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WO2005021000A1 - Solid oral dosage forms of gatifloxacin - Google Patents

Solid oral dosage forms of gatifloxacin Download PDF

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Publication number
WO2005021000A1
WO2005021000A1 PCT/IB2004/002802 IB2004002802W WO2005021000A1 WO 2005021000 A1 WO2005021000 A1 WO 2005021000A1 IB 2004002802 W IB2004002802 W IB 2004002802W WO 2005021000 A1 WO2005021000 A1 WO 2005021000A1
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WO
WIPO (PCT)
Prior art keywords
dosage form
oral dosage
combinations
form according
process according
Prior art date
Application number
PCT/IB2004/002802
Other languages
French (fr)
Inventor
Romi Barat Singh
Pananchukunnath Manoj Kumar
Vishnubhotla Nagaprasad
Sanjeev Sethi
Rajiv Malik
Original Assignee
Ranbaxy Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
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Publication date
Application filed by Ranbaxy Laboratories Limited filed Critical Ranbaxy Laboratories Limited
Publication of WO2005021000A1 publication Critical patent/WO2005021000A1/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets

Definitions

  • the present invention relates to solid oral dosage forms of gatifioxacin 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.
  • 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.
  • 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.
  • 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.
  • U.S. Patent No. 6,291,462 discloses solid dosage forms of gatifioxacin which are characterized as having reproducible disintegration times.
  • the dosage forms have a granular phase and an extragranular phase.
  • the granules contain gatifioxacin, 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 gatifioxacin tablets.
  • a solid oral dosage form that includes an intragranular phase and an extragranular phase.
  • the intragranular phase includes gatifioxacin 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 oral dosage form may include one or more of the following features.
  • 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.
  • 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.
  • 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.
  • a process for the preparation of a solid oral dosage form includes blending gatifioxacin 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.
  • 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.
  • 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.
  • a method of treating infections and conditions for which gatifioxacin is indicated includes administering a solid dosage form that includes an intragranular phase and an extragranular phase.
  • the intragranular phase includes gatifioxacin 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.
  • a particularly suitable solid dosage form is that of tablets.
  • the solid dosage form can include gatifioxacin and pharmaceutically acceptable excipients, including one or more of fillers, binders, wicking agents, disintegration aids, and lubricants.
  • gatifioxacin includes gatifioxacin or a pharmaceutically acceptable salt or hydrate thereof, such as, but not limited to, gatifioxacin anhydrous, gatifioxacin hydrochlori.de, gatifioxacin hemihydrate or sesquihydrate, and any other pharmaceutically acceptable form known to the skilled in the art.
  • the amount of gatifioxacin 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.
  • Gatifioxacin is currently approved by FDA in various forms and strengths, including 200 mg and 400 g 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.
  • the binder can be dissolved in the granulating liquid and used as a solution/dispersion.
  • gatifioxacin tablets may be prepared by blending gatifioxacin 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.
  • gatifioxacin tablets may be prepared by blending gatifioxacin 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.
  • intragranular excipients such as filler, binder, wicking agent, and disintegrant
  • gatifioxacin tablets may be prepared by blending gatifioxacin 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.
  • a wicking agent such as silicon dioxide, colloidal silicon dioxide and sodium chloride
  • gatifioxacin tablets may be prepared by blending gatifioxacin, 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.
  • gatifioxacin tablets may be prepared by blending gatifioxacin, 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.
  • an extragranular water- soluble filler such as lactose, mannitol, dextrose, sorbitol or sucrose and a lubricant
  • the gatifioxacin solid oral dosage form may be prepared by blending gatifioxacin 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.
  • Gatifioxacin 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.
  • Gatifioxacin 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
  • Gatifioxacin 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.
  • Gatifioxacin 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 ⁇ 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

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Abstract

The present invention relates to solid oral dosage forms of gatifloxacin having reproducible release characteristics and processes for their preparation. The solid oral dosage form 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.

Description

SOLID ORAL DOSAGE FORMS OF GATIFLOXACIN Technical Field of the Invention The present invention relates to solid oral dosage forms of gatifioxacin 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 gatifioxacin which are characterized as having reproducible disintegration times. The dosage forms have a granular phase and an extragranular phase. The granules contain gatifioxacin, 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 gatifioxacin 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 gatifioxacin 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 gatifioxacin 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 gatifioxacin is indicated. The method includes administering a solid dosage form that includes an intragranular phase and an extragranular phase. The intragranular phase includes gatifioxacin 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 gatifioxacin 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 gatifioxacin and pharmaceutically acceptable excipients, including one or more of fillers, binders, wicking agents, disintegration aids, and lubricants. The term "gatifioxacin" as used herein includes gatifioxacin or a pharmaceutically acceptable salt or hydrate thereof, such as, but not limited to, gatifioxacin anhydrous, gatifioxacin hydrochlori.de, gatifioxacin hemihydrate or sesquihydrate, and any other pharmaceutically acceptable form known to the skilled in the art. Generally, the amount of gatifioxacin 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. Gatifioxacin is currently approved by FDA in various forms and strengths, including 200 mg and 400 g 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 gatifioxacin tablets may be prepared by blending gatifioxacin 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, gatifioxacin tablets may be prepared by blending gatifioxacin 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, gatifioxacin tablets may be prepared by blending gatifioxacin 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, gatifioxacin tablets may be prepared by blending gatifioxacin, 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, gatifioxacin tablets may be prepared by blending gatifioxacin, 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 gatifioxacin solid oral dosage form may be prepared by blending gatifioxacin 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
Figure imgf000008_0001
Procedure: Gatifioxacin 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
Figure imgf000008_0002
Procedure: Gatifioxacin 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
Figure imgf000009_0001
Procedure: Gatifioxacin 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
Figure imgf000009_0002
Procedure: Gatifioxacin 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 π 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
Figure imgf000010_0001
As illustrated in Table 1, between about 93% and about 100% of the gatifioxacin in the tablets of Examples 1 - 4 is released within 10 minutes. This indicates the effective dissolution of a gatifioxacin 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.

Claims

We Claim:
1. A solid oral dosage form comprising: an intragranular phase comprising gatifioxacin and one or more of a filler, a binder, a wicking agent, and a disintegration aid, and an extragranular phase, 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 4 wherein the wicking agent comprises a water soluble excipient.
6. The oral dosage form according to claim 5 wherein the water-soluble excipient comprises one or more of sodium chloride, sugar, and sugar alcohols.
7. The oral dosage form according to claim 6 wherein the sugar or sugar alcohol is selected from dextrose, mannitol, sorbitol, lactose, sucrose, and combinations thereof.
8. The oral dosage form according to claim 4 wherein the hydrophilic polymer is selected from croscarmellose sodium, crosslinked polyvinylpyrrolidone, starches, gums, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, carbopol, and combinations thereof.
9. 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.
10. The oral dosage form according to claim 9 wherein the disintegration aid comprises croscarmellose sodium.
11. The oral dosage form according to claim 9 wherein the disintegration aid comprises an ion exchange resin.
12. The oral dosage form according to claim 11 wherein the ion exchange resin comprises polacrillin potassium.
13. The oral dosage form according to claim 1 wherein the extragranular phase further comprises one or more lubricants.
14. The oral dosage form according to claim 13 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.
15. The solid dosage form according to 13 wherein the lubricant comprises a water soluble lubricant selected from one or more of sodium stearyl fumarate, polyethylene glycol, sodium chloride, and combinations thereof.
16. The solid dosage form according to claim 15 wherein the lubricant comprises sodium stearyl fumarate.
17. The oral dosage form according to claim 1 wherein the extragranular phase further comprises one or more water soluble fillers.
18. The oral dosage form according to claim 17 wherein the water soluble filler is selected from lactose, mannitol, dextrose, sorbitol, sucrose and sodium chloride.
19. The oral dosage form according to claim 1 wherein the oral dosage form comprises a tablet and the tablet includes an outer coating.
20. A process for the preparation of a solid oral dosage form, the process comprising: blending gatifioxacin 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.
21. The process according to claim 20 wherein the granulation comprises wet granulation.
22. The process according to claim 21 wherein the wet granulation comprises a granulating liquid selected from water, ethanol, isopropyl alcohol, acetone, dichloromethane, and a binder solution.
23. The process according to claim 20 wherein the granulation comprises dry granulation.
24. The process according to claim 23 wherein the dry granulation comprises compaction or slugging.
25. The process according to claim 24 wherein the dry granulation comprises compaction.
26. The process according to claim 20 wherein the filler is selected from starch, dicalcium phosphate, calcium carbonate, lactose, mannitol, dextrose, sorbitol, sucrose, sodium chloride and combinations thereof.
27. The process according to claim 20 wherein the binder is selected from polyvinylpyrrolidone, hydroxypropylmethylcellulose, hydroxypropylcellulose, starch mucilage, carbopols and gums.
28. The process according to claim 20 wherein the wicking agent is selected from water soluble excipient, hydrophilic polymers, silicon dioxide, colloidal silicon dioxide, microcrystalline cellulose, and combinations thereof.
29. The process according to claim 28 wherein the wicking agent comprises a water- soluble excipient.
30. The process according to claim 29 wherein the water-soluble excipient is selected from sodium chloride, sugar, sugar alcohols, and combinations thereof.
31. The process according to claim 20 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.
32. The process according to claim 20 further comprising adding one or more of a lubricant and water soluble filler to the extragranular phase.
33. The process according to claim 20 further comprising coating the solid dosage form.
34. A method of treating infections and conditions for which gatifioxacin is indicated, the method comprising administering a solid dosage form comprising: an intragranular phase comprising gatifioxacin and one or more of a filler, a binder, a wicking agent, and a disintegration aid; and an extragranular phase, wherein the extragranular phase is free of any disintegration aid.
PCT/IB2004/002802 2003-08-28 2004-08-30 Solid oral dosage forms of gatifloxacin WO2005021000A1 (en)

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US9095509B2 (en) 2005-09-15 2015-08-04 Genzyme Corporation Sachet formulation for amine polymers
US9579343B2 (en) 1999-10-19 2017-02-28 Genzyme Corporation Direct compression polymer tablet core
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US9579343B2 (en) 1999-10-19 2017-02-28 Genzyme Corporation Direct compression polymer tablet core
US9931358B2 (en) 1999-10-19 2018-04-03 Genzyme Corporation Direct compression polymer tablet core
US7985418B2 (en) * 2004-11-01 2011-07-26 Genzyme Corporation Aliphatic amine polymer salts for tableting
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