FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
LIQUID DOSAGE FORMS OF NADIFLOXACIN OR SALT THEREOF FOR
OPHTHALMIC, OTIC AND NASAL ADMINISTRATION
2. APPLICANT (S)
(a) NAME: WOCKHARDT LTD.
(b) NATIONALITY: INDIAN
(c) ADDRESS: Wockhardt Towers, Bandra-Kurla Complex, Bandra (East),
Mumbai-400051.
3. PREAMBLE TO THE DESCRIPTION
The present invention provides liquid dosage forms of nadifloxacin or salt
thereof for the treatment of ophthalmic, otic or nasal bacterial infections.
The following specification particularly describes the invention and the manner
in which it is to be performed.
The present invention provides liquid dosage forms of nadifloxacin or salt thereof
for the treatment of ophthalmic otic or nasal bacterial infections.
Nadifloxacin is chemically, 9-ftuoro-6,7-dihydro-8-(4-hydroxy-1-pyperidinyl)-5-
methyl-1-oxo-1H,5H-benzo(l,j)quinolizine-2-carboxylic acid of Formula I provided
below.


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FORMULA I
Nadifloxacin is a synthetic quinolone with potent broad-spectrum anti-bacterial
activity. Nadifloxacin inhibits the enzyme DNA gyrase that is involved in bacterial
DMA synthesis and replication, thus inhibiting the bacterial multiplication. RS-
nadifloxacin and S-nadifloxacin, in particular, exhibit strong antibacterial activity
against Gram-positive, Gram-negative and anaerobic bacteria, resistant Gram-
positive organisms such as methicillin-resistant Staphylococcus aureus (MRSA),
quinolone-resistant Staphylococcus aureus, coagulase negative staphylococci,
such as methicillin-resistant Staphylococcus epidermidis (MRSE), enterococci,
betahemolytic streptococci and viridans group of streptococci, mycobacteria and
newly emerging nosocomial pathogens such as Chryseobacterium
meningosepticum, and Gram-negative pathogens such as E.coli, Klebsiella,
Proteus, Serratia, Citrobacter and Pseudomonas. Recently, it has also been
shown that S-(-)-nadifloxacin, in particular exhibits potent antibacterial activity
against glycopeptide intermediate S. aureus (GISA),vancomycin intermediate S.
aureus (VISA) and vancomycin-resistant S. aureus (VRSA). Nadifloxacin is also
active against quinolone-resistant Staphylococci.
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Nadifloxacin is marketed in the form of cream for topical application for the
treatment of acne vulgaris, folliculitis and sycosis vulgaris. It is also indicated for
the treatment of topical bacterial infections with susceptible bacteria.
US Patent No 4,399,134 disclose processes for preparation of nadifloxacin or
salt thereof and antibacterially effective pharmaceutical compositions of
nadifloxacin. Typical dosage forms provided in the '134 Patent are: tablets, pills,
powders, liquid preparations, suspensions, emulsions, granules, capsules,
suppositories, and injectable preparations (solutions, suspensions, etc).
PCT Patent Application WO 04/00360 provides pharmaceutical compositions of
several active ingredients including nadifloxacin for topical use for treatment of
dermatosis.
US Patent No 6,884,768 provide solid oral pharmaceutical compositions
comprising active compound which also includes nadifloxacin, an absorbefacient
and taurine compounds.
PCT Patent Application WO 00/06122 provide taste-masked pharmaceutical
compositions for oral administration, which comprises of nadifloxacin.
The use of quinolone antibiotics to treat infections is known the art in the field of
ophthalmic pharmaceutical compositions and methods of treatment. Several
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quinolone antibacterial such as gatifloxacin (available as Zymar®), Levofloxacin
(available as Quixin® or Iquix®), Ciprofloxacin (available as Ciloxan®), Ofloxacin
(available as Ocuflox®), Lomefloxacin (available as Lomeflox®), Moxifloxacin
(available as Vigamox®) and Norfloxacin (available as Chibroxin®).
US Patent No 6,333,045 provide liquid pharmaceutical compositions of
gatifloxacin or salt thereof and disodium edetate. European Patent EP 275,515
and US Patent No 4,923,862 provide aqueous pharmaceutical compositions of
levofloxacin and ofloxacin or salt thereof. US Patent No 6,716,830 provide
ophthalmic dosage forms of moxifloxacin or salt thereof in a concentration of
0.1% to 1% w/w and pharmaceutically acceptable vehicle.
The foregoing quinolone antibiotic compositions are generally effective in treating
ophthalmic infections, and have distinct advantages over prior ophthalmic
antibiotic compositions, particularly those having relatively limited spectrums of
antimicrobial activity, such as: neomycin, polymyxin B, gentamicin and
tobramycin, which are primarily useful against gram negative pathogens; and
bacitracin, gramicidin, and erythromycin, which are primarily active against gram
positive pathogens. However, despite the general efficacy of the ophthalmic
quinolone therapies currently available, there is a need for improved
compositions and methods of treatment based on the use of antibiotics that are
more effective than existing antibiotics against key ophthalmic pathogens, and
less prone to the development of resistance by those pathogens.
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There is an even greater need for effective topical compositions and methods for
treating otic and nasal infections, particularly bacterial infections. The use of oral
antibiotics to treat otic infections in children has limited efficacy, and creates a
serious risk of pathogen resistance to the orally administered antibiotics.
The present inventors while working on the pharmaceutical compositions of
nadifloxacin or salt thereof have surprisingly found that nadifloxacin can be
formulated in to an liquid dosage form that is suitable for the treatment of ocular,
otic and nasal infections. Ophthalmic dosage forms of nadifloxacin are not known
in the art. The present inventors have found that the low resistance of microbes
to nadifloxacin, effectiveness in treating MRSA infections and no cross-
resistance with other quinolones makes nadifloxacin an ideal candidate for the
treatment of bacterial infections of ophthalmic, otic and nasal origin. When
compared with other known quinolone anti-bacterial drugs used in liquid dosage
forms for ophthalmic, otic or nasal use, nadifloxacin is effective in low dosages
and is relatively well tolerable.
Additionally it was also found that nadifloxacin is the only acidic quinolone
available in the market. Other known quinolones tend to lose their antibacterial
activity in acidic conditions while nadifloxacin activity potentiates in acidic
medium. Since ocular environment is near neutral or acidic; nadifloxacin offers
excellent advantage over other quinolones. In some specific pathological
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conditions wherein ocular pH is lowered significantly, nadifloxacin exhibits
excellent bactericidal activity whereas other known quinolones tend to be
ineffective.
The term "nadifloxacin or salt thereof referred in this invention means racemic
nadifloxacin and its salts, its single enantiomer such as R-Nadifloxacin or S-
nadifloxacin or salts thereof with organic or inorganic bases. (S)-Nadifloxacin
salts with amino acids such as argenine salt is also covered in this invention.
In one of the aspects of the present invention there is provided a liquid dosage
form for ophthalmic, otic or nasal administration which comprises of nadifloxacin
or salt thereof in a concentration of 0.01% to 1% by weight and suitable
pharmaceutically acceptable vehicle therefor.
In another aspect of the present invention there is provided a liquid dosage form
for ophthalmic, otic or nasal administration, which comprises of nadifloxacin or
salt thereof, pharmaceutically effective quantity of hydroxypropyl-p-cyclodextrin
(HP-p-CD) and pharmaceutically acceptable vehicle therefor.
In yet another aspect of the present invention there is provided a liquid dosage
form for the treatment of ophthalmic, otic or nasal administration which comprises
of nadifloxacin or salt thereof, effective amount of antibacterial agent and
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effective amount of viscosity modifying agent in a suitable pharmaceutically
acceptable vehicle therefor.
In yet another aspect of the present invention there is provided an ophthalmic or
otic solution dosage form which comprises of nadifloxacin or salt thereof,
pharmaceutically effective quantity of hydroxypropyl-p-cyclodextrin (HP-p-CD)
and pharmaceutically acceptable vehicle therefor.
The liquid dosage form for the ophthalmic, otic or nasal use as part of present
invention can be present as solution, suspension or drops in a single use or
multi-use container. The compositions are preferably sterile, and have physical
properties (e.g., osmolaltty and pH) that are specially suited for application to
ophthalmic, otic and nasal tissues, including tissues that have been
compromised as the result of preexisting disease, trauma, surgery or other
physical conditions.
The compositions are typically administered to the affected ophthalmic, otic or
nasal tissues by topically applying one to four drops of a sterile solution or
suspension, or a comparable amount of an ointment, gel or other solid or
semisolid composition, one to four times per day. However, the compositions
may also be formulated as irrigating solutions that are applied to the affected
ophthalmic, otic or nasal tissues during surgical procedures.
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Normally, the amount of nadifloxacin or its salt to be formulated in the liquid
pharmaceutical composition of the present invention is varied according to the
degree of infection of a particular subject, but normally, nadifloxacin is formulated
within the range of 0.01 to 1.0% w/v, preferably 0.1 to 0.8% w/v, more preferably
0.3 to 0.5% w/v.
To increase the solubility of nadifloxacin in the liquid pharmaceutical vehicle
amino acids, for example L-Argenine can be added to affect the dissolution.
The ophthalmic, otic and nasal compositions of the present invention will typically
have a pH in the range of 4.5 to 8.0. The ophthalmic compositions must also be
formulated to have osmotic values that are compatible with the aqueous humor
of the eye and ophthalmic tissues. Such osmotic values will generally be in the
range of from about 200 to about 400 milliosmoles per kilogram of water
("mOsm/kg"), but will preferably be about 300 mOsm/kg.
Ophthalmic, otic and nasal pharmaceutical products are typically packaged in
multidose form. Preservatives are thus required to prevent microbial
contamination during use. Suitable preservatives include: polyquaternrum-1,
benzalkonium chloride, thimerosal, chlorobutanol, methyl paraben, propyl
paraben, phenylethyl alcohol, edetate disodium, sorbic acid, or other agents
known to those skilled in the art. Typically such preservatives are employed at a
level of from 0.001% to 1.0% by weight.
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A surfactant or other appropriate co-solvent in the composition may enhance the
solubility of the components of the present compositions. In case of nadifloxacin
due to its poor water solubility use of co-solvents or complex forming agents
helps in achieving the desired results. Such co-solvents include polysorbate 20,
60, and 80, polyoxyethylene/polyoxypropylene surfactants (e.g., Pluronic F-68, F-
84 and P-103), cyclodextrin especially HP-p-CD, or other agents known to those
skilled in the art. Typically such co-solvents are employed at a level of from
0.01% to 5% by weight. HP-p-CD has a tendency to form inclusion complex with
many drugs including nadifloxacin. This complex offers several advantages, such
as reduced irritation, increased tolerability and efficacy. The dose of nadifloxacin
can be further reduced based on complexation with HP-p-CD.
The use of viscosity enhancing agents to provide the compositions of the
invention with viscosities greater than the viscosity of simple aqueous solutions is
desirable to increase ocular absorption, and reduce irritability of the active
compounds by the target tissues or increase the retention time in the eye, ear or
nose. Such agents include, for example, polyvinyl alcohol, polyvinyl pyrrolidone,
methylcelJulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose,
carboxymethyl cellulose, hydroxypropyl cellulose or other agents know to those
skilled in the art. Such agents are typically employed at a level of from 0.01% to
2% by weight.
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While the present invention has been described in terms of its specific
embodiments, certain modifications and equivalents will be apparent to those
skilled in the art and are intended to be included within the scope of the present
invention.
Examples
The composition of the liquid formulations is provided in Table 1.
Nadifloxactn, amino acid and HP-β- CD were dissolved in water for injection. To
this was added a solution of polyvinyl alcohol and benzalkonium chloride in water
for injection. A solution of disodium edetate is added to this and the pH of the
resultant solution is adjusted using 1N HCI between 5.5 to 7.5. The solution was
then adjusted to required osmolarity using a solution of sodium chloride (0.1 to
0.9%) in water for injection. Osmolality of solution was adjusted to 250-350
mmOsm. The resultant solution was filtered using 0.22 nmembrane filters and
filled in desired containers under laminar flow.
Table 1:

Ingredient Example 1 Example 2 Example 3 Example 4

%w/v % w/v %w/v %w/v
Nadifloxacin 0.01 0.1 0.3 0.8
L-Arginine 0.02 0.2 0.6 1.76
HP-β-CD 0.08 0.85 3.0 2.5
Pofyvinyl alcohol 0.3 0.3 0.3 —
Benzatkonium chloride 0.01 0.01 0.01 0.01
Disodium edetate 0.05 0.05 0.05 0.05
HPMC — — 0.5
Sodium chloride 0.4 0.4 0.4 0.4
Water for Injection q.s. q.s. q.s. q.s.
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WE CLAIM:
1. A liquid dosage form for ophthalmic, otic or nasal administration which
comprises of nadifloxacin or salt thereof in a concentration of 0.01 % to 1%
by weight and suitable pharmaceutically acceptable vehicle therefor.
2. A liquid dosage form for ophthalmic, otic or nasal administration, which
comprises of nadifloxacin or salt thereof, pharmaceutically effective
quantity of hydroxypropyl-p-cyclodextrin (HP-β-CD) and pharmaceutically
acceptable vehicle therefor.
3. A liquid dosage form for the treatment of ophthalmic, otic or nasal
administration, which comprises of nadifloxacin or salt thereof, effective
amount of antibacterial agent and effective amount of viscosity modifying
agent in a suitable pharmaceutically acceptable vehicle therefor.
4. An ophthalmic or otic solution dosage form which comprises of
nadifloxacin or salt thereof, pharmaceutically effective quantity of
hydroxypropyl-β-cyclodextrin (HP-β-CD) and pharmaceutically acceptable
vehicle therefor.

5. A liquid dosage form of claims 1 to 3 in solution, suspension or drops
form.
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6. A liquid dosage forms of claims 1 to 5 as single dose, multi-dose or as
irrigation fluid.
7. A liquid dosage form of claims 1 to 4 having 0.01 to 1.0-w/v % of
nadifloxacin.
8. A liquid dosage form of claims 1 to 4 further comprising an amino acid.
9. A liquid dosage form of claims 1 to 4 further comprising an osmolarity
modifier and a preservative.
10. A liquid dosage form of claims 1 to 4 having pH of about 4.5 to 8.0.

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