SK91496A3 - A galenical form of 5-nitro imidazole derivatives and pharmaceutical composition containing same - Google Patents

Abstract

A galenic form of 5-nitro imidazole derivatives, including a combination of microgranules of 5-nitro imidazole derivatives, i.e. enteric microgranules and sustained release microgranules, which are an effective component of the pharmaceutical preparation in the form of tablets, quickly spreading tablets and gelatinous capsules. Galenic form is used for preparation of medicament against vermins and infection of digestive tract, especially amebiases and infections joint with the presense of Heliobacter pilori.

Description

The galenical form of the 5-nitroimidazole derivatives and a pharmaceutical composition thereof

Technical field

The invention relates to a novel galenic form of 5-nitroimidazole derivatives which is effective in controlling parasites and infections throughout the gastrointestinal tract.

In particular, it relates to a novel galenical form intended to combat parasites and infections producing resistant forms in the lower part of the digestive tract, in particular in the sigmoid colon and rectum.

BACKGROUND OF THE INVENTION

Intestinal parasites such as amebiasis, colon parasitosis, which can be complicated by extracorporeal placement, form resistant forms in the lower intestine, which are responsible for the transmission of these conditions.

The amebiases are cysts of Entamoebacter histolytica. These cysts, which are in the lower part of the digestive tract of infected subjects, are extracted by stool. The lack of personal and collective hygiene guarantees the spread of the disease, as well as self-infecting individuals who carry these parasites.

Entamoebacter histolytica also exists in a more labile form

Entamoebacter histolytica misses that causes no damage but can turn into a pathogenetic form

Entamoebacter histolytica, which penetrates the intestinal mucous membrane and causes the disease to spread in both the upper and lower intestines in the form of cysts. This form is also responsible for the most widespread complications of amebiasis that migrates to the liver or even to the lungs or brain.

It is possible to treat parasites and digestive tract infections quickly with medicaments that are used to treat a tourist. Since these treatments are not applied systematically, they do not take into account the hygiene problems that are responsible for the spread of these diseases.

Similarly, there is routine and inexpensive treatment of amebiasis with azole-containing derivatives, especially 5-nitroimidazole (e.g., metronidazole, secnidazole). However, this treatment, which is effective against upper bowel, minute and histolytic forms, is not very effective in treating cysts. In addition, these 5-nitroimidazole derivatives, administered in too high an amount, are absorbed in the upper part of the digestive tube, which can cause unpleasant side effects (metallic taste in the mouth) or even toxic effects.

With the same disadvantages, other conditions forming resistant forms in the lower intestine may be treated with 5-nitroimidazole derivatives. These are, for example, infections caused by Heliobacter pilori, a bacterium present in the stomach and in the lower part of the gastrointestinal tract, and which is implicated in the pathogenesis of gastritis and ulcers of the stomach and heliobacter.

His contribution to the genesis of stomach cancer is also mentioned.

Due to the increasing importance of parasites and infections of the entire gastrointestinal tract, it has become important to invent inexpensive treatment while considering the problems of transmission of conditions associated with poor hygiene, that is, to allow effective treatment of resistant forms present in the lower intestines.

SUMMARY OF THE INVENTION

The essence of the galenic form of 5-nitroimidazole derivatives according to the invention is that it is a combination of microgranules of derivatives

5-nitroimidazole formed by both gastroresistant microgranules and sustained release microgranules.

The gastroresistant granules are intended to guarantee the efficacy of the forms of the invention, particularly in the upper part of the gastrointestinal tract, with the sustained release microgranules acting essentially in the lower part.

The ratio of the various microgranules is adapted to the desired effect promoting the action of the form of the invention in substantially the lower or upper part of the gastrointestinal tract, or alternatively, to ensure a constant action over its entire length. It will also depend on the excipients used to prepare the microgranules.

The weight ratio of gastroresistant microgranules to prolonged action microgranules is 6: 4 to 1: 9, preferably 4: 6 to 1: 9. In order to ensure high efficacy of the form of the invention in the lower intestine conditions, the ratio of gastroresistant microgranules to sustained action microgranules is preferably 25:75 to 15:85.

To ensure high efficiency of the form according to the invention, the microgranules should correspond to the following solubility parameters:

- gastroresistant microgranules:

hours in 0.1N hydrochloric acid for one hour at pH 6.0

- prolonged-action microgranules:

<15%> 75% hour at 0.1 IN acid hour at hour value at hour value at value

other hydrochloric acid < 15 6.8 £ pH £ 7.5 4 50 6.8 £ pH £ 7.5 40 until 6.8 £ pH £ 7.5 7 70

%%

%%

wherein the percentages relate to the weight of the dissolved active ingredient relative to the total weight before dissolution.

The microgranules, all useful in the form of the invention, preferably consist of a neutral granular carrier coated with an active layer consisting of a mixture of the active ingredient, a 5-nitroimidazole derivative and a binder.

The neutral carrier is preferably starch particles and a mixture of starch and sucrose with a mean diameter of 400 to 800 microns.

The 5-nitroimidazole derivative is preferably selected from metronidazole, secnidazole, tinidazole and mixtures thereof.

The binder is generally known to form microgranules, preferably polyvinylpyrrolidone of various molecular weights (preferably the class Kollidon K30 and K17 of BASF): the class corresponds to a constant K value which is a function of the molecular weight and the viscosity of the product. The constant K is also subject to specifications in various official monographs in common use (with respect to polyvinylpyrrolidone): furthermore, hydroxypropylmethylcellulose of different molecular weights (preferably species 615, HPMC species being a function of product substitution rates with methoxy and hydroxypropoxy groups and reflect viscosity). Various types are described in the official monographs of this product (especially USP XXII): furthermore, hydroxypropylcellulose of various molecular weights, poly (meth) acrylic acid ester (commercial product of ROHM GmbH with the trade name EUDRAGIT *) and mixtures thereof.

However, the invention also encompasses microgranules having a core simply composed of the active ingredient and a binder.

The gastroresistant microgranules and the sustained release microgranules differ in their outer layer, which covers the active core. It is both the gastroresistant outer layer of the gastroresistant microgranules and the outer layer of the prolonged action microgranules.

The gastroresistant outer layer is comprised of conventional excipients used in the technique of preparing gastroresistant microgranules. It contains excipients guaranteeing the resistance of the coating to pH values below 5, preferably selected from the group consisting of poly (meth) acrylic acid esters (commercial product of ROHM GmbH designated EUDRAGIT * L 100-55, EUDRAGIT ® 100, EUDRAGIT * L 30D -55), hydroxypropylmethylcellulose phthalate, (commercial product of SHIN ETSU Chemical Co. Ltd designated HP 50 * and HP 55 *), and mixtures thereof.

The extended release outer layer consists of conventional excipients used in the technique of preparing sustained release microgranules, independently of the pH of the environment in which they operate, preferably selected from the group consisting of poly (meth) acrylic acid esters (marketed by EUHRA GmbH under the name EUDRAGIT). * L 100, EUDRAGIT® L 30D), ethylcellulose (a commercial product of FMC Corporation, Philadelphia AQUACOAT ⁸ ), and mixtures thereof. In this case, it determines the release time of the active ingredient, the transit time of the microgranules in the intestines.

The sustained release outer layer may also consist of an excipient which depends on the pH of the environment through which the microgranules pass, in particular pH-dependent poly (meth) acrylic acid esters (a commercial product of ROHM GmbH under the name EUDRAGIL's). In this case, it is no longer the passage time of the microgranules that determines the release point of the active ingredient, but the Ph value of the environment through which they pass. In order to ensure the release of the active ingredient in the lower intestine, an excipient which is soluble at pH values greater than 7, such as EUDRAGIT® S, is also selected. However, depending on the desired effect, the sustained release microgranules may also consist of a microgranule mixtures of pH microgranules as a function of the inner layer with conventional additives, such as to facilitate the coating with their lubricating properties, silica derivatives or stearic acid plasticizers, which mainly facilitate (poly) citric acid esters (mainly pH dependent) to be effective the component released at different pH values, or alternatively, dependent or independent of the etching time and pH value.

The sustained-release gastroresistant outer layer may also contain talc or oxide derivatives and / or one or more carboxylic film coatings (such as triethyl citrate), dibutyl sebacate and mixtures thereof.

Due to the importance of the dimensions of the microgranules for the rate of their passage through the intestines, the mean diameter of the microgranules is suitable for the embodiment of the invention, preferably 0.4 to 1.5 mm, preferably 0.8 to 1.1 mm.

The microgranules suitable according to the invention are preferably prepared as follows:

- the neutral core is coated with an active layer,

- the active layer is coated with either a gastroresistant layer or a sustained release layer according to microgranules,

- the product is sifted

- and dries.

The microgranules are then mixed according to the desired proportions and processed into a suitable form for administration, especially in the form of tablets, fast dissolving tablets, gelatin capsules or sachets.

The invention therefore also relates to a pharmaceutical composition comprising the form described above.

The invention also relates to intermediates for preparing the galenical form of the invention into the above described gastrochran granules and into sustained release microgranules.

However, since gastroresistant microgranules and sustained release microgranules are prepared separately with and can be separately formed, the invention also relates to combinations of products containing the above microgranules of 5-nitroimidazole gastrochranated derivatives and 5-nitroimidazole sustained release derivatives for use in combination, separately or at intervals of time to control parasites and gastrointestinal infections, particularly amebiases and Helicobacter pilori-associated infections.

The invention illustrates, but is not limited to, the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Mixture 2: 8 metronidazole microgranules The following mixture is prepared:

A% B% metronidazole 63.8 64.5 Neutral core 21.3 21.5 PVP K30 5.7 5.7 HP50 9.2 4.7 Ethylcellulose N7 - 1.8 talc 1.8 100.0 100.0

The percentages are by weight and refer to the total weight of the microgranules. ingredients:

- Neutral core: composed of sucrose (approximately 75%) and corn starch (approximately 25%)

- PVP: Polyvinylpyrrolidone K30

- HP50: Hydroxypropylmethylcellulose phthalate solution, solubility from pH 5,0

- Ethyl cellulose N7: Ethyl cellulose whose type N7 represents the viscosity of the product.

The microgranules are prepared as described below.

Example 2.

Mixture of 3: 7 metronidazole microgranules

Using the same procedure, prepare the following mixture:

A% B% metronidazole 52.6 56.9 Neutral core 19.9 21.6 PVP K30 2.7 2.8 EUDRAGIT * L30D-55 11, 8 - triethylcitrate 1.2 3.7 talc 11, 8 7.5 EUDRAGIT * S - 7.5

100.0

100.0

The percentages are by weight and refer to the total weight of the microgranules. ingredients:

- Neutral core: composed of sucrose (approximately 75%) and corn starch (approximately 25%)

- PVP: Polyvinylpyrrolidone K30

- EUDRAGIT * L30D-55: Aqueous dispersion of methacrylic acid copolymers of type C: dissolution from pH 5,5

- Talc

- EUDRAGIT S: Methacrylic acid copolymer type B: dissolution from pH 7.0

Example 3

25:75 metronidazole microgranules

Using the same procedure, prepare the following mixture:

A% B% metronidazole 51, 8 59.7 Neutral core 19.6 22.6 EUDRAGIT * E 100 3.4 3.9 EUDRAGIT * L30D-55 12.0 - EUDRAGIT * RS 3OD - 6.3 triethylcitrate 1.2 1.2 talc 12.0 1 1 1 1 1 1 1 ro i * I kD 1 1 1 1 1 1 1 1 1 1 100.0 100.0

The percentages are by weight and refer to the total weight of the microgranules. ingredients:

- Neutral core: composed of sucrose (approximately 75%) and corn starch (approximately 25%)

- EUDRAGIT * E 100: Methacrylic acid copolymer used as binder here

- EUDRAGIT L30D-55

- EUDRAGIT * RS 30D: Aqueous dispersion of methacrylic acid copolymers of type B: prolonged-release dissolution

- Talc

Example 4

Mixture corresponding to lot XM285

Using the same procedure, prepare the following mixture:

Composition of batch XM 285:

metronidazole 65.1 Neutral core 21.7 PVP K30 4.8 Ethylcellulose N7 1.3 HP50 5.0 Ethylcellulose N7 1.3 triethylcitrate 0.5 talc 1.6

100.0

Example 5: Secnidazole formulation

Using the same procedure, prepare the following mixture:

A% B% Secnidazol 47.8 45.5 Neutral core 33.0 31.9 PVP KI7 3.4 3.2 EUDRAGIT * L30D-55 12.6 - EUDRAGIT * RS 3 OD - 10.5 triethylcitrate 1.3 2.1 talc 1.9 6.8

100.0

100.0

Mixture of 25% A and 75% B

Dissolution patterns

The dissolution tests of the forms of Examples 1 and 4 were carried out with a 0.1N hydrochloric acid solution and at pH 6.8. The results are shown in the following table. The percentages by weight of the dissolved microgranules relative to the total weight of the microgranules before dissolution are given.

Example 1 Example 4 Gastroresistance test 0.1N HCl for 2 hours 6,7% 8.5% Dissolution test pH 6.8 1 hour 42.2% 47.2% 4 hours 78.2% 72.3% 6 hours 86.9% 81.5%

Clinical tests

A clinical study of the efficacy of the form of the invention is conducted with 60 patients of both sexes, aged 15 to 75 years, suffering from amebiasis and showing cysts in the colon.

The study is conducted according to a rigorous randomized double placebo and double blind methodology by comparing the form of Example 1 with metronidazole commercially available under the trademark Flagyl.

The doses administered are 1.5 g / day (in 3 daily doses of two gelatin capsules containing 250 mg metrodinazole) for 10 days.

The results of this study show a cure rate of 85% for the form of the invention versus 15% for Fragyl.

Method of production of metronidazole microgranules (batch XM 415/2) Phase 1: Preparation of binder solution: alcoholic solution of PVP and 20% alcohol

- the solution is prepared in a stainless steel mixer

- 95% ethyl alcohol is poured into the mixer

- start mixing with the introduction of PVP in small doses

stirring is continued until complete dissolution.

Phase 2: Application

- the neutral carrier grains are introduced into the rotary turbine

- applied by dusting the active ingredient on neutral microgranules with alternate spraying of the binder solution

- the microgranules are sieved (a sieve with a diameter of 0.50, 0.71, 0.99, 1.12 and 1.25 mm is used)

- microgranules are dried by hot air in a rotary turbine.

Phase 3: Splitting the mass of microgranules into two parts

- the mass of microgranules is divided into parts A and B in a ratio of 75% to 25%

- each of the two parts is introduced into a different turbine.

Stage 4: Preparation of preforming solution: alcoholic solution of ethyl cellulose N7 at 10%

- the solution is prepared in a stainless steel mixer

- 95% ethyl alcohol is poured into the mixer

- start mixing with the introduction of PVP in small portions

stirring is continued until complete dissolution.

Phase 5: Preforming Part

- preforming solution is applied to the microgranules by spraying

- at the same time sprinkles with talc

- the microgranules are sieved (a sieve with a diameter of 0.50, 0.71, 0.99, 1.12 and 1.25 mm is used)

- the microgranules are dried by hot air in a rotating turbine.

Phase 6: Preparation of the screed solution: Aceto / Alcoholic solution 20/80, pH 5.0 at 7.5%

- the solution is prepared in a stainless steel mixer

- 95% ethyl alcohol is poured into the mixer followed by acetone

- start mixing with the introduction of HP 50 in small portions

stirring is continued until complete dissolution.

Phase 7: Coating Parts A and B: Coating over Parts A and B over time

- the coating solution is applied by spraying

- the microgranules are sieved (a sieve with a diameter of 0.50, 0.71, 0.99, 1.12 and 1.25 mm) is used) the microgranules are dried with hot air in a rotary turbine.

Stage 8: Lubrication-kneading in two parts

the parts A and B and the lubricating talc are introduced into the rotary turbine

- the mass is mixed

- the turbine stops.

The novel galenical form of the invention also appears to be suitable for the preventive treatment of anerobic germ infections in surgical operations at high risk of infections of the type such as gastrointestinal surgery.

Technical usability

Galenic form of 5-nitroimidazole derivatives effective in the control of parasites and infections throughout the gastrointestinal tract, in particular for the control of parasites and infections producing resistant forms in the lower part of the gastrointestinal tract, especially in the skull colon and rectum.

Claims (17)

PATENT CLAIMS Galenic form of 5-nitroimidazole derivatives, characterized in that it is a combination of 5-nitroimidazole derivatives of microgranules consisting of both gastroresistant microgranules and sustained release microgranules. Galenic form according to claim 1, characterized in that the weight ratio of gastroresistant microgranules to sustained release microgranules is 6: 4 to 1: 9. The galenical form according to claim 2, wherein the weight ratio of gastroresistant microgranules to sustained release microgranules is 25:75 to 15:85. Galenic form according to claims 1 to 3, characterized in that the microgranules correspond to the following dissolution parameters: - gastroresistant microgranules: 2 hours in 0.1N hydrochloric acid 4 15% 1 hour at pH 6.0 775% - prolonged-action microgranules: 2 hours in 0.1N hydrochloric acid 4 15% 1 hour at 6.8 i pH ^ 7.5 4 50% 4 hours at 6.8i pH - 7.5 40 to 90% 6 hours at 6.8 pH pH 7.5> 70%, the percentages referring to the weight of dissolved active ingredient relative to the total weight before dissolution. Galenic form according to claims 1 to 4, characterized in that the gastroresistant microgranules consist of a neutral granular carrier coated with an active layer consisting of a mixture of the active ingredient, a 5-nitroimidazole derivative and a binder and a gastroresistant outer layer. Galenic form according to claim 5, characterized in that the gastroresistant outer layer is composed of excipients guaranteeing the resistance of the coating to pH values of 4.5 to 5.5, which are preferably selected from poly (meth) acrylic acid esters of hydroxypropylmethylcellulose and mixtures thereof, and optionally talc and / or at least one plasticizer. 7. The galenical form according to claim 1, wherein the sustained release microgranules consist of a neutral granular carrier coated with an active layer consisting of a mixture of 5-nitroimidazole derivatives and a binder and an outer release layer. Galenic form according to claim 7, characterized in that the sustained release outer layer consists of conventional excipients used in the technique of preparing sustained release microgranules, independently of the pH of the medium in which they operate, preferably selected from the group consisting of poly ( met) acrylic acid, ethylcellulose, and mixtures thereof, and optionally talc and / or at least one plasticizer. Galenic form according to claim 8, characterized in that the gastroresistant outer layer is formed by at least one pH-dependent excipient of the environment through which the microgranules pass, in particular pH-dependent poly (meth) acrylic acid esters and optionally talc and / or at least with one plasticizer. A galenical form according to claims 5 to 9, characterized in that the neutral carrier comprises starch particles or a mixture of starch and sucrose having an average particle diameter of 400 to 800 mm. Galenic form according to claims 5 to 10, characterized in that the binder is an agent known for the preparation of microgranules, preferably selected from the group consisting of polyvinylpyrrolidone of different molecular weights, hydroxypropylmethylcelluloses of different molecular weights, hydroxypropylcellulose of different molecular weights, poly (meth) esters. acrylic and mixtures thereof. Galenic form according to claims 1 to 11, characterized in that the gastroresistant microgranules and the sustained release microgranules have a mean particle diameter of 0.4 to 1.5 mm, preferably 0.8 to 1.1 mm. The galenic form according to claims 1 to 12, wherein the 5-nitroimidazole derivative is selected from the group consisting of metronidazole, secnidazole, tinidazole and components thereof. Pharmaceutical composition, characterized in that it is constituted by the galenic form according to claims 1 to 13, in particular in the form of tablets, fast-disintegrating tablets and gelatin capsules. Gastro-protected microgranules of 5-nitroimidazole derivatives particularly suitable for the preparation of the galenic form according to claims 1 to 13. Prolonged-release microgranules of 5-nitroimidazole derivatives particularly suitable for the preparation of the galenic form according to claims 1 to 13. 17. Combination product for use in combination at the same time, separately or separately at intervals to control parasites and gastrointestinal infections, in particular amebiases and infections associated with the presence of Heliobacter pilori, characterized in that it contains gastro-protected microgranules of derivatives 5 nitroimidazole and sustained release microgranules of 5-nitroimidazole derivatives according to claim 1.