CN1138826A - Microgranules of 5-nitro imidazole derivatives - Google Patents
Microgranules of 5-nitro imidazole derivatives Download PDFInfo
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- CN1138826A CN1138826A CN95191222A CN95191222A CN1138826A CN 1138826 A CN1138826 A CN 1138826A CN 95191222 A CN95191222 A CN 95191222A CN 95191222 A CN95191222 A CN 95191222A CN 1138826 A CN1138826 A CN 1138826A
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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
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- 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
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- 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
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- 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
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- 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
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Abstract
A galenic form of 5-nitro imidazole derivatives, including a combination of microgranules of 5-nitro imidazole derivatives, i.e. enteric microgranules and sustained release microgranules, pharmaceutical compositions containing same, and microgranules for use as intermediates in the preparation of said galenic form, are disclosed.
Description
The present invention relates to a kind of new 5-nitro imidazole derivatives galenical, this derivant can effectively be treated the sick and infection of whole gastrointestinal parasite.
The present invention be more particularly directed to the new galenical of a kind of lower intestine for the treatment of, particularly sigmoid colon drug resistance parasitic disease and infection.
Intestinal parasitical diseases, for example amebiasis, colon parasitic disease (its can owing to the intestinal outside fix becomes complicated) occur with the drug resistance form in lower intestine, and these forms are relevant with this transmission of disease.
With regard to amebiasis, it is the Entamoeba histolytica cyst.These cysts that are present in infected patient's digestive tract bottom are excretory with feces.Lack individual and collective's health and can quicken transmission of disease, also can make the parasite carrier take place self to infect once again simultaneously.
Entamoeba histolytica also can exist with a kind of more unsettled form, be Entamoebaterhistolytica minuta, this form can not cause any damage, but it can be converted into pathogenic form, be Entamoebacter histolytica histolytica, its penetrable intestinal mucosa also causes this transmission of disease (with the cyst form, in upper intestines and bottom).This form is also relevant with the most popular complication of amebiasis, and these complication are transferred to liver even are transferred to lung or brain.
It is possible treating acute intestinal parasitical diseases and infect with the medicine of treatment tourista.But because these treatments can not system's medication, so it does not consider to cause the problems such as health of this pathophoresis.
Similarly, have use contain azole derivatives particularly 5-nitro imidazole derivatives (metronidazole, flagentyl etc.) come amebiasis is carried out conventional and cheap treatment.But these treatments that can effectively resist upper intestines disease-promptly resist minuta and histolytica's form are but not really effective for the treatment of cyst.And these 5-nitro imidazole derivatives (with a large number of administration) absorb on digestive tract top, and this can cause side effect beastly (metallic taste in the oral cavity) or even toxic action.
Also can treat the disease that other can produce the drug resistance form in lower intestine with the 5-nitro imidazole derivatives, but same defective is also arranged.The microbial stimulation of infection, screw rod that these diseases have Helicobacter pylori (a kind of antibacterial and participation gastritis and gastric duodenal ulcer pathogeny that reaches the digestive tract bottom in the stomach that be present in) to cause, it can make the gastric acid excessive secretion, thereby causes the ulcer of harmonization of the stomach duodenum film.Someone has mentioned its participation in the generation of digestive tract cancer.
Sick and infect more and more important along with whole gastrointestinal parasite, the Therapeutic Method of seeking a kind of cheapness is also more and more important, this method is considered owing to paying no attention to hygiene problems such as causing pathophoresis, that is to say, makes the drug resistance form in effective treatment lower intestine become possibility.
In order to address these problems, the present invention relates to a kind of galenical of new 5-nitro imidazole derivatives.
Preparation of the present invention comprises 5-nitro imidazole derivatives microgranule coalition, and it comprises the microgranule of stomach juice-resistant on the one hand, comprises sustained-release microparticle on the other hand.
The stomach juice-resistant microgranule be in order to ensure preparation of the present invention mainly at the effectiveness of upper gastro-intestinal tract, and sustained-release microparticle mainly plays a role in the gastrointestinal tract bottom.
The ratio of different microgranules should adapt with required effect, should help preparation of the present invention mainly in the effect on gastrointestinal tract bottom or top, or for guaranteeing its continuous action in whole length.This also depends on the excipient that is used to prepare microgranule.
The weight ratio of stomach juice-resistant microgranule/sustained-release microparticle is between 6/4 and 1/9, advantageously between 4/6 and 1/9.Preferably, for guaranteeing the high effect of preparation of the present invention to the lower intestine disease, stomach juice-resistant microgranule/sustained-release microparticle is than between 25/75 and 15/85.
For guaranteeing the high effect of preparation of the present invention, should meet following dissolution mechanism in conjunction with microgranule :-stomach juice-resistant microgranule:
In 0.1N hydrochloric acid 2 hours＜15%
1 hour＞75%-sustained-release microparticle in pH value 6.0:
In 0.1N hydrochloric acid 2 hours＜15%
In 6.8≤pH≤7.5 1 hour＜50%
In 6.8≤pH≤7.5 4 hours 40% to 90%
In 6.8≤pH≤7.5 6 hours＞70%
Given percent is the dissolved active component weight gross weight preceding with respect to dissolving.
The microgranule that is used for preparation of the present invention preferably includes the neutrophil granule carrier of using the active layer coating, and this active component layer is made up of the mixture of active component, 5-nitro imidazole derivatives and binding agent.
Neutral carrier preferably is made up of the compound particles (average diameter is between 400 and 800 microns) of starch granules or starch and sucrose.
The 5-nitro imidazole derivatives is preferably selected from metronidazole, flagentyl, sulphur metronidazole and composition thereof.
Binding agent is the conventional binding agent that becomes known for preparing microgranule, is preferably selected from polyvinylpyrrolidone (the preferred K30 and the K17 Kollidon level (being produced by BASF) of various molecular weight; Progression is consistent with the value of constant K, and the K value is the function of molecular weight and product viscosity.Constant K be at present in the used various official documents about the explain principals of polyvinylpyrrolidone), (preferred 615 grades of the hydroxypropyl emthylcelluloses of various molecular weight; The progression of hydroxypropyl emthylcellulose be product by the function of methoxyl group and hydroxyl propoxyl group substitution level, it reflects viscosity.Various progression are described in the official document of this product to some extent, particularly USP XXII), the hydroxypropyl cellulose of various molecular weight, poly-(methyl) acrylate be (by ROHM GmbH with trade (brand) name EUDRAGIT
Sell) and composition thereof.
Certainly, the present invention also is applicable to the microgranule that contains core, and this core only contains active component and binding agent.
The difference of stomach juice-resistant and sustained-release microparticle is that their bags are by the skin of active layer.The skin of stomach juice-resistant is used for the stomach juice-resistant microgranule on the one hand, and the skin of slow release is used for sustained-release microparticle on the other hand.
The stomach juice-resistant skin comprises the conventional excipients that is used for stomach juice-resistant microgranule technology of preparing.It contains can guarantee coating tolerance pH value less than 5.0 excipient, and this excipient is preferably selected from poly-(methyl) acrylate (by R HM GmbH with trade (brand) name EUDRAGIT
L 100-55, EUDRAGIT
L100, EUDRAGIT
L 30D-55 sale), Hydroxypropyl Methylcellulose Phathalate (selling with trade (brand) name HP50 and HP55) and composition thereof by SHIN ETSU Chemical Co. company limited.
The slow release skin comprises the conventional excipients that is used for the sustained-release microparticle technology of preparing, and is irrelevant with the pH value of its interaction medium, is preferably selected from poly-(methyl) acrylate (by R HM with trade (brand) name EUDRAGIRS 100, EUDRAGIT
RS 30D sale), (by FMC Corp., philadelphia is with trade (brand) name AQUACOAT for ethyl cellulose
Sell) and composition thereof.In this case, the passing time of microgranule in intestinal determining the release time of active component.
The slow release skin also can comprise the excipient that depends on medium (microgranule transmits therein) pH value, and poly-(methyl) acrylate that particularly depends on pH value is (by ROHM with trade (brand) name EUDRAGIT
S sells).In this case, no longer be that the passing time of microgranule decides the release time of active component, but determine by the PH values of transmitting it.Therefore, in order to ensure the release of active component, should be chosen in pH value greater than 7 dissolved excipient, for example EUDRAGIT in lower intestine
S.Certainly; for required effect, sustained-release microparticle also can comprise the particle mixture that depends on pH value release, therefore can be at different pH value release of active ingredients; or comprising the particle mixture that depends on pH value or do not rely on pH value, its function with passing time and pH value comes adjustment release.
Stomach juice-resistant skin and slow release skin also can comprise conventional additive, Talcum for example, its lubricating property helps coating, perhaps Silicon stone or stearic acic derivative, and/or one or more can promote the plasticizer of the fine formation of coating membrane, particularly (gather) carboxylate, as citrate (particularly triethyl citrate), dibutyl sebacate and composition thereof.
Because the importance of particle size (relevant with its transmission speed at intestinal), the microgranule average diameter that is used for preparation of the present invention is preferably between 0.4 and 1.5 millimeter, more preferably between 0.8 and 1.1 millimeter.
Be used for microgranule between the present invention preferably by the preparation of following general fashion :-with active layer with neutral core coating ,-according to microgranule with stomach juice-resistant layer or slow release layer with the active layer coating ,-sieve, and-drying.
Be suitable for the packaged of administration, particularly tablet, quickly disintegrating tablet, gelatine capsule or lozenge form according to required ratio with the microgranule mixing and with it then.
Therefore the present invention relates to the pharmaceutical composition that contains above-mentioned preparation.
The present invention simultaneously also relates to above-mentioned stomach juice-resistant and sustained-release microparticle as the intermediate product of preparation galenical of the present invention.
Certainly, because stomach juice-resistant and sustained-release microparticle can be prepared and the energy independent packaging, therefore the present invention also relates to a kind of bonded products, it comprises 5-nitro imidazole derivatives microgranule and slow release 5-nitro imidazole derivatives microgranule as the above-mentioned stomach juice-resistant of coalition, it is used for simultaneously, respectively or compartment of terrain treatment gastrointestinal parasite sick and infect, particularly amebiasis with have relevant infection with Helicobacter pylori.
Other character of novel formulation of the present invention is as described in the following embodiment.
The metronidazole particle mixture of embodiment 1:2/8
Prepare following mixture:
| ??A％ | ????B％ | |
| Metronidazole | ??63.8 | ????64.5 |
| Neutral core | ??21.3 | ????21.5 |
| PVP?K30 | ??5.7 | ????5.7 |
| HP50 | ??9.2 | ????4.7 |
| Ethyl cellulose N7 | ??- | ????1.8 |
| Talcum | ??- | ????1.8 |
| ??100.0 | ????100.0 |
Given percent is the weight with respect to the microgranule gross weight.Composition :-neutral core: form-PVP by sucrose (about 75%) and corn starch (about 25%): polyvinylpyrrolidone K30-HP50: Hydroxypropyl Methylcellulose Phathalate, from pH5.0 dissolving-ethyl cellulose N7: ethyl cellulose, progression N7 represents the viscosity of this product.
Prepare this microgranule according to the aftermentioned step.
The metronidazole particle mixture of embodiment 2:3/7
Prepare following mixture according to same step:
| ????A％ | ????B％ | |
| Metronidazole | ????52.6 | ????56.9 |
| Neutral core | ????19.9 | ????21.6 |
| PVP?K30 | ????2.7 | ????2.8 |
| EUDRAGIT L?30D-55 | ????11.8 | ????- |
| Triethyl citrate | ??1.2 | ????3.7 |
| Talcum | ??11.8 | ????7.5 |
| EUDRAGIT S | ??- | ????7.5 |
| ??100.0 | ????100.0 |
Given percent is the weight with respect to the microgranule gross weight.Composition :-neutral core: form-PVP by sucrose (about 75%) and corn starch (about 25%): polyvinylpyrrolidone K30-EUDRAGIT
The aqueous dispersion of L 30D-55:C type methacrylic acid copolymer; From pH5.0 dissolving-Talcum-EUDRAGIT
S:B type methacrylic acid copolymer; Dissolve from pH7.0.
The metronidazole particle mixture of embodiment 3:25/75
Prepare following mixture according to same step:
| ????A％ | ????B％ | |
| Metronidazole | ????51.8 | ????59.7 |
| Neutral core | ????19.6 | ????22.6 |
| EUDRAGIT E?100 | ????3.4 | ????3.9 |
| EUDRAGIT L?30D-55 | ????12.0 | ????- |
| EUDRAGIT RS?30D | ????- | ????6.3 |
| Triethyl citrate | ????1.2 | ????1.2 |
| Talcum | ????12.0 | ????6.3 |
| ????100.0 | ????100.0 |
Given percent is the weight with respect to the microgranule gross weight.Composition :-neutral core: form-EUDRAGIT by sucrose (about 75%) and corn starch (about 25%)
E 100: methacrylic acid copolymer is used as binding agent-EUDRAGIT at this
L 30D-55-EUDRAGIT
The aqueous dispersion of RS 30D:B type methacrylic acid copolymer; Sustained-release dissolution.Talcum.
Embodiment 4: meet XM285 mixture in batches
The compositions for preparing following mixture: batch X M285 according to same step:
-metronidazole: 65.1%
-neutral core: 21.7%
-PVP?K30：????????????????????????????????????4.8％
-ethyl cellulose N7:1.3%
-HP50：???????????????????????????????????????5.0％
-ethyl cellulose N7:1.3%
-triethyl citrate: 0.5%
-Talcum: 1.6%
100.0％
Embodiment 5: the flagentyl prescription
Prepare following mixture according to same step:
A???????????????????B
Flagentyl 47.8% 45.5%
Neutral core 33.0% 31.9%
PVP?K17???????????????????3.4％????????????????3.2％
EUDRAGIT
L?30D-55???????12.6％???????????????-
EUDRAGIT
RS30D??????????-????????????????????10.5％
Triethyl citrate 1.3% 2.1%
Talcum 1.9% 6.8%
100.0????????????????100.0
The mixture of 25% A and 75% B
Dissolution mechanism
The solubility test of embodiment 1 and 4 preparations is to carry out in pH value 6.8 in the hydrochloric acid solution of 0.1N.The result is as shown in the table.Given percent is the gross weight of dissolved microgranule with respect to the preceding microgranule of dissolving.
| Embodiment 1 | Embodiment 4 | |
| The stomach juice-resistant test | ||
| 0.1N in the hydrochloric acid 2 hours | ??6.7％ | ??8.5％ |
| PH is 6.8 o'clock a solubility test | ||
| 1 hour | ??42.2％ | ??47.2％ |
| 4 hours | ??78.2％ | ??72.3％ |
| 6 hours | ??86.9％ | ??81.5％ |
Clinical trial
The clinical research of preparation effect of the present invention is to carry out in the age is 60 men and women patients of 15 to 75 years old, and these patients suffer from the amebiasis of colon cyst form.
The research is carried out according to strictness " at random ", two placebo and double blind method, and the preparation of embodiment 1 is compared with the metronidazole of selling with trade (brand) name Flagyl.
Dosage is 1.5 gram/skies (contain the gelatine capsule of 250 milligrams of dosage metronidazoles every day three times), totally 10 days.
The result of this research shows the cure rate of preparation 85% of the present invention, and Flagyl is 14%.
Produce the metronidazole microgranule step of (XM 415/2 in batches)
Step 1: the alcoholic solution of the preparation of adhesive solution: PVP (20% alcohol)-this solution of preparation in the rustless steel blender ,-95% ethanol is poured in the blender ,-begin stirring also on a small quantity in conjunction with PVP ,-continue to stir this until dissolving fully.
Step 2: use-the neutral carrier granule is placed rotation steam turbine ,-active component is sprinkling upon on the neutral corpuscle, spray adhesive solution then, group sieves with microgranule, (spendable sieve: sieve aperture 0.50; 0.71; 0.99; 1.12; 1.25mm)-in rotation steam turbine, be blown into hot-air and dry particles.
Step 3: microgranule is rolled into a ball separated into two parts-microgranule group is divided into two parts A and the B that is respectively microgranule group 75% and 25% ,-these two parts are packed in the different steam turbine.
Step 4: the preparation of prepackage solution: the alcoholic solution of 10% ethyl cellulose N7-this solution of preparation in the rustless steel blender ,-95% ethanol is poured in the blender ,-begin stirring also on a small quantity in conjunction with ethyl cellulose ,-continue to stir this until dissolving fully.
The prepackage of step 5:A part-will pre-install solution and impose on microgranule by spraying ,-spray Talcum simultaneously ,-microgranule group is sieved (spendable sieve: sieve aperture 0.50; 0.71; 0.99; 1.12; 1.25mm)-in rotation steam turbine, be blown into hot-air and dry particles.
Step 6: acetyl-ethanol of the preparation of coating solution: 7.5%HP50 (20/80) solution-this solution of preparation in the rustless steel blender,-95% ethanol is poured in the blender, pour acetone then into ,-begin stirring also on a small quantity in conjunction with HP50 ,-continue to stir until dissolving fully.
The coating of step 7:A part and B part: carry out coating-coating solution is imposed on microgranule at A part and B interval partly by sprinkling ,-microgranule group is sieved (spendable sieve: sieve aperture 0.50; 0.71; 0.99; 1.12; 1.25mm)-in rotation steam turbine, be blown into hot-air and dry particles.
Step 8: lubricated-two-part mixing-that A part and B part are rotated in the steam turbine together with lubricated pouring into Talcum, mixed material ,-stop steam turbine.
The prophylactic treatment of anaerobic infection during new galenical of the present invention also can be used for performing the operation, for example operation very easily so infected such as operation on digestive tract.
Claims (17)
1. the galenical of 5-nitro imidazole derivatives is characterized in that it comprises the coalition of 5-nitro imidazole derivatives microgranule, and it contains the stomach juice-resistant microgranule on the one hand, contains sustained-release microparticle on the other hand.
2. the galenical of claim 1, the weight ratio that it is characterized in that stomach juice-resistant microgranule/sustained-release microparticle is between 6/4 and 1/9.
3. the galenical of claim 2, the weight ratio that it is characterized in that stomach juice-resistant microgranule/sustained-release microparticle is between 25/75 and 15/85.
4. the galenical of arbitrary claim in the claim 1 to 3 is characterized in that bonded microgranule should meet following dissolution mechanism:
-stomach juice-resistant microgranule:
In 0.1N hydrochloric acid 2 hours＜15%
In pH value 6.0 1 hour＞75%
-sustained-release microparticle:
In 0.1N hydrochloric acid 2 hours＜15%
In 6.8≤pH≤7.5 1 hour＜50%
In 6.8≤pH≤7.5 4 hours 40% to 90%
In 6.8≤pH≤7.5 6 hours＞70%
Given percent is the dissolved active component weight gross weight preceding with respect to dissolving.
5. the galenical of arbitrary claim in the claim 1 to 4 is characterized in that the stomach juice-resistant microgranule contains the neutrophil granule carrier of useful active layer coating, and this active layer is by the mixture of 5-nitro imidazole derivatives and binding agent, and the outer composition of stomach juice-resistant.
6. the galenical of claim 5, it is characterized in that the stomach juice-resistant skin contains can guarantee that coating tolerance pH value is the excipient between 4.5 and 5.5, it is preferably selected from poly-(methyl) acrylate, hydroxypropyl emthylcellulose and composition thereof, and selectivity contains Talcum and/or one or more plasticizers.
7. the galenical of arbitrary claim in the claim 1 to 4 is characterized in that sustained-release microparticle contains the neutrophil granule carrier of useful active layer coating, and this active layer is by the mixture of 5-nitro imidazole derivatives and binding agent, and the outer composition of slow release.
8. the galenical of claim 7, it is characterized in that the slow release skin contains the excipient that is useful on routine in the sustained-release microparticle technology of preparing, the pH value of these excipient and its interaction medium is irrelevant, it is preferably selected from poly-(methyl) acrylate, ethyl cellulose and composition thereof, and selectivity contains Talcum and/or one or more plasticizers.
9. the galenical of claim 8 is characterized in that the stomach juice-resistant skin contains at least a microgranule that depends on and transmits the excipient of PH values, particularly depends on poly-(methyl) acrylate of pH, and selectivity contains Talcum and/or one or more plasticizers.
10. the galenical of arbitrary claim in the claim 5 to 9 is characterized in that neutral carrier is that the compound particles of starch granules or starch and sucrose is formed between 400 and 800 microns by average diameter.
11. the galenical of arbitrary claim in the claim 5 to 10, it is characterized in that binding agent is the conventional binding agent that becomes known for preparing microgranule, be preferably selected from the hydroxypropyl cellulose of the hydroxypropyl emthylcellulose of the polyvinylpyrrolidone of various molecular weight, various molecular weight, various molecular weight, poly-(methyl) acrylate and composition thereof.
12. the galenical of arbitrary claim in the claim 1 to 11, the average diameter that it is characterized in that stomach juice-resistant and sustained-release microparticle 0.4 and 1.5mm between, preferred 0.8 and 1.1mm between.
13. the galenical of arbitrary claim in the claim 1 to 12 is characterized in that the 5-nitro imidazole derivatives is selected from metronidazole, flagentyl, sulphur metronidazole and composition thereof.
14. pharmaceutical composition is characterized in that it contains the form of the galenical of arbitrary claim in the claim 1 to 13, particularly tablet, rapid disintegration tablet or gelatine capsule.
15. be particularly useful for making the stomach juice-resistant microgranule of the 5-nitro imidazole derivatives of arbitrary claim galenical in the claim 1 to 13.
16. be particularly useful for making the sustained-release microparticle of the 5-nitro imidazole derivatives of arbitrary claim galenical in the claim 1 to 13.
17. bonded products, it comprises stomach juice-resistant 5-nitro imidazole derivatives microgranule and slow release 5-nitro imidazole derivatives microgranule as coalition, it is used for simultaneously, respectively or compartment of terrain treatment gastrointestinal parasite sick and infect, particularly amebiasis with have relevant infection with Helicobacter pylori.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9400394 | 1994-01-14 | ||
| 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. |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1138826A true CN1138826A (en) | 1996-12-25 |
| CN1088357C CN1088357C (en) | 2002-07-31 |
Family
ID=9459066
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN95191222A Expired - Fee Related CN1088357C (en) | 1994-01-14 | 1995-01-12 | Microgranules of 5-nitro imidazole derivatives |
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| Country | Link |
|---|---|
| JP (1) | JPH09507499A (en) |
| KR (1) | KR100320140B1 (en) |
| CN (1) | CN1088357C (en) |
| AT (1) | ATE187068T1 (en) |
| AU (1) | AU705570B2 (en) |
| BR (1) | BR9506507A (en) |
| CZ (1) | CZ286080B6 (en) |
| DE (1) | DE69513632T2 (en) |
| DK (1) | DK0739201T3 (en) |
| ES (1) | ES2139883T3 (en) |
| MA (1) | MA23429A1 (en) |
| MX (1) | MX9602772A (en) |
| NZ (1) | NZ279238A (en) |
| OA (1) | OA10583A (en) |
| PL (1) | PL178424B1 (en) |
| PT (1) | PT739201E (en) |
| RU (1) | RU2152212C1 (en) |
| SK (1) | SK282066B6 (en) |
| UA (1) | UA28031C2 (en) |
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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 |
| KR20190026962A (en) | 2014-09-05 | 2019-03-13 | 심바이오믹스 세러퓨틱스 엘엘씨 | Secnidazole for use in the treatment of bacterial vaginosis |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US5256684A (en) * | 1985-06-13 | 1993-10-26 | The Procter & Gamble Company | Methods and compositions for the treatment of gastrointestinal disorders |
| DE3822095A1 (en) * | 1988-06-30 | 1990-01-04 | Klinge Co Chem Pharm Fab | NEW MEDICAMENT FORMULATION AND METHOD FOR THE PRODUCTION THEREOF |
| EP0528971B1 (en) * | 1990-05-14 | 1999-09-01 | JERNBERG, Gary R. | Surgical implant and method incorporating chemotherapeutic agents |
-
1995
- 1995-01-12 DK DK95907683T patent/DK0739201T3/en active
- 1995-01-12 MX MX9602772A patent/MX9602772A/en not_active IP Right Cessation
- 1995-01-12 KR KR1019960703797A patent/KR100320140B1/en not_active IP Right Cessation
- 1995-01-12 BR BR9506507A patent/BR9506507A/en not_active IP Right Cessation
- 1995-01-12 NZ NZ279238A patent/NZ279238A/en unknown
- 1995-01-12 JP JP7518878A patent/JPH09507499A/en active Pending
- 1995-01-12 AT AT95907683T patent/ATE187068T1/en not_active IP Right Cessation
- 1995-01-12 CN CN95191222A patent/CN1088357C/en not_active Expired - Fee Related
- 1995-01-12 UA UA96083232A patent/UA28031C2/en unknown
- 1995-01-12 PL PL95315530A patent/PL178424B1/en not_active IP Right Cessation
- 1995-01-12 CZ CZ19962055A patent/CZ286080B6/en not_active IP Right Cessation
- 1995-01-12 AU AU15803/95A patent/AU705570B2/en not_active Ceased
- 1995-01-12 RU RU96117257/14A patent/RU2152212C1/en not_active IP Right Cessation
- 1995-01-12 SK SK914-96A patent/SK282066B6/en unknown
- 1995-01-12 DE DE69513632T patent/DE69513632T2/en not_active Expired - Fee Related
- 1995-01-12 ES ES95907683T patent/ES2139883T3/en not_active Expired - Lifetime
- 1995-01-12 PT PT95907683T patent/PT739201E/en unknown
- 1995-01-13 MA MA23756A patent/MA23429A1/en unknown
-
1996
- 1996-07-12 OA OA60863A patent/OA10583A/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MX9602772A (en) | 1997-05-31 |
| UA28031C2 (en) | 2000-10-16 |
| PL178424B1 (en) | 2000-04-28 |
| JPH09507499A (en) | 1997-07-29 |
| NZ279238A (en) | 1998-03-25 |
| SK91496A3 (en) | 1996-12-04 |
| KR100320140B1 (en) | 2002-07-02 |
| ES2139883T3 (en) | 2000-02-16 |
| OA10583A (en) | 2002-07-10 |
| BR9506507A (en) | 1997-09-09 |
| DK0739201T3 (en) | 2000-05-01 |
| ATE187068T1 (en) | 1999-12-15 |
| PT739201E (en) | 2000-05-31 |
| RU2152212C1 (en) | 2000-07-10 |
| CZ205596A3 (en) | 1996-10-16 |
| MA23429A1 (en) | 1995-10-01 |
| SK282066B6 (en) | 2001-10-08 |
| DE69513632T2 (en) | 2000-04-06 |
| AU705570B2 (en) | 1999-05-27 |
| CN1088357C (en) | 2002-07-31 |
| DE69513632D1 (en) | 2000-01-05 |
| AU1580395A (en) | 1995-08-01 |
| CZ286080B6 (en) | 2000-01-12 |
| PL315530A1 (en) | 1996-11-12 |
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