Field of the Invention
The present invention relates to a lyophilized pharmaceutical composition comprising moxifloxacin hydrochloride.
Background of the Invention
Moxifloxacin is an antibiotic from the class of the quinolone carboxylic acids and is also named as l-cyclopropyl-7-([S, S]-2, 8-diazabicyclo [4.3.0] non-8-yl)-6-fluoro-l, 4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic acid.
It is a highly effective anti-infective agent and was described for the first time in EP 350,733. However, EP 350,733 does not describe any pharmaceutical preparations which are suitable for parenteral administration. Such solutions for infusion, which can be administered parenterally, are however needed for treating those patients in -intensive care units that cannot be treated orally.
U.S. Patent No 6,548,079 describes a ready-to-use aqueous formulation comprising moxifloxacin hydrochloride (0.04% to 0.4% M/V) and sodium chloride (0.4% to 0.9% M/V) wherein the medicament is used for preventing or treating bacterial infections in humans and animals. The patent also mentions that moxifloxacin has a problem of solubility and stability. The drug is poorly soluble in the presence of sodium chloride salt and is unstable in the presence of sugars or sugar alcohols, which are the most commonly used agents to make the parenteral products isotonic with the blood.
PCT Application No. WO 01/10408 relates to an aqueous formulation of a medicament comprising moxifloxacin or its salt and a sugar or sugar alcohol. It is characterized in that it contains less than 20 ppb of iron.
Summary of the Invention
The present invention relates to a stable lyophilized pharmaceutical composition comprising moxifloxacin hydrochloride as an active drug substance and the use of said preparation for preventing or treating bacterial infections in humans or animals.
The lyophilized compositions of the invention are characterized by comprising, in addition to the active drug substance, one or more solubilizing agents that are able to enhance the solubility of moxifloxacin hydrochloride.

Thus, the object of present invention is to provide a stable lyophilized pharmaceutical composition for parenteral administration comprising moxifloxacin hydrochloride and a process of its preparation.
Hence, in one aspect there is provided a stable lyophilized pharmaceutical composition for parenteral administration comprising moxifloxacin or pharmaceutically acceptable salts thereof and one or more solubilizing agents.
Embodiments of the pharmaceutical composition may include one o rmore of the following features. For example, the parenteral administration may include intravenous, intra-arterial, subcutaneous, intramuscular and intraperitoneal administration.
The solubilizing agent may be one or more of L-arginine, histidine or lysine. The moxifloxacin and solubilizing agent are present in the range of 1:0.1 to 1:10. The composition may further include excipients selected from one or more of bulking agents, buffers, antioxidants, chelating agents, cryoprotectants and lyoprotectants.
In various embodiments, the composition may include about 400 mg of moxifloxacin hydrochloride and may include about 112.5 mg of L-arginine.
The pharmaceutical composition may have not more than 0.16% of related substances after storage for three months at 40°C and 75% relative humidity.
The lyophilized composition is reconstituted shortly before use. Reconstitution may include using a sterile physiological solution. The sterile physiological solution may be selected from one or more of sodium lactate solution and sodium bicarbonate solution. The pH of the reconstituted solution remains constant for up to one hour storage at room temperature after reconstitution. The reconstituted solution may have moxifloxacin hydrochloride being present at from 0.04% to 3% w/v.
In another general aspect there is provided a process for preparing a lyophilized pharmaceutical composition for parenteral administration that includes moxifloxacin or pharmaceutically acceptable salts thereof and one or more solubilizing agents. The process includes the steps of: dissolving moxifloxacin and one or more solubilizing agents in a solvent, filtering to eliminate the bacteria, subpackaging into sterile containers, lyophilizing, and drying.

Embodiments of the process may include one or more of the following features. For example, the solvent may include water for injection. The process may further include reconstituting the lyophilized product.
In another general aspect there is provided a method for preventing or treating bacterial infections in human or animals. The method includes administering to the human or animal a stable lyophilized pharmaceutical composition that includes moxifloxacin or pharmaceutically acceptable salts thereof and one or more solubilizing agents.
Embodiments of the method of use may include one or more of the following features or those described above. For example, the solubilizing agent may be one or more of L-arginine, histidine or lysine. The lyophilized composition may be reconstituted shortly before use by using a sterile physiological solution selected from one or more of sodium lactate solution and sodium bicarbonate solution. The pH of the reconstituted solution may remain constant for up to one hour storage at room temperature after reconstitution.
The details of one or more embodiments of the inventions are set forth in the description below. Other features, objects and advantages of the inventions will be apparent from the description and claims.
Detailed Description of the Invention
Lyophilization or freeze drying is a process in which water is removed from a product by freezing the product and placing it under a vacuum, which allows the ice to change directly from the solid phase to the vapor phase without passing through the liquid phase. The process consists of three separate, unique, and interdependent processes: freezing, primary drying (sublimation), and secondary drying (desorption). There are several advantages associated with lyophilization, such as: (i) ease of processing a liquid, which simplifies aseptic handling; (ii) enhanced stability of a dry powder; (iii) removal of water without excessive heating of the product; (iv) enhanced product stability in a dry state; and (v) rapid and easy dissolution of the reconstituted product.
The lyophilization process generally includes the following steps:
- Dissolving the drug and excipients in a suitable solvent, generally water for injection (WFI).

- Sterilizing the bulk solution by passing it through a 0.22 micron bacteria-retentive
filter.
- Filling into individual sterile containers and partially stoppering the containers under
aseptic conditions.
- Transporting the partially stoppered containers to the lyophilizer and loading into the
chamber under aseptic conditions.
- Freezing the solution by placing the partially stoppered containers on cooled shelves in
a freeze-drying chamber or pre-freezing in another chamber.
- Applying a vacuum to the chamber and heating the shelves in order to evaporate the
water from the frozen state.
- Complete stoppering of the vials usually by hydraulic or screw rod stoppering
mechanisms installed in the lyophilizers.
The term lyophilized as used herein refers to a freeze-dried powder composition comprising moxifloxacin hydrochloride and a solubilizing agent.
The term physiologic solutions as used herein refer to various injectable solutions that can be used for reconstitution in order to obtain isotonic solutions, i.e., a solution having a tonicity comparable to that of blood. The solutions may be, for example, selected from sodium lactate solution, sodium bicarbonate solution and the like.
The solubilizing agent as used herein refers to a substance that is able to enhance the solubility of the lyophilized cake on reconstitution with physiological solutions. The solubilizing agent may be selected from L-arginine, histidine, and lysine. The ratio of moxifloxacin to solubilizing agent is in the range of 1:0.1 to 1:10, and more particularly it can be in the range of 1:0.2 to 1:1.
In addition to one or more solubilizing agents, the composition may comprise other excipients. Excipients are used in lyophilization primarily to provide a stable liquid environment for the active ingredient for some finite time. The excipient may also cryoprotect, or otherwise protect the active ingredient during the freezing process. The excipient may also serve only as a bulking agent. The addition of bulking agents such as mannitol and dextran strengthen cake structure.

Most formulations for lyophilization are totally aqueous solutions, although others contain solvents, such as tertiary butyl alcohol, to increase the solubility of some compounds.
Examples of other excipients include buffers, antioxidants, chelating agents, cryoprotectants and lyoprotectants. Examples of buffers suitable for lyophilization include Tris, citrate, and histidine buffers. Examples of lyoprotectants include sugars, PEG and certain inorganic salts. Examples of cryoprotectants include sugars such as lactose, trehalose, and sucrose; and polymers such as polyvinyl-pyrrolidone and PEG.
The production process for making lyophilized powder includes the steps of aseptic filtration of a solution of moxifloxacin hydrochloride and arginine in water for injection.
Specific amounts of this solution are placed in 30 ml capacity vials, which are then plugged partially with a slotted rubber plug. These vials are then placed in a lyophilizer. The vials, which have the solution in an aqueous phase, are then subjected to a very cold temperature, which causes the water to freeze into ice. The ice is then removed by a process called sublimation; during this process, the frozen mixture is subjected to an intense vacuum. Since ice has a low but significant level of "vapor pressure", the vacuum gradually pulls the molecules of water out of and away from the ice, and removes them. The intense vacuum inside a lyophilization chamber can thereby remove the water from the solution, leaving behind the dry powder containing moxifloxacin hydrochloride and L-arginine.
The dry powder so obtained can be reconstituted with physiological solutions to result in solutions that have known stability periods. For example, a first dilution is done with a small amount of physiologic solution, which remains stable for 30 min at room temperature, and then this solution is subject to a second, further dilution up to 250ml with physiologic solution. This solution remains stable for 2 hours at room temperature and 24 hrs at 2-8°C.
In one of the embodiments moxifloxacin hydrochloride and L-arginine are dissolved in water for injection and then aseptically filtered. A specific amount of this solution is placed in a vial of 30 ml capacity and lyophilized leaving behind the dry powder in the form of cake containing moxifloxacin hydrochloride and L-arginine. The lyophilized powder so formed can be reconstituted in sodium lactate before use.
The reconstituted solution comprises moxifloxacin hydrochloride from 0.04% to 3% w/v, in particular from 0.1% to 0.2% w/v, and most particularly about 0.16% w/v of

moxifioxacin hydrochloride, corresponding to 400 mg of moxifloxacin hydrochloride in 250 ml of physiologic solution.
The lyophilized injectable preparations serve as a medicament for parenteral administration, in particular as a medicament for preventing and treating bacterial infections. Parenteral administration includes, for example, intravenous, intra-arterial, subcutaneous, intramuscular and intraperitoneal administration. A dose, which is considered to be suitable, is 400 mg of active compound for intravenous infusion once per day. The daily infusion volume administered should not exceed 200 to 250 ml. As the amount of active compound is 400 mg in the lyophilized cake, after reconstitution with physiologic solutions this results in an active compound concentration of about 0.16% (w/v), corresponding to 400 mg of moxifloxacin hydrochloride in 250 ml of physiologic solution.
The lyophilized pharmaceutical composition when reconstituted with physiologic solutions at final concentration may be stored for up to 2 hours at controlled room temperature 15-25°C and for up to 24 hours at 4°C.
The following examples are illustrative of the invention, and are not to be construed as limiting the invention.
(Table Remove)

1. Moxifloxacin hydrochloride and L-arginine are dissolved in water for injection, which is
then aseptically filtered through a 0.2 micron filter.
2. 5.7 ml of this solution is filled in vials of 30 ml capacity, which are then plugged
partially with a slotted rubber plug.
3. The vials of step 2 are then placed in a lyophilizer.
4. The vials in the lyophilizer, which contain the solution in an aqueous phase, are then
subjected to a very cold temperature, causing the water to freeze into ice.

5. The ice is then removed by subjecting the frozen mixture to an intense vacuum and by
slowly elevating the temperature.
6. Lyophilized dry powder containing moxifloxacin hydrochloride and L-arginine is
reconstituted with 13.3 ml of sodium lactate injection USP and further diluted up to 250
ml with sodium lactate injection USP before use.
All the steps as well as the composition were the same as Example 1 except at step 6 where 2.5 % sodium bicarbonate injection was used for reconstitution.
All the steps as well as the composition were the same as Example 1 except at step 6 where 5% sodium bicarbonate injection was used for reconstitution.
The composition of Example 1 was subjected to stability studies both in dry form as well as reconstituted form. The results of these studies are provided in Tables 1-3. The reconstituted products of Examples 2 and 3 were also subjected to stability studies. The results for these studies are provided in Tables 2 and 3. The colour of the lyophilized powder and reconstituted solution was yellow, and no change in colour was observed during the entire stability study. In addition, there was no particulate matter observed in the reconstituted solutions during and at the end of stability study.
(Table Remove)

a- sodium lactate indicates sodium lactate injection USP; b- sodium bicarbonate indicates sodium bicarbonate injection; # 2hr/RT for Sodium Lactate and 1 hr/RT for Sodium Bicarbonate $ 4hr/2-8°C for Sodium Bicarbonate & 24hr/4°C for Sodium Lactate
Table 3: Stability study of moxifloxacin composition in reconstituted form

- sodium lactate indicates sodium lactate injection USP; b- sodium bicarbonate indicates sodium bicarbonate injection;
Lyophilized powder was stable for 3 months at 45°C at 75% RH as given in Table 1. No substantial change in pH was observed when the reconstituted solution was subjected to the various conditions as reported in Table 2. Thus, as used herein, Table 2 shows that the pH of the reconstituted solutions remain constant for up to one hour storage at room temperature after reconstitution. In addition, the reconstituted solution (both sodium lactate as well as sodium bicarbonate) was also stable at 45°C at 75% RH for 3 months as reported in Table 3.
While several particular forms of the inventions have been described, it will be apparent that various modifications and combinations of the inventions detailed in the text can be made without departing from the spirit and scope of the inventions. Accordingly, it is not intended that the inventions be limited, except as by the appended claims.

WE CLAIM:
1. A lyophilized pharmaceutical composition for parenteral administration comprising
moxifloxacin or pharmaceutically acceptable salts thereof and solubilizing agents
selected from the group consisting of L-arginine, histidine, lysine or mixtures thereof.
2. The pharmaceutical composition according to claim 1, wherein moxifloxacin and
solubilizing agent are present in the range of 1:0.1 to 1:10.
3. The pharmaceutical composition according to claim 1, wherein the lyophilized
composition is reconstituted shortly before use using a sterile physiological solution
selected from the group consisting of sodium lactate solution and sodium bicarbonate
solution or mixture thereof.
4. The pharmaceutical composition according to claim 3, wherein the pH of the
reconstituted solution remains constant for up to one hour storage at room temperature
after reconstitution.
5. The pharmaceutical composition according to claim 3 wherein the reconstituted solution
comprises moxifloxacin hydrochloride being present at from 0.04% to
3% w/v.
6. The pharmaceutical composition according to claim 1 wherein the composition further
comprises excipients selected from one or more of bulking agents, buffers, antioxidants,
chelating agents, cryoprotectants and lyoprotectants.
7. The pharmaceutical composition according to claim 1 wherein the composition
comprises about 400 mg of moxifloxacin hydrochloride.
8. The pharmaceutical composition according to claim 1, wherein the composition has not
more than 0.16% of related substances after storage for three months at 40°C and 75%
relative humidity.
9. A process for the preparation of a lyophilized pharmaceutical composition according to
claim 1, wherein the process comprises the steps of:
dissolving moxifloxacin and solubilizing agents in water for injection;

filtering to eliminate any bacteria or other contaminants; subpackaging into sterile containers; lyophilizing; and drying.
10. A lyophilized pharmaceutical composition for parenteral administration comprising Moxifloxacin or pharmaceutically acceptable salt thereof as described herein.