Patent Description:
The present invention concerns a composition as defined in the claims for use in the treatment of constipation comprising a PEG-based water solution for rectal use.

Chronic constipation is a functional disorder of the gastrointestinal tract characterised by infrequent bowel movements in the absence of identifiable abnormalities. This condition is very common in the general population, with a prevalence ranging from <NUM>% to <NUM>%. Women (female-male ratio <NUM>-<NUM>:<NUM>), the elderly (over the age of <NUM>), non-Europeans and people living in poorer socio-economic conditions have a greater probability of suffering from this disorder. Like other functional diseases of the gut (for example, irritable bowel syndrome and dyspepsia), chronic constipation entails a considerable reduction in patient quality of life.

Chronic constipation can be associated with a further degree of disability if the patients present faecal impaction in the rectum or in the most proximal segments of the colon.

This can lead to overflow or soiling, which further deteriorates the patient's quality of life.

Patients with constipation often tend to self-medicate by changing their diet (increase in fibre intake) and, above all, by using irritating laxatives.

In addition to changes in lifestyle, which are not always fully effective, doctors can prescribe different types of laxatives. Laxatives are agents that stimulate defecation or modify faecal consistency and ease of passage.

There are at least three broad categories of laxatives based on their mechanism of action: laxatives that form a mass (bulk forming agents), osmotic laxatives and stimulants (also called "irritants"). In some countries (for example the United States), a fourth category is available: laxatives that soften the faeces (stool softeners), such as docusate.

In the United States, approximately <NUM> million dollars are spent in over-the-counter laxatives and every year approximately <NUM> million medical prescriptions are issued for the treatment of constipation. However, approximately <NUM>% of patients are still dissatisfied with their treatment. Remedies for constipation are generally unsatisfactory because, although they can ensure regular bowel movements, they do not always solve (and can even worsen) the signs and symptoms (for example pain and abdominal bloating, flatulence and tension) responsible for the negative impact on the patient's quality of life.

As has been known for some time in the sector, glycerol-based water solutions are widely used for the treatment of constipation. Although glycerol is effective in solving constipation, it is known to produce an irritating effect.

<CIT> discloses an aqueous enema comprising PEG, preferably PEG <NUM>-<NUM> Dalton, for treating constipation.

There is therefore a need for compositions for the treatment of constipation that are more effective and have fewer undesired effects than the current pharmacological treatments.

The inventors of the present invention have unexpectedly found that the use of a combination of two types of polyethylene glycol (PEG), with different molecular weight, in rectal-use compositions produces improvements in terms of both effectiveness against constipation and side effects.

The subject of the present invention is a rectal-use composition by enema for use in treatment of constipation, characterized in that it comprises a water solution comprising (a) <NUM> to <NUM>% by weight of a first polyethylene glycol having a mean molecular weight ranging from <NUM> to <NUM> Dalton and (b) a second polyethylene glycol having a mean molecular weight ranging from <NUM> to <NUM> Dalton; said first polyethylene glycol being in a quantity comprised between two and six times by weight the quantity of said second polyethylene glycol; said second polyethylene glycol being present in said water solution in a quantity comprised between <NUM> and <NUM>% by weight.

Preferably, said first polyethylene glycol is in a quantity comprised between <NUM> and <NUM>% by weight.

Preferably, said first polyethylene glycol is in a quantity comprised between three and five times by weight the quantity of said second polyethylene glycol.

Preferably, said first polyethylene glycol has a mean molecular weight of <NUM> Dalton.

Preferably, said second polyethylene glycol has a mean molecular weight of <NUM> Dalton.

Preferably, said water solution comprises <NUM> to <NUM>%, more preferably <NUM> to <NUM>% by weight, of honey.

Preferably, said water solution comprises <NUM> to <NUM>%, more preferably <NUM> to <NUM>% by weight of an antimicrobial preservative.

The mean molecular weight values of the polymer species reported in the present description and in the claims were calculated with the international standard method ASTM D4001-<NUM>.

Some examples are provided below for purely illustrative and non-limiting purposes.

Three water solutions were prepared (<NUM> - <NUM>). The first two water solutions (<NUM>, <NUM>) represent the solution of the invention and are distinguished from each other by the presence or absence of honey, while solution <NUM> represents a comparison solution comprising only the high molecular weight PEG.

Table I shows the compositions by weight of the three water solutions in <NUM>µl of distilled water.

In solutions <NUM> and <NUM> of Table I the PEG <NUM> and the PEG <NUM> are present in a % by weight of approximately <NUM> and approximately <NUM> respectively.

The two PEG's are marketed by the company BRENNTAG under the commercial name PEG <NUM> and PEG <NUM> FLAKES.

The preservatives are benzyl alcohol, dehydroacetic acid and water.

The honey is marketed by the company ACEF under the commercial name WILDFLOWER HONEY.

The above water solutions were produced by the following procedure:
The PEG <NUM> in flakes was poured into a melter and thermostatted to a temperature of <NUM> until a clear uniform solution was obtained. For solutions <NUM> and <NUM>, the liquid PEG <NUM> was added to the PEG <NUM> solution produced as described above. For all three solutions, the stirring system was activated for <NUM> minutes. For solution <NUM>, the honey was dissolved in water in a dissolution apparatus by applying a temperature of <NUM>. The honey solution prepared as described was added to the solution of PEG <NUM> and PEG <NUM> previously prepared, keeping the resulting solution under stirring for <NUM> minutes. Lastly, the preservative was added and the solution was kept under stirring for a further <NUM> minutes.

The viscosity of the water solutions <NUM> and <NUM> was measured and it was found that the presence of low molecular weight PEG increases the viscosity. The measurement was taken with an S02 type rotor at a value of <NUM> RPM. Table II shows the viscosity values identified.

The three water solutions reported in Table I were tested to verify their effectiveness in the treatment of constipation. For comparison, the same tests were repeated using 100µl of pure glycerol (Comp. ) (<NUM>% OP (official pharmacopoeia) grade). The glycerol is marketed by the company BRENNTAG under the commercial name VEGETABLE GLYCERIN <NUM>% OP.

For a better evaluation of the effects of the above single water solutions, the test was repeated using 100µl of distilled water (Ref.).

The tests used male CD1 mice weighing <NUM>-<NUM> (Charles River, Italy). The animals were kept in cages (<NUM>-<NUM> animals per cage) in standard light conditions (with a light/dark cycle of <NUM> hours), temperature (<NUM> ± <NUM>) and relative humidity (<NUM>% ± <NUM>%), for at least one week prior to the experimental sessions.

Food and water were available ad libitum. Groups of <NUM>-<NUM> animals were used for each experiment.

All the experiments were performed as indicated by Decree-Law <NUM>/<NUM> and by the new EU directives to minimize the number of animals used and their suffering.

The water solutions reported in Table I were used. It should be highlighted that the two solutions of the invention (<NUM> and <NUM>) reported in Table I have the same quantity of PEG <NUM> and PEG <NUM> so as to represent a significant comparison. Furthermore, again to obtain a significant comparison, the comparison solution <NUM> has a quantity of PEG <NUM> equal to the sum of the quantities of PEG <NUM> and PEG <NUM> of solutions <NUM> and <NUM> of the invention.

The animals in the same cage received, rectally, a micro-enema of one specific composition of the above five 100µl compositions (Ref., Comp. , solution <NUM> and solution <NUM>). For each individual cage, the number of faeces was measured after <NUM> and after <NUM>. At the same time, the weight of the wet faeces and of the dry faeces was measured <NUM> after administration and <NUM> after administration.

Table III shows the results of the above tests.

From the values reported in Table III it can be clearly seen that the solutions according to the present invention (<NUM> and <NUM>) are comparable to, if not better than, the glycerol. It was found that, unlike the glycerol, solutions <NUM> and <NUM> do not cause the pain relative to the typical irritating effect of the glycerol.

Furthermore, a comparison of the data relative to solutions <NUM> and <NUM> with the data relative to the comparison solution <NUM> clearly highlights the presence of a synergic action between the PEG <NUM> and the PEG <NUM> which leads to an increase in the viscosity and, consequently, an increase in the pharmacological action (laxative effect). The comparison between the data relative to solutions <NUM> and <NUM> and the data relative to solution <NUM> is extremely significant. In fact, solution <NUM>, although it comprises a greater quantity of the type of PEG (high mean molecular weight) with pharmacologically higher action, is less effective due to the absence of the low molecular weight PEG.

The presence of the low molecular weight PEG (between <NUM> and <NUM> Dalton) is necessary for the effectiveness of the composition.

In fact, the solutions containing only high molecular weight PEG (between <NUM> and <NUM> Dalton) are not viscous enough, with the result that the patient will be obliged to remain in a horizontal position for an excessively long time, to avoid the product leaking from the rectal ampulla. Furthermore, it has been hypothesized that the solutions with such a low viscosity do not remain in contact with the rectal mucosa for a sufficient time to guarantee therapeutic efficacy.

The inventors of the present invention have had the merit of solving the problem with the addition of low molecular weight PEG and predicting the viscosizing effect produced by the low molecular weight PEG from its humectant properties. In this way, it was possible to produce a useful viscosizing effect and improve the therapeutic efficacy of the solution overall. The presence of the low molecular weight PEG considerably improves patient compliance (and therefore also effectiveness) because it requires the patient to rest in a horizontal position for a considerably shorter time, ensuring that the solution, which is more viscous, does not leak out and remains inside the rectum.

However, it has been experimentally proved that a concentration of low molecular weight PEG higher than that claimed entails a reduction in the laxative activity. Furthermore, an excessive quantity of low molecular weight PEG also reduces the technological performance of the product since the micro-enema is unstable at temperatures below <NUM>, thus resulting solid and non-performing.

Furthermore, from the values of Table II it can be seen that the presence of the honey in the solution guarantees an improvement in therapeutic efficacy.

Claim 1:
A rectal-use composition by enema for use in the treatment of constipation, characterized in that it comprises a water solution comprising (a) <NUM> to <NUM>% by weight of a first polyethylene glycol having a mean molecular weight ranging from <NUM> to <NUM> Dalton and (b) a second polyethylene glycol having a mean molecular weight ranging from <NUM> to <NUM> Dalton; said first polyethylene glycol being in a quantity ranging from two to six times by weight the quantity of said second polyethylene glycol; said second polyethylene glycol being present in said water solution in a quantity ranging from <NUM> to <NUM>% by weight.