Methods and compositions for treating bacterial infection using optically pure (R)-lomefloxacin

Methods and compositions are disclosed utilizing the optically pure (R)-isomer of lomefloxacin. This compound is a potent drug for the treatment of infection or other diseases requiring antibiotics while avoiding the concomitant liability of adverse effects that are associated with the racemic mixture of lomefloxacin.

BACKGROUND OF THE INVENTION 
This invention relates to novel compositions of matter containing optically 
pure (R)-lomefloxacin. These compositions possess potent activity in 
treating various infections while avoiding adverse effects associated with 
racemic lomefloxacin including but not limited to headache, stomach 
discomfort, gastrointestinal disorders, hypoglycemia, renal and 
dysfunction, allergic reactions and respiratory distress, and arthropathy, 
such as cartilage lesions and erosion and abnormalities in bone growth in 
immature patients. Additionally, these novel compositions of matter 
containing optically pure (R)-lomefloxacin are useful in treating 
infection in those patients with impaired renal function. Also disclosed 
are methods for treating the above-described conditions in a human while 
avoiding adverse effects that are associated with the racemic mixture of 
lomefloxacin, by administering the (R)-isomer of lomefloxacin to said 
human. 
STERIC RELATIONSHIP AND DRUG ACTION 
Many organic compounds exist in optically active forms, i.e., they have the 
ability to rotate the plane of plane-polarized light. In describing an 
optically active compound, the prefixes D and L or R and S are used to 
denote the absolute configuration of the molecule about its chiral 
center(s). The prefixes d and 1 or (+) and (-) are employed to designate 
the sign of rotation of plane-polarized light by the compound, with (-) or 
1 meaning that the compound is levorotatory. A compound prefixed with (+) 
or d is dextrorotatory. For a given chemical structure, these compounds, 
called stereoisomers, are identical except that they are mirror images of 
one another. A specific stereoisomer may also be referred to as an 
enantiomer, and a mixture of such isomers is often called an enantiomeric 
mixture. A 50:50 mixture of enantiomers if referred to as a racemic 
mixture. 
Stereochemical purity is of importance in the field of pharmaceuticals, 
where 12 of the 20 most prescribed drugs exhibit chirality. A case in 
point is provided by the L-form of the .beta.-adrenergic blocking agent, 
propranolol, which is known to be 100 times more potent than the 
D-enantiomer. 
Furthermore, optical purity is important since certain isomers may actually 
be deleterious rather than simply inert. For example, it has been 
suggested that the D-enantiomer of thalidomide was a safe and effective 
sedative when prescribed for the control of morning sickness during 
pregnancy, and that the corresponding L-enantiomer was a potent teratogen. 
RACEMIC LOMEFLOXACIN 
Lomefloxacin is described in U.S. Pat. No. 4,528,287 and Japan Patent 
Publication No. 64979 (1985). Lomefloxacin is currently available 
commercially in Argentina, Japan, Mexico, and other countries in Asia and 
Eastern Europe, as the racemic mixture, i.e., it is a 1:1 mixture of 
optical isomers. It is the optically pure, or substantially optically pure 
(R)-isomer of lomefloxacin, which is the subject of the present invention, 
hereinafter referred to as (R)-lomefloxacin. 
Racemic lomefloxacin, having the chemical name 
1-ethyl-6,8-difluoro-1,4-dihydro-7-(3-methyl-1-piperazinyl)-4-oxo-3-quinol 
inecarboxylic acid, belongs to the quinoline class of antibiotics. The 
quinoline antibiotics, in general, exhibit a broad spectrum of 
antibacterial action, demonstrating effectiveness against both 
Gram-positive and Gram-negative bacterial strains. Quinoline antibiotics 
have been shown to be effective in treating infections of the respiratory, 
genito-urinary, and gastrointestinal tracts. They have also demonstrated 
utility in the treatment of patients with cystic fibrosis and pulmonary 
infections. Effectiveness has also been demonstrated in the treatment of 
intra-abdominal, bone and joint, skin, soft-tissue, pelvic, and eye, ear, 
nose, and throat infections. 
The quinoline antibiotics derive their activity through inhibition of the 
bacterial enzyme, DNA gyrase, which is responsible for catalyzing the 
bacterial DNA supercoiling necessary to pack DNA filaments into bacterial 
cells. This inhibition causes irreversible chromosome damage leading to 
bacterial cell death. The selectivity of quinoline antibiotics for 
bacterial cells is the result of the supercoiling mechanism in eukariotic 
cells being mediated by a different set of enzymes not susceptible to 
quinoline inhibition. Quinoline antibiotics are also thought to interfere 
with proper bacterial cell membrane function, also contributing to cell 
death. 
The first quinoline antibiotic to be commercialized, nalidixic acid, was 
discovered following the observation that the structurally similar 
6-chloro-1H-ethyl-4-oxoquinolone-3-carboxylic acid, a minor by-product of 
the commercial production of the antimalarial agent chloroquine, exhibited 
weak antibacterial action. Since the discovery of nalidixic acid, some 
7,000 analogs belonging to approximately 16 different ring systems have 
been synthesized and tested for antibacterial action. From this data, a 
comprehensive structure/activity relationship has been elucidated. 
Structural activity studies have demonstrated that substitution at position 
1 and a carbonyl substitution at position 4 on the quinoline ring appear 
to be required for antimicrobial activity. No substitution at position 2 
and a carboxyl function at position 3 also appear to be required for 
activity. The only exception appears to be a thiazolidone ring fused at 
positions 2 and 3. Depending on modification, the presence of additional 
fused rings, as well as various ring substitutions, can be either 
beneficial or detrimental to activity. 
##STR1## 
Racemic lomefloxacin exhibits a broad spectrum of antibacterial action, 
demonstrating effectiveness against both gram-positive and gram-negative 
bacterial strains. Lomefloxacin has shown to be more effective against 
Gram-negative bacteria. In particular, lomefloxacin has shown excellent 
bacteriocidal activity against strains of Enterobacteriaceae, Haemophilus 
influenzae, Neisseria gonorrhoeae, Branhamella catarrhalis , L. 
pneumophilia, and good-to-moderate activity against strains of 
Acinetobacter, Pseudomonas aeruginosa, Staphylococcus aureus and 
Staphylococcus epidermidis, but poor activity against Pseudomonas cepacia. 
There is only a low propensity for bacteria to develop a resistance to 
lomefloxacin by spontaneous mutation. However, development of resistance 
is facilitated when bacteria are exposed to sub-inhibitory concentrations 
of the antibiotic. 
Lomefloxacin has an average elimination half-life of approximately 8 hours 
with peak plasma concentrations occurring at approximately 1 hour after 
oral dosing in humans. Its long half-life and dose proportionality have 
lead to introduction of lomefloxacin as the first, once-daily 4-quinoline 
antibiotic. 
Furthermore, unlike ciprofloxacin, lomefloxacin does not interfere with the 
metabolism of theophylline. Likewise, co-administration of ranitidine with 
lomefloxacin has no effect on lomefloxacin's pharmacokinetics. However, 
co-administration of sucralfate with lomefloxacin, presumably through 
aluminum complexation, does reduce the absorption of the antibiotic. In 
patients with reduced renal function, lomefloxacin exhibits reduced renal 
clearance, with a consequential prolongation of the half-life by up to 24 
hours. Antibacterial levels of lomefloxacin are therefore maintained in 
patients with reduced renal function for up to five days. 
Little is known about the pharmacology of the individual isomers of 
lomefloxacin. The pure enantiomer form of ofloxacin, a related quinoline 
antibiotic, has been studied (Antimicrob. Agents Chemother., 1988, 32(9), 
1336-1340). The (S)-isomer of ofloxacin has been reported to be twice as 
potent a bactericide as the racemate against a variety of gram-positive 
and gram-negative pathogens. 
The racemic mixture of lomefloxacin is presently used primarily as an 
antibiotic agent for treatment of infection of the upper respiratory and 
urinary tract. Viral infections of the respiratory tract are acute 
illnesses with local and systemic manifestations. Coryza (common cold), 
pharyngitis, laryngitis (including croup), and tracheobronchitis are 
common respiratory syndromes. See, for example, Merck Manual 5th Ed., p. 
169, Merck, Sharpe & Dohme Research Laboratories (1987). Bacterial 
infections of the lower urinary tract are very common. The majority of 
urinary tract infections are caused by gram-negative bacteria. Organisms 
gaining access to the urethra may colonize on the periurethral glands and 
produce acute and chronic infection. This condition is termed urethritis. 
Infections of the prostate gland give rise to the condition prostatitis. 
Enteric, gram-negative organisms are the most common cause of prostate 
infection. Merck Manual 5th Ed., p. 1610, Merck, Sharpe & Dohme Research 
Laboratories (1987). 
Additionally, racemic lomefloxacin has also been used in treating 
enteritis, sexually transmitted diseases, obstetric and gynecological 
infections, surgical infections, skin, soft tissue and joint infections, 
otorhinolaryngologic infections and ophthalmological infections. 
Although lomefloxacin and quinoline antibiotics have several advantages, 
they also have disadvantages, namely, adverse effects. The adverse effects 
of quinoline antibiotics in general include arthropathy, headache, stomach 
discomfort, gastrointestinal disorders, hypoglycemia, renal and hepatic 
dysfunction, allergic reactions and respiratory distress, and central 
nervous system effects including convulsions, increased intracranial 
pressure, and toxic psychoses. The adverse effects of lomefloxacin, in 
particular, include but are not limited to headache, stomach discomfort, 
gastrointestinal disorders, hypoglycemia, renal and hepatic dysfunction, 
allergic reactions and respiratory distress and arthropathy, such as 
cartilage lesions and erosion and abnormalities in bone growth in immature 
patients. Thus, it would be particularly desirable to find a compound with 
the advantages of the racemic mixture of lomefloxacin which would not have 
the aforementioned disadvantages. 
SUMMARY OF THE INVENTION 
It has now been discovered that the optically pure (R)-isomer of 
lomefloxacin is effective in treating infection in a human while avoiding 
adverse effects associated with the administration of racemic 
lomefloxacin, including but not limited to headache, stomach discomfort, 
gastrointestinal disorders, hypoglycemia, renal and hepatic dysfunction, 
allergic reactions and respiratory distress, and arthropathy, such as 
cartilage lesions and erosion and abnormalities in bone growth in immature 
patients. The present invention also includes methods for treating the 
above-described conditions in a human while avoiding the adverse effects 
that are associated with the racemic mixture of lomefloxacin, by 
administering the optically pure (R)-isomer of lomefloxacin to said human. 
DETAILED DESCRIPTION OF THE INVENTION 
The present invention is a method of treating infection in a human which 
comprises administering to the human, an amount of (R)-lomefloxacin, or a 
pharmaceutically acceptable salt thereof, substantially free of its 
(S)-stereoisomer, said amount being sufficient to alleviate infection. 
The present invention encompasses a method of treating infection in a human 
while avoiding the concomitant liability of adverse effects associated 
with the administration of racemic lomefloxacin, which comprises 
administering to said human, an amount of (R)-lomefloxacin, or a 
pharmaceutically acceptable salt thereof, substantially free of its 
(S)-stereoisomer, said amount being sufficient to alleviate infection, but 
insufficient to cause said adverse effects associated with administration 
of racemic lomefloxacin. 
The present invention also encompasses an antibiotic composition for 
treating infection in a human which comprises, an amount of 
(R)-lomefloxacin or a pharmaceutically acceptable salt thereof, 
substantially free of its (S)-stereoisomer, said amount being sufficient 
to alleviate said infection but insufficient to cause adverse effects 
associated with lomefloxacin. 
The available racemic mixture of lomefloxacin (i.e., a 1:1 mixture of the 
two enantiomers) possesses antibiotic activity, and provides therapy and a 
reduction of symptoms in a variety of conditions and disorders related to 
bacterial infection; however, this racemic mixture, while offering the 
expectation of efficacy, causes adverse effects. Utilizing the 
substantially optically pure (R)-isomer of lomefloxacin results in clearer 
dose-related definitions of efficacy, diminished adverse effects, and 
accordingly, an improved therapeutic index. It is therefore, more 
desirable to use the (R)-isomer of lomefloxacin. 
The term "adverse effects" includes, but is not limited to headache, 
stomach discomfort, gastrointestinal disorders, hypoglycemia, renal and 
hepatic dysfunction, allergic reactions and respiratory distress, and 
arthropathy, such as cartilage lesions and erosion and abnormalities in 
bone growth in immature patients. 
The term "substantially free of its (S)-stereoisomer" as used herein means 
that the composition contains a greater proportion of the (R)-isomer of 
lomefloxacin in relation to the (S)-isomer of lomefloxacin. In a preferred 
embodiment the term "substantially free of its (S)-isomer" as used herein 
means that the composition contains at least 90% by weight of 
(R)-lomefloxacin, and 10% by weight or less of (S)lomefloxacin. These 
percentages are based on the total amount of lomefloxacin present in the 
composition. In the most preferred embodiment the term "substantially free 
of the (S)-stereoisomer" means that the composition contains at least 99% 
by weight (R)-lomefloxacin, and 1% or less of (S)-lomefloxacin. In another 
preferred embodiment, the term "substantially free of its 
(S)-stereoisomer" as used herein means that the composition contains 100% 
by weight of (R)-lomefloxacin. The terms "substantially optically pure 
(R)-isomer of lomefloxacin" and "optically pure (R)-isomer of 
lomefloxacin" are also encompassed by the above-described amounts. 
The term "amount sufficient to alleviate infection" as used herein means an 
amount which eliminates or inhibits the growth of foreign microorganisms 
that are harmful to the normal functioning of the host organism, 
particularly humans. 
The chemical synthesis of the racemic mixture of lomefloxacin can be 
performed by the method described in U.S. Pat. No. 4,528,287. The method 
involves the reaction of 1,4-dihydro-4-oxoquinoline-3-carboxylic acid 2 
(where X=C1 or F) with piperazine 1. The preparation of the type 2 
compounds has previously been described in Japanese Patent Publication No. 
141286/1978, Japanese Patent Publication No. 47658/1980 and Japanese 
Patent Publication No. 30964/1981. 
##STR2## 
Furthermore, the (R)-isomer of lomefloxacin may be obtained by resolution 
of the mixture of enantiomers of lomefloxacin using conventional means 
such as an optically active resolving acid; see, for example 
"Stereochemistry of Carbon Compounds," by D. L. Eliel (McGraw Hill 1962) 
and Lochmuller, C. H. et al., J. Chromatogr. 113:(3) 283-302 (1975). 
(R)-Lomefloxacin can be prepared from the racemate through the 
diastereomeric crystallization scheme shown below: 
##STR3## 
Racemic lomefloxacin is treated with an optically pure base (an amine is 
shown above) to give a pair of diastereomeric salts. The difference in 
solubility between the two diastereomers allows one to be selectively 
crystallized from the solvent while the other remains in solution. 
Crystals of the single diastereomer are then separated from the other 
diastereomer by filtration. Once separated, the diastereomers can be 
converted back to the original enantiomers by treatment with acid. 
The magnitude of a prophylactic or therapeutic dose of (R)-lomefloxacin in 
the acute or chronic management of disease will vary with the severity of 
the condition to be treated and the route of administration. The dose, and 
perhaps the dose frequency, will also vary according to the age, body 
weight, and response of the individual patient. In general, the total 
daily dose ranges, for the conditions described herein, is from about 100 
mg to about 400 mg. However, the dosage may be as high as about 800 mg. 
Preferably, a daily dose range should be between about 100 mg to about 200 
mg. In managing the patient, the therapy should be initiated at a lower 
dose, perhaps about 100 mg to about 200 mg and increased up to about 400 
mg or higher depending on the patient's global response. It is further 
recommended that children, patients over age 65, and those with impaired 
renal or hepatic function, initially receive low doses. Those dosages 
should also be titrated based on global response and blood level. In some 
cases, it may be necessary to use dosages outside these ranges in some 
cases. 
The term, "an amount sufficient to alleviate infection but insufficient to 
cause said adverse effects," is encompassed by the above described dosage 
amounts and dose frequency schedule. 
The term, "method of treating infection" as used herein, includes but is 
not limited to infections such as urinary tract infection, upper 
respiratory tract infection, sexually transmitted infection, 
ophthalmological infection, gastrointestinal infections such as those 
caused by H. pylori and any other infections which may arise in cells or 
tissues of a human and which require treatment with antibiotics. 
Any suitable route of administration may be employed for providing the 
patient with an effective dosage of (R)-lomefloxacin. For example, oral, 
rectal, parenteral, transdermal, subcutaneous, intramuscular, and the like 
may be employed as appropriate. Dosage forms include tablets, coated 
tablets, troches, dispersions, suspensions, solutions, caplets, capsules, 
patches, and the like. 
The pharmaceutical compositions of the present invention comprise 
(R)-lomefloxacin as active ingredient, or a pharmaceutically acceptable 
salt thereof, and may also contain a pharmaceutically acceptable carrier, 
and optionally, other therapeutic ingredients. (R)-lomefloxacin 
hydrochloride is a pharmaceutically acceptable salt of (R)-lomefloxacin. 
The most preferred pharmaceutically acceptable salt of (R)-lomefloxacin is 
the monohydrochloride salt. 
The term "pharmaceutically acceptable salts" refers to salts prepared from 
pharmaceutically acceptable non-toxic acids or bases including inorganic 
acids and bases and organic acids and bases. 
Since the compound of the present invention is both basic and acidic, salts 
may be prepared from pharmaceutically acceptable non-toxic acids or bases 
including inorganic and organic acids or inorganic and organic bases. Such 
salts may contain any of the following anions: acetate, benzensulfonate, 
benzoate, camphorsulfonate, citrate, fumarate, gluconate, hydrobromide, 
hydrochloride, lactate, maleate, mandelate, mucate, nitrate, pamoate, 
phosphate, succinate, sulfate, tartrate and the like. Particularly 
preferred are benzensulfonate, hydrobromate, hydrochloride and sulfate. 
Such salts may also contain the following cations: aluminum, calcium, 
lithium, magnesium, potassium, sodium, zinc, benzathine, chloroprocaine, 
choline, diethanolamine, ethylenediamine, meglumine, and procaine. 
The compositions include compositions suitable for oral, rectal and 
parenteral (including subcutaneous, intramuscular, and intravenous) 
administration, although the most suitable route in any given case will 
depend on the nature and severity of the condition being treated. The most 
preferred route of the present invention is the oral route. The 
compositions may be conveniently presented in unit dosage form, and 
prepared by any of the methods well known in the art of pharmacy. 
In the case where an oral composition is employed, a suitable dosage range 
for use is e.g., from about 100 mg to about 400 mg total daily dose, given 
as a once daily administration in the morning or in divided doses if 
required. Preferably, a dose of 400 mg is given as a once daily 
administration. More preferably, a dose range of between about 100 mg to 
about 200 mg is given as a once daily administration or in divided doses 
if required. Patients may be upward titrated from below to within this 
dose range to a satisfactory control of symptoms. 
In practical use, (R)-lomefloxacin can be combined as the active ingredient 
in intimate admixture with a pharmaceutical carrier according to 
conventional pharmaceutical compounding techniques. The carrier may take a 
wide variety of forms depending on the form of the preparation desired for 
administration, e.g., oral or parenteral (including intravenous injections 
or infusions). In preparing the compositions for oral dosage form any of 
the usual pharmaceutical media may be employed. Usual pharmaceutical media 
includes, for example, water, glycols, oils, alcohols, flavoring agents, 
preservatives, coloring agents, and the like in the case of oral liquid 
preparations (such as for example, suspensions, solutions, and elixirs); 
aerosols; or carriers such as starches, sugars, microcrystalline 
cellulose, diluents, granulating agents, lubricants, binders, 
disintegrating agents and the like, in the case of oral solid preparations 
(such as for example, powders, capsules, and tablets) with the oral solid 
preparations being preferred over the oral liquid preparations. The most 
preferred oral solid preparation is tablets. 
Because of their ease of administration, tablets and capsules represent the 
most advantageous oral dosage unit form, in which case solid 
pharmaceutical carriers are employed. If desired, tablets may be coated by 
standard aqueous or nonaqueous techniques. The parenteral dosage form can 
consist of a sterile solution of the active ingredient, either in its free 
or salt form, in physiological buffer or sterile water. 
In addition to the common dosage forms set out above, the compounds of the 
present invention may also be administered by controlled release means 
and/or delivery devices such as those described in U.S. Pat. Nos.: 
3,845,770; 3,916,899; 3,536,809; 3,598,123; 3,630,200; 4,008,719; 
4,687,660 and 4,769,207, the disclosures of which are hereby incorporated 
by reference. 
Pharmaceutical compositions of the present invention suitable for oral 
administration may be presented as discrete units such as capsules, 
cachets, or tablets, or aerosols sprays, each containing a predetermined 
amount of the active ingredient, as a powder or granules, or as a solution 
or a suspension in an aqueous liquid, a non-aqueous liquid, an 
oil-in-water emulsion, or a water-in oil liquid emulsion. Such 
compositions may be prepared by any of the methods of pharmacy, but all 
methods include the step of bringing into association the active 
ingredient with the carrier which constitutes one or more necessary 
ingredients. In general, the compositions are prepared by uniformly and 
intimately admixing the active ingredient with liquid carriers or finely 
divided solid carriers or both, and then, if necessary, shaping the 
product into the desired presentation. 
For example, a tablet may be prepared by compression or molding, 
optionally, with one or more accessory ingredients. Compressed tablets may 
be prepared by compressing in a suitable machine the active ingredient in 
a free-flowing form such as powder or granules, optionally mixed with a 
binder, lubricant, inert diluent, surface active or dispersing agent. 
Molded tablets may be made by molding in a suitable machine, a mixture of 
the powdered compound moistened with an inert liquid diluent. Desirably, 
each tablet contains from about 100 mg to about 200 mg of the active 
ingredient, and each cachet or capsule contains from about 100 mg to about 
200 mg of the active ingredient, (R)-lomefloxacin. Most preferably, the 
tablet, cachet or capsule contains either one of two dosages, about 100 mg 
or about 200 mg of the active ingredient. 
The invention is further defined by reference to the following examples 
describing in detail, the preparation of the compound, and the 
compositions of the present invention. It will be apparent to those 
skilled in the art, that many modifications, both to materials, and 
methods, may be practiced without departing from the purpose and interest 
of this invention.