Note: Descriptions are shown in the official language in which they were submitted.
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PFLARMACEUTICAL COMPOSITIONS AND METHODS
FOR IMPROVED BACTERIAL ERADICATION
By: Henry H. Flarmer, M.S.; Robert J. Guttendorf, Ph.D.; Susan P.
Clausen, Ph.D.;
Donald Treacy, Ph.D. and Beth A. Burnside, Ph.D.
This invention is directed to compositions and methods for improving the
efficacy of time-
dependent antibiotics when used in the treatment of humans or animals having
bacterial infections.
As used herein the term "time-dependent antibiotic" shall denote those
antimicrobial compounds in
general, and antibiotics in particular, having an efficacy that is believed to
be more dependent on the
daily time that the compound's concentration is above the minimum inhibitory
concentration (MIC)
rather than the number of multiples of that MIC achieved. Non-limiting
examples of such time-
dependent antibiotics shall include the penicillins, the beta-lactams, the
cephalosporins, and the
carbapenams. This invention is particularly directed to compositions and
methods for improving the
efficacy of beta-lactam antibiotics when used in the treatment of humans or
animals having bacterial
infections. This invention is more particularly directed to compositions and
methods for improving
the efficacy of arnoxicillin and cephalexin when either is used in the
treatment of humans or animals
having bacterial infections.
In the bacterial infection treating discipline it has been widely accepted
that the efficacy of
any given dosing regimen utilizing a time-dependent antibiotic is founded upon
achieving and / or
maintaining a minimum inhibitory concentration (MIC) of the time-dependent
antibiotic (not bound
to serum proteins) for a certain minimum percentage of time in a day (i.e. a
Daily T>MIC). (See
Auckenthaler R, Pharmacokinetic and pharmacodynamics of oral beta-lactam
antibiotics as a two-
dimensional approach to their efficacy; J Antimicrob Chemother. 2002 Jul; 50
Supp1:13-7). (See
also V anderkooi 0, Low D, Antimicrobial Resistance and the Pneumacoccus,
Infectious Diseases
and Microbiology Rounds, May 2004, Vol. 3, Issue 5).
The instant invention provides both new and improved therapeutic paradigms and
products
for use with a given time-dependent antibiotic against a given bacterial
pathogen having a known, or
determinable, MIC for the given (or predictably similar acting) time-dependent
antibiotic, which
paradigms and products are derived from Applicants' development of a unique
model parameter.
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=
This model parameter may serve as a more accurate barometer for predicting the
efficacy of a given
dosing regimen than has the prior art's heretofore and enduring focus on daily
T>MIC.
In accordance with an aspect of the present invention, there is provided a
product and
treatment regimen for use of a time-dependent antibiotic for treating a
bacterial infection, in which
the treatment is based on achieving a Total T>MIC to achieve a desired result,
generally a percent
eradication (or clinical outcome) of the bacterial pathogen that causes the
infection.
The course of treatment may be determined for a specified dosage of antibiotic
and for the
MIC of the bacteria being treated by such antibiotic.
Based on PK data for the antibiotic of interest (or a closely related
antibiotic) and the
specified dosage, the daily time over MIC is determined.
In addition, based on actual treatment data (e.g., clinical trial data) for
such antibiotic (or
closely related antibiotic) there is determined the percent eradication (or
clinical cure rate) of the
bacteria over the specified course of treatment at a specified dosage.
By using (1) the daily time over MIC (Daily T>MIC) determined from the PK data
and (2)
the percent eradication (or clinical cure rate) over the course of treatment
reported in the actual
treatment, the total time over MIC (Total T>MIC) that achieved the bacterial
eradication (or clinical
cure rate) can be determined.
Such data is then plotted and art-recognized techniques may be used to
establish an equation
based on the data.
=
By way of mathematical and statistical modeling Applicants calculated the
actual
pharrnacokinetic (PK) curves from the data from their own failed amoxicillin
Phase III Trial against
Streptococcus pyogenes, and from the data of published studies. Those
published studies used
various dosing regimens of penicillin VK also against Streptococcus pyogenes.
This modeling led
to Applicants' novel finding that duration of the dosing regimen is a
statistically important factor in
the bacterial eradication rate.
=
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From those actual pharmacokinetic curves Applicants have developed their model
parameter
that takes dosing regimen duration into account as a determinant of bacterial
eradication, while
providing an excellent fit to the (PK) data of Applicants own failed
amoxicillin Phase III Trial and
to the (PK) data of the literature Applicants surveyed. Applicants have termed
this novel treatment
duration-encompassing model parameter as "Total T>MIC," which they define by
the general
equation:
Total 'T>MIC = Daily T>MIC x Duration of Dosing Regimen
Thus, the Total T>MIC parameter includes both Daily T>MIC and Duration in a
single
parameter that provides a better model and explanation of the eradication rate
of various regimens
than either Daily T>MIC or Duration alone.
In accordance with one aspect of the method of the instant invention actual
pharmacokinetic
(PK) data is used to determine the concentration in serum of a drug at a given
dosage, so as to
further determine the Daily T>MIC provided by the drug at that given dosage.
Studies reported in
the literature are then consulted to determine. the number of days that the
drug was used at that given
dosage to obtain a percent eradication. Based on the number of days of
duration and the PK data,
Applicants have found that they can then calculate the Total T>MIC that
provides that percent
eradication.
In another aspect this invention relates to an antibiotic product, to its
formulation, and to its
use in treating bacterial infections. Particularly, this invention relates to
an antibiotic product that
contains a penicillin-type antibiotic, as well as to the product's formulation
and to its use in treating
bacterial infections, wherein the infecting pathogen has an MIC90 > 0.06
ptg/mL. for the penicillin-
type antibiotic used. More particularly, this invention relates to such an
antibiotic product that
contains a beta-lactam antibiotic, as well as to the product's formulation and
to its use in treating
bacterial infections. Still more particularly, this invention relates to such
a product that contains
amoxicillin, to the product's formulation, and to the product's use in
treating bacterial infections.
In accordance with an aspect of the invention there is provided a once-a-day
penicillin-type
antibiotic product for treating a bacterial infection in a patient or subject,
comprising a penicillin-
type antibiotic composition.
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In accordance with a further aspect of the invention the penicillin-type
antibiotic composition
comprises at least one dosage form, which dosage form comprises at least one
penicillin-type
antibiotic and a pharmaceutically acceptable carrier. The dosage form(s) is /
are formulated such
that when the penicillin-type antibiotic composition is administered to a
patient or subject in need
thereof, the composition provides (or maintains) a concentration of the given
penicillin-type
antibiotic in the serum at or above the MIC90 for an infecting bacterial
pathogen for at least 5 hours
within a 24-hour dosing interval. The dosage form(s) is / are further
formulated such that the
penicillin-type antibiotic composition provides (and preferably maintains) a
serum concentration of
the given penicillin-type antibiotic that is > 0.06 1.1g/mL., and such that
the penicillin-type antibiotic
composition contains the total dosage of the given penicillin-type antibiotic
for a 24-hour dosing
interval.
In a further aspect, the once-a-day pharmaceutical formulation providing a
daily dosage of
penicillin-type antibiotic such as to provide (or maintain) a serum
concentration of penicillin-type
antibiotic in a patient or subject at or above a bacterial pathogen's drug-
specific MIC90 for at least
five hours (preferably for at least five consecutive hours) of a 24-hour
dosing interval, comprises a
modified release dosage form(s) or an immediate release dosage form(s) in
combination with a
modified release dosage form(s), with such modified release dosage form(s)
being: a delayed
release dosage form(s), a sustained (or extended) release dosage form(s), and
/ or combinations of
the forgoing. Such sustained (or extended) release dosage forms may be
formulated so that
initiation of release of the penicillin-type antibiotic therefrom is not
substantially delayed after
administration of the penicillin-type antibiotic composition or it may be
formulated so that initiation
of release of the penicillin-type antibiotic therefrom is substantially
delayed after administration of
the penicillin-type antibiotic composition.
In accordance with a still further aspect of the invention the penicillin-type
antibiotic
composition may be labeled for use. Such labeling for use may comprise
directives conveyed in any
tangible or verbal medium of expression to administer the composition once-a-
day to a patient or
subject in need thereof, to treat an indication known, or suspected, to be
caused by a bacterial
pathogen, known, or suspected, to have an MICK, > 0.06 pg/mL. for the
penicillin-type antibiotic
used. As non-limiting examples of the forms in which and / or on which the
labeling for use of the
penicillin-type antibiotic composition may be expressed there may be
mentioned: prescriptions;
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protocols; labels; packaging; packaging inserts; coatings; embossings;
scorings; trademarks
and/or trade-dress, or portions thereof such as by way of marks and/or dress,
or portions
thereof, denoting daily, once-a-day, one-a-day, 24-hour, and like marks and/or
like dress, or
portions thereof imprinted blister packets; capsule shells; and combinations
of the foregoing.
In a preferred embodiment of the once-a-day product the penicillin-type
antibiotic composition is formulated so as to maintain a concentration of the
penicillin-type
antibiotic in the serum of the patient or subject at or above the MIC90 of the
infecting bacterial
pathogen for that penicillin-type antibiotic for at least five consecutive
hours out of a 24-hour
dosing interval.
As referred to herein, and as is known in the art, the term "MIC90" refers to
the
minimum concentration of a specific antibiotic that is required to inhibit the
growth of ninety
percent (90%) of the strains of a specific microoganism (bacterial pathogen)
species.
As referred to herein, and as is known in the art, the term "penicillin-type
antibiotic" generally and broadly refers to an antibiotic from the penicillin
class of antibiotics,
and shall include beta-lactams, such as amoxicillin.
According to one aspect of the present invention, there is provided a once-a-
day amoxicillin antibiotic product comprising; first, second, and third
amoxicillin antibiotic
dosage forms, each of said amoxicillin antibiotic dosage forms comprising at
least one
amoxicillin antibiotic and a pharmaceutically acceptable carrier, said first
amoxicillin
antibiotic dosage form being, an immediate release dosage form, said second
and third
amoxicillin antibiotic dosage forms being delayed release dosage forms,
wherein said second
amoxicillin antibiotic dosage form comprises amoxicillin coated with a
methacrylic acid
copolymer dispersion, wherein the methacrylic acid copolymer dispersion
comprises
Eudragit0 L30D-55, and said third amoxicillin antibiotic dosage form comprises
amoxicillin
coated with a first layer of the methacrylic acid copolymer dispersion and a
second layer of
AQOAT AS-HF, and wherein each of said first, second, and third amoxicillin
antibiotic
dosage forms is for initiation of release at different times and Cmax of the
total amoxicillin
antibiotic for release from said amoxicillin antibiotic product is for
achievment in less that 12
hours from administration; wherein said product contains the total dosage of
amoxicillin, for
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a 24-hour dosing interval.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 is a graphical representation showing four different model fits of
data,
a portion of which is shown in Table 1, wherein percentage of bacterial
eradication is
expressed as functions of Total T>MIC.
Figure 2 is a graphical representation showing plots of fractional daily T>MIC
plotted against the duration of treatment, wherein the various plots are the
plots at different
percentages of bacterial eradication.
Figure 3 is a flow chart illustrating the general procedure to make a
multiparticulate tablet.
DETAILED DESCRIPTION OF THE INVENTION
In the treatment of bacterial infections, penicillin-type antibiotics, such as
beta-
lactams, are generally dosed in formulations that require multiple
administrations over the
course of any given 24-hour period. As is known in the art, such dosing
regimens may be
twice-a-day (b.i.d.), whereby the composition is administered every 12 hours;
three times
daily (t.i.d.), whereby the composition is administered every 8 hours; four
times daily (q.i.d.),
whereby the composition is administered every 6 hours; or such dosing regimens
may even
conceive of dosing the composition in excess of four administrations per day.
Repeated
administrations of a drug throughout a 24-hour period may be disruptive to
meals or sleep,
thereby presenting a significant inconvenience for patients. In the treatment
of elderly or
incapacitated patients multiple administration regimens can result in poor
compliance, and
hence an ineffective treatment of the infection. Existing immediate release
and modified
release amoxicillin formulations are designed and intended to be administered
at least twice-a-
day or more, to thereby prolong delivery of the drug throughout the duration
of a 24-hour
period. Some of these formulations contain relatively high doses of
amoxicillin that can
exacerbate untoward gastrointestinal side effects, including nausea and
diarrhea.
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Accordingly, there is a need in the art for effective once-a-day compositions
and regimens,
that would allow for less frequent dosing, but would neither compromise the
effectiveness of the
given antibiotic, nor require such a high dosage thereof as would exacerbate
side effects or multiply
production costs.
General Description of the Total T>MIC Aspects of the Invention
The data necessary for a determination of this modeling parameter such as
drug, regimen,
Days Tx, and Eradication are culled from the studies published in the
literature, or otherwise known
to the formulation artisan from clinical trials or similar sources. Table 1 is
a compilation of a
portion of the data from the various penicillin VK / Streptococcus pyogenes
studies that the
Applicants utilized to calculate the actual pharmacokinetic curve and to
develop the Total T>MIC
model parameter.
=
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Table 1.
Mug Regimen MIC-9Q Pally T>MIC Days Ta %Erad Total
T>M1C RQt
Pen VK 500 TID 0.015 48.10% 0 7 0 Zwart et al. BMJ 2000
Pen VK 500 TID 0.015 48.10% 3 41 1.443 Zwart et A810.12000
Peri VK 500 TID 0.015 48.10% 7 72 3.367 2wart et al, EIMJ
2000
Pen VK 500 TID 0.015 48.10% 10 89 4.81 Ketek SBA: Norrby et
al. Scand J Infect DIs 2001
Pen VK BOO TID 0.015 49.80% 10 86 4.98 Carbon et al, J
Antanicrob Chemother 1995
Pan VK 250 010 0.015 55.30% 10 100 5.53 McCarty 1993
Pen VK 25001D 0.015 65.30% 10 85.5 5.53 Milner 1 992
Pen VK 250010 0.03 48.40% 10 82 4.54 OrnnIcef label: Tack
et al, AAC 1998
Pen VK 250 T1D 0.015 39.29% 10 98 3.929 Gerber et at. AMC
1987
Pen VK 250T10 0.015 39.29% 6 92 1.9645 Gerber et al, A-MC
1987
Pen VK 800 010 0.015 35.00% 10 94 3.5 Stromberg et al, Scand
J Infect DIs 1988
Pen VK 800 81D 0.015 3.6.00% 5 73 1.75 Stromberg et al,
Scand J Infect Ns 1988
Pen VK 750 00 0.015 17.30% 10 82 1.73 Garber et al, AJDC
1989
= "Zwart et al, BMJ 2000" is Zwart S, Sachs AP, Ruijs GJ, Gubbels JW, Hoes
AW, de
Melker RA; Penicillin for acute sore throat: randomised double blind trial of
seven days versus
three days treatment or placebo in adults; BMJ; 2000 Jan 15; 320(7228):150-4.
= "Norrby et al, Scan J Infect Dis 2001" is Norrby SR, Rabie WJ, Bacart P,
Mueller 0,
Leroy B, Rangaraju M, Butticaz-Iroudayassamy E; Efficacy of short-course
therapy with the
ketolide telithromycin compared with 10 days of penicillin V for the treatment
of
pharyngitis/tonsillitis; Scand J Infect Dis; 2001; 33:883-890.
= "Carbon et al, J Antimicrob Chemother 1995" is Carbon C, Chatelin A,
Bingen E,
Zuck P, Rio Y, Guetat F, Orvain J, A double-blind randomized trial comparing
the efficacy
and safety of a 5-day course of cefotiam hexetil with that of a 10-day course
of penicillin V in
adult patients with pharyngitis caused by group A beta-haemolytic
streptococci; J Antimicrob
= Chemother; 1995 Jun; 35(6):843-54.
= "McCarty 1993" is McCarty JM; Comparative efficacy and safety of
cefprozil versus
penicillin, cefaclor and erthyromycin in the treatment of streptococcal
pharyngitis and
. tonsillitis; Eur J Clin Microbiol Infect Dis; 1994 Oct; 13(10):846-50.
= "Muller 1992" is Muller 0, Spirer Z, Wettich K.; Loracarbef versus
penicillin V in the
treatment of streptococcal pharyngitis and tonsillitis; Infection; 1992 Sep-
Oct; 20(5):301-8.
= "Tack et al, AAC 1998" is Tack KJ, Hemy DC, Gooch WM, Brink DN,
Keyserling
CH, and The Cefdinir Pharyngitis Study Group; Five-Day Cefdinir Treatment for
= Streptococcal Pharyngitis; Antimicrob. Agents Chemother; May 1998;
42:1073-1075.
= "Gerber et al, AJDC 1987" is Gerber MA, Randolph MF, Chanatry J, Wright
LL, De
Meo K, Kaplan EL; Five vs ten days of penicillin V therapy for streptococcal
pharyngitis; Am
J Dis Child; 1987 Feb; 141(2):224-7.
= "Stromberg et al, Scand J Infect Dis 1988" is Stromberg A, Schwan A, Cars
0; Five
versus ten days treatment of group A streptococcal pharyngotonsillitis: a
randomized
controlled clinical trial with phenoxymethylpenicillin and cefadroxil; Scand J
Infect Dis; 1988;
20(1):37-46.
= "Gerber et al, AJDC 1989" is Gerber MA, Randolph MF, DeMeo K, Feder HM
Jr.,
Kaplan EL; Failure of once-daily penicillin V therapy for streptococcal
pharyngitis; Am J Dis
Child; 1989 Feb; 143(2):153-5.
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Fig. 1 shows four different model fits of data a portion of which is shown in
Table 1 wherein
% bacterial eradication is expressed as functions of Total T>MIC. Fig. 1 also
graphically illustrates
how the model may be used to select regimens having adequate doses (which
relate to the Daily
T>MIC) and sufficient Durations (more importantly), so as to achieve desired
eradication of
= Streptococcus pyogenes, or desired eradication of other infectious
microbial species that have been
similarly studied in existing literature and / or clinical trials, or that may
be similarly studied in
future literature and / or clinical trials.
=
It should be understood that in accordance with the invention, the model
parameter, Total
.-T>MIC, can be accurately related to the observed eradication of various
regimens through various
mathematical equations and functions. For the data presented in Figure 1
either a simple Emax
model or a sigmoid Emax model can provide an adequate fit. However, in
accordance with the
invention there are manifold mathematical models and relationships that can be
used to provide an
adequate relationship of Total T>MIC to % Eradication, as is demonstrated by
the four different
model fits shown in Figure 1. One of ordinary skill in the art of PK / PD
modeling will select which
model is appropriate for the given=data set depending on his experience, the
type and origin of the
data, and a variety of statistical measures such as akaike information
criterion, root mean square
error, r2, residual analysis, and others. The artisan of ordinary skill in PK
/ PD modeling will
appreciate that very often more than one mathematical model form can provide
an adequate fit.
Example 1
Total T>MIC in a Simple Emax Model or Sigmoid Emax Model
Determination of the Total T>MIC parameter requires two separate tennis,
Duration and
Daily T>MIC. Both of these are derived from the dosing regimen or clinical
trial studied and / or
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53449-9
reported in the literature. For example, some of the data in Figure 1 is
presented in tabular form in
Table 1 above.
The information in Table 1 was collected from several studies published in the
literature.
Information such as drug, regimen, Days Tx and Eradication can be taken
directly from the literature
articles. Information such as the MIC will often have been determined as part
of the study and may
be reported in the article, but in many cases it may not have been determined
or reported. In those
cases wherein the MIC was not determined and reported Applicants assumed that
the MIC was
equal to 0.015 g/mL, the MIC determined in the Phase III Clinical Trial
conducted by Applicants.
The Daily T>MIC must also be calculated for each different regimen, and at the
relevant
MIC. This information was not presented in any of the articles and so it was
calculated by
Applicants. The Daily T>MIC is calculated for each regimen by creating a
plasma profile from
pharmacokinetic data published in the literature. Prior to creating the plasma
profile a
pharmacokinetic model is developed from plasma profiles from one or more doses
reported in the
literature. The PK model is first checked for accuracy against the profiles
used in the derivation of .
the model and then the PK profile of regimens for which actual plasma data do
not exist are
simulated so that the Daily T>MIC may be calculated. The models are industry
standard
compartmental models, generated with WinNonlin, a common program used in the
pharmaceutical
industry for pharmacokinetic analysis and modeling.
Once the Daily T>MIC for each regimen has been calculated, the Total T>MIC is
calculated
by multiplying the Daily T>MIC by the Duration of Therapy (Days Tx in the
table). Thus a
composite parameter, Total T>MIC, is constructed that includes both factors
relevant to eradication
of Streptococcus pyogenes by a given regimen. The equation can then be used to
determine the
Total T>MIC required to achieve eradication rates > 85% (or any other desired
eradication rate).
Penicillin and amoxicillin are both beta-lactam antibiotics and have the same
mechanism of
action against Streptococcus pyogenes. Therefore, the pen VK Total T>MIC model
can be applied
to assist in the prediction or selection of the appropriate dosing regimen of
amoxicillin PulsysTM.
The PulsysTm technology is illustrated in U.S. Patent 6,544,555.
Applicants found that when the Daily T>mic of
Applicants' once-daily 775 mg tablets and the clinical trial's 7 day dosing
Duration were plugged
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into the Total T>MIC model the predicted eradiation rate was 87%. The actual
eradication rate was
77% . thus the prediction is within the error of
the model.
In order to determine the optimum dose and duration of amoxicillin PU1SYSTM
the Daily
T>MIC of amoxicillin was obtained from phannacokinetic studies conducted by
Applicants on
various amoxicillin PulsysTM formulations. Bearing in mind that it is
desirable from therapy
compliance, convenience, and marketing perspectives to keep the duration of a
dosing regimen to 10
days or less, Applicants selected a formulation that provided a Daily T>MIC
that when multiplied
by 10 days of Duration exceeded the Total T>MIC corresponding to an 85%
(actually 90% was used
to provide a margin of error) eradication rate.
Emax is a typical model used to describe pharmacodymic relationships between a
parameter
of interest and a pharmacodynamic effect. Illustrating an aspect of the
instant invention a simple
Emax model provides an excellent relationship between the Total T>MIC
parameter and the
eradication rate.
In accordance with an aspect of one embodiment of the instant invention a
simple Emax
>model takes the following mathematical form:
E = E0 + (Emax ¨ E0)*(TotalT>MIC/(Total T>MIC + Total T>MIC50)
wherein,
E is the % eradication, these values are taken from the reference data set;
E0 is the % eradication at Total T>MIC of 0, i.e. spontaneous eradication or
placebo effect;
Emax is the maximimum eradication, set to a constant 100% in the model;
Total T>MIC is the parameter calculated by multiplying daily T>MIC times the
number of days the product was administered; and
Total T>MIC50 is a fitted parameter that corresponds to Total T>MIC where
E=50%.
In development of the above equation for a given set of reference literature
data, a computer
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program such as WinNonlin, Statgraphics, SigmaPlot, SAS, JMP, Excel or other
modeling software
is employed to fit the parameters EO and Total T>MIC50. For the data in Figure
1 the fitted Emax
model was determined to be:
%Eradication = 5.75 + 94.3*Total 'T>MIC/(Total T>MIC + 0.74)
This equation can now be utilized to solve for the optimum duration to achieve
a given
eradication rate. This is especially useful for developing novel products,
because once the daily
time above MIC of the novel product is determined, the number of studies
required to determine an
effective dosing regimen can be greatly reduced, thus saving valuable time to
market and clinical
study costs. It is to be understood that the constants of the hereinabove
equation will vary
depending on the drug formulation that is used.
Example 2
General Linear Modeling Methodology
As earlier noted, alternative modeling methodologies may also be employed in
practicing the
:instant invention. One such method is termed general linear modeling (GLM)
and is a common
method for developing models that include multiple variables. The advantage of
GLM is that each
of the important variables, Duration and Daily T>MIC, are modeled
independently and do not have
to be combined into a single composite factor. In application of the GLM with
2 variables (Duration
and Daily T>MIC) the data are handled in 3 dimensions, instead of 2 as for the
Total T>MIC case.
This can lead to a greater understanding of the relationship between Duration
and Daily T>MIC, and
detection of possible synergistic effects not detected in the single variable
model. To illustrate this
two dosing regimens may be considered, wherein Formulation A provides 100%
Daily T>MIC and
is administered for 5 days thereby providing a Total T>MIC of 5 days; and
wherein Formulation B
provides 50% Daily 'T>MIC and is administered for 10 days thereby providing a
Total T>MIC of 5
days. There is no guarantee that the eradication rate from both regimens would
be equivalent, but
the Total T>MIC model would predict them to be equivalent. The GLM model would
have two
different points on a 3 dimensional surface for the two regimens in question,
thus the GLM model is
able account for effects not detectable in the single parameter Total 'T>MIC
model. In fact, the
synergy term in the GLM is actually the Total T>MIC parameter. A contour plot
of the response
surface from the GLM approach for the data shown in Figure 1 is provided below
in Figure 2.
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Succinctly, GLM is a statistical modeling approach based on the determination
of significant
factors in a data set, and finding coefficients to those factors that fit the
data. A benefit of this type
of approach when used for the data in Figure 1 is that it breaks the Total
T>MIC into its component
parts, daily T>MIC and Duration, and weights each according to the data. Total
T>MIC may also
be included in the model as an interaction term if it is determined be a
significant factor. In this
approach there is no specific model form as there is with the Emax model: the
model form is based
on the analysis of data and can take many forms such as a simple linear or
complex polynomial
form. Typically a statistical software package, such as Statgraphics, SAS,
IMP, Statistica, or
Minitab is used to develop a GLM. For the data in Figure 1 a general linear
model approach yielded
the following equation:
% Eradication = 6.81 *Duration + 0.48*Daily T>MIC
wherein,
% Eradication is the eradication rate;
Duration is the number of days the dose is administered; and
Daily T>MIC is the percent T>MIC per day provided by the dose regimen.
The GLM equation may now be solved as the Emax model above to derive the
optimum
duration given a T>MIC or the required daily T>MIC for a known duration. This
model approach
provides an improved ability to fit effects that are dependent upon more than
one factor. The Total
T>MIC is such a parameter because it is actually made up of two factors,
duration and daily T>MIC.
The GLM provides a means to generate different eradication rates in the case
where two regimens
provide the same Total T>MIC, such as when a product with 50% daily T>MIC is
administered for
days versus a product with a 100% daily T>MIC administered for 5 days.
Figure 2 illustrates the strong effect of Duration on % eradication. Relative
changes in
Duration increase % eradication more than the same magnitude of change in
Daily T>MIC. To
Applicants' knowledge this effect has never been disclosed previously and is
the basis for changing
the amoxicillin PulsysTM regimen from 7 days to 10 days.
11
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Example 3
Modified Multiple Parameter Emax
One potential limitation of the GLM approach is that in the case of lower
order models there
is a potential for the predicted effect to go above the maximum allowable
effect, e.g. 100%
eradication. In. order to overcome this limitation, the inventors have
modified the simple Emax
model to be able to incorporate more than just the Total T>MIC term. This
improved equation
provides the ability to model each important term in the data set, Duration,
Daily T>MIC and Total
T>MIC, thus best fitting each data point in the appropriate factor space, but
adding the maximum
effect limitation, e.g. 100% eradication. The equation has the same form as
the simple Emax model,
except that the Total T>MIC50 term is changed to a term that incorporates the
Duration and the
Daily T>MIC, as shown below:
E = EO + (Emax-E0)*(Total T>MIC)/(Total T>MIC + (a + b*Duration + c*Daily
T>MIC))
wherein,
E = Eradication rate, expressed here as a fraction not as percent in this
model;
EO is the fraction eradicated at a Total T>MIC of 0, i.e. spontaneous
eradication
or placebo effect;
Emax is the maximum eradication, set to a constant of 1.0 (representing 100%
in
this model);
Total T>MIC is the parameter calculated by multiplying daily T>MIC times the
number of days the product was administered;
Duration is the number of days the dose is administered;
Daily T>MIC is the fraction T>MIC per day provided by the dose regimen; and
a, b, and c are coefficients determined during the fitting of the reference
data.
In development of the above equation for a given set of reference literature
data, a computer
program such as Statgraphics, SigrnaPlot, SAS, JMP, Excel, or other modeling
software is employed
to fit the parameters EO, a, b, and c. For the data in Figure 1 the fitted
model was determined to be:
Fraction Eradicated = 0.058 + 0.942*Total T>MIC /
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=
(-2.99 + 0.316*Duration + 10.94*Daily T>MIC)
This equation may now be utilized to determine the optimum Duration of a novel
therapy
provided the daily T>MIC is known or vice versa. The equation developed here
can maintain the
maximum effect below the 100% limit, and, unlike the simple Emax model, can
fit individual points
with a common Total T>MIC but, different duration or daily T>MIC, that may
lead to different
eradication rate because of the response to duration and daily T>MIC, can be
different.
Each of the three different approaches above are only example of the types of
model fitting
that may be conducted in the type of analysis disclosed by the inventors.
Depending on the nature
of the data set being modeled one of the above forms may be preferred, or
perhaps a modification of
the above models will be required. One skilled in the art will be able to
develop alternative models
by rearranging model terms or using different model forms, and, these
modifications are within the
scope of the present invention.
For further illustration, below is a plot of the fitted data from all models
vs the actual literature data.
% Eradiction vs Total T>MIC for Various Models
100 _____________________________________________________
x
90 ______________________________________________________
g
A 0 g
6.9. 80 __________________________________________________________ =
g,- 70 0
c2 60 ___________________________________________________
0
e 50
tiJ A
0
11 40 ___________________________________________________
.49 30 ______________________________________________________
03
m 20 ____________________________________________________
- __________________________________________________
K
0 a ___________________________________________________
0 1 2 = 3 4 5 6
Total T>MIC (Days)
* Simple Emax 0 GLM a Mod. Emax x Literature Data
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For further illustration, below is a plot of the actual data vs. the Simple
Emax fitted data.
Actual Data vs. Simple Emax Fitted Data
100 ________________________________________________________
x
90 _________________________________________________________
o g *
80 _________________________________________________________
z,:z 70 ___________________________________________________
0 60 _______________________________________________________
2 50 _______________________________________________________
To
a 30
10
0
0 1 2 .3 4 5 6
Total T>MIC (Days)
o Simple Emax x Literature Data
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For further illustration, below is a plot of the actual literature data vs the
GLM and modified Emax
models.
% Eradiction vs Total T>MIC for Various Models
100 ________________________________________________________
x a
90 Ei Si 2 __
A a
A 0
80 _________________________________________________________
A
e 70 _______________________________________________________
CI 60 ________________________________________________________
."5
2 50 _______________________________________________________
A
7*-0 40 ____________________________________________________
Vcs
02 30 ______________________________________________________
10
0ç
0 1 2 3 4 5 6
Total T>MIC (Days)
GLM A Mod. Emax x Literature Data
In preferred embodiments of the product the desired percentage of eradication
of the known
bacterial pathogen is one that achieves clinical efficacy in the host for a
condition caused by, or
suspected to be caused by, the bacterial pathogen.
In a preferred embodiment of the product the antibiotic is a beta-lactam
antibiotic. In a more
preferred embodiment of the product the antibiotic is a penicillin antibiotic.
In a particularly
preferred embodiment of the product the antibiotic is amoxicillin.
In preferred embodiments of the method the desired percentage of eradication
of the known
bacterial pathogen is one that achieves clinical efficacy in the host for a
condition caused by, or
suspected to be caused by, the bacterial pathogen.
In a preferred embodiment of the method the antibiotic is a beta-lactam
antibiotic. In a more
preferred embodiment of the method the antibiotic is a penicillin antibiotic.
In a particularly
preferred embodiment of the method the antibiotic is amoxicillin.
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In another embodiment of the invention, there is provided a once-a-day
antibiotic product
comprised of at least one modified release antibiotic dosage form. The
modified release antibiotic
dosage form comprises at least one antibiotic and a pharmaceutically
acceptable carrier. The
modified release antibiotic dosage form is formulated such that it contains
the proper dose of
antibiotic as a single unit for repeated once-daily administration in a
treatment regimen of specified
duration, whereby a plurality of once-daily administrations of the units
ultimately achieves a desired
"Total T>MIC" in the patient's blood.
In another embodiment of the invention, there is provided a method of
therapeutically
effectively treating a patient in need of treatment for bacterial infection,
comprising administering a
once-a-day antibiotic product comprised of at least one modified release
antibiotic dosage form.
The modified release antibiotic dosage form comprises at least one antibiotic
and a pharmaceutically
acceptable carrier. The modified release antibiotic dosage form is formulated
such that it contains
the proper dose of antibiotic as a single unit for repeated once-daily
administration in a treatment
regimen of speczfied duration, whereby a plurality of once-daily
administrations of the units
ultimately achieves a desired "Total T>MIC" in the patient's blood.
In another embodiment of the invention, there is provided a once-a-day
antibiotic product
comprised of at least one modified release antibiotic dosage form. The
modified release antibiotic
dosage form comprises at least one antibiotic and a pharmaceutically
acceptable carrier. The
modified release antibiotic dosage form is administered such that it provides
the proper duration of
antibiotic therapy as a single unit for repeated once-daily administration in
a treatment regimen of
specified daily dosage, whereby a plurality of once-daily administrations of
the units ultimately
achieves a desired "Total T>MIC" in the patient's blood.
In another embodiment of the invention, there is provided a method of
therapeutically
effectively treating a patient in. need of treatment for bacterial infection,
comprising administering a
once-a-day antibiotic product comprised of at least one modified release
antibiotic dosage form.
The modified release antibiotic dosage form comprises at least one antibiotic
and a pharmaceutically
acceptable carrier. The modified release antibiotic dosage form is
administered such that it provides
the proper duration of antibiotic therapy as a single unit for repeated once-
daily administration in a
treatment regimen of specified daily dosage., whereby a plurality of once-
daily administrations of the
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units ultimately achieves a desired "Total T>MIC" in the patient's blood. It
is to be understood that
the embodiment of the invention with respect to total time over MIC90 may or
may not incorporate a
formulation that provides for the herein described daily time over MIC;
however, such a formulation
is preferred.
Although embodiments of the instant invention allow for a Daily T>MIC that is
less than
that generally believed to be required in the art, in preferred embodiments
the Daily T>MIC is
generally not less than about 20%.
In one preferred embodiment the invention is directed to an antibiotic product
that contains a
beta-lactam antibiotic, as well as to the product's formulation and to its use
in treating bacterial
infections, wherein the infecting pathogen has an MIC90 > 0.015 ii.g/mL. for
the beta-lactam
antibiotic used. In a more preferred embodiment, the invention is directed to
such an antibiotic
product that contains a beta-lactam antibiotic, as well as to the product's
formulation and to its use
in treating bacterial infections, wherein the infecting pathogen has an MIC90
> 0.015 g/mL. for the
beta-lactam antibiotic used. In a particularly preferred embodiment, the
invention is directed to
such an antibiotic product that contains amoxicillin, as well as to the
product's formulation and to its
use in treating bacterial infections, wherein the infecting pathogen has an
MIC90 0.015 i.tg/mL. for
anzoxicillin.
Daily T>MIC Embodiments
In one aspect the present invention provides for a once-a-day pharmaceutical
formulation
providing a daily dosage of penicillin-type antibiotic, such as to provide a
serum concentration of
penicillin-type antibiotic in a patient or subject at or above an infecting
bacterial pathogen's drug-
specific MIC90 for at least five hours within the 24-hour period following
administration.
=
In a preferred aspect the present invention provides for a once-a-day
pharmaceutical
formulation providing a daily dosage of penicillin-type antibiotic, such as to
maintain a serum
concentration of penicillin-type antibiotic in a patient or subject at or
above an infecting bacterial
pathogen's drug-specific MIC90 for at least five consecutive hours within the
24-hour period
following administration.
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More specifically, in accordance with one aspect of the invention there is
provided a once-a-
day penicillin-type antibiotic composition comprising at least one dosage form
that contains a
penicillin-type antibiotic and a pharmaceutically acceptable carrier. In a
further aspect of the
invention the once-a-day penicillin-type antibiotic composition is formulated
so that when
administered to a patient, or to subject, it provides a T>MIC90 in the serum
for at least 5 hours
within the 24-hour period following administration. In a still further aspect
of the invention the
serum concentration that is provided for at least 5 hours is one that is >
0.06 u.g/mL. In a yet still
further aspect of the invention the once-a-day penicillin-type antibiotic
composition contains the
total dosage of the penicillin-type antibiotic for a twenty-four hour dosing
interval.
Preferably, in one aspect of the invention there is provided a once-a-day
penicillin-type
antibiotic composition comprising at least one dosage form that contains a
penicillin-type antibiotic
and a pharmaceutically acceptable carrier. In a further preferred aspect of
the invention the once-a-
day penicillin-type antibiotic composition is formulated so that when
administered to a patient, or to
a subject, it maintains a T>MIC90 in the serum for at least 5 consecutive
hours within the 24-hour
period following administration. In a still further preferred aspect of the
invention the serum
concentration that is maintained for at least 5 consecutive hours is one that
is > 0.06 u.g/mL. In a yet
still further preferred aspect of the invention the once-a-day penicillin-type
antibiotic composition
contains the total dosage of the penicillin-type antibiotic for a twenty-four
dosing interval.
In one once-a-day embodiment, the composition provides a serum concentration
of
penicillin-type antibiotic in a patient or subject that is at least equivalent
to the drug-specific MIC90
of the bacterial pathogen causing the infection in the patient or subject, for
at least five hours within
the 24-hour period following administration. =
In another once-a-day embodiment, the composition maintains a serum
concentration of
penicillin-type antibiotic in a patient or subject that is at least equivalent
to the drug-specific MIC90
of the bacterial pathogen causing the infection in the patient or subject, for
at least five consecutive
hours within the 24-hour period following administration.
In one embodiment the composition provides a serum concentration of penicillin-
type
antibiotic in a patient or subject at or above a given bacterial pathogen's
drug-specific 1v1IC90 for at
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least five hours within the 24-hour period following administration. In
another embodiment the
composition provides a serum concentration of penicillin-type antibiotic in a
patient or subject at or
above a given bacterial pathogen's MIC90 for at least six hours within the 24-
hour period following
administration. In another embodiment the composition provides a serum
concentration of
penicillin-type antibiotic in a patient or subject at or above a given
bacterial pathogen's MIC90 for at
least eight hours within the 24-hour period following administration. In
another embodiment the
composition provides a serum concentration of penicillin-type antibiotic in a
patient or subject at or
above a given bacterial pathogen's MIC90 for at least nine hours within the 24-
hour period following
administration. Generally, the composition does not provide a serum
concentration of penicillin-
type antibiotic in a patient or subject at or above a given bacterial
pathogen's MIC90 for more than
nine hours within the 24-hour period following administration.
In one embodiment the composition maintains a serum concentration of
penicillin-type
antibiotic in a patient or subject at or above a given bacterial pathogen's
drug-specific MIC90 for at
least five consecutive hours within the 24-hour period following
administration. In another
embodiment the composition maintains a serum concentration of penicillin-type
antibiotic in a
patient or subject at or above a given bacterial pathogen's MIC90 for at least
six consecutive hours
within the 24-hour period following administration. In another embodiment the
composition
maintains a serum concentration of penicillin-type antibiotic in a patient or
subject at or above a
given bacterial pathogen's M1C90 for at least eight consecutive hours within
the 24-hour period
following administration. In another embodiment the composition maintains a
serum concentration
of penicillin-type antibiotic in a patient or subject at or above a given
bacterial pathogen's MIC90 for
at least nine consecutive hours within the 24--hour period following
administration. Generally, the
composition does not maintain a serum concentration of penicillin-type
antibiotic in a patient or
subject at or above a given bacterial pathogen's MIC90 for more than nine
consecutive hours within
the 24-hour period following administration.
In particularly preferred embodiments the penicillin-type antibiotic is
amoxicillin.
Generally, the daily dosage of penicillin-type antibiotic will depend on
various factors such
as the bacterial pathogen to be targeted, the known resistance or
susceptibility of the bacterial
pathogen to the given penicillin-type antibiotic, and the known MIC90 of the
given bacterial
pathogen for the given penicillin-type antibiotic.
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Generally, the daily dosage of amoxicillin used in the invention comprises
from about 250 to
about 3000 mg. Preferably the daily dosage of amoxicillin used in the
invention comprises from
about 500 to about 2500 mg. More preferably the daily dosage of amoxicillin
used in the invention
comprises from about 775 to about 1550 mg.
In an embodiment the daily dosage of amoxicillin is 775 mg.
In a further aspect, the present invention provides a method of treating
infection in a patient
or subject caused by bacterial pathogens, comprising administering to the
patient or subject once-a-
day the herein-above described and herein-below described penicillin-type
antibiotic compositions
so as to maintain a serum concentration of penicillin-type antibiotic in a
patient or subject at or
above a given bacterial pathogen's drug-specific MIC90 for at least five hours
(preferably for at least
five consecutive hours) of a 24-hour dosing interval. As non-limiting examples
of the infectious
bacterial pathogens against which the herein-above described and herein-below
described penicillin-
type antibiotic compositions may be used there may be mentioned Aerobic Gram-
positive
microorganisms such as Staphylococcus aureus, Streptococcus pneumoniae,
Streptococcus
pyogenes, Streptococcus agalactiae, Streptococci (Groups C, F, G), and
Viridans group
streptococci; Aerobic Gram-negative microorganisms such as Haemophilus
influenzae,
Haemophilus parainfluenzae, Moraxella catarrhalis, Bordetella pertussi,
Legionalla pneumophila,
Pasteurella multocida and Klebsiella pneumoniae; Anaerobic Gram-positive
microorganisms such
as Clostridium perfringens, Peptococcus niger, and Propionibacterium acnes;
Anaerobic Gram-
negative microorganisms such as Prevetolla melaninogenica (formerly
Bacterocides
melaninogenicus); Mycoplasina pneumoniae; Chlamydia pneumoniae; Mycobacterium
avium
complex (MAC) consisting of Mycobacterium avium and / or Mycobacterium
intracellulare;
Helicobacter pylori; Bacterocides fragilis; Fusobacterium nucleatum;
Peptostreptococcus magnus;
Peptostreptococcus micros; and Escherichia colt_
In a further aspect, the once-a-day pharmaceutical formulation providing a
daily dosage of
penicillin-type antibiotic such as to provide (or maintain) a serum
concentration of penicillin-type
antibiotic in a patient or subject at or above a bacterial pathogen's drug-
specific MIC90 for at least
five holm (preferably for at least five consecutive hours) of a 24-hour dosing
interval, may comprise
a modified release dosage form(s) or an immediate release dosage form(s) in
combination with a
CA 02635378 2014-01-15
, 53449-9
modified release dosage form(s), with such modified release dosage form(s)
being: a delayed
release dosage form(s), a sustained (or extended) release dosage form(s), and
/ or combinations of
the forgoing. The formulating of such dosage forms will be apparent to those
of skill in the art in
view of the disclosures herein further guided by the disclosures of U.S.
Patent Application Serial
Numbers 10/894,787; 10/894,786; 10/894,994; 10/917,059; 10/922,412; and
10/940,265; and by the
disclosures of U.S. Patents 6,544,555; 6,623,757; and 6,669,948.
In one preferred embodiment the once-a-day pharmaceutical formulation
providing a daily
dosage of penicillin-type antibiotic, such as to provide (or maintain) a serum
concentration of
penicillin-type antibiotic in a patient or subject at or above a bacterial
pathogen's drug-specific
MIC90 for at least five hours, (preferably for at least five consecutive
hours) of a 24-hour dosing
interval, comprises a sustained (or extended) release dosage form(s). In this
embodiment the
sustained (or extended) release dosage form(s) is designed and intended to
release the penicillin-type
antibiotic slowly over time, such as to maintain a serum concentration of
penicillin-type antibiotic in
a patient or subject at or above a bacterial pathogen's drug-specific MIC90
for at least five
consecutive hours.
In a preferred embodiment, the penicillin-type antibiotic composition is a
once a day
composition, whereby after administration of the penicillin-type antibiotic
composition, no further
composition is administered during the day; i.e., the preferred regimen is
that the composition is
administered only once over a twenty-four hour period. Thus, in accordance
with the present
invention, there is a single administration of a penicillin-type antibiotic
composition formulated so
as to provide (or maintain) a serum concentration of penicillin-type
antibiotic in. a patient or subject
at or above a bacterial pathogen's drug-specific MICR) for at least five hours
(preferably for at least
five consecutive hours) within the 24-hour period following administration.
The term single
administration means that the total penicillin-type 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.
In an embodiment of the invention the penicillin-type antibiotic composition
comprising at
least one modified release dosage form formulated so as to provide (or
maintain) a concentration of
the given penicillin-type antibiotic in the serum at or above the MIC90 for an
infecting bacterial
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pathogen for at least 5 hours within a 24-hour dosing interval, is further
formulated so as to achieve
Cmax in the serum for the total penicillin-type antibiotic released from the
composition in less than
about 12 hours following administration of the penicillin-type antibiotic
composition, or following
initial release of penicillin-type antibiotic from the penicillin-type
antibiotic composition. In this
embodiment (as in all embodiments) the dosage form(s) is / are further
formulated such that the
penicillin-type antibiotic composition provides (and preferably maintains) a
serum concentration of
the given penicillin-type antibiotic that is > 0.06 pg/mL., and such that the
penicillin-type antibiotic
composition contains the total dosage of the given penicillin-type antibiotic
for a 24-hour dosing
interval.
In another embodiment of the present invention there is provided a penicillin-
type antibiotic
pharmaceutical composition which is comprised of at least two, preferably at
least three, penicillin-
type antibiotic dosage forms (at least one of which is a modified release
dosage form). Such dosage
forms are formulated so that each of the dosage forms has a different release
profile and so that the
composition provides (and preferably maintains) a penicillin-type antibiotic
concentration in the
patient's semna that equals or exceeds the pathogen's drug-specific MIC90 for
at least five hours
(preferably for at least five consecutive hours) within the 24-hour period
following administration.
In another embodiment of the invention there are at least two, preferably at
least three
dosage forms (at least one of which is a modified release dosage form), each
of which has a different
release profile, the release profile of each of the dosage forms being such
that the dosage forms each
start release of the penicillin-type antibiotic contained therein at different
times after administration
of the penicillin-type antibiotic composition, and the composition provides
(and preferably
maintains) a penicillin-type antibiotic concentration in the patient's serum
that equals or exceeds the
pathogen's drug-specific MIC90 for at least five hours (preferably for at
least five consecutive hours)
within the 24-hour period following administration.
Thus, in accordance with this embodiment of the present invention, there is
provided a single
or unitary antibiotic composition that has contained therein at least two,
preferably at least three
penicillin-type antibiotic dosage forms (at least one of which is a modified
release dosage form),
each of which has a different release profile, whereby the penicillin-type
antibiotic contained in each
of such dosage forms is released at different times, and the penicillin-type
antibiotic composition
provides a daily dosage of penicillin-type antibiotic, such as to provide (or
maintain) a serum
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concentration of penicillin-type antibiotic in a patient or subject at or
above a bacterial pathogen's
drug-specific MIC90 for at least five hours (preferably at for least five
consecutive hours) within the
24-hour period following administration.
In accordance with another embodiment of the invention, the antibiotic
composition may be
comprised of at least four different dosage forms, each of which starts to
release the penicillin-type
antibiotic contained therein at different times after administration of the
penicillin-type antibiotic
composition, and the composition provides (or maintains) a penicillin-type
antibiotic concentration
in the patient's serum that equals or exceeds the pathogen's drug-specific
MIC90 for at least five
hours (preferably for at least five consecutive hours) within the 24-hour
period following
administration.
The penicillin-type antibiotic composition generally does not include more
than five dosage
forms with different release times.
In accordance with another embodiment, the penicillin-type antibiotic
composition has an
overall release profile such that when administered the maximum serum
concentration of the total
antibiotic released from the composition is reached in less than twelve hours,
preferably in less than
eleven hours, and that maximum serum concentration is at least equivalent to
the drug-specific
MIC90 of the bacterial pathogen.
In all embodiments of the invention as herein-above and herein-below described
the
penicillin-type antibiotic is formulated so as to provide (or maintain) a
penicillin-type antibiotic
concentration in the patient's serum that equals or exceeds the pathogen's
drug-specific MIC, for at
least five hours (preferably for at least five consecutive hours) within a 24-
hour period when
administered once-a-day.
In all embodiments of the invention the composition is designed and intended
to provide a
serum concentration of > 0.06 pg/mL. of penicillin-type antibiotic for at
least 5 hours.
In preferred embodiments of the invention the composition is designed and
intended to
provide a serum concentration of > 0.06 Itg/mL. of penicillin-type antibiotic
for at least 5
consecutive hours.
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Alternatively, in formulating an oral delivery system, each of the dosage
forms of the
composition may be formulated as a tablet, with each of the tablets being put
into a capsule to
produce a unitary antibiotic composition. Thus, as a non-limiting example, a
three dosage form
antibiotic composition 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 or a sustained release of the penicillin-type antibiotic, as
hereinabove described, to
provide (and preferably maintain) a serum concentration of the penicillin-type
antibiotic at least
equivalent to the drug-specific MIC90 of the bacterial pathogen for at least
five (preferably for at
least five consecutive hours) hours within a 24-hour dosing interval.
After administration to a subject, the concentration of antibiotic may be
measured in whole
blood or plasma obtained from the subject. As known in the art, such measured
antibiotic
concentration includes antibiotic bound to serum proteins. As known in the
art, unbound antibiotic
concentration may be determined by use of a correction factor based on known
or measured binding
of the antibiotic to serum proteins.
Further Description of the Invention
In accordance with an aspect of the invention there is provided a once-a-day
beta-lactam
antibiotic product for treating a bacterial infection in a patient or subject,
comprising a beta-lactam
antibiotic composition.
In particularly preferred embodiments the beta-lactam antibiotic is
amoxicillin.
As herein-above discussed and herein-below discussed, the daily dosage of beta-
lactam
antibiotic will depend on various factors such as the bacterial pathogen to be
targeted, the known
resistance or susceptibility of the bacterial pathogen to the given beta-
lactam antibiotic, and the
known MIC90 of the given bacterial pathogen for the given beta-lactam
antibiotic.
Generally, the daily dosage of amoxicillin used in the invention comprises
from about 250 to
about 3000 mg. Preferably the daily dosage of amoxicillin used in the
invention comprises from
about 500 to about 2500 mg. More preferably the daily dosage of amoxicillin
used in the invention
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comprises from about 775 to about 1550 mg.
In an embodiment the dail dosage of amoxicillin is 775 mg. and the optimal
duration of
therapy taking into account therapy, compliance, convenience, and marketing
concerns, is 10 days.
In an embodiment the daily dosage of a-moxicillin is 775 mg. and the optimal
duration of
therapy taking into account only efficacy concerns, is 10 days.
In a further aspect, the present invention provides a method of treating
various indications in
a patient, or in a subject, caused by bacterial pathogens, which treating
comprises administering to
the patient, or to the subject, once-a-day the herein-above described and
herein-below described
beta-lactam antibiotic compositions. As non-limiting examples of the
indications for which the
herein-above described and herein-below described beta-lactam antibiotic
compositions may be
used to treat a patient there may be mentioned.: pharyngitis, tonsillitis,
sinusitis, bronchitis,
= pneumoniae, ear infection (otitis media), uncomplicated skin and skin
structure infections, and
uncomplicated urinary infections.
As non-limiting examples of the infectious bacterial pathogens against which
the herein-
above described and herein-below described beta-lactam antibiotic compositions
may be used there
may be mentioned Aerobic Gram-positive microorganisms such as Staphylococcus
aureus,
Streptococcus pneumoniae, Streptococcus pyogenes, Streptococcus agalactiae,
Streptococci
(Groups C, F, G), and Viridans group streptococci; Aerobic Gram-negative
microorganisms such as
Haemophilus influenzae, Haemophilus parainfluenzae, Moraxella catarrhalis,
Bordetella pertussi,
Legionalla pneumophila, Pasteurella multocida and Klebsiella pneumoniae;
Anaerobic Gram-
positive microorganisms such as Clostridium peifringens, Peptococcus niger,
and
Propionibacteriurn acnes; Anaerobic Gram-negative microorganisms such as
Prevetolla
melaninogenica (formerly Bacterocides melaninogenicus); Mycoplasnu2
pneumoniae; Chlamydia
pneumoniae; Mycobacterium avium complex (MAC) consisting of Mycobacterium
avium and / or
Mycobacterium intracellulare; Helicobacter pylori; Bacterocides fragilis;
Fusobacterium
nucleatum; Peptostreptococcus magnus; Peptostreptococcus micros; and
Escherichia coli.
In a preferred embodiment the composition is formulated to specifically target
the bacterial
pathogen Streptococcus pyogenes.
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It will be appreciated by those of ordinary skill in the art that the methods
and formulations
hereinabove described and hereinbelow described for the beta-lactaan
antibiotic amoxicillin, or for
other beta-lactam antibiotics, are also applicable to amoxicillin, or to other
beta-lactam antibiotics,
in combination with clavulanate, or in combination with other beta-lactamase
inhibitors, particularly
for treating infections where beta-lactamase producing pathogens are
implicated.
While the hereinabove described and hereinbelow described compositions and
methods may
be used to improve the efficacy of any beta-lactam antibiotic, they are
particularly useful for
improving the efficacy of antibiotics that include a beta-lactam ring or a
portion thereof, as non-
limiting examples of such antibiotics there may be mentioned penicillin
derivatives, such as
penicillin V, penicillin G, penicillin, ampicillin, amoxicillin,
carbenicillin, ticarcillin, piperacillin,
=
nafcillin, cloxacillin, dicloxacillin, monobactams such as aztreonam, and
carbapenems such as
imipenem.
In accordance with another embodiment, the beta-lactam antibiotic composition
has an
overall release profile such that when administered the maximum serum
concentration of the total =
:antibiotic released from the composition is reached in less than twelve
hours, preferably in less than
eleven hours, and that maximum serum _concentration is at least equivalent to
the drug-specific
MIC90 of the bacterial pathogen.
In accordance with one embodiment of the invention, there are at least three
dosage forms (at
least one of which is a modified release dosage form). One of the at least
three dosage forms is an
immediate release dosage form whereby initiation of release of the beta-lactam
antibiotic therefrom
is not substantially delayed after administration of the beta-lactam
antibiotic composition. The
second and third of the at least three dosage forms are delayed release dosage
forms (each of which
may be a pH sensitive or a non-pH sensitive delayed dosage form, depending on
the type of beta-
lactam antibiotic composition), whereby the beta-lactam antibiotic released
therefrom is delayed
until after initiation of release of the beta-lactarn antibiotic from the
immediate release dosage form.
More particularly, the beta-lactam antibiotic released from the second of the
at least two dosage
forms achieves a Cmax (maximum serum concentration in the serum) at a time
after the beta-lactam
antibiotic released from the first of the at least three dosage forms achieves
a Cmax in the serum,
and the beta-lactam antibiotic released from the third dosage form achieves a
Cmax in the serum
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after the Cmax of beta-lactam antibiotic released from the second dosage form
and the overall Cmax
is at least equivalent to the drug-specific MIC90 of the baterial pathogen.
In one embodiment, the second of the at least two dosage forms initiates
release of the beta-
lactam antibiotic contained therein at least one hour after the first dosage
form, with the initiation of
the release therefrom generally occurring no more than six hours after
initiation of release of beta-
lactam antibiotic from the first dosage form of the at least three dosage
forms.
As hereinabove indicated, some embodiments of the beta-lactam antibiotic
composition may
contain three, four, or more different dosage forms (provided that at least
one is a modified release
dosage form).
In one three-dosage form embodiment, the beta-lactam antibiotic released from
the third
dosage form reaches a Cmax at a time later than the Cmax is achieved for the
beta-lactam antibiotic
released from each of the first and second dosage forms. In a preferred
embodiment, release of beta-
lactam antibiotic from the third dosage form is started after initiation of
release of beta-lactam
antibiotic from both the first dosage form and the second dosage form. In one
embodiment, Cmax
for beta-lactam antibiotic released from the third dosage form is achieved
within eight hours.
In another three-dosage form embodiment the release of beta-lactam antibiotic
from the
second dosage form may be contemporaneous with initiation of release of beta-
lactam antibiotic
from the first dosage form.
In another three-dosage form embodiment the release of beta-lactam antibiotic
from the third
dosage form may be contemporaneous with initiation of release of beta-lactam
antibiotic from the
second dosage form.
In another embodiment, the beta-lactam antibiotic composition may contain four
dosage
forms (at least one of which is a modified release dosage form), with each of
the four dosage forms
having different release profiles, whereby the beta-lactam antibiotic released
from each of the four
different dosage forms achieves a Cmax at a different time.
As hereinabove indicated, in an embodiment, irrespective of whether the
antibiotic contains
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=
at least two or at least three or at least four different dosage forms each
with a different release
profile, Cmax for all the beta-lactam antibiotic released from the beta-lactam
antibiotic composition
is achieved in less than twelve hours, and more generally is achieved in less
than eleven hours and is
at least equivalent to the drug-specific MIC90 of the bacterial pathogen.
In a preferred embodiment, the beta-lactam antibiotic composition is a once a
day
composition, whereby after administration of the beta-lactam antibiotic
composition, no further
composition is administered during the day; i.e., the preferred regimen is
that the composition is
administered only once over a twenty-four hour period. Thus, in accordance
with this preferred
embodiment, there is a single administration of an beta-lactam antibiotic
composition with the beta-
lactam antibiotic being released in a manner such that overall beta-lactam
antibiotic release is
effected with different release profiles in a manner such that the overall
Cmax for the beta-lactam
antibiotic composition is reached in less than twelve hours and is at least
equivalent to the drug-
specific MIC90 of the bacterial pathogen. The term single administration means
that the total beta-
lactam 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.
In general, each of the dosage forms in the beta-lactarn antibiotic
compositions may have one
or more beta-lactam antibiotics, and each of the dosage forms may have the
same beta-lactam
antibiotic or different beta-lactam antibiotics.
=
It is to be understood that when it is disclosed herein that a dosage form
initiates release after
another dosage form, such terminology means that the dosage form is designed
and is intended to
produce such later initiated release. It is known in the art, however,
notwithstanding such design
and intent, some "leakage" of antibiotic may occur. Such "leakage" is not
"release" as used herein.
In one four-dosage form embodiment, the fourth dosage form may be a sustained
release
dosage form or a delayed release dosage form. If the fourth dosage form is a
sustained release
dosage form, even though Cmax of the fourth dosage form is reached after the
Cmax of each of the
other dosage forms is reached, beta-lactam antibiotic release from such fourth
dosage form may be
initiated prior to or after release from the second or third dosage form.
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The beta-lactam antibiotic composition of the present invention, as
hereinabove described,
may be formulated for administration by a variety of routes of administration.
For example, the
beta-lactam antibiotic composition may be formulated in a way that is suitable
for topical
administration; administration in the eye or the ear; rectal or vaginal
administration; as a nasal
preparation; by inhalation; as an injectable; or for oral administration. In a
preferred embodiment,
the beta-lactam antibiotic composition is formulated in a manner such that it
is suitable for oral
administration.
For example, in formulating the beta-lactain antibiotic composition for
topical
administration, such as by application to the skin, the dosage forms, each of
which contains a beta-
lactam 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, an
immediate release
dosage form may be in the continuous phase, and a delayed release dosage form
may be in a
discontinuous phase. The formulation may also be produced in a manner for
delivery of three
dosage forms as hereinabove described. For example, there may be provided an
oil-in-water-in-oil
emulsion, with oil being a continuous phase that contains the immediate
release component, water
dispersed in the oil containing a first delayed release dosage form, and oil
dispersed in the water
containing a third delayed release dosage form.
It is also within the scope of the invention to provide a beta-lactam
antibiotic composition in
the form of a patch, which includes beta-lactam antibiotic dosage forms having
different release
profiles, as hereinabove described.
In addition, the beta-lactam antibiotic composition 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 beta-lactam antibiotic composition having at least one
modified release
dosage form (whether or not combined with additional dosage forms to provide a
plurality of
different release profiles) may be formulated for rectal or vaginal
administration, as known in the
art. This may take the form of a cream, an emulsion, a suppository, or other
dissolvable dosage
29
=
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form similar to those used for topical administration.
In a preferred embodiment, the beta-lactam antibiotic composition is
formulated in a manner
suitable for oral administration. Thus, for example, for oral administration,
each of the dosage
forms may be used as a pellet or a particle, with a pellet or particle then
being formed into a unitary
pharmaceutical composition, 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
composition may be formulated as a tablet, with each of the tablets being put
into a capsule to
produce a unitary antibiotic composition. Thus, as a non-limiting example, a
three dosage form
antibiotic composition 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 or a sustained release of the beta-lactam antibiotic, as
hereinabove described, to
provide (and preferably maintain) a serum concentration of the beta-lactam
antibiotic at least
equivalent to the drug-specific MIC90 of the bacterial pathogen.
The formulation of a beta-lactarn antibiotic composition including at least
Three dosage
forms with different release profiles 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 a variety of mechanisms such as pH,
coating thickness, choice
of polymer, and combinations of the foregoing.
In formulating a beta-lactam antibiotic composition in accordance with one
embodiment of
the invention, an immediate release dosage form of the composition generally
provides from about
20% to about 50% of the total dosage of beta-lactam antibiotic to be delivered
by the composition,
with such immediate release dosage form generally providing at least 25% of
the total dosage of the
beta-lactam antibiotic to be delivered by the composition. In many cases, an
immediate release
dosage form provides from about 20% to about 30% of the total dosage of beta-
lactam antibiotic to
be delivered by the composition; however, in some cases it may be desirable to
have an immediate
release dosage form provide for about 45% to about 50% of the total dosage of
beta-lactam
antibiotic to be delivered by the composition.
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The remaining dosage forms deliver the remainder of the beta-lactam
antibiotic. If more
than one modified release dosage form is used each of the modified release
dosage forms may
provide about equal amounts of beta-lactam 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 beta-
lactam antibiotic; however, each of the dosage forms may contain more than one
beta-lactam
antibiotic.
In one embodiment, where the composition contains one immediate release
component and
two modified release components, the immediate release component provides from
20% to 35%
(preferably 20% to 30%), by weight, of the total beta-lactam antibiotic; where
there are three
modified release components, the immediate release component provides from 15%
to 30%, by
weight, of the total beta-lactam antibiotic; and where there are four modified
release components,
the immediate release component provides from 10% to 25%, by weight, of the
total beta-lactam
antibiotic.
With respect to the modified release components, where there are two modified
release
components, the first modified release component (the one released earlier in
time) provides from
30% to 60%, by weight, of the total beta-lactam antibiotic provided by the two
modified release
components with the second modified release component providing the remainder
of the beta-lactam
antibiotic.
Where there are three modified release components, the earliest released
component
provides 20% to 35% by weight of the total beta-lactam antibiotic provided by
the three modified
release components, the next in time modified release component provides from
20% to 40%, by
weight, of the beta-lactam antibiotic provided by the three modified release
components and the last
in time providing the remainder of the beta-lactam antibiotic provided by the
three modified release
components.
When there are four modified release components, the earliest modified release
component
provides from 15% to 30%, by weight, the next in time modified release
component provides from
15% to 30%, the next in time modified release component provides from 20% to
35%, by weight,
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and the last in time modified release component provides from 20% to 35%, by
weight, in each case
of the total beta-lactam antibiotic provided by the four modified release
components.
The Immediate Release Component
The immediate release portion of this system can be a mixture of ingredients
that breaks
down quickly after administration to release the beta-lactam 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 beta-lactam 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 (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.
It may be useful to have these materials present in the range of 1.0 to 60%
(W/W).
In addition, it may be useful to have other ingredients in this system to aid
in the dissolution
of the drug, or the breakdown of the component after ingestion or
administration. These ingredients
can be= surfactants, such as sodium lauryl sulfate, sodium monoglycerate,
sorbitan monooleate,
sorbitan monooleate, polyoxyethylene sorbitan monooleate, glyceryl
monostearate, glyceryl
monooleate, glyceryl monobutyrate, one of the non-ionic surfactants such as
the Pluronic line of
surfactants, or any other material with surface active properties, or any
combination of the above.
These materials may be present in the range of 0.05-15% (W/W).
The non-pH Sensitive Delayed Release Component
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53449-9
The components in this 'composition are the same as the immediate release
unit, but with
additional polymers integrated into the composition, or as coatings over the
pellet or granule.
Several methods to affect a delayed release with non-pH dependent polymers are
laiown to
those skilled in the art. These include soluble or erodible barrier systems,
enzymatically degraded
barrier systems, rupturable coating systems, and plugged capsule systems among
others. These
systems have been thoroughly described in the literature (see "A Review of
Pulsatile Drug
Delivery" by Bussemer and Bodmeier in the Winter 2001 issue of American
Pharmaceutical
Review) and formulations and methods for their manufacture are hereby
incorporated by reference.
Materials that can be used to obtain a delay in release suitable for this
component of the
invention can be, but are not limited to, polyethylene glycol (PEG) with
molecular weight above
4,000 daltons (Carbowax, Polyox), waxes such as white wax or bees wax,
paraffin, acrylic acid
derivatives (Eudragit), propylene glycol, and ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this
component.
The pH Sensitive (Enteric) Release Component
The components in this composition are the same as the immediate release
component, but
with additional polymers integrated into the composition, or as coatings over
the pellet or granule..
The kind of materials useful for this purpose can be, but are not limited to,
cellulose acetate
pthalate, Eudragit L, Eudragit S, Eudragit FS, 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.
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The kind of materials useful for this purpose can be, but are not limited to,
ethylcellulose;
hydroxypropylmethylcellulose; hydroxypropylcellulose;
hydroxyethylcellulose;
carboxymethylcellulose; methylcellulose; nitrocellulose; Eudragit R; Eudragit
RS; 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).
When it is desired to delay inititiation of release of the sustained release
dosage form, an
appropriate coating may be used to delay inititiation of the sustained
release, such as a pH sensitive
or a non-pH sensitive coating.
The non-pH Sensitive Coating for Sustained Release Dosage Form
=
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 RS), cellulose acetate, and ethylcellulose.
Typically these materials can be present in the range of 0.5-25% (W/W) of this
component.
Preferably the materials are present in an amount just enough to provide the
desired in vivo lag time
and Trnax.
The pH Sensitive Coating for Sustained Release Dosage Form
The kind of materials useful for this purpose can be, but are not limited to,
cellulose acetate
pthalate, Eudragit L, Eudragit S, Eudragit FS, and other pthalate salts of
cellulose derivatives.
These materials can be present in concentrations from 4-20% (W/W) or more.
Preferably the
materials are present in an amount just enough to provide the desired in vivo
lag time and T.
As hereinabove indicated, the units comprising the beta-lactam antibiotic
composition of the
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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 beta-lactam 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 beta-lactam antibiotic, which amount will vary with
the beta-lactam
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
patient or subject in
an amount effective for treating a bacterial infection.
This system will be especially useful in extending the practical 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:
imipenem, ertapenem, (carbapenems) 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,
piperaclllin, piperacillin and taxobactam, ticarcillin, ticarcillin and
clavulanate potassium,
(penicillins).
The beta-lactam antibiotic composition should be administered for a sufficient
amount of
time to treat the infection. In one embodiment the beta-lactam antibiotic
composition is
administered for 10 days.
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
specification, unless otherwise
specified, are by weight.
The following examples detail the general procedures for making immediate
release, delayed
release (both pH sensitive and non-pH sensitive types), sustained release, and
delayed sustained
release. components for the dosage form of the present invention. Any
combination of the
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components that results in the desired time above MIC would be included as
part of this disclosure.
Specific examples of combinations of the components are given, but are not
limited to the ones
described herein. Additionally, there is an example of a multi-unit dosage
form specific to
amoxicillin type tablets, but any appropriate therapeutic agent could be
substituted.
Additional Examples
I. Immediate Release Component
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
dry blend. If
water or other solvent was used, dry the blend in a suitable pharmaceutical
drier,
such as a vacuum oven or forced-air oven. The product may be sieved or
granulated,
and compressed using a suitable tablet press, such as a rotary tablet press,
or filled
into a capsule or sachet with a suitable filler.
Ingredient Conc. (% W/W)
Example 1:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Povidone 10
Croscarmellose sodium 5
Example 2:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Povidone 10
Croscarmellose sodium 10
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Example 3:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 4:
Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10
= Polyethylene glycol 2000 10
HydroxypropylcelluloSe 5
Example 5:
Amoxicillin 75% (W/VV)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 6:
Clarithromycin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10 =
Croscarmellose sodium 5
Example 7:
Clarithromycin 75% (W/W)
Microcrystalline cellulose 15
=
Hydroxypropylcellulose 5 =
Croscarmellose sodium 5
Example 8:
Clarithromycin 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 9:
Clarithromycin 75% (W/VV)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 10:
Ciprofloxacin 65% (W/VV)
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Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 11:
Ciprofloxacin 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 12:
Ciprofloxacin 75% (W/W)
= Polyethylene glycol 4000 10
Polytheylen.e glycol 2000 10
Hydroxypropylcellulose 5
Example 13:
Cirpofloxacin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 14:
Ceftibuten 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 15:
Ceftibuten 75% (W/W)
Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
38
=
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IL non-pH Sensitive Delayed Release Component
Any of the methods described in "A Review of Pulsatile Drug Delivery" by
Bussemer and Bodmeier in the Winter 2001 issue of American Pharmaceutical
Review may be utilized to make the pH independent delayed release component
described. Examples 16 and 17 utilize an organic acid layer underneath a layer
of
Eudragit RS to result in a rapid increase in the permeability of the Eudragit
film after
a set amount of time depending on the permeability and thickness of the film
thus
allowing the inner core to release through the Eudragit membrane. Example 18
utilizes a core with a highly swellable polymer that ruptures the insoluble
coating
membrane after a certain amount of time determined by the permeability,
plasticity
and thickness of the external cellulose acetate membrane. The coatings are
applied
to the core via methods such as wurster column coating in a fluid bed
processor as
known to those skilled in the art.
Additionally, this component may be formed as in example 19. In this example
the
component is prepared 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 oven or forced-air oven.
After the component is allowed to cool, the product may be sieved or
granulated, and
compressed using a suitable tablet press, such as a rotary tablet press, or
filled into a
capsule with a suitable encapsulator.
Ingredient Conc. (% WfW)
Example 16:
Core from Example 4 65% (W/W)
= Citric Acid 10
Eudragit RS Polymer 20
Talc 4
TEC 1
Example 17:
Core from Example 9 75% (W/W)
Citric Acid 10
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Eudragit RS Polymer = 10
Talc 4
TEC 1
Example 18:
Core from Example 1 93% (wfw)
Cellulose Acetate 6.75
PEG 400 0.25
=
Example 19:
Ciprofloxacin 70% (W/VV)
Polyox 20 ,
Hydroxypropylcellulose 5
Croscarmellose sodium 5
III. Enteric Release Component
Examples 20-27 utilize film coating techniques commonly known to those skilled
in
the art to create the enteric release component by layering of such enteric
polymers
onto an active core. In general the steps involve first making a coating
dispersion or =
solution in organic or aqueous solvent. Second, the coating is applied at the
proper
conditions to produce an acceptably uniform film. This is done in a suitable
coating
apparatus such as a pan coater or a fluid bed wurster column coater.
Optionally the
product may be further cured if necessary.
To create a matrix type enteric component, formulate the ingredients of
examples 28-
32 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
oven or
=
forced-air oven. Allow the product to cool.
The product produced by either manner may be sieved or granulated, and
compressed using a suitable tablet press, such as a rotary tablet press, or
filled into
capsules using a suitable capsule filler such as a MG2 Futura.
Ingredient Conc. (% W/W)
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Example.20:
Core from Example 1 65% (W/W)
Cellulose Acetate Pthalate 30
TEC 5
Example 21:
Core from Example 5 75% (W/W)
Cellulose Acetate Pthalate 20
Triacetin 5
Example 22:
Core from Example 1 65% (W/W)
Eudragil L 25
Talc 8
TEC 2
Example 23:
Core from Example 1 65% (W/W)
Eudragit FS 28
Talc 5
TEC 2
=
Example 24:
Core from Example 1 65% (W/W)
Eudragit S 28
Talc 5
= TEC 2
Example 25:
Core from Example 7 75% (W/1,A1)
Eudragit L 20
Talc 3.5
TEC 1.5
Example 26:
Core from Example 11 60% (W/W)
Eudragit L 35
Talc 4
TEC 1
Example 27:
Core from Example 15 65% (W/W)
Cellulose Acetate Pthalate 32.5
TEC 2.5
Example 28:
= Axnoxicillin 75% (W/W)
41
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Microcrystalline Cellulose 5
= Hydroxypropylcellulose pthalate 20
Example 29:
Amoxicillin 60% (W/VV)
= Lactose 10
Eudgragit L 30D 30
Example 30:
Ciprofloxacin 70% (W/VV)
Polyethylene glycol 4000 10
Cellulose acetate pthalate 20
Example 31:
Clarithromycin 60% (W/VV)
Polyethylene glycol 2000 10
Lactose 20
Eudragit L 30D = 10
Example 32:
Ceftibuten 70% (W/VV)
Microcrystalline cellulose 20
Cellulose acetate pthalate 10
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IV. Sustained Release Component
Examples 33-38 utilize film coating techniques commonly known to those skilled
in
the art to create the sustained release component by layering of such
sustained
release polymers onto an active core. In general the steps involve first
making a
coating dispersion or solution in organic or aqueous solvent. Second, the
coating is
applied at the proper conditions to produce an acceptably uniform film. This
is done
in a suitable coating apparatus such as a pan coater or a fluid bed warster
column
coater. Optionally the product may be further cured if necessary. Curing
studies are
recommended with sustained release membranes.
To create a matrix type sustained release component, formulate the ingredients
of
example 39-42 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 oven or forced-air oven. Allow the product to cool.
The product produced by either manner may be sieved or granulated, and
compressed using a suitable tablet press, such as a rotary tablet press, or
filled into
capsules using a suitable capsule filler such as a MG2 Futura.
Ingredient Conc. (% W/W)
Example 33:
Core from Example 1 75% (W/W)
Ethylcellulose 20
HPC 5
Example 34:
Core from Example 5 80% (W/W)
Eudragit RS 10
Eudragit RL 5
Talc 3
TEC 2
Example 35:
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Core from Example 5 90% (W/W)
=
Ethylcellulose 9
Triacetin 1
Example 36:
Core from Example 7 90% (W/W)
Surelease 10
Example 37:
Core from Example 11 85% (W/W)
. Kollicoat SR 10
TBC 5
Example 38:
Core from Example 15 = 80% (W/W)
= Polyethylene glycol 8000 5
Eudgragit RS 30D 15
Example 39:
Amoxicillin 75% (WfW)
Hydroxyethylcellulose 10
Polyethylene glycol 4000 10
Hydroxypropylcellulose 5
Example 40:
Ciprofloxacin 75% (W/W)
Lactose 10
Povidone (PVP) 10
Polyethylene glycol 2000 5
Example 41:
Clarithromycin 75% (W/W)
Polyethylene glycol 4000 10
Povidone (PVP) 10
Hydroxypropylcellulose 5
Example 42:
Ceftibuten 75% (W/W)
Lactose 15
= Polyethylene glycol 4000 5
Polyvinylpyrrolidone 5
III. Sustained Release Dosage Form With Coating To Delay Initiation of
Sustained Release:
Delaying the initiation of the sustained release of antibiotic in the present
invention is
achieved by either coating the immediate release component bead with a
sustained release coating
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and then subsequently applying an enteric coating or non pH sensitive delayed
release coating to
that coated bead, or alternatively the sustained release matrix component bead
may be coated with
an enteric coating or non pH sensitive delayed release coating.
Coatings can be applied to either the sustained release coated beads or the
sustained release
matrix beads to form a product which pulses the therapeutical agent in a
desired environment or
location of the GI tract.
III A. The following examples describe the detailed preparation of the
sustained-release
coating materials to be applied to the immediate release beads from section I
of the examples,
resulting in a sustained release component of the invention.
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Example 43. Eudragit RS example ¨ organic coating
Component Percentage (%)
Part A
Eudragit RS-100 6.0
Triethyl Citrate 1.0
Talc 0.5
Acetone 92.5
Step 1. Dissolve Eudragit in Acetone.
Step 2. Mix TEC and talc in a separate container with some Acetone.
Step 3. Add step 2 to Step 1, and allow to mix for 20 minutes before spraying.
=
Example 44. SureleaseTM example- aqueous coating
Component Percentage (%)
Part A
Surelease 90
Purified Water 10.0
Step 1. Mix surelease and water for 30 minutes before spraying.
Directions for application of the sustained release coating to the beads:
Charge a wurster column equipped fluid bed with the beads to be coated. Spray
the coating
onto the beads at a rate and temperature known to those skilled in the art of
bead coating so as to
efficiently coat the beads to give a weight gain of between 4 and 20 %. Dry
the beads to the
specified level of coating solvent for optimum handling and stability. Cure
the beads for additional
congealing of the sustained release film if required.
III B. The following are examples of the pH sensitive, or enteric release,
coating that can be used to
optionally delay the onset of action of any or all of the second, third, or
additional dosage forms.
The composition of the aqueous Eudragit L30D-55 dispersion to be applied to
the immediate
release components that have been treated with the above-described sustained
release coatings, or to
the sustained-matrix pellets is provided below in Example 45.
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Example 45. Eudragit L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit L 30 D-55 55.0
Trietliy1 Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
=
Polymer Content 15.9
Preparation Procedure for an Eudragit L 30 D-55 Aqueous Dispersion
Stepl Suspend triethyl citrate and talc in deionized water.
Step 2 The TEC/talc suspension is then homogenized using a PowerGen 700
high shear
mixer.
Step 3 Add the TEC/talc suspension slowly to the Eudragit L 30 D-55
latex dispersion
while stirring.
Step 4 Allow the coating dispersion to stir for one hour prior to
application onto the matrix
pellets.
Example 46. Preparation of an Eudragit S 100 Aqueous Coating Dispersion
Dispersion Formulation
The composition of the aqueous Eudragit S 100 dispersion applied to the
matrix pellets is
provided below:
Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water = 8.0
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Solid Content 20.0
Polymer Content 12.0
=
Preparation Procedure for an Eudragit S 100 Aqueous Dispersion
Part I:
(i) Dispense Endragite S 100 powder in deionized water with stirring.
(ii) Add ammonium hydroxide solution drop-wise into the dispersion with
stirring.
(iii) Allow the partially neutralized dispersion to stir for 60 minutes.
(iv) Add triethyl citrate drop-wise into the dispersion with stirring. Stir
for about
2 hours prior to the addition of Part B.
Part II:
(i) Disperse talc in the required amount of water
(ii) Homogenize the dispersion using a PowerGen 700D high shear mixer.
(iii) Part B is then added slowly to the polymer dispersion in Part A with
a
mild stirring.
Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used to coat matrix pellets with each of
the Eudragite L 30
D-55 and Eudragit0 S 100 aqueous film coating.
Coating Equipment STREA 1TM Table Top Laboratory Fluid Bed Coater
= Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 30 to 33 C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
(i) Coat matrix pellets with L30 D-55 dispersion such that you apply 12%
coat
weight gain to the pellets.
(ii) Coat matrix pellets with S100 dispersion such that you apply 20% coat
weight
gain to the pellets.
III. C. The following examples describe the detailed preparation of the non pH
sensitive coating
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materials to be used to optionally delay the onset of action of any or all of
the second, third, or
additional dosage forms:
=
Example 47. Rupturable Film
Component Percentage (%)
Part A
Cellulose Acetate 398-10 6.0
PEG 400 1.5
Acetone 92.5
Step 1. Dissolve cellulose acetate in Acetone.
Step 2. Add TEC to Step 1, and allow to mix for 20 minutes.
Directions for application of the sustained release coating to the beads:
Charge a wurster column equipped fluid bed with the beads to be coated. The
beads must
contain a component which will swell rapidly upon exposure to moisture. Beads
containing
croscarmellose sodium in Section I are good candidates as are beads with
swellable hydrophilic
polymers from Section II. Spray the coating onto the beads at a rate and
temperature known to those
skilled in the art of bead coating so as to efficiently coat the beads to give
a weight gain of between
4 and 20 %. Dry the beads to the specified level of coating solvent for
optimum handling and
stability.
Coating Conditions for the application of the rupturable film coating.
The following coating parameters were used to coat matrix mini tablets from a
previous
example with the rupturable film coating. A 2.5% weight gain provided the
desired lag time.
Coating Equipment Vector LDCS Coating System with 1.3L pan
Spray nozzle diameter 0.8 mm
Material Charge 800 grams
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 18 to 23 C
Atomization Air Pressure 25 psi
Pump Rate 6 grams per minute
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The enteric coatings and non-pH sensitive coatings as described above can be
applied to
either a sustained release matrix bead as in examples 16-25, or to the
immediate release component
beads that have been previously treated with a sustained release coating, to
thereby provide a
sustained release bead with a delayed onset of action. In addition, the
enteric coating or non-pH
sensitive coating can be applied to the immediate release component bead
directly to provide
delayed onset of action.
IV. Example Final Compositions
After one or all of the desired individual components are manufactured, the
final dosage
form is assembled and may take the shape of a tablet, capsule or sachet.
Preferably the final dosage
form takes the shape of a capsule or tablet. Most preferably the final dosage
form is a tablet.
One or more of the individual components can be used to achieve the desired
Daily T>MIC.
If one were to include three components in one's dosage form then preferably
the first, second, and
third dosage forms provide 20-70%, 10-70% and 10-70% of the total dosage form,
respectively.
More preferably the ratio of first, second and third dosage forms are in the
range of 25-66%, 15-60%
and 15-60% of the total dosage form respectively. Most preferably the ratio of
the first, second and
third dosage forms are in the range of 33-60%, 25-50%, And 25-50%
respectively. One can also
utilize one, two, three, or four or more components, and balance the ratio of
the components in such
a way to meet the Daily T>MIC
criteria.
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V. Example of three component Amoxicillin. Tablet and Sprinkle dosage
forms.
V-1. Description of the Dosage Form
API content can range for example from 10 to 80 % therapeutic compound, and in
the
case the therapeutic compound is amoxicilliri, it most preferably would
contain 775 mg
amoxicillin. The tablet can be of any desired shape, with a target gross
weight of approximately
1500 mg. The tablet can optionally be coated with a film, and/or imprinted.
The following specific example is written for components that contain
amoxicillin,
however other therapeutic agents can be substituted with proper proportion
adjustments known
to one skilled in the art of oral dosage form development.
The tablet of this invention is a rapidly disintegrating formulation
containing three active
intermediate compositions, an immediate-release granulation (Amoxicillin
Granules) and two
functionally coated delayed-release pellets (Amoxicillin Pulse 2 Pellets and
Amoxicillin Pulse 3
Pellets). Non-functional, color and clear film coats are optionally applied to
the outer surface
and/or the coated tablets are imprinted.
Figure 3 is a flowchart describing the General Procedure to Make a
Multiparticulate
Tablet.
Table 2 provides the qualitative and quantitative composition of three example
amoxicillin tablet formulations on a weight to weight (w/w%) basis of
individual ingredients.
For formulation B, an example set of procedures and component compositions for
making this
type of tablet is expanded. Table 3 provides the qualitative and quantitative
composition of an
example amoxicillin Tablet formulation on the basis of the tablet core,
coatings, and its active
intermediate compositions. Tables 4, 5, 6, and 7 provide the qualitative and
quantitative
composition of the Amoxicillin Granules, Amoxicillin Core Pellets, Amoxicillin
Pulse 2 Pellets,
and Amoxicillin Pulse 3 Pellets, respectively. An optional coating can be
applied and optional
tablet imprinting can be used to complete the product presentation.
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Table 2 Example Quantitative Compositions of Example Amoxicillin Tablets.
Component A (w/w%) B (w/v0/0) C
(w/w 00)
Amoxicillin, USP 78.476 59.524
62.821
Silicified Microcrystalline Cellulose 0.000 20.676 21.900
Crospovidone, NF 0.000 3.892
4.100
Methacrylic Acid Copolymer Dispersion, NF 4.272 2.926
2.879
Opadry Blue' 0.000 2.415
0.000
Talc, USP 3.617 2.036
1.804
Hydroxypropyl Methylcellulose Acetate Succinate 4.107 1.939
1.229
Microcrystalline Cellulose, NF 4.276 1.787
1.545
Povidone, USP 1.716 1.546
1.691
Opadry Clear 1 0.000 0.966
0.000
Magnesium Stearate, NF 0.000 0.966
1.000
Triethyl Citrate, NF 1.806 0.939
0.694
Polyoxyl 35 Castor Oil, NF 0.843 0.345
0.299
Sodium Lauryl Sulfate, NF 0.129 0.0152
0.039
Opadry II White, 33028523 0.761 0.000
0.000
Opacode Black 0.000 Trace Amount 0.0
Purified Water, USPI
Total 100.0 100.0
100.0
'Water removed during processing
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Table 3 Composition of an Example Amoxicillin Tablet by component.
Core
w/w%
Tablet
Amoxicillin Granules 28.6
Amoxicillin Pulse 2 Pellets 24.1
Amoxicillin Pulse 3 Pellets 20.9
Silicified Microcrystalline Cellulose 21.4
Crospovidone 4.0
,Magnesium Stearate 1.0
Core Tablet Weight 100
V-2 Amoxicillin Granules
Table 4 Qualitative and Quantitative Composition of Amoxicillin Granules
Component w/w%
Amoxicillin 97.0
Povidone 3.0
Purified Water' N/A
Total Amoxicillin Granules 100
'Water removed during processing
General Procedure for Manufacturing Arnoxicillin Granules:
=
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A standard wet granulation process known to one skilled in the art is used for
preparation
of the Amoxicillin Granules. The wet granules are discharged and fed into a
Dome Extrusion
Granulator. The wet extruded granules are then dried for a fixed period of
time or until the LOD
(loss on drying) of the granules is suitable for the formulation, typically
less than 15%. The
dried granules are then sized in a Rotating Impeller Screening Mill. The
milled material is
collected into drums.
V-3 Amoxicillin Core Pellets
The Core Pellets are used as the starting material for the later preparation
of the Pulse 2
Pellets and the Pulse 3 Pellets used in the tablet preparation. They also
serve as the core pellet
for the immediate release pellet in the sprinkle dosage form. The core pellets
are prepared using
the unit operations of wet granulating, extruding, spheronizing, fluid bed
drying and sizing. The
composition of the core pellets is listed in Table 5.
Table 5 Composition of Amoxicillin Core Pellets
Amoxicillin Trihydrate (92%) Pellet
Component = w/w%
Amoxicillin Trihydrate, Powder Grade, USP 92.0
Microcrystalline Cellulose, NF 5.0
Povidone K30, USP 2.0
Polyoxyl 35 Castor Oil, NF 1.0
Total 100
=
=
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=
V-4 Amoxicillin Pulse 2 Pellets
=Table 6 lists the composition of the example Amoxicillin Pulse 2 Pellets.
Table 6 Composition of Arno/derma Pulse 2 Pellets
Component = w/w Vo.
Amoxicillin 76.6
Microcrystalline Cellulose (Avicel PH-101) 4.19
Povidone (Ko11idor30) 1.69
Polyoxyl 35 Castor Oil (Cremophor EL)92( 0.80
Methacrylic Acid Copolymer Dispersion (Eudragit
1041
1.,30D-55)1
Talc 5.19
Triethyl Citrate 1.00
Purified Water2 N/A
Total Arno/derma Pulse 2 Pellets 100.0
Amount per tablet oldie solids content
zWater removed during processing
The Amoxicillin Pulse 2 Pellets are prepared by coating the previously
prepared
Amoxicillin Core Pellets with a functional film coat of methacrylic acid
copolymer dispersion,
20% w/w. Prior to the coating process, a dispersion of the methacrylic acid
copolymer is made
according to the manufacturer's instructions. The dispersion is applied to the
Amoxicillin Core
pellets using a Fluid Bed Bottom Spray Coster, equipped with appropriate spray
nozzles and a
fixed column gap distance.
The pellets are then appropriately sized. The Amoxicillin Pulse 2 Pellets may
be held in
ambient warehouse conditions until further processing.
V-5 Amoxicillin Pulse 3 Pellets
The amoxicillin pulse 3 pellets are prepared by coating the previously
prepared
Amoxicillin Core Pellets with a 5% w/w subcoat of methacrylic acid copolymer,
followed by a
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20 % w/w functional film coat of hypromellose acetate succinate.
Table 7 lists the composition of the example amoxicillin Pulse 3 pellets
Table 7. Composition of Amoxicillin Pulse 3 Pellets
Amount/Tablet
Component
(mg)
Amoxicillin 222.6
Microcrystalline Cellulose (Avicel PH-101) 12.1
Povidone (Kollidon 30) 4.8
Polyoxyl 35 Castor Oil (Cremophor EL) 2.4
Methacrylic Acid Copolymer Dispersion (Eudragit 7.6
L30D-55)
Hypromellose Acetate Succinate (AQOAT AS-HF) 29.0
Talc 12.4
Triethyl Citrate 10.6 =
Sodium Lauryl Sulfate 0.9
Purified Water2 N/A
Total Amoxicillin Pulse 3 Pellets 302.4
Amount per tablet of the solids content
2 Water removed during processing
Prior to the subcoating process, a dispersion of the methacrylic acid
copolymer is made
according to the manufacturer's instructions. The second coating material, the
hypromellose
acetate succinate dispersion is prepared according to the manufacturer's
instructions. The
. subcoat layer, is then applied to the Amoxicillin Core Pellets using the
same Fluid Bed Bottom
Spray Coater as used for preparation of the Pulse 2 Pellets.
The hypromellose acetate succinate coating dispersion is then immediately
applied to the
sub-coated pellets still in the Fluid Bed Bottom Spray Coater. The atomization
air used for the
second coating process is set at the same pressure as used for the sub coating
process. The
coating process is complete when all of the dispersion has been applied.
Following a drying
=
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period the final coated pellets are cooled.
The coated, dried and cooled Amoxicillin Pulse 3 Pellets are collected into
lined drums
The coated Pulse 3 Pellets are then sized. The Amoxicillin Pulse 3 Pellets may
be held in
ambient warehouse conditions until further processing.
V-6 Tabletting
The amoxicillin granules, pulse 2 pellets and pulse 3 pellets can be combined
at the
desired ratio and compressed on a rotary or other type of tablet press with
suitable tooling
installed for the desired size tablet. Ratios of Pulses or pellets can vary
depending on the
absorption characteristics of the desired drug. Ratios can range from front
loaded (middle loaded
or back loaded as per discussion in the specs section. The percent of each
component can range
from 10 ¨ 90 % for each of the at least 3 components in this example. For
example, but not in
anyway limiting, pulse 1 can be 10%, pulse 2 can be 80 % and pulse 3 can be 10
%. Or, as an
alternate non-limiting example, pulse 1 can be 30%, pulse 2 can be 50 % and
pulse 3 can be 20
%. In a preferred embodiment the tablet is manufactured by combining the
immediate-release
granulation (Pulse 1, 45%) with two functionally coated delayed-release
pellets (Pulse 2, 30%
and Pulse 3, 25%).
V-7 Optional Coatings
An additional optional coating can be applied to the tablet, or directly to
the core, pulse 2
and pulse 3 pellets according to the manufacturer's recommendation for the
coating process
conditions and procedures.
An optional printing on the tablets can be done using a formula as supplied by
the
manufacturer or as modified to suit the tablet characteristics. Additional
optional ingredients are
Microcrystalline Cellulose and Colloidal Silicon Dioxide. These can be added
to prevent tacking
and sticking if necessary. These two materials can be optionally obtained as
the composition
Prosolv SMCC 90 (FMC).
V-8 Sprinkle dosage form
These coated or uncoated pellets can be filled to give the desired dose into
an appropriate
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dosing device at the desired ratios as described above either separately or
all together, such as
a sachet, capsule, or other means of delivering the material to the consumer.
For example the core pellets may be coated with a non-functional immediate
release film coating to produce Pulse 1 pellets. The Pulse 1 pellets as well
as Pulse 2 and
Pulse 3 pellets may be used as a sprinkle product by placing the Pulse 1,
Pulse 2 and Pulse 3
pellets in a sachet, capsule or other form that can be used for simultaneous
delivery of the
three pulses in a particulate form. In one embodiment, Pulse 1, Pulse 2 and
Pulse 3 are
combined to provide 45%, 30% and 25% of Pulse 1, Pulse 2, and Pulse 3,
respectively.
Such combination of Pulses 1, 2 and 3 may be formulated into a sprinkle
product; e.g., a twice-a-day product that contains 475 mg or 775 mg of
amoxicillin. In
another embodiment, Pulse 1, 2 and 3 may be combined into a once-a-day
sprinlde product
that contains 775 mg or 1250 mg or 1550 mg of amoxicillin. The sprinkle
product may be
sprinkled over applesauce, yogurt, or other soft food for administration. The
product should
not be chewed or crushed.
The scope of the claims should not be limited by the preferred embodiments set
forth in the examples, but should be given the broadest interpretation
consistent with the
description as a whole. The present invention also extends to formulations
which are
bioequivalent to the pharmaceutical formulations of the present invention, in
terms of both
rate and extent of absorption, for instance as defined by the US Food and Drug
Administration
and discussed in the so-called "Orange Book" (Approved Drug Compositions with
Therapeutic Equivalence Evaluations, US Dept of Health and Human Services,
19th edn,
1999).
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