Link:  Pharm/Biotech Resources

Title:  Salt solution for colon cleansing

United States Patent:  6,946,149

Issued:  September 20, 2005

Inventors:  Cleveland; Mark vB. (Duxbury, MA)

Assignee:  Braintree Laboratories, Inc. (Braintree, MA)

Appl. No.:  135857

Filed:  April 30, 2002

The field of colonic diagnostic and surgical procedures is hampered by the lack of optimal means available to cleanse the colon. A compromise between convenient, distasteful, solid or low volume, hyperosmotic solutions which cause considerable fluid and electrolyte imbalances in patients and large volume, difficult to consume, iso-osmotic solutions has had to be made heretofore. This invention describes a low volume, hyper-osmotic solution consisting of sulfate salts with and with out polyethylene glycol. Unlike prior art, this composition is useful for the cleansing of the bowel and, in lower volumes, as a laxative, without producing clinically significant changes in bodily function.

SUMMARY OF THE INVENTION

I now disclose easily and conveniently administered dosage formulations of effective colonic purgatives.

The disclosed colonic purgative formulations provide safe and effective purgative activity at lower dosages of salt than prior art sodium phosphate tablets, solutions of phosphates and sulfates, or combinations thereof. In addition, a lower volume of fluid is ingested and there are no clinically significant changes in body electrolyte chemistry.

This colonic purgative can be administered with a minimum amount of patient discomfort and is better tolerated than prior art purgatives.

The colonic purgative may include an effective amount of one or more sulfate salts, Na₂SO₄, MgSO₄, and K₂SO₄ have been used. Polyethylene glycol may also be advantageously added to the colonic purgative composition.

DETAILED DESCRIPTION OF AN ILLUSTRATIVE EMBODIMENT

There are two currently used methods used for colonic lavage. These are: (1) gastrointestinal lavage with 4 liters of a balanced solution that causes negligible net water or electrolyte absorption or secretion or (2) oral ingestion of small volumes of concentrated (hypertonic) sulfate or sodium phosphate solutions, e.g. Fleet Phospho-Soda, or the non-aqueous tablet formulations of phosphates or salts, all of which cause clinically significant effects on bodily chemistry.

Clinical trials have shown use of the 4 liter balanced solution to be safe and efficacious. However, compliance is poor because of the large volume of solution that must be rapidly ingested. Additionally, these large volume solutions are not well tolerated by patients.

Use of the hypertonic sodium phosphate solutions is also efficacious in cleansing the colon. However, use of hypertonic sodium phosphate has been shown to cause upset in electrolyte balance including: hyperphosphatemia, hypocalcemia, positive sodium balance, and negative potassium balance. For example, in one published study the average serum phosphate concentration rose from 2.8 to 6.5 mg/dL (Kolts et al., Am. J. Gastroenterology, 88:1218-1223, 1993), and in another some patients developed serum phosphate concentrations as high as 11.6 mg/dL (Vanner et al., Am. J. Gastroenterology 85:422-427, 1990). The normal range for serum phosphate is generally considered to be 2.6 to 4.5 mg/dL. Also, serum potassium fell to as low as 2.9 mEq/L, while the normal range is 3.4 to 5.4. In a third published study, the Ca×P product rose from 35 to as high as 104, while the normal range is generally 22-47 (DiPalma et al., Digestive Diseases and Sciences, 41:749-753, 1996).

Hypertonic phosphate gastrointestinal cleansing solutions have also been associated with hypokalemia and hypocalcemia in some patients, resulting in serious injury and even death (Ahmed et al. Am. J. Gastro. 1998;91:1261-1262).

While Fleet Phospho-Soda preparation, and other hypertonic phosphate colonic lavages are generally considered safe for most healthy adults, they pose significant risks for adverse reactions in patients with renal, cardiac or hepatic diseases, and elderly patients in whom excess sodium absorption might be dangerous. Because of these risks of severe adverse reactions, renal and cardiac function should be evaluated and serum phosphate and serum calcium should be carefully monitored in all patients using hypertonic phosphate gastric lavage composition (Fleet and Visicol labeling). This monitoring is inconvenient, adds to expense and is infrequently performed resulting in dangerous incidents (Chan et al. Can. J. Gastro 1997; 11:334-338).

I have found a safe and effective small volume colonic purgative formulation that avoids the problems of the prior art, using poorly absorbable sulfate salts with a small quantity of polyethylene glycol. In performing this research, my objective was to find a well tolerated orally administered colonic purgative that was as effective as the well known hypertonic phosphate ravages, that avoided the risks of upset of electrolyte balance in patients.

I have found that hypertonic solutions of non-phosphate salts are effective in producing colonic purgation. Addition of an osmotic laxative agent such as polyethylene glycol improves the results in improved purgation and reduces the amounts of salts required. Because it is administered in small volumes, these formulations are better tolerated than formulations now used. These formulations are as effective as colonic purgatives now used, with a lower risk of adverse reactions.

Mixtures of sulfate salts that omit phosphates (which are avidly absorbed) can be effective to produce colonic purgation. In particular, formulations comprising effective amounts of one or more of the following sulfate salts Na₂SO₄, MgSO₄, and K₂SO₄ are effective. Dosage amounts of Na₂SO₄ from about 0.01 g to about 40.0 g can be effective to produce purgation. Doses of from about 0.1 g to about 20.0 g may be advantageously used. Dosages of 1.0 to 10.0 g may be preferred. Dosage amounts of MgSO₄ from about 0.01 g to about 40.0 g can be effective to produce purgation. Doses of from about 0.1 g to about 20.0 g may be advantageously used. Dosages of 1.0 to 10.0 g may be preferred. Dosage amounts of K₂SO₄ from about 0.01 g to about 20.0 g can be effective to produce purgation. Doses of from about 0.1 g to about 10.0 g may be advantageously used. Dosages of about 0.5 to about 5.0 g may be preferred. The formulation is advantageously a mixture of the foregoing salts.

Addition of an osmotic laxative agent, such as polyethylene glycol (PEG) improves the effectiveness of the above salt mixtures. Doses of PEG from about 1.0 to about 100 g are effective to produce Taxation. Doses from about 10.0 g to about 50 g of PEG have been shown to be effective. A dose of about 34 g of PEG has been used.

For ease of administration, the above mixture of salts can be dissolved in a convenient volume of water. A volume of less than one liter of water is well tolerated by most patients. The mixture can be dissolved in any volume of water, and volumes of between 100 and 500 ml are often convenient. Any volume may be administered. Optimally, the effective dose may be divided and administered, to the patient in two, or more administrations over an appropriate time period. Generally, 2 doses administered of equal portions of the effective dose, separated by 6 to 24 hours produce satisfactory purgation

EXAMPLES

Subjects were otherwise healthy adults between the ages of 18 and 55. There were no preferences or exclusions based on gender or ethnic background.

Dietary Preparation and Ingestion of Salt Solution

Each experiment began at midnight on the first day of a two day study period, and was completed at noon on the next day. The subjects did not consume any food or beverages after midnight on day 1. From 6 a.m. until 6 p.m. on day 1 the subjects consumed a clear liquid diet. Clear liquids included strained fruit juices without pulp (apple, white grape, lemonade), water, clear broth or bouillon, coffee or tea (without milk or non-dairy creamer), carbonated and non-carbonated soft drinks, Kool-Aid® (or other fruit flavored drinks), Jell-O® gelatin (without added fruits or toppings), and ice PopSicles® fruit bars. Solid foods, milk, and milk products are not allowed. The subjects kept a record of exactly what they consumed on day 1, and they were asked to consume the same liquids at the same time if and when they did subsequent studies with a different solution.

Subjects reported to the laboratory at 6 p.m. on day 1. At 7 p.m. they ingested the first dose of concentrated salt solution, either Fleet Phospho-Soda or the experimental solution, followed by 8 ounces of water. Eight ounces of water was also ingested at 8, 9, and 10 p.m.

At 5 a.m. on day 2, a second dose of the concentrated salt solution was ingested, followed by 8 ounces of water.

Formulation of Concentrated Salt Solutions:

Fleet Phospho-Soda (C. S. Fleet Co., Inc., Lynchburg, Va. 24506), 90 mL, was added to 240 mL of water, for a volume of 330 mL. One half of this diluted solution was ingested by the subjects on two occasions, at 7 p.m. on day 1 and again at 5 a.m. on day 2. Based on the manufacturer label, the 330 mL of ingested Phospho-Soda solution contained NaH₂PO₄.H₂O (43.2 g) and Na₂HPO₄₀.7H₂O (16.2 g).

The ingested experimental solutions were also 330 mL in volume, and their composition is shown in the tables below. All salts were obtained from Mallinckrodt (Paris, Ky. 40361) and Polyethylene glycol (PEG) was obtained from J. T. Baker (Phillipsburg, N.J. 08865). One half of each experimental solution was ingested by the subjects on two occasions, at 7 p.m. on day 1 and at 5 a.m. on day 2.

 

Solution E also contained 34 g of Polyethylene glycol (PEG).

Observations and Measurements:

Body weight was measured at 6:45 p.m. on day 1, and at noon on day 2. Blood pressure (lying and after standing for 30 seconds) was measured every two hours, starting at 6:45 p.m. on day 1 and finishing at 11:45 a.m. on day 2. Blood was drawn at 6:45 p.m. on day 1 and at 6 a.m., 8 a.m., 10 a.m. and 12 noon on day 2. Blood was analyzed for calcium, sulfate, magnesium, phosphate, sodium, chloride, potassium, bicarbonate, osmolality, albumin, total protein, BUN, creatinine, and hematocrit.

Each stool was quantitatively collected in separate containers and its weight and consistency were measured. The degree to which the stool contained fecal material was graded, using a scale from 0-5 (0 would be similar to urine, 5 would be a large amount of solid fecal material). Stools collected from 7 p.m. (day 1) until 5 a.m. (day 2) were pooled: this pool represents the effects of the first dose of salts. Stools collected from 5 a.m. until 12 noon were pooled; this pool represents the effect of the second dose of salts. The electrolyte composition of the two pooled specimens was measured (osmolality, Na, K, Cl, HCO₃, PO₄, S₄, Ca and Mg).

Urine was quantitatively collected from 6 a.m. until 6 p.m. on day 1 (prior to ingestion of salts), from 7 p.m. on day 1 until 5 a.m. on day 2, and from 5 a.m. on day 2 until 12 noon on day 2. Urine was analyzed for sulfate, phosphate, calcium, magnesium and monovalent electrolytes.

Results

Study results are shown in tables 3 and 4.