Gastric and colonic formulations and methods for making and using them

• US 10,092,573 B2
• Filed: 12/13/2011
• Issued: 10/09/2018
• Est. Priority Date: 12/13/2010
• Status: Active Grant

• Current Assignee: The Rite-Prep Unit Trust
• Original Assignee: Salix Pharmaceuticals Incorporated (Bausch Health Cos., Inc.)
• Inventors: Borody, Thomas Julius, Ramrakha, Sanjay, Saxon, John, Wettstein, Antony
• Primary Examiner(s): Brown-Pettigrew, Angela C
• Application Number:
  US13/993,294
• Publication Number:
  US 20130296314A1
• Time in Patent Office: 2,492 Days
• Field of Search: 5142305
• 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 31/047 having two or more hydroxy groups, e.g. sorbitol
• CPC Class Codes: A61K 31/4402 only substituted in position 2, e.g. pheniramine, bisacodyl
• CPC Class Codes: A61K 31/4412 having oxo groups directly attached to the heterocyclic ring
• CPC Class Codes: A61K 31/538 ortho- or peri-condensed with carbocyclic ring systems
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 1/10 Laxatives
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 1/14 Prodigestives, e.g. acids, enzymes, appetite stimulants, antidyspeptics, tonics, antiflatulents
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/14 for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/24 Antidepressants
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/02 Immunomodulators

Abstract

In alternative embodiments, the invention provides compositions, e.g., formulations, used for gastric, gastrointestinal and/or colonic treatments or lavage, e.g., orthostatic lavage, e.g., for inducing the purgation (e.g., cleansing) of a gastrointestinal (GI) tract, including a colon; and methods for making and using them. In alternative embodiments, compositions and methods of the invention are used for the amelioration, treatment and/or prevention of constipation, for the treatment of abdominal pain, particularly non-specific abdominal pain, and diarrhea, including diarrhea caused by a drug side effect, a psychological condition, a disease or a condition such as Crohn'"'"'s Disease, a poison, a toxin or an infection, e.g., a toxin-mediated traveler'"'"'s diarrhea. In alternative embodiments, the invention provides pharmaceuticals and products (articles) of manufacture for delivering these compositions and formulations to an individual, e.g., a human or an animal.

Claims

1. A composition comprising:

(i) from about 1 to about 25 milligrams (mg) bisoxatin (or 2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatin acetate,

(ii) from about 1 to about 25 grams of erythritol, or (2R,3S)-butane-1,2,3,4-tetraol, or isomers, sugar or polyol substitute isoforms, and

(iii) a pharmaceutically acceptable salt or salts, wherein the pharmaceutically acceptable salt or salts comprise from about 1 to about 40 grams of a pharmaceutically acceptable salt or pharmaceutically acceptable salts and comprise at least one sodium salt selected from the group of;

a monobasic sodium phosphate, dibasic sodium phosphate, and/or tribasic sodium phosphate, a sodium sulfate, a sodium chloride, a sodium gluconate, a sodium citrate and a sodium aspartate.

2. The composition of claim 1, wherein the composition comprises about 10 milligrams (mg) bisoxatin or (2,2-bis(4-hydroxyphenyl)-2H-benzo[b][1,4]oxazin-3(4H)-one), or bisoxatin acetate.

3. The composition of claim 1, wherein the composition is formulated for use as a purgative, a colonic cleanser, or for orthostatic lavage.

4. The composition of claim 1, wherein the composition comprises from about 8 to about 15 grams of erythritol.

5. The composition of claim 4, wherein the composition comprises about 10.24 grams of erythritol.

6. The composition of claim 4, wherein the composition comprises about 2 grams of erythritol.

7. The composition of claim 4, wherein the composition comprises about 3 grams of erythritol.

8. The composition of claim 4, wherein the composition comprises from about 7.24 grams of erythritol.

9. The composition of claim 1, wherein the composition comprises from about 8 to about 15 grams of the pharmaceutically acceptable salt or salts.

10. The composition of claim 1, wherein the composition comprises from about 15 to about 28 grams of the pharmaceutically acceptable salt or salts.

11. The composition of claim 1, wherein the pharmaceutically acceptable salt or salts further comprises a water-soluble salt.

12. The composition of claim 1, wherein the pharmaceutically acceptable salt or salts further comprises a water-soluble potassium salt.

13. The composition of claim 12, further comprising a sodium salt, wherein the water-soluble potassium salt is in an amount, by weight, of from about 0.05 to about 1 times the weight of a sodium salt in the composition.

14. The composition of claim 1, wherein the pharmaceutically acceptable salt or salts further comprises a water-soluble magnesium salt.

15. The composition of claim 14, further comprising a sodium salt, wherein the weight of magnesium ions of the magnesium salt in the composition is from about 0.1 to about 10 times the weight of sodium ions in the composition.

16. The composition of claim 1, further comprising at least one salt selected from the group consisting of:

a calcium salt, a calcium carbonate, a calcium acetate, a citrate salt, a calcium citrate, a magnesium salt, a magnesium sulfate, a magnesium citrate, a magnesium phosphate, a potassium salt, a potassium gluconate, a potassium tartrate, a potassium chloride, an acetate salt, an adipate salt, an alginate salt, an aspartate salt, a benzoate salt, a benzenesulfonate salt, a bisulfate salt, a butyrate salt, a camphorate salt, a camphor sulfonate salt, a digluconate salt, a glycerophosphate salt, a hemisulfate salt, a heptanoate salt, a hexanoate salt, a fumarate salt, a hydrochloride salt, a hydrobromide salt, a hydroiodide salt, a 2-hydroxyethansulfonate (isothionate) salt, a lactate salt, a maleate salt, a methane sulfonate salt, a nicotinate salt, a 2-naphthalene sulfonate salt, an oxalate salt, a palmitoate salt, a pectinate salt, a persulfate salt, a 3-phenylpropionate salt, a picrate salt, a pivalate salt, a propionate salt, a succinate salt, a tartrate salt, a thiocyanate salt, a phosphate salt, a glutamate salt, a bicarbonate salt, a p-toluenesulfonate salt, a undecanoate salt, or any equivalent salt, or any mixture thereof.

17. The composition of claim 1, wherein the composition further comprises one or more of a defoaming agent, a surfactant agent, a lubricant, an acid neutralizer, a marker, a cell marker, a drug, an antibiotic and/or a contrast agent.

18. The composition of claim 17, wherein the marker comprises (i) a hexaminolevulinate, an indigo carmine or a methylene blue or an equivalent cell marker, or (ii) an antibody specific for a normal or abnormal cell phenotype or genotype, or a cancer cell or a polyp.

19. The composition of claim 17, wherein the surfactant agent comprises a simethicone or any mixture of polydimethylsiloxane and silica gel, or equivalent.

20. The composition of claim 19, wherein the surfactant agent comprises simethicone in an amount of from about 5 to 450 mg.

21. The composition of claim 20, wherein the composition comprises simethicone in an amount of about 100 mg.

22. The composition of claim 17, wherein the lubricant is selected from one or more of a magnesium stearate, a hyaluronic acid, a glycerol and/or a silicone.

23. A pharmaceutical composition comprising:

the composition of claim 1.

24. The pharmaceutical composition of claim 23, wherein the composition is formulated as a liquid, a suspension, a gel, a semisolid, or as an enteral formulation.

25. The pharmaceutical composition of claim 23, wherein the composition is formulated as a plurality of dosage units, wherein the dosage unit is selected from the group consisting of:

a pill, a tablet, a geltab, a lozenge, a sachet and a capsule.

26. The pharmaceutical composition of claim 25, wherein the composition is administered as about 10 to 70 dosage units.

27. The pharmaceutical composition of claim 23, wherein the composition is manufactured with an encapsulating material, wherein optionally the encapsulating material comprises a lubricant.

28. A method of performing a procedure involving the intestine or colon on a subject, comprising administering a first composition comprising the composition of claim 1, optionally wherein the subject is a human or an animal.

29. The method of claim 28, wherein the procedure comprises a colonoscopy, an enteroscopy, an endoscopy, a capsule endoscopy, a viewing of the intestinal or colonic mucosa, a surgical procedure involving the intestine or colon, or a radiological procedure involving the intestine or colon to an individual in need thereof.

30. The method of claim 28, wherein the first composition is administered as a plurality of dosage units, wherein the dosage unit is selected from the group of:

a pill, a tablet, a geltab, a lozenge, a sachet and a capsule.

31. The method of claim 30, wherein the procedure is a colonoscopy, and the first composition is administered as about 10 to 40 dosage units.

32. The method of claim 31, wherein the first composition is administered in a dosing regimen of from about 1 to 20 dosage units per hour.

33. The method of claim 28, wherein the subject is administered at least a second composition.

34. The method of claim 33, wherein the at least second composition is administered about 6 to 24 hours after administration of the first composition.

35. The method of claim 33, wherein the at least second composition is administered as a plurality of dosage units comprising about 2 to 32 dosage units.

36. The method of claim 30, wherein the procedure is a capsule endoscopy, and the first composition is administered in a dosing regimen of from 1 to 10 dosage units per half-hour.

37. A method for the amelioration, treatment and/or prevention of constipation or bloating in a subject, comprising administering the composition of claim 1 to the subject in need thereof.

38. The method of claim 37, wherein the composition is administered as a plurality of dosage units, wherein the dosage unit is selected from the group consisting of:

a pill, a tablet, a geltab, a lozenge, a sachet and a capsule.

39. The method of claim 38, wherein the composition is administered in a dosing regimen of from about 5 to 15 dosage units per day.

40. The method of claim 37, wherein the constipation or bloating is due to at least one of:

travel;

change in daily routine;

lack of exercise;

immobility caused by injury, illness, or aging;

dehydration;

irritable bowel syndrome;

pregnancy;

diabetes;

hypothyroidism;

hypercalcemia;

cancer of the colon or rectum;

uterine prolapse;

vaginal vault prolapse;

rectal prolapse;

scarring from surgery;

injury of the colon or rectum;

Parkinson'"'"'s disease;

multiple sclerosis;

stroke;

hemorrhoids or anal fissures;

delaying bowel movements;

anxiety;

depression;

eating disorders; and

/or obsessive-compulsive disorder, coeliac disease, muscular dystrophy, myotonic dystrophy, nonspecific abdominal pain, or a neurological condition or any cause of constipation.

41. A method for the treatment of abdominal pain in a subject, comprising administering the composition of claim 1 to the subject in need thereof.

42. A method for the amelioration or treatment of a bowel disease in a subject, comprising administering a composition of claim 1 to the subject in need thereof.

43. The method of claim 42, wherein the bowel disease or condition having a bowel dysfunction component, comprises:

an inflammatory bowel disease (IBD), Crohn'"'"'s disease, hepatic encephalopathy, enteritis, colitis, irritable bowel syndrome (IBS), fibromyalgia (FM), chronic fatigue syndrome (CFS), depression, attention deficit/hyperactivity disorder (ADHD), multiple sclerosis (MS), systemic lupus erythematosus (SLE), travelers'"'"' diarrhea, small intestinal bacterial overgrowth, chronic pancreatitis, or a pancreatic insufficiency.

44. A package or kit comprising:

the composition of claim 1 and instructions for its use.

45. The package or kit of claim 44, wherein the composition is contained within a first container, wherein the package or kit further comprises at least a second container comprising the composition of claim 1, and the contents of the two containers are designed to be taken in sequence.

46. The package or kit of claim 45, wherein the first container comprises a bottle, a blister pack, or equivalents thereof and the second container comprises a bottle, a blister pack, or equivalents thereof.

47. The package or kit of claim 45, wherein the compositions of the first and second containers are provided as a plurality of dosage units, wherein the dosage unit is selected from the group consisting of:

a pill, a tablet, a geltab and a capsule.

48. The package or kit of claim 47, wherein the first container comprises from about 10 to 40 dosage units.

49. The package or kit of claim 47, wherein the second container comprises from about 2 to 32 dosage units.

50. The package or kit of claim 45, wherein the composition of the first container and the composition of the second container are administered from 6 to 24 hours apart.

51. The package or kit of claim 45, wherein the composition of the second container is administered the next day relative to the composition of the first container.