Pharmaceutical formulations of ciprofloxacin

A pharmaceutical formulation comprising by weight 30 to 95% of 1cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-carb oxylic 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.

The invention relates to pharmaceutical formulations of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car 
boxylic acid, also called ciproflaxacin below, processes for their 
preparation and capsules and tablets containing such formulations. 
The use of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car 
boxylic acid and its physiologically acceptable derivatives is known from 
European Patent Application 49,355 and German Patent Application 
3,142,854. Lactic acid solutions of ciproflaxacin which are suitable for 
injection and infusion are described in German Patent Application 
3,333,719. 
The invention relates to pharmaceutical formulations which can be 
administered 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-car 
boxylic 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 
derivatives and/or cross-linked polyvinylpyrrolidones, 0.0 to 2.0% by 
weight of a flow-improving agent; and 0.0 to 3.0% by weight of a 
lubricant. 
The pharmaceutical formulations according to the invention combine high 
biological availability with excellent storage life. 
The formulations according to the invention preferably contain 60.0 to 
90.0% by weight of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car 
boxylic acid as the HCl salt monohydrate. 
Pharmaceutical formulations containing 60 to 90% by weight of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car 
boxylic 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 cellulose derivatives and/or cross-linked 
polyvinylpyrrolidone; 0.5 to 1.0% by weight of a flow-improving agent; and 
0.5 to 1.0% by weight of a lubricant, and those containing 72.4 to 78.8% 
by weight of 
(1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-ca 
rboxylic 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 cellulose derivatives and/or cross-linked 
polyvinylpyrrolidone; 0.6 to 0.8% by weight of a flow-improving agent; and 
0.6 to 0.8% by weight of a lubricant, are furthermore preferred. 
However, pharmaceutical formulations which contain 72.4 to 78.8% by weight 
of 
1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-7-(1-piperazinyl)-quinoline-3-car 
boxylic acid as the HCl salt monohydrate, 7.0 to 9.0% by weight of 
microcrystalline cellulose; 9.0 to 12.0% by weight of corn starch; 4.0 to 
5.0% by weight od crosslinked polyvinylpyrrolidone; 0.6 to 0.8% by weight 
of colloidal silicon dioxide; and 0.6 to 0.8% by weight of magnesium 
stearate, are especially preferred. 
A highly purified microcrystalline cellulose with a molecular weight of 
30,000 to 50,000, a particle size of 10 to 50 .mu. and a water content of 
4 to 6% by weight is preferably used as the dry binder. 
Disintegration auxiliaries which can be used are on the one hand the 
customary types of starch, but in particular corn starch, and on the other 
hand also cellulose or derivatives and/or cross-linked 
polyvinylpyrrolidone. 
Cellulose derivatives which are customary for this purpose are: for 
example, sodium carboxymethylcellulose. Cross-linked PVP is commercially 
available. For example under the tradenames Kollidon.RTM. Cl (BASE AG, 
Ludwigshafen (D) or Plasdone.RTM. XL (General Aniline & Film Corp., New 
York (USA)). 
Possible flow control agents are pulverulent substances which are 
frequently also used as powder bases or as powder foundations and which 
have the properties of imparting a better flowing and pouring capacity to 
other pulverulent substances with a certain adherence. Suitable substances 
are, for example, Aerosil.RTM., a highly pure X-ray-amorphous silicon 
dioxide (&gt;99.8% SiO.sub.2), Aerosil.RTM. 972, a pure silicon dioxide which 
has hydrophobic properties due to chemically changed methyl groups, and 
NAL.RTM. and NAL.RTM. RS, a pulverulent product prepared from rice starch 
(see also H.P. Fiedler, Lexikon der Hilfsstoffe fur Pharmazie. Kosmetik 
und angrenzende Gebiete (Dictionary of Auxiliaries for Pharmacy, Cosmetics 
and associated fields), Editio Captor KG, Aulendorf i. Wurtt. (D)). 
Lubricants are, for example, talc, calcium stearate, magnesium stearate and 
solid polyethylene glycols. Magnesium stearate is preferred. 
The invention furthermore relates to processes for the preparation of the 
active compound formulations 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 of the formulation, with 4.5 
to 25.0% by weight of a dry binder based on cellulose, if appropriate with 
up to 30.0% by weight of a disintegration auxiliary based on starch, with 
0.5 to 10.0% by weight 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-improving agent, and if appropriate 
with up to 3.0% by weight of a lubricant, the mixture is compressed in the 
dry state, comminuted, sieved and,if appropriate, pressed to tablets or 
introduced into capsules. 
One variant of the process described above comprises granulating the active 
compound mixture in a fluidized bed 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 with the remaining additives and the mixture is pressed into tablets 
or introduced into capsules. 
Granules with a cross-section of 0.8 to 2 mm for further processing to 
tablets or capsules are advantageously provided by the sieving-out 
process. 
A procedure can also preferably be followed in which the active compounds 
are mixed with corn starch, Avicel.RTM. and Aerosil.RTM., 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 useful properties enable them to be used as chemotherapeutic active 
compounds in medicine. 
The formulations according to the invention are active against a very broad 
spectrum of micro-organisms. With their aid, it is 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 invention are particularly active against 
bacteria and bacteria-like micro-organisms. They are therefore 
particularly suitable in human and veterinary medicine for the prophylaxis 
and chemotherapy of local and systemic infections caused by these 
pathogens. 
Local and/or systemic diseases which are caused by the following pathogens 
or by mixtures of the following pathogens, for example, can be treated 
and/or prevented: Micrococcaceae, such as Staphylococci, for example 
Staph. aureus and Staph. Epidermidis, (Staph.=Staphyloccoccus); 
Lactobacteriaceae, such as Streptococci, for example Streptococcus 
pyogenes, .alpha.- and .beta.-haemolysing Streptococci and 
non-.gamma.-haemolysing Streptococci, Enterococci and Diplocuccus 
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.=Klebsiella), Serratia, 
for example Serratia marcescens, Proteae bacteria of the Proteus group; 
Proteus, for example Pr. vulgaris, Pr. morganii, Pr. retgeri and Pr. 
mirabilis (Pr.=Proteus); Pseudomonadaceae, such as Pseudomonas bacteria, 
for example Ps. aeruginosa (Ps.=Pseudomonas); Bacteroidaceae, such as 
Bacteriodes bacteria, for example Bacteroides fragilis; Mycoplasma, for 
example Mycoplasma pneumonia, and also mycobacteria, for example 
Mycobacterium tuerculosis, Mycobacterium leprae and atypical 
microbacteria. 
The above list of pathogens is merely by way of example and is in no way to 
be interpreted as limiting. Examples which 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; cystitis; endocarditis; systemic infections; 
bronchitis; arthritis; local infections; and septic diseases. 
The present invention also includes pharmaceutical formulations in dosage 
units. This means that the formulations are in the form of individual 
parts, for example tablets, dragees, capsules and pills, the 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 individual 
dose preferably contains the amount of active 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 the active compound 
or compounds only or preferentially in a certain part of the intestinal 
tract, optionally in a delayed manner, examples of embedding compositions 
which can be used being polymeric substances and waxes. 
The active compound or compounds can also be in a micro-encapsulated form, 
if appropriate with one or more of the abovementioned excipients. 
The formulation forms according to the invention can also contain coloring 
agents, preservatives and additives for improving the smell and taste, for 
example peppermint oil and eucalyptus oil, and sweeteners, for example 
saccharin. 
The following examples relate to the HCl salt monohydrate, other salts, 
derivatives or the pure base can likewise be used.