EP1154765A1 - Effervescent laxatives - Google Patents

Effervescent laxatives

Info

Publication number
EP1154765A1
EP1154765A1 EP00914689A EP00914689A EP1154765A1 EP 1154765 A1 EP1154765 A1 EP 1154765A1 EP 00914689 A EP00914689 A EP 00914689A EP 00914689 A EP00914689 A EP 00914689A EP 1154765 A1 EP1154765 A1 EP 1154765A1
Authority
EP
European Patent Office
Prior art keywords
peg
formulation according
effervescent
formulation
acid
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00914689A
Other languages
German (de)
French (fr)
Other versions
EP1154765A4 (en
Inventor
Bruce P. Daggy
Kenneth G. Mandel
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SmithKline Beecham Corp
Original Assignee
SmithKline Beecham Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by SmithKline Beecham Corp filed Critical SmithKline Beecham Corp
Publication of EP1154765A1 publication Critical patent/EP1154765A1/en
Publication of EP1154765A4 publication Critical patent/EP1154765A4/en
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A61K9/0007—Effervescent
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/10—Laxatives

Definitions

  • the present invention is directed to a novel over-the-counter (OTC) laxative as an improved, replacement therapy to current stimulant laxatives.
  • OTC over-the-counter
  • 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 HI (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, June 19, 1998).
  • TBM tentative final monographs
  • PEG polyethylene glycol
  • 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.
  • 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.
  • US Patent 5,710,183, Halow, G. discloses a PEG composition with a fiber bulking agent for clinical treatment of constipation and/or diarrhea.
  • WO 87/00754 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 ⁇ -aminoacid. for colon irrigation.
  • the -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.
  • the present invention is directed to a pharmaceutical formulation comprising polyethylene glycol (PEG) 3350, and a pharmaceutically acceptable effervescent coupling system.
  • PEG polyethylene glycol
  • 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.
  • the present invention is directed towards an effervescent formulation of an osmotic bowel evacuant solution, such as a polyethylene glycol based product.
  • an effervescent formulation of an osmotic bowel evacuant solution such as a polyethylene glycol based product.
  • 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.
  • 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.
  • 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.
  • a suitable volume of a liquid such as water, or juice.
  • the effervescent couple comprises a basic ingredient and an acidic ingredient, the basic ingredient liberating carbon dioxide when it and the acidic ingredient are contacted with added water.
  • the amount of the effervescent couple is selected at a level sufficient to cause a "fizzy reaction" without itself causing discomfort in the patients mouth.
  • the effervescent couple typically comprises citric acid or sodium hydrogen citrate and sodium bicarbonate, but other physiologically acceptable acid/alkaline or alkaline earth metal carbonate mixtures may be used, for example tartaric, adipic, fumaric or malic acids, and sodium, potassium or calcium (bi)carbonates or sodium glycine carbonate.
  • flavouring agents may result in optimization of taste characteristics when there is an excess of acidic component, for example, on a chemical molecular equivalent basis of from about 11:3 to 4:3 expressed as the ratio of acidic to basic component.
  • acidic component for example, on a chemical molecular equivalent basis of from about 11:3 to 4:3 expressed as the ratio of acidic to basic component.
  • citric acid and sodium bicarbonate this may represent 5: 1 to 1: 1 on a weight basis.
  • the weight of the acidic component in the formulation may be in the range 7% to 31%, preferably 9% to 18%, by weight.
  • the weight of the basic component in the formulation may be in the range 7% to 32%, preferably 9% to 18%, by weight.
  • Preferred combinations comprise sodium bicarbonate with citric acid (or sodium hydrogen citrate) or malic acid in a weight ratio of 2: 1 to 1: 1.
  • potassium bicarbonate for part or all of the sodium bicarbonate as the basic component of the effervescent couple.
  • substitution of potassium bicarbonate for sodium bicarbonate is at a ratio of approximately 1.2: 1.
  • Potassium bicarbonate can be used with any of the above acid components.
  • the preferred level of the coupling agents, preferably bicarbonate and citrate for an effervescence mixture is about 2.3 gram NaHCO3 (sodium bicarbonate) and 2.2 gram citric acid. This dose provides very significant ANC (acid neutralizing capacity) approximately 20 mEq. However, the levels can be reduced by a factor of 4-5 and still provide some degree of effervescence (e.g., 0.5 g NaHCO3 and 0.4 g citric acid).
  • excipients may be added to the formulation, such as flavouring agents, colouring agents, sweetning agents, antioxidants, and other well known agents for stability and packaging considerations.
  • a preferred PEG for use herein is PEG 3350, a nonabsorbable and inert polymer of about 3,000 molecular weight.
  • PEG 3350 a nonabsorbable and inert polymer of about 3,000 molecular weight.
  • the range of PEG 3350 for a 125 to 240 ml reconstitution in liquid will be from a about 5 grams to about 30 gms, preferably from about 10 to about 20 gms, more preferably 13 to 17 grams. Treatment may be once or more daily, up to 4 times daily, but preferably once daily.
  • the resulting effervescent/PEG-based formulations when made into a liquid dosage are non-viscous and are optimally be provided to consumers as either bulk powder, or preferably as single dose powder sachets, for dissolution in a suitable liquid, such as water or juice.
  • a suitable liquid such as water or juice.
  • the product would dissolve rapidly (within seconds) and completely, and does not thicken on standing.
  • performance attributes Based on volume consumed (e.g., one or two 4-8 oz doses), performance attributes would be consistent with those presently desired by stimulant laxative users (rapid action, clean-out), but without the negative side-effects of cramping and gas, and without systemic exposure potentially harmful agents.
  • the required dosage for use as a laxative may be one which is equivalent to the "minimally effective dose", i.e., one that requires 2 to 3 days treatment before significant effect, having a similar onset and action to the bulk fiber based laxatives. Or the dosage could be increased to be equivalent in action to the current stimulant based products, having an earlier onset of action (a few hours to overnight).
  • the present invention is useful as primary treatment for both occasional and chronic constipation, and for the treatment of fecal impaction (at a higher dose).
  • Another aspect of the present invention is the treatment of upper GI symptoms associated with such constipation, such as heartburn or bloating.
  • the composition herein may also be used for other constipation related disorders, such as irritable bowel syndrome, diverticular disease, and hemorrhoids.
  • EXAMPLE 1 A preferred example provides as sachet for reconstitution in 240 ml water for use as laxative.
  • PEG System
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 8 ounce glass of water.
  • EXAMPLE 2 Another preferred examples provides as sachet for reconstitution in 240 ml water for use as laxative.
  • PEG System
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 8 ounce glass of water.
  • PEG System Another preferred examples provides as sachet for reconstitution in 125 - 180 ml water for use as laxative.
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
  • PEG System 13.12 g PEG 3350
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
  • EXAMPLE 5 Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
  • PEG System
  • PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
  • EXAMPLE 6 Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
  • EXAMPLE 7 Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
  • the PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Epidemiology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Inorganic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
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Abstract

The present invention is directed to a novel osmotic/effervescent system for the treatment of constipation and fecal impaction in a human or mammal in need thereof.

Description

EFFERVESCENT LAXATIVES
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 HI (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, June 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, MA, 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, MA, 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.
US Patent 5,710,183, Halow, G., discloses a PEG composition with a fiber bulking agent for clinical treatment of constipation and/or diarrhea.
US 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 α-aminoacid. for colon irrigation. The -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 acidic ingredient, the basic ingredient liberating carbon dioxide when it and the acidic ingredient are contacted with added water.
The amount of the effervescent couple is selected at a level sufficient to cause a "fizzy reaction" without itself causing discomfort in the patients mouth.
The effervescent couple typically comprises citric acid or sodium hydrogen citrate and sodium bicarbonate, but other physiologically acceptable acid/alkaline or alkaline earth metal carbonate mixtures may be used, for example tartaric, adipic, fumaric or malic acids, and sodium, potassium or calcium (bi)carbonates or sodium glycine carbonate.
In general it has been found that preferred taste characteristics are exhibited when the relative proportions of the components of the effervescent couple on a chemical molecular equivalent basis are in the range of 3: 1 to 3:4, more preferably about 1.4 to
1.9: 1, expressed as the ratio of molecular equivalents of the basic component to the acidic component, where the basic and acid components are sodium bicarbonate (NaHCO3) and citric acid, respectively. However, it is possible to utilize much less bicarbonate and acid than a number of well known effervescent systems. The examples herein will demonstrate usefulness of high and low levels of effervescent coupling reagents. In terms of a preferred combination of sodium bicarbonate and citric acid, these values represent on a weight basis, a range from 3:1 to 0.6-0.8: 1, preferably approximately 1:1 expressed as the ratio of basic to acidic component.
However, in some formulations, the choice of flavouring agents may result in optimization of taste characteristics when there is an excess of acidic component, for example, on a chemical molecular equivalent basis of from about 11:3 to 4:3 expressed as the ratio of acidic to basic component. For the combination of citric acid and sodium bicarbonate this may represent 5: 1 to 1: 1 on a weight basis.
The weight of the acidic component in the formulation may be in the range 7% to 31%, preferably 9% to 18%, by weight.
The weight of the basic component in the formulation may be in the range 7% to 32%, preferably 9% to 18%, by weight.
Preferred combinations comprise sodium bicarbonate with citric acid (or sodium hydrogen citrate) or malic acid in a weight ratio of 2: 1 to 1: 1.
Other preferred combinations may substitute potassium bicarbonate for part or all of the sodium bicarbonate as the basic component of the effervescent couple. To maintain molecular equivalence, substitution of potassium bicarbonate for sodium bicarbonate is at a ratio of approximately 1.2: 1. Potassium bicarbonate can be used with any of the above acid components. The preferred level of the coupling agents, preferably bicarbonate and citrate for an effervescence mixture, is about 2.3 gram NaHCO3 (sodium bicarbonate) and 2.2 gram citric acid. This dose provides very significant ANC (acid neutralizing capacity) approximately 20 mEq. However, the levels can be reduced by a factor of 4-5 and still provide some degree of effervescence (e.g., 0.5 g NaHCO3 and 0.4 g citric acid).
It is recognized that additional excipients may be added to the formulation, such as flavouring agents, colouring agents, sweetning agents, antioxidants, and other well known agents for stability and packaging considerations.
A preferred PEG for use herein is PEG 3350, a nonabsorbable and inert polymer of about 3,000 molecular weight. Generally, the range of PEG 3350 for a 125 to 240 ml reconstitution in liquid will be from a about 5 grams to about 30 gms, preferably from about 10 to about 20 gms, more preferably 13 to 17 grams. Treatment may be once or more daily, up to 4 times daily, but preferably once daily.
In contrast to bulk-fibers, the resulting effervescent/PEG-based formulations when made into a liquid dosage, are non-viscous and are optimally be provided to consumers as either bulk powder, or preferably as single dose powder sachets, for dissolution in a suitable liquid, such as water or juice. The product would dissolve rapidly (within seconds) and completely, and does not thicken on standing.
Based on volume consumed (e.g., one or two 4-8 oz doses), performance attributes would be consistent with those presently desired by stimulant laxative users (rapid action, clean-out), but without the negative side-effects of cramping and gas, and without systemic exposure potentially harmful agents.
The required dosage for use as a laxative may be one which is equivalent to the "minimally effective dose", i.e., one that requires 2 to 3 days treatment before significant effect, having a similar onset and action to the bulk fiber based laxatives. Or the dosage could be increased to be equivalent in action to the current stimulant based products, having an earlier onset of action (a few hours to overnight).
The present invention is useful as primary treatment for both occasional and chronic constipation, and for the treatment of fecal impaction (at a higher dose). Another aspect of the present invention is the treatment of upper GI symptoms associated with such constipation, such as heartburn or bloating. Suitably, the composition herein may also be used for other constipation related disorders, such as irritable bowel syndrome, diverticular disease, and hemorrhoids.
METHODS OF PREPARATION
The following examples illustrates the invention but is not intended to limit the scope thereof. All parts and percentages are by weight unless otherwise indicated.
EXAMPLE 1 A preferred example provides as sachet for reconstitution in 240 ml water for use as laxative. PEG System:
17.0 g polyethylene glycol (PEG) 3350 NF
Effervescent Coupling Reagents: 1.50 g NaHCO3 1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 8 ounce glass of water.
EXAMPLE 2 Another preferred examples provides as sachet for reconstitution in 240 ml water for use as laxative. PEG System:
17.0 g polyethylene glycol (PEG) 3350 NF
Effervescent Coupling Reagents: 2.32 g NaHCO3 2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 8 ounce glass of water.
EXAMPLE 3
Another preferred examples provides as sachet for reconstitution in 125 - 180 ml water for use as laxative. PEG System:
13.12 g PEG 3350
0.78 g flavoring ingredients Effervescent Coupling Reagents: 2.32 g NaHCO3
2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
EXAMPLE 4
Another preferred examples provides as sachet for reconstitution in 125 - 180 ml water for use as laxative. PEG System: 13.12 g PEG 3350
0.78 g flavoring ingredients Effervescent Coupling Reagents:
1.50 g NaHCO3
1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
EXAMPLE 5 Provided as sachet for reconstitution in 125-200 ml water for use as laxative. PEG System:
8.5 g PEG 3350
0.06 g flavoring mixture (for flavored product)
Effervescent Coupling Reagents: 2.32 g NaHCO3 2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water. EXAMPLE 6 Provided as sachet for reconstitution in 125-200 ml water for use as laxative. PEG System:
8.5 g PEG 3350 0.06 g flavoring mixture (for flavored product)
Effervescent Coupling Reagents: 1.50 g NaHCO3 1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
EXAMPLE 7 Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG System:
13.125 g PEG 3350
Effervescent Coupling Reagents:
2.32 g NaHCO3 2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
EXAMPLE 8
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG System:
13.125 g PEG 3350
Effervescent Coupling Reagents: 1.50 g NaHCO3
1.00 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water. EXAMPLE 7
Provided as sachet for reconstitution in 125-200 ml water for use as laxative.
PEG System:
13.125 g PEG 3350
Effervescent Coupling Reagents:
2.32 g NaHCO3
2.18 g Citric Acid
The PEG solution is combined with effervescent coupling system and packaged as a sachet to be added to a 4-6 ounce glass of water.
All publications, including but not limited to patents and patent applications, cited in this specification are herein incorporated by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein as though fully set forth.
The above description fully discloses the invention including preferred embodiments thereof. Modifications and improvements of the embodiments specifically disclosed herein are within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art can, using the preceding description, utilize the present invention to its fullest extent. Therefore the Examples herein are to be construed as merely illustrative and not a limitation of the scope of the present invention in any way. The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows.

Claims

What is Claimed Is:
1. A pharmaceutical formulation comprising an osmotic amount of polyethylene glycol (PEG) 3350, or PEG 4000, and a pharmaceutically acceptable effervescent coupling system.
2. The formulation according to Claim 1 wherein the effervescent couple comprises about 10 to about 30% of the total weight of the formulation.
3. The formulation according to Claim 1 wherein the effervescent couple comprises an acid component selected from citric acid, tartaric acid, adipic acid, fumaric acid, malic acid, or acid salts thereof, or mixtures thereof.
4. The formulation according to Claim 1 wherein the effervescent couple comprises an alkaline component selected from sodium, potassium or calcium (bi) carbonates or sodium glycine carbonate.
5. The formulation according to any one of Claims 1 to 4 which further comprises one or more flavoring, colouring or sweetening agents.
7. The formulation according to Claim 1 wherein the PEG is present in an amount of 7.5 to 30 grams per unit dose.
8. The formulation according to Claim 1 wherein the PEG is present in an amount of 10 to 20 grams per unit dose.
9. A method of treating constipation in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a formulation according to any of claims 1 to 8.
10. A method of treating fecal impaction in a mammal in need thereof, which method comprises administering to said mammal an effective amount of a formulation according to any of claims 1 to 8.
11. A formulation according to any one of claims 1 to 6 wherein the formulation is in a unit dose sachet.
EP00914689A 1999-02-22 2000-02-22 Effervescent laxatives Withdrawn EP1154765A4 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US12108999P 1999-02-22 1999-02-22
US121089P 1999-02-22
PCT/US2000/004701 WO2000048585A1 (en) 1999-02-22 2000-02-22 Effervescent laxatives

Publications (2)

Publication Number Publication Date
EP1154765A1 true EP1154765A1 (en) 2001-11-21
EP1154765A4 EP1154765A4 (en) 2004-12-01

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EP (1) EP1154765A4 (en)
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KR (1) KR20010102323A (en)
CN (1) CN1341016A (en)
AU (1) AU3604600A (en)
BR (1) BR0008385A (en)
CA (1) CA2362355A1 (en)
CZ (1) CZ20013043A3 (en)
EA (1) EA003064B1 (en)
HK (1) HK1043046A1 (en)
HU (1) HUP0105351A3 (en)
PL (1) PL349360A1 (en)
WO (1) WO2000048585A1 (en)
ZA (1) ZA200106888B (en)

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US6048901A (en) * 1999-04-20 2000-04-11 Braintree Laboratories, Inc. Method of reducing intestinal gas, cramping and anorectal irritation
DE102004023288A1 (en) * 2004-05-11 2005-12-15 Stefan Spiess Macrogol preparation
AU2005320935B2 (en) * 2004-12-30 2012-02-16 Given Imaging Ltd. Device, system and method for in-vivo examination
CN101002832B (en) * 2006-09-02 2011-01-05 江西农业大学 Granulated quickly dissolving medicine for relaxing bowel
PL2421373T3 (en) 2009-04-21 2020-03-31 Dale R. Bachwich Colon lavage system
MX346936B (en) 2011-01-28 2017-04-05 A Shaver William Method, composition and package for bowel cleansing.
EP2773362A4 (en) 2011-11-06 2015-08-26 Ssv Therapeutics Llc Formulations of concentrated prunes and prebiotics as laxatives and dietary supplements

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GB942743A (en) * 1959-05-22 1963-11-27 Welloome Foundation Ltd Oestrogen preparations and the manufacture thereof
GB1518364A (en) * 1976-05-05 1978-07-19 Beecham Group Ltd Pharmaceutical composition
US4093710A (en) * 1976-07-07 1978-06-06 Sandoz, Inc. Rapid dissolving effervescent granules
JPH01283222A (en) * 1988-05-10 1989-11-14 Tokai Kapuseru Kk Soft capsule agent of sodium picosulfate
IT1229568B (en) * 1989-04-17 1991-09-04 Giuliani Spa PHARMACEUTICAL COMPOSITION FOR ORAL USE SUITABLE FOR USE IN GASTRO-INTESTINAL WASHING, IN PARTICULAR FOR DIAGNOSTIC USE, OR AS A CATHARTIC LAXATIVE.
US4946939A (en) * 1989-05-30 1990-08-07 The Dow Chemical Company High purity polyether polyols
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US6048901A (en) * 1999-04-20 2000-04-11 Braintree Laboratories, Inc. Method of reducing intestinal gas, cramping and anorectal irritation

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ZA200106888B (en) 2002-09-27
EA200100785A1 (en) 2002-04-25
HUP0105351A2 (en) 2002-05-29
HUP0105351A3 (en) 2004-06-28
CA2362355A1 (en) 2000-08-24
KR20010102323A (en) 2001-11-15
CZ20013043A3 (en) 2001-11-14
BR0008385A (en) 2002-01-29
AU3604600A (en) 2000-09-04
EP1154765A4 (en) 2004-12-01
EA003064B1 (en) 2002-12-26
PL349360A1 (en) 2002-07-15
CN1341016A (en) 2002-03-20
JP2002537248A (en) 2002-11-05
HK1043046A1 (en) 2002-09-06
WO2000048585A1 (en) 2000-08-24

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