(12) United States Patent
`Rudnic et al.
`
`(10) Patent N0.:
`(45) Date of Patent:
`
`US 6,730,320 B2
`May 4, 2004
`
`US006730320B2
`
`(54) TETRACYCLINE ANTIBIOTIC PRODUCT,
`USE AND FORMULATION THEREOF
`
`5,213,808
`5,229,131
`5,395,626
`
`>>>>>>>>>>>>>>>>>>>>>>
`
`(75) Inventors: Edward M. Rudnic, N. Potomac, MD
`(Us)? James D‘ Isblster’ Potomac’ MD
`(US), Donald J. Treacy, J r., Arnold,
`_
`_
`MD (Us), Sandra E- Wassmk’
`Fredenck MD (Us)
`
`-
`
`.
`
`(73) Assignee: Advancis Pharmaceutical Corp.,
`GermantoWn, MD (US)
`
`( * ) Notice:
`
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 175 days.
`
`(21) Appl. No.: 10/028,590
`(22) Filed:
`Dec. 20, 2001
`
`(65)
`
`Prior Publication Data
`
`US 2002/0136766 A1 Sep. 26, 2002
`
`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.
`(60) Provisional application No. 60/184,546, ?led on Feb. 24,
`2000.
`
`(51) Int. Cl.7 .......................... .. A61K 9/00; A61K 9/20;
`A61K 9/22; A61K 9/54; A61K 9/14
`(52) US. Cl. ..................... .. 424/468; 424/400; 424/457;
`424/464; 424/471; 424/472; 424/484; 424/489;
`514/964
`(58) Field of Search ............................... .. 424/400, 451,
`424/452, 457, 458, 459, 463, 464, 465,
`468, 469, 471, 472, 474, 478, 484, 489;
`514/962, 963, 964, 965
`
`(56)
`
`References Cited
`
`U.S. PATENT DOCUMENTS
`
`3/1984 Siposs et al. ............. .. 609/155
`4,435,173 A
`4,616,008 A 10/1986 Hirai et al. ............... .. 514/200
`4,794,001 A 12/1988 Mehta et al. ...... ..
`424/458
`4,831,025 A
`5/1989 Godtfredsen et al.
`514/195
`4,904,476 A
`2/1990 Mehta et al. ...... ..
`424/456
`4,915,953 A
`4/1990 Jordan et al.
`424/473
`4,971,805 A 11/1990 Kitanishi et al. .
`424/494
`5,011,692 A
`4/1991 Fujioka et al.
`424/426
`5,110,597 A
`5/1992 Wong et al. .............. .. 424/438
`
`*
`
`5/1993 Bar-Shalom et al. ..... .. 424/473
`7/1993 Amidon et al. ........... .. 424/451
`3/1995 Kotwaletal. ......... .. 424/472
`gllllotclllestetlal
`5/1995 Schneider et al. ........ .. 514/535
`8
`.
`.
`/1995 Paradissis et al. ........ .. 424/480
`10/1995 Radebaugh et al. ...... .. 424/465
`12/1995 Chen ........................ .. 424/451
`
`e
`
`e a. . . . . . . . .
`
`. . . ..
`
`4/1996 Chen . . . . . . . .
`
`. . . .. 424/451
`
`514/53
`* 7/1996 Koch et al. ..
`10/1996 Chen ................. .. 424/494
`9/1997 Digenis et al.
`424/463
`2/1998 Lin et al. ................. .. 514/50
`10/1998 Morrison et al.
`424/450
`
`11/1998 Bai . . . . . . . . . . . . .
`
`. . . .. 424/458
`
`3/1999 Sarangapani .
`* 3/1999 Zopfetal.
`6/1999 Rivett et al. .
`2/2000 Conte et al. .
`* 9/2000 Wong et al. .
`
`10/2000 Depui et al. . . . . .
`9/2001 Conley et al.
`
`524/139
`..... .. 514/25
`424/484
`424/458
`424/473
`
`. . . .. 424/468
`424/468
`
`,
`
`,
`
`5,414,014
`5 445 829
`,
`,
`5,462,747
`5,472,708
`
`5,508,040
`
`5,538,954
`5,567,441
`5,672,359
`5,719,132
`5,827,531
`
`5,840,329
`
`5,877,243
`5,883,079
`5,910,322
`6,027,748
`6,120,803
`
`6,132,771
`6,294,199 B1
`
`6,358,525 B1
`3/2002 Guo et al. . . . . . . .
`. . . . . . .. 424/464
`2001/0046984 A1 11/2001 Rudnic et al. ....... .. 514/210.09
`2001/0048944 A1 12/2001 Rudnic et al. ............ .. 424/468
`
`2002/0004070 A1
`2002/0004499 A1
`
`1/2002 Rudnic et al. . . . . . .
`. . . .. 424/468
`1/2002 Rudnic et al. ............ .. 514/192
`
`FOREIGN PATENT DOCUMENTS
`
`W0
`W0
`W0
`W0
`
`WO 94/27557
`WO 95/20946
`WO 96/04908
`WO 98/22091
`
`* cited by examiner
`
`12/1994
`8/1995
`2/1996
`5/1998
`
`Primary Examiner—Thurman K. Page
`Assistant Examiner—Sharmila Gollamudi
`(74) Attorney, Agent, or Firm—Elliot M. Olstein; Raymond
`E. Stauffer
`
`(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 Cmwc
`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 Cmwc at
`different times.
`
`40 Claims, No Drawings
`
`1
`
`

`

`US 6,730,320 B2
`
`1
`TETRACYCLINE ANTIBIOTIC PRODUCT,
`USE AND FORMULATION THEREOF
`
`This application is a continuation-in-part of US. appli
`cation Ser. No. 09/792,092, ?led on Feb. 22, 2001, 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.
`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.
`AWide 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.
`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
`pro?le.
`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.
`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.
`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 ?ve dosage forms With different release times.
`In accordance With a preferred embodiment, the antibi
`otic 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.
`In accordance With one preferred embodiment of the
`inventions 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 anti
`biotic 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 Cmwc
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`(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 Cmwc in the serum, and the antibi
`otic 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 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.
`In general, the immediate release dosage form produces
`a Cmwc 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 Cmax for the
`antibiotic released therefrom in no more than about four
`hours. In general, the Cmax 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 Cmax 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
`Cmwc at a time later than the Cmax is achieved for the
`antibiotic released from each of the ?rst 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 ?rst 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 pro?les, Whereby the antibi
`otic 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 pro?le, 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 anti
`biotic being released in a manner such that overall antibiotic
`release is effected With different release pro?les in a manner
`such that the overall Cmwc a 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.
`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
`
`2
`
`

`

`US 6,730,320 B2
`
`3
`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 “leak
`age” 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 Cmwc
`of the fourth dosage form of the at least four dosage forms
`is reached after the Cmwc 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 of the present invention, as here
`inabove 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 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 administration
`by including such dosage forms in an oil-in-Water emulsion,
`or a Water-in-oil emulsion. In such a formulation, the imme
`diate 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 ?rst 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 pro?les, 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 of the emulsion.
`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.
`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
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`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.
`Alternatively, in formulating an oral delivery system,
`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 herein
`above described, Whereby the Cmax of the antibiotic released
`from each of the tablets is reached at different times, With the
`Cmwc 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 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.
`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.
`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 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, 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.
`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.
`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 component
`provides from 20% to 40%, by Weight, of the antibiotic
`
`3
`
`

`

`US 6,730,320 B2
`
`5
`provided by the three delayed release components and the
`last in time providing the remainder of the antibiotic pro
`vided 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 of the 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 admin
`istration 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, hydroxypropylmethyl
`cellulose, hydroxyethylcellulose, ethylcellulose, chitosan,
`hydroxychitosan, hydroxymethylatedchitosan, cross-linked
`chitosan, cross-linked hydroxymethyl chitosan,
`maltodextrin, mannitol, sorbitol, dextrose, maltose, fructose,
`glucose, levulose, sucrose, polyvinylpyrrolidone (PVP),
`acrylic acid derivatives (Carbopol, Eudragit, etc.), polyeth
`ylene 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%
`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 administra
`tion. 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 imme
`diate 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, paraf?n, acrylic acid
`derivatives (Eudragit), propylene glycol, and ethylcellulose.
`Typically these materials can be present in the range of
`0.5—25%
`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%
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`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,hydroxypropylmethyl
`cellulose,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%
`As hereinabove indicated, the units comprising the anti
`biotic 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, ce?xime, 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 V, 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, piper
`acillin and taxobactam, ticarcillin, ticarcillin and clavulanate
`potassium, clindamycin, vancomycin, novobiocin, ami
`nosalicylic 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, sulfamethixole, sulfasalaZine, sul?soxaZole,
`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 of the invention is
`not limited thereby. All percentages in this speci?cation,
`unless otherWise speci?ed, are by Weight.
`EXAMPLES
`Immediate Release Component
`Formulate the composition by mixing the ingredients in a
`suitable pharmaceutical mixer or granulator such as a plan
`
`4
`
`

`

`US 6,730,320 B2
`
`7
`etary mixer, high-shear granulator, ?uid 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
`
`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:
`
`65% 20
`
`10
`5
`
`55% 25
`
`10
`10
`
`65% 20
`
`10
`5
`
`75% 10
`
`10
`5
`
`Amoxicillin
`Polyethylene glycol 8000
`Polyvinylpyrrolidone
`
`Example 6:
`
`75% (W/W)
`20
`5
`
`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:
`
`Cipro?oxacin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`Example 11:
`
`Cipro?oxacin Microcrystalline cellulose
`
`Hydroxypropylcellulose
`Croscarmellose sodium
`Example 12:
`
`
`
`Cipro?oxacin Polyethylene glycol 4000
`
`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
`
`8
`
`-continued
`
`Ingredient
`
`Conc. (% W/W)
`
`Polyethylene glycol 2000
`Hydroxypropylcellulose
`Example 13:
`
`Cipro?oxacin Polyethylene glycol 8000
`
`Polyvinylpyrrolidone
`
`Example 14:
`
`Ceftibuten Polyethylene glycol 4000
`
`Polyethylene glycol 2000
`Hydroxypropylcellulose
`Example 15:
`
`Ceftibuten Polyethylene Glycol 4000
`
`Polyvinylpyrrolidone
`
`10
`5
`
`75% 20
`
`5
`
`75% 10
`
`10
`5
`
`75% 20
`
`5
`
`non-pH Sensitive Delayed Release Component
`Formulate the composition by mixing the ingredients in a
`suitable pharmaceutical mixer or granulator such as a plan
`etary mixer, high-shear granulator, ?uid 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.
`
`10
`
`15
`
`20
`
`25
`
`30
`
`35
`
`Ingredient
`
`Conc. (% W/W)
`
`Example 16:
`
`Amoxicillin
`Microcrystalline cellulose
`Polyox
`Croscarmellose sodium
`Example 17:
`
`Amoxicillin
`Microcrystalline cellulose
`Polyox
`Glyceryl monooleate
`
`Example 18:
`
`Amoxicillin
`Polyox
`Hydroxypropylcellulose
`Croscarmellose sodium
`Example 19:
`
`Clarithromycin
`Polyox
`Hydroxypropylcellulose
`Croscarmellose sodium
`
`65%
`20
`10
`5
`
`55%
`25
`10
`10
`
`65%
`20
`10
`5
`
`70%
`20
`5
`5
`
`Enteric Release Component
`Formulate the ingredients by mixing the ingredients in a
`suitable pharmaceutical mixer or granulator such as a plan
`etary mixer, high-shear granulator, ?uid 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.
`
`40
`
`45
`
`50
`
`55
`
`60
`
`65
`
`5
`
`

`

`US 6,730,320 B2
`
`9
`
`Ingredient
`
`Conc. (% W/W)
`
`Example 20:
`
`Amoxicillin
`Microcrystalline cellulose
`Cellulose Acetate Pthalate
`Example 21:
`
`Amoxicillin
`Microcrystalline cellulose
`Cellulose Acetate Pthalate
`Hydroxypropylmethylcellulose
`Example 22:
`
`Amoxicillin
`Polyox
`Hydroxypropylcellulose pthalate
`Eudragit L30D
`
`Example 23:
`
`Amoxicillin
`Microcrystalline Cellulose
`Cellulose Acetate Pthalate
`Example 24:
`
`Clarithromycin
`Hydroxypropylcellulose pthalate
`Croscarmellose sodium
`Example 25:
`
`Clarithromycin Polyethylene glycol 2000
`
`Eudragit E 30D
`
`Example 26:
`
`Clarithromycin Lactose
`
`Eudgragit L 30D
`
`Example 27:
`
`Cipro?oxacin
`Microcrystalline Cellulose
`Eudragit L 30D
`Example 28:
`
`Cipro?oxacin
`Microcrystalline Cellulose
`Hydroxypropylcellulose pthalate
`Example 29:
`
`Cipro?oxacin
`Lactose
`Eudgragit L 30D
`
`Example 30:
`
`Cipro?oxacin
`Polyethylene glycol 4000
`Cellulose acetate pthalate
`Example 31:
`
`Ceftibuten Polyethylene glycol 2000
`
`Lactose
`Eudragit L 30D
`
`Example 32:
`
`Ceftibuten Microcrystalline cellulose
`
`Cellulose acetate pthalate
`
`65%
`20
`15
`
`55%
`25
`10
`10
`
`65%
`20
`10
`5
`
`40%
`40
`10
`
`70%
`15
`10
`
`75% 10
`
`15
`
`40% 50
`
`10
`
`65%
`20
`10
`
`75%
`15
`10
`
`80%
`10
`10
`
`70%
`20
`10
`
`60% 10
`
`20
`10
`
`70% 20
`
`10
`
`10
`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
`
`Conc. (% W/W)
`
`Example 33:
`
`Amoxicillin Ethylcellulose
`
`Polyox
`Hydroxypropylmethylcellulose
`Example 34:
`
`Amoxicillin Lactose
`
`Polyox
`Glyceryl monooleate
`
`Example 35:
`
`Amoxicillin Polyox
`
`Hydroxypropylcellulose
`Example 36:
`
`Clarithromycin Lactose
`
`Hydroxypropylcellulosee
`Ethylcellulose
`
`Example 37:
`
`Clarithromycin Polyethylene glycol 4000
`
`Lactose
`Eudragit RL 30D
`
`Example 38:
`
`Clarithromycin
`Polyethylene glycol 8000
`Hydroxypropylmethylcellulose
`Eudgragit RS 30D
`
`Example 39:
`
`
`
`Cipro?oxacin Hydroxyethylcellulose
`
`Polyethylene glycol 4000
`Hydroxypropylcellulose
`Example 40:
`
`
`
`Cipro?oxacin Lactose
`
`Povidone (PVP)
`Polyethylene glycol 2000
`Example 41:
`