MXPA01008492A - Effervescent laxatives - Google Patents

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 LAXANTS Field of the Invention The present invention is directed to a novel over laxative (OTC) as an improved, replacement therapy for current stimulant laxatives.

Background of the Invention Within the next 2 to 3 years, the Food and Drug Administration (FDA) seems likely to discontinue OTC approval of many current stimulant laxatives. During the last decade, positive results of carcinogenicity and / or genotoxicity have resulted in the FDA's ban on Danthron (mid 80's). and in 1997, the FDA removed phenolphthalein from the list as an OTC laxative due to safety concerns. Specifically, in June 1998, the FDA has continued to push the OTC stimulant laxative category, re-classifying the remaining approved stimulants: sena, peel, aloe, bisacodyl, from Category I (safe and effective) to Category III ( they need more data), and requesting that manufacturers provide updated carcinogenicity and genotoxicity evaluations for these laxative assets. Failure to comply with this mandate, and / or to prove safety, will result in the removal of the laxative assets of experimental final monitors (TFM) from the list (Fed. Reg. 63: 33592-33595, June 19). 1998). In fact, in a recent review of the scientific literature, van Gorkom and colleagues concluded that anthranoid laxatives, which include active fractions in the sena extracts, and the chemical laxatives phenolphthalein and bisacodyl, may have a potential role in both the promotion as in the initiation of tumorgénesis, and may be associated with the increased risk for colorectal cancer (van Gorkom, BAP, de Vries, EGE, Karrenbeld, A., Kleibeuker, JH Anthranoid laxatives and their potential carcinogenic effects.; Therapeutics, Volume 13: pages 443-452, 1999). Consequently, the potential for further eliminations is strong. Consequently, there is a strong potential for a dramatic change to this segment of the OTC laxative market over the next many years. If the events that followed FDA action are resubmitted to ban phenolphthalein, any action by the FDA will be followed by removal from the list in other countries. Although raw fiber products are currently available, such as Metamucil® and Citrucel®, a large number of individuals have found that these products have unacceptable product aesthetics (eg, taste, viscosity, volume, etc.). Therefore, new alternative therapies to these raw fiber laxatives are desired based on ease of use and aesthetic properties. A group of the newer alternative therapies for bowel cleansing before a colonoscopic examination or gastrointestinal surgery are the isosmotic evacuating solutions by prescription, such as Golytely® and Nulytely® (Braintree Labs, Braintree, MA, USA). Similar prescription products have been marketed in the United States of America by means of Colyte® by Schwarz Pharma, and in Europe by means of an osmotic laxative by Movicol® (Norgine, Lmtd, Middlesex, United Kingdom). Recently, a new laxative containing only polyethylene glycol 3350 NF (Miralax®, Braintree Labs, Braintree, MA, USA) has also been introduced in the United States of America, where it is available only by prescription. All these products contain polyethylene glycol (PEG) as the active ingredient. In most products, PEG is mixed with different salts to provide a laxative action with osmotic equilibrium. This is required when using the products in the high volumes (2-4 liters) that are required for purging and colon cleansing. In high volume these agents that contain PEG provide an excellent colon cleansing before gastrointestinal surgery or colonoscopic procedures. These neither stimulate the secretion of water and electrolytes within the gastrointestinal tract, nor do the products result in significant absorption of water and electrolytes.; Essentially, the volume of fluid ingested simply passes through the gastrointestinal tract. For this use indicated as a bowel evacuator, patients are instructed to take 2 to 4 liters over many hours. U.S. Patent No. 5,710,183, Halo, G., discloses a PEG composition with a fiber filler for the clinical treatment of constipation and / or diarrhea. U.S. Patent No. 5,124,144, Castagnola et al., Discloses what a PEG / electrolyte product is to be used as a cathartic laxative. WO 87/00754, Fordtran, J., discloses a low sodium laxative and wash solution containing PEG with different added electrolytes such as sodium, potassium, chloride and bicarbonate. DE 3807712, Deyhle et al., Describes a laxative formulation which also contains electrolytes, PEG, alkali hydrogen carbonate and citric acid. RU 2111741, Chumak et al., Describes the use of a reduced wash 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 describes a liquid preparation of PEG and electrolytes, together with α-amino acids, for the irrigation of the colon. The amino acids are used as antioxidants to stabilize the PEG and prevent the formation of formaldehyde. This was a problem characteristic of PEG-based laxatives early in the life of the product. The use of highly purified PEGs currently overcomes these issues. The product range levels of 0.01 percent (0.1 g / L) are also too low to provide any noticeable 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 for administering to a mammal, an effective amount of the pharmaceutical formulation noted above, for the treatment of constipation, or for the treatment of faecal impaction, in a mammal in need thereof.

Detailed Description of the Invention The present invention is directed toward an effervescent formulation of an osmotic bowel evacuating solution, such as a polyethylene glycol based product. These formulations allow for an acceptable level of laxative efficacy, with superior safety advantages over current stimulants, which are under FDA review for safety issues. In addition, these formulations must be safe and appropriate for use in pediatric constipation. The effervescent osmotic formulation / PEG offers an alternative that provides a new and safe product, as a replacement for current technologies. Osmotic formulations based on PEG have proven to be both safe and highly recommended by physicians. However, an effervescent / PEG-based formulation, to be used as an OTC laxative would require consumption of a much smaller volume, such as one or two doses of 4-8 ounces during a 24-hour period. Many published studies have shown the utility of PEG-based technology to be used as a laxative at low volume doses. 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. Balanced isosmotic solution of small volume polyethylene glycol electrolytes (PMF-100) in the treatment of chronic non-organic constipation. Digestive Diseases & Sciences, Volume 41: 1636-1642, 1996. J.A. DiPalma, P.H. deRidder, R.C. Orlando, B.E. Kolts, M.v.B. Cleveland. A multi-center randomized study, controlled with placebos, on the safety and efficacy of the Braintree 851 laxative. Gastroenterology, Volume 112: A722, 1997. P. Culbert, H. Gillett, A. Ferguson. Highly effective oral therapy (polyethylene glycol / electrolyte solution) for fecal impaction and severe constipation. Clinical Drug Investigation, Volume 16: 355-360, 1998. A. Attar, M. Lemann, A. Ferguson, M. Halphen, M.-C.

Boutron, B. Flourie, E. Alix, M. Salmerón, 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 the treatment of chronic constipation. Gut, Volume 44: 226-230, 1999. Therefore, one aspect of the present invention is the use of an osmotic performance composition containing systems based on polyethylene glycol, (preferably, PEG 3350 NF, or PEG 4000 NF, in combination with an effervescent coupling system, which is diluted with an adequate volume of a liquid, such as water, or juice.The effervescent coupling comprises a basic ingredient and an acidic ingredient, the basic ingredient releasing carbon dioxide when put into contact this and the acidic ingredient with added water The amount of the effervescent coupling is selected at a level sufficient to cause a "gas reaction" without itself causing discomfort in the patient's mouth Effervescent coupling typically comprises citric acid or hydrogen citrate of sodium and sodium bicarbonate, but other mixtures of acid / alkaline or alkaline-physiological earth metal carbonate can be used acceptable, for example, tartaric, adipic, fumaric, or melic acids, and (bi) carbonates of sodium, potassium, or calcium or sodium glycine carbonate. In general, it has been found that preferred flavor characteristics are exhibited when the relative proportions of effervescent coupling components, on a chemical molecular equivalent basis, are in the range of 3: 1 to 3: 4, more preferably of about 1.4 to 1.9: 1, expressed as the ratio of molecular equivalents of the basic component to the acidic component, wherein the Basic and acidic components are sodium bicarbonate (NaHCO3) and citric acid, respectively. However, it is possible to use much less bicarbonate and acid than a number of well-known effervescent systems. The examples herein will demonstrate the utility 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 of 3: 1 to 0.6-0.8: 1, preferably of about 1: 1, expressed as the ratio of basic component to acidic. However, in some formulations, the choice of flavoring agents may result in the optimization of taste characteristics when there is an excess of the acidic component, for example, on a chemical molecular equivalent basis of from about 11: 3 to 4. : 3, expressed as the proportion of acidic to basic component. For the combination of citric acid and sodium bicarbonate this could represent 5: 1 to 1: 1 on a weight basis. The weight of the acidic component in the formulation can be in the range of 7 percent to 31 percent, preferably 9 percent to 18 percent by weight. The weight of the basic component in the formulation can be in the range of 7 percent to 32 percent, preferably 9 percent to 18 percent by weight. Preferred combinations comprise sodium bicarbonate with citric acid (or sodium hydrogen citrate) or malic acid in a ratio of but from 2: 1 to 1: 1. Other preferred combinations can substitute potassium bicarbonate for parts or all of the sodium bicarbonate as the basic component of the effervescent coupling. To maintain molecular equivalence, the substitution of potassium bicarbonate for sodium bicarbonate is in a ratio of approximately 1.2: 1. Potassium bicarbonate can be used with any of the above acid components. The preferred level of coupling agents, preferably bicarbonate and citrate for an effervescent mixture is about 2.3 grams of NaHCO 3 (sodium bicarbonate) and 2.2 grams of citric acid. This dose provides an ANC (acid neutralizing capacity) of about 20 mEq. However, the levels can be reduced by a factor of 4-5 and still provide some degree of effervescence (for example, 0.5 grams of NaHCO3 and 0.4 grams of citric acid).

It is recognized that additional excipients can be added to the formulation, such as flavoring agents, coloring agents, sweetening agents, antioxidants, and other well-known agents for stability and packing considerations. A preferred PEG for use herein is PEG 3350, a non-absorbable and inert polymer with a molecular weight of about 3,000. Generally, the range of PEG 3350 for a liquid reconstitution of 125 to 240 milliliters will be from about 5 grams to about 30 grams, preferably from about 10 to about 20 grams, more preferably from 13 to 17 grams. The treatment may be once or more daily, up to 4 times a day, but preferably once daily. In contrast to the raw fibers, the resulting effervescent / PEG-based formulations, when made in a liquid dose, are non-viscous, and are optimally provided to consumers either as raw powder, or preferably as sachea of individual dose powder, for dissolution in a suitable liquid, such as water or juice. The product will dissolve quickly (in seconds) and completely, and will not thicken at rest. Based on the volume consumed (for example, one or two doses of 4-8 ounces), the performance attributes will be consistent with those currently desired by users of stimulant laxatives (fast action, cleansing), but without the negative side effects of abdominal cramps and gas, and without systematic exposure to potentially harmful agents. The dose required to be used as a laxative can be one that is equivalent to the "minimally effective dose", that is, one that requires a treatment of 2 to 3 days before a significant effect, that has a start and action similar to those laxatives based on raw fiber. Or you can increase the dose to be equivalent in action to current products based on stimulants, which has an earlier onset of action (a few hours to a night). The present invention is useful as a primary treatment for both occasional and chronic constipation, and for the treatment of faecal impaction (at a higher dose). Another aspect of the present invention is the treatment of symptoms of the upper Gl, associated with that constipation, such as heartburn (hyperacidity) or gas indigestion. Conveniently, the composition herein may also be used for other disorders related to constipation, such as irritable bowel syndrome, diverticular disease, and hemorrhoids.

METHODS OF PREPARATION The following examples illustrate the invention, but are not intended to limit the scope thereof. All parts and percentages are by weight, unless otherwise indicated.

EXAMPLE 1 A preferred example provides a bag for reconstitution in 240 milliliters of water, to be used as a laxative. PEG System: 17.0 grams of polyethylene glycol (PEG) 3350 NF Effervescent Coupling Reagents: 1.50 grams of NaHCO3 1.00 grams of Citric Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a glass of water. 8 oz. water EXAMPLE 2 Another preferred example provides a bag for reconstitution in 240 milliliters of water, to be used as a laxative. PEG System: 17.0 grams of polyethylene glycol (PEG) 3350 NF Effervescent Coupling Reagents: 2.32 grams of NaHC03 2.18 grams of Citric Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a glass of water. 8 oz. water EXAMPLE 3 Another preferred example provides a pouch for reconstitution in 125-180 milliliters of water, to be used as a laxative. PEG System: 13.12 grams of PEG 3350 0.78 grams of flavoring ingredients Effervescent Coupling Reagents: 2.32 grams of NaHC03 2.18 grams of Citric Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a glass of water of 4-6 ounces.

EXAMPLE 4 Another preferred example provides a pocket for reconstitution in 125-180 milliliters of water, to be used as a laxative.

PEG System: 13.12 grams of PEG 3350 0.78 grams of flavoring ingredients Effervescent Coupling Reagents: 1.50 grams of NaHC03 1.00 grams of Citric Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a glass of water of 4-6 ounces.

EXAMPLE 5 It is provided as a pocket for reconstitution in 125-200 milliliters of water, to be used as a laxative. PEG system: 8.5 grams of PEG 3350 0.06 grams of flavor mixture (for flavored product) Effervescent Coupling Reagents: 2.32 grams of NaHC03 2.18 grams of Citrus Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch that will be added to a 4-6 ounce glass of water.

EXAMPLE 6 It is provided as a pocket for reconstitution in 125-200 milliliters of water, to be used as a laxative. PEG System: 8.5 grams of PEG 3350 0.06 grams of flavor mixture (for flavored product) Effervescent Coupling Reagents: 1.50 grams of NaHC03 1.00 grams of Citrus Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch that will be added to a 4-6 ounce glass of water.

EXAMPLE 7 It is provided as a pocket for reconstitution in 125-200 milliliters of water, to be used as a laxative. PEG System: 13.125 grams of PEG 3350 Effervescent Coupling Reagents: 2.32 grams of NaHC03 2.18 grams of Citrus Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a 4-ounce glass of water. 6 oz.

EXAMPLE 8 It is provided as a pocket for reconstitution in 125-200 milliliters of water, to be used as a laxative. PEG system: 13.125 grams of PEG 3350 Effervescent Coupling Reagents: 1.50 grams of NaHC03 1.00 grams of Citric Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a 4-ounce glass of water. 6 oz.

EXAMPLE 7 It is provided as a pocket for reconstitution in 125-200 milliliters of water, to be used as a laxative. PEG System: 13.125 grams of PEG 3350 Effervescent Coupling Reagents: 2.32 grams of NaHC03 2.18 grams of Citrus Acid The PEG solution is combined with the effervescent coupling system and packaged as a pouch to be added to a 4-ounce glass of water. 6 oz. All publications, including but not limited to the patents and patent applications cited in this specification are incorporated herein by reference, as if each individual publication was specifically and individually indicated to be incorporated by reference herein as fully declared. The foregoing description fully describes the invention, including preferred embodiments thereof. Modifications and improvements of the modalities specifically described 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 will be considered as merely illustrative, and not a limitation of the scope of the present in any way. The embodiments of the invention in which a unique property or privilege is claimed are defined as follows.

Claims (10)

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 coupling comprises from about 10 to about 30 percent of the total weight of the formulation.

3. The formulation according to claim 1, wherein the effervescent coupling comprises an acid component selected from citric acid, tartaric acid, adipic acid, fumaric acid, malic acid, or acid salts thereof, or mixtures thereof. the same .

4. The formulation according to claim 1, wherein the effervescent coupling comprises an alkaline component selected from sodium, potassium or calcium (bi) carbonates or sodium glycine carbonate.

5. The formulation according to any of claims 1 to 4, which also comprises one or more flavoring agents, colorants or sweeteners.

6. The formulation, according to Claim 1, wherein the PEG is present in an amount of 7.5 to 30 grams per unit dose. The formulation, according to claim 1, wherein the PEG is present in an amount of 10 to 20 grams per unit dose. 8. A method for 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. 9. A method for treating fecal impaction in a mammal in need thereof, which method comprises administering to the mammal an effective amount of a formulation according to any one of claims 1 to 8. 10. A formulation, according to any of Claims 1 to 6, wherein the formulation it is a unit dose pouch.