AU2002312652B2 - Laxative preparation - Google Patents

Description

WO 03/000299 PCT/AU02/00819 .Laxative Preparation Field of the Invention The present invention relates to a laxative preparation. The laxative preparation of the present invention is particularly suited to oral administration for treatment of occasional and intractable constipation, and as an agent for complete bowel preparation prior to colonoscopy, barium enema x-ray examination and intestinal surgery.

Background Art There are many different types of laxatives. Fibre supplements are popular because of their "healthy" image, because they are generally mild and because they are not habit forming. Their main disadvantages are that they are generally mild and that they result in considerable gas formation. Ironically, for people with moderate-severe constipation, fibre supplements rarely overcome the problem and often compound symptoms like abdominal pain and bloating as gas becomes "trapped" in the large intestine.

As second group of laxatives are the herbal laxatives. There are an uncountable number of different products made from varying combinations of Senna, Frangula bark, Cascara and other "natural" substances. They appeal because of their generally palatable format (tablets, usually) and their prompt and reliable action.

They have the disadvantage of producing abdominal cramps due to their mechanism of action they directly stimulate the intestinal smooth muscle whether the intestine is full or not. However, the biggest drawback of the herbal laxatives is that they induce tolerance, that is, the need for ever-increasing doses to produce the same effect. Many people commence these laxatives at low doses but steadily require them at higher dosage or at increasing dose frequency or both, a phenomenon termed "laxative addiction".

A further group of laxatives are the osmotic agents. These are typically concentrated salts or sugars and act to attract intracellular and intravascular water WO 03/000299 PCT/AU02/00819 -2into the intestine. The column of water that this creates then distends the intestine and stimulates a genuinely natural contractile response from the intestinal smooth muscle.

Sugars include lactulose (Duphulac, Actilax), sorbitol (Sorbilax, diabetic sweets) and mannitol (also used in diabetic sweets). These tend to be relatively mild but are unpopular because of the substantial volumes of gas associated with their use and because they are of only mild-moderate activity.

Salts include Epsom salts (magnesium sulphate heptahydrate), sodium sulphate, magnesium oxide, sodium picosulphate and others. These are typically 'administered as an aqueous solution. The salts are much more potent than the sugars but are almost universally despised by patients because of their offensive taste many people cannot tolerate them at all. Further, significant quantities of the salts must be ingested for the laxative effect. On the other hand, salts are effective, non-habit forming and (relatively) gasless.

The preceding discussion of the background to the invention is intended to facilitate an understanding of the present invention. However, it should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was part of the common general knowledge in Australia as at the priority date of the application.

Throughout the specification, unless the context requires otherwise, the word "comprise" or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers.

Throughout this specification, unless the context requires otherwise, the term "dehydrated magnesium sulphate" refers to solid magnesium sulphate with fewer waters of hydration that the heptahydrate MgSO 4 .7H 2 0, and/or a mixture of such magnesium sulphates that may include but does not exclusively comprise the heptahydrate.

PCT/AU02/00819 Received on 18 December 2002 -3- Disclosure of the Invention In accordance with the present invention, there is provided a laxative preparation comprising dehydrated magnesium sulphate, wherein the dehydrated magnesium sulphate is coated to substantially inhibit absorption of atmospheric water.

It has been found that dehydrated magnesium sulphate is a substantially more potent laxative than the conventionally administered aqueous solutions of magnesium sulphate heptahydrate.

The dehydrated magnesium sulphate is coated to substantially inhibit rehydration by absorption of atmospheric water, and to negate the unpalatable bitter taste associated with the magnesium sulphate, thereby significantly improving palatability. Thus, the present invention provides a more effective laxative than the existing salt type laxatives, with the substantial advantage of superior palatability. Preferably, the dehydrated magnesium sulphate is substantially provided in the form of anhydrous magnesium sulphate, magnesium sulphate monohydrate, magnesium sulphate dihydrate, magnesium sulphate trihydrate, magnesium sulphate tetrahydrate and/or a mixture thereof.

In a highly specific form of the invention, the dehydrated magnesium sulphate is substantially provided in the form of magnesium sulphate monohydrate.

Preferably, the laxative preparation comprises a plurality of discrete units containing dehydrated magnesium sulphate, such as capsules, cachets, or tablets. Preferably still, each discrete unit contains a predetermined amount of dehydrated magnesium sulphate.

Where the discrete units are provided in the form of tablets, each tablet of dehydrated magnesium sulphate may be coated to substantially inhibit absorption of atmospheric water. Where the discrete units are provided in the form of AMENDED SHEET

IPEAIAU

WO 03/000299 PCT/AU02/00819 -4cachets, the coating is provided in the form of the cachet, the dehydrated magnesium sulphate being contained therein. Where the discrete units are provided in the form of capsules, the coating is provided in the formrn of the capsule, the dehydrated magnesium sulphate being contained therein.

Where the discrete units are provided in the form of capsules, the capsules may be provided in the form of standard pharmaceutical capsules, such as those formed from gelatine or cellulose. Preferably, the capsules are provided in the form of soft gelatine capsules.

In accordance with the present invention, there is further provided a method for the treatment of a patient suffering from constipation, including occasional and intractable constipation, the method including the step of administration of dehydrated magnesium sulphate to the patient.

In accordance with the present invention, there is further provided a method for preparation of the bowel of a patient, prior to colonoscopy, barium enema x-ray examination, intestinal surgery or the like, the method including the step of administration of dehydrated magnesium sulphate to the patient.

The present invention further provides a method for the preparation of a medicament for the treatment of a patient suffering from constipation, including occasional and intractable constipation, using dehydrated magnesium sulphate.

The present invention further provides a method for the preparation of a medicament for the preparation of the bowel of a patient, prior to colonoscopy, barium enema x-ray examination, intestinal surgery or the like, using dehydrated magnesium sulphate.

In a preferred form of the invention, the patient is mammalian. In a highly preferred form of the invention, the patient is human.

WO 03/000299 PCT/AU02/00819 Best Mode(s) for Carrying Out the Invention The best mode for performing the invention will now be described. It should be noted that the following description does not limit the scope of the invention as described in the preceding disclosure.

Dehydrated magnesium sulphate is prepared by heating magnesium sulphate heptahydrate in the presence of a hygroscopic agent, then allowing such to cool in the presence of dry air. The temperature to which the hydrate is heated determines the degree of dehydration. At a temperature of approximately 1200C, six waters of crystallisation will be removed, leaving the monohydrate. Removal of the last waters of crystallisation requires temperatures of approximately 2500C.

Accordingly, it is anticipated that balancing the energy required to remove the last water of crystallisation against the increase in the efficacy of the laxative will mean the monohydrate is the best compromise.

The dehydrated magnesium sulphate (substantially monohydrate) may then be introduced into sdft gelatine type pharmaceutical capsules,, for consumption by a patient. Given the quantity of the preparation required for the laxative effect, larger capsules are preferred.

Examples The efficacy of the present invention will now be demonstrated with by way of the following examples. It should be noted that the description of the examples does not limit the scope of the invention as described in the preceding disclosure.

Example I Preparation of dehydrated magnesium sulphate A quantity of magnesium sulphate of unknown hydration was obtained from a commercial supplier. An 11.52 g sample of such as heated to 160'C for a period of 1 hour, after which the mass of the sample had reduced to 7.49 g. It was observed that the mass of the sample had remained at 7.49 g for the final minutes of heating. After being left overnight in a dry environment, the mass of WO 03/000299 PCT/AU02/00819 -6the sample increased to 8.23 g. Thus, it is theorised that the monohydrate was formed initially, and at least partially reverted to the tetrahydrate overnight.

Example 2 Efficacy of encapsulation preventing rehydration A sample of dehydrated magnesium sulphate, presumably predominantly the monohydrate, prepared as described above was placed in 40 hard gelatine capsules, the total mass of the filled capsules being 13.46 g. The capsules were left overnight and reweighed, the mass having increased only to 13.89 g, considerably less than the rehydration observed in uncoated dehydrated magnesium sulphate.

It is known that hard gelatine type capsules may be made airtight by moistening the two components of the capsule prior to joining such. However, this technique is obviously of limited utility in the present application, where the purpose is to exclude water, not simply air. Accordingly, it is envisaged that the soft-gelatine type capsules, usually used to contain liquids, would be the most appropriate means of coating the dehydrated magnesium sulphate.

Example 3 Efficacy of encapsulation palatability To demonstrate the efficacy of capsules in rendering magnesium sulphate palatable, portions of magnesium sulphate heptahydrate were placed in capsules and administered to two subjects that had previously been unable to ingest a solution of magnesium sulphate. The patients had no difficulty ingesting the capsules.

Example 4 Laxative Effect Approximately 320 mg of magnesium sulphate tetrahydrate was placed in each of a quantity of capsules, which were administered to three subjects. Effective bowel cleansing was achieved with from 60 80 capsules taken 10 at a time on the hour.

WO 03/000299 PCT/AU02/00819 -7- Even allowing for the need to take 100 capsules (10 capsules every 30 minutes would be acceptable), this represents a total of only 32gm clearly more potent than other agents in current use. It is anticipated that the monohydrate would be more potent still.

Example 5 Comparison to Epsom Salts (i) A quantity of commercially available Epsom salts and a quantity of commercially available dehydrated magnesium sulphate, predominantly tetrahydrate were placed in capsules. A comparative trial of the efficacy of the capsules was conducted in 20 patients undergoing a large bowel resection for a variety of pathological conditions. Patents were not aware of whether they had received Epsom salts or the dehydrated magnesium sulphate. The group that received the Epsom salt capsules comprised 4 men and 6 women, ranging in age from 13 to 87 years (median 68.5 years). The group that received the dehydrated magnesium sulphate comprised 6 men and 4 women, ranging in age from 27 to 73 (median 54 years).

Each group was issued with identical dietary instructions and 150 capsules, and each group member was instructed to take 10 capsules on an hourly basis until their bowel actions were 'liquid and clear'.

None of the 20 patients had difficulty taking the preparations, and of the 18 that had used presently available commercial bowel preparation compositions, all indicated that they preferred the capsules.

The number of capsules required by the group that received Epsom salts varied between 80 and 120, with a median of 100. The number of capsules required by the group that received dehydrated magnesium sulphate varied between 60 and 100, with a median of 70. Accordingly, a significantly lower number of capsules were required by the patients receiving the dehydrated magnesium sulphate.

On admission, each patient was administered a standard 'Fleet' enema and the nurse (also unaware of the group to which the patient belonged) was asked to WO 03/000299 PCT/AU02/00819 -8grade the nature of the enema effluent on a scale of 1 to 4, where 1 represented heavy faecal contamination, 2 represented moderate faecal contamination, 3 represented residual faecal particles and 4 represented clear effluent.

The ratings for the Epsom salts group varied between 1 and 4, with a median of 2.5, corresponding to between moderate faecal contamination and residual faecal particles. The ratings for the dehydrated magnesium sulphate group varied between 2 and 4, with a median of 3.3, corresponding to between residual faecal particles and clear effluent.

Accordingly, not only did the patients supplied with dehydrated magnesium sulphate require fewer capsules, but the efficacy of such was greater.

Example 6- Comparison to Epsom Salts (ii) Two patients who required 2 heaped teaspoons of Epsom salts to achieve a laxative effect (approximately 20 grams) were each supplied with 20 hard gelatine capsules, each containing approximately 325 mg of dehydrated magnesium sulphate (predominantly monohydrate, the preparation of which being described above), and asked to take 10 capsules (corresponding to approximately 3.25 g of dehydrated magnesium sulphate) and report the effect, then a further ten capsules and report the effect if the first 10 capsules had not produced the desired effect. The first patient reported that the 10 capsules of dehydrated magnesium sulphate gave the same effect as the 20 g of Epsom salts, thus demonstrating the vastly improved efficacy of dehydrated magnesium sulphate.

The second patient took 10 capsules, then a further 10, and reported that the effect of the 20 capsules was superior to the 20 g of Epsom salts.

As the preceding examples demonstrate, the dehydrated magnesium sulphate of the present invention is substantially more effective than Epsom salts, and when coated, such as when provided in capsules, has the advantage of overcoming the extreme unpalatability of magnesium sulphate salts.

WO 03/000299 PCT/AU02/00819 Modifications and variations such as would be apparent to the skilled addressee are considered to fall within the scope of the present invention.

Claims (15)

1. A laxative preparation comprising dehydrated magnesium sulphate characterised in that the dehydrated magnesium sulphate is coated to substantially inhibit absorption of atmospheric water.

2. A laxative preparation according to claim 1 characterised in that the dehydrated magnesium sulphate is substantially provided in the form of anhydrous magnesium sulphate, magnesium sulphate monohydrate, magnesium sulphate dihydrate, magnesium sulphate trihydrate, magnesium sulphate tetrahydrate and/or a mixture of two or more thereof.

3. A laxative preparation according to claim 1 or claim 2 characterised in that the dehydrated magnesium sulphate is substantially provided in the form of magnesium sulphate monohydrate.

4. A laxative preparation according to any one of the preceding claims characterised in that the laxative preparation comprises a plurality of discrete units containing dehydrated magnesium sulphate, such as capsules, cachets, or tablets. A laxative preparation according to claim 4 characterised in that each discrete unit contains a predetermined amount of dehydrated magnesium sulphate.

6. A laxative preparation according to claim 4 or 5 characterised in that, where the discrete units are provided in the form of tablets, each tablet of dehydrated magnesium sulphate is coated to substantially inhibit absorption of atmospheric water.

7. A laxative preparation according to claim 4 or 5 characterised in that, where the discrete units are provided in the form of cachets, the coating is provided in the form of the cachet, the dehydrated magnesium sulphate being contained therein. AW 12-N r, F 0 IQB E E (A rM0 1119

11-_ 8. A laxative preparation according to claim 4 or 5characterised in that, where the discrete units are provided in the form of capsules, the coating is provided in the form of the capsule, the dehydrated magnesium sulphate being contained therein. 9. A laxative preparation according to claim 8 characterised in that the capsules are provided in the form of standard pharmaceutical capsules, such as those formed from gelatine or cellulose. A laxative preparation according to claim 9 characterised in that the capsules are provided in the form of soft gelatine capsules. 11. A method for the treatment of a patient suffering from constipation, including occasional and intractable constipation, the method including the step of administration of the laxative preparation of any one of claims 1 to 10 to the patient.

12. A method for preparation of the bowel of a patient, prior to colonoscopy, barium enema x-ray examination, intestinal surgery or the like, the method including the step of administration of the laxative preparation of any one of claims 1 to 10 to the patient.

13. A method for the preparation of a medicament for the treatment of a patient suffering from constipation, including occasional and intractable constipation, using dehydrated magnesium sulphate characterised in that the dehydrated magnesium sulphate is coated to substantially inhibit absorption of atmospheric water.

14. A method for the preparation of a medicament for the preparation of the bowel of a patient, prior to colonoscopy, barium enema x-ray examination, intestinal surgery or the like, using dehydrated magnesium sulphate, characterised in that the dehydrated magnesium sulphate is coated to substantially inhibit absorption of atmospheric water. 44MIENIDMDED SHEES (Al:r, 0,51. 1 D -12-. A method according to any one of claims 12 to 14 characterised in that the patient is mammalian.

16. A method according to claim 15 characterised in that the patient is human.

17. A laxative preparation substantially as described herein with reference to Example 1 or 2.

18. A method for the treatment of a patient suffering from constipation substantially as described herein with reference to Example 6.

19. A method for preparation of the bowel of a patient, prior to colonoscopy, barium enema x-ray examination, intestinal surgery or the like, substantially as described herein with reference to Examples 4 or A method for the preparation of a medicament for the treatment of a patient suffering from constipation, including occasional and intractable constipation, substantially as described herein with reference to Example 1 or 2.

21. A method for the preparation of a medicament for the preparation of the bowel of a patient, prior to colonoscopy, barium enema x-ray examination, intestinal surgery or the like, substantially as described herein with reference to Example 1 or 2. AMIEN~~o rcri 19,~~l