Note: Descriptions are shown in the official language in which they were submitted.
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THERAPEUTIC PRODUCT, USE AND FORMULATION THEREOF
This invention relates to an therapeutic product, as well as the use and
formulation thereof.
A wide variety of antibiotics, anti-fungal, anti-viral and anti-neoplastic
agents
have been used, and will be used, in order to treat a patient. In general,
such
therapeutics can be administered by a repeated dosing of immediate release
dosage
forms, which results in poor compliance or as a controlled release formulation
(slow
release) at higher administered doses. The present invention is directed to
providing
for an improved therapeutic product.
In accordance with one aspect of the present invention, there is provided a
pharmaceutical product which is comprised of at least two, preferably at least
three,
dosage forms, each comprised of at least one therapeutic agent and a
pharmaceutically
acceptable carrier. Such dosage forms are formulated so that each of the
dosage
forms has a different release profile. As used in this application the term
"therapeutic" or "therapeutic agent" means an antibiotic, or an anti-fungal or
an anti-
viral or an anti-neoplastic agent.
In a particularly preferred embodiment, there are at least two, preferably at
least three dosage forms, each of which has a different release profile and
the release
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profile of each of the dosage forms is such that the dosage forms each start
release of
the therapeutic contained therein at different times after administration of
the
therapeutic product.
Thus, in accordance with an aspect of the present invention, there is provided
a single or unitary therapeutic product that has contained therein at least
two,
preferably at least three therapeutic dosage forms, each of which has a
different
release profile, whereby the therapeutic contained in each of such dosage
forms is
released at different times.
In accordance with a further aspect of the invention, the therapeutic product
may be comprised of at least four different dosage forms, each of which starts
to
release the therapeutic contained therein at different times after
administration of the
therapeutic product.
The therapeutic product generally does not include more than five dosage
forms with different release times.
In accordance with a preferred embodiment, the therapeutic product has an
overall release profile such that when administered the maximum serum
concentration
of the total therapeutic released from the product is reached in less than
twelve hours,
preferably in less than eleven hours. In an embodiment, the maximum serum
concentration of the total therapeutic released from the therapeutic product
is
achieved no earlier than four hours after administration.
In accordance with one preferred embodiment of the invention, there are at
least three dosage forms. One of the at least three dosage forms is an
immediate
release dosage form whereby initiation of release of the therapeutic therefrom
is not
substantially delayed after administration of the therapeutic product. The
second and
third of the at least three dosage forms is a delayed dosage form (which may
be a pH
sensitive or a non-pH sensitive delayed dosage form, depending on the type of
therapeutic product), whereby the therapeutic released therefrom is delayed
until after
initiation of release of the therapeutic from the immediate release dosage
form. More
particularly, the therapeutic release from the second of the at least two
dosage forms
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achieves a Cmax (maximum serum concentration in the serum) at a time after the
therapeutic released from the first of the at least three dosage forms
achieves a Cma,, in
the serum, and the therapeutic released from the third dosage form achieves a
CJ. in
the serum after the Cmax of therapeutic released from the second dosage form.
In one embodiment, the second of the at least two dosage forms initiates
release of the therapeutic 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 therapeutic from the first dosage form of
the at least
three dosage forms.
In general, the immediate release dosage form produces a Cmax for the
therapeutic released therefrom within from about 0.5 to about 2 hours, with
the
second dosage form of the at least three dosage forms producing a C,,,ax for
the
therapeutic released therefrom in no more than about four hours. In general,
the Cmax
for such second dosage form is achieved no earlier than two hours after
administration
of the therapeutic product; however, it is possible within the scope of the
invention to
achieve C,,,ax in a shorter period of time.
As hereinabove indicated, the therapeutic product may contain at least three
or
at least four or more different dosage forms. For example, if the therapeutic
product
includes a third dosage form, the therapeutic released therefrom reaches a
Cmax at a
time later than the C,,,ax is achieved for the therapeutic released from each
of the first
and second dosage forms. In a preferred embodiment, release of therapeutic
from the
third dosage form is started after initiation of release of therapeutic from
both the first
dosage form and the second dosage form. In one embodiment, CIõax for
therapeutic
released from the third dosage form is achieved within eight hours.
In another embodiment, the therapeutic product contains at least four dosage
forms, with each of the at least four dosage forms having different release
profiles,
whereby the therapeutic released from each of the at least four different
dosage forms
achieves a C,,,ax at a different time.
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As hereinabove indicated, in a preferred embodiment, irrespective of whether
the therapeutic contains at least two or at least three or at least four
different dosage
forms each with a different release profile, Cmax for all the therapeutic
released from
the therapeutic product is achieved in less than twelve hours, and more
generally is
achieved in less than eleven hours.
In a preferred embodiment, the therapeutic product is a once a day product,
whereby after administration of the therapeutic product, no further product is
administered during the day; i.e., the preferred regimen is that the product
is
administered only once over a twenty-four hour period. Thus, in accordance
with the
present invention, there is a single administration of a therapeutic product
with the
therapeutic being released in a manner such that overall therapeutic release
is effected
with different release profiles in a manner such that the overall Cmax for the
therapeutic product is reached in less than twelve hours. The term single
administration means that the total therapeutic administered over a twenty-
four hour
period is administered at the same time, which can be a single tablet or
capsule or two
or more thereof, provided that they are administered at essentially the same
time.
Applicant has found that a single dosage therapeutic product comprised of at
least three therapeutic dosage forms each having a different release profile
is an
improvement over a single dosage therapeutic product comprised of an
therapeutic
dosage form having a single release profile. Each of the dosage forms of
therapeutic
in a pharmaceutically acceptable carrier may have one or more therapeutics of
the
same type (for example, one or more antibiotics; one or more anti-viral
agents, etc.)
and each of the dosage forms may have the same therapeutic or different
therapeutics,
each of the same type (the same or different antibiotics; the same or
different anti-
virals, etc.).
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
therapeutic may occur. Such "leakage" is not "release" as used herein.
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If at least four dosage forms are used, the fourth of the at least four dosage
form may be a sustained release dosage form or a delayed release dosage form.
If the
fourth dosage form is a sustained release dosage form, even though Cmax of the
fourth
dosage form of the at least four dosage forms is reached after the Cmax of
each of the
other dosage forms is reached, therapeutic release from such fourth dosage
form may
be initiated prior to or after release from the second or third dosage form.
The therapeutic product of the present invention, as hereinabove described,
may be formulated for administration by a variety of routes of administration.
For
example, the therapeutic product may be formulated in a way that is suitable
for
topical administration; administration in the eye or the ear; rectal or
vaginal
administration; as nose drops; by inhalation; as an injectable; or for oral
administration. In a preferred embodiment, the therapeutic product is
formulated in a
manner such that it is suitable for oral administration.
For example, in formulating the therapeutic product for topical
administration,
such as by application to the skin, the at least two different dosage forms,
each of
which contains an therapeutic, may be formulated for topical administration by
including such dosage forms in an oil-in-water emulsion, or a water-in-oil
emulsion.
In such a formulation, the immediate release dosage form is in the continuous
phase,
and the delayed release dosage form is in a discontinuous phase. The
formulation
may also be produced in a manner for delivery of three dosage forms as
hereinabove
described. For example, there may be provided an oil-in-water-in-oil emulsion,
with
oil being a continuous phase that contains the immediate release component,
water
dispersed in the oil containing a first delayed release dosage form, and oil
dispersed in
the water containing a third delayed release dosage form.
It is also within the scope of the invention to provide an therapeutic product
in
the form of a patch, which includes therapeutic dosage forms having different
release
profiles, as hereinabove described.
In addition, the therapeutic product may be formulated for use in the eye or
ear
or nose, for example, as a liquid emulsion. For example, the dosage form may
be
coated with a hydrophobic polymer whereby a dosage form is in the oil phase of
the
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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 therapeutic product with at least three different dosage
forms
with different release profiles may be formulated for rectal or vaginal
administration,
as known in the art. This may take the form of a cream or emulsion, or other
dissolvable dosage form similar to those used for topical administration.
As a further embodiment, the therapeutic product may be formulated for use in
inhalation therapy by coating the particles and micronizing the particles for
inhalation.
In a preferred embodiment, the therapeutic product is formulated in a manner
suitable for oral administration. Thus, for example, for oral administration,
each of
the dosage forms may be used as a pellet or a particle, with a pellet or
particle then
being formed into a unitary pharmaceutical product, for example, in a capsule,
or
embedded in a tablet, or suspended in a liquid for oral administration.
Alternatively, in formulating an oral delivery system, each of the dosage
forms
of the product may be formulated as a tablet, with each of the tablets being
put into a
capsule to produce a unitary therapeutic product. Thus, for example,
therapeutic
products may include a first dosage form in the form of a tablet that is an
immediate
release tablet, and may also include two or more additional tablets, each of
which
provides for a delayed release of the therapeutic, as hereinabove described,
whereby
the Cmax of the therapeutic released from each of the tablets is reached at
different
times, with the Cmax of the total therapeutic released from the therapeutic
product
being achieved in less than twelve hours.
The formulation of an therapeutic product 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 the
concentration
of therapeutics in the coating and/or the thickness of the coating.
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In formulating a therapeutic product in accordance with the invention, in one
embodiment, the immediate release dosage form of the product generally
provides
from about 20% to about 50% of the total dosage of therapeutic to be delivered
by the
product, with such immediate release dosage forms generally providing at least
25%
of the total dosage of the therapeutic to be delivered by the product. In many
cases,
the immediate release dosage form provides from about 20% to about 30% of the
total
dosage of therapeutic to be delivered by the product; however, in some cases
it may
be desirable to have the immediate release dosage form provide for about 45%
to
about 50% of the total dosage of therapeutic to be delivered by the product.
The remaining dosage forms deliver the remainder of the therapeutic. If more
than one delayed release dosage form is used, in one embodiment, each of the
delayed
release dosage forms may provide about equal amounts of therapeutic; 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 therapeutic; however, each of the dosage forms may contain more than
one
therapeutic.
In one embodiment, where the composition contains one immediate release
component and two delayed release components, the immediate release component
provides from 20% to 35% (preferably 20% to 30%), by weight, of the total
therapeutic; where there is three delayed release components, the immediate
release
component provides from 15% to 30%, by weight, of the total therapeutic; and
where
there are four delayed release components, the immediate release component
provides
from 10% to 25%, by weight, of the total therapeutic.
With respect to the delayed release components, where there are two delayed
release components, the first delayed release component (the one released
earlier in
time) provides from 30% to 60%, by weight, of the total therapeutic provided
by the
two delayed release components with the second delayed release component
providing the remainder of the therapeutic.
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Where there are three delayed release components, the earliest released
component provides 20% to 35% by weight of the total therapeutic provided by
the
three delayed release components, the next in time delayed release component
provides from 20% to 40%, by weight, of the therapeutic provided by the three
delayed release components and the last in time providing the remainder of the
therapeutic provided by the three delayed release components.
When there are four delayed release components, the earliest delayed release
component provides from 15% to 30%, by weight, the next in time delayed
release
component provides from 15% to 30%, the next in time delayed release component
provides from 20% to 35%, by weight, and the last in time delayed release
component
provides from 20% to 35%, by weight, in each case of the total therapeutic
provided
by the four delayed release components.
The Immediate Release Component
The immediate release portion of this system can be a mixture of ingredients
that breaks down quickly after administration to release the therapeutic. 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 therapeutics 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).
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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, glviceryl
monobutyrate, one of the non-ionic surfactants such as the Pluronic line of
surfactants, or any other material with surface active properties. or any
combination of
the above.
These materials may be present in the rate of 0.05-15% (WIW).
The non-pH Sensitive Delayed Release Component
The components in this composition are the same immediate release unit, but
with additional polymers integrated into the composition, or as coatings over
the
pellet or granule.
Materials that can be used to obtain a delay in release suitable for this
component of the invention can be, but are not limited to, polyethylene glycol
(PEG)
with molecular weight above 4,000 daltons (Carbowax, PolyoxTM), waxes such as
white
wax or bees wax, paraffin, acrylic acid derivatives (EudragitTM), 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.
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The kind of materials useful for this purpose can be, but are not limited to,
cellulose acetate pthalate, Eudragit L, and other pthalate salts of cellulose
derivatives.
These materials can be present in concentrations from 4-20% (W/W).
Sustained Release Component
The components in this composition are the same as the immediate release
component, but with additional polymers integrated into the composition, or as
coatings over the pellet or granule.
The kind of materials useful for this purpose can be, but are not limited to,
ethylcellulose,hydroxypropylmethyl cellulose,hydroxypropylcellul ose,
hydroxyethylcellulose, carboxymethylcellulose, methylcellulose,
nitrocellulose,
Eudragit R, and Eudragit RL, CarbopolTM, or polyethylene glycols with
molecular
weights in excess of 8,000 daltons.
These materials can be present in concentrations from 4-20% (W/W).
As hereinabove indicated, the units comprising the therapeutic composition of
the present invention can be in the form of discrete pellets or particles
contained in the
capsule, or particles embedded in a tablet or suspended in a liquid
suspension.
The therapeutic 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 therapeutic, which amount
will vary
with the therapeutic to be used, the disease or infection to be treated, and
the number
of times that the composition is to be delivered in a day. The composition is
administered to a host in an amount effective for treating the disease or
infection.
Thus, the therapeutic composition or product may be used for treating an
infection in
a host that is caused by bacteria or virus or fungus and may be used to treat
cancer.
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This system will be especially useful in extending the practial therapeutic
activity for antibiotics with elimination half lives of less than 20 hours and
more
particularly with elimination half-lives of less than 12 hours, and will be
particularly
useful for those drugs with half-lives of 2-10 hours. The following are
examples of
some antibiotics with half-lives of about 1 to 12 hours: Cefadroxil,
cefazolin,
cephalexin, cephalothin, cephapirin, cephacelor, cephprozil, cephadrine,
cefamandole,
cefonicid, ceforanide, cefuroxime, cefixime, cefoperazone, cefotaxime,
cefpodoxime,
ceftaxidime, ceftibuten, ceftizoxime, ceftriaxone, cefepime, cefinetazole,
cefotetan,
cefoxitin, loracarbef, imipenem, erythromycin (and erythromycin salts such as
estolate, ethylsuccinate, gluceptate, lactobionate, stearate), azithromycin,
clarithromycoin, dirithromycin, troleanomycin, penicillin V, peniciliin salts,
and
complexes, methicillin, nafcillin, oxacillin, cloxacillin, dicloxacillin,
amoxicillin,
amoxicillin and clavulanate potassium, ampicillin, bacampicillin,
carbenicillin indanyl
sodium (and other salts of carbenicillin) mezlocillin, piperacillin,
piperacillin and
taxobactam, ticarcillin, ticarcillin and clavulanate potassium, clindamycin,
vancomycin, novobiocin, aminosalicylic acid, capreomycin, cycloserine,
ethambutol
HC 1 and other salts, ethionamide, and isoniazid, ciprofloxacin, levofloxacin,
lomefloxacin, nalidixic acid, norfloxacin, ofloxacin, sparfloxacin,
sulfacytine,
suflamerazine, sulfamethazine, sulfamethixole, sulfasalazine, sulfisoxazole,
sulfapyrizine, sulfadiazine, sulfmethoxazole, sulfapyridine, metronidazole,
methenamine, fosfomycin, nitrofurantoin, trimethoprim, clofazimine, co-
triamoxazole, pentamidine, and trimetrexate.
The following are representative examples of some antifungals that can be
employed in the composition of the invention: amphotericin B, flucytosine,
fluconazole, griseofulvin, miconazole nitrate, terbinafine hydrochloride,
ketoconazole, itraconazole, undecylenic acid and chloroxylenol, ciclopirox,
clotrimazole, butenafine hydrochloride, nystatin, naftifine hydrochloride,
oxiconazole
nitrate, selenium sulfide, econazole nitrate, terconazole, butoconazole
nitrate, carbol-
fuchsin, clioquinol, methylrosaniline chloride, sodium thiosulfate,
sulconazole nitrate,
terbinafine hydrochloride, tioconazole, tolnaftate, undecylenic acid and
undecylenate
salts (calcium undecylenate, copper undecylenate, zinc undecylenate)
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The following are representative examples of some antivirals that may be used
in the invention: Acyclovir, Amantadine, Amprenavir, Cidofovir, Delavirdine,
Didanosine, Famciclovir, Foscarnet, Ganciclovir, Indinavir, Interferon,
Lamivudine,
Nelfinavir, Nevirapine, Palivizumab, Penciclovir, Ribavirin, Rimantadine,
Ritonavir,
Saquinavir, Stavudine, Trifluridine, Valacyclovir, Vidarabine, Zalcitabine,
Zidovudine
The following are representative examples of agents for the treatment of
cancer that may be used in accordance with the invention: carboplatin,
busulfan,
cisplatin, thiotepa, melphalan hydrochloride, cyclophosphamide, ifosfamide,
chlorambucil, mechlorethamine hydrochloride, carmustine, lomustine,
streptozocin,
polifeprosan 20, dexrazoxane, dronabinol, granisetron hydrochloride,
fluconazole,
erythropoietin, octreotide acetate, pilocarpine hydrochloride, etidronate
disodium,
pamidronate disodium, allopurinol sodium, amifostine, filgrastim, mesna,
ondansetron
hydrochloride, dolasetron mesylate, leucovorin calcium, sargramostim,
levamisole
hydrochloride, doxorubicin hydrochloride, idarubicin hydrochloride, mitomycin,
daunorubicin citrate, plicamycin, daunorubicin hydrochloride, bleomycin
sulfate,
mitoxantrone hydrochloride, valrubicin, dactinomycin, fludarabine phosphate,
cytarabine, mercaptopurine, thioguanine, methotrexate sodium, cladribine,
floxuridine, capecitabine, anastrozole, bicalutamide, tamoxifen citrate,
testolactone,
nilutamide, methyltestosterone, flutamide, toremifene citrate, goserelin
acetate,
estramustine phosphate sodium, ethinyl estradiol, esterified estrogen,
leuprolide
acetate, conjugated estrogens, megestrol acetate, aldesleukin,
medroxyprogesterone
acetate, dacarbazine, hydroxyurea, etoposide phosphate, megestrol acetate,
paclitaxel,
etoposide, teniposide, trastuzumab, rituximab, vinorelbine tartrate,
denileukin diftitox,
gemcitabine hydrochloride, vincristine sulfate, vinblastine sulfate,
asparaginase,
edrophonium chloride, bacillus calmette and guerin, irinotecan hydrochloride,
pegaspargase, docetaxel, interferon alfa-2a, recombinant, tretinoin, porfimer
sodium,
interferon alfa-2b, recombinant, procarbazine hydrochloride, topotecan
hydrochloride,
altretamine, fluorouracil, prednisolone sodium phosphate, cortisone acetate,
dexamethasone, dexamethasone sodium sulfate, dexamethasone acetate,
hydrocortisone sodium phosphate, hydrocortisone, prednisolone,
methylprednisolone
sodium succinate, betamethasone sodium phosphate, betamethasone acetate,
letrozole,
mithramycin, mitotane, pentostatin, perfosfamide, raloxifene
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In accordance with another aspect of the present invention there is provided a
procedure or regimen for treating a patient with a therapeutic agent that is
an
antibiotic, anti-viral, anti-fungal or anti-neoplastic agent by injection
thereof that
provides results similar to those achieved by the use of a product as
hereinabove
described that includes at least two and preferably at least three dosage
forms.
In accordance with this aspect of the invention, there is provided a regimen
for
treating a patient with a therapeutic agent wherein the therapeutic agent is
administered by injection, with the daily dosage being delivered over a period
that is
less than eleven hours (which period is measured from the first injection),
and
wherein there are at least two delivery pulses, and no more than thirty-two
delivery
pulses during a period of less than eleven hours, and preferably a period of
less than
eight hours. As used herein, "delivery pulses" means and may be accomplished
by at
least two spaced injections with periods between such spaced injections
wherein
essentially no therapeutic agent is injected into the host or alternatively,
between the
spaced injections, therapeutic agent is continuously injected in an amount
different
than that which is injected in the spaced injections. In addition, at least
two delivery
pulses can be achieved by continuous injection of the agent at one dosage,
followed
by continuous injection at a different dosage. In such a case there is a first
continuous
delivery pulse over a period of time, followed by a second continuous delivery
pulse
over a period of time. Thus, for example, in the latter case, there can be an
initial
injection wherein the therapeutic agent is continuously administered over a
period of
time followed by an increase in the dosage of the therapeutic agent that is
administered by injection over a period of time whereby in effect there are
two
delivery pulses even though there may be continuous administration of the
therapeutic
agent.
In one embodiment, in less than an eleven hour period, there is at least two
spaced injections of the therapeutic agent and generally no more than thirty-
two
spaced injections of the therapeutic agent. There may or may not be a
continuous
injection of the agent between the spaced injections and if there is such a
continuous
injection, the dosage of the agent is less than or more than the spaced
injections. In a
preferred embodiment, there is no injection of agent between the spaced
injections.
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In one preferred embodiment wherein there are spaced injections of the
therapeutic agent, up to about sixty percent, and preferably up to about fifty
percent of
the dosage that is to be injected in a period of less than eleven hours is
injected during
the first four hours of such period.
In one embodiment, there is provided two injections in less than a six hour
period. In another there is provided no more than six injections preferably in
less than
six hours. In a further embodiment there is provided at least four injections
preferably
over less than 6 hours.
In a preferred embodiment, the delivery pulses are accomplished by spaced
injections of the therapeutic agent in a pharmaceutically acceptable carrier.
There are
at least two and no more than 32 spaced injections, all of which are delivered
within
11 hours and preferably within 8 hours of the first injection. The daily
dosage is
delivered within such eleven or eight hour period and the spaced injections
provide
for at least 75%, preferably at least 90% and more preferably at least 100% of
the
agent that is to be delivered.
The therapeutic agent may be injected by any procedures known in the art. In
a preferred embodiment, the therapeutic agent may be injected by use of a
controlled
pump of a type known in the art for injecting pharmaceutical products.
Alternatively, the regimen of the invention may be employed in a hospital
wherein controlled injections are administered by use of a catheter.
Injections can be
made into any body structure, organ or blood vessel, such as intravenous,
intramuscular, subcutaneous, intradermal, intrathecal, intraperitoneal,
intraarticular,
intraocular, or other routes of injectable delivery.
In accordance with the invention by employing delivery pulses for injecting
the therapeutic agent in a period that is less than eleven hours and
preferably less than
eight hours, there is provided distinct maximum serum concentration pulses of
the
therapeutic agent in the blood of the patient in a period of less than 11
hours. In a
preferred embodiment, such distinct Cmax pulses occur in a period of less than
eight
hours and preferably within a period of six hours.
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In accordance with a preferred embodiment, all of the Cmax pulses are
achieved in a period of less than 11 hours, preferably less than eight hours,
and such
pulses provide the daily dosage of the therapeutic agent; i.e., the
therapeutic agent is
injected in at least two delivery pulses within eleven hours and there is no
further
administration over the remainder of a twenty-four hour period.
All or a portion of the delivery pulses of the therapeutic agent delivered by
spaced injections may be the same or different dosages of the therapeutic
agent.
In general at a minimum each spaced injection provides at least 5% of the
total
daily dosage of the therapeutic agent.
It is to be understood that each delivery pulse may include one or more
different therapeutic agents (for example two or more different antibiotics),
and each
delivery pulse may contain the same or different therapeutic agents (for
example, one
delivery pulse may contain two or more antibiotics and one may contain only
one of
the two or more antibiotics).
As hereinabove indicated the therapeutic agent is preferably an antibiotic or
an
anti-viral agent or an anti-fungal agent or an anti-neoplastic agent.
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.
WO 01/62229 CA 02400784 2002-08-23 PCT/US01/05758
Examples
Immediate Release Component (Antibiotic)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
dry blend. If
water or other solvent was used, dry the blend in a suitable pharmaceutical
drier,
such as a vacuum over or forced-air oven. The product may be sieved or
granulated,
and compressed using a suitable tablet press, such as a rotary tablet press.
Ingredient 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
Example 3:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 4:
Amoxicillin 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 5:
Amoxicillin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 6:
Clarithromycin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
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Croscarmellose sodium 5
Example 7:
Clarithromycin 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 8:
Clarithromycin 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 9:
Clarithromycin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 10:
Ciprofloxacin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 11:
Ciprofloxacin 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 12:
Ciprofloxacin 75% (W/W)
Polyethylene glyco14000 10
Polytheylene glyco12000 10
Hydroxypropylcellulose 5
Example 13:
Cirpofloxacin 75% (W/W)
Polyethylene glyco18000 20
Polyvinylpyrrolidone 5
Example 14:
Ceftibuten 75% (W/W)
Polyethylene glyco14000 10
Polyethylene glyco12000 10
Hydroxypropylcellulose 5
Example 15:
Ceftibuten 75% (W/W)
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Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
non-pH Sensitive Delayed Release Component (Antibiotic)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
In reg dient Conc. (% W/W)
Example 16:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Polyox 10
Croscarmellose sodium 5
Example 17:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 18:
Amoxicillin 65% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 19:
Clarithromycin 70% (W/W)
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Polyox 20
Hydroxypropylcellulose 5
Croscarmellose sodium 5
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Enteric Release Component (Antibiotic)
Formulate the ingredients by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 20:
Amoxicillin 65% (W/W)
Microcrystalline cellulose 20
Cellulose Acetate Pthalate 15
Example 21:
Amoxicillin 55% (W/W)
Microcrystalline cellulose 25
Cellulose Acetate Pthalate 10
Hydroxypropylmethylcellulose 10
Example 22:
Amoxicillin 65% (W/W)
Polyox 20
Hydroxypropylcellulose pthalate 10
Eudragit L30D 5
Example 23:
Amoxicillin 40% (W/W)
Microcrystalline Cellulose 40
Cellulose Acetate Pthalate 10
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Example 24:
Clarithromycin 70% (W/W)
Hydroxypropylcellulose pthalate 15
Croscarmellose sodium 10
Example 25:
Clarithromycin 75% (W/W)
Polyethylene glycol 2000 10
Eudragit E 30D 15
Example 26:
Clarithromycin 40% (W/W)
Lactose 50
Eudgragit L 30D 10
Example 27:
Ciprofloxacin 65% (W/W)
Microcrystalline Cellulose 20
Eudragit L 30D 10
Example 28:
Ciprofloxacin 75% (W/W)
Microcrystalline Cellulose 15
Hydroxypropylcellulose pthalate 10
Example 29:
Ciprofloxacin 80% (W/W)
Lactose 10
Eudgragit L 30D 10
Example 30:
Ciprofloxacin 70% (W/W)
Polyethylene glycol 4000 20
Cellulose acetate pthalate 10
Example 31:
Ceftibuten 60% (W/W)
Polyethylene glycol 2000 10
Lactose 20
Eudragit L 30D 10
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Example 32:
Ceftibuten 70% (W/W)
Microcrystalline cellulose 20
Cellulose acetate pthalate 10
Sustained Release Component (Antibiotic)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 33:
Amoxicillin 65% (W/W)
Ethylcellulose 20
Polyox 10
Hydroxypropylmethylcellulose 5
Example 34:
Amoxicillin 55% (W/W)
Lactose 25
Polyox 10
Glyceryl monooleate 10
Example 35:
Amoxicillin 70% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Example 36:
Clarithromycin 75% (W/W)
Lactose 15
Hydroxypropylcellulose 5
Ethylcellulose 5
Example 37:
Clarithromycin 75% (W; W)
Polyethylene glycol 4000 10
Lactose 10
Eudragit RL 30D 5
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Example 38:
Clarithromycin 80% (W/W)
Polyethylene glycol 8000 10
Hydroxypropylmethylcellulose 5
Eudgragit RS 30D 5
Example 39:
Ciprofloxacin 75% (W/W)
Hydroxyethylcellulose 10
Polyethylene glycol 4000 10
Hydroxypropylcellulose 5
Example 40:
Ciprofloxacin 75% (W/W)
Lactose 10
Povidone (PVP) 10
Polyethylene glyco12000 5
Example 41:
Ceftibuten 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
Immediate Release Component (Anti-fungal)
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.
Example 43:
Fluconazole 65% (W/W)
Microcrystalline cellulose 20
Povidone 10
Croscarmellose sodium 5
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Example 44:
Fluconazole 55% (W/W)
Microcrystalline cellulose 25
Povidone 10
Croscarmellose sodium 10
Example 45:
Fluconazole 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 46:
Fluconazole 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 47:
Fluconazole 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 48:
Ketoconazole 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 49:
Ketoconazole 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 50:
Ketoconazole 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 51:
Ketoconazole 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 52:
Griseofulvin 65% (W/W)
Microcrystalline cellulose 20
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Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 53:
Griseofulvin 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 54:
Griseofulvin 75% (W/W)
Polyethylene glyco14000 10
Polytheylene glycol 2000 10
Hydroxypropylcellulose 5
Example 55:
Cirpofloxacin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 56:
Terbinafine HCl 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 57:
Terbinafine HC1 75% (W/W)
Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
Non pH Sensitive Delayed Release Component (Anti-fungal)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 58:
Fluconazole 65% (W/W)
Microcrvstalline cellulose 20
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Polyox 10
Croscannellose sodium 5
Example 59:
Fluconazole 55% (W/W)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 60:
Fluconazole 65% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 61:
Ketoconazole 70% (W/W)
Polyox 20
Hydroxypropylcellulose 5
Croscarmellose sodium 5
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Enteric Release Component (Anti-fungal)
Formulate the ingredients by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
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Example 62:
Fluconazole 65% (W/W)
Microcrystalline cellulose 20
Cellulose Acetate Pthalate 15
Example 63:
Fluconazole 55% (W/W)
Microcrystalline cellulose 25
Cellulose Acetate Pthalate 10
Hydroxypropylmethylcellulose 10
Example 64:
Fluconazole 65% (W/W)
Polyox 20
Hydroxypropylcellulose pthalate 10
Eudragit L30D 5
Example 65:
Fluconazole 40% (W/W)
Microcrystalline Cellulose 40
Cellulose Acetate Pthalate 10
Example 66:
Ketoconazole 70% (W/W)
Hydroxypropylcellulose pthalate 15
Croscarmellose sodium 10
Example 67:
Ketoconazole 75% (W/W)
Polyethylene glycol 2000 10
Eudragit L 30D 15
Example 68:
Ketoconazole 40% (W/W)
Lactose 50
Eudgragit L 30D 10
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Example 69:
Griseofulvin 65% (W/W)
Microcrystalline Cellulose 20
Eudragit L 30D 10
Example 70:
Griseofulvin 75% (W/W)
Microcrystalline Cellulose 15
Hydroxypropylcellulose pthalate 10
Example 71:
Griseofulvin 80% (W/W)
Lactose 10
Eudragit L. 30D 10
Example 72:
Griseofulvin 70% (W/W)
Polyethylene glycol 4000 20
Cellulose acetate pthalate 10
Example 73:
Terbinafine HC1 60% (W/W)
Polyethylene glycol 2000 10
Lactose 20
Eudragit L 3 OD 10
Example 74:
Terbinafine HC1 70% (W/W)
Microcrystalline cellulose 20
Cellulose acetate pthalate 10
Sustained Release Component (Anti-fungal)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 75:
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Fluconazole 65% (W/W)
Ethylcellulose 20
Polyox 10
Hydroxypropylmethylcellulose 5
Example 76:
Fluconazole 55% (W/W)
Lactose 25
Polyox 10
Glyceryl monooleate 10
Example 77:
Fluconazole 70% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Example 78:
Ketoconazole 75% (W/W)
Lactose 15
Hydroxypropylcellulose 5
Ethylcellulose 5
Example 79:
Ketoconazole 75% (W/W)
Polyethylene glyco14000 10
Lactose 10
Eudragit RL 30D 5
Example 80:
Ketoconazole 80% (W/W)
Polyethylene glycol 8000 10
Hydroxypropylmethylcellulose 5
Eudgragit RS 30D 5
Example 81:
Griseofulvin 75% (W/W)
Hydroxyethylcellulose 10
Polyethylene glycol 4000 10
Hydroxypropylcellulose 5
Example 82:
Griseofulvin 75% (W/W)
Lactose 10
Povidone (PVP) 10
Polyethylene glycol 2000 5
Example 83:
Terbinafine HCI 75% (W; W)
Polyethylene glycol 4000 10
Povidone (PVP) 10
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Hydroxypropylcellulose 5
Example 84:
Terbinafine HCI 75% (W/W)
Lactose 15
Polyethylene glycol 4000 5
Polyvinylpyrrolidone 5
Example 85:
Ketoconazole 40% (W/W)
Eudragit S 100 50
Triethyl Citrate 10
Example 86:
Ketoconazole 50% (W/W)
Sureteric 50
Example 87:
Ketoconazole 50% (W/W)
Eudragit S 100 45
Triethyl Citrate 5
Immediate Release Component (Anti-viral)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
dry blend. If
water or other solvent was used, dry the blend in a suitable pharmaceutical
drier,
such as a vacuum over or forced-air oven. The product may be sieved or
granulated,
and compressed using a suitable tablet press, such as a rotary table press.
In redient Conc. (% W/W)
Example 88:
Acyclovir 65% (W/W)
Microcrystalline cellulose 20
Povidone 10
Croscarmellose sodium 5
Example 89:
Acyclovir 55% (W/W)
Microcrystalline cellulose 25
Povidone 10
Croscarmellose sodium 10
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Example 90:
Acyclovir 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 91:
Acyclovir 75% (W/W)
Polyethylene glyco14000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 92:
Acyclovir 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 93:
Zidovudine 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 94:
Zidovudine 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 95:
Zidovudine 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 96:
Zidovudine 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 97:
Valacyclovir 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
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Example 98:
Valacyclovir 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 99:
Valacyclovir 75% (W/W)
Polyethylene glyco14000 10
Polytheylene glycol 2000 10
Hydroxypropylcellulose 5
Example 100:
Cirpofloxacin 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 101:
Ribavirin 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 102:
Ribavirin 75% (W/W)
Polyethylene Glyco14000 20
Polyvinylpyrrolidone 5
Non pH Sensitive Delayed Release Component (Anti-viral)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 103:
Acyclovir 65% (W/W)
Microcrystalline cellulose 20
Polyox 10
Croscarmellose sodium 5
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Example 104:
Acyclovir 55% (W/W)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 105:
Acyclovir 65% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 106:
Zidovudine 70% (W/W)
Polyox 20
Hydroxypropylcellulose 5
Croscarmellose sodium 5
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Enteric Release Component (Anti-viral)
Formulate the ingredients by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
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Example 107:
Acyclovir 65% (W/W)
Microcrystalline cellulose 20
Cellulose Acetate Pthalate 15
Example 108:
Acyclovir 55% (W/W)
Microcrystalline cellulose 25
Cellulose Acetate Pthalate 10
Hydroxypropylmethylcellulose 10
Example 109:
Acyclovir 65% (W/W)
Polyox 20
Hydroxypropylcellulose pthalate 10
Eudragit L30D 5
Example 110:
Acyclovir 40% (W/W)
Microcrystalline Cellulose 40
Cellulose Acetate Pthalate 10
Example 111:
Zidovudine 70% (W/W)
Hydroxypropylcellulose pthalate 15
Croscarmellose sodium 10
Example 112:
Zidovudine 75% (W/W)
Polyethylene glycol 2000 10
Eudragit L. 30D 15
Example 113:
Zidovudine 40% (W/W)
Lactose 50
Eudgragit L 30D 10
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Example 114:
Valacyclovir 65% (W/W)
Microcrystalline Cellulose 20
Eudragit L 30D 10
Example 115:
Valacyclovir 75% (W/W)
Microcrystalline Cellulose 15
Hydroxypropylcellulose pthalate 10
Example 116:
Valacyclovir 80% (W/W)
Lactose 10
Eudragit L. 30D 10
Example 117:
Valacyclovir 70% (W/W)
Polyethylene glycol 4000 20
Cellulose acetate pthalate 10
Example 118:
Ribavirin 60% (W/W)
Polyethylene glycol 2000 10
Lactose 20
Eudragit L 30D 10
Example 119:
Ribavirin 70% (W/W)
Microcrystalline cellulose 20
Cellulose acetate pthalate 10
Sustained Release Component (Anti-viral)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum over or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
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Example 120:
Acyclovir 65% (W/W)
Ethylcellulose 20
Polyox 10
Hydroxypropylmethylcellulose 5
Example 121:
Acyclovir 55% (W/W)
Lactose 25
Polyox 10
Glyceryl monooleate 10
Example 122:
Acyclovir 70% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Example 123:
Zidovudine 75% (W/W)
Lactose 15
Hydroxypropylcellulose 5
Ethylcellulose 5
Example 124:
Zidovudine 75% (W/W)
Polyethylene glyco14000 10
Lactose 10
Eudragit RL 30D 5
Example 125:
Zidovudine 80% (W/W)
Polyethylene glycol 8000 10
Hydroxypropylmethylcellulose 5
Eudgragit RS 30D 5
Example 126:
Valacyclovir 75% (W/W)
Hydroxyethylcellulose 10
Polyethylene glycol 4000 10
Hydroxypropylcellulose 5
Example 127:
Valacyclovir 75% (W/W)
Lactose 10
Povidone (PVP) 10
Polyethylene glycol 2000 5
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Example 128:
Ribavirin 75% (W/W)
Polyethylene glycol 4000 10
Povidone (PVP) 10
Hydroxypropylcellulose 5
Example 129:
Ribavirin 75% (W/W)
Lactose 15
Polyethylene glyco14000 5
Polyvinylpyrrolidone 5
Example 130:
Zidovudine 40% (W/W)
Eudragit S 100 50
Triethyl Citrate 10
Example 131:
Zidovudine 50% (W/W)
Sureteric 50
Example 132:
Zidovudine 50% (W/W)
Eudragit S 100 45
Triethyl Citrate 5
Immediate Release Component (Cancer)
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.
Example 133:
Fluorouracil 65% (W/W)
Microcrystalline cellulose 20
Povidone 10
Croscarmellose sodium 5
Example 134:
Fluorouracil 55% (W/W)
Microcrystalline cellulose 25
Povidone 10
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Croscarmellose sodium 10
Example 135:
Fluorouracil 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 136:
Fluorouracil 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 137:
Fluorouracil 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 138:
Dexamethasone 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 139:
Dexamethasone 75% (W/W)
Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 140:
Dexamethasone 75% (W/W)
Polyethylene glycol 4000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 141:
Dexamethasone 75% (W/W)
Polyethylene glycol 8000 20
Polyvinylpyrrolidone 5
Example 142:
Valrubicin 65% (W/W)
Microcrystalline cellulose 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 143:
Valrubicin 75% (W/W)
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Microcrystalline cellulose 15
Hydroxypropylcellulose 5
Croscarmellose sodium 5
Example 144:
Valrubicin 75% (W/W)
Polyethylene glyco14000 10
Polytheylene glyco12000 10
Hydroxypropylcellulose 5
Example 145:
Cirpofloxacin 75% (W/W)
Polyethylene glyco18000 20
Polyvinylpyrrolidone 5
Example 146:
Tretinoin 75% (W/W)
Polyethylene glyco14000 10
Polyethylene glycol 2000 10
Hydroxypropylcellulose 5
Example 147:
Tretinoin 75% (W/W)
Polyethylene Glycol 4000 20
Polyvinylpyrrolidone 5
Non pH Sensitive Delayed Release Component (Cancer)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. ( /a W/W)
Example 148:
Fluorouracil 65% (W/W)
Microcrystalline cellulose 20
Polyox 10
Croscarmellose sodium 5
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Example 149:
Fluorouracil 55% (W/W)
Microcrystalline cellulose 25
Polyox 10
Glyceryl monooleate 10
Example 150:
Fluorouracil 65% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Croscarmellose sodium 5
Example 151:
Dexamethasone 70% (W/W)
Polyox 20
Hydroxypropylcellulose 5
Croscarmellose sodium 5
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Enteric Release Component (Cancer)
Formulate the ingredients by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 152:
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Fluorouracil 65% (W/W)
Microcrystalline cellulose 20
Cellulose Acetate Pthalate 15
Example 153:
Fluorouracil 55% (W/W)
Microcrystalline cellulose 25
Cellulose Acetate Pthalate 10
Hydroxypropylmethylcellulose 10
Example 154:
Fluorouracil 65% (W/W)
Polyox 20
Hydroxypropylcellulose pthalate 10
Eudragit I:_30D 5
Example 155:
Dexamethasone 70% (W/W)
Hydroxypropylcellulose pthalate 15
Croscarmellose sodium 10
Example 156:
Dexamethasone 70% (W/W)
Eudragit I., 30D 15
Hydroxypropylcellulose 10
Ethylcellulose 5
Example 157:
Dexamethasone 75% (W/W)
Polyethylene glycol 2000 10
Eudragit L 30D 15
Example 158:
Dexamethasone 40% (W/W)
Lactose 50
Eudgragit 1, 30D 10
Example 159:
Valrubicin 65% (W/W)
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Microcrystalline Cellulose 20
Eudragit I. 30D 10
Example 160:
Valrubicin 75% (W/W)
Microcrystalline Cellulose 15
Hydroxypropylcellulose pthalate 10
Example 161:
Valrubicin 80% (W/W)
Lactose 10
Eudragit L 30D 10
Example 162:
Valrubicin 70% (W/W)
Polyethylene glycol 4000 20
Cellulose acetate pthalate 10
Example 163:
Tretinoin 60% (W/W)
Polyethylene glyco12000 10
Lactose 20
Eudragit L 30D 10
Example 164:
Tretinoin 70% (W/W)
Microcrystalline cellulose 20
Cellulose acetate pthalate 10
Sustained Release Component (Cancer)
Formulate the composition by mixing the ingredients in a suitable
pharmaceutical
mixer or granulator such as a planetary mixer, high-shear granulator, fluid
bed
granulator, or extruder, in the presence of water or other solvent, or in a
hot melt
process. If water or other solvent was used, dry the blend in a suitable
pharmaceutical drier, such as a vacuum oven or forced-air oven. Allow the
product
to cool, the product may be sieved or granulated, and compressed using a
suitable
tablet press, such as a rotary tablet press.
Ingredient Conc. (% W/W)
Example 165:
Fluorouracil 65% (W/W)
Ethylcellulose 20
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Polyox 10
Hydroxypropylmethylcellulose 5
Example 166:
Fluorouracil 55% (W/W)
Lactose 25
Polyox 10
Glyceryl monooleate 10
Example 167:
Fluorouracil 70% (W/W)
Polyox 20
Hydroxypropylcellulose 10
Example 168:
Dexamethasone 75% (W/W)
Lactose 15
Hydroxypropylcellulose 5
Ethylcellulose 5
Example 169:
Dexamethasone 75% (W/W)
Polyethylene glyco14000 10
Lactose 10
Eudragit RL 30D 5
Example 170:
Dexamethasone 80% (W/W)
Polyethylene glycol 8000 10
Hydroxypropylmethylcellul.ose 5
Eudgragit RS 30D 5
Example 171:
Valrubicin 75% (W/W)
Hydroxyethylcellulose 10
Polyethylene glyco14000 10
Hydroxypropylcellulose 5
Example 172:
Valrubicin 75% (W/W)
Lactose 10
Povidone (PVP) 10
Polyethylene glycol 2000 5
Example 173:
Tretinoin 75% (W/W)
Polvethylene glycol 4000 10
Povidone (PVP) 10
Hydroxypropylcellulose 5
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Example 174:
Tretinoin 75% (W/W)
Lactose 15
Polyethylene glyco14000 5
Polyvinylpyrrolidone 5
Example 175:
Dexamethasone 40% (W/W)
Eudragit S 100 50
Triethyl Citrate 10
Example 176:
Dexamethasone 50% (W/W)
Sureteric 50
Example 177:
Dexamethasone 50% (W/W)
Eudragit S 100 45
Triethyl Citrate 5
Three Pulses
Example 178.
1. Metronidazole Matrix Pellet Formulation and Preparation Procedure
(Immediate Release)
A. Pellet Formulation
The composition of the metronidazole matrix pellets provided in Table 1.
Table 1 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 50
Avicel PH 101 20
Lactose 20
PVP K29/32* 10
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Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
B. Preparation Procedure for Metronidazole Matrix Pellets
1.2.1 Blend metronidazole and Avicel PH 101 using a Robot Coupe high shear
granulator.
1.2.2 Add 20% Povidone K29/32 binder solution slowly into the powder blend
under continuous mixing.
1.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The diameter
of the screen of the Bench Top Granulator was 1.0 mm.
1.2.4 Spheronize the extrudate using a Model SPH2O Caleva Spheronizer.
1.2.5 Dry the spheronized pellets at 50 C overnight.
1.2.6 Pellets between 16 and 30 Mesh were collected for further processing.
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1.1 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
metronidazole matrix pellets is provided below in Table 2.
Table 2 Eudragit L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Purified Water 37.4
Solids Content 25.5
Polymer Content 15.9
B. Preparation Procedure for an Eudragit L 30 D-55 Aqueous
Dispersion
1.2.7 Suspend triethyl citrate and talc in deionized water.
1.2.8 The TEC/talc suspension is then homogenized using a PowerGen 700 high
shear mixer.
1.2.9 Add the TEC/talc suspension slowly to the Eudragit L 30 D-55 latex
dispersion while stirring.
1.2.10 Allow the coating dispersion to stir for one hour prior to application
onto
the metronidazole matrix pellets.
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1.3 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion
A. Dispersion Formulation
The composition of the aqueous Eudragit0 S 100 dispersion applied to the
metronidazole matrix pellets is provided below in Table 3.
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Table 3 Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc 2.0
Purified Water 8.0
Solid Content 20.0
Polymer Content 12.0
B. Preparation Procedure for an Eudragit S 100 Aqueous Dispersion
Part I:
(i) Dispense Eudragit S 100 powder in deionized water with
stirring.
(ii) Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
(iii) Allow the partially neutralized dispersion to stir for 60 minutes.
(iv) Add triethyl citrate drop-wise into the dispersion with stirring.
Stir for about 2 hours prior to the addition of Part B.
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Part II:
(i) Disperse talc in the required amount of water
(ii) Homogenize the dispersion using a PowerGen 700D high shear
mixer.
(iii) Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
1.4 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used to coat matrix pellets with each of
the
Eudragit L 30 D-55 and Eudragit S 100 aqueous film coating.
Coating Equipment STREA 1 T"" Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 30 to 33 C
Atomization Air Pressure 1.8 Bar
Pump Rate 2 gram per minute
(i) Coat matrix pellets with L30 D-55 dispersion such that you
apply 12% coat weight gain to the pellets.
(ii) Coat matrix pellets with S 100 dispersion such that you apply
20% coat weight gain to the pellets.
1.5 Encapsulation of the Metronidazole Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 30%: 30%:
40%:
Immediate-release matrix pellets uncoated, L30 D-55 coated pellets and S 100
coated
pellets respectively.
The capsule is filled with the three different pellets to achieve a total dose
of
375mg/capsule.
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Three Pulses
Example 179
Amoxicillin Pellet Formulation and Preparation Procedure
179.1 Pellet Formulations for subsequent coating
The composition of the Amoxicillin trihydrate matrix pellets provided in Table
4.
Table 4 Composition of Amoxicillin Matrix Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during
wet
massing.
179.2 Preparation Procedure for Amoxicillin Matrix Pellets
179.2.1 Blend Amoxicillin and Avicel0 PH 101 using a low shear
blender.
179.2.2 Add the hydroxypropyl methylcellulose binder solution slowly
into the powder blend under continuous mixing.
179.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
179.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a
small cross section plate.
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179.2.5 Dry the spheronized pellets at 60 C -using a fluid bed dryer
until the exhaust temperature reaches 40 C.
179.2.6 Pellets between 20 and 40 Mesh were collected for further
processing.
179.3 Preparation of an Eudragit0 L 30 D-55 Aqueous Coating Dispersion
179.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
amoxicillin matrix pellets is provided below in Table 5.
Table 5 Eudragit0 L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit0 L 30 D-55 41.6
Triethyl Citrate 2.5
Talc 5.0
Purified Water 50.9
Solids Content 20.0
Polymer Content 12.5
179.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion
179.4.1 Suspend triethyl citrate and talc in deionized water.
179.4.2 The TEC/taic suspension is mixed using laboratory mixer.
179.4.3 Add the TEC/talc suspension from slowly to the Eudragit0 L
30 D-55 latex dispersion while stirring.
179.4.4 Allow the coating dispersion to stir for one hour prior to
application onto the amoxicillin matrix pellets.
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179.5 Preparation of an Eudragit S 100 Aqueous Coating Dispersion
179.5.1 Dispersion Formulation
The composition of the aqueous Eudragit S 100 dispersion applied to the
Amoxicillin matrix pellets is provided below in Table 6.
Table 6 Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
179.6 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion
Part A:
179.6.1 Dispense Eudragit S 100 powder in deionized water with
stirring.
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179.6.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
179.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
179.6.4 Add triethyl citrate drop-wise into the dispersion with stirring
and let stir overnight prior to the addition of Part B.
Part B:
179.6.5 Disperse talc in the required amount of water
179.6.6 Stir the dispersion using an overhead laboratory mixer.
179.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
179.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for both the Eudragit L 30 D-55
and
Eudragit S 100 aqueous film coating processes.
Coating Equipment STREA 1T"" Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 30 to 33 C
Atomization Air Pressure 1.8 Bar
Pump Rate 2-6 gram per minute
179.7.1 Coat matrix pellets with L30 D-55 dispersion such that you
apply 20% coat weight gain to the pellets.
179.7.2 Coat matrix pellets with S 100 dispersion such that you apply
37% coat weight gain to the pellets.
179.8 Preparation of Amoxicillin Granulation (Immediate Release Component) for
tabletting
Table 7 Composition of Amoxicillin Granulation
Component Percentage (%)
Amoxicillin Trihydrate powder 92
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Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during
wet massing.
179.8.1 Blend Amoxicillin and Avicel PH 101 using a low shear
blender.
179.8.2 Add the hydroxypropyl methylcellulose binder solution slowly
into the powder blend under continuous mixing.
179.8.3 Dry the granulation at 60 C using a fluid bed dryer until the
exhaust temperature reaches 40 C.
179.8.4 Granules between 20 and 40 Mesh are collected for further
processing.
179.9 Tabletting of the Amoxicillin Pellets
Table 8 Composition of Amoxicillin Tablets
Component Percentage (%)
Amoxicillin granules 32.5
Avicel PH 200 5.0
Amoxicillin L30D-55 coated pellets 30
Amoxicillin S 100 coated pellets 30
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
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179.9.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin
pellets and colloidal silicon dioxide for 15 minutes in a tumble
blender.
179.9.2 Add the magnesium stearate to the blender, and blend for 5
minutes.
179.9.3 Compress the blend on a rotary tablet press.
179.9.4 The fill weight should be adjusted to achieve a 500 mg dose
tablet.
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Three Pulses
Example 180
Clarithromycin Pellet Formulation and Preparation Procedure
180.1 Pellet Formulation
The composition of the clarithromycin matrix pellets provided in Table 1.
Table 9 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 50.6
Lactose monohydrate, spray dried 32.1
Silicified microcrystalline cellulose 14.6
Polyoxyl 35 Castor Oil* 1.7
Hydroxypropyl methylcellulose* 1.0
Total 100
*Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w
aqueous
solution during wet massing.
180.2 Preparation Procedure for Clarithromycin Matrix Pellets
180.2.1 Blend clarithromycin, silicified microcrystalline cellulose and
lactose monohydrate using a Robot Coupe high shear
granulator.
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180.2.2 Prepare the binder solution by adding the Polyoxyl to the
purified water while stirring. After that is mixed, slowly add
the hydroxypropyl methylcellulose and continue to stir until a
solution is achieved.
180.2.3 Add binder solution slowly into the powder blend under
continuous mixing.
180.2.4 Granulate the powders in the high shear granulator with the
binder solution.
180.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.2
mm.
180.2.6 Spheronize the extrudate using a Model SPH2O Caleva
Spheronizer.
180.2.7 Dry the spheronized pellets at 50 C overnight.
180.2.8 Pellets between 18 and 30 Mesh were collected for further
processing.
180.3 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion
180.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
clarithromycin matrix pellets is provided below in Table 10.
Table 10 Eudragit L 30 D-55 Aqueous Coating Dispersion
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Component Percentage (%)
Eudragit0 L 30 D-55 40.4
Triethyl Citrate 1.8
Talc 6.1
Water 51.7
Solids Content 20.0
Polymer Content 12.1
180.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion
180.4.1 Suspend triethyl citrate and talc in deionized water.
180.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer.
180.4.3 Add the suspension from 4.2.2 slowly to the Eudragit0 L 30 D-
55 latex dispersion while stirring.
180.4.4 Allow the coating dispersion to stir for one hour prior to
application onto the clarithromycin matrix pellets.
180.5 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion
180.5.1 Dispersion Formulation
The composition of the aqueous Eudragit0 S 100 dispersion applied to the
clarithromycin matrix pellets is provided below in Table 11.
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Table 11 Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 10.0
I N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
180.6 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion
Part A:
180.6.1 Dispense Eudragit S 100 powder in deionized water with
stirring.
180.6.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
180.6.3 Allow the partially neutralized dispersion to stir for 60 minutes
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180.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for
60 minutes prior to the addition of Part B.
Part B:
180.6.5 Disperse talc in the required amount of water
180.6.6 Homogenize the dispersion using a PowerGen 700D high shear
mixer.
180.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
180.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating the matrix pellets with
each
of the Eudragit L 30 D-55 and Eudragit S 100 aqueous film coating.
Coating Equipment STREA IT"' Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 30 to 33 C
Atomization Air Pressure 1.6 Bar
Pump Rate 2 gram per minute
180.7.1 Coat matrix pellets with L30 D-55 dispersion such that you
apply 20% coat weight gain to the pellets.
180.7.2 Coat matrix pellets with S 100 dispersion such that you apply
37% coat weight gain to the pellets.
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4. Capsules were filled with the uncoated pellets, the L30D-55 coated pellets
and
S100 coated pellets in weight percentages of 30%:30%:40%, respectively to
provide
250 mg. capsules.
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Four pulses
Example 181.
1 Metronidazole Matrix Pellet Formulation and Preparation Procedure
181.1 Pellet Formulation
The composition of the metronidazole matrix pellets provided in Table 12.
Table 12 Composition of Metronidazole Pellets
Component Percentage (%)
Metronidazole 50
Avicel PH 101 20
Lactose 20
PVP K29/32* 10
Purified Water
Total 100
*PVP K29/32 was added as a 20% w/w aqueous solution during wet massing.
181.2 Preparation Procedure for Metronidazole Matrix Pellets
181.2.1 Blend metronidazole and Avicel0 PH 101 using a Robot
Coupe high shear granulator.
181.2.2 Add 20% Povidone K29/32 binder solution slowly into the
powder blend under continuous mixing.
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181.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.0
mrn.
181.2.4 Spheronize the extrudate using a Model SPH2O Caleva
Spheronizer.
181.2.5 Dry the spheronized pellets at 50 C overnight.
181.2.6 Pellets between 16 and 30 Mesh were collected for further
processing.
181.3 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion
181.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
metronidazole matrix pellets is provided below in Table 13.
Table 13 Eudragit L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit L 30 D-55 55.0
Triethyl Citrate 1.6
Talc 8.0
Puri fied Water 37.4
Solids Content 25.5
Polymer Content 15.9
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181.4 Preparation Procedure for an Eudragit L 30 D-55 Aqueous Dispersion
181.4.1 Suspend triethyl citrate and talc in deionized water.
181.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer.
181.4.3 Add the TEC/talc suspension slowly to the Eudragit L 30 D-
55 latex dispersion while stirring.
181.4.4 Allow the coating dispersion to stir for one hour prior to
application onto the metronidazole matrix pellets.
181.5 Preparation of an Eudragit S 100 Aqueous Coating Dispersion
181.5.1 Dispersion Formulation
The composition of the aqueous Eudragit S 100 dispersion applied to the
metronidazole matrix pellets is provided below in Table 14.
Table 14 Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 12.0
1 N Ammonium Hydroxide 6.1
Triethyl Citrate 6.0
Purified Water 65.9
Part B
Talc ?.0
Purified Water 8.0
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Solid Content 20.0
Polymer Content 12.0
181.6 Preparation Procedure for an Eudragit0 S 100 Aqueous Dispersion
Part A:
181.6.1 Dispense Eudragit0 S 100 powder in deionized water with
stirring.
181.6.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
181.6.3 Allow the partially neutralized dispersion to stir for 60 minutes.
181.6.4 Add triethyl citrate drop-wise into the dispersion with stirring.
Stir for about 2 hours prior to the addition of Part B.
Part B:
181.6.5 Disperse talc in the required amount of water
181.6.6 Homogenize the dispersion using a PowerGen 700D high shear
mixer.
181.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
181.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating with each of the
Eudragit0 L
30 D-55 and Eudragit0 S 100 aqueous film coatings.
Coating Equipment STREA 1 T"" 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
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181.7.1 Coat matrix pellets with L30 D-55 dispersion such that you
apply 12% coat weight gain to the pellets.
181.7.2 Coat matrix pellets with L30 D-55 dispersion such that you
apply 30% coat weight gain to the pellets.
181.7.3 Coat matrix pellets with S 100 dispersion such that you apply
20% coat weight gain to the pellets.
181.8 Encapsulation of the Metronidazole Pellets
Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%:
20%: 30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12%
weight
gain, L30D-55 coated pellets 30% weight gain and S 100 coated pellets
respectively.
The capsule is filled with the four different pellets to achieve a total dose
of
375mg/capsule.
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Example 182
Amoxicillin Pellet Formulation and Preparation Procedure
182.1 Pellet Formulations
The composition of the Amoxicillin trihydrate matrix pellets provided in Table
15.
Table 15 Composition of Amoxicillin Matrix Pellets
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during
wet
massing.
182.2 Preparation Procedure for Amoxicillin Matrix Pellets
182.2.1 Blend Amoxicillin and Avicel PH 101 using a low shear
blender.
182.2.2 Add the hydroxypropyl methylcellulose binder solution slowly
into the powder blend under continuous mixing.
182.2.3 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator is 0.8 mm.
182.2.4 Spheronize the extrudate using a QJ-230 Spheronizer using a
small cross section plate.
182.2.5 Dry the spheronized pellets at 60 C using a fluid bed dryer
until the exhaust temperature reaches 40 C.
182.2.6 Pellets between 20 and 40 Mesh were collected for further
processing.
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182.3 Preparation of an Eudragit0 L 30 D-55 Aqueous Coating Dispersion
182.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
amoxicillin matrix pellets is provided below in Table 16.
Table 16 Eudragit0 L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit0 L 30 D-55 41.6
Triethyl Citrate 2.5
Talc 5.0
Purified Water 50.9
Solids Content 20.0
Polymer Content 12.5
182.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion
182.4.1 Suspend triethyl citrate and talc in deionized water.
182.4.2 The TEC/taic suspension is mixed using laboratory mixer.
182.4.3 Add the TEC/taic suspension from slowly to the Eudragit0 L
30 D-55 latex dispersion while stirring.
182.4.4 Allow the coating dispersion to stir for one hour prior to
application onto the amoxicillin matrix pellets.
182.5 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion
182.6 Dispersion Formulation
The composition of the aqueous Eudragit0 S 100 dispersion applied to the
Amoxicillin matrix pellets is provided below in Table 17.
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Table 17 Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 2.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
182.7 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion
Part A:
182.7.1 Dispense Eudragit S 100 powder in deionized water with
stirring.
182.7.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
182.7.3 Allow the partially neutralized dispersion to stir for 60 minutes.
1822.7.4 Add triethyl citrate drop-wise into the dispersion with stirring
and let stir overnight prior to the addition of Part B.
Part B:
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182.7.5 Disperse talc in the required amount of water
182.7.6 Stir the dispersion using an overhead laboratory mixer.
182.7.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
182.8 Preparation of Aquacoat Coating Dispersion
182.8.1 Dispersion Formulation
The composition of the aqueous Aquacoat dispersion applied to Amoxicillin L30
D-
55 coated pellets is provided below in Table 18.
Table 18
Component Percentage (%)
Aquacoat ECD 79.3
Hydroxypropyl methylcellulose 15.9
Dibutyl Sebacate 4.8
Purified Water (300g)
182.8.1.1 Prepare Hydroxypropyl methylcellulose (Methocel E15)
solution by dispersing in water with continuous stirring.
182.8.1.2 Add Aquacoat and dibutyl sebacate to the dispersion with
stirring and continue to stir overnight.
182.9 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating with each of the
Eudragit0 L
30 D-55 and Eudragit0 S 100 aqueous film coatings.
Coating Equipment STREA 1 T" Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 30 to 33 C
Atomization Air Pressure 1.8 Bar
Pump Rate 2-6 gram per minute
182.9.1 Coat Amoxicillin matrix pellets with L30 D-55 dispersim to
achieve a 20% coat weight gain.
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182.9.2 Coat another batch of Amoxicillin matrix pellets with L30 D-
55 dispersion to achieve a 20% weight gain. Coat the L30 D-
55 pellets with the Aquacoat Dispersion to achieve a 10% coat
weight gain.
182.9.3 Coat Amoxicillin matrix pellets with S 100 dispersion to
achieve a 37% coat weight gain.
182.10 Preparation of Amoxicillin Granulation for tabletting
Table 19 Composition of Amoxicillin Granulation (Immediate Release)
Component Percentage (%)
Amoxicillin Trihydrate powder 92
Avicel PH 101 7.0
Hydroxypropyl methylcellulose, NF* 1.0
Total 100
*Hydroxypropyl methylcellulose was added as a 2.9% w/w aqueous solution during
wet massing.
182.10.1 Blend Amoxicillin and Avicel PH 101 using a low shear
blender.
182.10.2 Add the hydroxypropyl methylcellulose binder solution slowly
into the powder blend under continuous mixing.
182.10.3 Dry the granulation at 60 C using a fluid bed dryer until the
exhaust temperature reaches 40 C.
182.10.4 Granules between 20 and 40 Mesh are collected for further
processing.
182.11 Tabletting of the Amoxicillin Pellets
Table 20 Composition of Amoxicillin Tablets
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Component Percentage (%)
Amoxicillin granules 32.5
Avicel PH 200 5.0
Amoxicillin L30D-55 coated pellets 20
Amoxicillin Aquacoated pellets 20
Amoxicillin S 100 coated pellets 20
Colloidal silicon dioxide 1.5
Magnesium stearate 1.0
Total 100
182.11.1 Blend the Amoxicillin granules, Avicel PH-200, Amoxicillin
pellets and colloidal silicon dioxide for 15 minutes in a tumble
blender.
182.11.2 Add the magnesium stearate to the blender, and blend for 5
minutes.
182.11.3 Compress the blend on a rotary tablet press.
182.11.4 The fill weight should be adjusted to achieve a 500 mg dose
tablet.
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Example 183
Clarithromycin Pellet Formulation and Preparation Procedure
183.1 Pellet Formulation
The composition of the clarithromycin matrix pellets provided in Table 21.
Table 21 Composition of Clarithromycin Pellets
Component Percentage (%)
Clarithromycin 50.6
Lactose monohydrate, spray dried 32.1
Silicified microcrystalline cellulose 14.6
Polyoxy135 Castor Oil* 1.7
Hydroxypropyl methylcellulose* 1.0
Total 100
*Hydroxypropyl methylcellulose and Polyoxyl 35 were added as an 8.7% w/w
aqueous
solution during wet massing.
183.2 Preparation Procedure for Clarithromycin Matrix Pellets
183.2.1 Blend clarithromycin, silicified microcrystalline cellulose and
lactose monohydrate using a Robot Coupe high shear
granulator.
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183.2.2 Prepare the binder solution by adding the Polyoxyl to the
purified water while stirring. After that is mixed, slowly add
the hydroxypropyl methylcellulose and continue to stir until a
solution is achieved.
183.2.3 Add binder solution slowly into the powder blend under
continuous mixing.
183.2.4 Granulate the powders in the high shear granulator with the
binder solution.
183.2.5 Extrude the wet mass using an LCI Bench Top Granulator. The
diameter of the screen of the Bench Top Granulator was 1.2
mm.
183.2.6 Spheronize the extrudate using a Model SPH2O Caleva
Spheronizer.
183.2.7 Dry the spheronized pellets at 50 C overnight.
183.2.8 Pellets between 18 and 30 Mesh were collected for further
processing.
183.3 Preparation of an Eudragit L 30 D-55 Aqueous Coating Dispersion
183.3.1 Dispersion Formulation
The composition of the aqueous Eudragit L30D-55 dispersion applied to the
clarithromycin matrix pellets is provided below in Table 22.
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Table 22 Eudragit0 L 30 D-55 Aqueous Coating Dispersion
Component Percentage (%)
Eudragit0 L 30 D-55 40.4
Triethyl Citrate 1.8
Talc 6.1
Water 51.7
Solids Content 20.0
Polymer Content 12.1
183.4 Preparation Procedure for an Eudragit0 L 30 D-55 Aqueous Dispersion
183.4.1 Suspend triethyl citrate and talc in deionized water.
183.4.2 The TEC/talc suspension is then homogenized using a
PowerGen 700 high shear mixer.
183.4.3 Add the suspension from 4.2.2 slowly to the Eudragit0 L 30 D-
55 latex dispersion while stirring.
183.4.4 Allow the coating dispersion to stir for one hour prior to
application onto the clarithromycin matrix pellets.
183.5 Preparation of an Eudragit0 S 100 Aqueous Coating Dispersion
183.5.1 Dispersion Formulation
The composition of the aqueous Eudragit0 S 100 dispersion applied to the
clarithromycin matrix pellets is provided below in Table 23.
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Table 23 Eudragit S 100 Aqueous Coating Dispersion
Component Percentage (%)
Part A
Eudragit S 100 10.0
1 N Ammonium Hydroxide 5.1
Triethyl Citrate 5.0
Water 64.9
Part B
Talc 5.0
Water 10.0
Solid Content 25.0
Polymer Content 10.0
183.6 Preparation Procedure for an Eudragit S 100 Aqueous Dispersion
Part A:
183.6.1 Dispense Eudragit S 100 powder in deionized water with
stirring.
183.6.2 Add ammonium hydroxide solution drop-wise into the
dispersion with stirring.
183.6.3 Allow the partially neutralized dispersion to stir for 60 minutes
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183.6.4 Add the triethyl citrate drop-wise to the dispersion and stir for
60 minutes prior to the addition of Part B.
Part B:
183.6.5 Disperse talc in the required amount of water
183.6.6 Homogenize the dispersion using a PowerGen 700D high shear
mixer.
183.6.7 Part B is then added slowly to the polymer dispersion in Part A
with a mild stirring.
183.7 Coating Conditions for the Application of Aqueous Coating Dispersions
The following coating parameters were used for coating with each of the
Eudragit L
30 D-55 and Eudragit S 100 aqueous film coatings.
Coating Equipment STREA 1T"' Table Top Laboratory Fluid Bed
Coater
Spray nozzle diameter 1.0 mm
Material Charge 300 gram
Inlet Air Temperature 40 to 45 C
Outlet Air Temperature 30 to 33 C
Atomization Air Pressure 1.6 Bar
Pump Rate 2 gram per minute
183.7.1 Coat matrix pellets with L30 D-55 dispersion such that you
apply 12% coat weight gain to the pellets.
183.7.2 Coat matrix pellets with L30 D-55 dispersion such that you
apply 30% coat weight gain to the pellets.
183.7.3 Coat matrix pellets with S 100 dispersion such that you apply
37% coat weight gain to the pellets.
183.8 Encapsulation of the Clarithromycin Pellets
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Pellets are filled into size 00 hard gelatin capsules at a ratio of 20%: 30%:
20%: 30%
Immediate-release matrix pellets (uncoated), L30 D-55 coated pellets 12%
weight
gain, L30D-55 coated pellets 30% weight gain and S 100 coated pellets
respectively.
The capsule is filled with the four different pellets to achieve a total dose
of
250mg/capsule.
The antifungal, antiviral and antineoplastic dosage forms can be formulated
into a single product (for example, a product containing three or four dosage
forms of
an antifungal) by a procedure similar to Examples 230-235, substituting the
desired
antifungal or antiviral or antineoplastic agent for the antibiotic.
The present invention is particularly advantageous in that there is provided
an
therapeutic product which provides an improvement over twice a day
administration
of the therapeutic and an improvement over a once a day administration of the
therapeutic.
Numerous modification and variations of the present invention are possible in
light of the above teachings and therefore, within the scope of the appended
claims
the invention may be practiced otherwise than as particularly described.
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