EP1465591A1 - Antibiotic product, use and formulation thereof - Google Patents

Antibiotic product, use and formulation thereof

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Publication number
EP1465591A1
EP1465591A1 EP20020794328 EP02794328A EP1465591A1 EP 1465591 A1 EP1465591 A1 EP 1465591A1 EP 20020794328 EP20020794328 EP 20020794328 EP 02794328 A EP02794328 A EP 02794328A EP 1465591 A1 EP1465591 A1 EP 1465591A1
Authority
EP
European Patent Office
Prior art keywords
dispersion
eudragit
pellets
antibiotic
coating
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP20020794328
Other languages
German (de)
French (fr)
Inventor
James D. Isbister
Edward M. Rudnic
Donald J. Treacy, Jr.
Sandra E. Wassink
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Advancis Pharmaceutical Corp
Original Assignee
Advancis Pharmaceutical Corp
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 to US27366 priority Critical
Priority to US28595 priority
Priority to US27837 priority
Priority to US10/028,590 priority patent/US6730320B2/en
Priority to US10/027,366 priority patent/US6667057B2/en
Priority to US10/028,595 priority patent/US6663891B2/en
Priority to US10/027,609 priority patent/US6669948B2/en
Priority to US10/027,866 priority patent/US6663890B2/en
Priority to US10/027,837 priority patent/US6667042B2/en
Priority to US27609 priority
Priority to US28590 priority
Priority to US27866 priority
Application filed by Advancis Pharmaceutical Corp filed Critical Advancis Pharmaceutical Corp
Priority to PCT/US2002/040809 priority patent/WO2003086344A1/en
Publication of EP1465591A1 publication Critical patent/EP1465591A1/en
Application status is Withdrawn legal-status Critical

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/41641,3-Diazoles
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/429Thiazoles condensed with heterocyclic ring systems
    • A61K31/43Compounds 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K45/00Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2072Pills, 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
    • A61K9/2077Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1635Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605Excipients; Inactive ingredients
    • A61K9/1629Organic macromolecular compounds
    • A61K9/1652Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

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.
EP20020794328 2000-02-24 2002-12-20 Antibiotic product, use and formulation thereof Withdrawn EP1465591A1 (en)

Priority Applications (13)

Application Number Priority Date Filing Date Title
US27366 1987-03-18
US28595 1998-02-23
US10/028,590 US6730320B2 (en) 2000-02-24 2001-12-20 Tetracycline antibiotic product, use and formulation thereof
US10/027,366 US6667057B2 (en) 2000-02-24 2001-12-20 Levofloxacin antibiotic product, use and formulation thereof
US10/028,595 US6663891B2 (en) 2000-02-24 2001-12-20 Erythromyacin antibiotic product, use and formulation thereof
US10/027,609 US6669948B2 (en) 2000-02-24 2001-12-20 Antibiotic product, use and formulation thereof
US10/027,866 US6663890B2 (en) 2000-02-24 2001-12-20 Metronidazole antibiotic product, use and formulation thereof
US10/027,837 US6667042B2 (en) 2000-02-24 2001-12-20 Fluroquinilone antibiotic product, use and formulation thereof
US27609 2001-12-20
US28590 2001-12-20
US27866 2001-12-20
US27837 2001-12-20
PCT/US2002/040809 WO2003086344A1 (en) 2001-12-20 2002-12-20 Antibiotic product, use and formulation thereof

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Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6544555B2 (en) 2000-02-24 2003-04-08 Advancis Pharmaceutical Corp. Antibiotic product, use and formulation thereof
US20020068078A1 (en) 2000-10-13 2002-06-06 Rudnic Edward M. Antifungal product, use and formulation thereof
US8313776B2 (en) * 2003-07-21 2012-11-20 Shionogi Inc. Antibiotic product, use and formulation thereof
BRPI0610683A2 (en) 2005-05-18 2010-07-20 Da Volterra applying absorbent colÈnica
CA2635606A1 (en) * 2006-12-04 2008-06-12 Advancis Pharmaceutical Corporation Modified release amoxicillin products
US8048413B2 (en) 2006-05-17 2011-11-01 Helene Huguet Site-specific intestinal delivery of adsorbents, alone or in combination with degrading molecules
JP5318400B2 (en) * 2006-11-20 2013-10-16 第一三共株式会社 Levofloxacin tablets containing
WO2012075015A2 (en) * 2010-11-29 2012-06-07 Dr. Reddy's Laboratories Ltd. Oral metronidazole pharmaceutical compositions
US9119793B1 (en) 2011-06-28 2015-09-01 Medicis Pharmaceutical Corporation Gastroretentive dosage forms for doxycycline
GB201210184D0 (en) * 2012-06-11 2012-07-25 Univ Leuven Kath Formulations of metronidazole for the treatment of pouchitis

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
DE3684446D1 (en) * 1985-12-28 1992-04-23 Sumitomo Pharma Drugs with delayed shock wise release.
US5260069A (en) * 1992-11-27 1993-11-09 Anda Sr Pharmaceuticals Inc. Pulsatile particles drug delivery system
IL119627A (en) * 1996-11-17 2002-03-10 Yissum Res Dev Co PHARMACEUTICAL PREPARATIONS FOR THE CONTROLLED-RELEASE OF AN ACTIVE AGENT COMPRISING AT LEAST ONE β-LACTAM ANTIBIOTIC AGENT

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* Cited by examiner, † Cited by third party
Title
See references of WO03086344A1 *

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