CA1296634C - Pharmaceutical formulations of ciprofloxacin - Google Patents
Pharmaceutical formulations of ciprofloxacinInfo
- Publication number
- CA1296634C CA1296634C CA000527579A CA527579A CA1296634C CA 1296634 C CA1296634 C CA 1296634C CA 000527579 A CA000527579 A CA 000527579A CA 527579 A CA527579 A CA 527579A CA 1296634 C CA1296634 C CA 1296634C
- Authority
- CA
- Canada
- Prior art keywords
- weight
- quinoline
- oxo
- cyclopropyl
- fluoro
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- 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
- A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
-
- 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
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
-
- 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
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
-
- 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
- A61P31/04—Antibacterial agents
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Veterinary Medicine (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- General Chemical & Material Sciences (AREA)
- Oncology (AREA)
- Communicable Diseases (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
ABSTRACT
A pharmaceutical formulation comprising by weight 30 to 95% of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25% of a dry binder based on cellulose; 0 to 30% of a disintegration auxiliary based on starch; 0.5 to 10% of a disintegration auxiliary based on a cellulose derivative and/or a cross-linked polyvinyl-pyrrolidone; 0 to 2 % of a flow-improving agent, and 0 to 3% of a lubricant. Tablets and capsules made from granules of the formulation, about 0.8 to 2 mm in size, exhibit high bioavailability and excellent storage stability.
A pharmaceutical formulation comprising by weight 30 to 95% of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25% of a dry binder based on cellulose; 0 to 30% of a disintegration auxiliary based on starch; 0.5 to 10% of a disintegration auxiliary based on a cellulose derivative and/or a cross-linked polyvinyl-pyrrolidone; 0 to 2 % of a flow-improving agent, and 0 to 3% of a lubricant. Tablets and capsules made from granules of the formulation, about 0.8 to 2 mm in size, exhibit high bioavailability and excellent storage stability.
Description
~91 ~3~
The invention relates to pharmaceut;cal formula-tions of 1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, also called c;profloxac;n below, processes for the;r preparation and capsules and tablets containing such formulat;ons.
The use of 1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-7-(1-piperaz;nyl)-quinoline-3-carboxylic acid and its physiologically acceptable derivat;ves is known fro~
European Patent Application 49,355 and Ger~an Patent Applicat;on 3,142,854. Lact;c acid solutions of cipro-floxacin which are suitable for injection and infusion are described in German Patent Application 3,333,719.
The invention relates to pharmaceutical formula-tions ~hich can be ad~inistered orally and contain 30.0 to 95.0~ by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25.0% by weight of a dry binder based on cellulose;
0.0 to 30~0% by weight of a disintegration auxil;ary based on starch; 0.5 to 10.0% by weight of a disintegration auxiliary based on cellulose derivatives and/or cross-linked polyvinyl-pyrrolidones, 0.0 to 2.0% by weight of a flow-;mprov;ng agen~; and 0.0 to 3.0~ by we;ght ot a lubricant.
The pharmaceutical formulations according to the ;nvention combine high biological availability with excellent storage life.
The formulations according to the invention pre-ferably contain 60.0 to 90.0% by weight of 1~cyclopropyl-6-fluoro-1~4-dihydro-4-oxo-7-~1-piperaz;nyL)-quinoLine-3-carboxyLic acid as the HCl salt monohydrate.
Pharmaceutical formuLations containing 60 to 90%
by weight of 1-rycLopropyL-6-fluoro~1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxyLic acid as the HCl salt ~onohydrate, 3.0 to 15.0% by weigh~ of a dry binder based on cellulose; 5.0 to 16.0% by weight of a Le A_24 311 ~ ~6~
disintegrat;on auxiliary based on starch; 1.0 to 7.0% by ~eight of a disintegration auxiLiary based on cellulose derivatives and/or cross-linked polyvinylpyrrolidone; 0.5 to 1.0 % by ~eight of a flow-improving agent; and 0.5 to 1.0~ by weight o~ a lubricant, and those containing 72~4 to 78.8 by weight of (1-cyclopropyl-6-fluoro-1,4-dihydro-~-oxo-7-(1-piperazinyl)-quinoline-3-carboxyl;c acid as the HCl salt monohyclrate, 7.0 to 9.0~ by weight of a dry binder based on cellulose; 9.0 to 12.0X by weight of a disinte-gration auxiliary based on starch; 4.0 to 5.0% by weightof a disintegration auxiliary based on cellulose deriva-tives and/or cross-linked polyvinylpyrrolidone; 0.6 to 0.8 % by weight of a flow-;mproving agent; and 0 6 to 0.8% by weight oF a lubricant, are furthermore preferred.
However~ pharmaceutical ~ormulations ~hich contain 72.4 to 78.8% by weight of 1-cyclopropyl-6-~luoro-1,4-di-hydro-4-oxo-7-t1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate, 7.0 to 9.0% by weight of microcrystalline cellulose; ~.0 to 12.0% by weight of maize starch; 4.0 to 5.0% by ~eight of crosslinked poly-vinylpyrroLidone; O.h to 0.8% by weight of coLloidal sili-con dioxide; and 0.6 to 0.8% by weight o~ magnesiuM
stearate, are espec;ally pre~erred.
A highly pur;fied microcrystalline cellulose with a molecular ~eight of 30,000 to 50,000, a particle s;ze of 10 to S0 ~ and a water content of 4 to 6% by weight ;s preferably used as the dry binder.
Disintegrat;on auxil;aries wh;ch can be used are on the one hand the customary types of starch, but in par-ticuLar ma;ze starch, and on the other hand also cellu-lose or derivatives andlor cross-linked polyvinylpyrrolidone.
Cellulose derivatives which are customary for this purpose are- for example, sodium carboxymethylcellulose.
Le A 24 311 ~ 3!~
Cross-linked PVP is commercially available~ for example under the tradenames KollidonR Cl (BASF AG, Ludwigshafen (D) or PlasdoneR XL (General Aniline & Film Corp., New York (~SA)) Possible flow control agents are pulverulent sub-stances wh;~h are frequently also used as po~der bases or as powder foundations and which have the properties of ;mpart;ng a better flow;ng and pour;ng capacity to other pulverulen~ substances with a certain adherence. Suitable substances are, for example, AerosilR, a h;ghly pure X-ray-amorphous s;licon diox;de (> 99.8% SiO2), Aeros;l~
972, a pure silicon dioxide which has hydrophob;c proper ties due to chemically changed methyl groups, and NALR
and NAL RS, a pulverulent product prepared from rice starch tsee also H.P. Fiedler~ Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik und angrenzende Gebiete tDictionary of Auxiliaries for Pharmacy, Cosmetics and associated fields), Editio Captor KG, Aulendorf i. Wurtt. ~D)).
Lubricants are, for exampley talc, calcium stear-ate, ma~nesium stearate and solid polyethylene glycols~
Magnesium stearate is preferred.
The invention furthermore rela~es to processes for the preparation of the active compound formulat;ons according to the invention.
For this, the active compound ciprofloxacin is mixed in an amount of 30.0 to 95~0% by weight, based on the total amount o~ the formulation, with 4.5 to 25~0~ by weight of a dry binder based on cellulose, if appropriate ~ith up to 30.0% by ~eight of a disin~egration auxiliary based on starch, with 0.5 to 10.0~ by weiyht of a disintegration auxiliary based on cellulose derivatives and/or cross-linked polyvinylpyrrolidones, and if appropriate with up to 2~0%
by weight of a flow-improvin~ agent, and if appropriate Le A Z4 311 ~2~
with up to 3.0% by wei~ht of a lubricant, the mixture ls compressed in the dry state~ comminuted, sieved and, if appropriate, pressed to ~ablets or introduced into capsules.
One variant of the process described above comprises granulating the active compound mixture in a fluidized hed granulator by continuously spraying with water or aqueous binder solutions and simultaneously passing in warm air, sieving the resulting granules and if appropriate pressing the mixture to tablets.
In another variant, the active compound ciprofloxacin is granulated with the dry binder based on cellulose, if appropriate in the presence of a disintegration auxiliary based on starch and with the other disintegration auxiliary based on cellulose derivatives and/or cross-linked polyvinylpyrrolidone and the granules are sieved and, if appropriate, mixed wikh the remaining additives and the mixture is pressed into tablets or introduced inko capsules, Still another variant of the process comprises mixiny 30 to 95% by weight of 1-cyclopropyl-6~fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl~-quinoline-3-carboxylic ac:Ld wikh 4.5 to 25.0% by weight o a dry binder based on cellulose; 0O0 to 30.0 by weigh~ o~ a disintegration auxiliary based on starch and 0.0 to 2.0~ by weight of a flow-improving agent, adding water to the mixture unt.il a composition which can be granulated is ormed, granulaking the mixture, and mixing the granules with 0.5 to 10% by weiyht of a disintegration auxiliary based on a cellulose derivative or a cxoss-linked polyvinylpyrrolidone and 0.0 to 3.0% by weiyht o~ a lubricant.
, Ei6~
Granules with a cross-~ection o~ 0~8 to 2 mm for further processing to tablets or capsules are advantageously provided by the sieving-out process.
A procedure can also preerably be followed in which the active compounds are mixed with maize starch, AvicelR and AerosilR, these mixtures are combined, after granulation, with cross-linked polyvinylpyrrolidone and magnesium stearate and the resulting material is then pressed to tablets.
The formulations according to the invention exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative germs, in particular against enterobacteriaceae, above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines, coupled with a low toxicity.
These use~ul properties enable them to be used as chemotherapeutic active compounds in medicine.
- 4a -.
~36~3~
The formulations according to the invention are active against a very broad spectrum of micro-or~anisms~
With their aid, ;t ;s possible for Gram-negative and Gram-positive bacteria and bacteria-like micro-organisms to be combated and for the diseases caused by these pathogens to be prevented, alleviated and/or cured.
The formulations according to the invent;on are particularly active against bacteria and bacteria-like micro-organisms. They are therefore partic~larly suitable in human and veterinary medicine for the prophylaxis and chemo~herapy of local and systemic infections caused by ~hese pathogens.
Local and/or systemic diseases which are caused by the following pathogens or by mixtures of the folLowing pathoger,s, for exampLe, can be trea~ed and/or prevented:
Micrococcaceae, such as Staphylococci, for example Staph.
aureus and Staph. Epidermidis, (Staph. = Staphyloccoccus), Lactobacteriaceae, such as Streptococci, for example Streptococcus pyogenes, a- and ~-haemolysing Streptococci and non-y-haemolysing Streptococci, Enterococc; and Diplo-cuccus pneumoniae (pneumococci) Enterobacteriaceae, such as Escherichiae bacteria of the Escheridrion group, for example Escherichia coli, Enterobacter bacteria, for example E. aerogenes and E. Cloacae ~E~ = Enterobacter), Klebsiella bacteria, for example K. pneumoniae ~K~ = Kleb-siella), Serratia, for example Serratia marcescens, Pro-teae bacter;~ of the Proteus ~roup; Proteus, for example Pr. vulgaris~ Pr. morgani;, Pr. retgeri and Pr. mirabilis (Pr. = Proteus~; Pseudomonadaceae, such as Pseudomonas bacter;a, for example Ps. aeruginosa (Ps~ = Pseudomonas);
Bacter~idaceae, such as ~acteriodes bacteria, for example Bacteroides fragilis; Mycoplasma, for example Mycoplasma pneumonia, and also mycobacteria, for example Mycobac-terium tuerculosis~ Mycobacterium leprae and atypical microbacteria.
The above list of pathogens is merely by way of Le A 24 311 -i3~
example and is ;n no way to be int0rpreted as limitingu Examples ~hich may be mentioned of diseases which can be prevented, alleviated and/or cured by the formulations according to the invention are: otitis; pharyngitis;
pneumonia; peritonitis; pyelonephritis; cyst;t;s; endo-carditis; systemic infections; bronchitis; arthritis;
local infections; and septic diseases.
The present invention also includes pharmaceutical formulations in dosage units. This means that the formu-lations are in the form of individual parts, for exampletablets, dragees, capsules and pills, ~he active compound content of which correspond to a fraction or a multiple of an individual dose. The dosage units can contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An ;ndividual dose preferably con-tains the amount of act;ve compound which is given in one administration and which usually corresponds to a whole, one half, one third or one quarter of a daily dose.
The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of such composition that they release ~he active compound or compounds only or preferentially in a certain part of the ;ntest;nal tract, optionally in a delayed manner, examples of embedding compositions wh;ch can be used being polymeric substances and waxes~
The active compound or compounds can also be in a micro-encapsulated form, i~ appropriate with one or more of the abovementioned excipients.
The formulation forms according to the invention can also contain colouring agents, preservatives and addi-tives for improving the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
The following examples relate to the HSl salt monohydrate, other salts, derivatives or the pure base can Le A 24 311 likewise be used.
Examples 1. Ciprofloxacin monohydrate583.0 mg (- 500 mg of betain) microcristalline cellulose55.0 ~9 moist corn starch 72.0 mg Crosslinked PVP 30~0 mg Siliciumdioxide ` 5.0 mg magnesium stearate 5.0 mg non-lacquered tablet 750.0 mg Lacquer shelL.
Hydroxypropylmethyl cellulose 15 cp 6.2 mg PEG 4000 200.0 mg titanium dioxide 2.0 mg lacquered tablet 760.0 mg 2. Ciprofloxacin monohydrate 291.5 mg (A- 250 mg of betain) microcristalline cellul ose ~7.5 mg : moist corn starch 36.0 mg Crosslinked PVP lS~0 mg Siliciumdioxide 2.5 mg magnes;um stearate __ _ _ Z.5 mg non-lacquered tablet 375.0 mg Lacquer shell:
Hydroxypropylmethylcellulose 15 cp3.9 mg PEG 4000 1.3 mg titanium diox1de 1.3_mg lacquered tablet 381~5 mg 3. Ciprofloxacin monohydrate 233.2 mg (- 200 mg of betain) microcristalline cellulose 22.0 mg Le A 24 311 - 8 ~
moist corn starch 2B.8 mg Cross1inked PVP 12.0 mg Siliciumdioxide 1 2.0 mg magnesium stearate_ 2.0 mg non-lacquered tablet 300~0 mg Lacquer shell:
Hydroxypropylmethylcellulose 15 cp 3.0 mg PEG 4000 1.0 mg titanlum dioxide _ 1.0 mg lacquered tablet 305.0 mg 4. Ciprofloxacin monohydrate 116.6 mg (~ 100 mg of betain~
microcristalline cellulose 11.0 mg moist corn starch 14.4 mg Crosslinked PVP 6~0 mg Siliciumdioxide 1.0 mg magnesium stearate 1.0 mg non-lacquered tablet 150.0 mg Lacquer shell:
Hydroxypropylme~hylcellulose 15 cp 1.8 mg PEG 4000 0.~ mg titanium dioxide __ _ _ _ 0 6 ~9 lacquered tablet153.0 mg 5. Ciprofloxacin monohydrate 874.5 mg (~ 750 mg of b~ta;n) microcristalline cellulose 82.5 mg mo;st corn starch108.0 mg Crosslinked PVP 45.0 mg Siliciumdioxide 7.5 mg 3~ ma~e~
non-lacquered tablet1,125.0 mg Le A 24 311 : ~ .
i3~
g Lacquer shell:
Hydroxypropylmethylcellulose 15 cp 9.0 mg PEG 4000 3.0 mg titanium dioxide 3.0 mg ~acquered tablet 1,140.0 mg 6. C;profloxacin monohydrate 58.3 mg (~ 50 mg of betain) microcristal1ine cel1u1 ose 40.5 mg moist corn starch 7.2 mg Crosslinked PVP 3.0 mg Siliciumdioxide O.S mg magnesium stearate _ _ _ OnS mg Contents of capsule 110.0 mg Weight of empty_capsule _ 35.0 mg Filled capsule 145.0 mg It will be understood that the specification and examples are illustrative but not limitative of the present inventian and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
: Le A 24 311 _
The invention relates to pharmaceut;cal formula-tions of 1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid, also called c;profloxac;n below, processes for the;r preparation and capsules and tablets containing such formulat;ons.
The use of 1-cyclopropyl-6-fluoro-1,4-d;hydro-4-oxo-7-(1-piperaz;nyl)-quinoline-3-carboxylic acid and its physiologically acceptable derivat;ves is known fro~
European Patent Application 49,355 and Ger~an Patent Applicat;on 3,142,854. Lact;c acid solutions of cipro-floxacin which are suitable for injection and infusion are described in German Patent Application 3,333,719.
The invention relates to pharmaceutical formula-tions ~hich can be ad~inistered orally and contain 30.0 to 95.0~ by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25.0% by weight of a dry binder based on cellulose;
0.0 to 30~0% by weight of a disintegration auxil;ary based on starch; 0.5 to 10.0% by weight of a disintegration auxiliary based on cellulose derivatives and/or cross-linked polyvinyl-pyrrolidones, 0.0 to 2.0% by weight of a flow-;mprov;ng agen~; and 0.0 to 3.0~ by we;ght ot a lubricant.
The pharmaceutical formulations according to the ;nvention combine high biological availability with excellent storage life.
The formulations according to the invention pre-ferably contain 60.0 to 90.0% by weight of 1~cyclopropyl-6-fluoro-1~4-dihydro-4-oxo-7-~1-piperaz;nyL)-quinoLine-3-carboxyLic acid as the HCl salt monohydrate.
Pharmaceutical formuLations containing 60 to 90%
by weight of 1-rycLopropyL-6-fluoro~1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxyLic acid as the HCl salt ~onohydrate, 3.0 to 15.0% by weigh~ of a dry binder based on cellulose; 5.0 to 16.0% by weight of a Le A_24 311 ~ ~6~
disintegrat;on auxiliary based on starch; 1.0 to 7.0% by ~eight of a disintegration auxiLiary based on cellulose derivatives and/or cross-linked polyvinylpyrrolidone; 0.5 to 1.0 % by ~eight of a flow-improving agent; and 0.5 to 1.0~ by weight o~ a lubricant, and those containing 72~4 to 78.8 by weight of (1-cyclopropyl-6-fluoro-1,4-dihydro-~-oxo-7-(1-piperazinyl)-quinoline-3-carboxyl;c acid as the HCl salt monohyclrate, 7.0 to 9.0~ by weight of a dry binder based on cellulose; 9.0 to 12.0X by weight of a disinte-gration auxiliary based on starch; 4.0 to 5.0% by weightof a disintegration auxiliary based on cellulose deriva-tives and/or cross-linked polyvinylpyrrolidone; 0.6 to 0.8 % by weight of a flow-;mproving agent; and 0 6 to 0.8% by weight oF a lubricant, are furthermore preferred.
However~ pharmaceutical ~ormulations ~hich contain 72.4 to 78.8% by weight of 1-cyclopropyl-6-~luoro-1,4-di-hydro-4-oxo-7-t1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate, 7.0 to 9.0% by weight of microcrystalline cellulose; ~.0 to 12.0% by weight of maize starch; 4.0 to 5.0% by ~eight of crosslinked poly-vinylpyrroLidone; O.h to 0.8% by weight of coLloidal sili-con dioxide; and 0.6 to 0.8% by weight o~ magnesiuM
stearate, are espec;ally pre~erred.
A highly pur;fied microcrystalline cellulose with a molecular ~eight of 30,000 to 50,000, a particle s;ze of 10 to S0 ~ and a water content of 4 to 6% by weight ;s preferably used as the dry binder.
Disintegrat;on auxil;aries wh;ch can be used are on the one hand the customary types of starch, but in par-ticuLar ma;ze starch, and on the other hand also cellu-lose or derivatives andlor cross-linked polyvinylpyrrolidone.
Cellulose derivatives which are customary for this purpose are- for example, sodium carboxymethylcellulose.
Le A 24 311 ~ 3!~
Cross-linked PVP is commercially available~ for example under the tradenames KollidonR Cl (BASF AG, Ludwigshafen (D) or PlasdoneR XL (General Aniline & Film Corp., New York (~SA)) Possible flow control agents are pulverulent sub-stances wh;~h are frequently also used as po~der bases or as powder foundations and which have the properties of ;mpart;ng a better flow;ng and pour;ng capacity to other pulverulen~ substances with a certain adherence. Suitable substances are, for example, AerosilR, a h;ghly pure X-ray-amorphous s;licon diox;de (> 99.8% SiO2), Aeros;l~
972, a pure silicon dioxide which has hydrophob;c proper ties due to chemically changed methyl groups, and NALR
and NAL RS, a pulverulent product prepared from rice starch tsee also H.P. Fiedler~ Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik und angrenzende Gebiete tDictionary of Auxiliaries for Pharmacy, Cosmetics and associated fields), Editio Captor KG, Aulendorf i. Wurtt. ~D)).
Lubricants are, for exampley talc, calcium stear-ate, ma~nesium stearate and solid polyethylene glycols~
Magnesium stearate is preferred.
The invention furthermore rela~es to processes for the preparation of the active compound formulat;ons according to the invention.
For this, the active compound ciprofloxacin is mixed in an amount of 30.0 to 95~0% by weight, based on the total amount o~ the formulation, with 4.5 to 25~0~ by weight of a dry binder based on cellulose, if appropriate ~ith up to 30.0% by ~eight of a disin~egration auxiliary based on starch, with 0.5 to 10.0~ by weiyht of a disintegration auxiliary based on cellulose derivatives and/or cross-linked polyvinylpyrrolidones, and if appropriate with up to 2~0%
by weight of a flow-improvin~ agent, and if appropriate Le A Z4 311 ~2~
with up to 3.0% by wei~ht of a lubricant, the mixture ls compressed in the dry state~ comminuted, sieved and, if appropriate, pressed to ~ablets or introduced into capsules.
One variant of the process described above comprises granulating the active compound mixture in a fluidized hed granulator by continuously spraying with water or aqueous binder solutions and simultaneously passing in warm air, sieving the resulting granules and if appropriate pressing the mixture to tablets.
In another variant, the active compound ciprofloxacin is granulated with the dry binder based on cellulose, if appropriate in the presence of a disintegration auxiliary based on starch and with the other disintegration auxiliary based on cellulose derivatives and/or cross-linked polyvinylpyrrolidone and the granules are sieved and, if appropriate, mixed wikh the remaining additives and the mixture is pressed into tablets or introduced inko capsules, Still another variant of the process comprises mixiny 30 to 95% by weight of 1-cyclopropyl-6~fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl~-quinoline-3-carboxylic ac:Ld wikh 4.5 to 25.0% by weight o a dry binder based on cellulose; 0O0 to 30.0 by weigh~ o~ a disintegration auxiliary based on starch and 0.0 to 2.0~ by weight of a flow-improving agent, adding water to the mixture unt.il a composition which can be granulated is ormed, granulaking the mixture, and mixing the granules with 0.5 to 10% by weiyht of a disintegration auxiliary based on a cellulose derivative or a cxoss-linked polyvinylpyrrolidone and 0.0 to 3.0% by weiyht o~ a lubricant.
, Ei6~
Granules with a cross-~ection o~ 0~8 to 2 mm for further processing to tablets or capsules are advantageously provided by the sieving-out process.
A procedure can also preerably be followed in which the active compounds are mixed with maize starch, AvicelR and AerosilR, these mixtures are combined, after granulation, with cross-linked polyvinylpyrrolidone and magnesium stearate and the resulting material is then pressed to tablets.
The formulations according to the invention exhibit a broad antibacterial spectrum against Gram-positive and Gram-negative germs, in particular against enterobacteriaceae, above all also against those which are resistant towards various antibiotics, such as, for example, penicillins, cephalosporins, aminoglycosides, sulphonamides and tetracyclines, coupled with a low toxicity.
These use~ul properties enable them to be used as chemotherapeutic active compounds in medicine.
- 4a -.
~36~3~
The formulations according to the invention are active against a very broad spectrum of micro-or~anisms~
With their aid, ;t ;s possible for Gram-negative and Gram-positive bacteria and bacteria-like micro-organisms to be combated and for the diseases caused by these pathogens to be prevented, alleviated and/or cured.
The formulations according to the invent;on are particularly active against bacteria and bacteria-like micro-organisms. They are therefore partic~larly suitable in human and veterinary medicine for the prophylaxis and chemo~herapy of local and systemic infections caused by ~hese pathogens.
Local and/or systemic diseases which are caused by the following pathogens or by mixtures of the folLowing pathoger,s, for exampLe, can be trea~ed and/or prevented:
Micrococcaceae, such as Staphylococci, for example Staph.
aureus and Staph. Epidermidis, (Staph. = Staphyloccoccus), Lactobacteriaceae, such as Streptococci, for example Streptococcus pyogenes, a- and ~-haemolysing Streptococci and non-y-haemolysing Streptococci, Enterococc; and Diplo-cuccus pneumoniae (pneumococci) Enterobacteriaceae, such as Escherichiae bacteria of the Escheridrion group, for example Escherichia coli, Enterobacter bacteria, for example E. aerogenes and E. Cloacae ~E~ = Enterobacter), Klebsiella bacteria, for example K. pneumoniae ~K~ = Kleb-siella), Serratia, for example Serratia marcescens, Pro-teae bacter;~ of the Proteus ~roup; Proteus, for example Pr. vulgaris~ Pr. morgani;, Pr. retgeri and Pr. mirabilis (Pr. = Proteus~; Pseudomonadaceae, such as Pseudomonas bacter;a, for example Ps. aeruginosa (Ps~ = Pseudomonas);
Bacter~idaceae, such as ~acteriodes bacteria, for example Bacteroides fragilis; Mycoplasma, for example Mycoplasma pneumonia, and also mycobacteria, for example Mycobac-terium tuerculosis~ Mycobacterium leprae and atypical microbacteria.
The above list of pathogens is merely by way of Le A 24 311 -i3~
example and is ;n no way to be int0rpreted as limitingu Examples ~hich may be mentioned of diseases which can be prevented, alleviated and/or cured by the formulations according to the invention are: otitis; pharyngitis;
pneumonia; peritonitis; pyelonephritis; cyst;t;s; endo-carditis; systemic infections; bronchitis; arthritis;
local infections; and septic diseases.
The present invention also includes pharmaceutical formulations in dosage units. This means that the formu-lations are in the form of individual parts, for exampletablets, dragees, capsules and pills, ~he active compound content of which correspond to a fraction or a multiple of an individual dose. The dosage units can contain, for example, 1, 2, 3 or 4 individual doses or 1/2, 1/3 or 1/4 of an individual dose. An ;ndividual dose preferably con-tains the amount of act;ve compound which is given in one administration and which usually corresponds to a whole, one half, one third or one quarter of a daily dose.
The tablets, dragees, capsules, pills and granules can be provided with the customary coatings and shells, optionally containing opacifying agents, and can also be of such composition that they release ~he active compound or compounds only or preferentially in a certain part of the ;ntest;nal tract, optionally in a delayed manner, examples of embedding compositions wh;ch can be used being polymeric substances and waxes~
The active compound or compounds can also be in a micro-encapsulated form, i~ appropriate with one or more of the abovementioned excipients.
The formulation forms according to the invention can also contain colouring agents, preservatives and addi-tives for improving the smell and taste, for example peppermint oil and eucalyptus oil, and sweeteners, for example saccharin.
The following examples relate to the HSl salt monohydrate, other salts, derivatives or the pure base can Le A 24 311 likewise be used.
Examples 1. Ciprofloxacin monohydrate583.0 mg (- 500 mg of betain) microcristalline cellulose55.0 ~9 moist corn starch 72.0 mg Crosslinked PVP 30~0 mg Siliciumdioxide ` 5.0 mg magnesium stearate 5.0 mg non-lacquered tablet 750.0 mg Lacquer shelL.
Hydroxypropylmethyl cellulose 15 cp 6.2 mg PEG 4000 200.0 mg titanium dioxide 2.0 mg lacquered tablet 760.0 mg 2. Ciprofloxacin monohydrate 291.5 mg (A- 250 mg of betain) microcristalline cellul ose ~7.5 mg : moist corn starch 36.0 mg Crosslinked PVP lS~0 mg Siliciumdioxide 2.5 mg magnes;um stearate __ _ _ Z.5 mg non-lacquered tablet 375.0 mg Lacquer shell:
Hydroxypropylmethylcellulose 15 cp3.9 mg PEG 4000 1.3 mg titanium diox1de 1.3_mg lacquered tablet 381~5 mg 3. Ciprofloxacin monohydrate 233.2 mg (- 200 mg of betain) microcristalline cellulose 22.0 mg Le A 24 311 - 8 ~
moist corn starch 2B.8 mg Cross1inked PVP 12.0 mg Siliciumdioxide 1 2.0 mg magnesium stearate_ 2.0 mg non-lacquered tablet 300~0 mg Lacquer shell:
Hydroxypropylmethylcellulose 15 cp 3.0 mg PEG 4000 1.0 mg titanlum dioxide _ 1.0 mg lacquered tablet 305.0 mg 4. Ciprofloxacin monohydrate 116.6 mg (~ 100 mg of betain~
microcristalline cellulose 11.0 mg moist corn starch 14.4 mg Crosslinked PVP 6~0 mg Siliciumdioxide 1.0 mg magnesium stearate 1.0 mg non-lacquered tablet 150.0 mg Lacquer shell:
Hydroxypropylme~hylcellulose 15 cp 1.8 mg PEG 4000 0.~ mg titanium dioxide __ _ _ _ 0 6 ~9 lacquered tablet153.0 mg 5. Ciprofloxacin monohydrate 874.5 mg (~ 750 mg of b~ta;n) microcristalline cellulose 82.5 mg mo;st corn starch108.0 mg Crosslinked PVP 45.0 mg Siliciumdioxide 7.5 mg 3~ ma~e~
non-lacquered tablet1,125.0 mg Le A 24 311 : ~ .
i3~
g Lacquer shell:
Hydroxypropylmethylcellulose 15 cp 9.0 mg PEG 4000 3.0 mg titanium dioxide 3.0 mg ~acquered tablet 1,140.0 mg 6. C;profloxacin monohydrate 58.3 mg (~ 50 mg of betain) microcristal1ine cel1u1 ose 40.5 mg moist corn starch 7.2 mg Crosslinked PVP 3.0 mg Siliciumdioxide O.S mg magnesium stearate _ _ _ OnS mg Contents of capsule 110.0 mg Weight of empty_capsule _ 35.0 mg Filled capsule 145.0 mg It will be understood that the specification and examples are illustrative but not limitative of the present inventian and that other embodiments within the spirit and scope of the invention will suggest themselves to those skilled in the art.
: Le A 24 311 _
Claims (18)
1. A pharmaceutical formulation containing 30.0 to 95.0% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25.0%
by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch; 0.5 to 10.0% by weight of a disintegration auxiliary based on a cellulose derivative or a crosslinked polyvinylpyrrolidone;
0.0 to 2.0% by weight of a flow-improving agent; and 0.0 to 3.0%
by weight of a lubricant.
by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch; 0.5 to 10.0% by weight of a disintegration auxiliary based on a cellulose derivative or a crosslinked polyvinylpyrrolidone;
0.0 to 2.0% by weight of a flow-improving agent; and 0.0 to 3.0%
by weight of a lubricant.
2. A pharmaceutical formulation according to claim 1, containing 60.0 to 90.0% by weight of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate.
3. A pharmaceutical formulation according to claim 1, containing 60 to 90% by weight of 1-cyclopropyl-6-fluoro-1,
4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate, 3.0 to 15.0% by weight of a dry binder based on cellulose; 5.0 to 16.0% by weight of a disintegration auxiliary based on starch; 1.0 to 7.0% by weight of a disintegration auxiliary based on a cellulose derivative or a crosslinked polyvinylpyrrolidone; 0.5 to 1.0% by weight of a flow-improving agent; and 0.5 to 1.0% by weight of a lubricant.
Le A 24 311-CA
4. A pharmaceutical formulation according to claim 1 containing 72.4 to 78.8% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate; 7.0 to 9.0% by weight of a dry binder based on cellulose; 9.0 to 12.0% by weight of a disintegration auxiliary based on starch; 4.0 to 5.0% by weight of a disintegration auxiliary based on a cellulose derivative and/or a crosslinked polyvinylpyrrolidone; 0.6 to 0.8% by weight of a flow-improving agent; and 0.6 to 0.8% by weight of a lubricant.
Le A 24 311-CA
4. A pharmaceutical formulation according to claim 1 containing 72.4 to 78.8% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate; 7.0 to 9.0% by weight of a dry binder based on cellulose; 9.0 to 12.0% by weight of a disintegration auxiliary based on starch; 4.0 to 5.0% by weight of a disintegration auxiliary based on a cellulose derivative and/or a crosslinked polyvinylpyrrolidone; 0.6 to 0.8% by weight of a flow-improving agent; and 0.6 to 0.8% by weight of a lubricant.
5. A pharmaceutical formulation according to claim 4, containing 72.4 to 78.8% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate; 7.0 to 9.0% by weight of microcrystalline cellulose; 9.0 to 12.0% by weight of maize starch; 4.0 to 5.0% by weight of crosslinked polyvinylpyrroli-done; 0.6 to 0.8% by weight of cocoidal silicon chloride;
and 0.6 to 0.8% by weight of magnesium stearate.
and 0.6 to 0.8% by weight of magnesium stearate.
6. A process for preparing a pharmaceutical formulation according to claim 1, which process comprises mixing 30 to 95% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid with 4.5 to 25.0% by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch and 0.0 to 2.0% by weight of a flow-improving agent, adding water to the mixture until a composition which can be granulated is formed, granulating the mixture, and mixing the granules with 0.5 to 10% by weight of a disintegration auxiliary based on a cellu-lose derivative or a crosslinked polyvinylpyrrolidone and 0.0 to 3.0% by weight of a lubricant.
7. A process for preparing a capsule or a tablet containing the active compound 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid or a salt or a deriva-tive thereof, characterized in that a formulation according to claim 1 is introduced into a capsule or pressed to a tablet.
8. A capsule containing a pharmaceutical formulation con-sisting of 30.0 to 95.0% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25.0% by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch; 0.5 to 10.0% by weight of a disintegration auxiliary based on a cellu-lose derivative and/or crosslinked polyvinylpyrrolidone; 0.0 to 2.0% by weight of a flow-improving agent; and 0.0 to 3.0% by weight of a lubricant.
9. A tablet consisting of a pharmaceutical formulation containing 30.0 to 95.0% by weight of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid; 4.5 to 25.0% by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch; 0.5 to 10.0% by weight of a disintegration auxiliary based on cellulose derivative and/or crosslinked polyvinyl-pyrrolidone, 0.0 to 2.0% by weight of a flow-improving agent;
and 0.0 to 3.0% by weight of a lubricant.
and 0.0 to 3.0% by weight of a lubricant.
10. A tablet consisting of a pharmaceutical formulation containing 72.4 to 78.8% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate, 7.0 to 9.0% by weight of microcrystalline cellulose; 9.0 to 12.0% by weight of maize starch; 4.0 to 5.0% by weight of crosslinked polyvinylpyrrolidone;
0.6 to 0.8% by weight of cocoidal silicon chloride; and 0.6 to 0.3% by weight of magnesium stearate.
0.6 to 0.8% by weight of cocoidal silicon chloride; and 0.6 to 0.3% by weight of magnesium stearate.
11. A process for preparing a pharmaceutical formulation according to claim 1, which process comprises mixing 30 to 95% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid with 4.5 to 25.0%
by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch; 0.5 to 10% by weight of a disintegration auxiliary based on a cellulose derivative or a crosslinked polyvinylpyrrolidone; 0.0 to 2.0%
by weight of a flow-improving agent; and 0.0 to 3.0% by weight of a lubricant.
by weight of a dry binder based on cellulose; 0.0 to 30.0% by weight of a disintegration auxiliary based on starch; 0.5 to 10% by weight of a disintegration auxiliary based on a cellulose derivative or a crosslinked polyvinylpyrrolidone; 0.0 to 2.0%
by weight of a flow-improving agent; and 0.0 to 3.0% by weight of a lubricant.
12. A process according to claim 6 wherein the granules are dried prior to mixing with the disintegration auxiliary and the lubricant.
13. A process according to claim 6 or 12 wherein the granules are sieved to select those with a cross-section of between about 0.3 to 2 mm.
14. A process according to claim 6 or 11 wherein the 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid is used as the HCl salt monohydrate in an amount of 60 to 90% by weight.
15. A process according to claim 6 or 11 which comprises mixing 60 to 90% by weight of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate, 3.0 to 15.0% by weight of a dry binder based on cellulose; 5.0 to 16.0% by weight of a disintegration auxiliary based on starch; 1.0 to 7.0% by weight of a disintegration auxiliary based on a cellulose derivative or a crosslinked polyvinylpyrrolidone; 0.5 to 1.0% by weight of a flow-improving agent; and 0.5 to 1.0% by weight of a lubricant.
16. A process according to claim 6 or 11 which comprises mixing 72.4 to 78.8% by weight of 1-cyclopropyl-6-fluoro-1, 4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate; 7.0 to 9.0% by weight of a dry binder based on cellulose; 9.0 to 12.0% by weight of a disintegration auxiliary based on starch; 4.0 to 5.0% by weight of a disintegration auxiliary based on a cellulose derivative and/or a crosslinked polyvinylpyrrolidone; 0.6 to 0.8% by weight of a flow-improving agent; and 0.6 to 0.8% by weight of a lubricant.
17. A process according to claim 6 or 11 which comprises mixing 72.4 to 78.8% by weight or 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid as the HCl salt monohydrate; 7.0 to 9.0% by weight of microcrystalline cellulose;
9.0 to 12.0% by weight of maize starch; 4.0 to 5.0% by weight of crosslinked polyvinylpyrrolidone; 0.6 to 0.8% by weight of cocoidal silicon chloride; and 0.6 to 0.8% by weight of magnesium stearate.
9.0 to 12.0% by weight of maize starch; 4.0 to 5.0% by weight of crosslinked polyvinylpyrrolidone; 0.6 to 0.8% by weight of cocoidal silicon chloride; and 0.6 to 0.8% by weight of magnesium stearate.
18. A pharmaceutical formulation of high biological availability and storage life consisting of by weight 583 parts of 1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carboxylic acid HCl monohydrate; 55 parts of microcrystalline cellulose; 72 parts of moist starch; 30 parts of cross-linked polyvinyl-pyrrolidone; 5 parts of silicon dioxide;
and 5 parts of magnesium stearate.
and 5 parts of magnesium stearate.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| DE19863601566 DE3601566A1 (en) | 1986-01-21 | 1986-01-21 | PHARMACEUTICAL PREPARATIONS OF CIPROFLOXACIN |
| DEP3601566.0 | 1986-08-18 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1296634C true CA1296634C (en) | 1992-03-03 |
Family
ID=6292236
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000527579A Expired - Lifetime CA1296634C (en) | 1986-01-21 | 1987-01-19 | Pharmaceutical formulations of ciprofloxacin |
Country Status (13)
| Country | Link |
|---|---|
| EP (1) | EP0230881B1 (en) |
| JP (1) | JPH0643308B2 (en) |
| KR (1) | KR910009364B1 (en) |
| CN (1) | CN1084188C (en) |
| AT (1) | ATE63460T1 (en) |
| CA (1) | CA1296634C (en) |
| DE (2) | DE3601566A1 (en) |
| ES (1) | ES2038128T3 (en) |
| GR (1) | GR3001953T3 (en) |
| HK (1) | HK63196A (en) |
| HU (1) | HU196710B (en) |
| IL (1) | IL81290A (en) |
| PT (1) | PT84134B (en) |
Families Citing this family (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2655545B1 (en) * | 1989-12-11 | 1994-06-10 | Rhone Poulenc Sante | NEW THERAPEUTIC APPLICATION OF FLUOROQUINOLONE DERIVATIVES. |
| PA8466701A1 (en) | 1998-01-21 | 2000-09-29 | Pfizer Prod Inc | TROVAFLOXACINO MESYLATE TABLET |
| AU745282B2 (en) * | 1998-11-10 | 2002-03-21 | Bayer Intellectual Property Gmbh | Pharmaceutical moxifloxacin preparation |
| HU227070B1 (en) * | 1999-08-11 | 2010-06-28 | Egis Gyogyszergyar Nyilvanosan | Immediate release pharmaceutical composition containing ciprofloxacin and process for its production |
| DE10031043A1 (en) * | 2000-06-26 | 2002-02-14 | Bayer Ag | Retarded preparations of quinolone antibiotics and process for their preparation |
| JP2004231520A (en) * | 2003-01-28 | 2004-08-19 | Nichiko Pharmaceutical Co Ltd | Medicinal composition having excellent preservation stability and elution rate |
| WO2006015545A1 (en) * | 2004-08-11 | 2006-02-16 | Shenzhen Tys R & D Co., Ltd. | Gelatin capsule of moxifloxacin and method for its prepartion |
| CN107669645A (en) * | 2017-10-31 | 2018-02-09 | 瑞阳制药有限公司 | The preparation method of ciprofloxacin hydrocloride tablets |
| CN114306257A (en) * | 2022-01-14 | 2022-04-12 | 陕西必康制药集团控股有限公司 | Ciprofloxacin hydrochloride tablet and preparation method thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4017622A (en) * | 1972-12-18 | 1977-04-12 | Dainippon Pharmaceutical Co., Ltd. | Piperazine derivatives |
| DE3033157A1 (en) * | 1980-09-03 | 1982-04-01 | Bayer Ag, 5090 Leverkusen | 7-AMINO-1-CYCLOPROPYL-4-OXO-1,4-DIHYDRO-NAPHTHYRIDINE-3-CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| US4620007A (en) * | 1980-09-03 | 1986-10-28 | Bayer Aktiengesellschaft | 6-fluoro-7-chloro-1-cyclopropyl-4-oxo-1,4-dihydro-quinoline-3-carboxylic acid |
| DE3306771A1 (en) * | 1983-02-25 | 1984-08-30 | Bayer Ag, 5090 Leverkusen | CHINOLONIC CARBONIC ACIDS, METHOD FOR THE PRODUCTION THEREOF AND THE ANTIBACTERIAL AGENTS CONTAINING THEM |
| DE3420796A1 (en) * | 1984-06-04 | 1985-12-05 | Bayer Ag, 5090 Leverkusen | 2,4,5-TRIHALOGEN OR 2,3,4,5-TETRAHALOGENBENZENE DERIVATIVES AND METHOD FOR THE PRODUCTION THEREOF |
| IT1213173B (en) * | 1984-06-04 | 1989-12-14 | Chiesi Farma Spa | ANTIBACTERIAL ACTIVITY COMPOUNDS, PROCEDURE FOR THEIR PREPARATION AND RELATED PHARMACEUTICAL COMPOSITIONS. |
-
1986
- 1986-01-21 DE DE19863601566 patent/DE3601566A1/en not_active Withdrawn
-
1987
- 1987-01-09 ES ES198787100173T patent/ES2038128T3/en not_active Expired - Lifetime
- 1987-01-09 EP EP87100173A patent/EP0230881B1/en not_active Expired - Lifetime
- 1987-01-09 DE DE8787100173T patent/DE3770001D1/en not_active Expired - Lifetime
- 1987-01-09 AT AT87100173T patent/ATE63460T1/en not_active IP Right Cessation
- 1987-01-19 PT PT84134A patent/PT84134B/en unknown
- 1987-01-19 CA CA000527579A patent/CA1296634C/en not_active Expired - Lifetime
- 1987-01-19 IL IL81290A patent/IL81290A/en not_active IP Right Cessation
- 1987-01-20 JP JP62009171A patent/JPH0643308B2/en not_active Expired - Lifetime
- 1987-01-20 KR KR1019870000396A patent/KR910009364B1/en not_active IP Right Cessation
- 1987-01-20 HU HU87155A patent/HU196710B/en unknown
- 1987-01-21 CN CN87100810A patent/CN1084188C/en not_active Expired - Lifetime
-
1991
- 1991-05-16 GR GR91400537T patent/GR3001953T3/en unknown
-
1996
- 1996-04-11 HK HK63196A patent/HK63196A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| PT84134A (en) | 1987-02-01 |
| HUT42951A (en) | 1987-09-28 |
| IL81290A0 (en) | 1987-08-31 |
| EP0230881A3 (en) | 1987-11-04 |
| CN87100810A (en) | 1987-10-14 |
| CN1084188C (en) | 2002-05-08 |
| DE3601566A1 (en) | 1987-07-23 |
| ATE63460T1 (en) | 1991-06-15 |
| DE3770001D1 (en) | 1991-06-20 |
| IL81290A (en) | 1991-03-10 |
| KR870006899A (en) | 1987-08-13 |
| PT84134B (en) | 1989-07-31 |
| GR3001953T3 (en) | 1992-11-23 |
| KR910009364B1 (en) | 1991-11-14 |
| EP0230881A2 (en) | 1987-08-05 |
| JPS62169727A (en) | 1987-07-25 |
| HK63196A (en) | 1996-04-19 |
| ES2038128T3 (en) | 1993-07-16 |
| HU196710B (en) | 1989-01-30 |
| JPH0643308B2 (en) | 1994-06-08 |
| EP0230881B1 (en) | 1991-05-15 |
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