Dosage form derivatives of 5-intorimidazole

 

(57) Abstract:

The invention relates to the field of pharmacy and relates to dosage forms of derivatives of 5-intorimidazole. The proposed combination of microgranules comprising gastroresistant micro granules and microgranules with prolonged release of the active substance. The proposed pharmaceutical composition based on the combination of components and intermediate products. The proposed form does not have undesirable side effects. 5 C. and 14 C.p. f-crystals, 5 PL.

The invention relates to a new pharmaceutical form derivatives of 5-intorimidazole, which is effective for the treatment of parasitic and infectious diseases of the entire gastro-intestinal tract.

In particular, it relates to a new form, intended for the treatment of parasitic and infectious diseases, demonstrating resistant forms in the lower intestine, especially in the sigmoid and rectum.

Parasitic diseases of the intestine, such as amebiasis, a parasitic disease of the large intestine, which can be complicated extraintestinal localization, shown in the lower intestine resistant forms responsible These cysts, present in the lower part of the digestive tube of infected subjects stand out with the faeces. The lack of personal and collective hygiene contributes to the spread of the disease, as well as re-infection of individuals who are carriers of these parasites.

Entamoebacter histolytica also exists in a more labile form, Entamoebacter histolytica minuta, which does not cause damage, but can turn into a pathogenic form, Entamoebacter histolytica histolytica, which is embedded in the intestinal mucosa and causes the spread of the disease across the upper and lower parts of the intestine in the form of cysts. This form is also responsible for the most frequent complication of amebiasis, which migrates to the liver or even lung, or brain.

Possible rapid treatment of parasitic diseases and infections of the intestine medicines that are used to treat travelers. However, this treatment is not applied systematically and does not take into account hygienic problems responsible for the spread of these diseases.

There are also conventional and inexpensive ways to treat amebiasis azole-containing derivatives, in particular derivatives of 5-nitroimidazole intestine forms minuta and histolytica, not too effective against cysts. Moreover, these derivatives of 5-intorimidazole, which is administered in too large quantities, are absorbed in the upper part of the digestive tube, which can cause unwanted side effects metallic taste in the mouth) or even toxic effects.

Other conditions under which develop resistant forms in the lower intestine, can also be treated with the same disadvantages, derivatives of 5-intorimidazole. This is, for example, infections that are caused by Helicobacter pilori, bacteria that are present in the stomach and in the lower part of the digestive tube and which are involved in the pathogenesis of gastritis and gastric ulcers and duodenal ulcers; stimulation which causes Helicobacter by increasing the secretion of hydrochloric acid in the stomach, leads to ulceration of the membranes of the stomach and duodenum. The participation of these bacteria also mentioned in the Genesis of cancer of the digestive tract.

Recognising the growing importance of parasitic and infectious diseases of the entire gastro-intestinal tract, the researchers realized the importance of finding inexpensive ways of treatment, taking into account the problems of transmission of these diseases that are associated with otsutstviyem intestines.

To resolve these various problems, the present invention therefore relates to a new form of derivatives of 5-intorimidazole.

Dosage form of the present invention contains a combination of microgranules derivatives of 5-intorimidazole, consisting, on the one hand, from gastroresistant of microgranules, and, on the other hand, from microgranules slow release of the drug.

Gastrorresistente microspheres are designed to ensure the effectiveness of dosage forms of the present invention, mainly in the upper part of the gastrointestinal tract, while the microspheres slow release drugs act mainly in its lower part.

The ratio of different microgranules should correspond to the desired effect, favoring the effective action dosage forms of the present invention mainly in the upper or lower digestive tract or, alternatively, providing constant action throughout its length. This ratio will also depend on the fillers that are used for the preparation of microgranules.

In order to guarantee the high efficiency of the dosage form of the present invention, the composite microspheres must meet the following dissolution characteristics:

gastrorresistente microspheres:

2 hours in HCl 0.1 N. - Less than 15%

1 hour at a pH of 6.0 - Over 75%

microspheres slow release drugs:

2 hours in HCl 0.1 N. - Less than 15%

1 hour at a pH of 6.8 to 7.5 - Less 50%

4 hours at a pH of 6.8 to 7.5 - 40 - 90%

6 hours at a pH of 6.8 to 7.5 - 70%

The percentages are given by weight of the active ingredient that is dissolved, relative to the total weight before the dissolution.

Microspheres suitable for dosage forms of the present invention, preferably consists of a neutral granular media, covered with an active layer consisting of a mixture of the active ingredient, a derivative of 5-intorimidazole, and sumala and sucrose, having an average diameter of between 400 and 800 microns.

Derived 5-intorimidazole preferably selected from metronidazole, secnidazole, tinidazole and mixtures thereof.

The binding agent is a common agent, which is known for the preparation of microgranules, and preferably is selected from polyvinylpyrrolidone different molecular weights (preferably grade Kollidon K30 and K17 (produced by BASF)); type corresponds to the value of the constant K, which is a function of molecular weight and viscosity of the product. The constant K is subject to the specifications of various official publications, currently in force, in regard polyvinylpyrrolidone; from hydroxypropylmethylcellulose different molecular weights (preferably grade 615; grades of HPMC are a function of the level of product substitution with methoxy and hydroxypropoxy and reflect viscosity; different varieties described in official publications for this product, in particular in the standard edition of the U.S. Pharmacopoeia XXII); from hydroxypropylcellulose different molecular weights of poly(meth)acrylic esters (produced by the company ROHM GmbH under the trade name EUDRAGIT) and mixtures thereof.

Resumeediting and a binding agent.

Gastrorresistente microspheres and microspheres slow release medicines differ outer layer covering the active layer. For gastroresistant of microgranules it will be gastroresistant outer layer, and, on the other hand, for the microgranules slow release drug - outer layer for prolonged release of the drug.

Gastroresistant the outer layer consists of conventional fillers used for cooking gastroresistant of microgranules. It contains fillers, guaranteeing resistance coating at pH values less than 5.0, preferably chosen from poly(meth)acrylic esters (produced by the firm ROHM under the trade names EUDRAGITL 100-55, EUDRAGITL 100, EUDRAGITL 30D-55), phthalate of hydroxypropylmethylcellulose (produced by the company SHIN ETSU Chemical Co., Ltd., under the trade names HP 50and HP 55) and mixtures thereof.

The outer layer extended release consists of the usual fillers, which are used for the preparation of microgranules slow release of drug is x esters (produced by the firm ROHM under the trade names EUDRAGITRS 100, EUDRAGITRS 30D), ethyl cellulose (manufactured by a company FMC Corporation, Philadelphia, under the trade name AQUACOAT) and mixtures thereof. In this case, the time of the release of the active ingredient will be determined by the transit time of the microgranules according to the intestines.

External prolonged release layer may include a filler, which depends on the pH of the environment in which microspheres are, in particular, pH-sensitive poly(meth)acrylic esters (produced by the firm ROHM under the trade name EUDRAGITS). In this case, the time of the release of the active ingredient will be determined not by way of the microgranules according to the intestines, and the pH value of the medium, on which they pass. Thus, in order to ensure release of the active ingredient in the lower intestine, it is necessary to choose a filler which is soluble at a pH greater than 7, such as EUDRAGITS. of Course, depending on the desired effect microspheres slow release medications may also consist of a mixture of microgranules with pH-dependent release of the drug, so that the active ingredient vysvobozhdavshej release depending on the time of passage through the intestines and pH.

Gastroresistant the outer layer and the outer layer extended release may also contain conventional excipients, such as talc, facilitating the coating due to its lubricating properties, or derivatives of silicon oxide or stearic acid and/or one or more plasticizers, which facilitate the formation of the covering film, especially esters of (poly)carboxylic acids, such as esters of citric acid (especially triethylcitrate), dibutylsebacate and mixtures thereof.

Since great importance is the size of the microgranules from the point of view of speed of their passage through the intestines, the average diameter of the micro granules that are used in the dosage form of the present invention is preferably 0.4-1.5 mm, preferably from 0.8 to 1.1 mm Microspheres, which are used in the dosage form of the present invention, preferably made according to the following scheme:

- floor neutral cores active layer,

- coating of the active layer gastroresistant layer or layer extended release, depending on the form of microgranules,

- screening and

- drying.

The microspheres are then mixed in the desired soodesh tablets in gelatin capsules or, alternatively, Sasha.

The present invention therefore relates to pharmaceutical compositions containing dosage form as described above.

It also applies to gastroresistant microspheres and microspheres slow release medicines described above as intermediate products in the manufacture of galenical form according to the present invention.

Of course, since gastrorresistente microspheres and microspheres slow release medicines are manufactured and packaged separately, the present invention relates also to the combined product containing microspheres gastro-protected derivatives of 5-intorimidazole and microspheres slow release 5-intorimidazole as described above for use in combination, simultaneously, separately or separated in time, for the treatment of parasitic and infectious diseases of the gastrointestinal tract, in particular of amebiasis and infection associated with the presence of Helicobacter pilori.

Other characteristics of the new form of the present invention in the e l e C presented in table. 1.

Percentages represent weight relative to the total weight of the microgranules. Ingredients:

Neutral core: consists of sucrose (about 75%) and corn starch (about 25%)

- PVP: polyvinylpyrrolidone K30

- FG: phthalate of hydroxypropylmethylcellulose, dissolution from pH 5.0

- ethylcellulose N 7: ethylcellulose whose grade N 7 corresponds to the viscosity of this product.

The microspheres produced in accordance with the procedure described below.

Example 2: a mixture of 3/7 of microgranules of metronidazole

The following mixture was prepared according to the same procedure (see tab. 2).

Percentages represent weight relative to the total weight of the microgranules. Ingredients:

Neutral core: consists of sucrose (about 75%) and corn starch (about 25%)

- PVP: polyvinylpyrrolidone K30

- EUDRAGITL30D-55; aqueous dispersion of a copolymer of methacrylic acid type C; dissolution from pH 5.5

- Talc

- EUDRAGITS: methacrylic acid copolymer type B; dissolution from pH 7.0.

Example 3: a 25/75 mixture of microgranules of metronidazole

The following mixture was prepared according to the same procedure (the options:

Neutral core: consists of sucrose (about 75%) and corn starch (about 25%)

- EUDRAGITE 100; methacrylic acid copolymer used as the binder

- EUDRAGITL30D-55

- EUDRAGITRS 30D: aqueous dispersion of a copolymer of methacrylic acid type B; the dissolution of slow release

- Talc

Example 4: a mixture of the corresponding series XM285

The following mixture was prepared according to the same procedure:

Part of a series XM285:

Metronidazole - 65,1

The neutral core - 21,7%

PVP K30 - 4,8%

Ethylcellulose N 7 - 1.3% OF

FG 50 - 5,0%

Ethylcellulose N 7 - 1.3% OF

Triethylcitrate - 0,5%

Talc - 1,6%

Total 100.0% of

Example 5: composition of secnidazole

The following mixture was prepared according to the same procedure (see tab. 4).

Characteristics of dissolution

Experiments on the dissolution of the forms of examples 1 and 4 were carried out in 0.1 N. HCl solution and at a pH of 6.8. The results are presented in table. 5. Percentages represent weight dissolved microgranules with respect to the total weight of the microgranules before dissolution.

Clinical trials

Clinical study of the effectiveness of the form p is the presence of cysts in the colon.

The study was performed using strict randomized double blind method with double placebo; comparing the shape of the example 1 with metronidazole, which is sold under the trade name Flagyl.

Input dose was 1.5 g/day (3 day dose of two capsules containing 250 mg of metronidazole) for 10 days.

The results of this study showed the frequency of recovery of 85% for the form of the present invention and 14% for Flagyl.

Manufacturing technology of microgranules metronidazole (series XM 415/2)

Phase 1: Preparation of binder solution: 20% alcoholic solution of PVP

the solution prepared in the mixer stainless steel

is poured into 95% ethyl alcohol with a stirrer,

- started stirring and added PVP in small portions,

- continued stirring until complete dissolution.

Phase 2: Application

- put the granules neutral media in the rotating turbine,

- applying is performed by spraying the active ingredient over a neutral microspheres alternately with spraying a binding solution,

- sifting through the mass of microgranules (you can use a sieve with cells 0,50; 0,71; 0,99; 1,12; 1.25 mm),

the of mass into two parts

- divided the mass into two parts, A and B, respectively 75% and 25% of the mass of microgranules,

- put each of the two parts in different turbines.

Phase 4: Preparation of primers: alcohol solution of ethyl cellulose N-7, 10%.

the solution prepared in the mixer stainless steel

is poured into the mixer 95% ethyl alcohol,

- started stirring and add ethylcellulose small portions,

- continued stirring until complete dissolution.

Phase 5: the Coating part A priming solution

- applied primer solution of microspheres by spraying,

simultaneously sprayed talc,

- sift the mass of microgranules (you can use a sieve with cells 0,50; 0,71; 0,99; 1,12; 1.25 mm),

- dried microspheres by blowing hot air inside Uralalmaz turbine.

Phase 6: Preparation of coating solution: atmosphereby solution (20/80) at 7.5% per 50 FG

the solution prepared in the mixer stainless steel

is poured into the mixer 95% ethanol and then acetone,

- started stirring and added a FG of 50 small portions,

- continued stirring until complete dissolution.

Phase 7: the Floor is and the granules by spraying,

- sift the mass of microgranules (you can use a sieve with cells 0,50; 0,71; 0,99; 1,12; 1.25 mm),

- drying of microgranules by blowing hot air inside the rotating turbine.

Phase 8: the Blurring and blending of two parts

- put the two parts A and B, as well as lubricating agent is talc in a rotating turbine,

- mixed mass,

- stopped the turbine.

New herbal form of the present invention is also suitable for the prevention of infection by anaerobic microorganisms during surgical interventions with a high risk of infection such, for example during operations on the gastrointestinal tract.

1. Dosage form derivatives of 5-intorimidazole, characterized in that it contains a combination of microgranules derivatives of 5-intorimidazole, consisting, on the one hand, from gastroresistant of microgranules and, on the other hand, from microgranules slow release of the drug.

2. Dosage form under item 1, characterized in that the weight ratio between gastrorresistente the microspheres and the microspheres slow release medicines costal is resistant microspheres and microspheres slow release medicines is from 25/75 to 15/85.

4. Pharmaceutical form according to one of paragraphs.1 to 3, characterized in that the composite microspheres must meet the following characteristics of dissolution, expressed in wt.% dissolved microgranule of the total weight before the dissolution:

gastrorresistente microspheres:

2 h in HCl 0.1 N. - Less than 15%

1 h at pH 6,0 - More than 75%

microspheres slow release drugs:

2 h in HCl 0.1 N. - Less than 15%

1 h at 6,8pH7,5 - Less than 50%

4 h in 6,8 pH7,5 - 40 - 90%

6 h at 6,8pH7,5 - More than 70%.

5. Pharmaceutical form according to one of paragraphs.1 to 4, characterized in that gastrorresistente microspheres consist of a neutral granular media, covered with an active layer consisting of a mixture of a derivative of 5-intorimidazole and a binding agent, and gastrorresistente outer layer.

6. Dosage form under item 5, characterized in that gastroresistant outer layer contains fillers, guaranteeing resistance coating at pH values of 4.5 to 5.5, preferably chosen from poly(meth)acrylic esters, hydroxypropylmethylcellulose and mixtures thereof.

7. Dosage form under item 5,characterized in that gastroresistant outer layer equipment from poly(meth)acrylic esters, hydroxypropylmethylcellulose and mixtures thereof, talc and/or one or more plasticizers.

8. Pharmaceutical form according to one of paragraphs.1 to 4, characterized in that the microspheres slow release medicines consist of neutral granular media, covered with an active layer consisting of a mixture of a derivative of 5-intorimidazole and a binding agent, and the outer layer of sustained release.

9. Dosage form under item 8, characterized in that the outer layer extended release contains the usual fillers, which are used in the manufacture of microgranules slow release medicines that are not dependent on the pH of the environment in which we operate microspheres, and which are selected from poly(meth)acrylic esters, ethyl cellulose and mixtures thereof.

10. Dosage form under item 8, characterized in that the outer layer extended release contains the usual fillers, which are used in the manufacture of microgranules slow release medicines that are not dependent on the pH of the environment in which we operate microspheres, and which are selected from poly(meth)acrylic esters, Atila and 7, characterized in that gastroresistant outer layer contains at least one filler, which depends on the pH of the medium through which the microspheres, in particular, pH-sensitive poly(meth)acrylic esters, and optionally talc and/or one or more plasticizer.

12. Pharmaceutical form according to one of paragraphs.5 to 11, characterized in that a neutral carrier comprises particles of starch or a mixture of starch and sucrose, which have an average diameter of 400 to 800 μm.

13. Pharmaceutical form according to one of paragraphs.5 to 12, characterized in that the binding agent is a common agent, known for the preparation of microgranules, which is preferably selected from polyvinylpyrrolidone different molecular weights, hydroxypropylmethylcellulose different molecular weights, hydroxypropylcellulose different molecular weights of poly(meth)acrylic esters and mixtures thereof.

14. Pharmaceutical form according to one of paragraphs.1 - 13, characterized in that gastrorresistente microspheres and microspheres slow release medicines have an average diameter of 0.4 - 1.5 mm, preferably from 0.8 to 1.1 mm

15. Pharmaceutical form according to one of paragraphs.1 - 14, SS="ptx2">

16. Pharmaceutical composition for the treatment of parasitic and infectious diseases of the gastrointestinal tract, characterized in that it is a pill or a quick-dissolving tablet or capsule containing a combination of microgranules derivatives of 5-intorimidazole according to any one of paragraphs.1 - 15.

17. Mastrosimone microspheres derivatives of 5-intorimidazole, which are particularly suitable for the preparation of dosage forms in one of the paragraphs.1 - 15, characterized in that it consists of a neutral granular media, covered with an active layer consisting of a mixture of a derivative of 5-intorimidazole and a binding agent and gastrorresistente outer layer.

18. Microspheres are derivatives of 5-intorimidazole slow release, which is particularly suitable for the preparation of dosage forms in one of the paragraphs.1 - 15, characterized in that it consists of a neutral granular media, covered with an active layer consisting of a mixture of a derivative of 5-intorimidazole and a binding agent, and the outer layer of sustained release.

19. Combination product containing microspheres gastronomists derivatives of 5-intorimidazole and microspheres with prolonging or separated in time for the treatment of parasitic and infectious diseases of the gastrointestinal tract, in particular, amebiasis and infection associated with the presence of Helicobacter pilori.

 

Same patents:

The invention relates to medicine, pharmacology, veterinary medicine and biology
The invention relates to medicine, in particular to infectious diseases and can be used for the treatment of infectious mononucleosis
The invention relates to medicine, more specifically, neurology, and can be used in the treatment of multiple sclerosis

The invention relates to medicine, in particular to pharmacology relates to stable water-soluble compositions of triiodide 1,2,3-dialkylanilines formula I, where R1, R3=alk; R2= alk, H

The invention relates to the field of medicine and is suitable for the treatment of urinary tract infections (pyelonephritis, cystitis, prostatitis), and also to prevent infections after surgery for the kidneys and urinary tract
The invention relates to antidepressant drug DULOXETINE in the form of enteric granules

The invention relates to medicine

The invention relates to the field of medicine

The invention relates to medicine, specifically to new granules with controlled release, containing a core of inert material'm entwined layer containing the drug, and method of production thereof
Up!