# Patent

## Title
Methods and formulations for treating ineffective or decreased esophageal motility

## Abstract

Pharmaceutical compositions and methods for treating ineffective esophageal motility in which bethanechol and pharmaceutically acceptable absorption enhancers comprising bile acids and mixtures thereof are topically introduced to the esophagus. Therapeutically effective amounts of bethanechol are delivered while reducing or eliminating parasympathetic nervous system side effects normally associated with systemic bethanechol delivery.

## Background
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of prior U.S. Provisional Application Nos. 60/972,123, filed Sep. 13, 2007, and 61/039,448, filed Mar. 26, 2008. The disclosures of the above applications are incorporated herein by reference.


TECHNICAL FIELD
This description relates generally to the treatment of ineffective or decreased esophageal motility and particularly to methods and formulations comprising bethanechol to enhance the swallowing mechanism.
BACKGROUND
The mechanism of swallowing, also known as deglutition, while generally not given much consideration by healthy individuals, is highly complex and involves the control and coordination of a number of physiologic processes within the body. Initially, food in the mouth is prepared for entry into the esophagus and eventually the stomach and the rest of the gastrointestinal (GI) tract. In the case of solid food, it is chewed, or masticated, and formed into a bolus using the jaw muscles, the teeth, and the tongue. In the case of liquids, the appropriately sized amount of liquid is prepared. Next, the bolus enters the pharynx and subsequently into the esophagus. Peristalsis moves the bolus from the pharynx, through the esophagus, and into the stomach. The swallowing process in the pharynx and the esophagus is coordinated by the autonomic nervous system. Located within the smooth and striated muscle layers of the pharynx and the esophagus are various muscarinic receptors which, although not currently completely understood, when activated, appear to effect peristalsis. These muscarinic receptors help control the smooth and striated muscle layers not only of the esophagus, however, but of the lower gastrointestinal tract, and the bladder. They thus effect peristaltic waves to move materials through the esophagus and the rest of the GI tract and, in the case of the bladder, discharge urine.
Ineffective esophageal motility is associated with many disorders affecting humans. For example, human immunodeficiency virus (HIV) and cancer chemotherapy and radiation patients often have esophageal motility problems related to the disease processes themselves and/or from side effects of treatment. HIV patients, in particular, are currently treated with multi-medication regimens often requiring multiple daily doses. Unfortunately, missing doses of medication can lead to medication resistance in those patients, compromising treatment. In addition, the elderly and patients suffering from strokes or traumatic brain or spinal cord injury, Parkinson's Disease, multiple sclerosis, multiple system atrophy with autonomic phenomena (formerly known as Shy-Drager syndrome), and amyotrophic lateral sclerosis often suffer from ineffective esophageal motility. It has been reported that over one-half of all stroke victims suffer from acute ineffective esophageal motility. It has also been reported that the majority of elderly Parkinson's patients die from bronchial pneumonia and infectious shock and choking is one of the main causes of aspiration pneumonia. Finally, certain drugs can cause such an effect. Examples include antimuscarinics (muscarinic receptor antagonists), including, for example, tolterodine.
Bethanechol, available as 2-carbamoyloxpropyl-trimethyl-amonium chloride, is a parasympathomimetic drug that exerts its effect directly and selectively on the muscarinic M2 receptors and, it is believed, to a certain extent, on the M4 receptors and the M3 receptors and is not inactivated by acetylcholinesterase. See, Liwang L., et al., “Pharmacological discrimination between muscarinic receptor signal transduction cascades with bethanechol chloride.” British Journal of Pharmacology, 138 (2003) 1259-70, incorporated herein by reference, Bethanechol has been used for some time for the treatment of urinary retention associated with neurogenic bladder, to stimulate lower gastrointestinal motility, and to help prevent GERD. Formulations of bethanechol consist of either tablets, sublingual tablets, subcutaneous injection, or an oral solution consisting of, for example, bethanechol chloride (5 mg/ml) combined with a suspending vehicle of Ora-Plus® (Paddock Laboratories, Inc., Minneapolis, Minn.) and either Ora-Sweet® (Paddock Labs) or cherry syrup. Recently, in 50 mg oral doses, bethanechol was shown, after 20 and 40 minutes, to improve esophageal motility. See, Agrawal, A., et al., “Bethanechol improves smooth muscle function in patients with severe ineffective esophageal motility.” Journal of Clinical Gastroenterology, 41(4) (2007) 366-70, incorporated herein by reference. All such dosing is designed to be absorbed into the blood stream to be made available to the muscarinic receptors. When provided systemically, however, bethanechol can cause undesirable side effects, including diarrhea, flushing, increased sweating, nausea, stomach pain, or gas, and, importantly, urinary urgency. In the case of HIV and cancer chemotherapy patients, moreover, since nutrient absorption is important in treating these patients, the side effects of diarrhea and abdominal cramping precludes the systemic application of bethanechol for esophageal motility problems in these patients. In fact, there is currently no safe and effective treatment for esophageal motility disorders in these patients. Thus, there exists a need for a formulation and method for effectively treating ineffective esophageal motility while eliminating or reducing undesirable side effects associated with systemic dosing.
SUMMARY
To meet these needs, the present disclosure describes a low-dose bethanechol formulation comprising bethanechol, a pharmaceutically acceptable absorption enhancer such as an ox bile acid mixture, and a pharmaceutically acceptable carrier such as water and a method of treatment for applying the formulation to the pharynx and esophagus. This formulation and method of treatment allows for the topical delivery of a therapeutically effective amount of bethanechol to the muscarinic receptors in the pharynx and esophagus while reducing or eliminating the undesirable side effects associated with traditional bethanechol formulations and methods of delivery for the treatment of ineffective esophageal motility.
In one general aspect, a pharmaceutical composition for the treatment of ineffective esophageal motility is described. In one embodiment, the composition comprises 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. In a further embodiment, the concentration of bethanechol is about 25 millimolar. In a further embodiment, the parasympathetic nervous side effects normally associated with the administration of bethanechol are reduced or virtually eliminated. In a further embodiment, the bile acids comprise taurocholic 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; and taurodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof. In a further embodiment, the pharmaceutically acceptable liquid carrier is water.
In a further embodiment, a pharmaceutical composition for the treatment of ineffective esophageal motility is described which composition comprises a pharmaceutically acceptable muscarinic receptor agonist; a pharmaceutically acceptable absorption enhancer; 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. In a further embodiment, the muscarinic receptor agonist is selective to M2 receptors. In a further embodiment, the muscarinic receptor agonist is bethanechol. In a further embodiment, the absorption enhancer comprises a bile acid mix of taurocholic 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; and taurodeoxycholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof. In a further embodiment, the muscarinic receptor agonist is bethanechol and the molar ratio of the bile acid mix to bethanechol is about 40:1. In a further embodiment, the absorption enhancer is chosen from the group 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; glychocholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof; taurochenodeoxycholic acid, pharmaceutically acceptable salts, 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; 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, glycocholic acid, pharmaceutically acceptable salts thereof, pharmaceutically acceptable metabolically related derivatives thereof, or its monosodium phosphate derivative, mono- and diglycerides or their monosodium phosphate derivatives, and combinations thereof. In a further embodiment, the absorption enhancer comprises about 500 millimolar bile acids, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof. In a further embodiment, the absorption enhancer is lipophilic and carries a negative charge at mammalian physiological pH ranges. In a further embodiment, the absorption enhancer concentration is about 500 millimolar. In a further embodiment, a method is disclosed for applying a bethanechol, absorption enhancer, liquid carrier composition to the posterior pharynx. In a further embodiment, the application is spraying, swabbing, squirting, or gargling. In a further embodiment, the muscarinic receptor agonist is bethanechol; the application is spraying and each spray delivers greater than 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. In a further embodiment, the concentration of bethanechol is about 5 mg/ml.
In another general aspect, a method of treating a patient suffering from ineffective esophageal motility is described. The method comprises 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. In a further embodiment, the therapeutically effective amount is between about 3 mg and about 7.5 mg.
In another general aspect, a method is disclosed for facilitating a therapeutic esophageal peristaltic effect to a patient in need of treatment while reducing or virtually eliminating a parasympathetic nervous system side effect. The method comprises 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. In a further embodiment, the therapeutically effective amount of bethanechol is between about 3 mg and about 7.5 mg. In a further embodiment, 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.
Other exemplary embodiments of the invention will become apparent from the detailed description provided hereinafter. It should be understood that the detailed description and specific examples, while disclosing exemplary embodiments of the invention, are intended for purposes of illustration only and are not intended to limit the scope of the invention.


DETAILED DESCRIPTION
Bethanechol is known to be poorly absorbed by the mucosal lining of the gastrointestinal tract. It is a stable, water-soluble molecule, but has a positive charge on a quaternary amine which hampers its absorption. Thus, to achieve the beneficial effects of bethanechol on esophageal motility, systemic dosages in the range of 25-50 mg are required. Further, absorption of bethanechol at these dosage levels by the stomach and lower GI tract results in systemic distribution to other areas of the body such as the urinary tract and colon. A 50 mg oral dosage, for example, is believed to be about 22 percent absorbed in the stomach and intestines, which are rich in blood supply. This would result in a systemic level of about 11 mg of bethanechol. As described herein, however, bethanechol delivered locally to the pharynx and esophagus in a form that can more easily be absorbed by the mucosal lining of the pharynx and esophagus and delivered to the muscarinic receptors, principally the M2 receptors, can provide esophageal motility benefits, as well as increased salivation, while minimizing or avoiding systemic absorption and reducing or eliminating undesirable side effects. Enhancing the reduction or elimination of undesirable side effects is the fact that the esophagus has low vascularization, thus inhibiting the systemic absorption of bethanechol.
As used herein, by “pharmaceutically acceptable” it is meant the named ingredient must be compatible with the other ingredients of the formulation, and not deleterious to the recipient thereof.
As used herein, by “therapeutically effective amount” it is meant an amount which provides a therapeutic benefit in the treatment, management, or prevention of conditions that are responsive to the named compound.
A pharmaceutically acceptable absorption enhancer can help provide a mechanism whereby the bethanechol is delivered to the esophageal mucosa M2 receptors and to the M2 receptors in the underlying deeper smooth and striated muscles. Included are those absorption enhancers which are lipophilic and carry a negative charge at mammalian physiological pH ranges (5-8). A member of the bile acid group, of which taurocholic acid is exemplary, allows for enhanced absorption of bethanechol by forming an ionic bond with bethanechol at the negative charge of the bile acid (e.g., the sulfate group of taurocholic acid), thereby carrying bethanechol chloride with it. It is also believed that a member of the bile acid group, of which taurocholic acid is exemplary, acts upon the M3 receptors to alleviate or ameliorate the swallowing dysfunction which is often associated with inflammation.
In addition to taurocholic acid, bile acids include, but are not limited to, cholic acid, desoxycholic acid, glycocholic acid, and ox bile extract. Special Bile Acid Mix (New Zealand Pharmaceuticals Ltd., Palmerston North, North Island, NZ) has, for example, the following composition:
















taurocholic acid
35.8 wt. percent 



glycholic acid
24.8 wt. percent 



taurochenodeoxycholic acid
2.0 wt. percent



taurodeoxycholic acid
9.5 wt. percent



glycochenodeoxycholic acid
1.3 wt. percent



glycodeoxycholic acid
5.0 wt. percent










Other agents include diacetyl tartaric esters of (M)mono- and diglycerides; mono- and diglycerides; monosodium phosphate derivatives of cholic acid; desoxycholic acid; diacetyl tartaric acid esters of (M)mono- and diglycerides, glycocholic acid, and mono- and diglycerides; and propylene glycol.
Without not attempting to be all-inclusive, absorption enhancers may be chosen from the following group: ox bile; taurocholic acid, pharmaceutically acceptable salts thereof, or pharmaceutically acceptable metabolically related derivatives thereof; glycocholic 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, 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; 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, glycocholic acid, pharmaceutically acceptable salts thereof, pharmaceutically acceptable metabolically related derivatives thereof, or its monosodium phosphate derivative, mono- and diglycerides or their monosodium phosphate derivatives, and combinations thereof.
Adding pharmaceutically acceptable thickening agents and viscosity enhancers will also increase the viscosity of the formulation which will act to increase adherence to the esophageal mucosa, and, thus increase contact time. This increased contact time, along with the presence of absorption enhancers will facilitate absorption of bethanechol.
Adding pharmaceutically acceptable flavorings, sweetening enhancers, and bitterness suppressors such as those offered by FlavorX, Inc. (Columbia, Md.) can make the formulation more palatable, and, thus, more likely to be used. Pharmaceutically acceptable antioxidants and antimicrobials can also be added.
It is believed that, as a result of activation of the M2 receptors, pressure within the upper esophagus will increase, initiating a peristaltic wave in the upper esophagus moving toward the LES. The formulation will continue to flow by gravitational forces and dissolution in saliva to the LES, where M2 receptors in the LES will be activated by bethanechol to increase pressure of the LES, helping to prevent reflux of gastric contents back into the esophagus.
An exemplary formulation may be prepared by combining between 360 and 900 mg bethanechol chloride, about 600 mg of sodium carboxymethylcellulose or about 240 mg of methylparaben, about 24 mg of glycerin, an absorption enhancer, and preserved water quantum sufficiat to 120 ml total volume of the formulation. Such formulation is suitable for topical spray application to the pharynx and esophagus.
In one general aspect, the composition is effective for treating a patient suffering from ineffective esophageal motility and comprises 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.
An exemplary formulation comprises 25 millimolar bethanechol, 500 millimolar Special Bile Acid Mix, and sufficient viscosity enhancers in an aqueous solution. In a further exemplary formulation, the molar concentration of taurocholic acid and taurodeoxycholic acid is present in a ratio of about 40:1 with the molar concentration of bethanechol. Such formulation is suitable for topical spray application to the pharynx and esophagus. The 40:1 ratio balances the need to have an excess of absorption enhancers relative to the bethanechol with cost. The higher the ratio, the less bethanechol that would be required to achieve similar absorption.
An exemplary method comprises treating ineffective esophageal motility while reducing or virtually eliminating an undesirable side effect, particularly a parasympathetic nervous system side effect, in a mammal in need of treatment by topically administering to the pharynx and esophagus of the mammal a therapeutically effective amount of bethanechol and an absorption enhancer to facilitate esophageal peristalsis so that the undesirable side effect, particularly the parasympathetic nervous system side effect, is reduced while maintaining the therapeutic esophageal peristaltic effect. A further exemplary method comprises delivering an amount of bethanechol of between about 3 mg and about 7.5 mg. A further exemplary method comprises introducing about ten 0.1 ml sprays comprising 5 mg bethanechol per ml and an absorption enhancer. Of the total 5 mg introduced, it is expected about 25 percent of the bethanechol, or about 1.25 mg, is adsorbed. The remaining 3.75 mg would proceed into the stomach and intestines, and, at about a 22 percent absorption rate would result in only about 0.8 mg bethanechol being systemically adsorbed, far below the threshold necessary to produce undesirable side effects.
In one general aspect, delivery is effected by methods effective to introduce the composition to the back of the throat, pharynx, and/or esophagus such that the composition topically contacts the tissues thereof. Examples include a pump spray, for example, a pump spray comprising an extension tube which facilitates delivery deep into the back of the throat. In another general aspect the composition is squirted as a stream or partial stream into the back of the throat. In a further general aspect, the composition is swabbed into the back of the throat. In a further embodiment, the composition is gargled in the back of the throat.
EXAMPLES
A formulation was prepared consisting essentially of 600 mg bethanechol chloride; 600 mg sodium carboxymethylcellulose; 24 ml glycerin; and 29.5 g Special Bile Acid Mix, the Special Bile Acid Mix consisting essentially of 35.8 wt. percent taurocholic acid, 24.8 wt. percent glycholic acid, 2.0 wt. percent taurochenodeoxycholic acid, 9.5 wt. percent taurodeoxycholic acid, 1.3 wt. percent glycochenodeoxycholic acid, and 5.0 wt. percent glycodeoxycholic acid; mixed in preserved water quantum sufficiat 120 ml total volume of formulation.
On three separate occasions, a healthy male volunteer introduced 10 about 0.1 ml sprays of the above formulation to the back of his throat. After about 10 minutes, the volunteer reported easier swallowing and increased salivation. These effects continued for approximately 90 minutes. At no time during the test did the volunteer experience any undesirable side effects and, particularly, no side effects commonly associated with the administration of high systemic doses of bethanechol.
On five separate occasions, a second healthy male volunteer also introduced 10 about 0.1 ml sprays of the above formulation to the back of his throat. As with the first volunteer, after about 10 minutes, the second volunteer also reported easier swallowing and increased salivation that continued for about 90 minutes. Also as with the first volunteer, at no time during the test did the second volunteer experience any undesirable side effects and, particularly, no side effects commonly associated with the administration of high systemic doses of bethanechol. Neither volunteer experienced any long-term effects.
This detailed description is intended principally as a description of the present embodiments of the invention, and is not intended to represent the only form in which the present invention may be synthesized, formed, or utilized. The description sets forth the designs, functions, means, and methods of implementing the invention in connection with the illustrated embodiments. It is to be understood, however, that the same or equivalent functions and features may be accomplished by different embodiments that are also intended to be encompassed within the spirit and scope of the invention and that various modifications may be adopted without departing from the invention or scope of the following claims.

## Claims

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.