Effervescent laxatives

Details Effervescent laxatives Effervescent laxatives

2002-02-07

2002-09-03

Reamer, James H (Department: 1614)

Drug, bio-affecting and body treating compositions

Digestive system regulator containing solid synthetic...

Reexamination Certificate

active

06444198

ABSTRACT:

FIELD OF THE INVENTION
The present invention is directed to a novel over-the-counter (OTC) laxative as an improved, replacement therapy to current stimulant laxatives.
BACKGROUND OF THE INVENTION
Within the next 2 to 3 years, the Food and Drug Administration (FDA) appears likely to discontinue OTC approval of several current stimulant laxatives. Over the last decade, positive carcinogenicity and/or genotoxicity results have resulted in FDA banning danthron (mid-1980's) and in 1997, the FDA delisted phenolphthalein as an OTC laxative due to safety issues.
Specifically, in June 1998, the FDA has continued to pressure the OTC stimulant laxative category, reclassifying remaining approved stimulants: senna, cascara, aloe, bisacodyl, from Category I (safe and effective) to Category III (more data needed), and requiring manufacturers to provide updated carcinogenicity and genotoxicity evaluations for these laxative actives. Failure to meet this mandate, and/or prove safety will result in further delisting of laxative actives from the tentative final monographs (TFM), (Fed. Reg. 63: 33592-33595, Jun. 19, 1998). Indeed, in a recent review of scientific literature, van Gorkom et al., concluded that anthranoid laxatives, which include the active moieties in senna extracts, and the chemical laxatives phenolphthalein bisacodyl, can have a potential role in both promotion and initiation of tumorgenesis, and may be associated with increased risk for colorectal cancer (van Gorkom, B. A. P.; de Vries, E. G. E.; Karrenbeld, A.; Kleibeuker, J. H. Anthranoid laxatives and their potential carcinogenic effects. Alimentary Pharmacology & Therapeutics, Vol. 13: pp. 443-452, 1999. Hence the potential for further delistings are strong.
Hence, there is a strong potential for dramatic change to this segment of the OTC laxative market over the next several years. If the events which followed the FDA action to ban phenolphthalein recur, any FDA action will be followed by similar delisting in other countries.
While bulk fiber products, such as Metamucil® and Citrucel®, are presently available, a large number of individuals have found that these products have unacceptable product aesthetics (e.g., taste, viscosity, volume etc). Therefore new alternative therapies to these bulk fiber laxatives based on ease of use and aesthetic properties are desired.
One group of the newer alternative therapies for bowel cleansing prior to colonoscopic exam or GI surgery are the prescription isosmotic bowel evacuant solutions, such as Golytely® and Nulytely® (Braintree Labs, Braintree, Mass., USA). Similar prescription products are marketed in the US by Colyte® by Schwarz Pharma, and in Europe an osmotic laxative by Movicol® (Norgine, Lmtd., Middlesex, UK). Recently, a new laxative containing only polyethylene glycol 3350 NF, has also been introduced in the US (Miralax®, Braintree Labs, Braintree, Mass., USA), where it is available only by prescription.
All of these products contain polyethylene glycol (PEG) as the active ingredient. In most products, the PEG is mixed with various salts to provide a laxative action with osmotic balance. This is required when the products are used in the high volumes (2-4 L) required for colonic purgation and cleansing. In high volume these PEG-containing agents provide excellent colonic cleansing prior to GI surgical or colonoscopic procedures. They neither stimulate water and electrolyte secretion into the GI tract, nor do the products result in significant water and electrolyte absorption; essentially, the volume of ingested liquid simply passes through the GI tract. For this indicated usage as a bowel evacuant, patients are instructed to drink 2 to 4 liters over several hours.
U.S. Pat. No. 5,710,183, Halow, G., discloses a PEG composition with a fiber bulking agent for clinical treatment of constipation and/or diarrhea.
U.S. Pat. No. 5,124,144, Castagnola et al., discloses what is a PEG/electrolyte product for use as a cathartic laxative.
WO 87/00754, Fordtran, J., discloses a low-sodium laxative and lavage solution containing PEG with various electrolytes added such as sodium, potassium, chloride and bicarbonate.
DE 3807712, Deyhle et al., discloses a laxative formulation also containing electrolytes, PEG, alkali hydrogen carbonate and citric acid.
RU 2111741, Chumak et al. discloses use of a reduced lavage volume, 2 liters, of PEG with an electrolyte solution. The electrolyte mixture contains sodium bicarbonate and citric acid which may be in an amount sufficient to provide effervescence.
WO 98/43654, Jacob et al., is directed towards a non-aqueous colonic purgative containing magnesium salts and potentially polyethylene glycol.
JP 4198126 OTSUKA PHARM CO LTD discloses a liquid preparation of PEG and electrolytes along with &agr;-aminoacid, for colon irrigation. The &agr;-amino acids are used as antioxidants to stabilize PEG and prevent formation of formaldehyde. This was an attributed problem of PEG-based laxatives early in their product life. Use of the highly purified PEG's today overcome these issues. The levels of product 0.01% range (0.1 g/L) are also too low to provide any appreciable effervescence.
SUMMARY OF THE INVENTION
The present invention is directed to a pharmaceutical formulation comprising polyethylene glycol (PEG) 3350, and a pharmaceutically acceptable effervescent coupling system.
Another aspect of the present invention is a method of administering to a mammal, an effective amount of the above noted pharmaceutical formulation for the treatment of constipation, or for the treatment of fecal impaction, in a mammal in need thereof.
DETAILED DESCRIPTION OF THE INVENTION
The present invention is directed towards an effervescent formulation of an osmotic bowel evacuant solution, such as a polyethylene glycol based product. These formulations provide for an acceptable level of laxative efficacy, with superior safety advantages over current stimulants, which are under FDA review for safety concerns. Further, these formulations should be safe and appropriate for use in pediatric constipation.
The effervescent/PEG osmotic formulation offers an alternative that provides for a new, and safe, product as a replacement to the current technologies. The PEG based osmotic formulations have proven to be both safe and highly physician recommended.
However, an effervescent/PEG based formulation, for use as an OTC laxative would require consumption of a much smaller volume, such as one or two 4-8 oz doses over a 24 hour period. Several published studies have shown utility of the PEG-based technology for use as a laxative with low-volume dosage. E. Corazziari, D. Badiali, F. L. Habib, G. Reboa, G. Pitto, G. Mazzacca, F. Sabbatini, R. Galeazzi, Te, Cilluffo, I. Vantini, E. Bardelli, F. Baldi. Small volume isosmotic polyethylene glycol electrolyte balanced solution (PMF-100) in treatment of chronic nonorganic constipation. Digestive Diseases & Sciences, Vol. 41: 1636-1642, 1996.
J. A. DiPalma, P. H. deRidder, R. C. Orlando, B. E. Kolts, M. v. B. Cleveland. A randomized placebo-controlled, multicenter study of the safety and efficacy of Braintree 851 laxative. Gastroenterology, Vol. 112: A722, 1997.
P. Culbert, H. Gillett, A. Ferguson. Highly effective oral therapy (polyethylene glycol/electrolyte solution) for faecal impaction and severe constipation. Clinical Drug Investigation, Vol. 16: 355-360, 1998.
A. Attar, M. Lemann, A. Ferguson, M. Halphen, M.-C. Boutron, B. Flourie, E. Alix, M. Salmeron, F. Guillemot, S. Chaussade, A.-M. Menard, J. Moreau, G. Naudin, M. Barthet. Comparison of a low dose polyethylene glycol electrolyte solution with lactulose for treatment of chronic constipation. Gut, Vol. 44: 226-230, 1999.
Therefore, one aspect of the present invention is the use of an osmotic acting composition containing polyethylene-glycol based systems, (preferably, PEG 3350 NF, or PEG 4000 NF, in combination with an effervescent coupling system, which is diluted with a suitable volume of a liquid, such as water, or juice.
The effervescent couple comprises a basic ingredient and an

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