KR100320140B1 - Micro granules of 5-nitroimidazole derivatives - 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

Micro granules of 5-nitroimidazole derivatives

The present invention relates to a novel formulation of 5-nitroimidazole derivatives effective for the treatment of parasitoses and infections of the entire gastrointestinal tract, in particular the lower part of the intestinal tract, in particular the S phase colon and rectum. Novel formulations are prepared for the treatment of parasitic and infectious diseases exhibiting resistant forms in the sigmoid colon and rectum.

Intestinal parasites, such as amoebiasis and colonic parasites, which can cause complications in the extra-intestinal tract, appear in a resistant form that causes these conditions to be transmitted in the lower intestine of the intestine.

In the case of amoeba, these are Entamoebacter histoolytica cysts. These cysts present in the lower digestive tract of an infected subject are excreted with feces. Lack of personal hygiene and group hygiene not only reinfects individuals who are carriers of these parasites, but also spreads the disease.

Entamobacter histolytica is also present in the more unstable form, entamoebter histolytica minuta, which does not cause lesions, but is in the form of a pathogen, i.e. After being reduced to Lytica, it can infiltrate the mucous membrane of the intestine in the form of cysts and spread the disease to the upper and lower parts of the intestine. This form also causes complications of the most prevalent amoeba disease, which spreads to the liver, even the lungs or the brain.

It is a drug used for the treatment of touristas and can quickly treat parasites and intestinal infections. However, such treatment cannot be applied systematically and does not take into account the hygiene problems that cause the transmission of these diseases.

Likewise, there is a conventional, low cost method of treating amoebasis using azole containing derivatives, in particular 5-nitroimidazole derivatives such as metronidazole, cecnidazole and the like. However, these treatments are effective against intestinal upper conditions for Minuta and histolytica forms, but not very effective for treating cysts. In addition, 5-nitroimidazole derivatives administered in large amounts can be absorbed in the upper part of the digestive tract, causing poor side effects (metallic taste in the mouth) and even toxic effects.

Other forms that produce a resistant form in the lower intestine can be treated with 5-nitroimidazole derivatives, but have similar drawbacks as described above. Examples include Helicobacter pilori, an infection caused by bacterium present in the stomach and in the lower part of the digestive tract, associated with the development of gastritis, gastric ulcer and duodenal ulcer. Stimulation by causes gastric acid secretion, leading to ulceration of the gastric and duodenal membranes. It is also involved in the development of cancer of the digestive tract.

As parasitic and infectious diseases of the entire gastrointestinal tract grew in importance, it became important to find an inexpensive treatment method that takes into account the problem of transmission of conditions related to hygiene deficiency, that is, to effectively treat the resistance forms in the lower part of the intestine.

In order to solve the above problems, the present invention provides a novel formulation of 5-nitroimidazole derivatives.

The formulation according to the invention consists of a mixture of micro granules of 5-nitroimidazole derivatives consisting of gastroresistant microgranules and prolonged-release microgranules.

Gastroresistant microgranules are used to confer efficacy of the formulations of the invention substantially above the gastrointestinal tract, whereas sustained release microgranules are used to induce efficacy substantially above the gastrointestinal tract.

The ratio of the various micro granules should be suitable to promote the action of the formulation of the present invention in the upper and lower parts of the intestine, or to obtain the desired efficacy of imparting a constant action over the entire length of the intestine. It will also depend on the excipients used to prepare the micro granules.

The weight ratio of gastroresistant microgranules / sustainable microgranules is 6/4-1/9, preferably 4/6-1/9. With respect to the state of the lower intestine, in order to obtain a formulation of the present invention having high potency, the weight ratio of gastroresistant microgranules / sustained microgranules is preferably 25/75-15/85.

To obtain a high potency, formulation of the present invention, the mixed micro granules must conform to the following dissolution pattern.

Gastric resistant micro granules

2 hours <15% in 0.1N HCl

1 hour> 75% at pH 6

Sustained Release Micro Granules

2 hours <15% in 0.1N HCl

1 hour <50% at 6.8 ≤ pH ≤ 7.5

4 hours 40-90% at 6.8 ≤ pH ≤ 7.5

6 hours> 70% at 6.8 ≤ pH ≤ 7.5

The percentage is expressed as the weight of dissolved active ingredient relative to the total weight before dissolution.

Preferably, the micro granules useful in the formulations of the present invention comprise a neutral granular carrier coated with an active layer consisting of a mixture of the active ingredient 5-nitroimidazole derivatives and a binder.

The neutral carrier is preferably a starch particle and a mixture of starch and sucrose, and the mean diameter of the particles is 400-800 mu (micron).

5-nitroimidazole derivatives are preferably selected from metronidazole, cecnidazole, tinidazole and mixtures thereof.

The binder used in the present invention is a known conventional reagent used in the preparation of micro granules, preferably

Polyvinylpyrrolidone of various molecular weights (preferably K30 and K17 Kollidon grades (manufactured by BASF); The grade corresponds to the value of the constant K which is a function of the molecular weight and viscosity of the product, the constant K being a subject of the description of the various formula monographs in the current application as far as polyvinylpyrrolidone is concerned;

Hydroxypropyl methylcellulose of various molecular weight [preferably grade 615, HPMC grade is a function of the substitution level of the product substituted with methoxy and hydroxy propoxy groups and reflects viscosity. Various grades are described in the formula monographs of the products, in particular USP XXII;

Hydroxypropyl cellulose and poly (meth) acrylic acid esters of various molecular weights [Brand name: "EUDRAGIT Marketed by ROHM GmbH];

And mixtures thereof.

The invention of course also applies to microgranules consisting of a core consisting solely of the active ingredient and the binder.

Gastric resistant and sustained release micro granules each have a different outer layer covering the active layer. The gastroresistant microgranules have a gastroresistant outer layer, while the sustained release microgranules have a sustained release outer layer.

Gastroresistant microgranules comprise conventional excipients used in the art of making gastroresistant microgranules. It consists of excipients which allow the coating layer to retain resistance to less than pH 5.0, preferably poly (meth) acrylic acid esters (trade name "EUDRAGIT L 100-55 "," EUDRAGIT L 100 "," EUDRAGIT Marketed by ROHM GmbH under L 30D-55 ", hydroxypropyl methylcellulose phthalate (trade name" HP 50 "And" HP 55 Commercially available from SHIH ETSU Chemical Co., Ltd.) and mixtures thereof.

The sustained release outer layer comprises, as a part, conventional excipients used in the art of making sustained release micro granules, which are independent of the pH of the medium on which the sustained release micro granules act, preferably poly (meth). Acrylic esters (trade name "EUDRAGIT RS 100 "," EUDRAGIT Sold by ROHM GmbH under "RS 30D)", ethyl cellulose (trade name "AQUACOAT (Available from FM C Corporation, Philadelphia) and mixtures thereof. In this case, the intestine will determine the release time of the active ingredient as the transit time of the micro granules.

The sustained release outer layer may also contain excipients, in particular pH dependent poly (meth) acrylic acid esters (trade name "EUDRAGIT", depending on the pH of the medium in which the micro granules run. Marketed by ROHM GmbH under S ". In this case, determining the release time of the active ingredient is no longer the transit time of the micro granules, but rather of the medium with which they travel (pass). pH, therefore EUDRAGIT to ensure that the active ingredient is released above the intestine Excipients that dissolve at a pH above 7, such as S, will be selected. Of course, depending on the desired efficacy, the sustained release micro granules may also be a mixture of pH dependent release micro granules to release the active ingredient at various pH values, or pH dependent or pH independent, which controls release as a function of run time and pH. It may consist of a mixture of micro granules.

The gastric resistant outer layer and the sustained release outer layer are conventional auxiliaries such as talc or silica or stearic acid derivatives which promote coating by lubricating properties, and / or one or more plasticizers, in particular citric acid esters, which promote good film formation ( (Poly) carboxylic acid esters such as triethyl citrate), dibutyl sebacate and mixtures thereof.

Given the importance of the size of the micro granules to the speed of travel in the intestine, the average diameter of the micro granules useful in the formulation of the present invention is preferably 0.4-1.5 mm, more preferably 0.8-1.1 mm.

Micro granules useful in the formulations of the present invention are preferably prepared according to the following procedure.

-Cover the neutral core with the active layer,

-Cover the active layer with a gas resistant layer or a sustained release layer according to the micro granules,

Screening,

-Dry it.

The micro granules are then mixed in the desired proportions and packaged in a form suitable for administration, in particular in the form of tablets, rapidly-disintegrating, gelatin capsules or sachets.

The present invention therefore relates to a pharmaceutical composition in the form described above.

The invention also relates to the above gastro-protected and sustained release micro granules as intermediate products obtained in the preparation of the preparations of the invention.

Of course, because the gastro-resistant and sustained-release micro granules can be prepared and packaged separately, the present invention also simultaneously provides for the treatment of parasitic parasites and infections of the gastrointestinal tract, especially infections associated with the presence of amoeba disease and Helicobacter pylori. The present invention relates to a mixed product comprising a micro granule of the above-protected 5-nitroimidazole derivative and a micro granule of a sustained-release 5-nitroimidazole derivative used in combination or used separately or at regular intervals.

Other properties of the novel formulations of the invention will appear in the examples below.

Example 1: 2/8 mixture of metronidazole micro granules.

The following mixtures were prepared.

The percentages are expressed as weight relative to the total weight of the micro granules.

Active Ingredients:

Neutral Core: Sucrose (75%) and Corn Starch (25%)

PVP: Polyvinylpyrrolidone K30

-HP 50: hydroxypropyl methylcellulose phthalate, dissolved from pH 5.0

-Ethyl cellulose N7: ethyl cellulose where grade N7 represents the viscosity of the product

Micro granules were prepared according to the method described below.

Example 2 Metronidazole Micro Granules 3/7 Mixture

The following mixtures were prepared according to the same method:

The percentages are expressed as weight relative to the total weight of the micro granules.

Active Ingredients:

Neutral core, consisting of sucrose (about 70%) and corn starch (about 25%).

PVP: Polyvinylpyrrolidone K30

-EUDRAGIT L 30D-55: Dissolve the water product of Form C methacrylic acid copolymer at pH 5.5

Talc

EUDRAGIT S: Form B methacrylic acid copolymer, dissolved in pH 7.0.

Example 3 25/75 Mixture of Metronidazole Micro Granules

The following mixtures were prepared according to the same method.

The percentages are expressed as weight relative to the total weight of the micro granules.

Active Ingredients:

Neutral core: Sucrose (about 70%) and corn starch (about 25%).

EUDRAGIT E 100: Methacrylic acid copolymer used as binder in the present invention

EUDRAGIT L30D-55

EUDRAGIT RS 30D: Aqueous product of Form B methacrylic acid copolymer, soluble in sustained release form.

Example 4 Mixture Corresponding to Batch XM 285

The following mixtures were prepared according to the same method.

The composition of the batch XM 285

Example 5 Cecnidazole Formulations

The following mixtures were prepared according to the same method.

Melting pattern

Dissolution tests for the formulations of Examples 1 and 4 were carried out in 0.1 N HCl solution and pH 6.8. The results are shown in the table below. Percentages are expressed as the weight of dissolved micro granules relative to the total weight of micro granules prior to dissolution.

Clinical trial

A clinical study of the efficacy of the formulations of the present invention was conducted in 60 male and female patients aged 15-75 years with cystic morphology in the colon.

This study is strict "randomized". In accordance with double placebo and double blind methodology, the formulation of Example 1 was compared to metronidazole sold under the trade name "Flagyl".

The dose was 1.5 g / day for 10 days (two gelatin capsules containing 250 mg dose of metronidazole were the three day dose).

As a result of this study, the treatment rate was 14% for Flagil, whereas the formulation of the present invention showed 85%.

Method for preparing metronidazole micro granules (batch XM 415/2)

Step 1: Preparation of the binding solution: Alcoholic solution of 20% PVP in alcohol

Preparation of solutions in stainless steel mixers,

Injecting -95% ethyl alcohol into the mixer,

Small amount of PVP mixed after stirring,

Continue stirring until complete dissolution.

Step 2: Application

-Put neutral carrier particles into the rotary turbine.

Alternating with spraying of the binding solution, spraying the active ingredient onto the neutral micro granules,

Screening of the micro granule mass,

(Available screen: mesh opening 0.50; 0.71; 0.99; 1.12; 1.25mm),

-Dry the micro granules by blowing hot air into the rotating turbine.

Step 3: split the mass into two parts

Splitting the micro granule mass into portions A and B comprising 75% and 25%, respectively.

-Inject each part into a different turbine.

Step 4: Preparation of Premounting Solution: Alcoholic Solution of 10% Ethylcellulose N7

Preparation of solutions in stainless steel mixers,

Injecting -95% ethyl alcohol into the mixer,

Stirring and incorporating a small amount of ethyl cellulose,

Continue stirring until complete dissolution.

Step 5: Premounting Part A

Application of the premounting solution to the micro granules by spraying,

-You can buy talc at the same time,

Screening Micro Granulation Masses

(Available screen: mesh opening 0.50; 0.71; 0.99; 1.12; 1.25mm),

-Dry the micro granules by blowing hot air into the rotating turbine.

Step 6: Preparation of Application Solution: 7.5% HP 50 Acetoalcoholic Solution (20/80)

Preparation of solutions in stainless steel mixers,

-95% ethyl alcohol followed by acetone in a mixer

Stir and mix small amount of HP-50

Continue stirring until complete dissolution.

Step 7: Application of Part A and Part B: Apply at intervals for Part A and Part B

Application of the application solution to the micro granules by spraying,

-Screening micro granule mass,

(Available screen: mesh opening 0.50; 0.71, 0.99; 1.12; 1.25 mm)

-Dry the micro granules by blowing hot air into the rotating turbine.

Step 8: Lubrication-Mixing the Two Parts

Inject two parts A and B and lubrication talc into the rotary turbine,

-Mix the mass

-Stop the turbine operation.

The novel formulations of the present invention appear to be useful for the prophylactic treatment of hepatitis caused by anaerobic microorganisms in high risk surgical operations such as surgery of the digestive organs.

Claims (27)

An oral preparation of a 5-nitroimidazole derivative, comprising a mixture of 5-nitroimidazole derivative micro granules, consisting of a gastro-resistant micro granule and a sustained release micro granule. The oral preparation of 5-nitroimidazole derivatives according to claim 1, wherein the weight ratio of the gastroresistant granules / sustainable micro granules is 6/4-1/9. The oral preparation of 5-nitroimidazole derivatives according to claim 2, wherein the weight ratio of the gastroresistant microgranules / sustainable microgranules is 25/75-15/85. The oral preparation of 5-nitroimidazole derivative according to any one of claims 1 to 3, wherein the micro granule mixture corresponds to the following dissolution pattern. Upper resistant micro granules: 2 hours in 0.1N HCl <1% at 15% pH 6.0> 75% Sustainable Micro Granules 2 h <15% in 0.1 N HCl 1 h <50% at 6.8≤p≤7.5 4 hours 40%-90% at 6.8≤pH≤7.5 6 hours> 70% at 6.8≤pH≤7.5 (The percentage is expressed as the weight of dissolved micro granules relative to the total weight before dissolving) The gastroresistant microgranule of claim 1, wherein the gastroresistant microgranule comprises a neutral particulate carrier coated with an active layer consisting of a mixture of 5-nitroimidazole derivatives and a binder, and a gastroresistant outer layer. Oral preparation of 5-nitroimidazole derivatives. 6. The gastric resistant outer layer of claim 5, wherein the gastroresistant outer layer comprises an excipient that allows the coating layer to resist resistance to pH 4.5-5.5, and further comprising or without talc and / or one or more plasticizers. Oral preparations of nitroimidazole derivatives. 4. The sustained release micro granules of claim 1, wherein the sustained release micro granules comprise a neutral particulate carrier coated with an active layer consisting of a mixture of 5-nitroimidazole derivatives and a binder, and a sustained release outer layer. An oral preparation of 5-nitroimidazole derivative characterized by the above-mentioned. The method of claim 7, wherein the sustained release outer layer comprises an excipient independent of the pH of the medium on which the sustained release micro granules act, and further comprising or without talc and / or one or more plasticizers. Oral preparations of 5-nitroimidazole derivatives. 9. The oral preparation of 5-nitroimidazole derivative according to claim 8, wherein the sustained release outer layer further comprises one or more excipients soluble at pH 7 or above. 6. The oral preparation of 5-nitroimidazole derivative according to claim 5, wherein the neutral carrier consists of starch particles or starch and sucrose mixture particles having an average diameter of 400-800 mu. The method according to any one of claims 1 to 3, 6 and 8 to 10, characterized in that the average diameter of the gastroresistant and sustained-release micro granules is 0.4-1.5 mm. Oral preparations of nitroimidazole derivatives. The method according to any one of claims 1 to 3, 6, 8 to 10, wherein the 5-nitroimidazole derivative is selected from metronidazole, cecnidazole, tinidazole and mixtures thereof. Oral preparation of 5-nitroimidazole derivative, characterized in that. A pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, characterized in that it consists of an oral preparation according to any one of claims 1 to 3, 6 and 8 to 10. Microgranulation and sustained release of gastro-protective 5-nitroimidazole derivatives used in combination, separately or at regular intervals in the treatment of gastrointestinal parasites and infections Oral mixed preparations comprising a micro granule of 5-nitroimidazole derivatives. 7. The oral preparation of claim 6, wherein the excipient is selected from poly (meth) acrylic acid esters, hydroxy propyl methylcellulose, and mixtures thereof. The oral preparation of claim 8, wherein the excipient is selected from poly (meth) acrylic acid aster, ethyl cellulose and mixtures thereof. 10. The oral preparation of claim 9, wherein the excipient is poly (meth) acrylic acid ester, 6. The oral preparation of claim 5, wherein the binder is selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropyl cellulose, poly (meth) acrylic acid esters, and mixtures thereof. 12. The oral preparation of claim 11, wherein the gastroresistant and sustained release microgranules have an average particle diameter of about 0.8 to 1.1 mm. 14. The oral formulation of claim 13, wherein the formulation is a tablet, or rapidly-disintegrating tablet or gelatin capsule. The pharmaceutical composition of claim 13 for the treatment of amoebiasis and Helicobacter pilori infection. 15. The oral combination formulation of claim 14, for the treatment of amoeba disease and Helicobacter pylori infection. A pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, comprising the oral preparation of claim 4. A pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, which is characterized by comprising an oral preparation according to claim 5. A pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, comprising the oral preparation of claim 7. A pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, comprising the oral preparation of claim 11. A pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, comprising the oral preparation of claim 12.