SOLID ORAL DOSAGE FORMS OF GATIFLOXACIN
Technical Field of the Invention
The present invention relates to solid oral dosage forms of gatifloxacin having reproducible release characteristics and processes for their preparation.
Background of the Invention
Tablet dosage forms are the most widely used of the various dosage forms. From the patient's perspective the tablet dosage forms provides a unit dose of the active substance accurately in a form that is easy to consume and is convenient for storage and transport. From the manufacturer's perspective, the tablet dosage forms are more economical to manufacture than any other dosage form. Tablets are available in various types, such as mouth-dissolving tablets, water-soluble tablets, dispersible tablets, effervescent tablets, buccal tablets, etc. In short, tablets are versatile and can be designed with considerations to the specific requirements of the patient.
It is imperative that a tablet should provide uniform therapeutic levels of the drug with each dose to the patient for maximum efficacy. The drug should be in solution form in the gastrointestinal fluid for absorption. For most tablets, the first important step towards going into the solution form is breaking down of the tablet into smaller particles or granules, a process known as disintegration. Thus, the disintegration time of the tablet may give an indication about the extent of the availability of the drug for absorption into the systemic circulation. Designing a manufacturing process to achieve a constant disintegration time, or at least with acceptable levels of variation, serves to minimize the batch-to-batch variability during the manufacturing process. An ideal tablet should have a reproducible disintegration time or an ultimately reproducible dissolution time to attain a predictable therapeutic effect of the intended dose.
U.S. Patent No. 6,291,462 discloses solid dosage forms of gatifloxacin which are characterized as having reproducible disintegration times. The dosage forms have a granular phase and an extragranular phase. The granules contain gatifloxacin, fillers, binders, and disintegration aids. The extragranular phase contains at least one disintegration aid and a lubricant. The use of an extragranular disintegration aid has been considered to be critical for the reproducible disintegration time of gatifloxacin tablets.

Summary of the Invention
In one general aspect there is provided a solid oral dosage form that includes an intragranular phase and an extragranular phase. The intragranular phase includes gatifloxacin and one or more of a filler, a binder, a wicking agent, and a disintegration aid. The extragranular phase is free of any disintegration aid.
Embodiments of the oral dosage form may include one or more of the following features. For example, the filler may be selected from starch, dicalcium phosphate, calcium carbonate, lactose, mannitol, dextrose, sorbitol, sucrose, sodium chloride and combinations thereof. The binder may be selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, starch mucilage, carbopols, gums, and combinations thereof.
The wicking agent may be selected from water soluble excipients, hydrophilic polymers, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose and combinations thereof. In particular, the wicking agent may be a water soluble excipient and the water-soluble excipient may be one or more of sodium chloride, sugar, and sugar alcohols. The sugar or sugar alcohol may be selected from dextrose, mannitol, sorbitol, lactose, sucrose, and combinations thereof. The hydrophilic polymer may be selected from croscarmellose sodium, crosslinked polyvinylpyrrolidone, starches, gums, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol, and combinations thereof.
The disintegration aid may be selected from ion exchange resins, hydroxypropylcellulose, crospovidone, croscarmellose sodium, starches, pectins, alginates, surfactants, microcrystalline cellulose, sodium starch glycolate, and combinations thereof. In particular, the disintegration may be croscarmellose sodium. The disintegration aid may be an ion exchange resin and, in particular, may be polacrillin potassium.
The extragranular phase may further include one or more lubricants. The lubricant may be selected from talc, polyethylene glycol, sodium chloride, stearic acid, calcium stearate, zinc stearate, magnesium stearate, sodium stearyl fumarate, and combinations thereof. The lubricant may be a water soluble lubricant selected from one or more of sodium stearyl fumarate, polyethylene glycol, sodium chloride, and combinations thereof. In particular, the lubricant may be sodium stearyl fumarate.

The extragranular phase may further include a water soluble filler. The water soluble filler may be selected from lactose, mannitol, dextrose, sorbitol, sucrose and sodium chloride.
The solid dosage form may be in the form of a tablet and the tablet may be coated.
In another general aspect there is provided a process for the preparation of a solid oral dosage form. The process includes blending gatifloxacin and one or more of fillers, binders, wicking agent and disintegration aids; granulating the blend to form granules; mixing the granules with an extragranular phase to form a mixture of the granules and the extragranular phase, the extragranular phase being free of any disintegration aid; and compressing the mixture into a solid dosage form.
Embodiments of the process may include one or more of the following features. For example, the granulation may be wet granulation and the wet granulation may include a granulating liquid selected from water, ethanol, isopropyl alcohol, acetone, dichloromethane, and a binder solution. The granulation may be dry granulation and the dry granulation may be compaction or slugging. In particular, the dry granulation may be compaction.
The filler may be selected from starch, dicalcium phosphate, calcium carbonate, lactose, mannitol, dextrose, sorbitol, sucrose, sodium chloride and combinations thereof. The binder may be selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, starch mucilage, carbopols and gums. The wicking agent may be selected from water soluble excipient, hydrophilic polymers, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and combinations thereof. In particular, the wicking agent may be a water-soluble excipient and the water-soluble excipient may be selected from sodium chloride, sugar, sugar alcohols, and combinations thereof. The disintegration aid may be selected from ion exchange resins, hydroxypropylcellulose, crospovidone, croscarmellose sodium, starches, pectins, alginates, surfactants, microcrystalline cellulose, sodium starch glycolate, and combinations thereof.
The process may further include adding one or more of a lubricant and water soluble filler to the extragranular phase. The solid dosage form may be in the form of a tablet and the tablet may be coated.
In another general aspect there is provided a method of treating infections and conditions for which gatifloxacin is indicated. The method includes administering a solid

dosage form that includes an intragranular phase and an extragranular phase. The intragranular phase includes gatifloxacin and one or more of a filler, a binder, a wicking agent, and a disintegration aid. The extragranular phase is free of any disintegration aid.
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
We have now discovered that tablets of gatifloxacin with a reproducible disintegration time or dissolution rate can be prepared without using any extragranular disintegration aid.
The term "solid dosage form" as used herein includes tablets or coated tablets, pellets and capsules filled with tablets, or pellets prepared as per the embodiments described herein. A particularly suitable solid dosage form is that of tablets. The solid dosage form can include gatifloxacin and pharmaceutically acceptable excipients, including one or more of fillers, binders, wicking agents, disintegration aids, and lubricants.
The term "gatifloxacin" as used herein includes gatifloxacin or a pharmaceutically acceptable salt or hydrate thereof, such as, but not limited to, gatifloxacin anhydrous, gatifloxacin hydrochloride, gatifloxacin hemihydrate or sesquihydrate, and any other pharmaceutically acceptable form known to the skilled in the art. Generally, the amount of gatifloxacin can be from about 20%w/w to about 80% w/w, particularly from about 40%w/w to about 80%w/w of the solid dosage from. Gatifloxacin is currently approved by FDA in various forms and strengths, including 200 mg and 400 mg tablets as a broad spectrum antibacterial agent for the treatment of infections due to susceptible strains of particular microorganisms, as approved by the FDA.
The fillers can be any substance which can provide bulk to the tablet and include, without limitation, starch, dicalcium phosphate, calcium carbonate, lactose, mannitol dextrose, sorbitol, sucrose, sodium chloride and combinations thereof. The filler may be up to about 40% by weight of the solid dosage form.
The binders can be selected from the group that includes polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropylcellulose, starch mucilage, carbopols and

gums. The binder may be present at an amount from about 0.1% to about 10% by weight of the solid dosage form.
Wicking agents are substances that are capable of drawing water into the dosage form and assist in the breaking of the tablets into granules. Any excipient that can serve to transport moisture as discussed above can be considered to be a wicking agent. These agents help in maintaining a reproducible disintegration time or drug release rate of the tablets even on aging of the tablet (e.g., storage). The wicking agent is present in the intragranular phase and includes, for example, water soluble excipients such as sodium chloride; sugars or sugar alcohols such as dextrose, mannitol, sorbitol, lactose and sucrose; hydrophilic polymers such as croscarmellose sodium, cross linked polyvinylpyrrolidone, starches, gums, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and carbopol; silicon dioxide, colloidal silicon dioxide and microcrystalline cellulose. Particularly suitable wicking agents are silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose and sugars or sugar alcohols. The wicking agent may make up from about 1% w/w to about 50% w/w, particularly from about 1% w/w to about 40% w/w, of the solid dosage form.
The disintegration aid is present intragranularly and can be selected from the group that includes ion exchange resins such as polacrillin potassium (Amberlite® IRP88), hydroxypropylcellulose, crospovidone, croscarmellose sodium, starches, pectins, alginates, surfactants, microcrystalline cellulose, sodium starch glycolate and the like. Particularly suitable disintegration aids are croscarmellose sodium, sodium starch glycolate, and polacrillin potassium. The disintegration aid can be present in a concentration of up to about 30%w/w of the solid dosage form.
Lubricants can be talc, polyethylene glycol, sodium chloride, stearic acid, calcium stearate, zinc stearate, magnesium stearate and sodium stearyl fumarate. Use of a water-soluble lubricant is particularly advantageous. The lubricant may be present in a concentration of about 0.1%w/w to about 5%w/w of the solid dosage form.
The granulating liquid can be, but is not limited to, water, ethanol, isopropyl alcohol, acetone, dichloromethane and the like. Alternatively, the binder can be dissolved in the granulating liquid and used as a solution/dispersion.
In one embodiment gatifloxacin tablets may be prepared by blending gatifloxacin with intragranular excipients such as filler, binder, wicking agent, and disintegrant;

granulating the above blend with a granulating liquid; drying and sizing the granules; and blending the granules with a lubricant and, optionally, other excipients such as fillers, and compressing to form a tablet.
In another embodiment, gatifloxacin tablets may be prepared by blending gatifloxacin and intragranular excipients such as filler, binder, wicking agent, and disintegrant; compacting or slugging the above blend; sizing the compacts or slugs to get granules; and blending the granules with a lubricant and optionally other excipients such as fillers and compressing to form a tablet.
In yet another embodiment, gatifloxacin tablets may be prepared by blending gatifloxacin and a wicking agent, such as silicon dioxide, colloidal silicon dioxide and sodium chloride, along with binders, fillers and disintegration aids, granulating the blend with a granulating liquid, drying and mixing the granules with lubricant and, optionally, fillers, and then compressing into tablets.
In still another embodiment, gatifloxacin tablets may be prepared by blending gatifloxacin, fillers, binders, wicking agents, and disintegrants, granulating the blend with a granulating liquid, drying and mixing the granules with sodium stearyl fumarate, and compressing into tablets.
In still another embodiment, gatifloxacin tablets may be prepared by blending gatifloxacin, fillers, binders, wicking agents and disintegration aids, granulating the blend with a granulating liquid, drying and mixing the granules with an extragranular water-soluble filler such as lactose, mannitol, dextrose, sorbitol or sucrose and a lubricant, and compressing into tablets.
In still another embodiment, the gatifloxacin solid oral dosage form may be prepared by blending gatifloxacin and ion exchange resin, binder, filler and wicking agent; granulating the blend with a granulating liquid; drying and mixing the granules with a lubricant; and compressing into tablets.
The tablets thus formed can additionally be coated with coating compositions such as Opadry® or Lustreclear® (sold by Colorcon) to impart aesthetic appeal. Such a coating may comprise up to about 3% w/w by weight of the tablet.
The invention described herein is further illustrated by the following examples, which should not be construed as limiting the scope of the invention.

Example 1

(Table Removed)
Procedure: Gatifloxacin was blended with microcrystalline cellulose, croscarmellose sodium, povidone, colloidal silicon dioxide and mannitol. The above blend was granulated with purified water. The granules were dried, sized, mixed with sodium stearyl fumarate, and compressed using appropriate tooling.
Example 2

(Table Removed)
Procedure: Gatifloxacin was blended with microcrystalline cellulose, croscarmellose sodium, povidone, colloidal silicon dioxide, mannitol and polacrillin potassium. The above blend was granulated with purified water. The granules were dried, sized, mixed with sodium stearyl fumarate, and compressed using appropriate tooling.
Example 3

(Table Removed)
Procedure: Gatifloxacin was blended with microcrystalline cellulose, croscarmellose sodium, povidone, colloidal silicon dioxide, mannitol and polacrillin potassium. The above blend was granulated with purified water. The granules were dried, sized, mixed with lactose and sodium stearyl fumarate, and compressed using appropriate tooling.
Example 4

(Table Removed)
Procedure: Gatifloxacin was blended with microcrystalline cellulose, croscarmellose sodium, povidone, colloidal silicon dioxide, mannitol and polacrillin potassium. The above blend was granulated with purified water. The granules were dried, sized, mixed with mannitol and sodium stearyl fumarate, and compressed using appropriate tooling.

The tablets of Examples 1 - 4 were subjected to dissolution in a USP type II dissolution apparatus, at 50 rpm in 1000 ml of 0.1 N hydrochloric acid. The resulting dissolution profiles are given in Table 1.
Table 1: Dissolution profiles of the tablets of Examples 1 - 4 measured in a USP type II dissolution apparatus, at 50 rpm in 1000 ml of 0.1 N hydrochloric acid

(Table Removed)
As illustrated in Table 1, between about 93% and about 100% of the gatifloxacin in the tablets of Examples 1 - 4 is released within 10 minutes. This indicates the effective dissolution of a gatifloxacin tablet formulated without using any disintegration aid in the extragranular phase.
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 solid oral dosage form comprising:
an intragranular phase comprising gatifloxacin and one or more of a filler, a binder, a wicking agent, and a disintegration aid, and
an extragranular phase comprising one or more lubricants and optionally one or more water soluble fillers , wherein the extragranular phase is free of any disintegration aid.
2. The oral dosage form according to claim 1 wherein the filler is selected from
starch, dicalcium phosphate, calcium carbonate, lactose, mannitol, dextrose,
sorbitol, sucrose, sodium chloride and combinations thereof.
3. The oral dosage form according to claim 1 wherein the binder is selected from
polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose,
starch mucilage, carbopols, gums, and combinations thereof.
4. The oral dosage form according to claim 1 wherein the wicking agent is
selected from water soluble excipients, hydrophilic polymers, silicon dioxide,
colloidal silicon dioxide, microcrystalline cellulose and combinations thereof.
5. The oral dosage form according to claim 1 wherein the disintegration aid is
selected from ion exchange resins, hydroxypropylcellulose, crospovidone,
croscarmellose sodium, starches, pectins, alginates, surfactants, microcrystalline
cellulose, sodium starch glycolate, and combinations thereof.
6. The oral dosage form according to claim 1 wherein the lubricant is selected
from talc, polyethylene glycol, sodium chloride, stearic acid, calcium stearate,
zinc stearate, magnesium stearate, sodium stearyl fumarate, and combinations
thereof.
7. The oral dosage form according to claim 1 wherein the water soluble filler is
selected from lactose, mannitol, dextrose, sorbitol, sucrose and sodium chloride.
8. A process for the preparation of a solid oral dosage form according to claim 1,
wherein the process comprises: blending gatifloxacin and one or more of fillers,
binders, wicking agent and disintegration aids; granulating the blend to form
granules; mixing the granules with an extragranular phase to form a mixture of
the granules and the extragranular phase, the extragranular phase being free of
any disintegration aid; and compressing the mixture into a solid dosage form.

9. The process according to claim 8 wherein the granulation comprises
granulating with a liquid selected from water, ethanol, isopropyl alcohol, acetone,
dichloromethane, and a binder solution.
10. The process according to claim 8 wherein the granulation comprises dry
granulation selected from compaction and slugging.