WO2008141368A1

WO2008141368A1 - Combination laxative compositions comprising a colonic stimulant and a bulking laxative

Info

Publication number: WO2008141368A1
Application number: PCT/AU2008/000690
Authority: WO
Inventors: David Lubowski
Original assignee: David Lubowski
Priority date: 2007-05-17
Filing date: 2008-05-16
Publication date: 2008-11-27
Also published as: AU2008253583A1; NZ580999A

Abstract

A combination dosage form including a colonic stimulant such as bisacodyl, preferably in a non-cramping amount and a bulking laxative such as natural bran fibre, sterculia husks, ispaghula husks or psyllium, preferably in a non-bloating amount. The combination dosage form may be in the form of a tablet, capsule, powder or the like or it may be packaged with foods, bulking agents; osmotic agents; surface active agents; slippery elm, desiccated fruit powders and so on. Also, methods of treating constipation or maintaining or improving the regularity and or ease of defecation comprising providing a combination of a colonic stimulant and a bulking laxative; and the use of a colonic stimulant in combination with a bulking laxative for the manufacture of a medicament for treating constipation or maintaining or improving the regularity and or ease of defecation.

Description

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 ofconstipation.

BACKGROUND ART

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 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 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 fijnctional constipation, consisting of infrequent bowel movements, straining at stool, hard stools, sensation of incomplete evacuation, sensation of anorectal obstruction, or manual evacuation of stool from the rectum.

There are a large number of causes ofconstipation. Inadequate dietary fibre; immobility particularly in the elderly; endocrine and metabolic causes (hypothyroidism, hypercalcaemia, diabetes, hypokalaemia, uraemia, hypopituitarism, porphyria); nervous system pathology (autonomic neuropathy, Parkinson's disease); drugs such as iron supplements, calcium channel blockers, anticholinergics, anti-depressants, narcotic 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 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 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 25gram 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 are a number of problems associated with laxative use.

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 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 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 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 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 the morning and another type in the evening in the belief that spreading them across the day will be more effective.

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

SUMMARY OF THE INVENTION

According to a first aspect the invention provides a combination dosage form including a 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 bisacodyl may be used. The dose of bisacodyl may be 0.05mg or above although preferably the dose of bisacodyl is between 0.5mg and 5mg.

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 0.25g 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 0.5mg bisacodyl and 500mg psyllium husk.

An alternative preferred combination dosage form includes a capsule containing 1 mg bisacodyl and 500mg 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 include other bulking agents; further include osmotic agents; surface active agents; slippery elm or desiccated fruit powders.

Preferred osmotic agents include magnesium sulphate, sodium phosphate, sodium picosulphate 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 mixtures thereof.

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 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 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 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.

According to a second aspect, 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.

The constipation is preferably associated with poor motility and/or DBS.

According to a third aspect 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 defecation comprises the step of providing to said subject a combination dosage form according to the first aspect.

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

The constipation is preferably associated with poor motility and/or IBS. According to a fifth aspect 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.

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

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

An alternative preferred medicament includes 1 mg bisacodyl and 500mg 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 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 300mg or powder. The medicament would contain between 280 mg and 297.5 mg of 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 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 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 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 sulphate, sodium phosphate, sodium picosulphate 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 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 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 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 5mg but less than lOmg to treat constipation. In such cases lOmg will cause pain while 5mg is not effective and does not induce a bowel action. These patients requiring between 5mg and lOmg will similarly often cease using the drug. The same applies for patients requiring between lOmg and 15mg, as 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 available in health stores and some pharmacies. It is presented as a powder in a container, generally containing up to 100Og. 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 525mg 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 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 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 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 amount of psyllium and bisacodyl.

Dosage:

1. The first strength is a capsule with bisacodyl 0.5mg and psyllium husk 500mg (capsule A)

2. The second strength is bisacodyl lmg and psyllium husk 500mg (capsule B)

3. The third strength is bisacodyl 2mg and psyllium husk 500mg (capsule C)

Instructions for use are generally be 5 capsules daily taken as a single dose. This delivers 2.5g of psyllium husk and 2.5mg bisacodyl in capsule A, and 2.5g of psyllium husk and 5mg bisacodyl in capsule B, and 2.5g of psyllium husk and lOmg bisacodyl in capsule C.

When 2.5mg bisacodyl is not sufficient, between 5 and 10 capsules A can be taken. When 5mg 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 0.25g and 5g. The dose of bisacodyl per capsule can be varied between 0.05mg and 5mg.

Addition of prune powder increases the effectiveness of the combination of psyllium and bisacodyl. Therefore one particularly preferred and effective combination is psyllium 500mg, prune powder 150mg, and bisacodyl 0.5mg. The dose of psyllium can be varied between 0.25g and 5g, the dose of bisacodyl 0.50mg to 5mg, and prune powder lOOmg to 1 g. 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 500mg, goji berry powder 150mg, and bisacodyl 0.5mg. The dose of psyllium can be varied between 0.25g and 5g, the dose of bisacodyl 0.50mg to 5mg, and goji berry powder lOOmg to Ig.

Other agents may be added to the capsules containing psyllium and bisacodyl. These include other bulking agents; osmotic agents such as Epsom salts (magnesium sulphate), sodium phosphate, sodium picosulphate; surface active agents (docusate); slippery elm; desiccated fruit 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 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 5mg bisacodyl or 10 mg bisacodyl 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 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 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 5-20mg together with Metamucil 2-4 teaspoonsful taken together at the same time, usually in the morning after breakfast. 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.

Outcome measures were stool frequency, stool consistency, straining at stool, and abdominal pain and bloating.

Twenty three of the 29 patients were improved on a combination of psyllium and bisacodyl; 6 were not improved. All 5 patients treated previously with bisacodyl and all 3 patients treated previously with psyllium were improved. Stool frequency increased and all 23 patients felt subjectively improved.

Claims

THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS:-

1. A combination dosage form including a colonic stimulant and a bulking laxative.

2. A combination dosage form according to claim 1 including a non-cramping amount of a colonic stimulant.

3. A combination dosage form according to claim 1 or claim 2 including a non- bloating amount of a bulking laxative.

4. A combination dosage form according to any one of the preceding claims wherein the colonic stimulant is bisacodyl.

5. A combination dosage form according to claim 4 wherein the dose of bisacodyl is between 0.05mg and 5mg.

6. A combination dosage form according to any one of the preceding claims wherein the bulking agent is one or more of natural bran fibre, sterculia husks, ispaghula husks or psyllium.

7. A combination dosage form according to claim 6 wherein the bulking agent is psyllium.

8. A combination dosage form according to claim 7 wherein the dose of psyllium husk is between 0.25g and 5g.

9. A combination dosage form according to any one of the preceding claims in the form of a tablet.

10. A combination dosage form according to any one of claims 1 to 8 in the form of a capsule.

1 1. A combination dosage form according to any one of claims 1 to 8 in the form of a powder.

12. A combination dosage form according to claim 11 in the form of a pre-packaged predetermined amount of a powder.

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

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

15. A combination dosage form according to any one of the preceding claims farther including prune powder.

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

17. 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.

18. A combination dosage form according to claim 17 wherein the osmotic agents are magnesium sulphate, sodium phosphate, sodium picosulphate or combinations thereof

19. A combination dosage form according to claim 17 or 18 wherein the surface active agents is docusate.

20. A combination dosage form according to any one of claims 17 to 19 wherein the desiccated fruit powder is apricot powder.

21. A combination dosage form according to any one of the preceding claims ftirther including an anthraquinone stimulant.

22. A combination dosage form according to claim 21 wherein the anthraquinone stimulant is senna, sennosides a and b, cascara segrada or mixtures thereof.

23. 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.

24. A method of treating constipation in a subject in need thereof comprising the step of providing to said subject a combination dosage form according to any one of claims 1 to 23.

25. 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.

26. A method of maintaining or improving the regularity and or ease of defecation comprising the step of providing to said subject a combination dosage form according to any one of claims 1 to 23.

27. The use of a colonic stimulant in combination with a bulking laxative for the manufacture of a medicament for the treatment of constipation.

28. 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.

29. The use according to claim 27 or 28 including a non-cramping amount of a colonic stimulant.

30. The use according to claim 27 or 28 including a non-bloating amount of a bulking laxative.

31. The use according to any one of claims 27 to 30 wherein the colonic stimulant is bisacodyl.

32. The use according to any one of claims 27 to 31 wherein the dose of bisacodyl is between 0.05mg and 5mg.

33. The use according to any one of claims 27 to 32 wherein the bulking agent is one or more of natural bran fibre, sterculia husks, ispaghula husks or psyllium.

34. The use according to any one of claims 27 to 33 wherein the bulking agent is psyllium.

35. The use according to any one of claims 27 to 34 wherein the dose of psyllium husk is between 0.25g and 5g.

36. The use according to any one of claims 27 to 35 wherein the medicament is in the form of a tablet.

37. The use according to any one of claims 27 to 35wherein the medicament is in the form of a capsule.

38 The use according to any one of claims 27 to 34 wherein the medicament is in the form of a powder.

39. The use according to claim 38 wherein the medicament is in the form of a pre- packaged predetermined amount of a powder.

40. The use according to any one of claims 29 to 39 including 0.5mg bisacodyl and 500mg psyllium husk.

41. The use according to any one of claims 29 to 40 including 1 mg bisacodyl and 500mg psyllium husk.

42. The use according to any one of claims 29 to 41 further including prune powder.

43. The use according to any one of claims 29 to 42 further including goji berry powder

44. The use according to any one of claims 29 to 43 further including other bulking agents; further including osmotic agents; surface active agents; slippery elm or desiccated fruit powders.

45. The use according to claim 44 wherein the osmotic agents are magnesium sulphate, sodium phosphate, sodium picosulphate or combinations thereof

46. The use according to any one of claims 44 to 45 wherein the surface active agents is docusate.

47. The use according to any one of claims 44 to 46 wherein the desiccated fruit powder is apricot powder.

48. The use according to any one of claims 27 to 47 further including an anthraquinone stimulant.

49. A kit comprising a discrete dosage of a colonic stimulant and a discrete dosage of a bulking laxative.

50. A kit according to claim 49 wherein the colonic stimulant is bisacodyl.

51. A kit according to claim 49 or 50 wherein the bulking laxative is psyllium.

52. A kit according to any one of claim 49 to 51 wherein the discrete dosage of a colonic stimulant and a discrete dosage of a bulking laxative are presented in a manner which facilitates their simultaneous or substantially simultaneous co-administration.

53. A kit according to claim 52 in the form of a blister pack.