WO2010003805A1

WO2010003805A1 - Novel therapeutic use of a pharmaceutical composition for the reduction of the number of aberrant crypt foci and for the prevention of colon cancer

Info

Publication number: WO2010003805A1
Application number: PCT/EP2009/057713
Authority: WO
Inventors: Cesar Molinero Egea; Anna Mª ANGUERA VILA; Xavier Llor Farre
Original assignee: Rottapharm, S.L.
Priority date: 2008-07-10
Filing date: 2009-06-22
Publication date: 2010-01-14

Abstract

The present invention relates to the use of a pharmaceutical composition comprising pharmaceutically accepted additives and Plantago ovata seed husk, rich in mucilages, for the preparation of a medicament for the reduction of the number of Aberrant Crypt Foci (ACF) in the colon of patients diagnosed with intestinal polyps and for the prevention of colon cancer.

Description

D E S C R I P T I O N

"NOVEL THERAPEUTIC USE OF A PHARMACEUTICAL COMPOSITION FOR THE REDUCTION OF THE NUMBER OF ABERRANT CRYPT FOCI AND FOR THE PREVENTION OF COLON CANCER"

Technical Field of the Invention

The present invention relates to the use of a pharmaceutical composition comprising pharmaceutically accepted additives and an active ingredient rich in mucilage for the preparation of a medicament for the reduction of the number of Aberrant Crypt Foci (ACF) in patients diagnosed with intestinal polyps.

Background of the Invention

Fibre consumption was higher and fat consumption was much lower in the past than today. In fact, the modern diet of Western cultures has a dietary balance totally different from the diet for which our bodies were prepared. About 150 years ago, the traditional diet was closer to what is currently considered an optimal diet. Since 80-90% of the origin of food was plants, with the consequent high fibre intake, heart diseases or cancer were not very frequent. Today, in the modern societies, this ratio is much closer to 50-60% and cancer or heart diseases are much more common.

Large intestine cancer is currently one of the most common in the Western culture countries. This type of cancer is extraordinarily frequent. Approximately one in fifty people will develop a colorectal cancer throughout his or her life. Colon cancer is a disease in which cancer cells are found in colon tissues.

Although today it is known that an excessive fat consumption plays an important role in the development of colon cancer, the mentality of Western cultures has not changed significantly, therefore it is necessary to find efficient treatments in the prevention of colorectal cancer. The protective effect of fibre on the colorectal cancer was studied for the first time in the 70s, when Burkitt discovered a surprisingly low frequency of colorectal cancer in African populations which consume a considerable amount of fibre. Since then, several correlation and control studies attempt to demonstrate this possible beneficial effect. Based on the large amount of studies conducted, the American Gastroenterological Association (AGA) recently concluded that dietary fibre consumption has a significant effect against colorectal cancer. In 2006, an in vitro study with colorectal cancer cells complemented with the products obtained from the fermentation of Plantago ovata seed husk, called Plantaben®, with human gut flora, showed an effect of Plantaben® against the development of colorectal cancer through two processes, which play an important role in the growth of a tumour: Plantaben® intensely induces apoptosis (cell death) of the studied cancer cells (Caco-2 and HT-29) and furthermore has important antiproliferative effects on the HT-29 cells (Giros et al, "Antineoplastic effects on colorectal cancer cells of Plantago ovata husk after fermentation with human gut flora", Digestive Disease Week/ESPEN Meetings May 2006 and Giros et al, "Antineoplastic effects on colorectal cancer cells of Plantago ovata husk and its interaction with 5-FU according to different molecular features", Digestive Disease Week/ESPEN Meetings May 2007).

Different mechanisms of action of the fibre for exerting a beneficial effect in the treatment of colorectal cancer are postulated; firstly, since the bowel transit time decreases, the potential carcinogens are in contact with the intestinal walls for less time; since the volume of faeces increases, the carcinogens are more diluted; and finally, since the faecal pH decreases, the transformation, by bacteria, of normal faecal constituents into possible carcinogens is prevented. In any case, it is difficult to differentiate the effects derived from fibre consumption through other anticancer elements present in nutritive substances rich in fibre such as vegetables, fruits, cereals, and seeds. It is possible that some interactions exist that are still not known between the nutritive substances and fibre, which lead to this protective effect. In addition, investigators attempt to obtain specific advances in the treatment of cancer in a more premature or early phase of the disease. In this context, Aberrant Crypt Foci (ACF) have been identified as early histological lesions in the sequence of adenoma to carcinoma, therefore it is suggested that they can be used as biomarkers useful for colon cancer. ACF are the first preneoplastic lesions which can be found in mouse colons after an exposure to carcinogens (McLellan EA, "Aberrant crypts: potential preneoplastic lesions in the murine colon", Cancer Res 1988; 48:6187-92). The same lesions have also been observed in surgical examinations of human colons with cancer and by means of the use of magnifying chromo-endoscopies in human colons with polyps (Yokota T., "Detection of aberrant crypt foci by magnifying colonoscopy", Gastrointest Endosc 1997; 46:61-5), which allows establishing their correlation with macroscopic neoplasms. As a result, ACF have been identified by some as colorectal cancer precursors in both humans and animals (Roncucci L., "Aberrant crypt foci in colorectal carcinogenesis. Cell and crypt dynamics", Cell Prolif 2000; 33:1-18). Several studies on the effects, in particular, of Psyllium for the reduction of the number of Aberrant Crypt Foci, such as for example that detailed in the publication Scand J Gastroenterol. 2006 Jun; 41(6):730-6, have been conducted simultaneously. However, this study concludes that the use of Psyllium, by itself, has no significant effect to prevent the development of Aberrant Crypt Foci and as a result for the prevention of colon cancer. The publication Cancer Letters 1993 Nov 30; 75(1):53-8, also considers that a treatment based on Psyllium alone does not introduce any significant difference in the subsequent development of tumours related to colorectal cancer.

Disclosure of the Invention

Based on a recent clinical study, it has first been confirmed that there is a relationship between the number of Aberrant Crypt Foci (ACF) and adenomatous polyps (internal data of the University of Illinois, Chicago), as well as a relationship between the population affected with colon cancer in humans depending on the age, the presence of this type of adenomas and other risk factors such as tobacco (internal data of the University of Illinois, Chicago). Secondly, it has been possible to establish a significant relationship between daily amounts of fibre consumption greater than 15g/day with a lower presence of the number of ACF.

All of this has led to conducting more detailed assays until surprisingly proving that the consumption of a specific type of fibre, Plantago ovata seed husk, also called Plantago ovata husk or lspaghula husk in the literature, significantly reduces the number of ACF in patients with at least 10 ACF in the left part of the colon in the initial visit.

Therefore, an object of the present invention is the use of Plantago ovata seed husk for the preparation of a medicament for the reduction of the number of Aberrant Crypt Foci in the human colon.

Another object of the present invention is the use of Plantago ovata seed husk for the preparation of a medicament for the prevention of colon cancer.

Said medicament or pharmaceutical composition contains Plantago ovata seed husk for the reduction of the number of Aberrant Crypt Foci in the human - A - colon. The administration to a patient of a composition containing Plantago ovata seed husk forms part of a method for the reduction of the number of Aberrant Crypt Foci and for the prevention of cancer.

Detailed Disclosure of the Invention

The unexpected effect of the composition based on Plantago ovata seed husk lies in the fact that, up until now, it was considered that Psyllium did not have any significant effect to prevent the development of the Aberrant Crypt Foci. In this sense, it is essential to point out that the term "Psyllium" used in the documents representative of the state of the art is confusing, since this term has been used frequently in the literature to designate both the plant "Plantago psyllium" and the plant "Plantago ovata", which are two different medicinal plants, although they belong to the same plant family, the Plantaginaceae. In any case, the specific use of Plantago ovata seed husk for the preparation of a medicament for the reduction of the number of Aberrant Crypt Foci in the human colon is not described in the literature.

It should be emphasized that, in the databases on medicinal plants of the Consejo General de Colegios Oficiales de Farmaceuticos (General Spanish Council of Official Pharmacist Associations), the two species, Plantago ovata and Plantago psyllium are classified independently. Both species belong to the therapeutic group PA06 (laxative medicinal plants) but their composition is different, since Plantago psyllium seeds contain only from 10 to 12% of mucilages and can absorb up to 10 times their weight in water (European Medicine Agency, Doc. Ref. EMEA/HMPC/340865/2005), whereas Plantago ovata seed husk contains about 85% of water-soluble fibres or mucilages, and can absorb up to 40 times its weight in water (European Medicine Agency, Doc. Ref. EMEA/HMPC/340857/2005).

Thus, although it can be interpreted that it is described that the use of the plant Plantago ovata, by itself, has no significant effect for preventing the development of Aberrant Crypt Foci, the inventors have maintained this research line and have discovered that different parts of the plant Plantago ovata, such as the seed husk, has a non-expected effect for reducing the number of ACF in the human colon.

Table 1 shows the result of the assays which lead to establishing a relationship between the presence of ACF, adenomas and colon cancer, based on which it is inferred that the reduction in the number of ACF is an interesting route for the prevention of colon cancer.

Table 1 : Relationship between ACF, adenomas and colon cancer

Likewise, Table 2 shows the results concluding the relationship existing between the daily minimum fibre consumption and the number of ACF developed.

Table 2: Relationship between fibre consumption and the number of ACF devel- oped.

P<0.05 h H

The results of Table 2 show that the total daily fibre consumption allows reducing the number of ACF with a significantly reduced number of ACF in patients who consume more than 15g of fibre a day. An example of the pharmaceutical composition comprising Plantago ovata seed husk as an active ingredient is detailed below.

Example 1: The attached Table 3 details the ingredients making up the pharmaceutical composition according to the invention. Specifically, the ingredients and the amounts of a single-dose sachet of approximately 5 grams are listed.

Table 3: Powdered pharmaceutical composition in the form of single-dose sachets.

The composition of Example 1 corresponds to a pharmaceutical preparation for oral administration, specifically it is provided in the form of a sachet.

Although in this Example 1 the single-dose sachets contain 5 grams of pharmaceutical composition, it is evident that this amount can be varied depending on the presentation which is to be manufactured and/or marketed.

Acidifiers, diluents, flavourings and sweeteners among others already known by the person skilled in the art, which can at the same time fulfil several of these functions due to their own chemical nature, are contemplated as pharmaceutically accepted excipients.

For their correct administration, it is indicated that the content of the sachet be dispersed in a glass of water or other beverages, i.e., in approximately 200 ml_.

The recommended dose of this fibre composition for this indication is at least 10.5 g/d, i.e., 3 single-dose sachets of 5 grams of product, distributed in 3 administrations.

Claims

C L A I M S

1 .- Use of a pharmaceutical composition comprising Plantago ovata seed husk for the preparation of a medicament for the reduction of the number of Aberrant Crypt Foci (ACF) in the human colon.

2.- Use of a pharmaceutical composition comprising Plantago ovata seed husk for the preparation of a medicament for the prevention of colon cancer.