorption of the substance in the small intestine and promoting an anti-atherogenic and/or anti-diarrheal effect.

61. The method of claim 26, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

27. An enteral anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition, comprising

a first component comprising an active ingredient to be absorbed through the small intestine;

a second component comprising a carrier dispersible form of an active lipid selected from the group consisting of saturated and unsaturated fats, fully hydrolyzed fats and mixtures thereof; and

an enteric coating which releases the first and the second components into the proximal segment of the small intestine, where the lipid slows transit and increases digestion, dissolution and/or residence time in, and absorption through, the small intestine without significant degradation and, thereby, increases absorption of the active ingredient thereof through in the presence of the active lipid than in its absence.

28. The anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 27, wherein the active ingredient is selected from the group consisting of nutrients and pharmacological agents.

29. The anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 28, wherein the nutrients are selected from the group consisting of foodstuffs, vitamins and minerals.

30. The anti-atherogenic anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 28, wherein the pharmacological agents are selected from the group consisting of somatostatin analogues, insulin release inhibitors, anti-diarrheal agents, antibiotics, fiber and electrolytes.

31. The anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 27, further comprising an additional ingredient selected from the group consisting of carriers, excipients, vehicles, lipid dispersants, detergents, bile acid salts, and suspending, emulsifying, stabilizing, thickening, buffering, preserving, coloring, disintegrating, solubilizing, flavoring and sweetening agents.

32. The anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 31, wherein the carriers are selected from the group consisting of solid, semisolid or liquid glucose, lactose, gum acacia, gelatin, mannitol, starch paste, magnesium trisilicate, talc, corn starch, keratin, colloidal silica, potato starch, urea, medium chain length triglycerides and dextrans.

33. A lipid dispersion, comprising the anti-diarrheal, anti-atherogenic, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 31, and a lipid dispersant comprising an aqueous solution of an agent selected from the group consisting of at least one bile salt, at least one agent alkaline buffer and a detergent.

34. A lipid emulsion, comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 31, and a lipid dispersant comprising an agent which in the presence of the active lipid forms a two-phase emulsion.

35. A lipid suspension, comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 31, and a lipid comprising a solid agent which forms a suspension with the active lipid.

36. An emulsion, comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 31, emulsifiers and suspending agents;

the emulsifiers and suspending agents being selected from the group consisting of gum acacia, agar, sodium alginates, bentonites, carbomers, celluloses, carrageenan, carboxymethyl celluloses, cholesterol, gelatins, octoxynol 9, oleyl alcohols, polyvinyl alcohols, povidone, propylene glycol monostearates, sodium lauryl sulfate, sorbitan esters, stearyl alcohol, tragacanth, xantham gum, chondrus, glycerin, trolamine, coconut oil, propylene glycol, ethyl alcohol, malt, malt extracts and mixtures thereof.

37. A cellulose emulsion, comprising the emulsion of claim 36, and celluloses which are selected from the group consisting of cellulose, hydroxyethyl celluloses, hydroxypropyl celluloses, hydroxypropyl methylcelluloses, methylcelluloses and mixtures thereof.

38. An oral formulation, comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 27, and an oral carrier.

39. The oral formulation of claim 38, being in a form selected from the group consisting of capsules, coated and uncoated microspheres and particles, which may be encapsulated, tablets, troches, lozenges, aqueous and oily suspensions, dispersible powders and granules, emulsions, hard and soft capsules, syrups and elixirs.

40. A controlled release formulation, comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 27, and a controlled release coating.

41. A slow release formulation comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 27 and a slow release coating.

42. A liquid enteric formulation comprising the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting, and/or gastrointestinal transit slowing composition of claim 27.

43. The liquid enteric formulation of claim 42, wherein the active ingredient comprises a dispersion of essential nutrients, pharmacological agents or mixtures thereof.

44. A method of prolonging small intestine transit time while promoting an anti-atherogenic and/or anti-diarrheal effect and/or promoting digestion, dissolution and/or absorption, comprising administering to a subject in need of treatment the composition of claim 27, wherein the active lipid is absorbed through the proximal segment of the small intestine in undegraded form and, thereby, increases small intestine transit time and produces an anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing effect.

45. The method of claim 44, wherein the substance comprises nutrients.

46. The anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 27, wherein the active lipid is selected from the group consisting of (C₄ to C₂₄) fatty acids and mixtures thereof.

47. The anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 46, wherein the fatty acids are selected from the group consisting of caprolic acid, caprulic acid, capric acid, lauric acid, myristic acid, oleic acid, palmitic acid, stearic acid, palmitoleic acid, linoleic acid, linolenic acid, trans-hexadecanoic acid, elaidic acid, columbinic acid, arachidic acid, behenic acid, eicosenoic acid, erucic acid, bressidic acid, cetoleic acid, nervonic acid, Mead acid, arachidonic acid, timnodonic acid, clupanodonic acid, docosahexaenoic acid and mixtures thereof.

48. The method of claim 44, wherein the of active lipid triggers at least one reflex selected from the group consisting of intestino-lower esophageal sphincter or relaxation of LES reflex, intestino-gastric feedback or inhibition of gastric emptying reflex, intestino-intestinal feedback or ileo-jejunal feedback/ileal brake reflex, jejuno-jejunal feedback/jejunal brake reflex, intestino-CNS feedback or satiety intensifying intestinal signaling reflex, intestino-pancreatic feedback or exocrine enzyme output control reflex, intestino-biliary feedback or bile flow control reflex, intestino-mesenteric blood flow feedback reflex for mucosal hyperemia control and intestine-colonic feedback, gastro-colonic reflex or colon contracting response to nutrients, in the proximal segment of the small intestine.

49. A method of treating a nutritional deficiency comprising administering to a subject afflicted with a nutritional deficiency the anti-atherogenic, anti-diarrheal, digestion, dissolution and/or absorption promoting and/or gastrointestinal transit slowing composition of claim 29, in an amount and in a form effective to deliver the active lipid to the subject'"'"'s proximal segment of the small intestine and, thereby, increase absorption of nutrients through the subject'"'"'s small intestine.

50. The method of claim 49, wherein the subject'"'"'s nutritional deficiency is associated with gastrointestinal symptoms selected from the group consisting of rapid intestinal transit, dumping syndrome, diarrhea, weight loss, distention, steatorrhea, asthenia and symptoms of specific nutrient deficiencies.

51. The method of claim 49, wherein the subject'"'"'s nutritional deficiency is associated with a gastrointestinal disorder selected from the group consisting of post-gastrectomy syndrome, dumping syndrome, AIDS-associated chronic diarrhea, diabetes-associated diarrhea, post-vagotomy diarrhea, bariatrics surgery-associated diarrhea, short bowel syndrome, tube-feeding related diarrhea, chronic secretory diarrhea, carcinoid syndrome-associated diarrhea, gastrointestinal peptide tumors, endocrine tumors, chronic diarrhea associated with thyroid disorders, chronic diarrhea associated with bacterial overgrowth, chronic diarrhea in gastronomy, choleraic diarrhea, chronic diarrhea associated with giardiasis, antibiotic-associated chronic diarrhea, diarrhea-predominant irritable bowel syndrome, chronic diarrhea associated with maldigestion and malabsorption, chronic diarrhea associated with idiopathic primary gastrointestinal motility disorders, chronic diarrhea associated with collagenous colitis, surgery-associated acute diarrhea, antibiotic-associated acute diarrhea and infection-associated acute infectious diarrhea.

52. The method of claim 51, wherein the bariatrics surgery-associated diarrhea comprises obesity surgeries selected from the group consisting of gastric bypass, gastroplasties and intestinal bypass.

53. The method of claim 51, wherein the short bowel syndrome is selected from the group consisting of including resection of the small intestine after trauma, radiation induced complications, Crohn'"'"'s disease and infarction of the intestine associated with vascular occlusion.

62. The method of claim 44, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.

63. The method of claim 49, wherein the active lipid is administered in an amount of about 0.5 to about 2.0 g/dose.