WO1996002261A1

WO1996002261A1 - Use of magnesium hydroxide as a stool softener

Info

Publication number: WO1996002261A1
Application number: PCT/US1995/009166
Authority: WO
Inventors: Kenneth J. O'keeffe; Pol Vandenbroucke
Original assignee: Sterling Winthrop Inc.
Priority date: 1994-07-19
Filing date: 1995-07-19
Publication date: 1996-02-01
Also published as: CA2154201A1; JPH10502930A; EP0771207A1; EP0771207A4

Abstract

Magnesium hydroxide, when used at subeffective laxative doses is an effective stool softener.

Description

USE OF MAGNESIUM HYDROXTDK AS A STOOT, SOFTENER

Background of the Invention

(a) Field of the Invention

This invention is related to the use of osmotic laxatives in sub-effective laxative doses as stool softeners.

(b) Information Disclosure Statement

Perhaps the most widely used and recommended stool softener is docusate sodium. Docusate sodium is sold under various names throughout the world. In the United States docusate sodium is sold primarily by Mead-Johnson under the name COLACE®. COLACE® is a surface active agent, and is indicated for constipation due to hard stool, painful rectal conditions, in cardiac conditions and other conditions (such as recent surgery) where maximum ease of passage is desirable to avoid difficult or painful defecation. Docusate sodium is not a laxative. 1991 PDR for Non-presrrip ion βrigs. pp. 614-615. A dosage of between 50 mg and 200 mg docusate is used to soften stools in patients.

Mead-Johnson also sells PERI-COLACE® which is a laxative mixed with COLACE®. This combination product is sold and used for mild laxation with stool softening.

The terms "laxative" and "soft stool" are often juxtaposed and confused by the literature. An example of such juxtaposition is found in Kinnunen, et al., Ann. Clin. Res., v. 19, pp. 321-323 (1987) . In this article, the authors comment that egested stool during magnesium hydroxide laxative use was softer.

As another example PCT Application SE 91/00317 describes a laxative effect as the elimination of soft stool.

References describing "soft stools" (perhaps loose stool is more appropriate) in the context of a laxative effect blur the distinction between a stool softening effect, (i.e. hydrating the stool) and a laxative effect (causing a bowel movement) . This confusion has been recognized by those in the field a evidenced by the commentary in the proposed revisions to th laxative monograph by the FDA. For example; A comment suggested that the Panel's definition of laxative, i.e., "any constipation," was too broad and could be misunderstood, especially when applied to stool softener and lubricant laxatives. According to the comment, the term "laxative aid" should apply to substances that act solely to modify the fecal contents and thereby aid or facilitate a laxative response, while the term "laxative" should apply only to agents that act upon the myoneural structures of the intestinal tract. The comment concluded that the terms "laxative" and "laxative aid" would more precisely set forth the pharmacologic activity of these different drugs.

The Panel's definition of laxative as "any agent used for the relief of constipation" includes all of the various mechanisms of action of OTC laxatives.

The intended effect of th se products Ls always laxa ion. even though this effect is achieved by different actions. Subdividing laxative ingredients into laxative and laxative aids would not be helpful and could be confusing to the consumer. • Federal

Register Vol. 50. No. 10 1/15/85, p. 2128 "Proposed Rules" (FDAOTC Compilation Pat I, Tab. 12, p. 83) .

Laxatives have long been used to treat occasiona constipation. Laxatives act by "laxation" or the causing of bowel movement.

Stool softeners act, not as laxatives but as agents whic change consistency of the stool, thus easing the evacuation o the stool. This can be in the form of non-digestible matter o water. Water is the preferred means.

With this distinction between a laxative and a stoo softener in mind, it would be advantageous to provide a singl product which can be used as either a laxative or a stool softener absent the laxative effect.

Magnesium hydroxide has long been used as an ingredient in antacids 400-1200 mg and in saline laxatives. It is known to be an effective laxative at doses of 2400 and 3600 up to 4800 mg. Below 1800 mg the laxative effect is no different than a placebo. Compositions of Mg(OH)2 are sold over the counter. Phillips Milk of Magnesia® is an example of such a composition.

Summary of the Invention

We have found that the use of low doses (1000-2000, preferably 1200-1800 mg) of magnesium hydroxide hydrates stool in patients and is thus effective as a stool softening regimen, without acting as a laxative.

Detailed Description of Preferred Embo imen s As used herein the term stool softening refers to the acti of hydrating stools.

"Stool softener" refers to any substance causing sto hydration, but not laxation.

"Placebo" refers to any dosage form looking like the acti form, but lacking any active ingredient.

We have found that magnesium hydroxide's laxation properti are distinct and separate from its stool softening properties. We have obtained data from clinical trials, using doub blind, placebo controlled, crossover studies comparing the we known and art prefered stool softener, docusate sodium Mg(OH)2- These studies clearly show that Mg(OH)2 is a bett stool softener than the commonly used docusate sodium. The studies described below used original Phillips* Milk Magnesia® (MoM) which contains nothing but Mg(OH2) and water (4 mg MgOH2/tsp.) . The examples used herein are not intended limit the claims of the invention in any way, but a illustrative of the efficacy of the invention.

Study T

200 mσ Docusate sodium vs 1200 m t MOM

A double-blind, randomized, placebo-controlled, doubl dummy, cross-over study to compare the stool softening effec associated with the use of MoM and docusate sodium was conduct as follows;

Sixteen normal subjects were housed for 14 consecutive da during each of the three treatment periods, with a 1 -day lap between treatment periods. The study medication, 2 capsules (1 mg) of 100 mg each COLACE® or placebo) and 15 mL (3 teaspoons)

(MoM or placebo) suspension (1200 mg) were dispensed at bedtim

Patient diaries recorded daily bowel function. Total daily fec samples were collected on Days 8-14 and analyzed for percenta water content. All subjects were between the ages of 35 and years, were able to follow instructions, claimed to be able defecate in a strange facility and gave written informed consent In each of the three study periods, subjects were housed from the evening of the day of the first medication administration until 24 hours after the Day 14 dose. The corresponding days' menus for each patient and trial period were identical, with a few minor exceptions.

Immediately following the administration of the Day 8 dose until the end of each study period, all fecal samples were collected in special collection pots which fit over a standard toilet seat . To minimize between-subject variability in total daily feces weights, subjects were instructed to flush the toilet paper. Each sample was stored in its own sealed container in a refrigerator at approximately 4"C. Samples were collected by the analytical staff after each daily collection perio (Days 8-14) . Each patient kept a daily log of time(s) of defecation. They also recorded, using a graded scale, the consistency of the sample, the severity of associated cramps and the ease of defecation.

The consistency of bowel movements was graded by each subject as 1) hard, 2) soft or 3) watery. Individual results are presented in Case Report Forms and in the data listings. The group consistency scores were totaled by week (Weeks 1 and 2) and overall (Weeks 1+2) . MoM produced statistically softer stools movements than the maximum dosage (200 mg) of COLACE®.

The data tabulations were performed using SAS for microcomputers. Version 6.04, (SAS, Statistical An-alysis System, Cary, N.C., 1989). Statistical comparisons of data for the MoM product with that for the COLACE® product were performed' using General Linear Models (GLM-ANOVA) . All significance levels were based on the 5% α-level. Stool weight, an indirect indication of the amount of water in each sample was also measured. MoM produced heavier total daily fecal samples than COLACE®, suggesting increased stool softening.

The primary stool softening "parameter" investigated in this study was the water content of fecal samples. The higher the water content, the softer the stool sample. Daily fecal % water content was analyzed similarly to the fecal weights. Fecal samples from MoM treated subjects contained a statistically significantly higher percentage of water than

COLACE ® fecal samples on Days 8-14. Fecal water content for patients taking MoM was also significantly higher than placebo on 6 out of 7 days. Based on the evaluation of this parameter, MoM proved to be a superior stool softening agent to COLACE®. On all of the 7 collection days, MoM produced significantly softer stool samples than did COLACE® and placebo.

TABLE T

SUMMARY OF RESULTS MEAN FECAT, % WATER CONTENT

DAY β DAY 9 DAY 10 DAY 11 DAY 12 DAY 13 DAY 14

MoM 81.867 83.043 82.504 82.599 82.548 83.591 83.888

Colace (B) 74.310 77.088 77.753 76.574 74.379 76.737 75.665

Placebo (C) 79.478 74.502 76.262 74.909 73.555 79.274 77.544

Ratio of Means

A vs B 1.10 1.08 1.06 1.08 1.11 1.09 1.11

A vs C 1.03 1.10 1.08 1.10 1.12 1.05 1.08

B vs C 0.94 1.02 1.02 1.02 1.01 0.97 0.98 p-Values

A vs B 0.0452 0.0257 0.0100 0.0303 0.0019 0.0005 0.0002

A vs C 0.0826 0.0108 0.0084 0.0021 0.0008 0.0244 0.0221

B vs C 0.6692 0.4769 0.8264 0.1267 0.9917 0.2246 0.0293

Based on the results of this study, MoM is a better stool softener than docusate sodium (COLACE®) .

Study II 200 mσ Dor-nsate Sodium vs 1700 Mσ (OH) £

The design of this study was the same as Study I. The percentage of water was obtained for the collected stools on days 8 through 14. Stools of those participants using MoM had a significantly higher water content than the stools of those using COLACE® or the placebo; close to 80% compared to app. 72% for COLACE® and placebo as shown below;

ahl Tl

P roduct N Ave rage Significant Differences

Day 8

Phillips 11 77 . 98182 MoM > COLACE®, Placebo

COLACE® 11 73 . 27277

Placebo 12 73 . 0

Day 9

Phillips 16 78 . 4875 MoM > COLACE®, Placebo

COLACE® 14 73 . 1786

Placebo 13 72 . 9

Day 10

Phillips 12 80 . 66666 MoM > COLACE®, Placebo

COLACE® 13 72 . 6923

Placebo 15 73.3

Day 11

Phillips 13 81.423087 MoM > COLACE®, Placebo COLACE® 11 73.63636 Placebo 11 76.3

Day 12

Phillips 12 79.41666 MoM > COLACE®, Placebo COLACE® 14 72.62147 COLACE® > Placebo Placebo 13 71.35387

Day 13

Phillips 14 79.10714 MoM > COLACE®, Placebo COLACE® 14 74.4 Placebo 13 73.87697

Day 14

Phillips 14 79.19287 MoM > COLACE®, Placebo COLACE® 15 74.50667 Placebo 12 74.125

These results confirm those of Study I Studv III Dosage of Mg ιOH > Required for Laxation

This study was undertaken to determine the lowest dose of MoM providing a laxative effect.

Twenty four healthy volunteers, 20 males and 4 females, between 34 and 69 years of age entered the study. There were 20 Caucasian and 4 blacks entered. The weight ranges was 129-214 pounds. The distribution of age and weight was balanced between the four treatment sequences.

Based on an analysis performed on average stool weight during three dose days in a period, 2400 and 3600 mg daily dose groups were significantly different from placebo. However, the difference between 1800 mg daily dose and placebo did not reach statistical significance. 1800 mg daily dose of MoM is not a laxative dose, according to this study.

Based on an analysis performed on weight of stool during 24 hours after the first dose in each period, the 3600 mg daily dose group was statistically significantly, different from placebo (p- value=.0001) , 2400 mg daily dose group was somewhat significantly different from placebo (p-value=.069) but 1800 mg daily dose was not significantly different from placebo (p-value=.284) .

Based on the analysis performed on average % water in stool during three dose days in a period, 1800, 2400 an 3600 mg daily dose groups were significantly different from placebo.

Note that the 1800 mg dose does not differ from the placebo as to laxative effect, but does provide increased hydration of stools. Also note that the highest laxative doses show much less hydration of stool or stool softening than the 1800 mg dose which is ineffective as a laxative.

From these studies we have shown that magnesium hydroxide is a superior stool softening agent at doses of 1200 and 1800 mg. Furthermore, it is expected that a dose of 1000 to 2000 mg is also effective as a stool softening dose of magnesium hydroxide. The optimum dosage and regimen for a patient in need of such stool softening treatment may vary, based upon age, weight, sex, severity of the condition and other commonly considered parameters.

In addition to its clinical advantages, magnesium hydroxide offers cost advantages too. For example, dosages used in the studies above are compared on table III below:

Table III

Magnesium hydroxide, when used alone or in conjunction with any other stool softening agent, is an effective stool softener. A stool softening effective amount of magnesium hydroxide can be formulated as a tablet, caplet, capsule, pill, suspension or, any other common dosage form, using formulation methods known in the antacid or laxative art. Thus the invention can be prepared and used in a variety of ways.

Claims

We claim:

1. A method of softening stools in a patient comprising administering a stool softening effective amount of osmotic laxative to a patient in need of such treatment.

2. A method of softening stools in a patient comprising administering a stool softening effective amount of magnesium hydroxide to a patient in need of such treatment, according to claim 1.

3. The method according to claim 2 wherein the dosage is from 1000 to 2000 mg.

. The method according to claim 3 wherein the dosage is from 1200 to 1800 mg.

5. The method according to claim 4 wherein the dosage is 1200 mg.

6. The method according to claim 2 wherein the dosage form is in a liquid or solid form.

7. The method according to claim 2 wherein the dosage form is a suspension comprising magnesium hydroxide and an excipient .

8. The method according to claim 2 wherein the dosage form is a tablet, caplet or capsule.

9. A pharmaceutical composition comprising a stool softening effective amount of magnesium hydroxide and an excipient.

10. A pharmaceutical composition according to claim 9 wherein the stool softening dosage form is in solid or suspension form.

11. The use of magnesium hydroxide as a stool softener.

12. The use of magnesium hydroxide according to claim 11, wherein the dosage is from 1000 to 2000 mg.

13. The use of magnesium hydroxide according to claim 12 wherein the dosage is 1200 to 1800 mg.

14. The use of magnesium hydroxide according to claim 13 wherein the dosage is 1200 mg.

1 5 . The use of magnesium hydroxide in a liquid or solid dosage form according to claim 11 .

1 6 . The use of a combination of a stool softening effective amount of magnesium hydroxide with another stool softener according to claim 11.

1 7 . The use of magnesium hydroxide in an ingested form according to claim 2 .

18. The use of a dosage form comprising magnesium hydroxide in a suspension form according to claim 15.

19. The use of a dosage form comprising magnesium hydroxide in a tablet, caplet or capsule according to claim 15.

20. A pharmaceutical composition comprising a stool softening effective amount of magnesium hydroxide and a laxative according to claim 9.

21. The method according to claim 5 comprising administering 2- 600 mg tablets, caplets, capsules or pills comprising magnesium hydroxide and- an excipient.

22. A pharmaceutical composition comprising a stool softening effective amount of magnesium hydroxide and a laxative for the use according to claim 11.

23. A pharmaceutical composition comprising a stool softening effective amount of magnesium hydroxide and a laxative for use in the method according to claim 2.

24. The use of a pharmaceutical composition comprising magnesium hydroxide in an ingestable form according to claim 9.

25. The use of magnesium hydroxide in an ingested form according to claim 11.