WO2000048577A1

WO2000048577A1 - Medicament for the treatment and prevention of cancer of the intestine

Info

Publication number: WO2000048577A1
Application number: PCT/EP2000/000549
Authority: WO
Inventors: Norbert Otterbeck
Original assignee: Dr. Falk Pharma Gmbh
Priority date: 1999-02-15
Filing date: 2000-01-25
Publication date: 2000-08-24
Also published as: DE19906290A1

Abstract

The invention is based on the surprising discovery that topically administered ursodesoxycholic acid can be used in the prevention and treatment of colon cancer. The invention thus relates to a medicament which is formulated such that the ursodesoxycholic acid is not released until said medicament reaches the terminal ileum and/or colon, so that only little of the active ingredient is resorbed and said active ingredient does not act systemically but topically, directly at the site of release.

Description

Medicines for the treatment or prevention of colon cancer

The invention relates to pharmaceuticals, in particular pharmaceuticals with a controlled release profile, with ursodeoxycholic acid (UDCA), pharmaceutically acceptable salts or derivatives thereof as an active ingredient. The drugs are used to treat or prevent cancer of the large intestine. In contrast to already known UDCA-containing medicaments, the active substance in the medicaments according to the invention is only released in the terminal ileum and / or large intestine, preferably in a controlled manner, so that the active substance is only slightly absorbed. According to the invention, UDCA thus does not act systemically but topically directly at the site of the release.

The positive effects of UDCA and Tauro-UDCA in the prevention of colon cancer in animal models or in cell culture have already been described several times (Earnest et al., Cancer Res. 1994: 54: 5071-5074; Batta et al., Gastroenterology 1995: 108, Vol. 4: 405; Shekels et al., J. Lab. Clin. Med. 1996: 57-66).

Pharmaceutical formulations containing UDCA with a controlled release profile are known in the prior art (US 5,234,697, US 5,352,460, US 5,405,621, US 5,415,872). The pharmaceutical forms described there are described as being suitable both for the treatment of liver diseases and for the prevention of colon cancer. Since the active substance for the treatment of liver diseases has to be absorbed from the intestine in order to be able to reach the site of action, the release is controlled in such a way that the active substance is quickly released in the duodenum shortly after leaving the stomach. Since UDCA is very effectively absorbed in the duodenum, high plasma levels are achieved with the pharmaceutical formulations described there, so that none or only a small part of the UDCA passes into the large intestine.

WO 97/34608 describes the use of UDCA and a non-steroidal anti-inflammatory active ingredient to prevent the reappearance of colorectal adenomas. In addition to parenteral formulations, orally administrable formulations in liquid or solid form are also described, the latter also being able to be enteric-coated, so that the active compounds are systemically active either directly or after absorption in the stomach or upper small intestine.

This prior art thus teaches a systemic effect of UDCA in the prevention of colon cancer.

Another pharmaceutical formulation with a controlled release profile of UDCA has been described in Roda et al., Pharm. Res. 1994: 11 (5): 642-7. The pharmaceutical formulation described there was produced in accordance with EP 0 510 404. It releases UDCA in the small intestine very early, so that high plasma levels are also achieved.

EP 0 510 404 describes pharmaceutical formulations containing salts of bile acids which are coated with two layers. The first layer, consisting of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and talc serves as an auxiliary layer to ensure optimal application of the second layer. The second layer consists of an enteric coating. With the help of these formulations, an absorption of the active substances which is approximately 40% higher than that of non-coated formulations can be achieved. For this reason, these formulations are particularly suitable for the treatment of liver diseases and the dissolution of gallstones, since the highest possible absorption of the active ingredient is desired for the treatment of these diseases.

WO 97/18816 describes derivatives of UDCA (e.g. UDCA-3 sulfate, UDCA-7 sulfate, UDCA-3, 7 disulfate), which are also said to be suitable for the prevention of colon cancer. Here, absorption in the small intestine is prevented by the sulfation of the hydroxyl groups at position 7, so that the majority of the UDCA derivatives reach the large intestine. It has not yet been investigated whether these UDCA derivatives have a positive effect on colon cancer prevention.

Successful treatment or prevention of colon cancer requires long-term use of the drug. The active ingredient should be dosed as low as possible to prevent side effects of long-term therapy that cannot be ruled out. Therefore, there is a great need to develop drugs that can be used safely and inexpensively even with long-term therapy. The object of the invention is therefore to provide medicinal products for the treatment or prevention of colon cancer which do not have the disadvantages of the prior art.

According to the invention, this object is achieved by a medicament, in particular by a medicament with a controlled release profile, which contains UDCA, a pharmaceutically acceptable salt or a derivative thereof as the active ingredient characterized in that the drug comprises from the inside out:

a) an active substance-containing core which is designed such that the active substance is released in the terminal ileum and / or in the large intestine and

b) an enteric coating.

The medicament is advantageously either designed so that it has an active substance-containing core in which the active substance is homogeneously distributed and which is surrounded by a release-controlling layer or, particularly preferably, that the active substance-containing core is a matrix core in which the active substance is in a matrix polymer is embedded. In this second embodiment with a matrix core, the presence of a release-controlling layer is optional.

Since UDCA is not or only very slightly absorbed in the terminal ileum and large intestine, the active ingredient comes into direct contact with the tissue to be treated through the release-controlling polymer matrix in the core and / or the release-controlling layer between the core and enteric coating act so topically, that is, not via the bloodstream.

According to the invention, the use of UDCA, a pharmaceutically acceptable salt or a derivative thereof for the topical treatment or prevention of colon cancer is also made available, that is to say to a large extent excluding the systemic effect.

According to the invention, methods for the production of such pharmaceuticals are also made available.

While it is known in the art that UDCA, when administered systemically, is used to prevent Colon cancer can be used, the prior art does not describe a UDCA-containing pharmaceutical formulation that only releases the active ingredient in the large intestine and is therefore topical due to the very low absorption in the large intestine.

The term large intestine in the context of this description refers to the cecum, the ascending colon, transverse colon, descending colon, the sigmoid and the rectum.

Surprisingly, it has now been found that UDCA is not only systemically effective in the treatment or prevention of colon cancer, but that UDCA is also extremely effective when administered topically in the colon. A systemic effect does not occur or only to a very small extent, since in the areas in which the active substance is released no or only small amounts of the active substance are absorbed. According to the invention, the effectiveness of UDCA is directly related to its concentration in the large intestine. Due to the topical administration and the greatly reduced absorption of the active ingredient, possible side effects, which are necessary after a very long period of use, as is necessary for treatment or prevention therapy.

The medicaments according to the invention contain UDCA or a pharmaceutically acceptable salt or derivative thereof as the active ingredient.

The pharmaceuticals according to the invention do not release the active ingredient in the stomach or upper part of the small intestine, but only in the terminal ileum and / or large intestine, so that as little as possible of the active ingredient is absorbed and thus the highest possible concentration of the active ingredient in the large intestine is achieved. According to the invention, the release of the active ingredient in the terminal ileum and / or large intestine is achieved in that it releases the active ingredient in a delayed or controlled manner.

According to the invention, the medicament is preferably formulated as tablets or pellets which are coated with an enteric lacquer and / or a release-controlling layer, so that an early release of the active ingredient is prevented. The pellets can in turn be filled into gelatin capsules or pressed into pellet tablets.

Methods are known in the prior art of how tablets or pellets can be formulated such that they release their active ingredient locally in the terminal ileum and / or large intestine. In principle, all of the techniques known in the art for making such sustained or controlled release tablets or pellets can be used to make the topical drugs of the present invention.

WO 92/14452 describes granules which consist of an active substance-containing core which is coated with (meth) acrylate and / or (meth) acrylic acid lacquers. These granules are filled into gelatin capsules and the glatin capsules are then coated with these varnishes so that they are enteric-coated.

WO 91/16042 describes granules with a diameter of not more than 5 mm, which are covered with two shells. One shell consists of a polymer which is soluble as a function of the pH and dissolves at a pH greater than 5.0, and the second shell consists of one or more polymers which are insoluble or only slightly soluble in gastrointestinal fluid. With these formulations, the active substances can be released in the small and / or large intestine. WO 91/07949 describes pharmaceutical formulations which contain an active ingredient and amorphous amylose in a core which is coated with a film-forming cellulose or another polymer. This ensures that the active ingredient is released in the large intestine.

EP 0 621 032 describes active substance-containing cores which are coated with a release-delaying layer, an overlying semi-permeable layer and optionally with an outer layer made of an enteric coating, so that the active substance is only released in the large intestine.

The formulations according to the invention are coated with an enteric coating. This coating should only dissolve after the formulation has left the stomach. Corresponding coatings are described in the prior art, for example in the above publications. Enteric coatings which are composed of polymers or copolymers derived from (meth) acrylates are particularly preferred.

Since the entire colon should come into contact with the active ingredient for the treatment or prevention of colon cancer, a pellet formulation is particularly preferred according to the invention since, in contrast to a tablet formulation, it reproducibly spreads the active ingredient over large areas of the large intestine. In order to bring the largest possible area of the colon into contact with active substance, mixtures according to the invention from two or more pellet formulations with different release behavior in a mixture ratio suitable for the treatment or prevention of colon cancer are particularly preferred. For example, a pellet type whose active ingredient release already begins in the terminal ileum can be combined with a pellet type whose active ingredient release only begins in the transverse colon, mixed and filled into a gelatin capsule or pressed in a pellet tablet.

Particularly preferred embodiments of the invention, as set out in the references mentioned above and in the examples below, are as follows:

An orally administrable pellet formulation in which the active ingredient is embedded in the pellet core in a polymer matrix is particularly preferred. Suitable polymers which form the matrix are all polymers known in the prior art and usable for this purpose (K.H. Bauer K.-H. Frömming, C. Führer: Pharmaceutical Technology, Georg Thieme Verlag Stuttgart, New York (1989)). The matrix-forming polymer is preferably selected from the group consisting of poly (ethyl acrylate, methyl acrylate) and poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride). Such copolymers are, for example, the commercial products Eudragit NE 30 D and Eudragit NE 40 D.

Those pellet formulations are particularly preferred in which a further layer of water-soluble cellulose derivatives such as, for example, is located between the active substance core and the enteric layer

Hydroxypropylmethylcellulose, methylcellulose, sodium carboxymethylcellulose or ethylcellulose «and / or depending on the pH value soluble polymers of acrylic acid (carbomers).

The enteric coating of the tablets or pellets is preferably based on water-insoluble and / or pH-dependent water-soluble polyacrylates. Suitable polyacrylates are e.g. Poly (ethyl acrylate, methyl acrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2,

Poly (ethyl acrylate, methyl methacrylate, trimethylammonio methacrylate chloride) 1: 2: 0.1. By varying the composition of the core components and / or the composition and thickness of the layer between the core and the enteric coating, the controlled release profile can be varied in a manner known per se to the person skilled in the art so that after reaching the terminal ileum or the colon, the active ingredient for Example is released immediately or evenly over a certain period of time.

In addition to the special auxiliaries mentioned above, the medicaments according to the invention can contain further customary auxiliaries and excipients, as are known in the prior art and are described, for example, in K.H. Frömming, C. Führer: Pharmaceutical Technology, Georg Thieme Verlag Stuttgart, New York (1989).

Because it has been found according to the invention that the pharmaceutical formulations described above allow topical use of UDCA and thus the active substance is only released specifically in the terminal ileum and / or large intestine, it is possible with the medicaments according to the invention for treatment or prevention of the colorectal cancer to reduce the necessary amount of active ingredient. A significant advantage of the specific release in the terminal ileum and / or large intestine is that even with an undiminished amount of active ingredient, the absorption of the active ingredient takes place only to a very small extent and thus side effects that could occur if the medication was taken over a very long time. be reduced.

The pharmaceuticals according to the invention can therefore contain the active ingredient in an amount as is also present in the already known UDCA-containing pharmaceuticals. If necessary for the treatment or prevention of colon cancer, a higher amount of UDCA than previously described can also be used due to the very low absorption due to the formulation according to the invention. The preferred dosage of the medicinal substances when administered by the medicaments according to the invention is 1 to 100 mg / kg of body weight per day, particularly preferred are 5 to 50 mg / kg of body weight per day. Accordingly, a single dose of the medicament according to the invention preferably contains 100 mg to 1000 mg, particularly preferably 150-500 mg, of active ingredient.

The invention is illustrated by the examples below.

example 1

1.) Example for matrix pellet cores:

I UDCA 250 g II sodium bicarbonate 100 g III sodium carbonate 50 g IV starch 50 g V poly (ethyl acrylate, methyl methacrylate) 50 g 2: 1 as a 40% aqueous dispersion, trade name Eudragit NE 40 D VI magnesium stearate 20 g

I-IV are mixed and moistened with V and kneaded intensively. VI is then sprinkled in. The moist mass is pressed through an extruder with the die hole 1 mm, cut into pieces approx. 1 mm long and rounded in a spheronizer. The pellets are dried at approx. 60 ° C.

The pellets are coated with a solution of 30 g hydroxypropylmethyl cellulose in 300 ml water (protective cover).

The pellets are coated with the following solution gastro-resistant:

I poly (methacrylic acid, methyl methacrylate)

1: 2; Trade name Eudragit ⁵ S; (Methacrylic acid copolymer, USP / NF Type B) 35. 0 g

II triethyl citrate 3. 5 g

III Talk 10. 0 g

IV titanium dioxide 12. 5 g

V Magnesium stearate 5. 0 g I is dissolved in 350 g of an ethanol / water mixture (8: 2). II-V are suspended in the solution; The paint suspension is sprayed on in a suitable apparatus at a supply air temperature of 40 ° C.

Example 2

Example of a release-controlled tablet formulation

I UDCA 250 g

II sodium hydrogen carbonate 100 g

III sodium carbonate 50 g

IV strength 50 g

V poly (ethyl acrylate, methyl methacrylate) 50 g

2: 1 as a 40% aqueous dispersion,

Trade name Eudragit NE 40 D

VI magnesium stearate 20 g

I-IV are mixed and moistened with V and kneaded intensively. VI is then sprinkled in. The moist mass is passed through a sieve with a mesh size of 1 mm. The resulting granulate is dried at approx. 60 ° C.

The granules are used as the outer phase

Wheat starch 50 g

Magnesium stearate 5 g mixed.

The mixture is pressed into tablets of 545 mg. The

Tablets are first made with a solution of 20 g

Hydroxypropylmethylcellulose coated in 200 ml of water (protective cover).

The tablets are then coated with the following solution, gastro-resistant:

I poly (methacrylic acid, methyl methacrylate)

1: 2; Trade name Eudragit ^" S; (Methacrylic acid copolymer, USP / NF Type B) 35.0 g

II triethyl citrate 3. 5 g

III Talk 10. 0 g

IV titanium dioxide 12. 5 g

Claims

Claims:

1. Medicament for oral administration, which contains UDCA as the active ingredient, a pharmaceutically acceptable salt or a derivative thereof, characterized in that the medicament comprises from the inside out:

b) an enteric coating.

2. Medicament according to claim 1, characterized in that the active substance-containing core contains the active substance distributed homogeneously and is surrounded by a release-controlling layer.

3. Medicament according to claim 1 or 2, characterized in that the active substance-containing core is a matrix core in which the active substance is embedded in a matrix polymer.

4. Medicament according to one of claims 1 to 3, characterized in that the enteric coating comprises polymers or copolymers which are derived from (meth) acrylates.

5. Medicament according to one of claims 3 to 4, characterized in that the matrix-forming polymer is poly (ethyl acrylate, methyl acrylate) and / or poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride).

6. Medicament according to one of claims 1 to 5, characterized in that the release-controlling layer water-soluble cellulose derivatives and / or polymers of acrylic acid (carbomers) which are soluble depending on the pH.

7. Medicament according to claim 6, characterized in that the water-soluble cellulose derivative is hydroxypropylmethyl cellulose, methyl cellulose, sodium carboxymethyl cellulose or ethyl cellulose.

8. Medicament according to one of claims 1 to 7, which is formulated in such a way that it has a controlled release profile, so that the active ingredient is immediately released completely or evenly over a certain period of time.

9. Medicament according to one of claims 1 to 8, characterized in that it is a pellet formulation.

10. Medicament according to claim 9, characterized in that it is a gelatin capsule or pellet tablet containing pellets according to one of claims 1 to 8.

11. Medicament according to claim 10, characterized in that the gelatin capsule or pellet tablet contains a mixture of 2 or more pellet formulations according to claims 1 to 7 with different release behavior.

12. Medicament according to one of claims 1 to 8, characterized in that it is a tablet formulation.

13. Use of UDCA, a pharmaceutically acceptable salt or derivative thereof, for topical treatment or prevention of colon cancer.

14. A method for producing a medicament according to one of claims 1 to 12, characterized in that a Drug core is coated with UDCA, a pharmaceutically acceptable salt or a derivative thereof in a manner known per se with an enteric coating and, if appropriate, a release-controlling layer.