WO2003086344A1 - Antibiotic product, use and formulation thereof - Google Patents

Antibiotic product, use and formulation thereof Download PDF

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Publication number
WO2003086344A1
WO2003086344A1 PCT/US2002/040809 US0240809W WO03086344A1 WO 2003086344 A1 WO2003086344 A1 WO 2003086344A1 US 0240809 W US0240809 W US 0240809W WO 03086344 A1 WO03086344 A1 WO 03086344A1
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WO
WIPO (PCT)
Prior art keywords
dispersion
eudragit
pellets
antibiotic
coating
Prior art date
Application number
PCT/US2002/040809
Other languages
French (fr)
Inventor
Edward M. Rudnic
James D. Isbister
Donald J. Treacy, Jr.
Sandra E. Wassink
Original Assignee
Advancis Pharmaceuticals Corporation
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.)
Filing date
Publication date
Priority claimed from US10/027,609 external-priority patent/US6669948B2/en
Priority claimed from US10/028,595 external-priority patent/US6663891B2/en
Priority claimed from US10/027,866 external-priority patent/US6663890B2/en
Priority claimed from US10/027,366 external-priority patent/US6667057B2/en
Priority claimed from US10/028,590 external-priority patent/US6730320B2/en
Priority claimed from US10/027,837 external-priority patent/US6667042B2/en
Application filed by Advancis Pharmaceuticals Corporation filed Critical Advancis Pharmaceuticals Corporation
Priority to EP20020794328 priority Critical patent/EP1465591A1/en
Priority to AU2002359768A priority patent/AU2002359768A1/en
Priority to JP2003583368A priority patent/JP2005523309A/en
Priority to CA002470016A priority patent/CA2470016A1/en
Publication of WO2003086344A1 publication Critical patent/WO2003086344A1/en

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Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • 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
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

  • This invention relates to an antibiotic product, as well as the use and formulation thereof.
  • the invention further relates to a levofloxacin antibiotic product, including derivatives thereof such as salts, esters, metabolites, etc.
  • the invention further relates to a metronidazole antibiotic product and derivatives thereof, such as salts, esters, metabolites, etc.
  • the invention further relates to a tetracycline antibiotic product and in particular doxycycline and its derivatives, salts, hydrates, esters, metabolites, etc.
  • the invention further relates to an erythromyacin antibiotic product, in particular an erythromyacin derivative or a macrolide or a ketolite (including derivatives thereof such as salts, esters, etc.); in particular Clarithromycin.
  • an erythromyacin antibiotic product in particular an erythromyacin derivative or a macrolide or a ketolite (including derivatives thereof such as salts, esters, etc.); in particular Clarithromycin.
  • the invention further relates to (a) fluroquinilone antibiotic products and in particular ciprofloxacin and its derivatives such as salts, esters, bases, etc., metabolites, etc.
  • the invention further relates to betalactam antibiotic products and in particular to products that include a cephalosporin, such as cefuroxime and/or cefpodoxime or a penicillin such as amoxicillin or dicloxacillin, as well as derivatives, metabolites and any active isomers thereof.
  • a cephalosporin such as cefuroxime and/or cefpodoxime
  • a penicillin such as amoxicillin or dicloxacillin
  • antibiotics have been used, and will be used, in order to combat bacterial infection.
  • such antibiotics can be administered by a repeated dosing of immediate release dosage forms, which results in poor compliance or as a controlled release formulation (slow release) at liigher administered doses.
  • the present invention is directed to providing for an improved antibiotic product.
  • an antibiotic pharmaceutical product which is comprised of at least two, preferably at least three, antibiotic dosage forms. Such dosage forms are formulated so that each of the dosage forms has a different release profile.
  • a single or unitary antibiotic product that has contained therein at least two, preferably at least three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in each of such dosage forms is released at different times.
  • the antibiotic product may be comprised of at least four different dosage forms, each of which starts to release the antibiotic contained therein at different times after administration of the antibiotic product.
  • the antibiotic product generally does not include more than five dosage forms with different release times.
  • the antibiotic product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration ofthe total antibiotic released from the antibiotic product is achieved no earlier than four hours after administration.
  • one of the at least three dosage forms is an immediate release dosage form whereby initiation of release of the antibiotic therefrom is not substantially delayed after administration of the antibiotic product.
  • the second and third ofthe at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antibiotic product), whereby the antibiotic released therefrom is delayed until after initiation of release of the antibiotic from the immediate release dosage form.
  • the antibiotic release from the second of the at least two dosage forms achieves a C max (maximum serum concentration in the serum) at a time after the antibiotic released from the first of the at least three dosage forms achieves a C max in the serum, and the antibiotic released from the third dosage form achieves a C max in the serum after the C max of antibiotic released from the second dosage form.
  • the second of the at least two dosage forms initiates release ofthe antibiotic contained therein at least one hour after the first dosage form, with the initiation ofthe release therefrom generally occurring no more than six hours after initiation of release of antibiotic from the first dosage form of the at least three dosage forms.
  • the immediate release dosage form produces a C ma ⁇ for the antibiotic released therefrom within from about 0.5 to about 2 hours, with the second dosage form of the at least three dosage forms producing a C ma ⁇ for the antibiotic released therefrom in no more than about four hours.
  • the C ma ⁇ for such second dosage form is achieved no earlier than two hours after administration of the antibiotic product; however, it is possible within the scope ofthe invention to achieve C m a in a shorter period of time.
  • the antibiotic product may contain at least three or at least four or more different dosage forms.
  • the antibiotic released therefrom reaches a C max at a time later than the C max is achieved for the antibiotic released from each of the first and second dosage forms.
  • release of antibiotic from the third dosage form is started after initiation of release of antibiotic from both the first dosage form and the second dosage form.
  • C max for antibiotic release from the third dosage form is achieved within eight hours.
  • the antibiotic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby the antibiotic release from each of the at least four different dosage forms achieves a C max at a different time.
  • C max for all the antibiotic released from the antibiotic product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours.
  • the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period.
  • the term single administration means that the total antibiotic administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are admimstered at essentially the same time.
  • a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile is an improvement over a single dosage antibiotic product comprised of an antibiotic dosage form having a single release profile.
  • Each ofthe dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics and each of the dosage forms may have the same antibiotic or different antibiotics.
  • the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though C max ofthe fourth dosage form of the at least four dosage forms is reached after the C max of each of the other dosage forms is reached, antibiotic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form.
  • the antibiotic product ofthe present invention may be formulated for administration by a variety of routes of administration.
  • the antibiotic product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration.
  • the antibiotic product is formulated in a manner such that it is suitable for oral administration.
  • the at least two different dosage forms may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion.
  • the immediate release dosage form is in the continuous phase
  • the delayed release dosage form is in a discontinuous phase.
  • the formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described.
  • an oil-in-water-in-oil emulsion with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.
  • an antibiotic product in the form of a patch which includes antibiotic dosage forms having different release profiles, as hereinabove described.
  • the antibiotic product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion.
  • the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase ofthe emulsion.
  • the antibiotic product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal admimstration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration.
  • the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
  • the antibiotic product is formulated in a manner suitable for oral administration.
  • each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
  • each ofthe dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product.
  • antibiotic products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release ofthe antibiotic, as hereinabove described, whereby the C max of the antibiotic released from each of the tablets is reached at different times, with the C max of the total antibiotic released from the antibiotic product being achieved in less than twelve hours.
  • an antibiotic product including at least three dosage forms with different release profiles for different routes of administration is deemed to be within the skill ofthe art from the teachings herein.
  • the time of release can be controlled by the concentration of antibiotics in the coating and/or the thickness ofthe coating.
  • the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antibiotic to be delivered by the product, with such immediate release dosage forms generally providing at least 25% ofthe total dosage ofthe antibiotic to be delivered by the product.
  • the immediate release dosage form provides from about 20% to about 30% of the total dosage of antibiotic to be delivered by the product; however, in some cases it may be desirable to have the immediate release dosage form provide for about 45% to about 50% ofthe total dosage of antibiotic to be delivered by the product.
  • each ofthe delayed release dosage forms may provide about equal amounts of antibiotic; however, they may also be formulated so as to provide different amounts.
  • each of the dosage forms contains the same antibiotic; however, each of the dosage forms may contain more than one antibiotic.
  • the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, ofthe total antibiotic; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, ofthe total antibiotic; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, ofthe total antibiotic.
  • the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, ofthe total antibiotic provided by the two delayed release components with the second delayed release component providing the remainder ofthe antibiotic.
  • the earliest released component provides 20% to 35% by weight ofthe total antibiotic provided by the three delayed release components
  • the next in time delayed release component provides from 20% to 40%, by weight, ofthe antibiotic provided by the three delayed release components and the last in time providing the remainder ofthe antibiotic provided by the three delayed release components.
  • the earliest delayed release component provides from 15% to 30%, by weight
  • the next in time delayed release component provides from 15% to 30%
  • the next in time delayed release component provides from 20% to 35%, by weight
  • the last in time delayed release component provides from 20% to 35%, by weight, in each case ofthe total antibiotic provided by the four delayed release components.
  • the immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
  • the materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PNP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000- 10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
  • ingredients in this system may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration.
  • These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above.
  • surfactants such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic
  • These materials may be present in the rate of 0.05-15% (W/W).
  • compositions in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
  • Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.
  • PEG polyethylene glycol
  • Carbowax, Polyox polyethylene glycol
  • waxes such as white wax or bees wax
  • paraffin acrylic acid derivatives
  • acrylic acid derivatives Eudragit
  • propylene glycol and ethylcellulose
  • these materials can be present in the range of 0.5-25% (W/W) of this component.
  • compositions in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
  • the kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives.
  • These materials can be present in concentrations from 4-20% (W/W).
  • Sustained Release Component The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
  • the kind of materials useful for this purpose can be, but are not limited to, ethylcellulose,hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons.
  • These materials can be present in concentrations from 4-20% (W/W).
  • the units comprising the antibiotic composition of the present invention can be in the form of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension.
  • the antibiotic composition of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably is administered orally.
  • the composition includes a therapeutically effective amount of the antibiotic, which amount will vary with the antibiotic to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day.
  • the composition is administered to a host in an amount effective for treating a bacterial infection.
  • This system will be especially useful in extending the practial therapeutic activity for antibiotics with elimination half lives of less than 20 hours and more particularly with elimination half-lives of less than 12 hours, and will be particularly useful for those drugs with half-lives of 2-10 hours.
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven.
  • a suitable pharmaceutical drier such as a vacuum over or forced-air oven.
  • the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • Polyethylene glycol 4000 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Clarithromycin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
  • Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Clarithromycin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
  • Example 11 Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
  • Example 11 Croscarmellose sodium 5
  • Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
  • Ciprofloxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5
  • Polyethylene glycol 4000 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder
  • a suitable pharmaceutical drier such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • Clarithromycin 80% (W/W) Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D 5
  • Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder
  • a suitable pharmaceutical drier such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15
  • Ciprofloxacin 70% (W/W)
  • Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder
  • a suitable pharmaceutical drier such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
  • Clarithromycin 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5
  • Povidone (PNP) 10 Polyethylene glycol 2000 5
  • composition ofthe aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 2.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • composition ofthe aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 3.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • 1.5 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used to coat matrix pellets with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%:
  • the capsule is filled with the three different pellets to achieve a total dose of
  • composition ofthe Amoxicillin trihydrate matrix pellets provided in Table 4.
  • Table 4 Composition of Amoxicillin Matrix Pellets
  • 57.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
  • 57.2.5 Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
  • composition ofthe aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 5.
  • TEC/talc suspension is mixed using laboratory mixer.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram per minute
  • 57.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
  • 57.9.3 Compress the blend on a rotary tablet press.
  • the fill weight should be adjusted to achieve a 500 mg dose tablet.
  • composition ofthe clarithromycin matrix pellets provided in Table 1.
  • 58.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.
  • 58.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
  • composition ofthe aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 10.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • the following coating parameters were used for coating the matrix pellets with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.
  • Capsules were filled with the uncoated pellets, the L30D-55 coated pellets and S100 coated pellets in weight percentages of 30%:30%:40%, respectively to provide 250 mg. capsules.
  • composition ofthe metronidazole matrix pellets provided in Table 12.
  • composition ofthe aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 13.
  • composition ofthe aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 14.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • the following coating parameters were used for coating with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and SI 00 coated pellets respectively.
  • the capsule is filled with the four different pellets to achieve a total dose of 375mg/capsule.
  • composition ofthe Amoxicillin trihydrate matrix pellets provided in Table 15.
  • Table 15 Composition of Amoxicillin Matrix Pellets
  • Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
  • composition ofthe aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 16.
  • the TEC/talc suspension is mixed using laboratory mixer.
  • composition ofthe aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 17.
  • composition ofthe aqueous Aquacoat dispersion applied to Amoxicillin L30 D- 55 coated pellets is provided below in Table 18.
  • Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C
  • 60.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim to achieve a 20% coat weight gain.
  • 60.9.2 Coat anotlier batch of Amoxicillin matrix pellets with L30 D-55 dispersion to achieve a 20% weight gain.
  • Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
  • the fill weight should be adjusted to achieve a 500 mg dose tablet.
  • composition ofthe clarithromycin matrix pellets provided in Table 21.
  • Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.
  • 61.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
  • composition ofthe aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 22.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30%
  • the capsule is filled with the four different pellets to achieve a total dose of
  • Blend Levofloxacin, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator ⁇ Blend Levofloxacin, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.
  • composition ofthe aqueous Eudragit L30D-55 coating dispersion applied to the Levofloxacin pellets is provided below in Table 2.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • the following coating parameters were used for coating ofthe Eudragit® L 30 D-55 film coating dispersion.
  • composition ofthe aqueous Opadry solution applied to the Levofloxacin pellets is provided below in Table 3.
  • composition ofthe aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated Levofloxacin pellets is provided below in Table 4.
  • composition ofthe aqueous Eudragit® S 100 dispersion applied to the Levofloxacin pellets is provided below in Table 5.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • the following coating parameters were used for coating ofthe Eudragit® S 100 aqueous film coating dispersion.
  • Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%
  • the capsule is filled with the four different pellets to achieve a total dose of
  • composition ofthe metronidazole pellets provided in Table 1.
  • composition ofthe aqueous Eudragit L30D-55 coating dispersion applied to the metronidazole pellets is provided below in Table 2.
  • the TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
  • the following coating parameters were used for coating ofthe Eudragit® L 30 D-55 film coating dispersion.
  • composition ofthe aqueous Opadry solution applied to the mefronidazole pellets is provided below in Table 3.
  • composition ofthe aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 4.
  • Coat Opadry coated metronidazole pellets with the AQOAT AS- HF/Eudragit FS30D coating dispersion such that you apply 30% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
  • composition ofthe aqueous Eudragit® S 100 dispersion applied to the metronidazole pellets is provided below in Table 5.
  • Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
  • the following coating parameters were used for coating ofthe Eudragit® S 100 aqueous film coating dispersion.
  • Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30%
  • the capsule is filled with the four different pellets to achieve a total dose of
  • composition ofthe Doxycycline hyclate pellets provided in Table 1.
  • Table 1 Composition of Doxycycline hyclate Pellets

Abstract

An antibiotic product is comprised of at least three dosages forms, each of which has a different release profile, with the Cmax for the antibiotic product being reached in less than about twelve hours. In one embodiment, there is an immediate release dosage form, as well as two or more delayed release dosage forms, with each of the dosage forms having a different release profile, wherein each reaches a Cmax at different times.

Description

ANTIBIOTIC PRODUCT, USE AND
FORMULATION THEREOF
This application claims the benefits of U.S. Application Serial No. 10/027,366, filed December 20, 2001; U.S. Application Serial No. 10/027,866, filed December 20, 2001; U.S. Application Serial No. 10/028,590, filed December 20, 2001; U.S. Application Serial No. 10/028,595, filed December 20, 2001; U.S. Application Serial No. 10/027,837, filed December 20, 2001; and U.S. Application Serial No. 10/027,609, filed December 20, 2001. Each of the foregoing is a continuation-in-part of U.S. Application Serial No. 09/792,092, filed on February 22, 2000, which is a continuation-in-part of U.S. Application Serial No. 09/687,229, filed on October 13, 2000, and also claims the priority of U.S. Provisional Application Serial No. 60/184,546 filed on February 24, 2000.
This invention relates to an antibiotic product, as well as the use and formulation thereof.
The invention further relates to a levofloxacin antibiotic product, including derivatives thereof such as salts, esters, metabolites, etc.
The invention further relates to a metronidazole antibiotic product and derivatives thereof, such as salts, esters, metabolites, etc. The invention further relates to a tetracycline antibiotic product and in particular doxycycline and its derivatives, salts, hydrates, esters, metabolites, etc.
The invention further relates to an erythromyacin antibiotic product, in particular an erythromyacin derivative or a macrolide or a ketolite (including derivatives thereof such as salts, esters, etc.); in particular Clarithromycin.
The invention further relates to (a) fluroquinilone antibiotic products and in particular ciprofloxacin and its derivatives such as salts, esters, bases, etc., metabolites, etc.
The invention further relates to betalactam antibiotic products and in particular to products that include a cephalosporin, such as cefuroxime and/or cefpodoxime or a penicillin such as amoxicillin or dicloxacillin, as well as derivatives, metabolites and any active isomers thereof.
A wide variety of antibiotics have been used, and will be used, in order to combat bacterial infection. In general, such antibiotics can be administered by a repeated dosing of immediate release dosage forms, which results in poor compliance or as a controlled release formulation (slow release) at liigher administered doses. The present invention is directed to providing for an improved antibiotic product.
In accordance with one aspect of the present invention, there is provided an antibiotic pharmaceutical product which is comprised of at least two, preferably at least three, antibiotic dosage forms. Such dosage forms are formulated so that each of the dosage forms has a different release profile.
In a particularly preferred embodiment, there are at least two, preferably at least three dosage forms, each of which has a different release profile and the release profile of each ofthe dosage forms is such that the dosage forms each start release of the antibiotic contained therein at different times after administration ofthe antibiotic product. Thus, in accordance with an aspect of the present invention, there is provided a single or unitary antibiotic product that has contained therein at least two, preferably at least three antibiotic dosage forms, each of which has a different release profile, whereby the antibiotic contained in each of such dosage forms is released at different times.
In accordance with a further aspect of the invention, the antibiotic product may be comprised of at least four different dosage forms, each of which starts to release the antibiotic contained therein at different times after administration of the antibiotic product.
The antibiotic product generally does not include more than five dosage forms with different release times.
In accordance with a preferred embodiment, the antibiotic product has an overall release profile such that when administered the maximum serum concentration of the total antibiotic released from the product is reached in less than twelve hours, preferably in less than eleven hours. In an embodiment, the maximum serum concentration ofthe total antibiotic released from the antibiotic product is achieved no earlier than four hours after administration.
In accordance with one preferred embodiment of the invention, there are at least three dosage forms. One of the at least three dosage forms is an immediate release dosage form whereby initiation of release of the antibiotic therefrom is not substantially delayed after administration of the antibiotic product. The second and third ofthe at least three dosage forms is a delayed dosage form (which may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on the type of antibiotic product), whereby the antibiotic released therefrom is delayed until after initiation of release of the antibiotic from the immediate release dosage form. More particularly, the antibiotic release from the second of the at least two dosage forms achieves a Cmax (maximum serum concentration in the serum) at a time after the antibiotic released from the first of the at least three dosage forms achieves a Cmax in the serum, and the antibiotic released from the third dosage form achieves a Cmax in the serum after the Cmax of antibiotic released from the second dosage form. In one embodiment, the second of the at least two dosage forms initiates release ofthe antibiotic contained therein at least one hour after the first dosage form, with the initiation ofthe release therefrom generally occurring no more than six hours after initiation of release of antibiotic from the first dosage form of the at least three dosage forms.
In general, the immediate release dosage form produces a Cmaχ for the antibiotic released therefrom within from about 0.5 to about 2 hours, with the second dosage form of the at least three dosage forms producing a Cmaχ for the antibiotic released therefrom in no more than about four hours. In general, the Cmaχ for such second dosage form is achieved no earlier than two hours after administration of the antibiotic product; however, it is possible within the scope ofthe invention to achieve Cma in a shorter period of time.
As hereinabove indicated, the antibiotic product may contain at least three or at least four or more different dosage forms. For example, if the antibiotic product includes a third dosage form, the antibiotic released therefrom reaches a Cmax at a time later than the Cmax is achieved for the antibiotic released from each of the first and second dosage forms. In a preferred embodiment, release of antibiotic from the third dosage form is started after initiation of release of antibiotic from both the first dosage form and the second dosage form. In one embodiment, Cmax for antibiotic release from the third dosage form is achieved within eight hours.
In another embodiment, the antibiotic product contains at least four dosage forms, with each of the at least four dosage forms having different release profiles, whereby the antibiotic release from each of the at least four different dosage forms achieves a Cmax at a different time.
As hereinabove indicated, in a preferred embodiment, irrespective of whether the antibiotic contains at least two or at least three or at least four different dosage forms each with a different release profile, Cmax for all the antibiotic released from the antibiotic product is achieved in less than twelve hours, and more generally is achieved in less than eleven hours. In a preferred embodiment, the antibiotic product is a once a day product, whereby after administration of the antibiotic product, no further product is administered during the day; i.e., the preferred regimen is that the product is administered only once over a twenty-four hour period. Thus, in accordance with the present invention, there is a single administration of an antibiotic product with the antibiotic being released in a manner such that overall antibiotic release is effected with different release profiles in a manner such that the overall Cmax for the antibiotic product is reached in less than twelve hours. The term single administration means that the total antibiotic administered over a twenty-four hour period is administered at the same time, which can be a single tablet or capsule or two or more thereof, provided that they are admimstered at essentially the same time.
Applicant has found that a single dosage antibiotic product comprised of at least three antibiotic dosage forms each having a different release profile is an improvement over a single dosage antibiotic product comprised of an antibiotic dosage form having a single release profile. Each ofthe dosage forms of antibiotic in a pharmaceutically acceptable carrier may have one or more antibiotics and each of the dosage forms may have the same antibiotic or different antibiotics.
It is to be understood that when it is disclosed herein that a dosage form initiates release after another dosage form, such terminology means that the dosage form is designed and is intended to produce such later initiated release. It is known in the art, however, notwithstanding such design and intent, some "leakage" of antibiotic may occur. Such "leakage" is not "release" as used herein.
If at least four dosage forms are used, the fourth of the at least four dosage form may be a sustained release dosage form or a delayed release dosage form. If the fourth dosage form is a sustained release dosage form, even though Cmax ofthe fourth dosage form of the at least four dosage forms is reached after the Cmax of each of the other dosage forms is reached, antibiotic release from such fourth dosage form may be initiated prior to or after release from the second or third dosage form. The antibiotic product ofthe present invention, as hereinabove described, may be formulated for administration by a variety of routes of administration. For example, the antibiotic product may be formulated in a way that is suitable for topical administration; administration in the eye or the ear; rectal or vaginal administration; as nose drops; by inhalation; as an injectable; or for oral administration. In a preferred embodiment, the antibiotic product is formulated in a manner such that it is suitable for oral administration.
For example, in formulating the antibiotic product for topical admimstration, such as by application to the skin, the at least two different dosage forms, each of which contains an antibiotic, may be formulated for topical administration by including such dosage forms in an oil-in-water emulsion, or a water-in-oil emulsion. In such a formulation, the immediate release dosage form is in the continuous phase, and the delayed release dosage form is in a discontinuous phase. The formulation may also be produced in a manner for delivery of three dosage forms as hereinabove described. For example, there may be provided an oil-in-water-in-oil emulsion, with oil being a continuous phase that contains the immediate release component, water dispersed in the oil containing a first delayed release dosage form, and oil dispersed in the water containing a third delayed release dosage form.
It is also within the scope of the invention to provide an antibiotic product in the form of a patch, which includes antibiotic dosage forms having different release profiles, as hereinabove described.
In addition, the antibiotic product may be formulated for use in the eye or ear or nose, for example, as a liquid emulsion. For example, the dosage form may be coated with a hydrophobic polymer whereby a dosage form is in the oil phase of the emulsion, and a dosage form may be coated with hydrophilic polymer, whereby a dosage form is in the water phase ofthe emulsion.
Furthermore, the antibiotic product with at least three different dosage forms with different release profiles may be formulated for rectal or vaginal admimstration, as known in the art. This may take the form of a cream or emulsion, or other dissolvable dosage form similar to those used for topical administration. As a further embodiment, the antibiotic product may be formulated for use in inhalation therapy by coating the particles and micronizing the particles for inhalation.
In a preferred embodiment, the antibiotic product is formulated in a manner suitable for oral administration. Thus, for example, for oral administration, each of the dosage forms may be used as a pellet or a particle, with a pellet or particle then being formed into a unitary pharmaceutical product, for example, in a capsule, or embedded in a tablet, or suspended in a liquid for oral administration.
Alternatively, in formulating an oral delivery system, each ofthe dosage forms of the product may be formulated as a tablet, with each of the tablets being put into a capsule to produce a unitary antibiotic product. Thus, for example, antibiotic products may include a first dosage form in the form of a tablet that is an immediate release tablet, and may also include two or more additional tablets, each of which provides for a delayed release ofthe antibiotic, as hereinabove described, whereby the Cmax of the antibiotic released from each of the tablets is reached at different times, with the Cmax of the total antibiotic released from the antibiotic product being achieved in less than twelve hours.
The formulation of an antibiotic product including at least three dosage forms with different release profiles for different routes of administration is deemed to be within the skill ofthe art from the teachings herein. As known in the art, with respect to delayed release, the time of release can be controlled by the concentration of antibiotics in the coating and/or the thickness ofthe coating.
In formulating an antibiotic product in accordance with the invention, in one embodiment, the immediate release dosage form of the product generally provides from about 20% to about 50% of the total dosage of antibiotic to be delivered by the product, with such immediate release dosage forms generally providing at least 25% ofthe total dosage ofthe antibiotic to be delivered by the product. In many cases, the immediate release dosage form provides from about 20% to about 30% of the total dosage of antibiotic to be delivered by the product; however, in some cases it may be desirable to have the immediate release dosage form provide for about 45% to about 50% ofthe total dosage of antibiotic to be delivered by the product.
The remaining dosage forms deliver the remainder of the antibiotic. If more than one delayed release dosage form is used, in one embodiment, each ofthe delayed release dosage forms may provide about equal amounts of antibiotic; however, they may also be formulated so as to provide different amounts.
In accordance with the present invention, each of the dosage forms contains the same antibiotic; however, each of the dosage forms may contain more than one antibiotic.
In one embodiment, where the composition contains one immediate release component and two delayed release components, the immediate release component provides from 20% to 35% (preferably 20% to 30%), by weight, ofthe total antibiotic; where there is three delayed release components, the immediate release component provides from 15% to 30%, by weight, ofthe total antibiotic; and where there are four delayed release components, the immediate release component provides from 10% to 25%, by weight, ofthe total antibiotic.
With respect to the delayed release components, where there are two delayed release components, the first delayed release component (the one released earlier in time) provides from 30% to 60%, by weight, ofthe total antibiotic provided by the two delayed release components with the second delayed release component providing the remainder ofthe antibiotic.
Where there are three delayed release components, the earliest released component provides 20% to 35% by weight ofthe total antibiotic provided by the three delayed release components, the next in time delayed release component provides from 20% to 40%, by weight, ofthe antibiotic provided by the three delayed release components and the last in time providing the remainder ofthe antibiotic provided by the three delayed release components. When there are four delayed release components, the earliest delayed release component provides from 15% to 30%, by weight, the next in time delayed release component provides from 15% to 30%, the next in time delayed release component provides from 20% to 35%, by weight, and the last in time delayed release component provides from 20% to 35%, by weight, in each case ofthe total antibiotic provided by the four delayed release components.
The Immediate Release Component
The immediate release portion of this system can be a mixture of ingredients that breaks down quickly after administration to release the antibiotic. This can take the form of either a discrete pellet or granule that is mixed in with, or compressed with, the other three components.
The materials to be added to the antibiotics for the immediate release component can be, but are not limited to, microcrystalline cellulose, corn starch, pregelatinized starch, potato starch, rice starch, sodium carboxymethyl starch, hydroxypropylcellulose, hydroxypropylmethylcellulose, hydroxyethylcellulose, ethylcellulose, chitosan, hydroxychitosan, hydroxymethylatedchitosan, cross-linked chitosan, cross-linked hydroxymethyl chitosan, maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose, glucose, levulose, sucrose, polyvinylpyrrolidone (PNP), acrylic acid derivatives (Carbopol, Eudragit, etc.), polyethylene glycols, such a low molecular weight PEGs (PEG2000- 10000) and high molecular weight PEGs (Polyox) with molecular weights above 20,000 daltons.
It may be useful to have these materials present in the range of 1.0 to 60% (W/W).
In addition, it may be useful to have other ingredients in this system to aid in the dissolution of the drug, or the breakdown of the component after ingestion or administration. These ingredients can be surfactants, such as sodium lauryl sulfate, sodium monoglycerate, sorbitan monooleate, sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl monostearate, glyceryl monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as the Pluronic line of surfactants, or any other material with surface active properties, or any combination of the above.
These materials may be present in the rate of 0.05-15% (W/W).
The non-pH Sensitive Delayed Release Component
The components in this composition are the same immediate release unit, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
Materials that can be used to obtain a delay in release suitable for this component of the invention can be, but are not limited to, polyethylene glycol (PEG) with molecular weight above 4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax, paraffin, acrylic acid derivatives (Eudragit), propylene glycol, and ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this component.
The pH Sensitive (Enteric) Release Component
The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to, cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose derivatives.
These materials can be present in concentrations from 4-20% (W/W).
Sustained Release Component The components in this composition are the same as the immediate release component, but with additional polymers integrated into the composition, or as coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to, ethylcellulose,hydroxypropylmethylcellulose,hydroxypropylcellulose, hydroxyethylcellulose, carboxymethylcellulose, methylcellulose, nitrocellulose, Eudragit R, and Eudragit RL, Carbopol, or polyethylene glycols with molecular weights in excess of 8,000 daltons.
These materials can be present in concentrations from 4-20% (W/W).
As hereinabove indicated, the units comprising the antibiotic composition of the present invention can be in the form of discrete pellets or particles contained in the capsule, or particles embedded in a tablet or suspended in a liquid suspension.
The antibiotic composition of the present invention may be administered, for example, by any of the following routes of administration: sublingual, transmucosal, transdermal, parenteral, etc., and preferably is administered orally. The composition includes a therapeutically effective amount of the antibiotic, which amount will vary with the antibiotic to be used, the disease or infection to be treated, and the number of times that the composition is to be delivered in a day. The composition is administered to a host in an amount effective for treating a bacterial infection.
This system will be especially useful in extending the practial therapeutic activity for antibiotics with elimination half lives of less than 20 hours and more particularly with elimination half-lives of less than 12 hours, and will be particularly useful for those drugs with half-lives of 2-10 hours. The following are examples of some antibiotics with half-lives of about 1 to 12 hours: Cefadroxil, cefazolin, cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine, cefamandole, cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime, cefpodoxime, ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefmetazole, cefotetan, cefoxitin, loracarbef, imipenem, erythromycin (and erythromycin salts such as estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin, clarithromycoin, dirithromycin, troleanomycin, penicillin N, peniciliin salts, and complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin, amoxicillin and clavulanate potassium, ampicillin, bacampicillin, carbenicillin indanyl sodium (and other salts of carbenicillin) mezlocillin, piperacillin, piperacillin and taxobactam, ticarcillin, ticarcillin and clavulanate potassium, clindamycin, vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine, ethambutol HCl and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin, lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin, sulfacytine, suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole, sulfapyrizine, sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole, methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, co- triamoxazole, pentamidine, and trimetrexate.
The invention will be further described with respect to the following examples; however, the scope ofthe invention is not limited thereby. All percentages in this specification, unless otherwise specified, are by weight.
Examples
Immediate Release Component
Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a dry blend. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. The product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
Ingredient Cone. (% W/W
Example 1:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Povidone 10
Croscarmellose sodium 5
Example 2:
Amoxicillin 55% (W/W) Microcrystalline cellulose 25 Povidone 10 Croscarmellose sodium 10
Example 3 :
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 4:
Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
Example 5:
Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 6:
Clarithromycin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 7:
Clarithromycin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
Example 8:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
Example 9:
Clarithromycin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 10:
Ciprofloxacin 65% (W/W) Microcrystalline cellulose 20 Hydroxypropylcellulose 10 Croscarmellose sodium 5 Example 11 :
Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Croscarmellose sodium 5
Example 12:
Ciprofloxacin 75% (W/W) Polyethylene glycol 4000 10 Polytheylene glycol 2000 10 Hydroxypropylcellulose 5
Example 13:
Cirpofloxacin 75% (W/W) Polyethylene glycol 8000 20 Polyvinylpyrrolidone 5
Example 14:
Ceftibuten 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Hydroxypropylcellulose 5
Example 15:
Ceftibuten 75% (W/W)
Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
non-pH Sensitive Delayed Release Component
Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
Ingredient Cone. (% W/W)
Example 16:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20 Polyox 10 Croscarmellose sodium 5 Example 17:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 18:
Amoxicillin 65% (W/W) Polyox 20
Hydroxypropylcellulose 10 Croscarmellose sodium 5
Example 19:
Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5
Example 20:
Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20 Ethylcellulose 5
Example 21:
Clarithromycin 70% (W/W) Polyox 20
Hydroxypropylcellulose 5 Croscarmellose sodium 5
Example 22:
Clarithromycin 75% (W/W) Polyox 15
Hydroxypropylcellulose 5 Ethylcellulose 5
Example 23 :
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5
Example 24:
Clarithromycin 80% (W/W) Polyethylene glycol 8000 10 Polyvinylpyrrolidone 5 Eudgragit R 30D 5
Example 25:
Ciprofloxacin 65% (W/W) Polyethylene glycol 4000 20 Hydroxypropylcellulose 10 Eudragit RL 30D 5
Example 26:
Ciprofloxacin 75% (W/W) Microcrystalline cellulose 15 Hydroxypropylcellulose 5 Ethylcellulose 5
Example 27:
Ciprofloxacin 80% (W/W) Polyethylene glycol 4000 10 Polyethylene glycol 2000 5 Eudgragit RL 30D 5
Example 28:
Ciprofloxacin 75% (W/W) Polyethylene glycol 8000 20 Ethylcellulose 5
Example 29:
Ceftibuten 75% (W/W)
Polyethylene glycol 4000 10 Polyethylene glycol 2000 10 Eudragit RL 30D 5
Example 30:
Ceftibuten 75% (W/W)
Polyethylene glycol 8000 20 Ethylcellulose 5
Enteric Release Component
Formulate the ingredients by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
Ingredient Cone. (% W/W)
Example 31:
Amoxicillin 65% (W/W) Microcrystalline cellulose 20 Cellulose Acetate Pthalate 15
Example 32:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Cellulose Acetate Pthalate 10
Hydroxypropylmethylcellulose 10
Example 33:
Amoxicillin 65% (W/W)
Polyox 20
Hydroxypropylcellulose pthalate 10
Eudragit L30D 5
Example 34:
Amoxicillin 75% (W/W)
Polyethylene glycol 2000 10 Eudragit L30D 10 Eudragit RL 30D 5
Example 35:
Amoxicillin 40% (W/W)
Microcrystalline Cellulose 40 Cellulose Acetate Pthalate 10
Example 36:
Clarithromycin 70% (W/W)
Hydroxypropylcellulose pthalate 15 Croscarmellose sodium 10
Example 37:
Clarithromycin 70% (W/W) Eudragit E30D 15 Hydroxypropylcellulose 10 Ethylcellulose 5
Example 38:
Clarithromycin 75% (W/W) Polyethylene glycol 2000 10 Eudragit E 30D 15
Example 39:
Clarithromycin 40% (W/W) Lactose 50 Eudgragit L 30D 10
Example 40:
Ciprofloxacin 65% (W/W) Microcrystalline Cellulose 20 Eudragit L 30D 10 Example 41:
Ciprofloxacin 75% (W/W)
Microcrystalline Cellulose 15
Hydroxypropylcellulose pthalate 10
Example 42:
Ciprofloxacin 80% (W/W)
Lactose 10
Eudgragit L 30D 10
Example 43 :
Ciprofloxacin 70% (W/W)
Polyethylene glycol 4000 20
Cellulose acetate pthalate 10
Example 44:
Ceftibuten 60% (W/W)
Polyethylene glycol 2000 10
Lactose 20
Eudragit L 30D 10
Example 45:
Ceftibuten 70% (W/W)
Microcrystalline cellulose 20
Cellulose acetate pthalate 10
Sustained Release Component
Formulate the composition by mixing the ingredients in a suitable pharmaceutical mixer or granulator such as a planetary mixer, high-shear granulator, fluid bed granulator, or extruder, in the presence of water or other solvent, or in a hot melt process. If water or other solvent was used, dry the blend in a suitable pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the product to cool, the product may be sieved or granulated, and compressed using a suitable tablet press, such as a rotary tablet press.
Ingredient Cone. (% W/W)
Example 46:
Amoxicillin 65% (W/W).
Ethylcellulose 20
Polyox 10
Hydroxypropylmethylcellulose 5 Example 47:
Amoxicillin 55% (W/W)
Lactose 25
Polyox 10
Glyceryl monooleate 10
Example 48:
Amoxicillin 70% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Example 49:
Clarithromycin 75% (W/W) Lactose 15
Hydroxypropylcellulose 5 Ethylcellulose 5
Example 50:
Clarithromycin 75% (W/W) Polyethylene glycol 4000 10 Lactose 10 Eudragit RL 30D 5
Example 51:
Clarithromycin 80% (W/W) Polyethylene glycol 8000 10 Hydroxypropylmethylcellulose 5 Eudgragit RS 30D 5
Example 52:
Ciprofloxacin 75% (W/W) Hydroxyethylcellulose 10 Polyethylene glycol 4000 10 Hydroxypropylcellulose 5
Example 53:
Ciprofloxacin 75% (W/W) Lactose 10
Povidone (PNP) 10 Polyethylene glycol 2000 5
Example 54:
Ceftibuten 75% (W/W)
Polyethylene glycol 4000 10 Povidone (PNP) 10 Hydroxypropylcellulose 5
Example 55:
Ceftibuten 75% (W/W) Lactose 15 Polyethylene glycol 4000 5 Polyvinylpyrrolidone 5
Three Pulses Example 56.
1. Metronidazole Matrix Pellet Formulation and Preparation Procedure (Immediate Release)
A. Pellet Formulation The composition ofthe metronidazole matrix pellets provided in Table 1.
Table 1 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 50
Avicel PH 101 20
Lactose 20
PNP K29/32* 10
Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
B. Preparation Procedure for Metronidazole Matrix Pellets 1.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high shear granulator.
1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing.
1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
1.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
1.2.5 Dry the spheronized pellets at 50°C overnight.
1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
1.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
A. Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
B. Preparation Procedure for an Eudragit® L 30 D-55 Aqueous
Dispersion
1.3.1 Suspend triethyl citrate and talc in deionized water.
1.3.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
1.3.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
1.3.4 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets. 1.4 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
A. Dispersion Formulation The composition ofthe aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 3.
Table 3 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
B. Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part i:
(i) Dispense Eudragit® S 100 powder in deionized water with stirring.
(ii) Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
(iii) Allow the partially neutralized dispersion to stir for 60 minutes.
(iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B. Part II:
(i) Disperse talc in the required amount of water (ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.
(iii) Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. 1.5 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used to coat matrix pellets with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
(i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
(ii) Coat matrix pellets with S 100 dispersion such that you apply 20% coat weight gain to the pellets.
1.6 Encapsulation of the Metronidazole Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%: 40%:
Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and SI 00 coated pellets respectively.
The capsule is filled with the three different pellets to achieve a total dose of
375mg/capsule.
26 Three Pulses
Example 57
Amoxicillin Pellet Formulation and Preparation Procedure
57.1 Pellet Formulations for subsequent coating
The composition ofthe Amoxicillin trihydrate matrix pellets provided in Table 4. Table 4 Composition of Amoxicillin Matrix Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
57.2 Preparation Procedure for Amoxicillin Matrix Pellets
57.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
57.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
57.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator is 0.8 mm.
57.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate. 57.2.5 Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
57.2.6 Pellets between 20 and 40 Mesh were collected for further processing.
57.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
57.3.1 Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 5.
Table 5 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 41.6
Triethyl Citrate 2.5
Talc 5.0
Purified Water 50.9
Solids Content 20.0
Polymer Content 12.5
57.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
57.4.1 Suspend triethyl citrate and talc in deionized water.
57.4.2 The TEC/talc suspension is mixed using laboratory mixer.
57.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
57.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.
57.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 57.5.1 Dispersion Formulation The composition ofthe aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 6.
Table 6 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
57.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
57.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
57.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring. 57.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
57.6.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.
Part B:
57.6.5 Disperse talc in the required amount of water
57.6.6 Stir the dispersion using an overhead laboratory mixer.
57.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
57.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for both the Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating processes.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C Atomization Air Pressure 1.8 Bar Pump Rate 2-6 gram per minute
57.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.
57.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets. 57.8 Preparation of Amoxicillin Granulation (Immediate Release Component) for tabletting
Table 7 Composition of Amoxicillin Granulation
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0 Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
57.8.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
57.8.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
57.8.3 Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
57.8.4 Granules between 20 and 40 Mesh are collected for further processing.
57.9 Tabletting of the Amoxicillin Pellets
Table 8 Composition of Amoxicillin Tablets
Component Percentage (%)
Amoxicillin granules 32.5
Avicel PH 200 5.0
Amoxicillin L30D-55 coated pellets 30
Amoxicillin SI 00 coated pellets 30
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
57.9.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
57.9.2 Add the magnesium stearate to the blender, and blend for 5 minutes. 57.9.3 Compress the blend on a rotary tablet press.
57.9.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.
Three Pulses Example 58
Clarithromycin Pellet Formulation and Preparation Procedure
58.1 Pellet Formulation
The composition ofthe clarithromycin matrix pellets provided in Table 1.
Table 9 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 50.6
Lactose monohydrate, spray dried 32.1
Silicified microcrystalline cellulose 14.6
Polyoxyl 35 Castor Oil 1.7
Hydroxypropyl methylcellulose* 1.0
Total 100
*Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.
58.2 Preparation Procedure for Clarithromycin Matrix Pellets
58.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator. 58.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
58.2.3 Add binder solution slowly into the powder blend under continuous mixing.
58.2.4 Granulate the powders in the high shear granulator with the binder solution.
58.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.2 mm.
58.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
58.2.7 Dry the spheronized pellets at 50°C overnight.
58.2.8 Pellets between 18 and 30 Mesh were collected for further processing.
58.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
58.3.1 Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 10.
Table 10 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 40.4
Triethyl Citrate 1.8
Talc 6.1
Water 51.7
Solids Content 20.0
Polymer Content 12.1
58.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
58.4.1 Suspend triethyl citrate and talc in deionized water.
58.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
58.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
58.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.
58.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 58.5.1 Dispersion Formulation The composition ofthe aqueous Eudragit® S 100 dispersion applied to the clarithromycin matrix pellets is provided below in Table 11.
Table 11 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
58.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion
Part A:
58.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
58.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
58.6.3 Allow the partially neutralized dispersion to stir for 60 minutes
58.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for 60 minutes prior to the addition of Part B. Part B:
58.6.5 Disperse talc in the required amount of water
58.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
58.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
58.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating the matrix pellets with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 2 gram per minute
58.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 20% coat weight gain to the pellets.
58.7.2 Coat matrix pellets with S100 dispersion such that you apply 37% coat weight gain to the pellets.
4. Capsules were filled with the uncoated pellets, the L30D-55 coated pellets and S100 coated pellets in weight percentages of 30%:30%:40%, respectively to provide 250 mg. capsules. Four pulses
Example 59.
1 Metronidazole Matrix Pellet Formulation and Preparation Procedure
59.1 Pellet Formulation
The composition ofthe metronidazole matrix pellets provided in Table 12.
Table 12 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 50
Avicel PH 101 20
Lactose 20
PNP K29/32* 10
Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
59.2 Preparation Procedure for Metronidazole Matrix Pellets
59.2.1 Blend metronidazole and Avicel® PH 101 using a Robot Coupe high
shear granulator.
59.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend under continuous mixing. 59.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
59.2.4 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
59.2.5 Dry the spheronized pellets at 50°C overnight.
59.2.6 Pellets between 16 and 30 Mesh were collected for further processing. 59.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
59.3.1 Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 dispersion applied to the metronidazole matrix pellets is provided below in Table 13.
Table 13 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
59.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion 59.4.1 Suspend triethyl citrate and talc in deionized water. 59.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
59.4.3 Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
59.4.4 Allow the coating dispersion to stir for one hour prior to application onto the metronidazole matrix pellets.
59.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
59.5.1 Dispersion Formulation The composition ofthe aqueous Eudragit® S 100 dispersion applied to the metronidazole matrix pellets is provided below in Table 14.
Table 14 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0 59.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
59.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
59.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
59.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
59.6.4 Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.
Part B:
59.6.5 Disperse talc in the required amount of water
59.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
59.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
59.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
59.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
59.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets. 59.7.3 Coat matrix pellets with S100 dispersion such that you apply 20% coat weight gain to the pellets. 59.8 Encapsulation of the Metronidazole Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30% Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and SI 00 coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of 375mg/capsule.
Four Pulses
Example 60
Amoxicillin Pellet Formulation and Preparation Procedure
60.1 Pellet Formulations
The composition ofthe Amoxicillin trihydrate matrix pellets provided in Table 15. Table 15 Composition of Amoxicillin Matrix Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
♦Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
60.2 Preparation Procedure for Amoxicillin Matrix Pellets
60.2.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
60.2.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
60.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator is 0.8 mm.
60.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
60.2.5 Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
60.2.6 Pellets between 20 and 40 Mesh were collected for further processing. 60.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion 60.3.1 Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 dispersion applied to the amoxicillin matrix pellets is provided below in Table 16.
Table 16 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 41.6
Triethyl Citrate 2.5
Talc 5.0
Purified Water 50.9
Solids Content 20.0
Polymer Content 12.5
60.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
60.4.1 Suspend triethyl citrate and talc in deionized water.
60.4.2 The TEC/talc suspension is mixed using laboratory mixer.
60.4.3 Add the TEC/talc suspension from slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
60.4.4 Allow the coating dispersion to stir for one hour prior to application onto the amoxicillin matrix pellets.
60.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion
60.6 Dispersion Formulation
The composition ofthe aqueous Eudragit® S 100 dispersion applied to the Amoxicillin matrix pellets is provided below in Table 17. Table 17 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 2.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
60.7 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
60.7.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
60.7.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
60.7.3 Allow the partially neutralized dispersion to stir for 60 minutes.
60.7.4 Add triethyl citrate drop-wise into the dispersion with stirring and let stir overnight prior to the addition of Part B.
Part B:
60.7.5 Disperse talc in the required amount of water
60.7.6 Stir the dispersion using an overhead laboratory mixer. 60.7.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring. 60.8 Preparation of Aquacoat Coating Dispersion
60.8.1 Dispersion Formulation The composition ofthe aqueous Aquacoat dispersion applied to Amoxicillin L30 D- 55 coated pellets is provided below in Table 18.
Table 18
Component Percentage (%)
Aquacoat ECD 79.3
Hydroxypropyl methylcellulose 15.9
Dibutyl Sebacate 4.8
Purified Water (300g)
60.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel El 5) solution by dispersing in water with continuous stirring.
60.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with stirring and continue to stir overnight.
60.9 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating with each ofthe Eudragit® L
30 D-55 and Eudragit® S .100 aqueous film coatings.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm Material Charge 300 gram Inlet Air Temperature 40 to 45 °C Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2-6 gram per minute
60.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim to achieve a 20% coat weight gain. 60.9.2 Coat anotlier batch of Amoxicillin matrix pellets with L30 D-55 dispersion to achieve a 20% weight gain. Coat the L30 D-55 pellets with the Aquacoat Dispersion to achieve a 10% coat weight gain.
60.9.3 Coat Amoxicillin matrix pellets with S100 dispersion to achieve a 37% coat weight gain.
60.10 Preparation of Amoxicillin Granulation for tabletting
Table 19 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
♦Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
60.10.1 Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
60.10.2 Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
60.10.3 Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
60.10.4 Granules between 20 and 40 Mesh are collected for further processing.
60.11 Tabletting of the Amoxicillin Pellets
Table 20 Composition of Amoxicillin Tablets
Component Percentage (%) Amoxicillin granules 32.5
Avicel PH 200 5.0
Amoxicillin L30D-55 coated pellets 20
Amoxicillin Aquacoated pellets 20
Amoxicillin SI 00 coated pellets 20
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
60.11.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
60.11.2 Add the magnesium stearate to the blender, and blend for 5 minutes.
60.11.3 Compress the blend on a rotary tablet press.
60.11.4 The fill weight should be adjusted to achieve a 500 mg dose tablet.
Four Pulses
Example 61
Clarithromycin Pellet Formulation and Preparation Procedure
61.1 Pellet Foπnulation
The composition ofthe clarithromycin matrix pellets provided in Table 21.
Table 21 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 50.6
Lactose monohydrate, spray dried 32.1
Silicified microcrystalline cellulose 14.6
Polyoxyl 35 Castor Oil* 1.7
Hydroxypropyl methylcellulose* 1.0
Total 100
♦Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w aqueous solution during wet massing.
61.2 Preparation Procedure for Clarithromycin Matrix Pellets
61.2.1 Blend clarithromycin, silicified microcrystalline cellulose and lactose monohydrate using a Robot Coupe high shear granulator.
61.2.2 Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
61.2.3 Add binder solution slowly into the powder blend under continuous mixing.
61.2.4 Granulate the powders in the high shear granulator with the binder solution.
61.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.2 mm.
61.2.6 Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
61.2.7 Dry the spheronized pellets at 50°C overnight.
61.2.8 Pellets between 18 and 30 Mesh were collected for further processing.
61.3 Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
61.3.1 Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 dispersion applied to the clarithromycin matrix pellets is provided below in Table 22.
Table 22 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 40.4
Triethyl Citrate 1.8
Talc 6.1
Water 51.7
Solids Content 20.0
Polymer Content 12.1
61.4 Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
61.4.1 Suspend triethyl citrate and talc in deionized water.
61.4.2 The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
61.4.3 Add the suspension from 4.2.2 slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
61.4.4 Allow the coating dispersion to stir for one hour prior to application onto the clarithromycin matrix pellets.
61.5 Preparation of an Eudragit® S 100 Aqueous Coating Dispersion 61.5.1 Dispersion Formulation The composition ofthe aqueous Eudragit® S 100 dispersion applied to the clarithromycin matrix pellets is provided below in Table 23.
Table 23 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
61.6 Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
61.6.1 Dispense Eudragit® S 100 powder in deionized water with stirring.
61.6.2 Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
61.6.3 Allow the partially neutralized dispersion to stir for 60 minutes
61.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for 60 minutes prior to the addition of Part B. Part B:
61.6.5 Disperse talc in the required amount of water
61.6.6 Homogenize the dispersion using a PowerGen 700D high shear mixer.
61.6.7 Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
61.7 Coating Conditions for the Application of Aqueous Coating Dispersions The following coating parameters were used for coating with each ofthe Eudragit® L 30 D-55 and Eudragit® S 100 aqueous film coatings.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 2 gram per minute
61.7.1 Coat matrix pellets with L30 D-55 dispersion such that you apply 12% coat weight gain to the pellets.
61.7.2 Coat matrix pellets with L30 D-55 dispersion such that you apply 30% coat weight gain to the pellets.
61.7.3 Coat matrix pellets with SI 00 dispersion such that you apply 37% coat weight gain to the pellets.
61.8 Encapsulation of the Clarithromycin Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12% weight gain, L30D-55 coated pellets 30% weight gain and SI 00 coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
250mg/capsule. Four pulses
Example 62.
Levofloxacin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition ofthe Levofloxacin pellets provided in Table 1.
Table 1 Composition of Levofloxacin Pellets
Component Percentage (%)
Levofloxacin 93
Avicel PH 101 3
Methocel E5P LN 4
Purified Water *
Total 100
* Removed during processing
Preparation Procedure for Levofloxacin Pellets
■ Blend Levofloxacin, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm. ■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is < 3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Levofloxacin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 coating dispersion applied to the Levofloxacin pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water* 37.4
Solids Content 25.5
Polymer Content 15.9
* Removed during processing
Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
Suspend triethyl citrate and talc in deionized water.
The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
Allow the coating dispersion to stir for one hour prior to application onto the Levofloxacin pellets. Coating Conditions for the Application of Eudragit L30D-55 Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
• Coat Levofloxacin pellets with Eudragit L30 D-55 film coating dispersion such that you apply 12% coat weight gain to the pellets.
Levofloxacin Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition ofthe aqueous Opadry solution applied to the Levofloxacin pellets is provided below in Table 3.
Table 3 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS- 1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1 -7006 to the water with continuous mixing.
Preparation of an AOOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated Levofloxacin pellets is provided below in Table 4.
Table 4 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudragit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
*Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aqueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
■ Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
■ Slowly add the Eudragit FS30D dispersion to the AQOAT AS- HF dispersion and continue to stir for a minimum of 1 hour. ■ Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
■ Screen the dispersion through a No. 60 mesh sieve.
■ Continue to stir the screened coating dispersion throughout the coating process.
Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D
Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Levofloxacin pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets. The following coating parameters were used for coating with the AQOAT AS- HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C Atomization Air Pressure 1.6 Bar
• Coat Opadry coated Levofloxacin pellets with the AQOAT AS- HF/Eudragit FS30D coating dispersion such that you apply 30% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Levofloxacin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® S 100 Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous Eudragit® S 100 dispersion applied to the Levofloxacin pellets is provided below in Table 5.
Table 5 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
■ Dispense Eudragit® S 100 powder in deionized water with stirring. ■ Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
■ Allow the partially neutralized dispersion to stir for 60 minutes.
■ Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.
Part B:
• Disperse talc in the required amount of water
• Homogenize the dispersion using a PowerGen 700D high shear mixer.
• Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating ofthe Eudragit® S 100 aqueous film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
• Coat pellets with S 100 dispersion such that you apply 20% coat weight gain to the pellets.
Encapsulation ofthe Levofloxacin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%
Immediate-release pellets (uncoated), Eudragit L30 D-55 coated pellets 12% weight gain, AQOAT AS-HF/Eudragit FS30D coated pellets 30% weight gain and Eudragit
SI 00 coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
250mg/capsule.
Tabletmg ofthe Levofloxacin Pellets
Levofloxacin Tablet Formula
Table 6 Levofloxacin Tablet
Component Percentage (%)
Eudragit® S 100 coated pellets
12.0
Eudragit® L30D coated pellets
12.0
AQOAT/Eudragit® FS30D coated pellets
12.0
Emcocel 200
28.0
Levofloxacin
25.0
Povidone K90 2.5
Povidone K30 7.5
Magnesium stearate 1.0 Preparation Procedure for a Levofloxacin Tablet
• Blend all the components together except magnesium stearate for 10 minutes using a tumble blender.
• Add the magnesium stearate to the blend and blend for an additional 3 minutes.
• Compress the blend on a rotary tablet press to achieve a dose of 250 mg.
Four pulses
Example 62.
Metronidazole Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition ofthe metronidazole pellets provided in Table 1.
Table 1 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 93
Avicel PH 101 3
Methocel E5P LN 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Metronidazole Pellets ■ Blend metronidazole, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is <
3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Metronidazole Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55 Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55 coating dispersion applied to the metronidazole pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water* 37.4
Solids Content 25.5
Polymer Content 15.9
*Removed during processing Preparation Procedure for an Eudragit® L 30 D-55 Aqueous Dispersion
Suspend triethyl citrate and talc in deionized water.
The TEC/talc suspension is then homogenized using a PowerGen 700 high shear mixer.
Add the TEC/talc suspension slowly to the Eudragit® L 30 D-55 latex dispersion while stirring.
Allow the coating dispersion to stir for one hour prior to application onto the metronidazole pellets. Coating Conditions for the Application of Eudragit L30D-55 Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
Coat metronidazole pellets with Eudragit L30 D-55 film coating dispersion such that you apply 12% coat weight gain to the pellets.
Metronidazole Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition ofthe aqueous Opadry solution applied to the mefronidazole pellets is provided below in Table 3.
Table 3 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS- 1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
* Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS- 1-7006 to the water with continuous mixing.
Preparation of an AQOAT AS-HF/Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF/ Eudragit FS30D coating dispersion applied to the Opadry coated metronidazole pellets is provided below in Table 4.
Table 4 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 5.25
Eudagit FS30D 5.83
Triethyl Citrate 1.96
Sodium Lauryl Sulfate 0.21
Talc 2.10
Purified Water* 84.65
Solid Content 11.27
Polymer Content 7.0
* Removed during processing Preparation Procedure for AQOAT AS-HF/ Eudragit FS30D Aqueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add sodium lauryl sulfate into the triethyl citrate dispersion with stirring.
■ Slowly add the AQOAT AS-HF powder to the dispersion above and stir for a minimum of 30 minutes.
■ Slowly add the Eudragit FS30D dispersion to the AQOAT AS- HF dispersion and continue to stir for a minimum of 1 hour. ■ Slowly add the talc to the coating dispersion and continue to stir for at least 2 hours.
■ Screen the dispersion through a No. 60 mesh sieve.
■ Continue to stir the screened coating dispersion throughout the coating process.
Coating Conditions for the Application of Opadry and AQOAT/Eudragit FS30D
Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat metronidazole pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets. The following coating parameters were used for coating with the AQOAT AS- HF/Eudragit FS30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C Atomization Air Pressure 1.6 Bar
Coat Opadry coated metronidazole pellets with the AQOAT AS- HF/Eudragit FS30D coating dispersion such that you apply 30% coat weight gain to the pellets. Dry the coated pellets in the fluid bed for 20 minutes at 50°C.
Metronidazole Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® S 100 Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous Eudragit® S 100 dispersion applied to the metronidazole pellets is provided below in Table 5.
Table 5 Eudragit® S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit® S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
Preparation Procedure for an Eudragit® S 100 Aqueous Dispersion Part A:
■ Dispense Eudragit® S 100 powder in deionized water with stirring. ■ Add ammonium hydroxide solution drop-wise into the dispersion with stirring.
■ Allow the partially neutralized dispersion to stir for 60 minutes.
■ Add triethyl citrate drop-wise into the dispersion with stirring. Stir for about 2 hours prior to the addition of Part B.
Part B:
• Disperse talc in the required amount of water
• Homogenize the dispersion using a PowerGen 700D high shear mixer.
• Part B is then added slowly to the polymer dispersion in Part A with a mild stirring.
Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating ofthe Eudragit® S 100 aqueous film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 °C
Outlet Air Temperature 30 to 33 °C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
• Coat pellets with S 100 dispersion such that you apply 20% coat weight gain to the pellets.
Encapsulation ofthe Metronidazole Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%: 20%: 30%
Immediate-release pellets (uncoated), Eudragit L30 D-55 coated pellets 12% weight gain, AQOAT AS-HF/Eudragit FS30D coated pellets 30% weight gain and Eudragit
SI 00 coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
375mg/capsule.
Tabletting ofthe Metronidazole Pellets
Metronidazole Tablet Formula
Table 6 Metronidazole Tablet
Component Percentage (%)
Eudragit® S 100 coated pellets
12.0
Eudragit® L30D coated pellets
12.0
AQOAT/Eudragit® FS30D coated pellets
12.0
Emcocel 200
28.0
Metronidazole
25.0
Povidone K90 2.5
Povidone K30 7.5
Magnesium stearate 1.0 Preparation Procedure for a Metronidazole Tablet
• Blend all the components together except magnesium stearate for 10 minutes using a tumble blender.
• Add the magnesium stearate to the blend and blend for an additional 3 minutes.
• Compress the blend on a rotary tablet press to achieve a dose of 375 mg.
Four pulses Example 62.
Doxycycline hyclate Pellet Formulation and Preparation Procedure Pellet Formulation
The composition ofthe Doxycycline hyclate pellets provided in Table 1. Table 1 Composition of Doxycycline hyclate Pellets
Component Percentage (%)
Doxycycline hyclate 93
Avicel PH 101 3
Methocel E5P LN 4
Purified Water *
Total 100
*Removed during processing
Preparation Procedure for Doxycycline hyclate Pellets
■ Blend Doxycycline hyclate, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator. ■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is <
3%.
■ Pellets between 16 and 30 Mesh were collected for further processing.
Doxycycline hyclate Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the doxycycline hyclate pellets is provided below in Table 2. Table 2 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than
55°C. • The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit E
30D Aqueous Coating Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/EudragitNE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat doxycycline hyclate pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Doxycycline hyclate Delayed Enteric-Release Pellet Formulation and
Preparation Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition ofthe aqueous Opadry solution applied to the Doxycycline hyclate pellets is provided below in Table 3.
Table 3 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS- 1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS- 1 -7006 to the water with continuous mixing.
Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Doxycycline hyclate pellets is provided below in Table 4.
Table 4 AQOAT AS-HF/ Eudragit FS 30D Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Aqueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add talc into the triethyl citrate dispersion with stirring.
■ Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.
■ Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.
■ Screen the dispersion through a No. 60 mesh sieve. Continue to stir the screened coating dispersion throughout the coating process.
Coating Conditions for the Application of Opadry and Eudragit FS 30D/ Eudragit L
30D-55 Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Doxycycline hyclate pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets. The following coating parameters were used for coating with the Eudragit FS 30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1 ™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
Coat Opadry coated Doxycycline hyclate pellets with the Eudragit FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 20% coat weight gain to the pellets.
89 Doxycycline hyclate Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition of the aqueous Eudragit® FS 30D dispersion applied to the doxycycline hyclate pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Doxycycline hyclate Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25% Immediate-Release Pellets (uncoated), Eudragit L30 D-55/EudragitNE 30D coated pellets 20% weight gain, Eudragit FS 30D/ Eudragit L 30 D-55 coated pellets 20% weight gain and Eudragit FS 30D coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of lOOmg/capsule or 200mg/capsule.
Four Pulses Example 62
Clarithromycin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition ofthe clarithromycin pellets provided in Table 1.
Table 1 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water *
Total 100
*Removed during processing
Preparation Procedure for Clarithromycin Pellets
• Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
• Blend clarithromycin, lactose monohydrate, and croscarmellose sodium using a Robot Coupe high shear granulator. • Add binder solution slowly into the powder blend under continuous mixing.
• Granulate the powders in the high shear granulator with the binder solution.
• Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
• Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
• Dry the spheronized pellets at 50°C until the moisture level is > 3%.
• Pellets between 16 and 30 Mesh were collected for further processing.
Clarithromycin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit E 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/EudragitNE 30D aqueous coating dispersion applied to the clarithromycin pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C. • Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30D Aqueous Coating Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/EudragitNE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Clarithromycin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF aqueous coating dispersion applied to the clarithromycin pellets is provided below in Table 3.
Table 3 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AOOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes. • Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat clarithromycin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Clarithromycin Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous Eudragit® FS 30D dispersion applied to the clarithromycin pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Clarithromycin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%
Immediate-Release Pellets (uncoated),Eudragit L30 D-55/EudagitNE 30D coated pellets 20% weight gain, AQOAT AS-HF coated pellets 30 -35% weight gain and
Eudragit FS 30D coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
250mg/capsule. Tableting of the Clarithromycin Pellets
Clarithromycin Tablet Formula
Table 5 Clarithromycin Tablet
Component Percentage (%)
Eudragit® L30D/NE 30D coated pellets
20.0
AQOAT AS-HF coated pellets
20.0
Eudargit FS 30D coated pellets
20.0
Emcocel
24.5
Clarithromycin
12.5
Povidone K30 2.0
Magnesium stearate 1.0
Purified water *
*Removed during processing Preparation Procedure for a Clarithromycin Tablet
• Blend all the components together except coated pellets and magnesium stearate for 10 minutes using a granulator.
• Granulate the blend with purified water.
• Screen the granulate through a No. 16 mesh sieve.
• Dry the screened granulate in a fluid bed dryer at 50-60°C until the moisture level is less than 3%.
• Add the dry granulate, coated pellets to a tumble blender and blend for 10 minutes.
• Add to the blend the magnesium stearate and blend an additional 3 minutes.
• Compress the blend on a rotary tablet press to achieve a dose of 500 mg.
Four pulses
Example 62.
Ciprofloxacin Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition ofthe Ciprofloxacin pellets provided in Table 1.
Table 1 Composition of Ciprofloxacin Pellets
Component Percentage (%)
Ciprofloxacin 93
Avicel PH 101 3 Methocel E5P LN
Purified Water
Total 100
*Removed during processing
Preparation Procedure for Ciprofloxacin Pellets
■ Blend Ciprofloxacin, Avicel® PH 101, and Methocel using a Robot Coupe high shear granulator.
■ Add the purified water slowly into the powder blend under continuous mixing.
■ Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
■ Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
■ Dry the spheronized pellets at 50°C until moisture level is <
3%.
■ Pellets between 16 and 30 Mesh were collected for further processing. Ciprofloxacin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/EudragitNE 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Ciprofloxacin pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55 Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C. • Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30D Aqueous Coating Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/EudragitNE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Ciprofloxacin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Ciprofloxacin Delayed Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Opadry Clear Coating Solution
Dispersion Formulation
The composition ofthe aqueous Opadry solution applied to the Ciprofloxacin pellets is provided below in Table 3.
Table 3 Opadry Clear Aqueous Coating Solution
Component Percentage (%)
Opadry Clear YS-1-7006 7.0
Purified Water* 93.0
Solid Content % 7.0
Polymer Content % 7.0
*Removed during processing
Preparation Procedure for Opadry Clear Aqueous Solution
• Charge the purified water into a container
• Slowly add the Opadry Clear YS-1-7006 to the water with continuous mixing.
Preparation of an Eudragit® FS 30D/Eudragit L 30D-55 Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous Eudragit FS 30D/Eudragit L 30D-55 coating dispersion applied to the Opadry coated Ciprofloxacin pellets is provided below in Table 4.
Table 4 Eudragit FS 30D Eudragit L 30D-55 Coating Dispersion
Component Percentage (%)
Eudragit L 30D-55 5.8
Eudagit FS 30D 17.5
Triethyl Citrate 1.3
Talc 1.4
Purified Water* 74.0
Solid Content 9.7
Polymer Content 7.0
*Removed during processing Preparation Procedure for Eudragit FS 30D/Eudragit L 30D-55 Aqueous Dispersion
■ Disperse triethyl citrate in purified water with stirring.
■ Slowly add talc into the triethyl citrate dispersion with stirring.
■ Slowly add the Eudragit L 30D-55 to the dispersion above and stir for a minimum of 10 minutes.
■ Slowly add the Eudragit FS 30D dispersion to the Eudragit L 30D-55 dispersion and continue to stir for a minimum of 1 hour.
■ Screen the dispersion through a No. 60 mesh sieve. Continue to stir the screened coating dispersion throughout the coating process.
Coating Conditions for the Application of Opadry and Eudragit FS 30D/ Eudragit L
30D-55 Aqueous Coating Dispersions
The following coating parameters were used for coating with the Opadry solution film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 350 gram
Inlet Air Temperature 60 °C
Outlet Air Temperature 40 °C
Atomization Air Pressure 1.6 Bar
• Coat Ciprofloxacin pellets with Opadry coating solution such that you apply 3% coat weight gain to the pellets. The following coating parameters were used for coating with the Eudragit FS 30D/Eudragit L30D-55 film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 50 °C
Outlet Air Temperature 30 °C
Atomization Air Pressure 1.6 Bar
Coat Opadry coated Ciprofloxacin pellets with the Eudragit FS30D/ Eudragit L 30D-55 coating dispersion such that you apply 20% coat weight gain to the pellets.
I l l
112 Ciprofloxacin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion Dispersion Formulation
The composition ofthe aqueous Eudragit® FS 30D dispersion applied to the Ciprofloxacin pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Ciprofloxacin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%
Immediate-Release Pellets (uncoated), Eudragit L30 D-55/Eudragit NE 30D coated pellets 20% weight gain, Eudragit FS 30D/ Eudragit L 30 D-55 coated pellets 20% weight gain and Eudragit FS 30D coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
250mg/capsule. Tableting of the Ciprofloxacin Pellets
Ciprofloxacin Tablet Formula
Table 6 Ciprofloxacin Tablet
Component Percentage (%)
Eudragit® FS 30D coated pellets
12.0
Eudragit® L30D/NE coated pellets
12.0
Eudragit® FS 30D/L30D coated pellets
12.0
Emcocel 200
28.0
Ciprofloxacin
25.0
Povidone K90 2.5
Povidone K30 7.5
Magnesium stearate 1.0 Preparation Procedure for a Ciprofloxacin Tablet
• Blend all the components together except magnesium stearate for 10 minutes using a tumble blender.
• Add the magnesium stearate to the blend and blend for an additional 3 minutes.
• Compress the blend on a rotary tablet press to achieve a dose of 500 mg or 750 mg.
Four pulses Example 62
Amoxicillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition ofthe Amoxicillin trihydrate pellets provided in Table 1.
Table 1 Composition of Amoxicillin Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
*Hydroxypropyl methylcellulose and Cremaphor '. were added as a 2.9% w/w aqueous solution during wet massing. ** Removed during processing
Preparation Procedure for Amoxicillin Pellets
• Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
• Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator is 0.8 mm.
• Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
• Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
• Pellets between 20 and 40 Mesh were collected for further processing.
Amoxicillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/EudragitNE 30D aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Pispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/Imwitor 900 dispersion to Eudragit L30P-55 latex dispersion and stir for at least 30 minutes. • Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30D Aqueous Coating Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/Eudragit NE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Amoxicillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Amoxicillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF aqueous coating dispersion applied to the amoxicillin pellets is provided below in Table 3.
Table 3 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature > 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat amoxicillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Amoxicillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion
Pispersion Fonnulation
The composition ofthe aqueous Eudragit® FS 3 OP dispersion applied to the
Amoxicillin pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30P 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating. Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Amoxicillin Tablets
Preparation of Amoxicillin Granulation for tableting
Table 5 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
• Blend Amoxicillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
• Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
• Granules between 20 and 40 Mesh are collected for further processing.
Tableting ofthe Amoxicillin Pellets
Table 6 Composition of Amoxicillin Tablets
Component Percentage (%)
Amoxicillin granules
32.5
Avicel PH 200 5.0
Eudragit L30D-55/NE 30D coated pellets 20
AQOAT coated pellets 20
Eudragit FS 30D coated pellets 20
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
• Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
• Add the magnesium stearate to the blender, and blend for 5 minutes.
• Compress the blend on a rotary tablet press.
• The fill weight should be adjusted to achieve a 500 mg dose tablet.
Encapsulation of the Amoxicillin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 30%: 30%: 20%: 20% Immediate-release pellets (uncoated), L30 D-55/Eudragit NE 30D coated pellets 20% weight gain, AQOAT coated pellets 30% weight gain and Eudragit FS 30D coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of 250mg/capsule. The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day administration ofthe antibiotic.
Numerous modification and variations ofthe present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described. Four Pulses
Example 63
Cefuroxime axetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition ofthe Cefuroxime axetil pellets provided in Table 1.
Table 1 Composition of Cefuroxime axetil Pellets
Component Percentage (%)
Cefuroxime axetil 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water *
Total 100
*Removed during processing
Preparation Procedure for Cefuroxime axetil Pellets • Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
• Blend Cefuroxime axetil, lactose monohydrate, and croscarmellose sodium using a Robot Coupe high shear granulator.
• Add binder solution slowly into the powder blend under continuous mixing.
• Granulate the powders in the high shear granulator with the binder solution.
• Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
• Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
• Dry the spheronized pellets at 50°C until the moisture level is > 3%.
• Pellets between 16 and 30 Mesh were collected for further processing.
Cefuroxime axetil Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Cefuroxime axetil pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55 Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C. • Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30D Aqueous Coating Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/EudragitNE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature ' 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with Eudragit L30 D-55/EudragitNE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Cefuroxime axetil Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AOOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF aqueous coating dispersion applied to the Cefuroxime axetil pellets is provided below in Table 3.
Table 3 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes. • Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefuroxime axetil pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Cefuroxime axetil Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit® FS 30D dispersion applied to the
Cefuroxime axetil pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating. Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Cefuroxime axetil Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%
Immediate-Release Pellets (uncoated), Eudragit L30 D-55/EudagitNE 30D coated pellets 20% weight gain, AQOAT AS-HF coated pellets 30 -35% weight gain and
Eudragit FS 30D coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
250mg/capsule.
Tableting of the Cefuroxime axetil Pellets
Cefuroxime axetil Tablet Formula
Table 5 Cefuroxime axetil Tablet
Component Percentage (%)
Eudragit® L30D/NE 30D coated pellets
20.0
AQOAT AS-HF coated pellets
20.0
Eudargit FS 30D coated pellets
20.0
Emcocel
24.5
Cefuroxime axetil
12.5
Povidone K30 2.0
Magnesium stearate 1.0
Purified water *
*Removed during processing Preparation Procedure for a Cefuroxime axetil Tablet
• Blend all the components together except coated pellets and magnesium stearate for 10 minutes using a granulator.
• Granulate the blend with purified water.
• Screen the granulate through a No. 16 mesh sieve.
• Dry the screened granulate in a fluid bed dryer at 50-60°C until the moisture level is less than 3%.
• Add the dry granulate, coated pellets to a tumble blender and blend for 10 minutes.
• Add to the blend the magnesium stearate and blend an additional 3 minutes.
• Compress the blend on a rotary tablet press to achieve a dose of 500 mg.
The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day adminisfration ofthe antibiotic.
Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described. Four Pulses
Example 64
Cefodoxime proxetil Pellet Formulation and Preparation Procedure
Pellet Formulation
The composition ofthe Cefodoxime proxetil pellets provided in Table 1. Table 1 Composition of Cefodoxime proxetil Pellets
Component Percentage (%)
Cefodoxime proxetil 77.0
Lactose monohydrate, spray dried 11.0
Croscarmellose sodium 5.0
Polyoxyl 35 Castor Oil* 5.0
Hydroxypropyl methylcellulose* 2.0
Purified water *
Total 100
*Removed during processing
Preparation Procedure for Cefodoxime proxetil Pellets
• Prepare the binder solution by adding the Polyoxyl to the purified water while stirring. After that is mixed, slowly add the hydroxypropyl methylcellulose and continue to stir until a solution is achieved.
• Blend Cefodoxime proxetil, lactose monohydrate, and croscarmellose sodium using a Robot Coupe high shear granulator.
• Add binder solution slowly into the powder blend under continuous mixing.
• Granulate the powders in the high shear granulator with the binder solution. • Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator was 1.0 mm.
• Spheronize the extrudate using a Model SPH20 Caleva Spheronizer.
• Dry the spheronized pellets at 50°C until the moisture level is > 3%.
• Pellets between 16 and 30 Mesh were collected for further processing.
Cefodoxime proxetil Enteric-Release Pellet Formulation and Preparation
Procedure
Preparation of an Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Cefodoxime proxetil pellets is provided below in Table 2. Table 2 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/EudragitNE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C. • Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes.
• Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/EudragitNE
30D Aqueous Coatmg Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/EudragitNE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefodoxime proxetil pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Cefodoxime proxetil Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF aqueous coating dispersion applied to the Cefodoxime proxetil pellets is provided below in Table 3.
Table 3 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
" Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes. • Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of AQOAT AS-HF Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Cefodoxime proxetil pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Cefodoxime proxetil Colonic-Release Pellets Formulation and Preparation Procedure
Preparation of an Eudragit® FS30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit® FS 30D dispersion applied to the
Cefodoxime proxetil pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Pxirified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
• Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Cefodoxime proxetil Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25%
Immediate-Release Pellets (uncoated), Eudragit L30 D-55/EudagitNE 30D coated pellets 20% weight gain, AQOAT AS-HF coated pellets 30 -35% weight gain and
Eudragit FS 30D coated pellets respectively.
The capsule is filled with the four different pellets to achieve a total dose of
200mg/capsule.
Tableting of the Cefodoxime proxetil Pellets
Cefodoxime proxetil Tablet Formula
Table 5 Cefodoxime proxetil Tablet
Component Percentage (%)
Eudragit® L30D/NE 30D coated pellets
20.0
AQOAT AS-HF coated pellets
20.0
Eudragit FS 30D coated pellets
20.0
Emcocel
24.5
Cefodoxime proxetil
12.5
Povidone K30 2.0
Magnesium stearate 1.0
Purified water *
*Removed during processing Preparation Procedure for a Cefodoxime proxetil Tablet
• Blend all the components together except coated pellets and magnesium stearate for 10 minutes using a granulator.
• Granulate the blend with purified water.
• Screen the granulate through a No. 16 mesh sieve.
• Dry the screened granulate in a fluid bed dryer at 50-60°C until the moisture level is less than 3%.
• Add the dry granulate, coated pellets to a tumble blender and blend for 10 minutes.
• Add to, the blend the magnesium stearate and blend an additional 3 minutes.
• Compress the blend on a rotary tablet press to achieve a dose of 400 mg.
The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day administration ofthe antibiotic.
Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described. Four pulses Example 65
Dicloxacillin Pellet Formulation and Preparation Procedure
Pellet Formulations
The composition ofthe Dicloxacillin trihydrate pellets provided in Table 1. Table 1 Composition of Dicloxacillin Pellets Component Percentage (%)
Dicloxacillin 92
Avicel PH 101 6.0
Polyoxyl 35 Castor Oil* 1.0
Hydroxypropyl methylcellulose, NF* 1.0
Purified Water **
Total 100
♦Hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil were added as a 2.9% w/w aqueous solution during wet massing.
** Removed during processing
Preparation Procedure for Dicloxacillin Pellets
• Blend Dicloxacillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose and Polyoxyl 35 Castor Oil binder solution slowly into the powder blend under continuous mixing.
• Extrude the wet mass using an LCI Bench Top Granulator. The diameter ofthe screen ofthe Bench Top Granulator is 0.8 mm.
• Spheronize the extrudate using a QJ-230 Spheronizer using a small cross section plate.
• Dry the spheronized pellets at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
• Pellets between 20 and 40 Mesh were collected for further processing. Dicloxacillin Enteric-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® L 30 D-55/EudragitNE 30D Aqueous Coating
Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit L30D-55/Eudragit NE 30D aqueous coating dispersion applied to the Dicloxacillin pellets is provided below in Table 2.
Table 2 Eudragit® L 30 D-55/Eudragit NE 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® L 30D-55 44.4
Eudragit NE 30D 14.8
Triethyl Citrate 1.3
Imwitor 900 0.9
Purified Water* 38.6
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® L 30D-55/Eudragit NE 30D Aqueous Dispersion
• Heat purified water to 75-80°C and then add triethyl citrate (TEC) and
Imwitor 900. Homogenize dispersion until temperature is less than 55°C.
• The TEC/Imwitor 900 dispersion is then stirred until the temperature is less than 35°C.
• Add the TEC/Imwitor 900 dispersion to Eudragit L30D-55 latex dispersion and stir for at least 30 minutes. • Add Eudragit NE 30D to the Eudragit L30D/TEC/Imwitor 900 dispersion and stir for at least 10 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete.
Coating Conditions for the Application of Eudragit L30D-55/Eudragit NE
30D Aqueous Coating Dispersion
The following coating parameters were used for coating ofthe Eudragit® L 30 D-
55/EudragitNE30D film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 45 °C
Outlet Air Temperature 32 to 35 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with Eudragit L30 D-55/Eudragit NE 30D film coating dispersion such that you apply 20% coat weight gain to the pellets.
Dicloxacillin Delayed Enteric-Release Pellets Formulation and Preparation Procedure
Preparation of an AQOAT AS-HF Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous AQOAT AS-HF aqueous coating dispersion applied to the Dicloxacillin pellets is provided below in Table 3.
Table 3 AQOAT AS-HF Aqueous Coating Dispersion
Component Percentage (%)
AQOAT AS-HF 7.0
Triethyl Citrate 2.0
Talc 2.1
Sodium lauryl sulfate 0.2
Purified Water* 88.7
Solid Content 11.3
Polymer Content 7.0
*Removed during processing
Preparation Procedure for an AQOAT AS-HF Aqueous Dispersion
• Add triethyl citrate (TEC) to the purified water with stirring.
• Add the sodium lauryl sulfate (SLS) to the TEC dispersion with stirring and completely until completely dissolved.
• Add the AQOAT to the TEC/SLS dispersion and stir for at least 30 minutes.
• Add the talc to the AQOAT dispersion and until completely mixed and for at least 30 minutes.
• Screen the dispersion through a No. 60 mesh sieve prior to coating.
• Continue to stir the dispersion until the coating process is complete. Coating Conditions for the Application of AQOAT AS-HF Aqueous Coating
Dispersion
The following coating parameters were used for coating ofthe AQOAT AS-HF film coating dispersion.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 48 °C
Outlet Air Temperature 27 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 3-4 gram per minute
Coat Dicloxacillin pellets with AQOAT AS-HF film coating dispersion such that you apply 30-35% coat weight gain to the pellets.
Dicloxacillin Colonic-Release Pellet Formulation and Preparation Procedure
Preparation of an Eudragit® FS 30D Aqueous Coating Dispersion
Dispersion Formulation
The composition ofthe aqueous Eudragit® FS 30D dispersion applied to the
Dicloxacillin pellets is provided below in Table 4.
Table 4 Eudragit® FS 30D Aqueous Coating Dispersion
Component Percentage (%)
Eudragit® FS 30D 54.8
Triethyl Citrate 0.9
Talc 3.3
Purified Water* 41.0
Solid Content 20.6
Polymer Content 16.4
*Removed during processing
Preparation Procedure for an Eudragit® FS 30D Aqueous Dispersion
• Disperse triethyl citrate (TEC) in the purified water.
• Add the talc in the triethyl citrate dispersion.
• Homogenize the dispersion using a homogenizer.
• Add slowly the Eudragit® FS 30D dispersion to the talc/TEC dispersion with stirring.
Continue to stir the coating dispersion until the coating process is complete. Coating Conditions for the Application of Eudragit FS30D Aqueous Coating
Dispersion
The following coating parameters were used for coating with each ofthe Eudragit®
FS 30 D aqueous film coating.
Coating Equipment STREA 1™ Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.2 mm
Material Charge 300 gram
Inlet Air Temperature 38 °C
Outlet Air Temperature 22 °C
Atomization Air Pressure 1.6 Bar
Pump Rate 6 gram per minute
Coat pellets with Eudragit FS 30D coating dispersion dispersion such that you apply 30% coat weight gain to the pellets.
Encapsulation of the Dicloxacillin Pellets
Pellets are filled into hard gelatin capsules at a ratio of 25%: 25%: 25%: 25% Immediate-release pellets (uncoated), L30 D-55/EudragitNE 30D coated pellets 20% weight gain, AQOAT coated pellets 30% weight gain and Eudragit FS 30D coated pellets respectively. The capsule is filled with the four different pellets to achieve a total dose of 250mg/capsule.
Dicloxacillin Tablets
Preparation of Dicloxacillin Granulation for tableting
Table 5 Composition of Dicloxacillin Granulation (Immediate Release)
Component Percentage (%)
Dicloxacillin 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during wet massing.
• Blend Dicloxacillin and Avicel® PH 101 using a low shear blender.
• Add the hydroxypropyl methylcellulose binder solution slowly into the powder blend under continuous mixing.
• Dry the granulation at 60°C using a fluid bed dryer until the exhaust temperature reaches 40°C.
• Granules between 20 and 40 Mesh are collected for further processing.
Tableting ofthe Dicloxacillin Pellets
Table 6 Composition of Dicloxacillin Tablets
Component Percentage (%)
Dicloxacillin granules
32.5
Avicel PH 200 5.0
Eudragit L30D-55/NE 30D coated pellets
20
AQOAT coated pellets 20
Eudragit FS 30D coated pellets 20
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
• Blend the Dicloxacillin granules, Avicel PH-200, Dicloxacillin coated pellets and colloidal silicon dioxide for 15 minutes in a tumble blender.
• Add the magnesium stearate to the blender, and blend for 5 minutes.
• Compress the blend on a rotary tablet press.
The fill weight should be adjusted to achieve a 500 mg dose tablet.
The present invention is particularly advantageous in that there is provided an antibiotic product which provides an improvement over twice a day administration of the antibiotic and an improvement over a once a day administration ofthe antibiotic.
Numerous modification and variations of the present invention are possible in light of the above teachings and therefore, within the scope of the appended claims the invention may be practiced otherwise than as particularly described.

Claims

WHAT IS CLAIMED IS:
1. An antibiotic product comprising: a first antibiotic dosage form, a second antibiotic dosage form, and a third antibiotic dosage form, each of said first, second and third antibiotic dosage forms comprising an antibiotic and a pharmaceutically acceptable carrier, said three dosage forms having different release profiles, said antibiotic product reaching a Cmax in less than about twelve hours, wherein the antibiotic is selected from the group consisting of: levofloxacin, metronidazole, tetracycline, doxycycline, erythromyacin, clarithromycin, fluroquinilone, ciprofloxacin, betalactam antibiotic, cephalsporin, cefuroxime, cefpodoxime, penicillin, amoxicillin, and dicloxacillin; said first dosage form being an immediate release dosage form, said second and third dosage forms, each being a delayed release dosage form, wherein the antibiotic released from the first dosage form reaches a Cmax in serum in from 0.5 to 2 hours after administration of the product, wherein the antibiotic released from the second dosage form reaches a Cmax in serum in no more than 4 hours after administration ofthe product and after Cmax is reached for antibiotic from the first dosage form and the antibiotic released from the third dosage form reaches a Cmax in serum within 8 hours, and after the Cmax is reached for the antibiotic released from the second dosage form.
2. The product of claim 1 wherein the second dosage form initiiates release ofthe antibiotic at least one hour after the first dosage form.
3. The product of claim 2 wherein the Cmax for the second dosage form is reached no earlier than two hours after product administration.
4. The product of claim 3 wherein the first dosage form contains from about 20% to about 50%, by weight, ofthe total antibiotic ofthe product, wherein the second dosage form contains from 30% to 60%, by weight, of the antibiotic that is contained in the second and third dosage forms.
5. The product of claim 4 wherein the first dosage form contains from 15% to 30%, by weight, ofthe total antibiotic present in the product.
6. The product of claim 1 wherein the product includes a fourth delayed release antibiotic dosage form having a different release profile from the first, second and third dosage forms.
7. The product of claim 6 wherein the second dosage form contains from 20% to 35%, by weight, of the total antibiotic present in the second, third and fourth dosage forms, the third dosage form contains from 20% to 40%, by weight, of the total antibiotic present in the second, third and fourth dosage forms, with the remainder being present in the fourth dosage form.
8. The product of claim 1 wherein Craax for the product is reached no earlier than four hours after administration.
9. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 1.
10. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 2.
11. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 3.
12. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 4.
13. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 5.
14. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 6.
15. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 7.
16. A process for treating a bacterial infection in a host comprising: administering to a host the antibiotic product of Claim 8.
PCT/US2002/040809 2001-12-20 2002-12-20 Antibiotic product, use and formulation thereof WO2003086344A1 (en)

Priority Applications (4)

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EP20020794328 EP1465591A1 (en) 2001-12-20 2002-12-20 Antibiotic product, use and formulation thereof
AU2002359768A AU2002359768A1 (en) 2001-12-20 2002-12-20 Antibiotic product, use and formulation thereof
JP2003583368A JP2005523309A (en) 2001-12-20 2002-12-20 Antibiotic products, their usage and formulation
CA002470016A CA2470016A1 (en) 2001-12-20 2002-12-20 Antibiotic product, use and formulation thereof

Applications Claiming Priority (12)

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US10/027,837 2001-12-20
US10/028,590 2001-12-20
US10/027,609 US6669948B2 (en) 2000-02-24 2001-12-20 Antibiotic product, use and formulation thereof
US10/028,595 US6663891B2 (en) 2000-02-24 2001-12-20 Erythromyacin antibiotic product, use and formulation thereof
US10/027,866 2001-12-20
US10/028,595 2001-12-20
US10/027,866 US6663890B2 (en) 2000-02-24 2001-12-20 Metronidazole antibiotic product, use and formulation thereof
US10/027,366 2001-12-20
US10/027,609 2001-12-20
US10/027,366 US6667057B2 (en) 2000-02-24 2001-12-20 Levofloxacin antibiotic product, use and formulation thereof
US10/028,590 US6730320B2 (en) 2000-02-24 2001-12-20 Tetracycline antibiotic product, use and formulation thereof
US10/027,837 US6667042B2 (en) 2000-02-24 2001-12-20 Fluroquinilone antibiotic product, use and formulation thereof

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AU2003218024B2 (en) * 2002-03-07 2008-09-11 Shionogi, Inc. Antibiotic composition
US8048413B2 (en) 2006-05-17 2011-11-01 Helene Huguet Site-specific intestinal delivery of adsorbents, alone or in combination with degrading molecules
US8106000B2 (en) 2005-05-18 2012-01-31 Da Volterra Colonic delivery of adsorbents
WO2012075015A3 (en) * 2010-11-29 2012-08-23 Dr. Reddy's Laboratories Ltd. Oral metronidazole pharmaceutical compositions
US8303988B2 (en) 2000-10-13 2012-11-06 Shionogi Inc. Antifungal once-a-day product, use and formulation thereof
WO2013186191A1 (en) * 2012-06-11 2013-12-19 Formac Pharmaceuticals N.V. Formulations of metronidazole for the treatment of pouchitis
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US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

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US8889187B2 (en) 2000-02-24 2014-11-18 Shionogi Inc. Once a day amoxicillin product comprising immediate and delayed release dosage forms
US8303988B2 (en) 2000-10-13 2012-11-06 Shionogi Inc. Antifungal once-a-day product, use and formulation thereof
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US8388984B2 (en) 2006-05-17 2013-03-05 Da Volterra Site-specific intestinal delivery of adsorbents, alone or in combination with degrading molecules
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. Modified release amoxicillin products
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US9119793B1 (en) 2011-06-28 2015-09-01 Medicis Pharmaceutical Corporation Gastroretentive dosage forms for doxycycline
WO2013186191A1 (en) * 2012-06-11 2013-12-19 Formac Pharmaceuticals N.V. Formulations of metronidazole for the treatment of pouchitis
US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

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