SK282066B6 - Galenic form of 5-nitro imidazole derivatives, pharmaceutical preparation and use - Google Patents

Abstract

Medicinal form contains a combination of microgranules of derivatives 5-nitroimidasole, consisting, on the one hand, of gastro-resistant microgranules and, on the other hand, of microgranules with a prolonged release of a medicinal agent. Gastroresistant microgranules are intended to guarantee the efficiency of the medicinal form of the present invention, primarily, in the upper part of gastrointestinal tract, while the microgranules with a prolonged medicinal agent release are operate mainly in the lower part of gastrointestinal tract.

Description

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 galenic form intended for the control of parasites and infections producing resistant forms in the lower part of the gastrointestinal tract, in particular in the S-part of the colon and rectum.

BACKGROUND OF THE INVENTION

Intestinal parasites, such as amebiasis, colon parasites, which may 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 of Entamoebacter histolytica that does not cause any damage but can be transformed into a pathogenetic form of Entamoebacter histolytica that penetrates the intestinal mucous membrane and causes the disease to spread both in 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 tourists. 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). But 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. For example, infections caused by Heliobacter pilori, a bacterium present in the stomach and at the bottom of the digestive tract, are implicated in the pathogenesis of gastritis and ulcers of the stomach and duodenum, the heliobacter irritation causing acidic gastric hypersecretion leading to gastric ulcers. His contribution to the genesis of stomach cancer is also mentioned.

In view of the increasing importance of parasites and infection of the entire digestive tract, it has become important to invent inexpensive treatments considering the problems of transmission of conditions associated with poor hygiene, i.e., those that allow effective treatment of resistant forms present in the lower intestines.

SUMMARY OF THE INVENTION

The essence of the galenical form of the 5-nitroimidazole derivatives is that according to the invention, the microgranules of 5-nitroimidazole derivatives consist of both gastroresistant microgranules and sustained release microgranules.

The gastroresistant granules are intended to guarantee the efficacy of the forms of the invention, especially in the upper part of the digestive tract, with the sustained release microgranules acting substantially 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 sustained action microgranules is 6: 4 to 1: 9, preferably 4: 6 to 1: 9. To ensure high efficacy of the form of the invention in lower intestinal conditions, the ratio of gastroresistant microgranules to sustained action microgranules is preferably 25: ; 75 to 15: 85.

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

- gastroresistant microgranules:

hours in 0.1N hydrochloric acid <15% hour at pH 6.0> 75%

- prolonged-action microgranules:

hours in 0.1N hydrochloric acid <15% hour at 6.8 <pH 7, 5 <50% hour at 6.8 <pH <7.5 40 to 90% hours at 6.8 <pH <7 , 5> 70%

The percentages refer to the weight of dissolved active ingredient based on the total weight before dissolution.

The microgranules, which are 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 an agent known for the preparation of microgranules, preferably a polyvinylpyrrolidone of different molecular weights (preferably the class Kollidon K30 and K17 from BASF): the class corresponds to a constant K value which is a function of the molecular weight and 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 various 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 in USP XXII): furthermore, hydroxypropylcellulose of various molecular weights, poly (meth) acrylic acid ester (commercial product of RÔHM GmbH with the trade name EUDRAGIT ^R ) and mixtures thereof.

However, the invention also encompasses microgranules having a core simply assembled from an active ingredient and a binder.

The gastroresistant and 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 microgranules with prolonged action.

The gastroresistant outer layer is comprised of conventional excipients used in the technique of preparing gastroresistant microgranules. It contains excipients guaranteeing the coating's resistance to pH values less than 5, preferably selected from the group consisting of poly (meth) acrylic acid esters (commercial product of ROHM GmbH designated EUDRAGIT ^R L 100-55, EUDRAGIT ^r L 100, EUDRAGIT ^r L 30D-55), hydroxypropyl methylcellulose phthalate (commercial product of SHIN ETSU Chemical Co. Ltd designated HP 50 ^R and HP 55 ^R ) 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 ROHM GmbH under the name EUDRAGIT® ^). L 100, EUDRAGIT ^RL 30D), ethyl cellulose (commercial product of FMC Corporation, Philadelphia designation AQUACOAT ^R), and mixtures thereof. In this case, the transit time of the microgranules in the intestines determines during the release of the active ingredient.

The extended release outer layer may also consist of an excipient which depends on the pH of the environment through which the microgranules pass, in particular a pH-dependent poly (meth) acrylic acid ester (commercial product of RÔHM GmbH under the name EUDRAGIT ¹¹ S). In this case, it is no longer the transition 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 release of the active ingredient in the lower intestinal, it decides whether the excipient which is soluble at pH values above 7, and ^Eudragit S. However, depending on the desired effect can be sustained release microgranules may also consist of a mixture of microgranules dependent release from a pH value such that the active ingredient is released at various pH values, or alternatively from a mixture of pH-dependent or pH-independent microgranules, such as the transit time and pH value.

The gastroresistant outer layer and the sustained release inner layer may also contain conventional additives, such as talc, to facilitate coating with their lubricating properties, or silica or stearic acid derivatives and / or one or more plasticizers, which facilitate the formation of a coating film, especially esters of acid (esters). poly) carboxylic acids such as citric acid esters (especially 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 average diameter of the microgranules suitable for making the present invention is 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 gastro-resistant layer or a prolonged-release layer according to micro-granules,

the product is sieved, and

- dries.

The microgranules are then mixed according to the desired proportions and formulated in a form suitable for administration, in particular in the form of tablets, rapidly dissolving tablets, gelatin capsules or sachets.

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

The invention also relates to intermediates for the preparation of the galenic form of the invention into the described gastrochran granules and into sustained release microgranules.

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

The invention is illustrated, but not limited, by the following examples.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

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

Al bt 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;

- Ethylcellulose N7: Ethylcellulose 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 * ijod-ss 11.8 - triethylcitrate 1.2 3.7 talc 11.8 7.5 kcdmsit ’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 (about 75%) and corn starch (about 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

Mixture 25: 75 metronidazole microgranules

Using the same procedure, prepare the following mixture:

A t B% metronidazole 51.8 59.7 Xeutral core 19.6 22.6 EUDRAGIT * B 100 3.4 3.9 BTOMGIT L30E-5S 12.0 - KTOimaiT * pcs 30D - 6.3 Trietylcltrát 1.2 1.2 talc 12.0 6.3 100.0 100.0

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

- Neutral core: composed of sucrose (about 75%) and corn starch (about 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: sustained release dissolution;

- Talc.

Example 4

Mixture corresponding to lot XM285

The following mixture was prepared in the same manner: Batch composition XM 285:

T

metronidazole 65.1 Neutral core 21.7 FVP K30 4.8 Btylcellulose N7 1.3 HF50 5.0 Btylcellulose N7 1.3 Trietylcltrát 0.5 talc 1.6

100.0

Example 5

Secnidazole formulation

Using the same procedure, prepare the following mixture:

A t B t

Secnidazol 47 B 45.5 Neutral core 33.0 31.9 PVP 117 3.4 3.2 BVDMGXT * L30D-S5 12.6 BUDRAGIT * US 3 OD 10, with Trietylcltrát 1.3 2.1 talc 1.9 6.6

100.0 100.0

Mixture 25% Aa75% B

Dissolution patterns

The dissolution tests of the forms of Examples 1 and 4 are carried out with a 0.1N hydrochloric acid solution and at a pH of 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 Test gascrareziscencie 0.1N HCl for 2 hours 6,7 4 8,5 t Dissolution Test pH 6.8 1 hour 42,2 4 47,2 * 4 hours 78,2 t 72.3 4 6 hours 86,9 4 81,5 k

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 having cysts in the colon.

The study is conducted according to a rigorous "random" double placebo and double blind methodology by comparing the form of Example 1 with metronidazole commercially available under the trade name 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: alcohol 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 sputtering the active ingredient on neutral microgranules with alternate spraying of the binder solution - microgranules are sieved (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 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% and 25% - each of the two parts being introduced into a different turbine.

SK 282066 Β6

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 ethylcellulose in small doses,

stirring is continued until complete dissolution.

Phase 5: Preforming Part

- preforming solution is applied by spraying on the microgranules

- at the same time sprinkles with talc,

- sieve the microgranules (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: 20/80 aceto / alcoholic solution with pH 5.0 at 7.5%

- the solution is prepared in a stainless steel mixer,

- 95% ethyl alcohol and then acetone are poured into the mixer,

- 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,

- sieve the microgranules (sieve with a 0,50,0,71, 0,99,1,12 and 1,25 mm sieve diameter), dry the hot microgranules 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 infection of the type such as gastrointestinal infection.

Industrial 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 of the colon and rectum.

Claims (15)

PATENT CLAIMS A galenic form of 5-nitroimidazole derivatives, characterized in that it is a combination of microgranules of 5-nitroimidazole derivatives 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 0.1 N hydrochloric acid <15% 1 hour at pH 6.0> 75% - prolonged-action microgranules: 2 hours in 0.1 N hydrochloric acid <15% 1 hour at 6.8 £ pH <7.5, 4 hours at 6.8 pH pH 7,5 7.5 <50% 40 to 90% 6 hours at 6.8 < pH < 7.5 > 70%, the percentages referring to the weight of the 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 coating's resistance to pH values of 4.5 to 5.5, preferably selected from the group consisting of poly (meth) acrylic acid esters, hydroxypropylmethylcellulose and mixtures thereof, and optionally talc and / or at least one plasticizer. The galenic form according to claims 1 to 4, characterized in that 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 sustained 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 poly (meth) esters. 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, optionally talc and / or at least with one plasticizer. Galenic form according to claims 5 to 9, characterized in that the neutral carrier is composed of 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 a microgranule preparation agent selected from the group consisting of polyvinylpyrrolidone of different molecular weight, hydroxypropylmethylcellulose and different molecular weight hydroxypropylcellulose, poly (meth) acrylic acid esters and mixtures thereof. Galenic form according to claims 1 to 11, characterized in that the gastroresistant microgranules and the sustained release granules have a mean particle diameter of 0.4 to 1.5 mm, preferably 0.8 to 1.1 mm. Galenic form according to claims 1 to 12, characterized in that the 5-nitroimidazole derivative is selected from the group consisting of metronidazole, secnidazole, tinidazole and salts thereof. 14. A pharmaceutical composition comprising, as the active ingredient, the galenic form of the 5-nitroimidazole derivatives of claims 1 to 13 in the form of tablets, fast-disintegrating tablets and gelatin capsules. Use of a galenic form of 5-nitroimidazole derivatives according to claims 1 to 13 for the preparation of a medicament against parasites and in the digestive tract infection, in particular amebiases and infections associated with the presence of Heliobacter pilori.