Methods and formulations for treating ineffective or decreased esophageal motility

1. A topical pharmaceutical composition for the treatment of ineffective esophageal motility, suitable for spraying on the posterior pharynx, comprising:

from about 15 millimolar to about 40 millimolar bethanechol or pharmaceutically acceptable salts thereof;

about 500 millimolar of a combination of pharmaceutically acceptable bile acids, the combination consisting of:

taurocholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

glycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

taurochenodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

taurodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

glycochenodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

glycodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof; and

a pharmaceutically acceptable liquid carrier.

2. The composition of claim 1 , wherein the concentration of bethanechol is about 25 millimolar.

3. The composition of claim 1 , wherein parasympathetic nervous system side effects normally associated with the administration of bethanechol are reduced or virtually eliminated.

4. The composition of claim 1 , wherein the pharmaceutically acceptable liquid carrier is water.

5. A pharmaceutical composition for the treatment of ineffective esophageal motility, comprising:

a pharmaceutically acceptable muscarinic receptor agonist;

a pharmaceutically acceptable absorption enhancer, the absorption enhancer comprising:

taurocholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

glycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

taurochenodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

taurodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

glycochenodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

glycodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof; and

a pharmaceutically acceptable liquid carrier, wherein:

the composition is suitable for topical application to the back of the throat, pharynx, or esophagus of a patient in need of treatment; and parasympathetic nervous system side effects normally associated with the muscarinic receptor agonist are reduced or virtually eliminated.

6. The composition of claim 5 , wherein the muscarinic receptor agonist is selective to M2 receptors.

7. The composition of claim 5 , wherein the muscarinic receptor agonist is bethanechol.

8. The composition of claim 6 , wherein:

the muscarinic receptor agonist is bethanechol; and the molar ratio of the bile acid mix to bethanechol is about 40:1.

9. The composition of claim 5 , wherein the absorption enhancer further comprises a component chosen from the group consisting of:

glychocholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof;

ox bile extract; propylene glycol; cholic acid, pharmaceutically acceptable salts thereof, pharmaceutically acceptable metabolically related derivatives thereof, or its monosodium phosphate derivative;

deoxycholic acid, pharmaceutically acceptable salts thereof, pharmaceutically acceptable metabolically related derivatives thereof, or its monosodium phosphate derivative;

diacetyl tartaric acid esters of (M)mono- and diglycerides or their monosodium phosphate derivatives.

10. The composition of claim 5 , wherein the absorption enhancer comprises about 500 millimolar bile acids, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof.

11. The composition of claim 5 , wherein the absorption enhancer is lipophilic and carries a negative charge at mammalian physiological pH ranges.

12. The composition of claim 5 , wherein the absorption enhancer concentration is about 500 millimolar.

13. A method of delivering the composition of claim 5 , comprising applying the composition to the posterior pharynx.

14. The method of claim 13 , wherein the application is spraying, swabbing, squirting, or gargling.

15. The method of claim 14 , wherein: the muscarinic receptor agonist is bethanechol;

the application is spraying and each spray delivers greater that about 0.1 ml but less than about 0.5 ml; and

the concentration of bethanechol is between about 3 mg/ml and about 7.5 mg/ml.

16. The method of claim 14 , wherein the concentration of bethanechol is about 5 mg/ml.

17. A method of treating a patient suffering from ineffective esophageal motility, comprising:

topically applying a therapeutically effective amount to the back of the esophagus of the patient, a composition comprising:

from about 15 millimolar to about 40 millimolar bethanechol or pharmaceutically acceptable salts thereof;

about 500 millimolar one or more pharmaceutically acceptable bile acids; and

a pharmaceutically acceptable liquid carrier; and

wherein parasympathetic nervous system side effects normally associated with bethanechol are reduced or virtually eliminated.

18. The method of claim 17 , wherein the therapeutically effective amount is between about 3 mg and about 7.5 mg.

19. A method of facilitating a therapeutic esophageal peristaltic effect to a patient in need of treatment while reducing or virtually eliminating a parasympathetic nervous system side effect, comprising topically administering to the esophagus a therapeutically effective amount of bethanechol to facilitate esophageal peristalsis so that the parasympathetic nervous system side effect is reduced while maintaining the therapeutic esophageal peristaltic effect.

20. The method of claim 19 , wherein the therapeutically effective amount of bethanechol is between about 3 mg and about 7.5 mg.

21. The method of claim 19 , wherein the patient in need suffers from acquired immune deficiency syndrome, stroke, amyotrophic lateral sclerosis, acid reflux disease, spinal cord injury, Parkinson's Disease, Alzheimer's Disease, multiple sclerosis, and combinations thereof.