NZ580999A - Combination laxative compositions comprising a colonic stimulant and a bulking laxative - Google Patents

Abstract

Disclosed is a combination dosage form including: a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g. Also disclosed is the use of the bisacodyl and psyllium in the manufacture of a medicament for treating constipation, maintaining or improving the regularity and/or ease of defecation and a kit comprising the composition.

Description

New Zealand Paient Spedficaiion for Paient Number 580999 RECEIVED at IPONZ on 20 April 2012 COMBINATION LAXATIVE COMPOSITIONS COMPRISING A COLONIC STIMULANT AND A BULKING LAXATIVE Field of the Invention The invention relates to laxative formulations, and to methods of prevention and treatment of constipation.

Background of the Invention Any discussion of the prior art throughout the specification should in no way be 10 considered as an admission that such prior art is widely known or forms part of common general knowledge in the field.

Constipation is a common clinical complaint. The prevalence is estimated to be up to 28% of the population, being up to 56 million adults in the United States and 5 million 15 people in Australia. In the United States about 2.5 million physician consultations per year are due to constipation, and annual expenditure on purchase of medications alone is about US$ 1 billion.

Constipation may be defined in a number of ways. The most common definition is that 20 of Drossman who described constipation as two or fewer bowel actions per week or straining at stool more than 25% of the time. More recently the Rome II and Rome III criteria have become the accepted means to describe the symptoms of functional constipation, consisting of infrequent bowel movements, straining at stool, hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, or manual 25 evacuation of stool from the rectum.

There are a large number of causes of constipation. Inadequate dietary fibre; immobility particularly in the elderly; endocrine and metabolic causes (hypothyroidism, hypercalcaemia, diabetes, hypokalemia, uraemia, hypopituitarism, porphyria); nervous 30 system pathology (autonomic neuropathy, Parkinson's disease); drugs such as iron supplements, calcium channel blockers, anticholinergics, anti-depressants, narcotic RECEIVED at IPONZ on 20 April 2012 agents, non-steroidal anti-inflammatory drugs, laxative abuse; psychiatric conditions such as depression, psychoses and anorexia nervosa.

Constipation caused by mechanical obstruction is treated by surgery, but this is a 5 relatively uncommon cause.

Functional constipation is far more common, of which there are three types. The first, slow-transit constipation (STC) is characterized by prolongation of transit time through the colon. The second, obstructed defecation, is an inability to initiate defecation 10 following the urge to do so associated with a feeling of incomplete evacuation of the rectum. The third, constipation-predominant irritable bowel syndrome, is characterized by constipation with associated abdominal pain and bloating, occurring in the presence of normal colonic transit time.

Non-propagated and propagated colonic contractions are found in normal colonic transit. High amplitude propagated contractions are responsible for mass migration of colonic contents and have been shown to be reduced in patients with constipation. In slow-transit constipation there is ineffective colonic propulsion.

Impaired propagated colonic contractile response to the laxative bisacodyl is found in patients with STC. This inactivity of the colon may be due to a disorder of the myenteric plexus of the colon. Colonic inertia reflects a severe disorder of colonic motor function that sometimes requires treatment with large doses of laxatives.

Empirical treatment with fibre supplementation using at least 25 gram daily is indicated for all patients presenting with functional constipation, and adequate fluid intake is important.

Laxatives will be required if constipation does not improve with fibre. However, there 30 are a number of problems associated with laxative use.

RECEIVED at IPONZ on 20 April 2012 There are three main classes of laxatives bulking agents (Normacol, psyllium eg Metamucil); osmotic agents (lactulose, Epsom salts); and stimulants (bisacodyl, senna).

Clinicians prescribe one of these at a time. If one is not successful, they will 5 occasionally add another, usually with one laxative taken in the morning and the other at night. There are several problems with laxative administration.

Firstly, many patients find laxatives unpalatable. For example, sterculia granules are difficult for some elderly patients to swallow. Osmotic laxatives such as polyethylene 10 glycol or Epsom salts have an unpalatable taste for many. Lactulose is very sweet and also has a high caloric value.

Secondly, osmotic laxatives such as Epsom salts and lactulose may exacerbate bloating. With lactulose, this occurs partly since it is metabolised into methane and hydrogen gas 15 in the colon.

Thirdly, many patients develop tolerance to a single laxative agent. This means that with prolonged usage, the drug becomes less effective as the bowel accommodates and "learns" to overcome the effect of the drug. It is therefore preferable for patients who 20 will require long-term use of a laxative to use more than one agent together. This tends to delay or even avoid development of tolerance to one or both of the drugs being used. It is best for two agents to be taken at the same time in order that they reach the bowel simultaneously.

Unfortunately compliance with taking more than one laxative is often poor. Many patients try to progressively increase the dose of one agent rather than using a lower dose of two agents.

When told to use more than one laxative, many patients will take one type of laxative in 30 the morning and another type in the evening in the belief that spreading them across the day will be more effective.

RECEIVED at IPONZ on 20 April 2012 Repeated explanation about the simultaneous use of laxatives is required in order to establish compliance, but despite this, many patients will revert to using them at different times in the day or on different days.

Combination laxatives in the market are generally supermarket products and usually comprise senna products together with other agents, many of which are poor laxatives. Prescription or OTC pharmaceutical laxatives tend to be single agent laxatives.

It is an object of the present invention to overcome or ameliorate at least one of the 10 disadvantages of the prior art, or to provide a useful alternative.

Unless the context clearly requires otherwise, throughout the description and the claims, the words "comprise", "comprising", and the like are to be construed in an inclusive sense as opposed to an exclusive or exhaustive sense; that is to say, in the sense of 15 "including, but not limited to".

Although the invention will be described with reference to specific examples it will be appreciated by those skilled in the art that the invention may be embodied in many other forms.

Summary of the Invention According to a first aspect of the present invention there is provided a combination dosage form including: a colonic stimulant in the form of bisacodyl in an amount of 25 between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g.

According to a second aspect of the present invention there is provided a combination 30 of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g, adapted for use in treating constipation.

RECEIVED at IPONZ on 20 April 2012 According to a third aspect of the present invention there is provided a combination dosage form according to the first aspect of the present invention, adapted for use in treating constipation.

According to a fourth aspect of the present invention there is provided a combination of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g, adapted for use in maintaining or improving the regularity and or 10 ease of defecation.

According to a fifth aspect of the present invention there is provided a combination dosage form according to the first aspect of the present mveniton, adapted for use in maintaining or improving the regularity and or ease of defecation.

According to a sixth aspect of the present invention there is provided the use of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g for the manufacture of a medicament for the treatment of constipation.

According to a seventh aspect of the present invention there is provided the use of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g for the manufacture of a medicament for maintaining or improving the 25 regularity and or ease of defecation.

According to an eighth aspect of the present invention there is provided a kit comprising a discrete dosage of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in 30 an amount of between about 0.25 g and 5 g, presented in a manner which facilitates their simultaneous or substantially simultaneous co-administration; and instructions for said administration, wherein said kit is adapted for use in treating constipation, RECEIVED at IPONZ on 20 April 2012 maintaining the regularity and/or ease of defecation, or improving the regularity and/or ease of defecation.

According to a first form the invention provides a combination dosage form including a 5 colonic stimulant and a bulking laxative. Preferably, the dosage form includes a non-cramping amount of a colonic stimulant and also preferably a non-bloating amount of a bulking laxative.

Preferably the colonic stimulant is bisacodyl. Any therapeutically effective amount of 10 bisacodyl may be used. The dose of bisacodyl may be 0.05 mg or above although preferably the dose of bisacodyl is between 0.5 mg and 5 mg.

Preferably the bulking agent is one or more of natural bran fibre, sterculia husks, ispaghula husks or psyllium. More preferably the bulking agent is psyllium, preferably 15 the dose of psyllium husk is between 0.25g and 5g.

The dosage form is preferably in the form of a tablet or more preferably in the form of a capsule.

One preferred combination dosage form includes a capsule containing 0.5 mg bisacodyl and 500 mg psyllium husk.

An alternative preferred combination dosage form includes a capsule containing 1 mg bisacodyl and 500 mg psyllium husk.

The dosage form preferably includes prune powder. Also preferably, the dosage form further includes goji berry powder.

The combination dosage form may further including other bulking agents; further 30 including osmotic agents; surface active agents; slippery elm or desiccated fruit powders.

RECEIVED at IPONZ on 20 April 2012 Preferred osmotic agents include magnesium sulfate, sodium phosphate, sodium picosulfate or combinations thereof.

A preferred surface active agents is docusate.

A preferred desiccated fruit powder is apricot powder.

The dosage forms of the present invention may further include an anthraquinone stimulant. For preference this may be senna, sennosides a and b, cascara segrada or 10 mixtures thereo f.

The combination dosage forms of the present invention also encompass those dosage forms in which the active ingredients are not physically mixed, but are presented to the patient in a manner which facilitates their co-administration, such that the dosage forms 15 function individually as an effective combination.

In such a case, the combination or kit preferably contains a discrete dosage of a colonic stimulant and a discrete dosage of a bulking laxative, preferably presented in a manner which facilitates their simultaneous or substantially simultaneous co-administration.

The combination in this case includes for preference a blister pack having a bulking laxative and a colonic stimulant positioned thereupon in a manner which ensures the simultaneous or substantially simultaneous co-administration of the bulking laxative and a colonic stimulant. The bulking laxative and a colonic stimulant may be placed in 25 adjacent blisters or compartments, or may be placed together in a single blister. The packaging may bear indicia to ensure correct administration.

In one preferred embodiment, the invention provides a blister pack having a blister including a bisacodyl tablet or capsule adjacent to a blister including a psyllium capsule 30 or tablet. The blister pack may bear instructions or have accompanying instructions to ensure that the two drugs are always taken together. The amounts of each individual medicament may be as disclosed above.

RECEIVED at IPONZ on 20 April 2012 According to a second form, the invention provides a method of treating constipation in a subject in need thereof comprising the step of providing to said subject a combination of a colonic stimulant and a bulking laxative.

Preferably, the method of treating constipation in a subject in need thereof comprises the step of providing to said subject a combination dosage form according to the first aspect.

According to a third form the invention provides a method of maintaining or improving the regularity and/or ease of defecation comprising providing to said subject a combination of a colonic stimulant and a bulking laxative.

Preferably, the method of maintaining or improving the regularity and/or ease of 15 defecation comprises the step of providing to said subject a combination dosage form according to the first aspect.

According to a fourth form the invention provides the use of a colonic stimulant in combination with a bulking laxative for the manufacture of a medicament for the 20 treatment of constipation.

According to a fifth form the invention provides the use of a colonic stimulant in combination with a bulking laxative for the manufacture of a medicament for maintaining or improving the regularity and/or ease of defecation.

Preferably, the use includes a non-cramping amount of a colonic stimulant and also preferably a non-bloating amount of a bulking laxative.

Preferably the colonic stimulant is bisacodyl. Any therapeutically effective amount of 30 bisacodyl may be used. The dose of bisacodyl may be 0.05 mg or above although preferably the dose of bisacodyl is between 0.5 mg and 5 mg.

RECEIVED at IPONZ on 20 April 2012 Preferably the bulking agent is one or more of natural bran fibre, sterculia husks, ispaghula husks or psyllium. More preferably the bulking agent is psyllium, preferably the dose of psyllium husk is between 0.25 g and 5 g.

The medicament is preferably in the form of a tablet or more preferably in the form of a capsule.

One preferred medicament includes 0.5 mg bisacodyl and 500 mg psyllium husk.

An alternative preferred medicament includes 1 mg bisacodyl and 500 mg psyllium husk.

In an alternative embodiment, the medicament is in the form of a powder. The powder may be available as a homogeneous powder in bulk form, or as a powder contained in a 15 standard, predetermined dosage form.

In those cases where the medicament is presented as homogeneous powder in bulk form, the material contains between 2.5 mg bisacodyl and 20 mg of bisacodyl per 300 mg or powder. The medicament would contain between 280 mg and 297.5 mg of 20 psyllium husk. Other ingredients may also be present, including agents added to ensure that the homogeneity of the formulation is maintained. There are two highly preferred formulations. One contains 5 mg bisacodyl and about 295 mg psyllium husk in 300 mg of medicament. The other highly preferred formulation contains 10 mg bisacodyl and about 290 mg psyllium husk in 300 mg of medicament. In the case of bulk 25 formulations, it is preferred if the bulk formulation is accompanied by a device which dispenses an accurate, predetermined amount of medicament. For instance, the bulk formulation could be accompanied by a measuring cylinder or spoon designed to dispense a predetermined amount, for example, 300 mg, of medicament.

In another alternative, the medicament is presented as a powder in the form of a discrete pre-packaged amount. This may be for preference in the form of a sachet. The discrete pre-packaged medicament may contain anywhere between 2.5 mg and 20 mg of RECEIVED at IPONZ on 20 April 2012 bisacodyl, and may contain between 250 and 2g of psyllium husk. However, it is preferred to use one of two preferred dosage forms. One preferred dosage form contains 5 mg bisacodyl and about 295 mg psyllium husk (about 300 mg altogether). The other preferred dosage form contains 10 mg bisacodyl and about 290 mg psyllium 5 husk in 300 mg of medicament.

The medicament preferably includes prune powder. Also preferably, the medicament further includes goji berry powder The medicament may further including other bulking agents; further including osmotic agents; surface active agents; slippery elm or desiccated fruit powders.

Preferred osmotic agents include magnesium sulfate, sodium phosphate, sodium pico sulfate or combinations thereof A preferred surface active agent is docusate.

A preferred desiccated fruit powder is apricot powder.

The medicament may further include an anthraquinone stimulant. For preference this may be senna, sennosides a and b, cascara segrada or mixtures thereof.

The present inventor has found in clinical practice that different classes of laxatives have a synergistic effect, so that the combined effect is greater than the sum of the two 25 effects. Also, and more importantly, in single laxative therapy, the bowel becomes resistant to any one laxative after a time and becomes less effective (or even ineffective), whilst in the combination therapy of the present invention, the bowel tends not to become resistant if two laxatives are used.

In order to achieve the full benefit of the combinations of the present invention, both in terms of effectiveness as well as overcoming resistance of the bowel, the laxatives should be taken at the same time in the day so that they reach the bowel at the same RECEIVED at IPONZ on 20 April 2012 time. It is very difficult to get patients to persist with taking laxatives together, and long-term compliance with this is poor.

The best combination of laxatives is a bulking agent together with a stimulant. A high 5 dose of a stimulant is a very effective laxative but the dosage required to be effective will sometimes cause abdominal cramps. The dose of a stimulant can be significantly reduced by taking the stimulant together with a bulking agent. Similarly a high dose of a bulking agent is also effective, but causes bloating in many patients. A lower dose of the bulking agent can be taken when combined with a stimulant.

Bisacodyl is an effective stimulant of the colon. It often causes crampy pain or diarrhoea when used in high doses. However when used together with a bulking agent then the dose of bisacodyl can be reduced and a lower dose does not cause pain. This combination is highly effective.

Bisacodyl is available in 5mg tablets in a variety of proprietary preparations. The tablets are small and hard and cannot easily or reliably be broken or cut. For some patients 5mg is too large a dose, causing pain or diarrhoea. Patients experiencing pain with 5mg will usually cease using the laxative.

Some patients require more than 5 mg but less than 10 mg to treat constipation. In such cases 10 mg will cause pain while 5 mg is not effective and does not induce a bowel action. These patients requiring between 5 mg and 10 mg will similarly often cease using the drug. The same applies for patients requiring between 10 mg and 15 mg, as 25 well as with higher doses.

Bisacodyl is also manufactured as a syrup. Using the syrup form, the dosage can be varied more effectively than the tablets.

There are several types of bulking agents. Natural bran fibre is widely used. Sterculia and ispaghula husks are other bulking agents. Psyllium is an effective bulking agent. It is a natural fibre which can be used safely over a prolonged period. It is widely RECEIVED at IPONZ on 20 April 2012 available in health stores and some pharmacies. It is presented as a powder in a container, generally containing up to 1000 g. It may contain coarse psyllium fibre or may be crushed very finely in order to dissolve in a liquid before drinking. It is also available in capsules containing 525 mg psyllium husk.

The optimal combination of laxative is psyllium as a bulking agent taken together with bisacodyl. Since the syrup form of bisacodyl cannot be mixed with a bulking agent, the preferred combination is the tablet form of bisacodyl together with psyllium. In order to have good compliance with taking the two agents they should be mixed together. This 10 ensures that they are both taken, and that they are taken at the same time together.

Since it is important to be able to titrate a precise dose of bisacodyl measured in mg, it is generally not satisfactory to present a mixture of psyllium and bisacodyl in a large container to be measured using a spoon as with plain psyllium. However, in some 15 circumstances, it may be acceptable to dispense the material in bulk, for example, where the bisacodyl concentration is sufficiently homogeneous throughout the whole material, and where the quantity of material used can be accurately and easily determined, ie by the use of a measuring cylinder, special spoon or other standardised dispenser. Whilst using a measuring cylinder or the like is reasonably accurate, patients may not 20 consistently take the correct dosage and there may still potentially be the problem that too much or too little bisacodyl being used. Significant variations in dosage are not be acceptable.

One of the best ways to present the combination is in a capsule containing a known 25 amount of psyllium and bisacodyl.

Dosage: 1. The first strength is a capsule with bisacodyl 0.5 mg and psyllium husk 500 mg (capsule A) 2. The second strength is bisacodyl 1 mg and psyllium husk 500 mg (capsule B) 3. The third strength is bisacodyl 2 mg and psyllium husk 500 mg (capsule C) RECEIVED at IPONZ on 20 April 2012 Instructions for use are generally be 5 capsules daily taken as a single dose. This delivers 2.5 g of psyllium husk and 2.5 mg bisacodyl in capsule A, and 2.5 g of psyllium husk and 5 mg bisacodyl in capsule B, and 2.5g of psyllium husk and 10 mg 5 bisacodyl in capsule C.

When 2.5 mg bisacodyl is not sufficient, between 5 and 10 capsules A can be taken. When 5 mg is not sufficient then more than 5 capsules B can be taken, the number being determined by the patient's response, 5 capsules C can be taken.

The dose of psyllium husk per capsule can be varied between 0.25 g and 5 g. The dose of bisacodyl per capsule can be varied between 0.05 mg and 5 mg.

Addition of prune powder increases the effectiveness of the combination of psyllium 15 and bisacodyl. Therefore one particularly preferred and effective combination is psyllium 500 mg, prune powder 150 mg, and bisacodyl 0.5 mg. The dose of psyllium can be varied between 0.25 g and 5 g, the dose of bisacodyl 0.50 mg to 5 mg, and prune powder 100 mg to lg. Attempting to get a patient to take three such substances at the same time in the day has very poor compliance.

Another combination will be psyllium 500 mg, goji bexxy powder 150 mg, and bisacodyl 0.5 mg. The dose of psyllium can be varied between 0.25 g and 5 g, the dose of bisacodyl 0.50 mg to 5 mg, and goji berry powder 100 mg to 1 g.

Other agents may be added to the capsules containing psyllium and bisacodyl. These include other bulking agents; osmotic agents such as Epsom salts (magnesium sulfate), sodium phosphate, sodium picosulfate; surface active agents (docusate); slippery elm; desiccated fiuit powders such as apricot powder.

In addition to tablets, the formulations may be dispensed as powders supplied in sachets or other forms of packaging which can deliver a single, predetermined dose. The sachets could contain any desired amount of bisacodyl and psyllium in accordance with RECEIVED at IPONZ on 20 April 2012 the invention, but most preferably they contain around 300 mg of material in total. The amount of bisacodyl under those circumstances is typically anywhere between 2.5 mg and 20 mg. In most cases, a clinician would wish to dispense either a higher or lower strength formulation, which would be respectively 5 mg bisacodyl or 10 mg bisacodyl 5 per 300 mg or material. Other excipients as discussed above can be added, but the balance of the material is generally psyllium husk.

In some cases, alternative stimulants may be used alone or in combination with bisacodyl. Stimulants such as anthraquinones (senna, sennosides a and b, cascara 10 segrada) may damage the colon when used over a long period of time, causing melanosis coli or damage to the nerve plexus of the colon. Their use in formulations of the present invention should therefore generally only be considered for short or medium-term use.

Clinical Studies 43 patients with severe constipation referred to a surgical practice with an interest in constipation were evaluated. At the time of follow-up 29 patients had been evaluated. Of these 29 patients, prior to being referred 5 had used bisacodyl alone, 3 had used 20 psyllium, and 16 had used other laxatives alone. These included a wide range of different agents. Therefore 24 of 29 patients had previously been treated with single agents. Some had also tried increasing dietary fibre. All patients had failed treatment and were referred for further evaluation.

Bowel frequency was variable but frequently 2 or less per week. Patients generally fitted the Rome II criteria for slow colonic transit.

Patients were treated with a combination of bisacodyl 5-20 mg together with Metamucil 2-4 teaspoonsful taken together at the same time, usually in the morning after breakfast. 30 The dosage was titrated according to the clinical response and patients were encouraged to persist with the regimen for at least two to three months in order to judge a clinical response. Assessment was made 3 to 18 months after treatment commenced.

Claims (42)

RECEIVED at IPONZ on 20 April 2012 -15 - Outcome measures were stool frequency, stool consistency, straining at stool, and abdominal pain and bloating. 5 Twenty three of the 29 patients were improved on a combination of psyllium and bisacodyl; 6 were not improved. Stool frequency increased and all 23 patients felt subjectively improved. Improvement could not be correlated with change in isotope transit in this study as a 10 result of incomplete data and further studies will be needed to assess this further. RECEIVED at IPONZ on 20 April 2012 - 16- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS

1. A combination dosage form including: a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g.

2. A combination dosage form according to claim 1, in the form of a tablet.

3. A combination dosage form according to claim 1, in the form of a capsule.

4. A combination dosage form according to claim 1, in the form of a powder.

5. A combination dosage form according to claim 4, in the form of a pre-packaged predetermined amount of a powder.

6. A combination dosage form according to any one of the preceding claims, including 0.5 mg bisacodyl and 500 mg psyllium husk.

7. A combination dosage form according to any one of the preceding claims, including 1 mg bisacodyl and 500 mg psyllium husk.

8. A combination dosage form according to any one of the preceding claims, further including prune powder.

9. A combination dosage form according to any one of the preceding claims, further including goji berry powder

10. A combination dosage form according to any one of the preceding claims, further including other bulking agents; further including osmotic agents; surface active agents; slippery elm or desiccated fruit powders. RECEIVED at IPONZ on 20 April 2012 17-

11. A combination dosage form according to claim 10, wherein the osmotic agents are magnesium sulfate, sodium phosphate, sodium picosufate or combinations thereof 5

12. A combination dosage form according to claim 10 or claim 11, wherein the surface active agent is docusate.

13. A combination dosage form according to any one of claims 10 to 12, wherein the 10 desiccated fruit powder is apricot powder.

14. A combination dosage form according to any one of the preceding claims, further including an anthraquinone stimulant.

15 15. A combination dosage form according to claim 14, wherein the anthraquinone stimulant is senna, sennosides a and b, cascara segrada or mixtures thereof.

16. A combination of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium 20 husk in an amount of between about 0.25 g and 5 g, adapted for use in treating constipation.

17. A combination dosage form according to any one of claims 1 to 15, adapted for use in treating constipation. 25 30

18. A combination of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g, adapted for use in maintaining or improving the regularity and or ease of defecation.

19. A combination dosage form according to any one of claims 1 to 15, adapted for use in maintaining or improving the regularity and or ease of defecation. RECEIVED at IPONZ on 20 April 2012 -18-

20. The use of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g for the manufacture of a medicament 5 for the treatment of constipation.

21. The use of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the form of psyllium husk in an amount of between about 0.25 g and 5 g for the manufacture of a medicament 10 for maintaining or improving the regularity and or ease of defecation.

22. The use according to claim 20 or claim 21, wherein the medicament is in the form of a tablet. 15

23. The use according to claim 20 or claim 21, wherein the medicament is in the form of a capsule.

24. The use according to claim 20 or claim 21, wherein the medicament is in the form of a powder. 20

25. The use according to claim 24, wherein the medicament is in the form of a prepackaged predetermined amount of a powder.

26. The use according to any one of claims 20 to 25, including 0.5 mg bisacodyl and 25 500 mg psyllium husk.

27. The use according to any one of claims 20 to 25, including 1 mg bisacodyl and 500 mg psyllium husk. 30 28. The use according to any one of claims 20 to 27, farther including prune powder.

RECEIVED at IPONZ on 20 April 2012 10 - 19-

29. The use according to any one of claims 20 to 28, further including goji berry powder

30. The use according to any one of claims 20 to 29, further including other bulking agents; further including osmotic agents; surface active agents; slippery elm or desiccated fruit powders.

31. The use according to claim 3 0, wherein the osmotic agents are magnesium sulfate, sodium phosphate, sodium picosulfate or combinations thereof.

32. The use according to claim 30 or claim 31, wherein the surface active agent is docusate.

33. The use according to any one of claims 30 to 32, wherein the desiccated fruit 15 powder is apricot powder.

34. The use according to any one of claims 20 to 33, further including an anthraquinone stimulant. 20

35. The use according to claim 24, wherein the anthraquinone stimulant is senna, sennosides a and b, cascara segrada or mixtures thereof.

36. A kit comprising a discrete dosage of a colonic stimulant in the form of bisacodyl in an amount of between about 0.05 mg and 5 mg; and a bulking laxative in the 25 form of psyllium husk in an amount of between about 0.25 g and 5 g, presented in a manner which facilitates their simultaneous or substantially simultaneous coadministration; and instructions for said administration, wherein said kit is adapted for use in treating constipation, maintaining the regularity and/or ease of defecation, or improving the regularity and/or ease of defecation. 30

37. A kit according to claim 36, in the form of a blister pack. RECEIVED at IPONZ on 20 April 2012 -20-

38. A combination dosage form according to claim 1, said dosage form substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples.

39. A combination according to claim 16 or claim 18, adapted substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples.

40. A combination dosage form according to claim 17 or claim 19, adapted substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples.

41. Use according to claim 20 or 21, said use substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples.

42. A kit according to claim 36, said kit adapted substantially as herein described with reference to any one of the embodiments of the invention illustrated in the accompanying examples. Dated this 20th day of April 2012 Shelston IP Attorneys for: David Lubowski