EP1465591A1 - Produit antibiotique, son utilisation et sa formulation - Google Patents

Produit antibiotique, son utilisation et sa formulation

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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Withdrawn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)
English (en)
Inventor
Edward M. Rudnic
James D. Isbister
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.)
MiddleBrook Pharmaceuticals Inc
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 claimed from US10/027,366 external-priority patent/US6667057B2/en
Priority claimed from US10/027,866 external-priority patent/US6663890B2/en
Priority claimed from US10/027,837 external-priority patent/US6667042B2/en
Priority claimed from US10/027,609 external-priority patent/US6669948B2/en
Priority claimed from US10/028,595 external-priority patent/US6663891B2/en
Priority claimed from US10/028,590 external-priority patent/US6730320B2/en
Application filed by Advancis Pharmaceutical Corp filed Critical Advancis Pharmaceutical Corp
Publication of EP1465591A1 publication Critical patent/EP1465591A1/fr
Withdrawn legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/429—Thiazoles condensed with heterocyclic ring systems
    • A61K31/43—Compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula, e.g. penicillins, penems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • A61K9/2081—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets with microcapsules or coated microparticles according to A61K9/50
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates

Definitions

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

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Abstract

Cette invention concerne un produit antibiotique comprenant au moins trois formes dosifiées, chacune de ces formes dosifiées présentant un profil de libération différent, la concentration sérique maximale Cmax de ce produit antibiotique étant atteinte en moins de douze heures environ. Dans un mode de réalisation, ce produit comprend une forme dosifiée à libération immédiate ainsi qu'au moins deux formes dosifiées à libération retardée, chacune de ces formes dosifiées présentant un profil de libération différent et atteignant une Cmax à des instants différents.
EP20020794328 2001-12-20 2002-12-20 Produit antibiotique, son utilisation et sa formulation Withdrawn EP1465591A1 (fr)

Applications Claiming Priority (13)

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

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EP1465591A1 true EP1465591A1 (fr) 2004-10-13

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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
WO2005009365A2 (fr) * 2003-07-21 2005-02-03 Advancis Pharmaceutical Corporation Produit antibiotique, son utilisation et sa formulation
CA2608505C (fr) 2005-05-18 2013-12-24 Da Volterra Administration colonique d'adsorbants
US8778924B2 (en) 2006-12-04 2014-07-15 Shionogi Inc. 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 (ja) * 2006-11-20 2013-10-16 第一三共株式会社 レボフロキサシン含有錠剤
JP5788142B2 (ja) * 2006-12-04 2015-09-30 シオノギ インコーポレイテッド 変性放出アモキシシリン製剤
WO2012075015A2 (fr) * 2010-11-29 2012-06-07 Dr. Reddy's Laboratories Ltd. Compositions pharmaceutiques orales de métronidazole
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
US10842802B2 (en) 2013-03-15 2020-11-24 Medicis Pharmaceutical Corporation Controlled release pharmaceutical dosage forms

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EP0230654B1 (fr) * 1985-12-28 1992-03-18 Sumitomo Pharmaceuticals Company, Limited Préparation pharmaceutique à libération retardée intermittante
US4794001A (en) * 1986-03-04 1988-12-27 American Home Products Corporation Formulations providing three distinct releases
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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Title
See references of WO03086344A1 *

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AU2002359768A1 (en) 2003-10-27
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JP2005523309A (ja) 2005-08-04

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