AU705570B2 - Microgranules of 5-nitro imidazole derivatives - Google Patents

Microgranules of 5-nitro imidazole derivatives Download PDF

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AU705570B2
AU705570B2 AU15803/95A AU1580395A AU705570B2 AU 705570 B2 AU705570 B2 AU 705570B2 AU 15803/95 A AU15803/95 A AU 15803/95A AU 1580395 A AU1580395 A AU 1580395A AU 705570 B2 AU705570 B2 AU 705570B2
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microgranules
prolonged
form according
release
galenic form
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AU1580395A (en
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Patrice Debregeas
Gerard Leduc
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Ethypharm SAS
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Ethypharm SAS
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/415—1,2-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

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  • Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Epidemiology (AREA)
  • Oncology (AREA)
  • Communicable Diseases (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

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

-2amoebiasis with azole-containing derivatives, in particular derivatives (metronidazole, secnidazole and the like), exist. However, these treatments, which are effective against conditions of the upper part of the intestines, against the minuta and histolytica forms, are not very effective for the treatment of cysts. Moreover, these 5-nitroimidazole derivatives, administered in too large quantities, 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.
Other conditions which develop resistant forms in the lower part of the intestines can also be treated, with the same drawbacks, with derivatives. They are for example infections caused by Helicobacter pilori, a bacterium present in the stomach and in the downstream part of the digestive tube and which is implicated in the pathogenesis of gastritis and of gastric and duodenal ulcer, the irritation caused by Helicobacter causing an acidic hypersecretion of the 15 stomach which results in ulceration of the gastric and duodenal membranes. Its participation has also been mentioned in the genesis of digestive cancers.
Given the increasing importance of parasitoses and infections of the entire gastrointestinal tract, it was becoming important to find an inexpensive treatment taking into account the problems of transmission of the conditions linked to lack of hygiene, that is to say which make it possible to treat effectively the resistant forms present in the lower part of the intestines.
In order to solve these various problems, the present invention therefore relates to a new galenic form of 5-nitroimidazole derivatives.
The form according to the invention comprises a combination of microgranules of 5-nitroimidazole derivatives consisting of gastroresistant microgranules and of prolonged-release microgranules, characterised in that the combined microgranules should correspond to the following dissolution patterns: gastroresistant microgranules: 2 hours in 0.1 N HC1 1 hour at pH 6.0 prolonged-release microgranules: l VG:JMD:#21107 29 January 1999 \Vx (C) -3- 2 hours in 0.1 N HC1 1 hour at 6.8 pH 7.5 4 hours at 6.8 5 pH 7.5 40% to 6 hours at 6.8 pH 7.5 the percentages being given by weight of active ingredient dissolved relative to the total weight before dissolution.
The gastroresistant microgranules are intended to ensure the efficacy of the form according to the invention essentially in the upper part of the gastrointestinal tract, whereas the prolonged-release microgranules act essentially in its lower part.
The ratio of the various microgranules will be appropriate to the desired effect, favouring action of the form according to the invention essentially in the lower or upper part of the tract, or alternatively so as to ensure a constant action over its entire length. It will also depend on the excipients used for preparing the 15 microgranules.
The gastroresistant microgranules/prolonged-release microgranule weight ratio is preferably between 6/4 and 1/9, advantageously between 4/6 and 1/9.
Preferably, in order to ensure a high efficacy of the form according to the invention on conditions of the lower part of the intestines, the gastroresistant microgranules/prolonged-release microgranule ratio is between 25/75 and 15/85.
The microgranules which are useful in the form according to the invention all advantageously consist of a neutral granular carrier coated with an active layer consisting of a mixture of active ingredient, 5-nitroimidazole derivative and a binding agent.
The neutral carrier advantageously consists of particles of starch and of a mixture of starch and DVG:JMD:#21107 29 January 1999 4 sucrose which have an average diameter of between 400 and 800 microns.
The 5-nitroimidazole derivative is advantageously chosen from metronidazole, secnidazole, tinidazole and mixtures thereof.
The binding agent is a customary agent known for its use in the preparation of microgranules, advantageously chosen from 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 the viscosity of the product. The constant K is the subject of specifications in the various official monographs in current usage, as regards polyvinylpyrrolidone); from hydroxypropyl methylcellulose of various molecular weights (preferably grade 615; the SHPMC grades are a function of the level of substitution of the product with Methoxy and Hydroxypropoxy groups and reflect the viscosity. The various grades are described in the official monographs of this product, in particular in USP XXII); from hydroxypropyl cellulose of various molecular weights, from poly(meth)acrylic esters (marketed by R6HM GmbH under the trade mark EUDRAGIT and mixtures thereof.
Of course, the present invention also applies to microgranules comprising a core simply consisting of the active ingredient and a binding agent.
The gastroresistant and prolonged-release microgranules differ in their external layer of coating of the active layer. This will be, on the one hand, a gastroresistant external layer for the gastroresistant microgranules and, on the other hand, a prolonged-release external layer for the prolonged-release microgranules.
The gastroresistant external layer consists of the customary excipients used in the technique for the preparation of gastroresistant microgranules. It comprises excipients ensuring the resistance of the coating to pH values of less than 5.0, which are advantageously chosen from poly(meth)acrylic esters (marketed by ROHM 5 under the trade marks EUDRAGIT" L 100-55, EUDRAGIT' L 100,
EUDRAGIT
L 30D-55), hydroxypropyl methylcellulose phthalate (marketed by the company SHIN ETSU Chemical Co., Ltd. under the trade marks HP 500 and HP and mixtures thereof.
The prolonged-release external layer comprises, for its part, the customary excipients used in the technique for the preparation of prolonged-release microgranules, independent of the pH of the medium in which they act, advantageously chosen from poly(meth)acrylic esters (marketed by ROHM under the trade marks EUDRAGIT' RS 100, EUDRAGIT RS 30D), ethyl cellulose (marketed by FMC Corporation, Philadelphia under the trade mark AQUACOAT'), and mixtures thereof. In this case, it is the transit time of the microgranules in the intestines which will determine the time of release of the active ingredient.
The prolonged-release external layer may also comprise an excipient which is dependent on the pH of the medium in which the microgranules transit, in particular the pH-dependent poly(meth)acrylic esters (marketed by ROKM under the trade mark EUDRAGIT" In this case, it is no longer the transit time of the microgranules which will determine the time of release of the active ingredient, but the pH of the medium in which they transit.
Thus, in order to ensure the release of the active ingredient in the lower part of the intestines, an excipient which is soluble at pH values greater than 7, such as EUDRAGIT S, will be chosen. Of course, depending on the desired effect, the prolonged-release microgranules may also consist of a mixture of pH-dependent release microgranules, so as to release the active ingredient at various pH values, or alternatively of a mixture of microgranules dependent or not dependent on the pH, modulating a release as a function of the transit time and the pH.
The gastroresistant external layer and the prolonged-release external layer may also comprise customary additives, such as talc which facilitates the 6 coating by its lubricating properties or derivatives of silica or stearic acid, and/or one or more plasticizers which facilitate good formation of the coating film, especially (poly)carboxylic acid esters such as citric acid esters (especially triethyl citrate), dibutyl sebacate and mixtures thereof.
Given the importance of the size of the microgranules with respect to their rate of transit in the intestines, the average diameter of the microgranules which are useful for the form according to the invention is advantageously between 0.4 and 1.5 mm, preferably of between 0.8 and 1.1 mm.
The microgranules which are useful in the form according to the invention are advantageously prepared according to the following general scheme: coating of the neutral core with the active layer, coating of the active layer either with a gastroresistant layer or with a prolongedrelease layer according to the microgranules, screening, and drying.
The microgranules are then mixed according to the desired proportions and packaged in a form appropriate for its administration, in particular in the form of tablets, of rapidly-disintegrating tablets, of gelatin capsules or alternatively in sachets.
The present invention therefore relates to a pharmaceutical composition comprising the form described above.
It also relates, as intermediate products in the preparation of the galenic form according to the invention, to the gastro-protected and prolonged-release microgranules described above.
Of course, since the gastro-resistant and prolonged-release microgranules are prepared and can be packaged separately, the present invention also relates to a combination product comprising microgranules of gastro-protected 5-nitroimidazole derivatives and M 7 microgranules of prolonged-release derivatives as described above for use as a combination simultaneously, separately or spaced out over time for the treatment of parasitoses and infections of the gastrointestinal tract, in particular amoebiases and infections linked to the presence of Helicobacter pilori.
Other characteristics of the new form according to the invention will emerge in the light of the examples below.
Example 1: 2/8 mixture of metronidazole microgranules The following mixture was prepared: A% B% Metronidazole 63.8 64.5 Neutral core PVP K30 HP50 Ethyl cellulose N7 Talc 21.3 5.7 9.2 21.5 5.7 4.7 1.8 1.8 100.0 100.0 4- \fNT0 0
"^I^L
The percentages are given by weight relative to the total weight of the microgranules. Ingredients: Neutral core: composed of sucrose (about and maize starch (about PVP: Polyvinylpyrrolidone HP 50: Hydroxypropyl methylcellulose phthalate, dissolution from pH Ethyl cellulose N7: Ethyl cellulose whose grade N7 represents the viscosity of the product.
The microgranules were prepared according to the procedure described later.
Example 2: 3/7 mixture of metronidazole microgranules The following mixture was prepared according to the same procedure: -8 A%
B%
Metronidazole 52.6 56.9 Neutral core 19.9 21.6 PVP K30 2.7 2.8 EUDRAGIT" L30D-55 11.8 Triethyl citrate 1.2 3.7 Talc 11.8 EUDRAGIT' S 100.0 100.0 The percentages are given by weight relative to the total weight of the microgranules. Ingredients: Neutral core: composed of sucrose (about and maize starch (about PVP: Polyvinylpyrrolidone EUDRAGIT' L30D-55: Aqueous dispersion of type C methacrylic acid copolymers; dissolution from pH Talc
EUDRAGIT
S: Type B methacrylic acid copolymer; dissolution from pH Example 3:25/75 mixture of metronidazole microgranules The following mixture was prepared according to the same procedure:
C)
NT
r^ z 9 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 30D 6.3 Triethyl citrate 1.2 1.2 Talc 12.0 6.3 100.0 100.0 The percentages are given by weight relative to the total weight of the microgranules. Ingredients: Neutral core: Composed of sucrose (about and maize starch (about EUDRAGIT' E 100: Methacrylic acid copolymer used here as binder EUDRAGIT" L30D-55
EUDRAGIT
RS 30D: Aqueous dispersion of type B methacrylic acid copolymers; prolonged-release dissolution.
Talc.
Example 4: Mixture corresponding to batch XM285 The following mixture was prepared according to the same procedure: Composition of the batch XM 285: Metronidazole: 65.1% Neutral core: 21.7% PVP K30: 4.8% Ethyl cellulose N7: 1.3% HP 50: Ethyl cellulose N7: 1.3% Triethyl citrate: Talc: 1.6% 100.0% 10 Example 5: Secnidazole formulation The following mixture was prepared according to the same procedure.
Secnidazole Neutral core PVP K17
EUDRAGIT
L30D-55 EUDRAGIT® RS30D Triethyl citrate Talc A
B
47.8% 45.5% 33.0% 31.9% 3.4% 3.2% 12.6% 10.5% 1.3% 2.1% 1.9% 6.8% 100.0 100.0 Mixture of 25% of A and 75% of B Dissolution patterns Dissolution tests of the forms of Examples 1 and 4 were carried out in a 0.1N HC1 solution and at pH 6.8.
The results are given in the table below. The percentages are given by weight of microgranules dissolved relative to the total weight of microgranules before dissolution.
Example 1 Example 4 Gastroresistance test 0.1N HC1 for 2 hours 6.7% Dissolution test pH 6.8 1 Hour 42.2% 47.2% 4 Hours 78.2% 72.3% 6 Hours 86.9% 81.5% Clinical trials A clinical study of the efficacy of the form according to the invention was carried out on 60 patients of both sexes, aged 15 to 75 years and suffering from amoebiasis exhibiting cystic forms in the colon.
11 The study was carried out according to a rigorous "randomized", double placebo and double blind methodology by comparing the form of Example 1 to the metronidazole marketed under the trade mark Flagyl.
The administered doses were 1.5 g/day (3 daily doses of two gelatin capsules containing 250 mg doses of metronidazole) for 10 days.
The results of this study show a cure rate of for the form according to the invention against 14% for Flagyl.
Procedure for the manufacture of metronidazole micro granules (batch XM 415/2) Phase 1: Preparation of the binding solution: alcoholic solution of PVP at 20% in alcohol the solution is prepared in a stainless steel mixer, pour the 95% ethyl alcohol into the mixer, initiate stirring and incorporate the PVP in small quantities, maintain the stirring until complete dissolution is obtained.
Phase 2: Application place the neutral carrier grains in the rotating turbine, the application is performed by dusting the active ingredient over the neutral microgranules, alternating with sequences of spraying of the binding solution, screening the mass of microgranules, (screens which can be used: mesh opening 0.50; 0.71; 0.99; 1.12; 1.25 mm), dry the microgranules by blowing hot air inside the rotating turbine.
Phase 3: Separation of the mass into two parts divide the mass into two parts A and B corresponding respectively to 75% and 25% of the mass of microgranules, place each of the two parts in a different turbine.
Phase 4: Preparation of the premounting solution: alcoholic solution of ethylcellulose N7 at 1.
12 the solution is prepared in a stainless steel mixer, pour the 95% ethyl alcohol into the mixer, initiate stirring and incorporate the ethylcellulose in small quantities maintain the stirring until complete dissolution is obtained.
Phase 5: Premounting of part A apply the premounting solution over the microgranules by spraying, sprinkle the talc simultaneously, screen the mass of microgranules, (screens which can be used: mesh opening 0.50; 0.71; 0.99; 1.12; 1.25 mm) dry the microgranules by blowing hot air inside the rotating turbine.
Phase 6: Preparation of the coating solution: acetoalcoholic solution (20/80) of HP 50 at the solution is prepared in a stainless steel mixer, pour the 95% ethyl alcohol and then the acetone into the mixer, initiate stirring and incorporate the HP 50 in small quantities, maintain the stirring until complete dissolution is obtained.
Phase 7: Coating of parts A and B: the coating is carried out with a time interval over parts A and B S apply the coating solution over the microgranules by spraying, screen the mass of microgranules, (screens which can be used: mesh opening 0.50; 0.71; 0.99; 1.12; 1.25 mm) S dry the microgranules by blowing hot air inside the rotating turbine Phase 8: Lubrication mixing of the two parts introduce the two parts A and B as well as the lubricating talc into the rotating turbine, mix the mass, stop the turbine.
NT
-13- The new galenic form according to the invention appears also usefull in the preventive treatment of infections with anaerobic germs during surgical operation with high risks of such type of infections like digestive surgery, etc.
I1iA '>SN 0 -14- THE CLAIMS DEFINING THE INVENTION ARE AS FOLLOWS: 1. Galenic form of 5-nitroimidazole derivatives characterised in that it comprises a combination of microgranules of 5-nitroimidazole derivates consisting of gastroresistant microgranules and of prolonged-release microgranules, characterised in that the combined microgranules should correspond to the following dissolution patterns: gastroresistant microgranules: 2 hours in 0.1 N HC1 1 hour at pH 6.0 prolonged-release microgranules: 2 hours in 0.1 N HC1 1 hour at 6.8 pH 5 7.5 4 hours at 6.8 pH 7.5 40% to i 6 hours at 6.8 pH 7.5 15 the percentages being given by weight of microgranules dissolved relative to the total weight before dissolution.
2. Galenic form according to Claim 1, characterised in that the gastroresistant o microgranules/prolonged-release microgranule weight ratio is between 6/4 and 1/9.
S3. Galenic form according to Claim 2, characterised in that the gastroresistant microgranules/prolonged release microgranule weight ratio is between 25/75 and 15/85.
4. Galenic form according to any one of Claims 1 to 3, characterised in that the gastroresistant microgranules consist of a neutral granular carrier coated with an active layer consisting of a mixture of 5-nitroimidazole derivate and a binding agent, and of a gastroresistant external layer.
5. Galenic form according to Claim 4, characterised in that the gastroresistant q4external layer comprises excipients ensuring the resistance of the coating to pH K, 0 4 $DVG:JMD:#21107 N,40 T-c .f 29 January 1999

Claims (11)

  1. 6. Galenic form according to any one of Claims 1 to 3, characterised in that the prolonged-release microgranules consist of a neutral granular carrier coated with an active layer consisting of a mixture of 5-nitroimidazole derivative and a binding agent, and of a prolonged-release external layer.
  2. 7. Galenic form according to Claim 6, characterised in that the prolonged- release external layer comprises customary excipients used in the technique for the preparation of prolonged-release microgranules, independent of the pH of the medium in which they act, advantageously chosen from poly(meth)acrylic esters, ethyl cellulose and mixtures thereof, and optionally talc and/or one or more S 15 plasticisers.
  3. 8. Galenic form according to Claim 7, characterised in that the gastroresistant external layer comprises at least one excipient which is dependent on the pH of the medium in which the microgranules transit, in particular pH-dependent S 20 poly(meth)acrylic esters, and optionally talc and/or one or more plasticisers.
  4. 9. Galenic form according to any one of Claims 4 to 8, characterised in that the neutral carrier consists of particles of starch or a mixture of starch and sucrose which have an average diameter of between 400 and 800 microns. Galenic form according to any one of Claims 4 to 9, characterised in that the binding agent is a customary agent known for its use in the preparation of microgranules, advantageously chosen from polyvinylpyrrolidone of various molecular weights, hydroxypropyl methylcellulose of various molecular weights, hydroxypropyl cellulose of various molecular weights, poly(meth)acrylic esters and mixtures thereof. 29 January 1999 -16-
  5. 11. Galenic form according to any one of Claims 1 to 10, characterised in that the gastroresistant and prolonged-release microgranules have an average diameter of between 0.4 and 1.5 mm.
  6. 12. Galenic form according to Claim 11 wherein the microgranules have an average diameter of between 0.8 and 1.1 mm.
  7. 13. Galenic form according to any one of Claims 1 to 12, characterised in that 10 the 5-nitroimidazole derivative is chosen form metronidazole, secnidazole, e. g. tinidazole and mixtures thereof. C. O• *14. Pharmaceutical composition characterised in that it comprises the galenic form according to any one of Claims 1 to 13, in particular in the form of tablets, of rapidly-disintegrating tablets or gelatin capsules.
  8. 15. Gastroresistant microgranules of 5-nitroimidazole derivatives which are CC useful especially for the preparation of the galenic form according to any one of Claims 1 to 13.
  9. 16. Prolonged-release microgranules of 5-nitroimidazole derivatives which are useful especially for the preparation of the galenic form according to any one of Claims 1 to 13. 0
  10. 17. Combination product comprising microgranules of gastroresistant nitroimidazole derivatives and microgranules of prolonged-release derivatives for use as a combination simultaneously, separately or spaced out over time for the treatment of parasitoses and infections of the gastrointestinal tract, in particular amoebiases and infections linked to the presence of Helicobacter pilori, characterised in that the combined microgranules should correspond to the following dissolution patterns: 16a- gastroresistant microgranules: 2 hours in 0.1 N HC 1 hour at pH 6.0 prolonged-release microgranules: 2 hours in 0.1 N HC1 1 hour at 6.8 pH 7.5 4 hours at 6.8 pH 7.5 6 hours at 6.8 pH 7.5 40% to a. 10 the percentages being given by weight of microgranules dissolved relative to the total weight before dissolution. a 0 G* a. a 0 0 -17-
  11. 18. Galenic form of 5-nitroimidazole derivatives substantially as hereinbefore described with reference to the non-comparative examples. r o glee o i m 29 January 1999 PATENT OF INVENTION "New galenic form of 5-nitroimidazole derivatives which is effective for the treatment of parasitoses and infections of the entire gastrointestinal tract" DESCRIPTIVE ABSTRACT The present invention relates to a galenic form of 5 -nitroimidazole derivatives which is characterized in that it comprises a combination of microgranules of nitroimidazole derivatives consisting, on the one hand, of gastroresistant microgranules and, on the other hand, of prolonged-release microgranules, the pharmaceutical compositions comprising them and the microgranules as intermediates in the preparation of the form according to the invention. T A fe V" M
AU15803/95A 1994-01-14 1995-01-12 Microgranules of 5-nitro imidazole derivatives Ceased AU705570B2 (en)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
FR9400394A FR2715067B1 (en) 1994-01-14 1994-01-14 New dosage form of 5-nitro-imidazole derivatives effective for the treatment of parasitic infections and infections of the entire gastrointestinal tract.
FR94/00394 1994-01-14
PCT/FR1995/000039 WO1995019168A1 (en) 1994-01-14 1995-01-12 Microgranules of 5-nitro imidazole derivatives

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JP4331930B2 (en) * 2001-10-17 2009-09-16 武田薬品工業株式会社 High content granules of acid labile drugs
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US5256684A (en) * 1985-06-13 1993-10-26 The Procter & Gamble Company Methods and compositions for the treatment of gastrointestinal disorders
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MX9602772A (en) 1997-05-31
SK282066B6 (en) 2001-10-08
CN1088357C (en) 2002-07-31
CZ205596A3 (en) 1996-10-16
KR100320140B1 (en) 2002-07-02
PT739201E (en) 2000-05-31
CN1138826A (en) 1996-12-25
RU2152212C1 (en) 2000-07-10
NZ279238A (en) 1998-03-25
BR9506507A (en) 1997-09-09
CZ286080B6 (en) 2000-01-12
PL315530A1 (en) 1996-11-12
AU1580395A (en) 1995-08-01

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