(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2002/0136766 A1
`(43) Pub. Date:
`Sep. 26, 2002
`Rudnic et al.
`
`US 20020136766A1
`
`(54) TETRACYCLINE ANTIBIOTIC PRODUCT,
`USE AND FORMULATION THEREOF
`
`(60) Provisional application No. 60/184,546, ?led on Feb.
`24, 2000.
`
`(76) Inventors: Edward M. Rudnic, N. Potomac, MD
`(US); James D. Isbister, Potomac, MD
`(US); Donald J. Treacy J R., Arnold,
`MD (US); Sandra E. Wassink,
`Frederick, MD (US)
`
`Publication Classi?cation
`
`(51) Int. Cl? ........................... ..A61K 31/65; A61K 9/52
`(52) Us. 01. .......................................... .. 424/457; 514/152
`
`Correspondence Address:
`CARELLA, BYRNE BAIN, GILFILLAN,
`CECCHI, STEWART& OLSTEIN
`Six Becker Farm Road
`Roseland, NJ 07068 (US)
`
`(21) Appl. No.:
`
`10/028,590
`
`(22) Filed:
`
`Dec. 20, 2001
`
`Related US. Application Data
`
`(63) Continuation-in-part of application No. 09/792,092,
`?led on Feb. 22, 2001, Which is a continuation-in-part
`of application No. 09/687,229, ?led on Oct. 13, 2000.
`
`(57)
`
`ABSTRACT
`
`An antibiotic product, in particular a tetracycline, such as
`doxycycline, is comprised of at least three dosages forms,
`each of Which has a different release pro?le, With the CrnaX
`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 pro?le, Wherein each reaches a CrnaX at
`different times.
`
`1
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 2002
`
`TETRACYCLINE ANTIBIOTIC PRODUCT, USE
`AND FORMULATION THEREOF
`
`[0001] This application is a continuation-in-part of US.
`application Ser. No. 09/792,092, ?led on Feb. 22, 2000,
`Which is a continuation-in-part of US. application Ser. No.
`09/687,229, ?led on Oct. 13, 2000, and also claims the
`priority of US. Provisional Application Serial No. 60/184,
`546 ?led on Feb. 24, 2000.
`
`[0002] This invention relates to an antibiotic product, as
`Well as the use and formulation thereof. The invention
`further relates to a tetracycline antibiotic product and in
`particular doXycycline and its derivatives, salts, hydrates,
`esters, metabolites, etc.
`[0003] 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 higher administered doses. The present invention
`is directed to providing for an improved antibiotic product.
`
`[0004] In accordance With one aspect of the present inven
`tion, 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
`pro?le.
`[0005] In a particularly preferred embodiment, there are at
`least tWo, preferably at least three dosage forms, each of
`Which has a different release pro?le and the release pro?le
`of each of the dosage forms is such that the dosage forms
`each start release of the antibiotic contained therein at
`different times after administration of the antibiotic product.
`
`[0006] 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 pro?le, Whereby the antibiotic contained in
`each of such dosage forms is released at different times.
`
`[0007] In accordance With a further aspect of the inven
`tion, 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 admin
`istration of the antibiotic product.
`
`[0008] The antibiotic product generally does not include
`more than ?ve dosage forms With different release times.
`
`[0009] In accordance With a preferred embodiment, the
`antibiotic product has an overall release pro?le 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 of the total
`antibiotic released from the antibiotic product is achieved no
`earlier than four hours after administration.
`
`[0010] 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 of the 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 CrnaX
`(maximum serum concentration in the serum) at a time after
`the antibiotic released from the ?rst of the at least three
`dosage forms achieves a CrnaX in the serum, and the antibi
`otic released from the third dosage form achieves a CrnaX in
`the serum after the CrnaX of antibiotic released from the
`second dosage form.
`
`[0011] In one embodiment, the second of the at least tWo
`dosage forms initiates release of the antibiotic contained
`therein at least one hour after the ?rst dosage form, With the
`initiation of the release therefrom generally occurring no
`more than siX hours after initiation of release of antibiotic
`from the ?rst dosage form of the at least three dosage forms.
`
`[0012] In general, the immediate release dosage form
`produces a CrnaX 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 CrnaX for
`the antibiotic released therefrom in no more than about four
`hours. In general, the CrnaX 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 of the invention to achieve CrnaX in a shorter period of
`time.
`
`[0013] 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 CrnaX at a time later than the CrnaX is achieved for
`the antibiotic released from each of the ?rst and second
`dosage forms. In a preferred embodiment, release of anti
`biotic from the third dosage form is started after initiation of
`release of antibiotic from both the ?rst dosage form and the
`second dosage form. In one embodiment, CrnaX for antibiotic
`release from the third dosage form is achieved Within eight
`hours.
`
`[0014] In another embodiment, the antibiotic product con
`tains at least four dosage forms, With each of the at least four
`dosage forms having different release pro?les, Whereby the
`antibiotic release from each of the at least four different
`dosage forms achieves a CrnaX at a different time.
`
`[0015] As hereinabove indicated, in a preferred embodi
`ment, 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 pro?le, CrnaX for all the antibi
`otic released from the antibiotic product is achieved in less
`than tWelve hours, and more generally is achieved in less
`than eleven hours.
`
`[0016] 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 anti
`biotic being released in a manner such that overall antibiotic
`
`2
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 2002
`
`release is effected With different release pro?les in a manner
`such that the overall CrnaX for the antibiotic product is
`reached in less than tWelve hours. The term single admin
`istration 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 administered at essentially the
`same time.
`[0017] Applicant has found that a single dosage antibiotic
`product comprised of at least three antibiotic dosage forms
`each having a different release pro?le is an improvement
`over a single dosage antibiotic product comprised of an
`antibiotic dosage form having a single release pro?le. Each
`of the 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.
`
`[0018] 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.
`
`[0019] 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
`CrnaX of the fourth dosage form of the at least four dosage
`forms is reached after the CrnaX 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.
`[0020] The antibiotic product of the present invention, as
`hereinabove described, may be formulated for administra
`tion 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.
`[0021] For eXample, in formulating the antibiotic product
`for topical administration, 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 admin
`istration 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 discon
`tinuous 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 ?rst delayed release dosage form, and
`oil dispersed in the Water containing a third delayed release
`dosage form.
`[0022] 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
`pro?les, as hereinabove described.
`
`[0023] In addition, the antibiotic product may be formu
`lated 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 of the emulsion.
`
`[0024] Furthermore, the antibiotic product With at least
`three different dosage forms With different release pro?les
`may be formulated for rectal or vaginal administration, 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.
`
`[0025] 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.
`[0026] 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 pharma
`ceutical product, for eXample, in a capsule, or embedded in
`a tablet, or suspended in a liquid for oral administration.
`[0027] Alternatively, in formulating an oral delivery sys
`tem, each of the 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 ?rst 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 of the antibiotic, as
`hereinabove described, Whereby the CrnaX of the antibiotic
`released from each of the tablets is reached at different times,
`With the C
`of the total antibiotic released from the
`antibiotic product being achieved in less than tWelve hours.
`
`max
`
`[0028] The formulation of an antibiotic product including
`at least three dosage forms With different release pro?les for
`different routes of administration is deemed to be Within the
`skill of the 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 of the coating.
`
`[0029] 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% of the total
`dosage of the 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% of the total
`dosage of antibiotic to be delivered by the product.
`
`[0030] The remaining dosage forms deliver the remainder
`of the antibiotic. If more than one delayed release dosage
`form is used, in one embodiment, each of the delayed release
`dosage forms may provide about equal amounts of antibi
`otic; hoWever, they may also be formulated so as to provide
`different amounts.
`
`3
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 2002
`
`[0031] 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.
`
`[0032] In one embodiment, Where the composition con
`tains one immediate release component and tWo delayed
`release components, the immediate release component pro
`vides from 20% to 35% (preferably 20% to 30%), by Weight,
`of the total antibiotic; Where there is three delayed release
`components, the immediate release component provides
`from 15% to 30%, by Weight, of the total antibiotic; and
`Where there are four delayed release components, the imme
`diate release component provides from 10% to 25%, by
`Weight, of the total antibiotic.
`
`[0033] With respect to the delayed release components,
`Where there are tWo delayed release components, the ?rst
`delayed release component (the one released earlier in time)
`provides from 30% to 60%, by Weight, of the total antibiotic
`provided by the tWo delayed release components With the
`second delayed release component providing the remainder
`of the antibiotic.
`
`[0034] Where there are three delayed release components,
`the earliest released component provides 20% to 35% by
`Weight of the total antibiotic provided by the three delayed
`release components, the neXt in time delayed release com
`ponent provides from 20% to 40%, by Weight, of the
`antibiotic provided by the three delayed release components
`and the last in time providing the remainder of the antibiotic
`provided by the three delayed release components.
`
`[0035] 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 com
`ponent 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 of the total
`antibiotic provided by the four delayed release components.
`
`[0036] The Immediate Release Component
`
`[0037] 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.
`
`[0038] 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, hydroXypropylmethylcellu
`lose,
`hydroXyethylcellulose,
`ethylcellulose,
`chitosan,
`hydroXychitosan, hydroXymethylatedchitosan, cross-linked
`chitosan, cross-linked hydroXymethyl chitosan, maltodeX
`trin, mannitol, sorbitol, deXtrose, maltose, fructose, glucose,
`levulose, sucrose, polyvinylpyrrolidone (PVP), 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.
`
`[0039] It may be useful to have these materials present in
`the range of 1.0 to 60%
`
`[0040] In addition, it may be useful to have other ingre
`dients in this system to aid in the dissolution of the drug, or
`the breakdoWn of the component after ingestion or admin
`istration. 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.
`
`[0041] These materials may be present in the rate of
`0.05-15%
`[0042] The non-pH Sensitive Delayed Release Compo
`nent
`
`[0043] The components in this composition are the same
`immediate release unit, but With additional polymers inte
`grated into the composition, or as coatings over the pellet or
`granule.
`[0044] 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, paraf?n, acrylic acid
`derivatives (Eudragit), propylene glycol, and ethylcellulose.
`[0045] Typically these materials can be present in the
`range of 05-25%
`of this component.
`[0046] The pH Sensitive (Enteric) Release Component
`[0047] 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.
`
`[0048] 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.
`
`[0049] These materials can be present in concentrations
`from 4-20%
`[0050] Sustained Release Component
`[0051] 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.
`
`[0052] The kind of materials useful for this purpose can
`be, but are not limited to, ethylcellulose,hydroXypropyl
`methylcellulose,hydroXypropylcellulose, hydroXyethylcel
`lulose, carboXymethylcellulose, methylcellulose, nitrocellu
`lose, Eudragit R, and Eudragit RL, Carbopol, or
`polyethylene glycols With molecular Weights in eXcess of
`8,000 daltons.
`[0053] These materials can be present in concentrations
`from 4-20%
`
`[0054] 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.
`[0055] The antibiotic composition of the present invention
`may be administered, for eXample, by any of the folloWing
`
`4
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 2002
`
`routes of administration: sublingual, transmucosal, transder
`mal, 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.
`
`[0056] This system Will be especially useful in extending
`the practical therapeutic activity for antibiotics With elimi
`nation 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, ce?xime, cefoperaZone, cefotaxime, cefpo
`doxime, ceftaxidime, ceftibuten, ceftiZoxime, ceftriaxone,
`cefepime, cefmetaZole, cefotetan, cefoxitin, loracarbef, imi
`penem, erythromycin (and erythromycin salts such as esto
`late, ethylsuccinate, gluceptate, lactobionate, stearate),
`aZithromycin, clarithromycoin, dirithromycin, troleanomy
`cin, penicillin V, peniciliin salts, and complexes, methicillin,
`nafcillin, oxacillin, cloxacillin, dicloxacillin, amoxicillin,
`amoxicillin and clavulanate potassium, ampicillin, bacampi
`cillin, carbenicillin indanyl sodium (and other salts of car
`benicillin) meZlocillin, piperacillin, piperacillin and taxo
`bactam, ticarcillin, ticarcillin and clavulanate potassium,
`clindamycin, vancomycin, novobiocin, aminosalicylic acid,
`capreomycin, cycloserine, ethambutol HCl and other salts,
`ethionamide, and isoniaZid, cipro?oxacin, levo?oxacin,
`lome?oxacin, nalidixic acid, nor?oxacin, o?oxacin, spar
`?oxacin, sulfacytine, su?ameraZine, sulfamethaZine, sul
`famethixole, sulfasalaZine, sul?soxaZole, sulfapyriZine, sul
`fadiaZine, sul?nethoxaZole, sulfapyridine, metronidaZole,
`methenamine, fosfomycin, nitrofurantoin, trimethoprim,
`clofaZimine, co-triamoxaZole, pentamidine, and trimetrex
`ate.
`
`[0057] The invention Will be further described With
`respect to the folloWing examples; hoWever, the scope of the
`invention is not limited thereby. All percentages in this
`speci?cation, unless otherWise speci?ed, are by Weight.
`
`EXAMPLES
`
`[0058] Immediate Release Component
`
`[0059] Formulate the composition by mixing the ingredi
`ents in a suitable pharmaceutical mixer or granulator such as
`a planetary mixer, high-shear granulator, ?uid bed granula
`tor, 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
`
`Conc. (% W/W)
`
`Example 1:
`
`Amoxicillin Microcrystalline cellulose
`
`Povidone
`Croscarmellose sodium
`
`Example 2:
`
`
`
`Amoxicillin Microcrystalline cellulose
`
`Povidone
`Croscarmellose sodium
`
`Example 3:
`
`Amoxicillin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`
`Example 4:
`
`Amoxicillin Polyethylene glycol 4000
`
`Polyethylene glycol 2000
`Hydroxypropylcellulose
`
`Example 5:
`
`Amoxicillin Polyethylene glycol 8000
`
`Polyvinylpyrrolidone
`
`Example 6:
`
`Clarithromycin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`
`Example 7:
`
`Clarithromycin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`
`Example 8:
`
`Clarithromycin Polyethylene glycol 4000
`
`Polyethylene glycol 2000
`Hydroxypropylcellulose
`
`Example 9:
`
`Clarithromycin Polyethylene glycol 8000
`
`Polyvinylpyrrolidone
`
`Example 10:
`
`Ciprofloxacin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`Example 11:
`
`Ciprofloxacin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`Example 12:
`
`Ciprofloxacin Polyethylene glycol 4000
`
`Polyethylene glycol 2000
`Hydroxypropylcellulose
`
`65% 20
`
`10
`5
`
`
`
`55% 25
`
`10
`10
`
`65% 20
`
`10
`5
`
`75% 10
`
`10
`5
`
`75% 20
`
`5
`
`65% 20
`
`10
`5
`
`75% 15
`
`5
`5
`
`75% 10
`
`10
`5
`
`75% 20
`
`5
`
`65% 20
`
`10
`5
`
`75% 15
`
`5
`5
`
`75% 10
`
`10
`5
`
`5
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 2002
`
`-continued
`
`-continued
`
`Ingredient
`
`COnC- (‘70 W/W)
`
`Ingredient
`
`Conc. (% W/W)
`
`Example 133
`
`Example 22:
`
`Cipro?oxacin Polyethylene glycol 8000
`
`Polyvinylpyrrolidone
`
`75% (W/W) 20
`
`5
`
`Ceftibuten
`Polyethylene glycol 4000
`Polyethylene glycol 2000
`Hydroxypropylcellulose
`Example 15:
`
`Clarithromycin P01 OX
`
`y
`Hydroxypropylcellulose
`Example 14:
`— Ethylcellulose
`75% (W/W)
`10
`10
`5
`
`_
`_
`Clanthromycm
`Polyethylene glycol 4000
`Polyethylene glycol 2000
`Eudragit RL 30D
`
`
`
`75% 15
`
`5
`5
`w
`
`75% (W/W)
`10
`10
`5
`
`80% (W/W)
`10
`5
`5
`
`65% (W/W)
`20
`5
`
`10
`
`75% (WW)
`15
`5
`5
`
`
`
`80% 10
`
`5
`5
`
`
`
`75% 20
`
`5
`
`75% (W/W)
`10
`10
`5
`
`75% 20
`
`5
`
`Ceftibuten
`Polyethylene Glycol 4000
`Polyvinylpyrrolidone
`
`75%
`20
`5
`
`.
`.
`[0060] non-pH Sensitive Delayed Release Component
`
`-
`
`-
`
`_
`
`[0061] Formulate the composition by mixing the ingredi-
`ents in a suitable pharmaceutical mixer or granulator such as
`a planetary mixer, high shear granulator, ?uid bed granula
`tor, 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
`f
`d .
`All
`h
`d
`1
`vacuum over or orce ~-211I‘ oven. oW t e pro not to coo ,
`the product may be sieved or granulated, and compressed
`using a suitable tablet press, such as a rotary tablet press.
`
`-
`
`_
`
`.
`I
`d t
`ngre len
`
`C . W
`one (% /W)
`
`Example 16:
`
`
`
`AInOXiCillin Microcrystalline cellulose
`
`_
`Polyox
`Croscarmellose sodium
`
`Amoxicillin
`Example 17:
`Microcrystalline cellulose
`Polyox
`Glyceryl monooleate
`
`Example 183
`
`
`
`65% 20
`
`1O
`5
`
`55% (W/W)
`25
`10
`10
`
`Amoxicillin
`
`Polyox Hydroxypropylcellulose
`
`Croscarmellose sodium
`Example 19:
`
`65%
`
`2O 1O
`
`5
`
`Example 24:
`
`Clarithromycin
`Polyethylene glycol 8000
`Polyvinylpyrrolidone
`E d
`'t R 30D
`u gragl
`
`_
`E
`xample 25.
`
`cipro?oxacin
`Polyethylene glycol 4000
`Eudragit RL 30D
`
`Hydroxypropylcellulose
`
`Example 26;
`
`C1Pr°?°Xa°m_
`Microcrystalline cellulose
`Hydroxypropylcellulose
`Ethylcellulose
`
`Example 271
`
`
`
`Cipro?oxacin Polyethylene glycol 4000
`
`Polyethylene glycol 2000
`Eudgragit RL 30D
`
`Example 28:
`
`
`
`Cipro?oxacin polyethylene glycol 8000
`
`Ethylcellulose
`
`Exam 1e 29_
`
`Ceftibuten
`Polyethylene glycol 4000
`Polyethylene glycol 2000
`Eudragit RL 30D
`
`Example 30:
`
`.
`
`Ceftibuten Polyethylene glycol 8000
`
`Ethylcellulose
`
`_
`[0062] Enteric Release Component
`
`xam e
`
`I
`
`.
`
`.
`
`.
`
`-
`
`75%
`Amoxicillin
`10
`Polyethylene glycol 4000
`10
`Polyethylene glycol 2000
`[0063] Formulate the ingredients by mixing the ingredi
`5
`1 2O
`EudragltRL 30D
`E
`; ents in a suitable pharmaceutical mixer or granulator such as
`75% (W/W)
`a planetary mixer, high-shear granulator, ?uid bed granula
`20
`_
`5
`tor, 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.
`
`AmOXiCillin
`Polyethylene glycol 8000
`Ethylcellulose
`
`Example 211
`
`clarithromycin
`PO1YOX
`Hydroxypropylcellulose
`Croscarmellose sodium
`
`70% (W/W)
`20
`5
`5
`
`6
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 2002
`
`Ingredient
`
`Lactose
`Eudragit L 30D
`
`-continued
`
`Example 45:
`
`
`
`Ceftibuten Microcrystalline cellulose
`
`Cellulose acetate pthalate
`
`Conc. (% W/W)
`
`20
`10
`
`
`
`70% 20
`
`10
`
`Ingredient
`
`Conc. (% W/W)
`
`Example 31:
`
`Amoxicillin
`Microcrystalline cellulose
`
`
`
`Cellulose Acetate Pthalate Example 32:
`
`
`Amoxicillin Microcrystalline cellulose
`Cellulose Acetate Pthalate
`Example 33;
`
`Hydroxypropylmethylcellulose
`
`_
`_
`_
`gnlloxlclnm
`Hygroxypropylcenulose pthalate
`Eudragit L 301)
`
`o ox
`
`Example 341
`
`_
`_
`_
`Amoxicillin
`Polyethylene glycol 2000
`Eudragit L 301)
`Eudragit RL 30D
`
`Example 35:
`
`Amoxicillin
`Microcrystalline Cellulose
`Cellulose Acetate Pthalate
`Example 36:
`
`65%
`20
`
`15
`
`
`55% 25
`10
`
`10
`
`65;? (W/W)
`1O
`5
`
`75%
`10
`10
`5
`
`40%
`40
`10
`
`_
`_
`Clarithromycin
`Hydroxypropylcellulose pthalate
`Croscarmenose Sodlum
`PM
`
`70%
`15
`1O
`
`
`
`Clarithromycin Eudragit E 30D
`
`
`
`70% 15
`
`Hydroxypropylcellulose
`Ethylcellulose
`
`10
`5
`w
`
`_
`
`_
`
`_
`
`_
`
`_
`
`_
`
`[0064] Sustained Release Component
`[0065] Formulate the composition by mixing the ingredi
`ents in a suitable pharmaceutical mixer or granulator such as
`a planetary mixer, high-shear granulator, ?uid bed granula
`tor, or extruder, 1n 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,
`h
`d
`b
`.
`d
`1
`d
`d
`d
`t e pro uct may e sieve or granu ate , an compresse
`using a suitable tablet press, such as a rotary tablet press.
`
`.
`
`.
`Ingredlent
`
`Conc' (% W/W)
`
`Example 46_
`—'
`
`Amoxicillin
`Ethylcellulose
`P 01y OX
`Hydroxypropylmethylcellulose
`Example 47:
`
`
`
`Amoxicinin Lactose
`
`POIYOX
`Glyceryl monooleate
`
`Example 48:
`
`65% W/W
`2O (
`)
`10
`5
`
`
`
`55% 25
`
`1O
`10
`
`
`
`Clarithromycin Polyethylene glycol 2000
`
`
`
`75% 10
`
`
`
`Amoxicinin POIYOX
`
`Eudraglt E 30D
`
`PM
`
`15
`
`Hydroxypropylcellulose
`Example 49:
`
`
`
`Clarithromycin Lactose
`
`Eudgraglt L 30D
`
`Cipro?oxacin
`
`
`
`40% 50
`
`
`
`Clarithromycin Lactose
`
`Hydroxypropylcellulose
`1O
`_
`w Ethylcellulose
`65%
`
`5
`5
`l 50:
`E
`&
`
`
`
`70% 2O
`
`10
`
`
`
`75% 15
`
`
`
`Clarithromycin Polyethylene glycol 4000
`
`
`
`75% 10
`
`Lactose
`Eudragit RL 30D
`
`10
`5
`
`Example 51_
`—'
`
`
`
`Microcrystalline Cellulose Eudraglt L 30D
`
`
`
`—Example 41:
`
`_
`_
`Cipro?oxacin
`Microcrystalline Cellulose
`
`
`
`
`
`Hydroxypropylcellulose pthalate —Example 42:
`
`_
`_
`Cipro?oxacin
`Lactose
`Eudgragit L 30D
`
`Example 432
`
`
`
`20 10
`
`75%
`15
`
`10
`
`80%
`10
`10
`
`
`
`Clarithromycin Polyethylene glycol 8000
`
`Hydroxypropylmethylcellulose
`Eudgragit RS 30D
`
`Example 52:
`
`Cipro?oxacin Hydroxyethylcellulose
`
`Polyethylene glycol 4000
`Hydroxypropylcellulose
`Example 53:
`
`Cipro?oxacin
`Polyethylene glycol 4000
`Cellulose acetate pthalate
`Example 44:
`— Cipro?oxacin
`
`70%
`20
`10
`
`.
`Ceftibuten
`Polyethylene glycol 2000
`
`60%
`10
`
`Lactose
`Povidone (PVP)
`Polyethylene glycol 2000
`
`
`
`80% 10
`
`5
`5
`
`75% 10
`
`10
`5
`
`75%
`
`10
`1O
`5
`
`7
`
`

`

`US 2002/0136766 A1
`
`Sep. 26, 20