KR20010102323A - Effervescent laxatives - Google Patents

Abstract

The present invention relates to an osmotic / foaming system for treating constipation and fecal ambushes in humans or mammals in need thereof.

Description

Effervescent Laxative {EFFERVESCENT LAXATIVES}

In the next two to three years, the Food and Drug Administration (FDA) is expected to withdraw OTC approval of many current irritant laxatives. Over the last decade, positive carcinogenicity and / or genotoxicity results have caused the FDA to ban danthron (mid-1980s), and in 1997, FDA has identified phenolphthalein as an OTC laxative due to safety concerns. Deleted from the list.

Specifically, in June 1998, the FDA continued to pressurize the OTC irritant laxative category to ensure that the remaining approved stimulants, senna, cascara, aloe and bisaccodyl, were applied. Reclassified from category I (safe and effective) to category III (more data is needed) and required manufacturers to submit up-to-date carcinogenicity and xenotoxicity assessments for these laxative actives. Failure to satisfy these requirements and / or to demonstrate safety will be further removed from the list of laxative actives from the temporary final monograph (TFM) (Fed. Reg. 63 : 33592-33595, June 19, 1998). Indeed, in a recent review of the scientific literature, van Gorkom et al. Have shown that anthranoid laxatives comprising the active moiety in the form contained in senna extracts and phenolphthalein bisaccordyl, a chemical laxative, both in the promotion and initiation of tumorigenesis. It was concluded that it could play a potential role and could be associated with increased risk for colorectal cancer (van Gorkom, BAP; de Vries, EGE; Karrenbeld, A .; Kleibeuker, JH Anthranoid laxatives and their potential carcinogenic effects. Pharmacology & Therapeutics, Vol. 13: pp. 443-452, 1999). Therefore, the potential for further removal from the list is high.

Therefore, there is a high potential that this segment of the OTC laxative market will change dramatically over the next few years. In the event of an event, such as an FDA action that banned phenolphthalein, any FDA action would lead to the removal of similar lists in other countries.

Metamucil ) And Citrucel Expandable fiber products, such as), are currently available, but many have found that these products have unacceptable product aesthetics (eg, aesthetics, viscosity, volume, etc.). Accordingly, new alternative therapies for such expandable fiber laxatives based on ease of use and aesthetic properties are desired.

A group of newer alternative therapies to clean the intestine prior to colonoscopy or GI surgery is Golytely. ) And widely (Nulytely) Osmotic intestinal diarrhea solution, such as (Braintree Labs, Braintree, MA. USA). Similar prescription products in the United States Marketed as Schwarz Pharma, and in Europe, the osmotic laxative is Movicol. (Norgine, Lmtd., Middlesex, UK). Recently, new laxatives containing only polyethylene glycol 3350 NF have also been introduced in the United States (Miralax , Braintree Labs, Braintree, MA, USA), which can only be obtained by prescription.

All these products contain polyethylene glycol (PEG) as the active ingredient. For most products, PEG is mixed with various salts to provide a laxative action with osmotic equilibrium. This is necessary if the product is used in high volumes (2-4 L) necessary for colon bowel movement and washing. For high volumes, such PEG containing formulations provide good colon lavage prior to GI surgery or colonoscopy. Such products do not promote water and electrolyte secretion into the GI tract, and do not cause significant water and electrolyte uptake; In essence, the volume of liquid ingested simply passes through the GI tract. For this indicated use as intestinal diarrhea, the patient is instructed to drink 2 to 4 liters over several hours.

Hollow, G. U.S. Patent 5,710,183 to (Halow, G.) describes PEG compositions containing fiber swelling agents for the clinical treatment of constipation and / or diarrhea.

US Pat. No. 5,124,144 to Castagnola et al. Describes PEG / electrolyte products used as laxatives.

Podtran, Jay. WO 87/00754 to (Fordtran, J.) describes low sodium mildewing and washing solutions containing PEG with the addition of a number of electrolytes such as sodium, potassium, chloride and bicarbonate.

DE 3807712 to Deyhle et al. Describes laxative formulations which also contain an electrolyte, PEG, alkaline hydrogen carbonate and citric acid.

RU 2111741 to Chuk et al. Describes the use of a reduced wash volume (2 liters) of electrolyte containing PEG solution. The electrolyte mixture contains sodium bicarbonate and citric acid, which can be in an amount sufficient to provide foaming.

WO 98/43654 to Jacob et al. Relates to nonaqueous colon laxatives containing magnesium salts and potentially polyethylene glycols.

JP 4198126 (OTSUKA PHARM CO LTD) describes liquid formulations containing PEG and electrolytes with α-amino acids for colon stimulation. α-amino acids are used as antioxidants to stabilize PEG and prevent the formation of formaldehyde. This was a problem with PEG based laxatives at the beginning of product life. Currently, highly purified PEG is used to solve this problem. The concentration of the product in the 0.01% range (0.1 g / L) is also too low to provide any significant foaming.

Summary of the Invention

The present invention is directed to pharmaceutical formulations comprising polyethylene glycol (PEG) 3350 and a pharmaceutically acceptable effervescent coupling system.

Another aspect of the invention is a method of administering an effective amount of the aforementioned formulation to a mammal for treating constipation or fecal ambush of a mammal in need thereof.

The present invention relates to novel over-the-counter (OTC) laxatives as improved replacement therapy for current irritant laxatives.

The present invention relates to effervescent formulations of osmotic enteric laxative solutions such as polyethylene glycol based products. These formulations, FDA-tested for safety issues, offer acceptable levels of laxative efficacy with safety advantages over current stimulants. In addition, such formulations must be safe and suitable for use in pediatric constipation.

Effervescent / PEG osmotic formulations provide an alternative that provides new and safe products as a replacement for current technology. PEG based osmotic formulations have proven to be safe and highly recommended by the physician.

However, the foamable / PEG based formulations used as OTC laxatives will need to be consumed in much smaller volumes, such as one or two 4-8 oz doses over 24 hours. Several published experiments have revealed the usefulness of PEG based techniques used as low volume dose laxatives (E. Corazziari, D. Badiali, FL Habib, G. Reboa, G. Pitto, G. Mazzacca, F. Sabbatini, R). Galeazzi, Te, Cilluffo, I. Vantini, E. Bardelli, F. Baldi.Small volume isosomotic polyethylene glycol electrolyte balanced solution (PMF-100) in treatment of chronic nonorganic constipation.Digestive Diseases & Sciences, Vol. 41: 1636-. 1642, 1996.

Thus, one aspect of the present invention is an osmotic containing polyethylene-glycol based system (preferably PEG 3350 NF or PEG 4000 NF) with an effervescent coupling system which is diluted with a suitable volume of liquid such as water or juice. Use of the functional composition.

Effervescent couples include a basic component and an acidic component, which releases carbon dioxide when contacted with the acidic component by the added water.

The amount of effervescent couple is selected at a level sufficient to cause a “fizzy reaction” without itself causing discomfort in the patient's mouth.

Effervescent couples typically include citric acid or sodium hydrogen citrate and sodium bicarbonate, but other physiologically acceptable acid / alkaline or alkaline earth metal carbonate mixtures such as tartaric acid, adipic acid, fumaric acid or malic acid, and (middle) Sodium carbonate, potassium (medium) carbonate or calcium (medium) carbonate or sodium glycerine may be used.

In general, the relative ratio of the components of the effervescent couple based on chemical molecular equilibrium is expressed as the ratio of the molecular equilibrium of the basic component to the acidic component (basic and acidic components are sodium bicarbonate (NaHCO ₃ ) and citric acid, respectively), When in the range of 3: 1 to 3: 4, more preferably about 1.4 to 1.9: 1, it has been found that desirable aesthetic properties are exhibited. However, much less bicarbonate and acid may be used than many well known foaming systems. The examples herein will demonstrate the usefulness of high and low levels of effervescent coupling reagents. In view of the preferred combination of sodium bicarbonate and citric acid, these values are expressed as a ratio of basic to acidic components, based on weight, ranging from 3: 1 to 0.6-0.8: 1, preferably about 1: 1. Indicates.

However, for some formulations, the choice of flavoring agent is in the presence of excess acidic components of about 11: 3 to 4: 3, for example expressed as the ratio of acidic to basic components based on chemical molecular equilibrium. This can optimize the aesthetic characteristics. In the case of a combination of citric acid and sodium bicarbonate, this may represent 5: 1 to 1: 1 based on weight.

The weight of the acidic components in the formulation may be 7% to 31% by weight, preferably 9% to 18% by weight.

The weight of the basic component in the formulation may be 7% to 32% by weight, preferably 9% to 18% by weight.

Preferred combinations include sodium bicarbonate and citric acid (or sodium hydrogen citrate) or malic acid in a weight ratio of 2: 1 to 1: 1.

Other preferred combinations may use potassium bicarbonate in place of some or all of the sodium bicarbonate as the basic component of the effervescent couple. To maintain molecular equilibrium, the replacement of sodium bicarbonate with potassium bicarbonate consists of a ratio of about 1.2: 1. Potassium bicarbonate can be used with any of the acid components.

Preferred levels of coupling agent for the effervescent mixture, preferably bicarbonate and citrate, are about 2.3 g NaHCO ₃ (sodium bicarbonate) and 2.2 g citric acid. This capacity gives a very significant ANC (acid neutralizing capacity) of about 20 mEq. However, this level can be reduced 4 to 5 times and still provide some foaming (eg 0.5 g NaHCO ₃ and 0.4 g citric acid).

It is recognized that additional excipients may be added to the formulation, such as flavorings, colorants, sweeteners, antioxidants, and other well known formulations related to stability and packaging.

Preferred PEG as used herein is PEG 3350, a nonabsorbable inert polymer having a molecular weight of about 3,000. In general, the range of PEG 3350 for 125-240 ml reconstitution in a liquid will be from about 5 g to 30 g, preferably from about 10 to about 20 g, more preferably from 13 to 17 g. Treatment may be at least once a day, up to four times a day, but preferably once a day.

In contrast to expandable fibers, the foamable / PEG based formulations produced when prepared in liquid doses are not viscous and, optimally, expandable powders or preferably single dose powders for dissolution in a suitable liquid such as water or juice. It is provided to the consumer as a sachet. The product dissolves quickly and completely (in seconds) and does not become dense when left to stand.

Based on the volume consumed (e.g., one or two 4-8 oz doses), the performance attributes are irritant laxative users without cramping and negative side effects of gases and systemic exposure to potentially harmful agents. Matches the current desired properties (quick action, cleansing).

The required dose for use as a laxative may be a dose equivalent to a "minimum effective dose", ie a dose requiring 2-3 days before significant effects, with similar initiation and action as the expandable fiber based laxative. Alternatively, the dose may be increased such that the action is equivalent to the current stimulant base product with a faster onset of action (several hours to overnight).

The present invention is useful as a primary therapy for the treatment of accidental constipation and chronic constipation and fecal ambush (in high doses). Another aspect of the invention is the treatment of upper GI symptoms associated with constipation, such as chest pain or bloating. Suitably, the compositions of the present invention can also be used for irritable bowel syndrome, diverticulosis, and other constipation related diseases such as hemorrhoids.

Manufacturing method

The following examples merely illustrate the invention and are not intended to limit the scope of the invention.

Example 1

One preferred embodiment is provided as a sachet which is reconstituted in 240 ml water for use as a laxative.

PEG system:

17.0g Polyethylene Glycol (PEG) 3350 NF

Effervescent Coupling Reagent:

1.50 g NaHCO ₃

1.00 g citric acid

The PEG solution is combined with the effervescent coupling system and packaged as a sachet added to an 8 oz cup of water.

Example 2

Another preferred embodiment is provided as a sachet which is reconstituted in 240 ml water for use as a laxative.

PEG system:

17.0g Polyethylene Glycol (PEG) 3350 NF

Effervescent Coupling Reagent:

2.32g NaHCO ₃

2.18 g citric acid

The PEG solution is combined with the effervescent coupling system and packaged as a sachet added to an 8 oz cup of water.

Example 3

Another preferred embodiment is provided as a sachet reconstituted in 125-180 ml water for use as a laxative.

PEG system:

13.12 g PEG 3350

0.78g Flavoring Ingredients

Effervescent Coupling Reagent:

2.32g NaHCO ₃

2.18 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

Example 4

Another preferred embodiment is provided as a sachet reconstituted in 125-180 ml water for use as a laxative.

PEG system:

13.12 g PEG 3350

0.78g Flavoring Ingredients

Effervescent Coupling Reagent:

1.50 g NaHCO ₃

1.00 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

Example 5

It is provided as a sachet reconstituted in 125-200 ml water for use as a laxative.

PEG system:

8.5 g PEG 3350

0.06 g flavor mixture (for flavored products)

Effervescent Coupling Reagent:

2.32g NaHCO ₃

2.18 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

Example 6

It is provided as a sachet reconstituted in 125-200 ml water for use as a laxative.

PEG system:

8.5 g PEG 3350

0.06 g flavor mixture (for flavored products)

Effervescent Coupling Reagent:

1.50 g NaHCO ₃

1.00 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

Example 7

It is provided as a sachet reconstituted in 125-200 ml water for use as a laxative.

PEG system:

13.125 g PEG 3350

Effervescent Coupling Reagent:

2.32g NaHCO ₃

2.18 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

Example 8

It is provided as a sachet reconstituted in 125-200 ml water for use as a laxative.

PEG system:

13.125 g PEG 3350

Effervescent Coupling Reagent:

1.50 g NaHCO ₃

1.00 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

Example 7

It is provided as a sachet reconstituted in 125-200 ml water for use as a laxative.

PEG system:

13.125 g PEG 3350

Effervescent Coupling Reagent:

2.32g NaHCO ₃

2.18 g citric acid

The PEG solution is combined with the foamable coupling system and packaged as a sachet added to 4-6 ounce cups of water.

All documents cited herein, including but not limited to patents and patent applications, are incorporated herein by reference as if each individual document were clearly and individually indicated to be incorporated herein by reference.

The foregoing description fully describes the invention, including the preferred embodiments. Modifications and improvements of the embodiments described in detail herein are included within the scope of the following claims. Without further elaboration, it is believed that one skilled in the art having the benefit of the above description can utilize the present invention to its fullest extent. Accordingly, the examples herein are illustrative only and are not to be construed as limiting the scope of the invention in any way. Aspects of the invention for which exclusive ownership or privilege are claimed are defined as follows.

Claims (10)

A pharmaceutical formulation comprising an osmotic amount of polyethylene glycol (PEG) 3350 or PEG 4000 and a pharmaceutically acceptable effervescent coupling system. The formulation of claim 1, wherein the foamable couple comprises about 10 to about 30% of the total weight of the formulation. The formulation of 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. The formulation according to claim 1, wherein the effervescent couple comprises an alkaline component selected from sodium (medium) carbonate, potassium or calcium, or sodium glycine carbonate. 5. The formulation as claimed in claim 1, further comprising at least one flavoring, coloring or sweetening agent. 6. The formulation of claim 1, wherein the PEG is present in an amount of 7.5 to 30 g per unit dose. The formulation of claim 1, wherein the PEG is present in an amount of 10 to 20 g per unit dose. A method of treating constipation in a mammal in need thereof, comprising administering to the mammal an effective amount of a formulation according to any one of claims 1 to 8. A method of treating fecal ambush of a mammal in need of treatment, comprising administering to the mammal an effective amount of a formulation according to any one of claims 1 to 8. 7. The formulation according to any one of claims 1 to 6, wherein the formulation is a unit dose sachet.