DE19850445A1 - Medicines for the topical treatment of inflammatory bowel disease - Google Patents

Abstract

Disclosed is a medicament containing a medicinal substance selected from the groups consisting of antiprotozoan substances, quinolone antibiotics, the group of the macrolide antibiotics, the group of antituberculosis agents or the group of chemotherapeutic agents consisting of a combination of sulfonamides and folic acid reductase inhibitors or a mixture thereof. The medicament is particularly suitable for the treatment of inflammatory intestinal diseases. Unlike known medicaments used in the treatment of inflammatory intestinal diseases containing a pharmaceutical substance from the above-mentioned groups, the medicament according to the invention has a coating that is resistant to gastric juice so that its effects are topical and not systemic.

Description

The invention relates to drugs with an antiprotozoal effective drug. The medicines are for treatment of inflammatory bowel disease. Contrary to known Medicaments with active against protozoa drugs in the case of the medicaments according to the invention the medicament controlled released so that he is not systemic but Topically acts directly on the site of inflammatory bowel disease.

Drugs effective against protozoa are known known to the art. Here, in particular, 5- Nitroimidazole derivatives are referred to, for. On azanidazole, Nimorazole, Oridazole, Propenidazole, Secnidazole, Ternidazole, Tinidazole and especially metronidazole. Such drugs and in particular metronidazole are used to treat used microbial infectious diseases, and in this Connection are also tablet formulations with modified release profile described. So can For example, refer to WO 95/20383, the Metronidazole tablet formulations with modified Release profile disclosed. The sharing profile is chosen that the active ingredient as completely as possible in the stomach and upper  Small intestine area is released. The funds should used in particular for controlling stomach ulcers become. WO 95/20383 does not concern intestinal Diseases such as inflammatory bowel disease, such as For example, ulcerative colitis and Crohn's disease.

Tablet formulations that are an enteric-coated Have coating are not disclosed in WO 95/20 383, im On the contrary, the tablet formulations of WO 95/20383 are intended just dissolve in the gastric juice.

The treatment of intestinal diseases such as Ulcerative colitis and Crohn's disease with agents that Fight protozoa, especially with metronidazole and its pharmaceutically acceptable salts, is known, though not undisputed. For the first time, this will be in "The Lancet", 1975, 775, reported. In this connection can also on Gastroenterology 108, 1995, 1617-1621. To recent studies appear to be certain that metronidazole in a daily dose of 10 to 20 mg / kg body weight the treatment of inflammatory bowel disease is successful, with a low dosage of 10 mg / kg body weight per day, however, as less effective has proven (Good 32, 1991, 1071-1075). A disadvantage However, especially the higher dosages is the occurrence of significant side effects such as gastrointestinal Disorders, headache, ataxia, encephalopathy, etc. (Gastroenterology 83, 1982, 383-387). Beyond that stands Metronidazole suspected of having a carcinogenic potential too have (Excerpta Medica, 1976, 138-141).

Since metronidazole in the oral administration of the state of the Technology is fully and rapidly absorbed, teaches the The prior art has a systemic effect of metronidazole in chronic intestinal diseases.

A successful treatment of chronic inflammatory Bowel disease requires a continuous intake of the Drug over a very long period of time. Therefore, there is one  significant need to develop drugs, too can be used in a long-term therapy and at which are the side effects and difficulties with the Drugs of the prior art occur reduced are. The object of the invention is therefore to medicaments for Treatment of inflammatory bowel disease, in particular for the treatment of ulcerative colitis and morbus Crohn, to provide the disadvantages of Medicaments of the prior art do not have.

These objects are achieved by a drug according to the invention solved, which is a drug effective against protozoa, in particular metronidazole, contained in a nucleus with an enteric coating is coated. According to the invention, the use of a against protozoa effective drug, in particular metronidazole, for topical treatment or prevention of inflammatory Bowel disease provided. According to the invention are also methods for the preparation of such drugs Provided.

If in the context of this description of drugs are spoken that are effective against protozoa are preferred 5-nitroimidazole derivatives, especially preferred are azanidazole, nimorazole, oridazole, propenidazole, Secnidazole, ternidazole, tinidazole and metronidazole, and am Most preferred is metronidazole.

While it is known in the art that active ingredients, the are effective against protozoa, such as metronidazole, at systemic administration for treatment chronic inflammatory bowel disease such as ulcerative colitis and Crohn's disease can be used in the state of Technique topical use of such against protozoa effective substances not described. Other than one Systemic use can be a topical or local application naturally include only a small part of the intestine.  

Surprisingly, it has now been found that for the treatment of inflammatory bowel disease such as ulcerative colitis and Crohn's disease against protozoan active substances, in particular Metronidazole, not only can be used systemically, but that such substances even with topical administration have excellent effectiveness. especially the preferred compounds of the invention as above defined and especially metronidazole therefore also act locally, that is by the contact of the active ingredient directly at the place of Disease in the intestine. A systemic effect takes place here not or only to a small extent, as in the inflammatory Intestinal areas where the active ingredient is largely released is, at best, low levels of the drug absorbed become. The effectiveness of the drug, in particular the Metronidazole in topical administration according to the invention is in direct relation to its local concentration on intestine area to be treated. By topical administration may be the concentration of the drug in the drug be significantly reduced. In particular, the Concentration of the active substance in the body, which is the significant Causes adverse effects, since the active substance, especially metronidazole no longer or only in very much is slightly absorbed through the intestine into the blood.

Such a topical effectiveness of substances that are against Protozoa are effective and in particular of metronidazole at the treatment of inflammatory bowel disease, in particular of ulcerative colitis and Crohn's disease, is in the state of Technique not previously described and surprising.

The medicaments according to the invention contain as active ingredient a substance effective against protozoa as above Are defined. This is according to the invention also a pharmaceutically acceptable salt or a pharmaceutical compatible derivative of such a substance understood. This should explicitly include so-called prodrugs, that is, compounds that are not themselves against protozoa are effective, but in vivo converted into a substance  be effective against protozoa. Suitable active ingredients, which are effective against protozoa, are known in the art. Such agents are commercially available or can be obtained by Standard methods of chemistry are produced. Especially Preferably, the drugs contain the present Invention the active ingredient metronidazole or a pharmaceutical acceptable salt thereof or a prodrug thereof.

It is essential to the invention that the medicaments are formulated in this way be that they are not already in the stomach or the drug release upper small intestine area, thereby already a Most of the drug would be resorbed before leaving the site Can reach inflammation. In particular, the active ingredient Metronidazole becomes rapid in the intestine and upper small intestine area absorbed and therefore acts in a conventional administration, as described, for example, in WO 95/20 383 (but in US Pat another context) is described in inflammatory Intestinal disease only systemic and not topical.

According to the invention, the local release of the Active ingredient achieved by the drug so formulates that it retards or controls the active ingredient releases. The invention is particularly preferred Medicines formulated as tablets or pellets with are coated with an enteric varnish, so that a early release of the active ingredients is prevented.

In the prior art, a variety of methods are known how tablets and pellets can be formulated so that they release their active ingredient locally in the intestinal area. Usually Such drugs are formulated to be derived from a consist of active ingredient-containing core, with a gastric juice-insoluble coating is coated. Basically can all known in the art techniques for Preparation of such tablets or pellets with delayed or controlled release used to control the topically acting drugs of the present invention manufacture.  

In particular, for example, to FR-A 2 692 484 refer to a tablet with a hydrophilic Matrix revealed. The tablet is made of water-soluble swelling slowly eroding cellulose derivatives and a enteric coating. After dissolution of the coating swells the matrix very much and forms a gel barrier through which the active ingredient diffuses out. The corresponding The medicaments prepared according to FR-A 2 692 484 use the Active substance in the intestine after about 2 hours lag phase a period of a further 14 hours linearly free.

The medicaments according to the invention can also according to EP-A 0 453 001 are produced. EP-A 0 453 001 discloses Medicines in which the active substance contains at least two Membranes coated, one of which at a pH of 5.5 Soluble, the other insoluble in this pH but for the Intestinal fluid is permeable.

Another suitable tablet composition is disclosed in EP-A 0 148 811 and consists of a core containing the active ingredient and surrounded by two layers. The inner of these two layers represents a diffusion membrane, the outer of the two layers is an anionic polymer and / or a fatty acid having a pK _a of 4.5 to 7.

Also EP-A 0 629 398 discloses pharmaceutical Compositions in which a drug-containing core of is surrounded by an enteric phase. The core can for example, small amounts of hydroxypropylcellulose contain. After dissolving the enteric-coated phase should the drug can be released quickly.

Finally, reference is made to EP-A 0 485 840, which also discloses an oral dosage form in which a Active core is enclosed by a shell material. The Covering material consists of a polysaccharide and a film-forming polymer material.  

Preferred according to the invention are those medicaments which coated with an enteric coating. The enteric coating should dissolve only after the formulation has left the stomach. Appropriate Coatings are in the prior art, for example from the above pamphlets known. Particularly preferred the coatings as described in EP-A 453 001.

Because inflammatory bowel disease often involves larger sections of the Involved intestinal tract is, according to the invention a Pellet formulation particularly preferred because they unlike a tablet formulation the drug form reproducible about wide areas of the intestine spreads. To the invention to achieve required local drug concentration must the drug at the site of inflammation within a relatively short time (a few hours) are released. Therefore, such are Delayed or controlled release drugs preferred, the drug within a short time, preferably within hours, most preferably within six hours, largely complete (more than 75%) release.

The medicaments according to the invention are generally topical Treatment of intestinal diseases, preferably of inflammatory bowel disease, suitable. You can both in the active phase as well as in the remission phase (period be used before the recurrence of the disease) and also serve to prevent the diseases, to prevent the recurrence of the diseases and the treatment or the prevention or prevention of the recurrence of arising consequential diseases as well as possible Concomitant diseases such as primary sclerosing cholangitis (PSC). Particularly preferred is the use of the against Protozoa effective substance or the pharmaceutical compatible salt thereof or a prodrug thereof and in particular metronidazole or a pharmaceutical compatible salt thereof for the treatment of inflammatory Intestinal diseases such as Crohn's disease and ulcerative colitis or  for the manufacture of a medicament for the treatment of these Diseases.

Particularly preferred embodiments of the invention, which can be prepared, as in the above References and the examples below is, are as follows:

Particularly preferred is an orally administrable Pellet formulation in which the active ingredient in the pellet core in embedded in a polymer matrix. The matrix-forming Polymer is preferably selected from the group consisting of Poly (ethyl acrylate / methyl methacrylate) and poly (ethyl acrylate / methyl methacrylate / trimethylammonioethyl methacrylate chloride). Such a copolymer is, for example, the commercial product Eudragit® N 30. Corresponding pellet formulations and Processes for their preparation are in the international Patent Application PCT / EP 98/02319. Especially preferred makes the matrix-forming polymer at least 5 wt .-% of Total weight of the core.

Particularly preferred are also those Pharmaceutical formulations in which between the active ingredient-containing core and the enteric coating a swellable diffusion layer is located. Such medicines and their preparation are described in EP-A 453 001 and in EP-A 0 148 811 described. Particularly preferred According to the invention, such drugs in which the Diffusion layer of cellulose derivatives and / or pharmaceutically acceptable gums such as xanthan gum, tragacanth, Gum arabic and pectin exist or such products contains.

Likewise preferred according to the invention are pellet formulations, in which between core and enteric coating a liquid permeable envelope is located. This shell preferably consists of water-insoluble and / or pH-dependent water-soluble polyacrylates. Suitable polyacrylates are  z. As poly (methacrylic acid, methyl methacrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2, poly (ethyl acrylate, methyl methacrylate, trimethylammino methacrylate chloride) 1: 2: 0.2 and poly (ethyl acrylate, methyl methacrylate, trimethylammino methacrylate chloride) 1: 2: 0.1. Appropriate Pellet formulations and their preparation are for. From K.H. Bauer, K.-H. Pious, C. Führer: Pharmaceutical Technology, Georg Thieme Verlag Stuttgart, New York (1989) known.

Also preferred are tablet formulations, in particular those in which a swellable tablet core is preferred consists of polyethylene glycol and / or Carbopol and the Contains active substance, with an enteric coating is covered. The enteric coating is preferred Base of water-insoluble and / or pH-dependent built up water-soluble polyacrylates. suitable Polyacrylates are z. B. poly (methacrylic acid, methyl methacrylate) 1: 1, poly (methacrylic acid, methyl methacrylate) 1: 2, poly (ethyl acrylate, methyl methacrylate, trimethylammino methacrylate chloride) 1: 2: 0.2 and poly (ethyl acrylate, methyl methacrylate, trimethylammino methacrylate chloride) 1: 2: 0.1. Appropriate orally administrable tablet formulations and methods their preparation are described, for example, K.H. Bauer, K.-H. Pious, C. Führer: Pharmaceutical Technology, Georg Thieme Verlag Stuttgart, New York (1989) known.

The medicaments according to the invention can be used in addition to the above mentioned special aids that are a topical Release at the site of inflammation in the gastrointestinal area ensure other common excipients and excipients contain, as they are known in the art and for example in K.H. Bauer, K.-H. Pious, C. Führer: Pharmaceutical Technology, Georg Thieme Verlag Stuttgart, New York (1989), a standard work for the production of Drug formulations are described.

By virtue of the invention, it has been found that the topical Use of active substances which are active against protozoa and  especially of metronidazole inflammatory bowel disease how it can combat Crohn's disease or ulcerative colitis possible with the medicaments according to the invention, which are suitable for the To combat the diseases required amount of active ingredient lower and thereby the side effects, which at the time usual systemic administration of the drug occurred, decrease. A significant advantage of Topical use lies in the fact that even at reduced amount of active substance in the medicinal products Absorption of the active substance, in particular metronidazole, only to a very small extent (the active substance is only on inflamed area of the intestine is released and thereby becomes the Concentration of the drug in the blood decreases). Even at Drug formulations containing an unrestrained amount Therefore, the side effects of the drug may contain Drugs, in particular metronidazole, in systemic administration can be reduced.

The medicaments according to the invention can therefore contain the active ingredient contained in an amount, as he also in the already known Medicinal products, for example known metronidazole containing medicinal products. Preferably included the medicaments of the invention but a smaller amount on metronidazole or another effective against protozoa Drug as the drugs of the prior art, or the daily dosage of the medicaments according to the invention lower (that is, with doses of the same dosage is a smaller number of individual formulations per day administer). The preferred dosage of the drugs Administration by the medicaments according to the invention especially when administering metronidazole, a pharmaceutically acceptable salt or prodrugs thereof of 1 to 50 mg / kg body weight per day, preferably 3 to 30 mg / kg Body weight per day. Accordingly, contains a single dose of the medicament according to the invention, for example a single capsule or tablet preferably from 100 mg to 1000 mg, more preferably from 250 mg to 500 mg of active ingredient.  

The exact daily dose depends on factors that the specialist are known, such as type and severity of the disease, more general Condition and age of the patient, specially selected Dosage form, etc. The amount of dosage required can be determined by a specialist.

The effectiveness of the medicaments according to the invention against inflammatory bowel disease and especially against morbus Crohn's and ulcerative colitis or comorbidities and Secondary diseases can be checked as it is in the state of Technique is well known. In particular, on the Clinical examinations are referred to, as described in the initially mentioned documents of the prior art are described. Here on "Lancet" 1975, 775-777, Gastroenterology 108, 1995, 1617-1621, Gastroenterology 83, 1982, 383-387 and in particular to Gut 32, 1991, 1071-1075 to get expelled. In these documents are methods described with which both the effectiveness and the appropriate dosage and the occurrence of side effects Administering the medicament according to the invention tested can be.

The examples illustrate the invention, but limit it not a.

1. Example of matrix pellet cores

example 1 I metronidazole 5000 g II strength 1000 g III lactose 500 g IV methylcellulose 200 g V silicon dioxide 25 g VI poly (ethyl acrylate, methyl methacrylate) 2: 1 as a 40% aqueous dispersion, trade name Eudragit® NE40 D 750 g VII magnesium stearate 250 g

I-V are mixed and moistened with VI. In addition will be 500 g of ethanol added. After intensive kneading of the mass becomes VII added. The moist mass is fed through an extruder The die hole pressed 1 mm, in about 1 mm long pieces cut and rounded in a Spheronizer. At 60 ° C the pellets dried.

2. Example of pellet cores with a swellable shell I metronidazole 5000 g II strength 1000 g III lactose 500 g IV povidone 300 g V silicon dioxide 25 g VI magnesium stearate 250 g

I, II, III and V are mixed. IV is in 1500 g of ethanol solved. With this solution, the mixture of I, II, III and V moisturizes. After intensive kneading of the mass, VI added. The wet mass is passed through an extruder with the Die hole pressed 1 mm, in about 1 mm long pieces cut and rounded in a Spheronizer. At 60 ° C the pellets dried.

A hydroxypropylmethylcellulose 750 g B polyethylene glycol 6000 150 g C water 4100 g

A and B are solved in C. The solution becomes the pellets sprayed in a rotating kettle.

3. Example of pellet cores with a permeable shell I metronidazole 5000 g II strength 1000 g III lactose 500 g IV povidone 300 g V silicon dioxide 25 g VI magnesium stearate 250 g

I, II, III and V are mixed. IV is in 1500 g of ethanol solved. With this solution, the mixture of I, II, III and V moisturizes. After intensive kneading of the mass, VI added. The wet mass is passed through an extruder with the Die hole pressed 1 mm, in about 1 mm long pieces cut and rounded in a Spheronizer. At 60 ° C the pellets dried.

A Eudragit®S (poly (methacrylic acid, methyl methacrylate) 1: 2) 350 g B Eudragit L (poly (methacrylic acid, methyl methacrylate) 1: 1) 350 g C Eudragit® RS (poly (ethyl acrylate, methyl methacrylate, trimethylammino methacrylate chloride) 1: 2: 0.1) 60 g D dibutyl phthalate 50 g E talk 40 g

A-D are dissolved in 7.5 kg of isopropanol / water (9: 1). E will suspended in the solution. The solution becomes the pellets sprayed in a rotating kettle.

The pellets from Examples 1.1-1.3 are with the the following solution is enteric-coated:

I poly (methacrylic acid, methyl methacrylate) 1: 2; Trade name Eudragit®S 350 g II triethyl citrate 35 g III talc 100 g IV titanium dioxide 125 g V magnesium stearate 50 g

I is dissolved in 3500 g of an ethanol / water mixture (8: 2). II-V are suspended in the solution; in a suitable The apparatus becomes the lacquer suspension at a supply air temperature of 40 ° C sprayed.  

Example of an approved controlled tablet formulation

Example 2 I polyethylene glycol 6000 40 g II polyacrylic acid (Carbopol 934) 10 g III metronidazole 200 g IV cellulose microcrystalline 50 g V strength 97 g VI magnesium stearate 3 g

I is melted on a water bath at about 70 ° C. In the melted mass II and III are suspended. To It cools and solidifies the mass with one Crushed shredded to about 1 mm large particles. The crushed mass is mixed with IV, V and VI and added to Compressed tablets weighing 400 mg. The tablets are treated with poly (methacrylic acid, methyl methacrylate) (Eudragit S) in a known manner enteric coated.

Example 3

To determine the release of the active substance from the pellets according to the invention was the "basket" method used. The "Basket" method is described in USP 23. The Stirrer speed was 100 revolutions / min. the Temperature was kept constant at 37 ° C. As artificial Gastric juice was used as artificial according to USP 0.1 M HCl Intestinal juice USP phosphate buffer (pH 6.8).

In Table 1, the drug release is a pellet formulation according to the invention under the above Conditions specified.  

Claims (22)

Medicinal product having a protozoal drug, characterized in that it comprises a protozoal active agent core and an enteric coating. 2. Medicament according to claim 1, characterized in that the antiprotozoal drug is a 5-nitroimidazole Represents derivative. 3. Drug according to claim 2, characterized in that the 5-nitroimidazole derivative azanidazole, nimorazole, oridazole, Propenidazole, secnidazole, ternidazole, tinidazole or Metronidazole or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof or Prodrug of it is. 4. Medicament according to claim 3, characterized in that the antiprotozoal drug Metronidazole or a pharmaceutically acceptable salt thereof or a pharmaceutically acceptable derivative thereof or a prodrug it is. 5. Medicament according to one of claims 1 to 4 for topical treatment or prevention and / or Remission maintenance of inflammatory bowel disease. 6. Medicament according to one of claims 1 to 5, the like formulated that it is a controlled release profile having. 7. Medicament according to one of claims 1 to 6, wherein the enteric coating is a polymer or copolymer  comprising monomer units derived from (meth) acrylates and / or phthalic acid monoesters are derived. 8. Medicament according to one of claims 1 to 7, characterized characterized in that it is a pellet formulation is. 9. Medicament according to claim 8, characterized in that the active ingredient in the pellet core embedded in a polymer matrix is. 10. Medicament according to claim 9, characterized in that the matrix-forming polymer poly (ethyl acrylate, methyl methacrylate) or poly (ethyl acrylate, methyl methacrylate, trimethylammonioethyl methacrylate chloride). 11. Medicament according to claim 10, characterized the matrix-forming polymer contains at least 5% by weight of the Total weight of the core. 12. Medicament according to one of claims 8 to 11, characterized characterized in that the core and the enteric-coated Cover are separated by a swellable diffusion layer. 13. Medicament according to claim 12, characterized that the swellable diffusion layer of cellulose derivatives and / or pharmaceutically acceptable gums. 14. Medicament according to one of claims 8 to 11, characterized characterized in that the core and the enteric-coated Cover separated by a permeable to liquids envelope are. 15. Medicament according to claim 14, characterized that the permeable shell of water-insoluble and / or pH depends on water-soluble polyacrylates.   16. A pharmaceutical formulation according to any one of claims 8 to 15, characterized in that it is a gelatin capsule or a pellet tablet, which pellets after a of claims 8 to 15 contains. 17. Medicament according to one of claims 1 to 7, characterized characterized in that it is a tablet formulation is. 18. Medicament according to claim 17, characterized that the active against protozoa drug in a swelling core is located and the tablet core with a gastro-resistant casing is coated. 19. Medicament according to claim 18, characterized that the swellable core of polyethylene glycol and Carbopol consists. 20. Use of a drug effective against protozoa for topical treatment or prevention and / or for Remission of inflammatory bowel disease or so associated comorbidities and secondary diseases. 21. Use according to claim 20, wherein the against protozoa effective drug is metronidazole. 22. A process for the preparation of a medicament according to of claims 1 to 19, characterized in that a Drug core with a protozoal effective Drug in a known manner with a enteric coating is coated.