U.S. patent application number 09/927772 was filed with the patent office on 2002-08-15 for pharmaceutical formulation containing demo for the treatment of cancer.
This patent application is currently assigned to Ilex Oncology, Inc.. Invention is credited to McGinity, James, ev Shaked, Ze?apos.
Application Number | 20020110590 09/927772 |
Document ID | / |
Family ID | 21853378 |
Filed Date | 2002-08-15 |
United States Patent
Application |
20020110590 |
Kind Code |
A1 |
Shaked, Ze?apos;ev ; et
al. |
August 15, 2002 |
Pharmaceutical formulation containing DEMO for the treatment of
cancer
Abstract
Preparations comprising a capsule, tablet or other dosage form
containing a core of different types of DFMO are provided. These
preparations are capable of providing for the direct and constant
delivery of DFMO to the entire GI tract or just the colon and
rectum. The DFMO-containing granules include granules specially
formulated to achieve rapid DFMO release, and granules formulated
to achieve slower DFMO release and/or granules formulated for
gastric, enteric or colorectal release. Methods of using the
preparations to flood the GI tract with relatively constant levels
of DFMO may thus be provided. The ratio of the (+) to the
(-)-enantiomeric forms of DFMO in the granules will be controlled
so as to enhance the pharmacological profile and reduce toxicity of
the preparation relative to racemic DFMO. Preparations and methods
for achieving systemic delivery as well as direct colon delivery of
DFMO are also described.
Inventors: |
Shaked, Ze?apos;ev; (Boston,
MA) ; McGinity, James; (Austin, TX) |
Correspondence
Address: |
Steven L. Highlander, Esq.
FULBRIGHT & JAWORSKI L.L.P.
Suite 2400
600 Congress Avenue
Austin
TX
78701
US
|
Assignee: |
Ilex Oncology, Inc.
|
Family ID: |
21853378 |
Appl. No.: |
09/927772 |
Filed: |
August 10, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09927772 |
Aug 10, 2001 |
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09210345 |
Dec 11, 1998 |
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09210345 |
Dec 11, 1998 |
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PCT/AU97/20424 |
Oct 31, 1997 |
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60030266 |
Nov 1, 1996 |
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Current U.S.
Class: |
424/469 |
Current CPC
Class: |
A61K 9/5084 20130101;
A61K 9/2081 20130101; A61K 31/198 20130101; A61P 35/00 20180101;
A61K 9/209 20130101 |
Class at
Publication: |
424/469 |
International
Class: |
A61K 009/26 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 31, 1997 |
US |
PCT/US97/20424 |
Oct 31, 1997 |
EP |
97946915.2 |
Oct 31, 1997 |
CA |
2/241,896 |
Oct 31, 1997 |
JP |
10-520855 |
Claims
What is claimed is:
1. A pharmaceutical formulation comprising: a core having a rapid
release DFMO-containing granules and a slow release granule, said
granules comprising (+)-DFMO, (-)-DFMO or a defined ratio thereof,
or pharmaceutically acceptable salts thereof; and an outer layer
surrounding said core comprising a pH responsive coating.
2. The pharmaceutical formulation of claim 1 wherein the rapid
release granule is capable of releasing DFMO within two hours after
dissolution of the outer layer and the slow release granule is
capable of releasing DFMO within eight hours after dissolution of
the outer layer in an animal.
3. The pharmaceutical formulation of claim 1 or 2 wherein the pH
responsive coating is further defined as responsive to a pH of
about 6.0.
4. An oral solid multiple drug release pharmaceutical formulation
comprising: a core comprising DFMO-containing granules; and a
pH-responsive outer layer surrounding the core; wherein the
granules comprise (+)-DFMO, (-)-DFMO or a defined ratio thereof, or
pharmaceutically acceptable salts thereof.
5. The pharmaceutical formulation of claim 1 wherein the
DFMO-containing granules are further defined as comprising: a
gastric release granule; an enteric release granule; and a
colorectal release granule, wherein each granule comprises
(+)-DFMO, (-)-DFMO or a defined ratio thereof, or pharmaceutically
acceptable salts thereof.
6. A pharmaceutical formulation core comprising: a rapid release
granule having a binder, and a slow release granule having a
polymer, each granule comprising (+)-DFMO, (-)-DFMO or a defined
ratio thereof or pharmaceutically acceptable salts thereof; and an
outer layer surrounding said granule comprising a pH-responsive
coating, said pH responsive coating providing for release of the
core granules at or above a pH of about 6.
7. A multiple drug release profile pharmaceutical formulation
comprising: a core comprising a gastric release granule having a
binder and an excipient; an enteric release granule comprising a
polymer suitable for enteric drug delivery; a colorectal release
granule comprising a polymer which dissolves at a pH greater than
or equal to about 6; and an outer layer surrounding the core,
wherein each granule comprises a therapeutic amount of (+) DFMO,
(-)-DFMO pharmaceutically acceptable salts thereof.
8. The pharmaceutical formulation of claim 1, 2 or 6 wherein the
formulation is capable of providing a detectable plasma
concentration of DFMO in the range of about 0.1 .mu.M to about 1000
.mu.M.
9. The sustained release pharmaceutical formulation of claim 8
wherein the formulation is capable of providing a detectable plasma
concentration of DFMO in the range of about 1 .mu.M to about 100
.mu.M.
10. The solid multiple drug release profile pharmaceutical
formulation of claim 4 wherein the formulation is capable of
providing a plasma concentration level of DFMO of about 0.1 .mu.M
to about 1000 .mu.M.
11. The solid multiple drug release pharmaceutical formulation of
claim 4 further defined as an oral solid multiple drug release
pharmaceutical formulation, wherein the detectable plasma level of
DFMO is about 1 .mu.M to about 100 .mu.M.
12. A multi-coated pharmaceutical formulation comprising a core
pellet of DFMO-containing granules in a slow-release matrix, a
first coat of a colonic protective material; a second coat
comprising a pore forming agent; a rapidly dissolving polymeric
material and DFMO; a third coat comprising an acid resistant
polymer; and a fourth coat comprising a pore-forming agent and
DFMO.
13. The multi-coated pharmaceutical formulation of claim 12 wherein
the DFMO-containing granules comprise coated DFMO-containing
granules and uncoated DFMO-containing granules.
Description
[0001] This application is related to PCT No. US97/20424, filed
Oct. 31, 1997, designating the United States, the EP Application
No. 97946915.2, filed Oct. 31, 1997, the Canadian Application No.
2/241,896, filed Oct. 31, 1997, the Japanese Application No.
10-520855, filed Oct. 31, 1997, and the Mexican Application No.
985376, filed Jul. 1, 1998.
FIELD OF THE INVENTION
[0002] The present invention relates to a pharmaceutical
formulation and its use for the treatment of cancer. More
specifically, the present invention relates to
alphadifluoromethylomithine (DFMO) containing oral pharmaceutical
formulations having a varied release profile for the treatment of
cancer. These formulations may be modified for treating specific
cancers.
BACKGROUND OF THE INVENTION
[0003] Both in vivo and in vitro, DFMO is an enzyme activated
irreversible inhibitor of ornithine decarboxylase (ODC) which is
responsible for the conversion of L-ornithine to putrescine, which
in turn is converted to longer chain polyamines such as spermidine
and spermine. These longer chain polyamines are required for
cellular proliferation. Therefore, by inhibiting ODC, DFMO
suppresses polyamine formation and consequently cellular
proliferation. Aberrant and accelerated cellular proliferation
occurs in carcinogenic tissues. Since DFMO is able to suppress
polyamine formation, it is able to suppress cellular proliferation
and ultimately to ameliorate or prevent cancer. A number of animal
studies and/or human clinical trials relate to use of racemic DFMO
and specific neoplastic disorders. In addition, a clinical study to
determine the pharmacokinetics of racemic DFMO in healthy men has
been reported. (Haegele, 1981). Racemic DFMO was reported to have a
short elimination half-life, i.e., t.sub.1/2 is about 3.5 hours, as
it undergoes rapid renal elimination. Peak plasma concentrations
occur within about 6 hours after oral administration of racemic
DFMO containing solutions. Mean total body clearance is about 1.20
mL/min/LcKg, where mean renal clearance is about 0.99 mL/min/LcKg
accounting for 83% of drug elimination. The mean apparent volume
distribution is about 0.337 L/LcKg, corresponding to 24L for a 70
LcKg man. The amount of unchanged drug in 24-hour urine samples is
about 44% after oral administration and about 80% after L.c.
administration.
[0004] At a dose of about 3 g/m.sup.2V, a steady state level of
DFMO, 386-622, .mu.M may be achieved. A DFMO dose of 2.25 g/m2
every six hours has been recommended for Phase II studies in
patients previously treated with cytotoxic drugs (Abeloff et al.,
1984).
[0005] The maximally tolerated dose (MTD) of oral DFMO has also
been examined (Abeloff et al., 1984). The MTD of a 4-day DFMO
course given orally, by CI, or by pulse IV infusions (Griffin et
al., 1987) to patients with advanced solid tumors or lymphomas has
also been studied. Some patients receiving twenty-four courses of
oral DFMO on a 28-day schedule developed thrombocytopenia (the
DLT). Gastrointestinal side effects have also been observed in
treated patients (Abeloff et al., 1984). Audiometric abnormalities
is a further side effect associated with DFMO treatment (Griffin et
al., 1987). No therapeutic responses were noted in these patient
populations.
[0006] A study by Griffin et al. (1987) compared routes (PO, CI and
IV) and schedules (bolus and continuous infusions) of DFMO
administration. Nausea and vomiting were the most frequent and
severe toxicities noted, but this occurred mainly in patients
receiving oral DFMO. Diarrhea was also observed in patients
receiving oral DFMO. Mild leukopenia was further observed with all
routes of administration. Mild thrombocytopenia also occurred in
some patients. No therapeutic responses were reported with any
route of drug administration.
[0007] The known minimum effective dose (MED) for racemic DFMO in
significantly reducing polyamine pools in vivo is about 0.43 g/day.
The maximum tolerated dose of these preparations reported is about
12 g/m.sup.2/day (oral administration). The reported minimum toxic
dose for these racemic preparations of DFMO, in terms of
ototoxicity, is about 150 g/m.sup.2 cumulative dose based upon
0.25-6.0 g/m.sup.2/day chronic oral administration. GI toxicity
occurs predominantly during P.O. rather than I.V. administration of
racemic DFMO preparations. (-)-DFMO has been reported by some to be
the enantiomer primarily responsible for ODC inhibition (Danzin,
1987). However, the side effects associated with DFMO have been
traced to a particular enantiomeric form.
[0008] Tricalcium phosphate (TCP) and aluminum calcium phosphate
(AlCAP) capsule formulations have been tested as implants in rats
and proposed for the treatment of trypanosomiasis. (Benghuzzi et
al., 1988) A layered tablet formulation comprising racemic DFMO and
a slow release layer compressed to a rapid release layer has been
tested for controlling fertility and gestation in rat and mouse
models. (Bey et al., U.S. Pat. No. 4,309,442). Conventional release
hard gelatin capsule and tablet formulations comprising racemic
DFMO are also known and have been tested in rat, dog and/or mouse
models for controlling gestation, treating non-malignant
proliferative skin diseases and/or cancer chemoprevention. (Bey et
al., U.S. Pat. No. 4,496,588).
[0009] A need continues to exist in the medical arts for
formulations capable of maintaining high plasma levels of DFMO
during therapy in spite of its rapid clearance rate, without the
toxic and/or non-pleasant side effects associated with available
DFMO therapies.
SUMMARY OF THE INVENTION
[0010] It is an object of the present invention to provide an oral
solid DFMO-containing pharmaceutical formulation for the treatment
or prophylaxis of cancer. The formulations of the invention in some
aspects maintain DFMO plasma levels in a patient below the minimum
toxic concentration or maximum tolerated concentration and above
the minimum effective concentration or minimum therapeutic
concentration.
[0011] It is yet another object of the invention to provide a
method of treating or reducing the risk of cancer by administering
to a patient a formulation as described above so as to provide to
the gastrointestinal (GI) tract for an extended period of time a
therapeutic amount of DFMO.
[0012] It is another object of the invention to provide a
DFMO-containing dosage form having improved pharmacological
activity relative to racemic DFMO. The dosage form will comprise
optically pure (-)-DFMO or (+)-DFMO or a defined ratio of (-)-DFMO:
(+)-DFMO with reduced side effects or toxicity, enhanced
therapeutic efficacy and/or improved pharmacokinetics relative to
racemic DFMO.
[0013] In one aspect, the invention provides an oral sustained
release pharmaceutical formulation for the treatment or prophylaxis
of colorectal cancer comprising an oral dosage form. In some
embodiments, this dosage form comprises a core and an outer layer
surrounding the core, where:
[0014] 1) the core comprises a rapid release granule and a slow
release granule, and each granule comprises a therapeutic amount of
(+)-DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)-DFMO or
pharmaceutically acceptable salts thereof; and
[0015] 2) the outer layer comprises a pH-responsive coating for
colorectal release of the core.
[0016] It is contemplated and within the scope of the invention
that a formulation as described above will be useful for the
inhibition of cancer or tumor cell proliferation and the
amelioration of colorectal cancer.
[0017] It is also contemplated and within the scope of the present
invention that the pharmaceutical formulation may comprise racemic,
optically pure or a defined ratio of the (+):(-) enantiomers of
DFMO in combination with other therapeutic compounds for the
treatment or prophylaxis of cancer.
[0018] It is also contemplated and within the scope of the present
invention that the granules which comprise the dosage form core may
individually or cooperatively exhibit zero-order, first-order or
second-order DFMO release profiles in vivo or in vitro. The rapid
release and slow release granules can also act cooperatively to
provide a patient being administered the oral sustained release
formulation a mean steady state plasma concentration level of
(+)-DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)DFMO in the
range of about 0.1 .mu.M to about 1000 .mu.M.
[0019] It is contemplated and within the scope of the invention
that the present formulation will provide a therapeutic benefit
regardless of the location of the cancer.
[0020] In another aspect, the present invention provides an oral
sustained release pharmaceutical formulation for the treatment or
prophylaxis of colorectal cancer comprising an oral dosage form
having a core and an outer layer surrounding the core, where:
[0021] 1) the core comprises a rapid release granule and a slow
release granule, and each granule comprises a therapeutic amount of
(+)-DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)-DFMO or
pharmaceutically acceptable salts thereof; and
[0022] a) the rapid release granule releases into the colorectal
tract a major portion of its DFMO within two hours after
dissolution of the outer layer; and
[0023] b) the slow release granule releases into the colorectal
tract a major portion of its DFMO within eight hours after
dissolution of the outer layer; and
[0024] 2) the outer layer comprises a pH-responsive coating or
bacteria sensitive for colorectal release of the core at or above a
pH of about 6.
[0025] In another aspect, the present invention provides an oral
solid multiple drug release profile pharmaceutical formulation for
the treatment or prophylaxis of cancer. In some embodiments, these
oral solid multiple drug release profile pharmaceutical
formulations comprise an oral dosage form having a core and an
outer layer surrounding the core for gastric release of the core,
wherein the core comprises DFMO-containing granules having
different release characteristics; and the granules comprise
(+)-DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)-DFMO, or
pharmaceutically acceptable salts thereof.
[0026] In another embodiment, the oral solid multiple drug release
profile pharmaceutical formulation for the treatment or prophylaxis
of cancer comprises: an oral dosage form having a core and an outer
layer surrounding the core for gastric release of the core, where
the core comprises:
[0027] a gastric release granule;
[0028] an enteric release granule; and
[0029] a colorectal release granule; and
[0030] where each granule comprises a therapeutic amount of
(+)DFMO, (-)-DFMO or a defined ratio thereof, or pharmaceutically
acceptable salts thereof.
[0031] It is contemplated and within the scope of the present
invention that the dosage form may contain a variety of DFMO
containing granules having different release properties for
delivery of DFMO throughout the GI tract. The granules maybe
present in a range of different weight ratios, may each contain a
different amount of DFMO, and may themselves be comprised of other
granules. The overall DFMO release profile of this multiple drug
release profile pharmaceutical formulation can approximate a
zero-ordered controlled release profile.
[0032] It is intended that DFMO concentration in plasma will be
maintained at or above the minimum effective concentration for a
major portion of time during which DFMO-containing granules are
present in a patient. The gastric release, enteric release and
colorectal release granules can also act cooperatively to provide a
patient being administered the oral solid multiple drug release
profile pharmaceutical formulation a mean steady state plasma
concentration level of (+)-DFMO, (-)-DFMO or a defined ratio of
(+)-DFMO: (-)-DFMO in the range of about 0.1.mu.M to about
1000.mu.M.
[0033] Following long-standing patent law convention, the terms "a"
and "an" mean "one or more" when used in this specification.
[0034] Another aspect of the invention provides an oral sustained
release pharmaceutical formulation for the treatment or prophylaxis
of colorectal cancer. In some embodiments, the formulation
comprises an oral dosage form having a core and an outer layer
surrounding the core, where:
[0035] 1) the core comprises a rapid release granule and a slow
release granule, and each granule comprises a therapeutic amount of
(+)-DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)-DFMO or
pharmaceutically acceptable salts thereof;
[0036] 2) the rapid release granule further comprises a binder;
[0037] 3) the slow release granule further comprises a polymer;
and
[0038] 4) the outer layer comprises a pH-responsive coating for
colorectal release of the core at or above a pH of about 6.
[0039] In yet another aspect, the invention provides an oral solid
multiple drug release profile pharmaceutical formulation. In some
embodiments, the formulation is employed for the treatment or
prophylaxis of cancer. Some of these formulations may be defined as
comprising: an oral dosage form having a core and an outer layer
surrounding the core for gastric release of the core, where the
core comprises:
[0040] a gastric release granule comprising a binder and an
excipient;
[0041] an enteric release granule comprising a polymer suitable for
enteric drug delivery; and
[0042] a colorectal release granule comprising a polymer which
dissolves at a pH greater than or equal to about 6;
[0043] wherein each granule comprises a therapeutic amount of
(+)DFMO, (-)-DFMO or a defined ratio thereof, or pharmaceutically
acceptable salts thereof.
[0044] In yet another aspect, the present invention provides an
oral sustained release pharmaceutical formulation for the treatment
or prophylaxis of colorectal cancer in a patient. In some
embodiments, these formulations comprise an oral dosage form having
a core and an outer layer surrounding the core where:
[0045] the core comprises a rapid release granule and a slow
release granule, and each granule comprises a therapeutic amount of
(+)-DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)-DFMO or
pharmaceutically acceptable salts thereof; and
[0046] the outer layer comprises a pH-responsive coating for
colorectal release of the core; wherein the slow release and rapid
release granules provide a mean steady state plasma concentration
level of total DFMO above the minimum effective concentration for a
major portion of the time that slow release and/or rapid release
granules containing (+)-DFMO, (-)-DFMO or a defined ratio of
(+)-DFMO: (-)-DFMO are present in a patient administered the
sustained release pharmaceutical formulation.
[0047] In another aspect, the invention provides an oral solid
multiple drug release profile pharmaceutical formulation for the
treatment or prophylaxis of cancer. In some embodiments, the
formulation may be defined as comprising: an oral dosage form
having a core and an outer layer surrounding the core for gastric
release of the core, where the core comprises:
[0048] a gastric release granule;
[0049] an enteric release granule; and
[0050] a colorectal release granule;
[0051] wherein each granule comprises a therapeutic amount of
(+)DFMO, (-)-DFMO or a defined ratio of (+)-DFMO: (-)-DFMO, or
pharmaceutically acceptable salts thereof, and the gastric release,
enteric release and colorectal release granules cooperatively
provide a mean steady state plasma concentration level of total
DFMO above the minimum effective concentration for a major portion
of the time that gastric release, enteric release and/or colorectal
release granules containing (+)-DFMO, (-)-DFMO or a defined ratio
of (+)-DFMO: (-)-DFMO are present in a patient administered the
multiple drug release profile pharmaceutical formulation.
[0052] In yet another aspect, the present invention provides a
sustained release or multiple drug release profile pharmaceutical
formulation as described above that provides a mean steady state
plasma concentration level of total DFMO in the range of about 0.1
.mu.M to about 1000 .mu.M, or about 1 .mu.M to about 100 .mu.M, or
about 1 M to about 50 .mu.M.
[0053] The components used in the present invention are available
from a variety of commercial sources as follows:"EUDRAGIT.TM."
polymers (Rohm Pharma, Germany), "AQUA-COAT.TM." and
"AQUATERIC.TM." (F.M.C. Corp., PA), "SURELEASE".TM. and
"COATERIC.TM." (Colorcon, Inc., PA), "AQOAT.TM." (Shin-Etsu
Chemical Corp., Japan).
[0054] Unless otherwise indicated, all other chemicals were
purchased from Aldrich Chemicals (Milwaukee, Wis.) or Sigma
Chemical Co. (St. Louis, Mo.). Racemic and enantiomeric forms of
DFMO are available from Ilex Oncology.
[0055] As used herein, the term "granule" is taken to mean
particle, crystal, minitablet, crystal, powder, particulate, or
other similar solid forms. The granules used in the invention may
display diffusion and/or dissolution controlled release rate
profiles according to the components from and processes by which
they are made.
[0056] As used herein, the term "adsorbent" is intended to mean an
agent capable of holding other molecules onto its surface by
physical or chemical (chemisorption) means. Such compounds include,
by way of example and without limitation, powdered and activated
charcoal and the like.
[0057] As used herein, the term "antioxidant" is intended to mean
an agent which inhibits oxidation and thus is used to prevent the
deterioration of preparations by the oxidative process. Such
compounds include, by way of example and without limitation,
ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole,
butylated hydroxytoluene, hypophophorous acid, monothioglycerol,
propyl gallate, sodium ascorbate, sodium bisulfite, sodium
formaldehyde sulfoxylate and sodium metabisulfite and the like.
[0058] As used in the description of the present invention, a
granule is defined as, in some embodiments, an agglomerate, a
pellet, a tablet, a collection of more than one particle, or a
combination of these.
[0059] As used herein, the term "buffering agent" is intended to
mean a compound used to resist change in pH upon dilution or
addition of acid or alkali. Such compounds include, by way of
example and without limitation, potassium metaphosphate, potassium
phosphate, monobasic sodium acetate and sodium citrate anhydrous
and dihydrate and the like.
[0060] As used herein, the term "colorant" is intended to mean a
compound used to impart color to liquid and solid (e.g., tablets
and capsules) pharmaceutical preparations. Such compounds include,
by way of example and without limitation, FD&C Red No. 3,
FD&C Red No. 20, FD&C Yellow No. 6, FD&C Blue No. 2,
D&C Green No. 5, D&C Orange No. 5, D&C Red No.8,
caramel, and ferric oxide, red and the like.
[0061] As used herein, the term "flavorant" is intended to mean a
compound used to impart a pleasant flavor and often odor to a
pharmaceutical preparation. In addition to the natural flavorants,
many synthetic flavorants are also used. Such compounds include, by
way of example and without limitation, anise oil, cinnamon oil,
cocoa, menthol, orange oil, peppermint oil and vanillin and the
like.
[0062] As used herein, the term "sweetening agent" is intended to
mean a compound used to impart sweetness to a preparation. Such
compounds include, by way of example and without limitation,
aspartame, dextrose, glycerin, mannitol, saccharin sodium, sorbitol
and sucrose and the like.
[0063] As used herein, the term "tablet antiadherents" is intended
to mean agents which prevent the sticking of tablet formulation
ingredients to punches and dies in a tableting machine during
production. Such compounds include, by way of example and without
limitation, magnesium stearate and talc and the like.
[0064] As used herein, the term "tablet binders" is intended to
mean substances used to cause adhesion of powder particles in
tablet granulations. Such compounds include, by way of example and
without limitation, acacia, alginic acid, carboxymethylcellulose
sodium, compressible sugar (e.g., NuTab), ethylcellulose, gelatin,
liquid glucose, methylcellulose, povidone and pregelatinized starch
and the like.
[0065] As used herein, the term "tablet and capsule diluent" is
intended to mean inert substances used as fillers to create the
desired bulk, flow properties, and compression characteristics in
the preparation of tablets and capsules. Such compounds include, by
way of example and without limitation, dibasic calcium phosphate,
kaolin, lactose, mannitol, microcrystalline cellulose, powdered
cellulose, precipitated calcium carbonate, sorbitol, and starch and
the like.
[0066] As used herein, the term "tablet direct compression
excipient" is intended to mean a compound used in direct
compression tablet formulations. Such compounds include, by way of
example and without limitation, dibasic calcium phosphate (e.g.,
DITAB) and the like.
[0067] As used herein, the term "tablet disintegrant" is intended
to mean a compound used in solid dosage forms to promote the
disruption of the solid mass into smaller particles which are more
readily dispersed or dissolved. Such compounds include, by way of
example and without limitation, alginic acid,
carboxymethylcellulose calcium, microcrystalline cellulose (e.g.,
AVICEL), polacrilin potassium (e.g., AMBERLITE), sodium alginate,
sodium starch glycollate, and starch and the like.
[0068] As used herein, the term "tablet glidant" is intended to
mean agents used in tablet and capsule formulations to reduce
friction during tablet compression. Such compounds include, by way
of example and without limitation, colloidal silica, cornstarch,
and talc and the like.
[0069] As used herein, the term "tablet lubricant" is intended to
mean substances used in tablet formulations to reduce friction
during tablet compression. Such compounds include, by way of
example and without limitation, calcium stearate, magnesium
stearate, mineral oil, stearic acid, and zinc stearate and the
like.
[0070] As used herein, the term "tablet capsule opaquant" is
intended to mean a compound used to render a capsule or a tablet
coating opaque. May be used alone or in combination with a
colorant. Such compounds include, by way of example and without
limitation, titanium dioxide and the like.
[0071] As used herein, the term "tablet polishing agent" is
intended to mean a compound used to impart an attractive sheen to
coated tablets. Such compounds include, by way of example and
without limitation, carnauba wax, and white wax and the like.
[0072] It should be understood, that compounds used in the art of
pharmaceutical formulation generally serve a variety of functions
or purposes. Thus, if a compound named herein is mentioned only
once or is used to define more than one term herein, its purpose or
function should not be construed as being limited solely to that
named purpose(s) or function(s).
[0073] The term "unit dosage form" is used herein to mean a single
or multiple dose form containing a quantity of the therapeutic
compound containing formulation, said quantity being such that one
or more predetermined units are normally required for a single
therapeutic dministration. In the case of multiple dose forms, such
as scored tablets, said predetermined unit will be one fraction,
such as {fraction (1/2)}, of a scored tablet. "Halo" or "halogen"
as used herein refers to fluoro, chloro, bromo, and iodo; and
"counterion" is used to represent a small, negatively charged
species such as chloride, bromide, hydroxide, acetate, sulfate, and
the like.
[0074] As used herein, the term DFMO is intended to mean
alpha-difluoromethylornithine in its pharmaceutically acceptable
salt and/or isomeric forms. (+)-DFMO is intended to mean a
substantially optically pure preparation of
alpha-difluoromethylornithine having the (D)-configuration around
the alpha-carbon of the molecule. (-)-DFMO is intended to mean a
substantially optically pure preparation of
alpha-difluoromethylornithine having the (L)-configuration around
the alpha carbon. By "a defined ratio of (+)-DFMO: (-)-DFMO" is
meant a ratio of the individual DFMO optical isomers in the range
of about 5-95% wt: 95-5% wt., respectively. By "substantially
optically pure preparation" is meant a preparation of a first
enantiomer which contains about 5% wt. or less of the opposite
enantiomer. By "total DFMO" is meant the total amount of DFMO
present, i.e., the sum total of its enantiomers, in plasma, for
example.
[0075] Other features, advantages and embodiments of the invention
will be apparent to those skilled in the art from the following
description, accompanying data and appended claims.
BRIEF DESCRIPTION OF THE DRAWINGS
[0076] The following drawings form part of the present
specification and are included to further demonstrate certain
aspects of the invention. The invention may be better understood by
reference to one or more of these drawings in combination with the
detailed description of specific embodiments presented herein.
[0077] FIG. 1. Representations of the approximate DFMO release
profiles for various embodiments of the multiple drug release
profile formulation (compound preparation (a rapid release uncoated
pellet of DFMO, on enteric coated rapid release pellet and colonic
coated, rapid release pellets in combination) in a solid dosage
form is represented. The plasma time release profile of DFMO after
oral administration of the product containing the above compound is
shown. The plasma time release profile of DFMO after oral
administration of the rapid gastric release preparation in a solid
dosage form is demonstrated in FIG. 1. The rapid gastric release
preparation is presented as solid squares
(-.box-solid.-.box-solid.-.box-solid.-). The plasma release profile
of DFMO after oral administration of the enteric coated rapid
enteric release preparation in a solid dosage form is presented as
solid circles (-.circle-solid.-.circle-solid.-.circle-solid.-). The
colonic coated rapid release preparation in a solid dosage form is
presented as open circles
(-.smallcircle.-.smallcircle.-.smallcircle.-). The "total" line is
presented as a dashed line ( - - - ), and represents DFMO drug
release in a composite tablet or capsule that includes the coated
and uncoated particles in combination. The combination of these
various pellets may be changed to provide the desired drug delivery
to target sites in the GI tract by modifying the amount of drug to
be delivered with the desired coating to achieve the gastric,
enteric or colorectal release of the agent.
[0078] FIG. 2. Representations of the approximate DFMO release
profiles for three embodiments of the sustained release
formulation. The rapid colorectal release profile is demonstrated
as open circles (-.smallcircle.-.smallcircle.-.smallcircle.-). The
slow colonic release profile is demonstrated as open diamonds
(-.diamond.-.diamond.-.diamond.-- ). The rapid release pellets in
this profile (-.diamond.-.diamond.-.diamon- d.-) were first coated
with EUDRAGIT.TM. 4110D RS 30D and RL 30D and then coated with
EUDRAGIT.TM. 4110D. The composite total formulation provides a DFMO
drug release profile that is presented in a graph as a dashed line
( - - - ). Modified ratios of these two types of coated granules
may be created to provide the desired drug delivery profile.
[0079] FIG. 3. The slow enteric release DFMO drug release labelled
profile comprises a slow release matrix pellet formulation as
described in Example 15, table 31. The slow enteric release coated
preparation provides a drug release profile as noted in the filled
diamonds (-.diamond-solid.-.diamond-solid.-.diamond-solid.-). The
rapid gastric release preparation is expected to provide a DFMO
drug release profile as noted in the solid squares
(-.box-solid.-.box-solid.-.box-solid.-). The slow colorectal
release preparation will provide an expected DFMO release profile
as presented in the open squares (-.quadrature.-.quadrature.-.qua-
drature.-). The slow release matrix pellets were first coated with
Opadry.RTM. II and then EUDRAGIT.TM. 4110D. The in vitro disolution
profile of these uncoated slow release matrix pellets appear at
FIG. 18.
[0080] FIG. 4. Proposed in vivo plasma release of DFMO for matrix
pellets coated with EUDRAGIT.TM. 4110D is demonstrated on the graph
as filled diamonds
(-.diamond-solid.-.diamond-solid.-.diamond-solid.-). The rapid
release granules of DFMO were first coated with AQUACOAT.RTM.
containing HPMC and then coated with EUDRAGIT.TM. 4110D (open
circles, -.smallcircle.-.smallcircle.-.smallcircle.-). The
combination of these two pellets is also shown as the dashed line (
- - - ).
[0081] FIG. 5. Proposed in vivo plasma release profile of DFMO. The
proposed enteric coated rapid gastric release pellet is presented
as filled circles (-.circle-solid.-.circle-solid.-.circle-solid.-).
The proposed slow release uncoated maxtix pellets provide a release
profile presented as open triangles (-.DELTA.-.DELTA.-.DELTA.-).
The proposed colorectal coated slow release matrix pellets are
presented as open squares
(-.quadrature.-.quadrature.-.quadrature.-). The proposed DFMO drug
release profile is presented as a dashed line ( - - - ).
[0082] FIG. 6. Proposed in vivo plasma release profile of DFMO. The
proposed rapid gastric release coated pellet profile is presented
as filled squares (-.box-solid.-.box-solid.-.box-solid.-). The
enteric coated slow release matrix pellets are presented as solid
diamonds (-.diamond-solid.-.diamond-solid.-.diamond-solid.-). The
colorectal coated rapid release pellets are presented as open
circles (-.smallcircle.-.smallcircle.-.smallcircle.-).
[0083] FIG. 7. A first embodiment of a dosage form for the multiple
drug release profile formulation. 1=hard gelatin capsule or caplet
shaped tablet; 2=coated pellet; 3=matrix slow release pellet;
4=rapid release pellet.
[0084] FIG. 8. A first embodiment of a dosage form for the
sustained release formulation. 5=coated pellet; 6=rapid release
pellet; 7=retardant coating or immediate release coating.
[0085] FIG. 9. Cross-sectional view of a matrix rapid release
granule of the invention. 8=spherical pellet; 9=drug in pellet
core.
[0086] FIG. 10. Cross-sectional view of a coated rapid release
granule of the invention. 10=drug in core; 11=coating.
[0087] FIG. 11. Cross-sectional view of a multi-layered rapid
release granule of the invention. 10=drug in core; 11=multi coated
pellet; 12=immediate release coating that may contain drugs;
13=coatings that dissolve or disintegrate as a function of pH or
microbial interaction.
[0088] FIG. 12. Cross-sectional view of a first tablet dosage form
of the sustained release formulation embodiment of the invention.
15=drug in matrix core for slow delivery to the GI tract; 16=drug
in priming dose in HPMC or similar rapid release coating.
[0089] FIG. 13. Cross-sectional view of a second tablet dosage form
containing sustained release coated pellets in a rapidly
disintegrating tablet compact. 19=rapid release pellet;
18=sustained release coating (EUDRAGIT.TM. 4110 or EUDRAGIT.TM.
4110D); 17=tablet granulation containing DFMO for immediate release
and absorption; 20=compressed tablet.
[0090] FIG. 14. Dissolution profile of uncoated rapid release
pellets in 500 ml, 0.1 N HCl using the USP method II.
[0091] FIG. 15. Dissolution profile in pH 1.0 and 6.8 of rapid
release DFMO pellets coated with 8% EUDRAGIT.TM. L30D 55.
[0092] FIG. 16. Influence of pH on the dissolution properties of
rapid release DFMO pellets coated with EUDRAGIT.TM. 4110D.
[0093] FIG. 17. Influence of pH on the release of DFMO from rapid
release, DFMO core pellets coated first with 10% EUDRAGIT.TM.
RS/RL30D (9:1) and then 8% EUDRAGIT.TM. 41100D as presented as open
squares ().
[0094] FIG. 18. Release profile in vitro of uncoated slow release
matrix pellets at pH 7.4 () and pH of 1.0 (). The data demonstrates
that the release achieved with these pellets is pH independent.
[0095] FIG. 19. Release of DFMO from coated wax containing matrix
pellets at pH 1.0 and pH 6.8. ()=EUDRAGIT.TM. 4110D coating;
()=EUDRAGIT.TM. L30D-55). Proposed percent DFMO released from a
preparation comprising a core of a wax matrix pellet having a first
coat of Opadry.RTM. II (as a subcoat), and a second coat of a
EUDRAGIT.TM. 4110D or S100, illustrated with dashed, filled squares
(). Proposed percent DFMO released from a preparation comprising a
core of a wax matrix pellet with a first coat of Opadry.RTM. II (as
a subcoat), and a second coat of EUDRAGIT.TM. L30D-55, is
illustrated in the dashed, dotted line ().
[0096] The subcoat of Opadry.RTM. II may comprise a 2% to 3% weight
gain of HPMC. The acrylic polymeric coating may then be applied by
spraying the polymer over the subcoat. The retardant polymer coat
in some embodiments may be expressed as an amount that comprises
about an 8% to an about 18% net weight gain. By way of example,
these polymers may comprise EUDRAGIT.TM. L30D-55 or EUDRAGIT.TM.
4110D.
[0097] The release profiles in an acidic media reflect poor
adhesion of the anionic polymers to the wax pellets containing
DFMO. The rapid release of the drug in the absence of the subcoat
was evident from both pellet formulations in the acidic medium as
demonstrated in FIG. 19.
[0098] FIG. 20. Demonstrates profile of a slow release matrix
pellet formulation that was first coated with an ethyl cellulose
dispersion (AQUACOAT.RTM.) containing HPMC, and then coated with
EUDRAGIT.TM. 4110D.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0099] The present invention provides a variety of combined
varied-release pharmaceutical formulations that include DFMO, and
provide for its delivery in preparations designed to be capable of
sustaining a desired release profile and/or plasma concentration
tailored to the pathology or condition being treated. The
particular preparations described below are examples of some of
these formulations and variations thereof in view of same are
intended as within the scope of the invention.
[0100] Dosage Form Outer Layer
[0101] The dosage form outer layer (7) which surrounds the dosage
form core comprising granules (5) and (6) will generally be
insoluble in gastric juices and will release the core in a pH
responsive fashion. Advantageously, the outer layer will release
the core upon exposure to a pH of about 6 or higher and will
generally have released the dosage form core contents directly into
the colorectal tract of a patient. By targeting the colorectal
tract for DFMO delivery, the present formulation will find use in
the treatment and/or prevention of colorectal cancer or other
polyamine dependent colorectal disorders such as premalignant
polyps.
[0102] By "pH-responsive" is meant a pH-dependent fashion, i.e. the
outer layer, when exposed to a certain pH, will deliver the dosage
form core to the colorectal tract. Advantageously, the outer layer
will be comprised of a pH-responsive polymer that will dissolve
when exposed to a pH greater than or equal to about 6; although,
the pH-responsive polymer may dissolve at a pH greater than or
equal to about 5.
[0103] The outer layer will comprise, by way of example and without
limitation, a polymeric compound such as EUDRAGIT.TM. RS and
EUDRAGIT.TM. RL. The EUDRAGIT.TM. products form latex dispersions
of about 30D by weight. EUDRAGIT.TM. RS 30D is designed for slow
release since it is not very water permeable as a coating and
EUDRAGIT.TM. RS 30D is designed for rapid release since it is
relatively water permeable as a coating. These two polymers are
generally used in combination. As contemplated herein, the
permissible ratios of EUDRAGIT.TM. RS 30D/EUDRAGIT.TM. RL 30D is
about 10:0 to about 8:2. Ethylcellulose or S100 or other equivalent
polymers designed for enteric or colorectal release can also be
used in place of the EUDRAGIT.TM. RS/EUDRAGIT.TM. RL combination
above. The outer layer can also comprise dyes, dissolution aids,
colorants and pigments. Such components for the outer layer are
available from Colorcon (Delaware) or Crompton & Knowles (New
Jersey).
[0104] Rapid Release Granule in the Dosage Form Core
[0105] With particular attention to FIG. 8, rapid release granules
(6) will comprise part of the dosage form core which is surrounded
in its entirety by the outer layer (7). The rapid release granule
will generally not be soluble in gastric juices and need not be
soluble in enteric or colorectal fluids. It may release DFMO in
either a pH-dependent or pH-independent fashion and/or a
zero-order, first-order or second-order fashion. The rapid release
granule will generally be a dissolution controlled formulation. The
rapid release granule may provide a patient with a loading dose of
DFMO to quickly establish in the patient a target DFMO plasma
concentration level which is generally above the minimum effective
concentration (MEC)of DFMO. Alternatively, the rapid release
granule will permit the direct rather than systemic exposure of
colorectal mucosa to DFMO.
[0106] The rapid release granule containing DFMO will
advantageously have released into the colorectal tract a major
portion of its DFMO within two hours after dissolution of the
dosage form outer layer. Although intended for colorectal release,
it is possible this granule will release some of its DFMO upstream
in the GI tract if the dosage form outer layer has dissolved
prematurely.
[0107] The rapid release granule will comprise DFMO and other
compounds such as starch, talc, sugar, magnesium stearate,
microcrystalline cellulose (MCC), lactose and pregelatinized
starch. The rapid release granule can also comprise dissolution
aids, stability modifiers, adsorption promoters, bioadhesive
polymers and density modifiers.
[0108] The rapid release granule may be, by way of example and
without limitation, a quickly dissolving polymeric matrix (9)
having DFMO (8) dispersed therein (FIG. 9), a DFMO core (10)
surrounded by a rapidly dissolving coating (11) (FIG. 10), a
multi-layered granule having a non-pareil core (12) surrounded by
alternating layers of DFMO (13) and a binder (14) (FIG. 11) or a
spheronized bead comprising DFMO, binder and excipient integrally
mixed therein.
[0109] Methods for the preparation of rapid release granules are
well known in the art and depend upon whether the release is to be
pH-dependent or pH-independent; or zero-order, first-order or
second-order. One method for the preparation of these granules is
detailed in Example 2.
[0110] By "binder" is meant compounds such as
hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC),
methylcellulose and the like. By "excipient" is meant an inactive
adjuvant ingredient used in processing pharmaceutical solid dosage
forms that aids in the manufacturing and processing or has a
functional purpose after administration to a patient, e.g.
disintegration aid. Binders include, by way of example and without
limitation, compounds such as microcrystalline cellulose (MCC),
carbohydrates, polysaccharides, pregelatinized starches, calcium
phosphate, calcium sulfate, starches and polymeric excipients.
[0111] Slow Release Granule in the Dosage Form Core
[0112] With particular attention to FIG. 8, slow release granules
(5) will comprise part of the dosage form core which is surrounded
in its entirety by the outer layer (7). The slow release granule
will generally not be soluble in gastric juices and may release its
DFMO in either a pH-dependent or pH-independent fashion. The slow
release granule can maintain DFMO plasma concentration levels at or
about the concentrations achieved by the rapid release granule. By
virtue of its release profile, the slow release granule will
provide the colorectal mucosa with both direct and systemic
exposure to DFMO.
[0113] The slow release granule containing DFMO will generally
release a major portion of its DFMO into the large intestine
(colon) and the rectum a major portion of its DFMO within eight
hours after dissolution of the dosage form outer layer. Although
intended for colorectal release, it is possible this granule will
release some of its DFMO prior to entering the colon if the dosage
form outer layer has dissolved prematurely.
[0114] The slow release granule will comprise DFMO and a polymer.
Such polymers include EUDRAGIT.TM. S100, EUDRAGIT.TM.
RS30D/EUDRAGIT.TM. RL30D, hydrophilic colloidal celluloses, aqueous
dispersions of cellulose, such as AQUA-COAT.TM. and SURELEASE,
polysaccharides, such as sodium alginate, xanthan gum, proteins,
gelatins, chitosan, clays, such asmerilonite, poly(ethylene oxide),
bioadhesives, acrylic vinyl resins, such as CARBOPOL, polyacrylic
acid resins, such as POLYCARBOPHYL, waxes, hydrogenated castor oil
and high molecular weight vegetable oils.
[0115] The slow release granule may be, by way of example and
without limitation, a slow dissolving/releasing polymeric matrix
having DFMO dispersed therein or a DFMO-containing core surrounded
by a slow releasing polymeric layer.
[0116] Methods for the preparation of slow release granules are
well known in the art and depend upon whether the release is to be
pH-dependent or pH-independent; diffusion or dissolution
controlled; or zero-order, first-order or second-order. One method
for the preparation of these granules is detailed in Example 3.
[0117] Dosage Formulation
[0118] FIG. 8 depicts one embodiment of the sustained release
formulation of the present invention. In this caplet dosage form,
the rapid release granules (6) together with the slow releases
granules (5) are surrounded by a pH responsive outer layer (7).
This embodiment comprises an outer layer (7), a rapid release
granule (6) and a slow release granule (5). This dosage form may be
a capsule, gelcap or caplet. With particular attention to FIG. 12,
the present dosage form may also be a tablet where a core (15),
comprising a slow releasing polymeric matrix having DFMO dispersed
therein is surrounded by a layer (16), comprising DFMO integrally
mixed with a binder and an excipient, which is then surrounded by a
pH responsive outer layer (7). Referring now to FIG. 13, the dosage
form can also be a tablet where the core (20) comprises DFMO (17)
and slow release granules (5) dispersed therein. The slow release
granules (5) comprise a pH responsive coating (18) surrounding a
DFMO core (19). The tablet core (20) is surrounded by a pH
responsive coating (7).
[0119] FIG. 2 shows the expected plasma DFMO concentration profile
expected when one embodiment of the sustained release formulation
of the present invention is used. MTC indicates the minimum toxic
concentration as determined by plasma concentration of DFMO. MEC
indicates the minimum effective concentration. It is intended that
the mean plasma drug concentration level, as indicated by the
curved dashed line, will not drop below the MEC for a major portion
of the time in which DFMO-containing granules remain in a patient.
It is also intended that the two granules will act cooperatively to
yield an approximate overall zero-order controlled release profile
for the formulation as a whole.
[0120] The DFMO plasma concentration profile in a patient is the
sum total of the release profiles of each given granule in a dosage
form. Thus, various combinations of granules having different
release profiles can act cooperatively to generate a DFMO plasma
concentration profile as shown in FIG. 2.25.
[0121] FIG. 2 shows how a first rapid colorectal releasing granule
and a second slow colorectal releasing granule can act
cooperatively to yield the desired overall DFMO plasma
concentration profile for the sustained release formulation of the
invention. DFMO plasma concentration is maintained between the MTC
and MEC for a major portion of the time in which DFMO-containing
granules are present in a patient. As per the area under the curve,
the total amount of DFMO released by the rapid release granules can
be less than that released by the slow release granules.
[0122] FIG. 4 shows how a first slow colorectal releasing granule
and a second rapid colorectal releasing granule can act
cooperatively to yield the desired DFMO plasma concentration
profile for the sustained released formulation of the
invention.
[0123] It should be understood that specific release profiles for
each granule will vary. It is contemplated and within the scope of
the invention that various release profile shapes may be attained
by each granule without departing from the spirit and scope of the
invention.
[0124] It should also be understood that the MEC will vary
according to the indication being treated, patient response, the
DFMO form being used, dosing regimen and a host of other reasons.
It is generally intended when referring to the MEC that the total
amount of DFMO present in plasma is being contemplated. When
administered acutely, the MEC for DFMO will generally be higher
than when it is administered chronically. When administered for
preventing or reducing the risk of cancer, the MEC for DFMO will
generally be lower than when it is administered for treating or
controlling the growth of cancer.
[0125] The MEC based upon mean steady state plasma concentration
for DFMO will generally fall in the range of about 0.1 .mu.M to
about 1000 .mu.M and preferably in the range of about 1 .mu.M to
about 100 .mu.M and more preferably in the range of about 1.mu.M to
about 50 .mu.M. It should be understood that the maximum
concentration level (Cmax) of DFMO will exceed the MEC but will
generally be less than the MTC.
[0126] Thus according to one embodiment of the sustained release
formulation of the invention, the slow release and rapid release
granules will act cooperatively to provide a mean steady plasma
concentration level for DFMO in the range of about 0.1 .mu.M to
about 1000 .mu.M and preferably in the range of about 1 .mu.M to
about 100 .mu.M and more preferably in the range of about 1 .mu.M
to about 50 .mu.M.
[0127] The rapid and slow release granules of the invention may
each be present in a wide range of amounts according to the
formulation DFMO release profile desired. By way of example and
without limitation, if both granules had the same amount of DFMO,
it may be desirable to include the granules in the following ratio
about 1:5 parts by weight (rapid: slow release granule) if
predominantly direct flooding of the colorectal tract by DFMO were
desirable and if greater emphasis on sustaining a long DFMO release
profile were desired. Conversely, the ratio of about 5:1 parts by
weight (rapid: slow release granule) would give predominantly
systemic exposure of the colorectal tract to DFMO and would
emphasize the rapid attainment of a maintenance plasma DFMO
concentration. The exact ratio chosen will depend upon individual
patient response to DFMO therapy, the extent of colorectal cancer
progression, the optical form of the DFMO administered, the actual
dosage of DFMO in each granule or the desired dosing regimen.
[0128] Generally, each granule will be present in the range of
about 1.0 to about 9.0 parts by weight using about 10 parts by
weight as the basis for the total number of parts which the dosage
form may contain, i.e. the granules will generally be present in
the ratio of about 1.0-about 9.0: about 1.0-about 9.0 parts by
weight (rapid: slow release granule). Rather than to vary the
relative amounts of rapid release and slow release it may be
desirable to vary the amount of DFMO is each granule.
[0129] The dosage form of the present invention can be a tablet,
caplet, gelcap or capsule, e.g. hard gelatin or soft gelatin
capsule. When the sustained release formulation of the invention
takes the form of a gelcap, caplet or tablet, the granules may be
held together by and coated with a pH responsive layer that
dissolves in colorectal fluids thereby releasing the granules in
the colorectal tract and directly flooding it with DFMO.
[0130] When the dosage form is a capsule containing rapid and slow
release particle, it may generally be prepared as follows. A
capsule outer layer comprised of an upper half and a lower half is
preformed of a material which is pH responsive and soluble in
colorectal fluids. The lower half is filled with core contents such
as rapid and slow release granules and then capped (sealed) with
the upper half to form a capsule shaped dosage form. The relative
sizes of the halves as well as the final size of the capsule outer
layer generally depend upon the size and weight of the capsule
core.
[0131] As used herein, the term "therapeutic compound" is taken to
mean a compound having the desired beneficial pharmacologic and
therapeutic effects in mammals. Advantageously, the therapeutic
compound is also cytoxic or cytostatic and indicated for the
treatment or prophylaxis of cancer.
[0132] The therapeutic compounds contemplated within the scope of
the invention may be in their free acid, free base, or
pharmaceutically acceptable salt forms. They may be derivatives or
prodrugs of a given compound. -Loading of the therapeutic compounds
into a pharmaceutical formulation may be accomplished following
well known techniques such as those described [in] Remington's
Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton,
Pa., 1985, the disclosure of which is hereby incorporated by
reference.
[0133] Therapeutic compound loading into the formulation may need
to be varied according to the pharmacological activity of the
compound, the indication being treated, the targeted dosing
regimen, the projected method of administration, the integrity or
stability of the final formulation or other such reasons.
[0134] Multiple Drug Release Profile Formulation
[0135] FIG. 7 shows a capsule or tablet dosage form (1) for the
multiple drug release profile formulation of the invention which
comprises a gastric release granule (4), an enteric release granule
(3) and a colorectal coated pellet (2). The multiple drug release
profile formulation will deliver DFMO throughout the entire
gastrointestinal (GI) tract. This type of delivery will permit its
use in treating, preventing and/or controlling the growth of a wide
variety of cancers and tumors such as, by way of example and
without limitation, neuroblastoma, colon carcinoma, leukemia,
hepatoma, mammary sarcoma, small cell lung cancer, pancreatic
tumor, Lewis lung carcinoma, B16 murine melanoma, M3 murine
adenocarcinoma, bladder carcinoma, endocervical carcinoma,
epithelial cancer, chemically induced cancer, metastatic colorectal
cancer, refractory childhood leukemia, cervical intraepithelial
neoplasia grade 3 (CIN III), hematological malignancies, acute and
chronic myeloid leukemia, recurrent glioma and glioblastoma, solid
tumor, lymphoma, mammary carcinoma, premalignant polyps and
Barrett's esophagus.
[0136] Dosage Form Outer Layer
[0137] The dosage form outer layer which surrounds the dosage form
core will be soluble in gastric juices and may release the core in
either a pH-dependent or pH-independent fashion.
[0138] The dosage form outer layer will generally have released the
dosage form core contents within two hours of administration of the
dosage form to a patient.
[0139] The dosage form outer layer can be a film coating comprising
a polymer such as, by way-of example and without limitation,
hydroxypropylcellulose (HPC), ethylcellulose (EC),
hydroxypropylmethylcellulose (HMPC), hydroxyethylcellulose (HEC),
sodium carboxymethylcellulose(CMC), poly(vinyl pyrrolidone) (PVP),
poly(ethylene glycol) (PEG), dimethylaminoethyl
methacrylate--methacrylic acid ester copolymer, or
ethylacrylate--methylmethacrylate copolymer (EA-MMA). The outer
layer can also comprise dyes, dissolution aids, colorants,
pigments, antiadhesives, surfactants, antifoaming agents and
stabilizers.
[0140] Gastric Release Granule in Dosage Form Core
[0141] In one aspect, the invention provides a dosage form core
that comprises a gastric release granule (4) and will be surrounded
in its entirety by the dosage form outer layer (1) (FIG. 7). The
gastric release granule need not be soluble in gastric juices and
may release DFMO in either a pH-dependent or pH-independent
fashion.
[0142] The gastric release granule containing DFMO will generally
have released into the stomach a major portion of its DFMO within
two hours of administration of the dosage form to a patient.
Although intended for gastric release, it is possible this granule
will release some of its DFMO farther down the GI tract.
[0143] The gastric release granule will comprise DFMO and a binder
such as, by way of example and without limitation,
hydroxypropylmethylcellulos- e (HPMC), ethylcellulose (EC),
hydroxyethylcellulose (HEC), sodium carboxymethylcellulose (CMC),
poly(vinyl pyrrolidone) (PVP), poly(ethylene glycol) (PEG),
dimethylaminoethyl methacrylate--methacrylic acid ester copolymer,
or ethylacrylate--methylmethacrylate copolymer (GA-MMA) along with
a filler excipient. The gastric release granule can also comprise
dissolution aids, stability modifiers, adsorption promoters,
bioadhesive polymers, and plasticizers.
[0144] Methods for the preparation of gastric release granules are
well known in the art and depend upon whether the release is to be
pH-dependent or pH-independent; or zero order, first-order or
second-order. One method for the preparation of the gastric release
granule is detailed in Example 5.
[0145] Enteric Release Granule in the Dosage Form Core
[0146] In one aspect of the invention, the dosage form core will
comprise an enteric release granule (3) and will be surrounded in
its entirety by the dosage form outer layer (1) (FIG. 7). The
enteric release granule will generally not be soluble in gastric
juices and may release its DFMO in either a pH-dependent or
pH-independent fashion.
[0147] The enteric release granule containing DFMO will generally
have released into the small intestine a major portion of its DFMO
within about six to eight hours of administration of the dosage
form to a patient. Although intended for intestinal release, it is
possible this granule will release some of its DFMO either prior to
entering the small intestine or farther down the GI tract.
[0148] The enteric release granule will comprise DFMO and a polymer
suitable for enteric drug delivery such as, by way of example and
without limitation, cellulose acetate phthalate (CAP), cellulose
acetate trimelletate (CAT), poly (vinyl acetate) phthalate (PVAP),
hydroxypropylmethylcellulose phthalate (HP), poly(methacrylate
ethylacrylate) (1:1) copolymer (MA-EA), poly(methacrylate
methylmethacrylate) (1:1) copolymer (MA MMA), poly(methacrylate
methylmethacrylate) (1:2) copolymer, EUDRAGIT.TM. L 30D (MA-EA,
1:1), EUDRAGIT.TM. L100 55 (MA-EA, 3:1),
hydroxypropylmethylcellulose acetate succinate (HPMCAS), SURETERIC
(PVAP), AQUATERIC.TM. (CAP), shellac or AQOAT.TM. (HPMCAS). The
enteric release granule can also comprise dissolution aids,
stability modifiers, adsorption promoters, bioadhesive polymers and
plasticizers.
[0149] Methods for the preparation of enteric release granules are
well known in the art and depend upon whether the release is to be
pH-dependent or pH-independent; diffusion or dissolution
controlled; zero-order, first-order or second-order; or rapid, slow
or sustained release. One method for the preparation of these
granules is detailed in Example 6.
[0150] Colorectal Release Granule in the Dosage Form Core
[0151] In one aspect of the invention, the dosage form core will
comprise a colorectal release granule (2) and will be surrounded in
its entirety by the dosage form outer layer (1) (FIG. 7). The
colorectal release granule need will generally not be soluble in
gastric juices and may release its DFMO in either a pH-dependent or
pH-independent fashion.
[0152] The colorectal release granule containing DFMO will
generally have released into the large intestine (colon) and the
rectum a major portion of its DFMO within about ten to sixteen
hours of administration of the dosage form to a patient. Although
intended for colorectal release, it is possible this granule will
release some of its DFMO prior to entering the colon.
[0153] The colorectal release granule will comprise DFMO and many
of the same or similar polymers employed in the enteric granule the
main difference being that a thicker coating of the polymer and
that a polymer which dissolves at a pH greater than or equal to
about 6 will be used. Targeted colonic delivery systems are known
and employ materials such as hydroxypropylcellulose,
microcrystalline cellulose (MCE, AVICEL.TM. from FMC Corp.), poly
(ethylene--vinyl acetate) (60:40) copolymer (EVAC from Aldrich
Chemical Co.), 2-hydroxyethylmethacrylate (HEMA), MMA, terpolymers
of HEMA: MMA:MA synthesized in the presence of N,N'-bis
(methacryloyloxyethyloxycarbonylamino)--azobenzene, azopolymers,
enteric coated timed release system (TIME CLOCK.RTM. from
Pharmaceutical Profiles, Ltd., UK) and calcium pectinate and the
osmotic minipump system (ALZA corp.). The colorectal release
granule can also comprise dissolution aids, stability modifiers,
adsorption promoters, bioadhesive polymers and plasticizers.
[0154] Methods for the preparation of colorectal release granules
are well known in the art and depend upon whether the release is to
be pH-dependent or pH-independent; diffusion or dissolution
controlled; zero-order, first-order or second-order; or rapid, slow
or sustained release. One method for the preparation of these
polymers is detailed in Example 7.
[0155] Sustained Release Granule
[0156] This granule is optionally present in the formulations of
the invention. When present, the sustained release granules will
comprise part of the dosage form core which is surrounded in its
entirety by the dosage form outer layer. The sustained release
granule may or may not be soluble in gastric or intestinal fluids
and may release its DFMO in either a pH-dependent or pH-independent
fashion.
[0157] The sustained release granule containing DFMO can release
DFMO throughout the entire digestive tract or in targeted portions
of the GI tract.
[0158] The sustained release granule will comprise DFMO and, by way
of example and without limitation, shellac, zein, ethylcellulose
(EC), cellulose esters (such as acetate), silicone elastomers,
acrylate esters or fats and waxes (such as beeswax, carnauba wax),
hydrogenated castor oil and vegetable oils, cetyl alcohol,
cetylstearyl alcohol, SURELEASE.TM. (EC), AQUA-COAT.TM. (EC),
EUDRAGIT.TM. NE 30D.TM. (EA-MMA), EUDRAGIT.TM. RL 30D.TM. (poly
[ethylacrylate--methylmethacrylate] triethylammonioethyl
methacrylate chloride, EA-MMA-TEAE, 1:2:0.2) or EUDRAGIT.TM. RS
30D.TM. (EA-MMA-TEAE, 1:2:0.1). The sustained release granule can
also comprise dissolution aids, stability modifiers, adsorption
promoters, bioadhesive polymers and plasticizers.
[0159] Methods for the preparation of sustained release granules
for release of therapeutic compound throughout the digestive tract
are well known in the art and depend upon whether the release is to
be pH-dependent or pH-independent; diffusion or dissolution
controlled; or zero-order, first order or second-order release. One
method for the preparation of these granules is detailed in Example
8.
[0160] Multiple Drug Release Profile Capsule Dosage Form
[0161] FIG. 7 depicts one embodiment of this dosage form. Within
the capsule core are enteric (3), gastric (4), and colorectal (2)
release granules. The outer layer (1) is shown as having a capsule
shape but may possess any desired shape.
[0162] FIG. 1 shows the expected plasma DFMO concentration profile
expected when one embodiment of the multiple drug release profile
formulation of the present invention is used. It is intended that
the mean plasma drug concentration level will be maintained at or
above the MEC for a major portion of the time in which
DFMO-containing granules remain in the GI tract. It is also
intended that the granules will act cooperatively to yield overall
an approximately zero-order controlled release profile. Three
different types of rapid gastric, enteric and colorectal release
granules can combine to yield the desired overall DFMO plasma
concentration profile.
[0163] Various combinations of rapid and slow gastric, enteric and
colorectal release granules can act cooperatively to yield the
desired overall DFMO plasma concentration profile. FIG. 3 shows the
combination of a rapid gastric release granule, a slow enteric
release granule and a slow colorectal release granule to yield the
desired DFMO plasma concentration profile. FIG. 5 shows the
combination of a slow gastric release granule, a rapid enteric
release granule and a slow colorectal release granule to yield the
desired overall DFMO plasma concentration profile. FIG. 6 shows the
combination of a rapid gastric release granule, a slow enteric
release granule and a rapid colorectal release granule to yield the
desired overall DFMO plasma concentration profile.
[0164] Though specific release profiles are shown for each granule,
it should be understood that such profiles will vary. It is
contemplated and within the scope of the invention that other
profile shapes may be attained by each granule without departing
from the spirit and scope of the invention.
[0165] According to one embodiment of the multiple drug release
profile formulation of the invention, the gastric release, enteric
release and colorectal release granules will act cooperatively to
provide a mean steady state plasma concentration level of total
DFMO in the range of about 0.1.mu.M to about 1000.mu.M and
preferably in the range of about 1 .mu.M to 100.mu.M and more
preferably in the range of about 1 .mu.M to about 50 .mu.M.
[0166] The gastric, enteric and colorectal release granules of the
invention may each be present in a wide range of amounts according
to the overall DFMO release profile desired. By way of example and
without limitation, it may be desirable to include the granules in
the following ratio 1:1:5 parts by weight (gastric: enteric:
colorectal release granule) if predominantly direct flooding of the
patient by DFMO were desirable, or in the ratio 5:3:2 parts by
weight (gastric: enteric: colorectal release granule) if
predominantly systemic exposure of the patient to DFMO were more
desirable. The exact ratio chosen will depend upon individual
patient response to DFMO therapy, toxicity, the extent of cancer
progression, the optical form of the DFMO administered, the actual
dosage of DFMO in each granule, the desired dosing regimen or the
type of cancer being treated.
[0167] Generally, each granule will be present in the range of
about 1.0 to about 9.0 parts by weight using 10 parts by weight as
the basis for the total number of parts by weight which the
formulation may contain, i.e. the granules will generally be
present in the ratio of about 1.0-9.0: about 1.0-9.0: about 1.0-9.0
parts by weight (gastric: enteric: colorectal release granule).
[0168] When the multiple drug release profile formulation of the
invention takes the form of a capsule the gastric, enteric,
sustained and colorectal release granules will be found in their
entirety enclosed within an outer layer, e.g. hard gelatin capsule,
formulated for rapid release.
[0169] Methods for the preparation of the dosage forms just
mentioned are well known in the art and depend upon whether release
of the dosage form core is to be pH-dependent or pH independent,
the type of granules within the dosage form, and upon the desire to
release the dosage form core contents into the stomach, intestines
or colon. Generally and as advantageously employed herein, the
dosage form has an outer layer surrounding a core which contents
are released into the stomach. A method for preparing such a dosage
form generally proceeds as follows. A capsule outer layer comprised
of an upper half and a lower half is preformed of a material which
is soluble in gastric fluids. The lower half is filled with capsule
core contents such as gastric, enteric and colorectal release
granules and then capped (sealed) with the upper half to form a
capsule dosage form. The relative sizes of the halves as well as
the final size of the capsule outer layer generally depend upon the
size and weight of the capsule core. One method for the preparation
of this formulation is detailed in Example 10.
[0170] When the multiple drug release profile formulation of the
invention takes the form of a gelcap, caplet or tablet, the
gastric, enteric and colorectal release granules may be held
together by and coated with an outer layer that dissolves in
gastric fluids thereby releasing the granules in the stomach. The
outer layer can be a hard gelatin capsule comprised of gelatin,
glycerin and sorbitol or other suitable plasticizers.
[0171] Pharmaceutical Formulation and Administration
[0172] The pharmaceutical formulation of the present invention is
intended for oral administration and may be provided in a variety
of ways. Any ingredients used in the present formulation should not
degrade or decompose a significant portion of the DFMO or other
therapeutic compound(s) used prior to administration.
[0173] The solid unit dosage form of the invention will comprise
DFMO and can be combined with conventional carriers, for example,
binders, such as acacia, corn starch or gelatin; disintegrating
agents, such as, corn starch, guar gum, potato starch or alginic
acid; lubricants, such as, stearic acid or magnesium stearate; and
inert fillers, such as lactose, sucrose or corn starch.
[0174] The dosage form may also comprise adsorbents, antioxidants,
buffering agents, colorants, flavorants, sweetening agents, tablet
antiadherents, tablet binders, tablet and capsule diluents, tablet
direct compression excipients, tablet disintegrants, tablet
glidants, tablet lubricants, tablet or capsule opaquants and/or
tablet polishing agents.
[0175] For gelcap preparations, the pharmaceutical formulation may
include oils, for example, fixed oils, such as peanut oil, sesame
oil, cottonseed oil, corn oil and olive oil; fatty acids, such as
oleic acid, stearic acid and isostearic acid; and fatty acid
esters, such as ethyl oleate, isopropyl myristate, fatty acid
glycerides and acetylated fatty acid glycerides; with alcohols,
such as ethanol, isopropanol, hexadecyl alcohol, glycerol and
propylene glycol; with glycerol ketals, such as
2,2-dimethyl-1,3-dioxolane-4 methanol; with ethers, such as
poly(ethylene glycol) 450, with petroleum hydrocarbons, such as
mineral oil and petrolatum; with water, or with mixtures thereof;
with or without the addition of a pharmaceutically suitable
surfactant, suspending agent or emulsifying agent.
[0176] Oils can also be employed in the preparation of formulations
of the soft gelatin type. Water, saline, aqueous dextrose and
related sugar solutions, and glycerols may be employed in the
preparation of suspension formulations which may suitably contain
suspending agents, such as pectin, carbomers, methyl cellulose,
hydroxypropyl cellulose or carboxymethyl cellulose, as well as
buffers and preservatives. Soaps and synthetic detergents may be
employed as surfactants and as vehicles for detergent compositions.
Suitable soaps include fatty acid alkali metal, ammonium, and
triethanolamine salts. Suitable detergents include cationic
detergents, for example, dimethyl dialkyl ammonium halides, alkyl
pyridinium halides, and alkylamine acetates; anionic detergents,
for example, alkyl, aryl and olefin sulfonates, alkyl, olefin,
ether and monoglyceride sulfates, and sulfosuccinates; nonionic
detergents, for example, fatty amine oxides, fatty acid
alkanolamides, and poly(oxyethylene) -block poly (oxypropylene)
copolymers; and amphoteric detergents, for example, alkyl
.beta.-aminopropionates and 2-alkylimidazoline quaternary ammonium
salts; and mixtures thereof.
[0177] Various other components, not listed above, may be added to
the present formulation for optimization of a desired DFMO release
profile including, by way of example and without limitation,
glycerylmonostearate, nylon, cellulose acetate butyrate, d, 1-poly
(lactic acid), 1,6-hexanediamine, diethylenetriamine, starches,
derivatized starches, acetylated. monoglycerides, gelatin
coacervates, poly (styrene--maleic acid) copolymer, glycowax,
castor wax, stearyl alcohol, glycerol palmitostearate, poly
(ethylene), poly (vinyl acetate), poly (vinyl chloride),
1,3-butylene-glycoldimethacrylate, ethyleneglycol dimethacrylate
and methacrylate hydrogels.
[0178] Since the present formulation may comprise a variety of
granules, it is contemplated that a combination of rapid acting,
short-acting, fast-releasing, long-acting, gastric release, enteric
release, colorectal release, sustained release, controlled release
or slow release granules may be used in the present invention.
[0179] The course and duration of administration of and the dosage
requirements for the formulation of the present invention will vary
according to the subject being treated, the formulation used, the
method of administration used, the severity and type of cancer
being treated, the coadministration of other drugs and other
factors.
[0180] Although each unit dosage form (capsule, tablet, gelcap or
caplet) contains therapeutically effective amounts of DFMO, it may
be necessary to administer more than one such unit dosage form in
order to obtain the full therapeutic benefit of the DFMO. More
particularly, since DFMO may require moderately high doses, vide
supra, for preventing and treating colorectal cancer, it is very
likely that more than one capsule, tablet, caplet or gelcap will
need to be administered to a patient in order to obtain the full
therapeutic benefit of DFMO.
[0181] For example, consider that the average 70 Kg man has a body
surface area of 1.73 m.sup.2. If DFMO is administered at a dosage
of up to about 3 g/m.sup.2/day, then a patient would have to
receive about 5 g of DFMO/day, about 10 tablets containing 0.5 g of
DFMO. Correspondingly, if the dosage administered is about 0.25
g/m.sup.2/day, then a patient would have to receive about 0.4
g/day, about 1 tablet containing 0.5 g of DFMO.
[0182] It is intended that the formulation of the invention will
maintain DFMO plasma levels within the limits of MTC and MEC for a
major portion of the time during which dosage form granules are
present in a patient. By the term "major portion" is meant at least
about 50%.
[0183] The therapeutic compound contained within the formulation
may be formulated as their pharmaceutically acceptable salts. As
used herein, "pharmaceutically acceptable salts" refer to
derivatives of the disclosed compounds wherein the parent
pharmacologically active compound is modified by making acid or
base salts thereof. Examples of pharmaceutically acceptable salts
include, but are not limited to, mineral or organic acid salts of
basic residues such as amines; alkali or organic salts of acidic
residues such as carboxylic acids; and the like. The
pharmaceutically acceptable salts include the conventional
non-toxic salts or the quaternary ammonium salts of the parent
compound formed, for example, from non-toxic inorganic or organic
acids. For example, such conventional non-toxic salts include those
derived from inorganic acids such as hydrochloric, hydrobromic,
sulfuric, sulfonic, sulfamic, phosphoric, nitric and the like; and
the salts prepared from organic acids such as amino acids, acetic,
propionic, succinic, glycolic, stearic, lactic, malic, tartaric,
citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic,
glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic,
fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic,
oxalic, isethionic, and the like.
[0184] The pharmaceutically acceptable salts of the present
invention can be synthesized from the parent pharmacologically
active compound which contains a basic or acidic moiety by
conventional chemical methods. Generally, such salts can be
prepared by reacting the free acid or base forms of these compounds
with a predetermined amount of the appropriate base or acid in
water or in an organic solvent, or in a mixture of the two.
Generally, nonaqueous media are preferred. Lists of suitable salts
are found in Remington's Pharmaceutical Sciences, 17th ed., Mack
Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of
which is hereby incorporated by reference.
[0185] The phrase "pharmaceutically acceptable" is employed herein
to refer to those compounds, materials, compositions, and/or dosage
forms which are, within the scope of sound medical judgment,
suitable for use in contact with the tissues of human beings and
animals without excessive toxicity, irritation, allergic response,
or other problem or complication, commensurate with a reasonable
benefit/risk ratio.
[0186] The compounds herein described may have asymmetric centers.
All chiral, diastereomeric, and racemic forms are included in the
present invention. Many geometric isomers of olefins, C.dbd.N
double bonds, and the like can also be present in the compounds
described herein, and all such stable isomers are contemplated in
the present invention unless the specific stereochemistry or isomer
form is specifically indicated. It will be appreciated that certain
compounds of the present invention contain an asymmetrically
substituted carbon atom, and may be isolated in optically active or
racemic forms. It is well known in the art how to prepare optically
active forms, such as by resolution of racemic forms or by
synthesis, from optically active starting materials. Also, it is
realized that cis and trans geometric isomers of the compounds of
the present invention are described and may be isolated as a
mixture of isomers or as separated isomeric forms.
[0187] The racemic and optically pure forms of DFMO may be prepared
according to the methods described by Bey et al. (U.S. Pat. No.
4,413,141), Sjoerdsmannetal. (U.S. Pat. No. 4,399,151), Bey et al.
(U.S. Pat. No. 4,438,270), ibid (U.S. Pat. No. 4,560,795), ibid (10
U.S. Pat. No. 4,743,691), ibid (U.S. Pat. No. 4,866,206), Au et al.
(EP 357029 AZ), Wagner et al. (Anal. Biochem. (1987) 164(1),
102-16), Lindner et al. (J. Liq. Chromatogr. (1986) 9 (2-3),
551-71) and Aldous et al. (J. Chromatogr. (1986) 357(2) 335-9)
which references are hereby incorporated in their entirety
herein.
[0188] The mean steady state plasma concentration level of racemic
DFMO can be determined according to the methods described in
Smithers (Pharm. Res. (1988) 5, 684-686), Bitonti et al. (Biochem.
Pharmacol. (1986), 35, 351-354) and Grove et al. (J. Chromatogr.
(1981), 223, 409-416) the disclosures of which are hereby
incorporated in their entirety herein.
[0189] The mean steady state plasma concentration level of the
individual DFMO enantiomers can be determined according to the
methods described in Schmitt-Hoffinann (Annual Report of the CIFRE
Convention, 1987) the disclosure of which is hereby incorporated in
its entirety herein.
EXAMPLE 1
Determination of Racemic DFMO in Plasma
[0190] An internal standard (IS), 4-amino-3-hydroxybutyric acid
(See FIG. 1 for structure of DFMO and IS) is added to 100 ul of
plasma sample. The plasma is deproteinized by the addition of
methanol. After centrifugation the supernatant is transferred to a
WISP.RTM. vial (0.9 mL, designed for the 96 position carousel).
Phosphate buffer of pH =7.5 is added to it. DFMO standards in
plasma are prepared similarly. The samples and standards are
analyzed by pre-column derivatization with 9-phthalaldehyde (OPA).
This is accomplished by Water's Auto-Tag technique which uses the
WISP.RTM. to alternately inject reagent and sample under zero flow
conditions. A controller activates the solvent pumps and the
reaction mixture is chromatographed by gradient elution. Detection
is by fluorescence and data acquisition and calculations are by
CALS. A linear curve regression of the peak area ratios of DFMO to
IS VS. DFMO concentrations is used to assign concentrations to
unknown samples. This procedure is used for the determination of
DFMO in plasma over the concentration range of 0.5 to 80 ug/mL.
Complete details of the method are described in the appendix.
1 Materials and Reagents Ethanol - absolute, 200 proof, 9A Methanol
(MeOH) - Burdick & Jackson, glass distilled (B&H)
Isopropanol (IPA) - (B&J), glass distilled acetonitrile (ACN) -
(B&J), glass distilled 0.1 M phosphate Buffer, pH = 7.5 (A) .1
M sodium hydrogen phosphate (Na2HPO4) (B) .1 M sodium dihydrogen
phosphate (NaH2PO4) (A) and (B) are combined in a ratio of
approximately 13 to 3 to give a pH of 7.5
[0191] O-Phthalaldehyde Reagent (OPA)-10.0 mg of o-phthalaldehyde
(Sigma Chemical Co.) is dissolved in 1 mL of ethanol. One hundred
mcL of 2-mercaptoethanol (Sigma Chemical Co.) and 10 mls of 0.1M
phosphate buffer, pH=7.5, is added to the ethanol solution.
[0192] Standard Solutions: Eflornithine. MDL 71 782A
[0193] Stock Solution
[0194] Accurately weight 50 mg of compound into a 25 mL volumetric
flask and 1.s. with glass distilled water (2 mg/mL).
[0195] Working Solutions A, B, C
[0196] A. Pipette 5 ml of stock solution into a 100 ml volumetric
flask and 1.s. with plasma (100 ug/ml).
[0197] B. Pipette 1 ml of stock solution into a 100 ml volumetric
flask and q.s. with plasma (20 ug/ml).
[0198] C. Pipette 5 ml of working solution B (above) into a 50 ml
volumetric and q.s. with plasma (2 ug/ml).
[0199] Internal Standard Solution:
[0200] 4-Amino-3-hydroxybutyric acid (Aldrich Chemical Co.) Weight
25 mg into a 100 ml volumetric flash and q.s. with glass distilled
water.
[0201] Equipment
[0202] Centrifuge--Beckman Model TJ-6, Beckman Instrument Co.
[0203] Vortex--Genie Mixer, Scientific Instruments Inc.
[0204] Instrumentation
[0205] Analysis are performed on a Waters HPLC System(Millipore,
Waters' Chromatography Division) consisting of a Model 720 System
Controller, two Model 510 pumps and a WISP.backslash., Model 710B
auto-injector. The chromatography column is a Waters' C18, 5
micron, Radial-Pak cartridge, preceded by a pre-column (Upchurch
Scientific, Inc.) packed with Waters Bondapak C18/corasil, 37-50
micron particle size. The fluorometer is a Kratos Model FS970
(Schoeffel Instrument Division) operated at an excitation of 335 nm
with a 418 nm cut-off filter.
[0206] Procedure
[0207] I. Preparation of Standard Curve
[0208] 1. A series of nine standards, ranging in concentration from
80 to 0.5 mcg/mL, and a blank are prepared as follows:
2TABLE 1 Volume (mL) of Working Std. Sample Solution Volume (mL) of
Conc. No. A, B or C Blank Plasma ug/mL 1 4 (A) 1 80 2 3 (A) 2 60 3
2 (A) 3 40 4 5 (B) 0 20 5 3 (B) 3 10 6 2 (B) 6 5 7 5 (C) 0 2 8 3
(C) 3 1 9 2 (C) 6 0.5 10 0 .sub. 5 0
[0209] 2. One hundred mL aliquots of each standard are assayed in
duplicate. The aliquot is placed in a 13.times.100 mm test
tube.
[0210] II. One hundred mcL of sample is placed in a 13.times.100 mm
test tube. The sample is assayed in duplicate.
[0211] III. Analysis of Standard and Samples
[0212] A. Sample Preparation
[0213] 1. Using a 1.0 mL Hamilton syringe with a PB60 repeating
dispenser, add 20 uL (56 ug) of the IS to each standard and
sample.
[0214] 2. Add 400 uL of methanol and mix on Vortex mixer to insure
complete precipitation of proteins.
[0215] 3. Centrifuge of 30 minutes at approximately 2,000 rpm.
[0216] 4. Remove the supernatant to a 0.9 mL WISP.RTM. vial
designed for the 96 position carousel. Add 200 uL of 0.02 M
phosphate buffer, pH=7.5.
[0217] 5. Fill a 0.9 mL WISP.RTM. vial with OPA reagent, cap and
place in the No. 1 position in the carousel.
[0218] 6. Under zero flow conditions 20 ul of OPA reagent is
injected followed by 15 uL of sample.
[0219] B. HPLC Operations and Conditions
[0220] Column: Radial-Pak, C18, 5 micron Nova)
[0221] Pre-column: 2 mm.times.2 cm, C18/Corasil, 37-50 microns.
[0222] Fluorometer: 335 nm excitation
[0223] 418 nm cut-off filter
[0224] Mobile Phases:
[0225] A. 92% 0.1 M Phosphate, pH=7.5,5% MeOH, 3% IPA
[0226] B. 80% MeOH, 10% H.sub.2O, 5% ACN, 5% IPA
[0227] Pump Controller Program:
3TABLE 2 Time (min) Flow Rate (ml/min) % A % B Curve Init 0 80 20
11 2 0.2 80 20 11 3 1.5 80 20 11 5 1.5 80 20 11 20 1.5 80 50 06 25
1.5 80 50 11 26 1.5 80 20 06 33 0 80 20 11
[0228] (There is an initial 3 min isocratic flow of 80% A and &
20% B. The flow rate the first minute is 0.2 ml/min. It changes to
1.5 ml/min and remains as such for the rest of the program. The
linear gradient is to 50%A, 50%B over 15 min, after which the
mobile phase changes to the initial conditions and the column
equilibrates for seven minutes before the next injection.)
[0229] WISP.RTM.
[0230] The WISP.RTM. is programmed to inject the OPA reagent, in
position no. 1 in the carousel, prior to each sample injection.
This is accomplished through programming system messages 82 and 72
as 8201 and 7201 (WISP.RTM. Operator's Manual, p.4.4, section
4.3.1). The programmed injection times for the OPA reagent and
sample are 1 min and 34 min respectively. The sample loop has a 2.0
ml capacity which acts as a mixing chamber for sample and
reagent.
EXAMPLE 2
Preparation of DFMO-Containing Rapid Release Granule
[0231] (-)-DFMO (100 g) and microcrystalline cellulose (MCC, AVICEL
PH101, 100 g) are mixed thoroughly. A sufficient amount of water to
make a wet mass is added to the mixture which is subsequently
extruded and spheronized according to well known procedures in the
art. The pellets are screened (size 14 to 20 mesh) and dried at 40
C. for 24 hours. Poly(vinyl pyrrolidone) (PVP, 2% by wt of total
mass) can optionally be included in the formulation. Increasing PVP
will generally lengthen the release profile of the formulation.
EXAMPLE 3
Preparation of DFMO-Containing Slow Release Granule
[0232] The granules are prepared similar to Example 9. Thus, DFMO
(500 g), MCC (500 g) and EUDRAGIT.TM. RS 30D (35-50 g) are mixed.
To this mixture is added sufficient water to yield a 30% wt.
suspension. To the suspension is added TEC (10% wt. based on dry
polymer weight of EUDRAGIT.TM.) to yield a dispersion which is wet
granulated and dried to remove as much water as possible. The
particles are then ground into a fine powder.
EXAMPLE 4
Preparation of DFMO-Containing Capsule Comprising Rapid and Slow
Release Granules
[0233] The following procedure details the preparation of the
dosage form described by FIG. 2. Rapid release granules (500 g
prepared according to Example 2) and slow release granules (750 g
prepared according to Example 3) are thoroughly mixed. The mixture
is used to fill 2000 hard gelatin capsules according to procedures
well known in the art.
EXAMPLE 5
Preparation of DFMO-Containing Gastric Release Granule
[0234] The same method detailed in Example 2 can be employed here
to prepare a rapid gastric release granule. Alternatively, a slow
gastric release granule can be prepared as follows. DFMO (600 g),
MCC (350 g) and HPC (50 g) are mixed thoroughly. To the mixture is
added sufficient water to make a wet mass which is extruded and
then spheronized using procedures well known in the art. The
particles are then dried and ground.
EXAMPLE 6
Preparation of DFMO-Containing Enteric Release Granule
[0235] Rapid release.
[0236] A latex dispersion is prepared as follows. To EUDRAGIT.TM. L
30D-55 (1000 g, 15% wt in water) is added a plasticizer (15% wt of
dry polymer weight in the EUDRAGIT.TM.) while mixing for 1 to 24
hours. Plasticizers such as triethylcitrate, tributylcitrate,
acetyltributylcitrate or dibutylsebacate can be used. To this
mixture is added talc (50% wt of dry polymer in the EUDRAGIT.TM.)
or glycerylmonostearate (10% wt of dry polymer in the EUDRAGIT.TM.)
to form a dispersion. The rapid release granules prepared in
Example 2 are coated in a fluidized bed with the latex dispersion
until a 10-15% wt increase in granule weight is achieved. The
fluidized bed inlet air temperature is adjusted to about 40-45 C.
and the outlet air temperature is adjusted to about 30-35 C. with a
spray rate of about 2 g/min.
[0237] Slow Release.
[0238] Granules prepared according to Example 3 are coated with
EUDRAGIT.TM. L 30D (10-12% wt.) or AQUATERIC (CAP, 10% wt.,
plasticized with TEC) until a 25-30% wt. increase in granule weight
is achieved.
EXAMPLE 8
Preparation of DFMO-Containing Colorectal Release Granule
[0239] Rapid Release.
[0240] A dispersion is prepared as follows. To EUDRAGIT.TM. S 100
(1000 g, 10% wt in water) is added a plasticizer (10% wt of dry
polymer weight in the EUDRAGIT.TM. ) while mixing for 1 to 24 hrs.
Plasticizers such as triethylcitrate, tributylcitrate,
acetyltributylcitrate or dibutylsebacate can be used. To this
mixture is added talc (50% wt of dry polymer in the EUDRAGIT.TM.)
to form a dispersion. The rapid release granules prepared in
Example 2 are coated in a fluidized bed with this dispersion until
a 15% wt increase in granule weight is achieved.
[0241] Slow Release.
[0242] A mixture is prepared as follows. EUDRAGIT.TM. RS 30D (1000
g, 15% wt. aqueous dispersion, AQUA-COAT.TM. OR SURELEASE) is
plasticized with triethylcitrate (TEC, 20% wt. of dry polymer in
the EUDRAGIT.TM.) for 1-24 hours. Talc (50% wt. of dry polymer in
the EUDRAGIT.TM. is added with mixing to form the mixture. The
rapid release granules prepared in Example 2 are coated with this
mixture until a 10-15% wt. increase in granule weight is achieved.
The coated granules are then coated with an EUDRAGIT.TM. S100
dispersion as done immediately above until a 10-15% wt. increase in
granule weight is achieved.
EXAMPLE 9
Preparation of DFMO-Containing Sustained Release Granule
[0243] This procedure employs a double granulation. Thus, DFMO (500
g), MCC (500 g) and EUDRAGIT.TM. RS 30D (75-100 g) are mixed. To
this mixture is added sufficient water to yield a 30% wt.
suspension. To the suspension is added TEC(10% wt. based on dry
polymer weight of EUDRAGIT.TM.) to yield a dispersion which is wet
granulated and dried to remove as much water as possible. The
granules are then ground into a fine powder. Th the powder is added
sufficient water to make a wet mass which is extruded, spheronized,
dried, ground and screened (size 14-20 mesh).
EXAMPLE 10
Preparation of DFMO-Containing Capsule Comprising Gastric. Enteric
and Colorectal Release Granules
[0244] The following procedure details the preparation of the
dosage form described by FIG. 5. Rapid gastric release granules
(450 g, prepared according to Example 2), rapid enteric release
granules (100 g, prepared according to Example 6) and slow
colorectal release granules (450 g, prepared according to Example
8) are mixed thoroughly. Hard gelatin capsules (2000) are then
filled with the mixture using procedures and equipment well known
in the art.
EXAMPLE 11
Preparation of DFMO-Containing Tablets Comprising Rapid and Slow
Colorectal Release Granules
[0245] The following procedure details the preparation of the
dosage form described by FIG. 12 and comprises a slow release core
surrounded by a rapid release layer which is then surrounded by a
pH responsive coating for colorectal release. Thus, DFMO (600 g) is
dry blended with AVICEL PH101 (260 g), PVP (30 g), HMPC (100 g,
KISM), fumed silicon dioxide (50 g, CAB-O-SIL M5P), and magnesium
stearate (50 g). The mixture is then compressed into tablets. HPMC
(70-80 g, aqueous coat, Opadry.RTM., plasticized with propylene
glycol) and DFMO (20-30 g) are mixed and turned into a dispersion
by the addition of water. The tablets just prepared are coated with
the HPMC/DFMO dispersion until the desired tablet weight gain has
been achieved to form a two layered tablet. The layered tablet is
then coated in a perforated pan coating unit with EUDRAGIT.TM. S100
until a 15% wt. increase in tablet weight is achieved.
EXAMPLE 12
Pellet Formulation
[0246] The present example is provided to demonstrate the utility
of the present invention for the preparation of pellets.
4 TABLE 3 Compound % (w/w) Eflornithine Hydrochloride 50 Lot #
A1981-004 Avicel .RTM. PH101 47 Kollidon .RTM. K90 3 Total 100
[0247] Procedure:
[0248] a. Kollidon.RTM. K90 prepared as a 10% w/w aqueous solution
with distilled water.
[0249] b. Particle size of bulk drug reduced with porcelain mortar
and pestle and dry blended for 10 minutes with Avicel.RTM. PH
101.
[0250] c. Powder blend transferred to a planetary mixer and the
Kollidon.RTM. K90 solution slowly added.
[0251] d. An additional aliquot of approximately 5% to 13% (based
on dry weight of formulation) of distilled water was added to the
powder/PVP mass to achieve desirable wet massing.
[0252] e. Final wet mass allowed to mix for an additional 3-5
minutes.
[0253] 1. Extrusion
[0254] Procedure:
[0255] a. Extrusion of the wet mass in Table 3 was accomplished
using a bench top extruder fitted with a 1.0 mm screen.
[0256] b. The rotation speed was set at maximum (approximately 25
rpm).
[0257] c. The extruded strands were collected periodically and
processed further.
[0258] 2. Spheronization
[0259] Procedure:
[0260] a. Spheronization was accomplished using a bench top
spheronizer fitted with a fine cut plate.
[0261] b. An aliquot of approximately 100-150 gm of extruded
material was charged into the chamber and spheronized as indicated
below.
[0262] c. Periodic dusting of the pellets with Avicel.RTM. PH101
was done to absorb expired moisture produced during the
spheronization in order to reduce particle adhesion and limit
particle growth.
[0263] d. The wet pellets were collected and gently screened
through a 14 and 18 mesh screen to remove fines and oversized
particles. The under/over sized material was recycled into the
extrusion mass to increase yield and decrease waste.
[0264] e.
5TABLE 4 Spheronization Time/Speed Time (min) Percent of Maximum 1
50% 1 75% 2-3 100% Total Spheronization Time 4-5 min
[0265] 3. Collection and Sizing
[0266] Procedure:
[0267] a. The wet pellets were collected and evenly spread onto
aluminum sheets.
[0268] b. These sheets were then placed in 40.degree. C. ovens, and
the pellets were allowed to dry overnight.
[0269] c. The dried pellets were collected and vacuumed dusted to
remove any free particulate matter.
[0270] d. The final bead distribution was assessed using standard
metal screens and is shown below.
[0271] e. The percent of lost material in processing was less than
3%.
[0272] f. Pellets of the 16-18 mesh and 18-20 mesh size were
blended and used in subsequent procedures.
6TABLE 5 Pellet Size Distribution Pass Through (mesh) Retained On
(mesh) % of Starting Material 12 16 19.7 16 18 54.9 18 20 16.4 20
30 6.2 Total 97.2
[0273] 4. Pellet Coating
[0274] Equipment:
[0275] a. All coatings were applied with using a fluidized bed
coater fitted with a Wurster insert and a bottom spray technique. A
filter bag assembly was used, and the insert adjusted from
{fraction (3/8)}" to {fraction (1/2)}" above the floor of the
coating chamber in order to obtain a desirable flow of pellets
through the spray path.
[0276] b. Coating material was supplied with a peristalic pump and
the spray rate adjusted as indicated.
[0277] c. The atomization pressure was 0.8-1.2 bar, and the filter
blow out pressure was set at 1-2 bar.
[0278] d. The coating charge unless otherwise stated was 300 gm of
size 16-20 mesh pellets as indicated above.
[0279] Enteric Coating
7TABLE 6 Coating Formulation Material Based On Weight EUDRAGIT .TM.
87.00 gm L30D-55 Triethyl Citrate (TEC) 15%, dry weight polymer
3.92 gm Talc 50%, dry weight polymer 13.05 gm Water Total solids to
be 15% 196.18 gm Total Suspension Weight 300.15 gm
[0280] Calculation:
[0281] For an 8% weight gain of polymer (x is dry weight of
polymer) 1 x 300 + x = 0.08
[0282] where x is 26.1 gm and is provided by 87.00 gm of 30%
polymer suspension.
[0283] Procedure:
[0284] a. The EUDRAGIT.TM. L30D-55 and TEC were combined and
allowed to stir for 30 minutes.
[0285] b. The talc was separately dispersed in the water for 10
minutes at 4500 rpm.
[0286] c. The talc suspension was added with stirring to the
EUDRAGIT.TM./TEC suspension.
8TABLE 7 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 5 0 45/33 50 15 1.5
40/32 60 130 2.5 40/30 50-60
[0287] Curing:
[0288] a. Coated beads were collected and spread evenly onto
aluminum sheets.
[0289] b. Final product allowed to dry at room temperature
overnight.
[0290] Colonic Coating
9TABLE 8 Coating Formulation Material Based On Weight EUDRAGIT .TM.
87.00 gm 4110D Triethyl Citrate (TEC) 5%, dry weight polymer 1.3 gm
Imwitor .RTM. 900 5%, dry weight polymer 1.3 gm Water Total solids
to be 15% 93.1 gm Total Suspension Weight 182.7 gm
[0291] Calculation:
[0292] For an 8% weight gain of polymer (x is dry weight of
polymer) 2 x 300 + x = 0.08
[0293] where x is 26.1 gm and is provided by 87.00 gm of 30%
polymer suspension.
[0294] Procedure:
[0295] a. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rmp for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGI.TM. 4110D.
[0296] b. The final dispersion is allowed to stir for 15 minutes
prior to application.
10TABLE 9 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 5 0 30/27 50 15 2.0
33/26 50 65 2.5 36/26 50
[0297] Curing:
[0298] a. Coated beads were collected and spread evenly onto
aluminum sheets.
[0299] b. Final product allowed to dry at room temperature
overnight.
[0300] Extended Release Coating
11TABLE 10 Coating Formulation Material Based On Weight EUDRAGIT
.TM. RS30D 100.00 gm EUDRAGIT .TM. RL30D 11.10 gm Triethyl Citrate
(TEC) 15%, dry weight polymer 5.00 gm Imwitor .RTM. 900 5%, dry
weight polymer 1.67 gm Water Total solids to be 15% 115.40 gm Total
Suspension Weight 233.13 gm
[0301] Calculation:
[0302] For a 10% weight gain of polymer (x is dry weight of
polymer) 3 x 300 + x = 0.1
[0303] where x is 33.3 gm and is provided by 111.10 gm of 30%
polymer suspension in a ratio of 9:1 RS30D to RL30D.
[0304] Pocedure:
[0305] a. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGIT.TM. RS/RL
dispersion.
[0306] b. The final dispersion is allowed to stir for 15 minutes
prior to application.
12TABLE 11 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 35/32 25 115 2.1-2.3
38/29 70 15 0 38/38 70
[0307] Curing:
[0308] 1. Coated beads were dried in situ for 15 minutes with the
filter screen in place in preparation for the next application
[0309] Colonic Coating of Extended Release Pellets
13TABLE 12 Coating Formulation Material Based On Weight EUDRAGIT
.TM. 4110D 95.70 gm Triethyl Citrate (TEC) 5%, dry weight polymer
1.40 gm Imwitor .RTM. 900 5%, dry weight polymer 1.40 gm Water
Total solids to be 15% 102.20 gm Total Suspension Weight 200.70
gm
[0310] Calculation:
[0311] For a 8% weight gain of polymer (x is dry weight of polymer)
4 x 300 + x = 0.08
[0312] where x is 28.7 gm and is provided by 95.70 gm of 30%
polymer suspension. Here, the coating charge is increased due to
the weight gain of solid material from the previous spray
application.
[0313] Procedure:
[0314] a. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rmp for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGIT.TM. 4110D
dispersion.
[0315] b. The final dispersion is allowed to stir for 15 minutes
prior to application.
14TABLE 13 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 35/30 70 65 2.1-2.5
38/29 70
[0316] Beads were immediately coated with a 0.2% Imwitor.RTM. 900
top coat to prevent sticking during drying and storage.
[0317] 0.2% GMS Top Coat
15TABLE 14 Coating Formulation Material Based On Weight Imwitor
.RTM. 900 0.70 gm Water Total solids to be 2% 34.30 gm Total
Suspension Weight 35.00 gm
[0318] Calculation:
[0319] For a 0.2% weight gain of polymer (x is dry weight of
polymer) 5 x 350 + x = 0.002
[0320] where x is 0.7 gm. Here, the coating charge is increased due
to the weight gain of solid material from the previous spray
applications.
[0321] Procedure:
[0322] 1. The Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes.
16TABLE 15 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 3 0 39/33 70 15 2.1-2.5
39/30 70 10 0 40/40 70
[0323] Curing:
[0324] a. Coated beads were collected and spread evenly onto
aluminum sheets.
[0325] Final product allowed to dry at room temperature over the
weekend.
[0326] Dissolution Testing
[0327] Apparatus
[0328] b. Testing was done using the USP Method II, rotating paddle
procedure.
[0329] c. All testing was done at 37.degree. C. and 100 rpm paddle
speed.
[0330] d. Various dissolution media was used to approximate the in
vivo conditions that the pellets may experience.
[0331] e. Three milliliter samples were drawn at set time points,
and blank dissolution media was added to maintain a constant
dissolution volume.
[0332] f. Final dissolution volumes were 500 ml except for testing
of the EUDRAGIT.RTM. L30D-55 product where the final volume was 467
ml.
[0333] g. Initial media was 0.1 N HCL and, if needed, aliquots of
0.2 M sodium phosphate tribasic was added to increase the pH. At pH
changes after the addition of the 0.2 M sodium phosphate, the pH of
the individual kettles was adjusted with 2 M HCL or 2 M NaOH prior
to sampling.
[0334] h. Dissolution samples were filtered with a 0.45 pm PTFE
filter prior to analysis.
17TABLE 16 Dissolution Time and Media Product Time Media pH
Uncoated Pellets 0-120 min 0.1 N HCI 1.0 500 ml EUDRAGIT .TM. 0-120
min 0.1 N HCI 1.0 L30D055 350 ml 120-165 min +117 ml 6.8 0.2 M NaPO
EUDRAGIT .TM. 0-120 min 0.1 N HCI 1.0 4110D 375 ml 120-240 min
+87.5 ml 6.0 0.2 M NaPO 240-360 min +37.5 ml 7.4 0.2 M NaPO
EUDRAGIT .TM. 0-120 min 0.1 N HCI 1.0 RS/RL w/ 375 ml EUDRAGIT .TM.
4110D 120-240 min +87.5 ml 6.0 0.2 M NaPO 240-870 min +37.5 ml 7.4
0.2 M NaPO
[0335] 5. Drug Content
[0336] Procedure:
[0337] a. An aliquot of pellets was ground with a porcelain mortar
and pestle.
[0338] b. Approximately 500 mg aliquot of the ground material was
transferred to a 250 ml volumetric flask and brought to 3/4 volume
with distilled water.
[0339] c. The flasks were then sonicated for 20 minutes and allowed
to cool to room temperature before bringing up to volume with
distilled water.
[0340] d. Sample aliquots were filtered with a 10 pm and then a
0.45 pm filter prior to analysis.
EXAMPLE 13
Pellet Formulation Rapid Release Core Pellet and Enteric Polymer
Coated Pellet
[0341] The present example is provided to demonstrate the DFMO
release profile of an uncoated rapid release pellet. The
dissolution profile of this formulation is demonstrated at FIG.
14.
18TABLE 17 Pellet Formulation Compound % (w/w) Eflornithine
Hydrochloride 50 Lot #A1981-004 Avicel .RTM. PH101 47 Kollidon
.RTM. K90 3 Total 100
[0342] The particle size distribution of the dried extruded pellets
is shown in Table 19. FIG. 14 shows the DFMO is rapidly released,
with over 90% of the drug being released within 5 minutes when
placed in 0.1 N HCl. (uncoated=() (see FIG. 14).
[0343] Procedure:
[0344] 1. Kollidon.RTM. K90 prepared as a 10% w/w aqueous solution
with distilled water.
[0345] 2. Particle size of bulk drug reduced with porcelain mortar
and pestle and dry blended for 10 minutes with Avicel.RTM. PH
101.
[0346] 3. Powder blend transferred to a planetary mixer and the
Kollidon.RTM. K90 solution slowly added.
[0347] 4. An additional aliquot of approximately 5% to 13% (based
on dry weight of formulation) of distilled water was added to the
powder/PVP mass to achieve desirable wet massing.
[0348] 5. Final wet mass allowed to mix for an additional 3-5
minutes.
[0349] Extrusion
[0350] Procedure:
[0351] 1. Extrusion of the wet mass was accomplished using a bench
top extruder fitted with a 1.0 mm screen.
[0352] 2. The rotation speed was set at maximum (approximately 25
rpm).
[0353] 3. The extruded strands were collected periodically and
processed further.
[0354] Spheronization
[0355] 1. Spheronization was accomplished using a bench top
spheronizer fitted with a fine cut plate.
[0356] 2. An aliquot of approximately 100-150 gm of extruded
material was charged into the chamber and spheronized as indicated
below.
[0357] 3. Periodic dusting of the pellets with Avicel.RTM. PH101
was done to adsorb expired moisture produced during the
spheronization in order to reduce particle adhesion and limit
particle growth.
[0358] 4. The wet pellets were collected and gently screened
through a 14 and 18 mesh screen to remove fines and oversized
particles. The under/over sized material was recycled into the
extrusion mass to increase yield and decrease waste.
19TABLE 18 Spheronization Time/Speed Time (min) Percent of Maximum
1 50% 1 75% 2-3 100% Total Spheronization Time 4-5 min
[0359] Collection and Sizing
[0360] Procedure:
[0361] 1. The wet pellets were collected and evenly spread onto
aluminum sheets.
[0362] 2. These sheets were then placed in 40.degree. C. ovens, and
the pellets were allowed to dry overnight.
[0363] 3. The dried pellets were collected and vacuumed dusted to
remove any free particulate matter.
[0364] 4. The final bead distribution was assessed using standard
metal screens and is shown below.
[0365] 5. The percent of lost material in processing was less than
3%.
[0366] 6. Pellets of the 16-18 mesh and 18-20 mesh size were
blended and used in subsequent procedures.
20TABLE 19 Pellet Size Distribution Pass Through (mesh) Retained On
(Mesh) % of Starting Material 12 16 19.7 16 18 54.9 18 20 16.4 20
30 6.2 Total 97.2
[0367] The following formula was employed to prepare the pellets
coated with an enteric polymer of the present invention.
[0368] As demonstrated in FIG. 15, release of the active ingredient
DFMO was less than 10% after 1 hour and less than 20% after 2
hours. These release rates could be decreased with higher levels of
polymer being applied to the pellets.
[0369] The profile mirrors the delayed plasma level drug (DFMO)
illustrated in FIG. 1, middle profile (Rapid enteric release).
[0370] Pellet Coating
[0371] Equipment:
[0372] 1. All coatings were applied with using a fluidized bed
coater fitted with a Wurster insert and a bottom spray
technique.
[0373] 2. Coating material was supplied with a peristaltic pump and
the spray rate adjusted as indicated.
[0374] 3. The atomization pressure was 0.8-1.2 bar, and the filter
blow out pressure was set at 1-2 bar.
[0375] 4. The coating charge unless otherwise stated was 300 gm of
size 16-20 mesh pellets as indicated above.
[0376] Enteric Coating
21TABLE 20 Coating Formulation Material Based On Weight EUDRAGIT
.TM. L30D-55 87.00 gm Triethyl Citrate (TEC) 15%, dry weight
polymer 3.92 gm Talc 50%, dry weight polymer 13.05 gm Water Total
solids to be 15% 196.18 gm Total Suspension Weight 300.15 gm
[0377] Calculation:
[0378] For an 8% weight gain of polymer (x is dry weight of
polymer) 6 x 300 + x = 0.08
[0379] where x is 26.1 gm and is provided by 87.00 gm of 30%
polymer suspension.
[0380] Procedure:
[0381] 1. The EUDRAGIT.TM. L30D-55 and TEC were combined and
allowed to stir for 30 minutes.
[0382] 2. The talc was separately dispersed in the water for 10
minutes at 4500 rpm.
[0383] 3. The talc suspension was added with stirring to the
EUDRAGIT.TM./TEC suspension.
22TABLE 21 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 45/33 50 15 1.5
40/32 60 130 2.5 40/30 50-60
[0384] Curing:
[0385] 1. Coated beads were collected and spread evenly onto
aluminum sheets.
[0386] 2. Final product allowed to dry at room temperature
overnight.
[0387] FIG. 15 illustrates that with 8% weight gain of EUDRAGIT.TM.
L30D-55, less than 20% of the drug was released in acidic medium.
Rapid drug release was evident when the medium was changed to pH
6.8.
[0388] Colonic Coating
23TABLE 22 Coating Formulation Material Based On Weight EUDRAGIT
.TM. 4110D 87.00 gm Triethyl Citrate (TEC) 5%, dry weight polymer
1.3 gm Imwitor .RTM. 900 5%, dry weight polymer 1.3 gm Water Total
solids to be 15% 93.1 gm Total Suspension Weight 182.7 gm
[0389] Calculation:
[0390] For an 8% weight gain of polymer (x is dry weight of
polymer) 7 x 300 + x = 0.08
[0391] where x is 26.1 gm and is provided by 87.00 gm of 30%
polymer suspension.
[0392] Procedure:
[0393] 1. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGIT.TM. 4110D.
[0394] 2. The final dispersion is allowed to stir for 15 minutes
prior to application.
24TABLE 23 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 30/27 50 15 2.0
33/26 50 65 2.5 36/26 50
[0395] Curing:
[0396] 1. Coated beads were collected and spread evenly onto
aluminum sheets.
[0397] 2. Final product allowed to dry at room temperature
overnight.
[0398] The DFMO release profile of the colonic coating preparation
(third peak) (-.smallcircle.-.smallcircle.-.smallcircle.-) is
further illustrated in FIG. 16. In FIG. 16 it is demonstrated that
less than 20% of the drug was released after 4 hours when the
coated pellets were first subjected to pH media 1.0 for 2 hours,
and then followed by pH media 6.0 for 2 hours. Since EUDRAGIT.TM.
4110D starts to dissolve at pH 6.8, rapid release of the drug was
seen when the pH of the media was adjusted to pH 7.4. The
anticipated plasma blood level profile is represented in the far
right profile of FIG. 1 (open circles,
-.smallcircle.-.smallcircle.-.smal- lcircle.-).
EXAMPLE 14
Extended Release Coating
[0399] To extend the release profile of this very water-soluble
drug (DFMO) in the colon, an extended release coating was applied
to the pellets.
25TABLE 24 Extended Release Coating Formulation Material Based On
Weight EUDRAGIT .TM. RS30 100.00 gm EUDRAGIT .TM. RL30D 11.10 gm
Triethyl Citrate (TEC) 15%, dry weight polymer 5.00 gm Imwitor
.RTM. 900 5%, dry weight polymer 1.67 gm Water Total solids to be
15% 115.40 gm Total Suspension Weight 233.13 gm
[0400] Calculation:
[0401] For a 10% weight gain of polymer (x is dry weight of
polymer) 8 x 300 + x = 0.1
[0402] where x is 33.3 gm and is provided by 111.10 gm of 30%
polymer suspension in a ratio of 9:1 RS30D to RL30D.
[0403] Procedure:
[0404] 1. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGIT.TM. RS/RL
dispersion.
26TABLE 25 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 35/32 25 115 2.1-2.3
38/29 70 15 0 38/38 70
[0405] Curing:
[0406] 1. Coated beads were dried in situ for 15 minutes with the
filter screen in place in preparation for the next application.
[0407] Colonic Coating of Extended Release Pellets:
[0408] Coat #2 (outside coat)
27TABLE 26 Coating Formulation Material Based On Weight EUDRAGIT
.TM. 4110D 95.70 gm Triethyl Citrate (TEC) 5%, dry weight polymer
1.40 gm Imwitor .RTM. 900 5%, dry weight polymer 1.40 gm Water
Total solids to be 15% 102.20 gm Total Suspension Weight 200.70
gm
[0409] This coat protects the pellet in the GI tract until a pH of
greater than 6.8 is achieved. At that pH and above, the 4110D
begins to dissolve.
[0410] Calculation:
[0411] For an 8% weight gain of polymer (x is dry weight of
polymer) 9 x 300 + x = 0.08
[0412] where x is 28.7 gm and is provided by 95.70 gm of 30%
polymer suspension. Here, the coating charge is increased due to
the weight gain of solid material from the previous spray
application.
[0413] Procedure:
[0414] 1. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30C before adding to the EUDRAGIT.TM. 4110D dispersion.
[0415] 2. The final dispersion is allowed to stir for 15 minutes
prior to application.
28TABLE 27 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 35/30 70 65 2.1-2.5
38/29 70
[0416] Beads were immediately coated with a 0.2% Imwitor.RTM. 900
top coat to prevent sticking during drying and storage.
[0417] 0.2% GMS Top Coat
29TABLE 28 Coating Formulation Material Based On Weight Imwitor
.RTM. 900 0.70 gm Water Total solids to be 2% 34.30 gm Total
Suspension Weight 35.00 gm
[0418] Calculation:
[0419] For a 0.2% weight gain of polymer (x is dry weight of
polymer) 10 x 300 + x = 0.002
[0420] where x is 0.7 gm. Here, the coating charge is increased due
to the weight gain of solid material from the previous spray
applications.
[0421] Procedure:
[0422] 1. The Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes.
30TABLE 29 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 3 0 39/33 70 15 2.1-2.5
39/30 70 10 0 40/40 70
[0423] Curing:
[0424] 1. Coated beads were collected and spread evenly onto
aluminum sheets.
[0425] 2. Final product allowed to dry at room temperature over the
weekend.
[0426] As shown in FIG. 17, drug release from the extended release
pellet formulations coated with EUDRAGIT.TM. 4110D did not release
drug during the first 5 hours that the pellets were exposed to pH
1.0, 6.0, and then 7.0 after 7 hours, approximately 17% of the drug
was released and after about 141/2 hours, approximately 55% of the
drug was released from the pellets. In FIG. 2, a pellet coated with
a combination of RS30 and RL30D and a top coat of 4110D
(-.diamond.-.diamond.-.diamond.-) is represented in an expected in
vivo blood release profile of DFMO. A rapid release pellet coated
with 4110D is illustrated in FIG. 2, open circles. The subcoat of
the various pharmaceutical preparations described herein may
include other materials with properties of EUDRAGIT.TM. 4110D, that
would produce similiar results. Such would include materials that
dissolve or disintegrate above pH 6.8. By example, these are
EUDRAGIT.TM. S100 or HPMC acetate succinate derivative, and
polyanhydrides and other retardant materials that are broken down
or degraded by enzymes and bacteria in the colon.
[0427] Dissolution Testing
[0428] Apparatus
[0429] 1. Testing was done using the USP Method II, rotating paddle
procedure.
[0430] 2. All testing was done at 37.degree. C. and 100 rpm paddle
speed.
[0431] 3. Various dissolution media was used to approximate the in
vivo conditions that the pellets may experience.
[0432] 4. Three milliliter samples were drawn at set time points,
and blank dissolution media was added to maintain a constant
dissolution volume
[0433] 5. Final dissolution volumes were 500 ml except for testing
of the EUDRAGIT.TM. L30D-55 product where the final volume was 467
ml.
[0434] 6. Initial media was 0.1 N HCL and, if needed, aliquots of
0.2 M sodium phosphate tribasic was added to increase the pH. At pH
changes after the addition of the 0.2 M sodium phosphate, the pH of
the individual kettles was adjusted with 2 Mm HCL or 2 M NaOH prior
to sampling.
31TABLE 30 Dissolution Time and Media Product Time Media pH
Uncoated Pellets 0-120 min 0.1 N HCl 1.0 500 ml EUDRAGIT .TM. 0-120
min 0.1 N HCl 1.0 L30D-55 350 ml 120-165 min +117 ml 6.8 0.2 M
NaPO.sub.4 EUDRAGIT .TM. 0-120 min 0.1 N HCl 1.0 4110D 375 ml
120-240 min +87.5 ml 6.0 0.2 M NaPO.sub.4 240-360 min +37.5 ml 7.4
0.2 M NaPO.sub.4 EUDRAGIT .TM. 0-120 min 0.1 N HCl 1.0 RS/RL w/ 375
ml EUDRAGIT .TM. 4110D 120-240 min +87.5 ml 6.0 0.2 M NaPO.sub.4
240-870 min +37.5 ml 7.4 0.2 M NaPO.sub.4
[0435] Drug Content
[0436] Procedure:
[0437] 1. An aliquot of pellets was ground with a porcelain mortar
and pestle.
[0438] 2. Approximately 500 mg aliquot of the ground material was
transferred to a 250 ml volumetric flask and brought to {fraction
(3/4)} volume with distilled water.
[0439] 3. The flasks were then sonicated for 20 minutes and allowed
to cool to room temperature before bringing up to volume with
distilled water.
[0440] 4. Sample aliquots were filtered with a 10 .mu.m and then a
0.45 .mu.m filter prior to analysis.
[0441] Drug Analysis
32 HPLC Conditions Column: Rainin Microsorb .TM. Short-One .RTM.
C18, ODS-1, 3 .mu.m Mobile Phase: 1.1 mM Sodium Dodecyl Sulfate in
23/77 Acetonitrile/ 0.039 M NaPO.sub.4 (pH = 2.3) Flow Rate: 1.0
ml/min Detection: 210 nm Injection Volume: 50 .mu.l Retention Time:
4.5 minutes
EXAMPLE 15
DFMO-Containing Slow Release Matrix Pellets--No Coating
[0442] The present example is provided to demonstrate the utility
of the present formulation in providing a slow release matrix
pellet formulation of DFMO.
[0443] I. Pellet Formulation
33 TABLE 31 Compound % (w/w) Eflornithine Hydrochloride 46.9 Lot
#R41063 Avicel .RTM. RC591 10.4 Sterotex K 26.1 EUDRAGIT .TM. NE40D
(dry polymer) 16.6 Total 100
[0444] Procedure:
[0445] 1. Aggregates of bulk drug were reduced with a porcelain
mortar and pestle and dry blended for 5 minutes with Avicel.RTM.
RC591 and Sterotex K.
[0446] 2. Powder blend transferred to a planetary mixer, and the
EUDRAGIT.TM. NE40D dispersion was slowly added.
[0447] 3. An additional aliquot of approximately 10% to 15% (based
on dry weight of formulation) of distilled water was added to the
powder/EUDRAGIT.TM. NE40D mass to achieve desirable wet
massing.
[0448] 4. Final wet mass allowed to mix for an additional 3-5
minutes.
[0449] II. Extrusion
[0450] Procedure:
[0451] 1. Extrusion of the wet mass in (I) was accomplished using a
bench top extruder fitted with a 1.0 mm screen.
[0452] 2. The rotation speed was set at maximum (approximately 25
rpm).
[0453] 3. The extruded strands were collected periodically and
processed further.
[0454] III. Spheronization
[0455] 1. Spheronization was accomplished using a bench top
spheronizer fitted with a fine cut plate.
[0456] 2. An aliquot of approximately 100-150 gm of extruded
material was charged into the chamber and spheronized as indicated
below.
[0457] 3. An air assist pressure of 0.2 Mpa was used to decrease
the tackiness of the beads during spheronization.
[0458] 4. The wet pellets were collected and gently screened
through a 14 mesh screen to remove oversized particles. The
oversized material was recycled into the extrusion mass to increase
yield and decrease waste.
34TABLE 32 Spheronization Time/Speed Time (min) Percent of Maximum
3-3.5 80% Total Spheronization Time 3-4 min
[0459] IV. Collection and Sizing
[0460] Procedure:
[0461] 1. The wet pellets were collected and evenly spread onto
aluminum sheets.
[0462] 2. These sheets were then left at room temperature to dry
overnight.
[0463] 3. The dried pellets were collected, and the final bead
distribution was assessed using standard metal screens and is shown
below.
[0464] 5. The percent of lost material in processing was less than
8%.
[0465] 6. Pellets of the 16-20 mesh size were used in subsequent
procedures.
35TABLE 33 Pellet Size Distribution Pass Through (mesh) Retained On
(Mesh) % of Starting Material 12 16 15.8 16 20 60.7 20 Collection
Plate 15.6 Total 92.1
[0466] V. Matrix Melting
[0467] Equipment:
[0468] 1. Melting of the wax matrix was accomplished with a
fluidized bed coater fitted with an acrylic coating chamber and a
filter screen.
[0469] 2. The pellet cores were heated at 65.degree. C. for 15
minutes and then allowed to cool at room temperature on aluminum
sheets.
[0470] The dissolution release profile of the uncoated slow-release
DFMO-containing matrix pellets are illustrated at FIG. 18. In FIG.
18 (-.circle-solid.-.circle-solid.-.circle-solid.-) the dissoltion
curve of DFMO from the matrix pellet is 0.1 N Hcl. The slight
decrease in DFMO release in pH 7.4 is due to the relatively lower
solubility of the drug DFMO at a neutral pH.
EXAMPLE 16
Release of DFMO from Coated Matrix Beads
[0471] The present example illustrates the use of the present
invention with coated matrix beads containing DFMO. The release
profiles here in an acidic media reflect poor adhesion of the
EUDRAGIT.TM. L30D-55 and EUDRAGIT.TM. 4110D to the wax containing
pellets containing DFMO. The rapid release of the drug was evident
from both pellet formulations in the acidic medium as demonstrated
in FIG. 19.
[0472] VI. Pellet Coating
[0473] Equipment.
[0474] 1. All coatings were applied with using a fluidized bed
coater fitted with a Wurster insert and a bottom spray technique. A
filter bag assembly was used, and the insert adjusted to {fraction
(1/2)}" above the floor of the coating chamber in order to obtain a
desirable flow of pellets through the spray path.
[0475] 2. Coating material was supplied with a peristaltic pump,
and the spray rate adjusted as indicated.
[0476] 3. The atomization pressure was 1.0-1.2 bar, and the filter
blow out pressure was set at 2 bar.
[0477] 4. The coating charge was 300 gm of size 16-20 mesh pellets
as described above except in the ethylcellulose/4110D coated
product. The ethylcellulose/4110D coated product utilizes 300 gm of
the rapid release beads detailed in the August 1997 report (lot
#07219701).
[0478] Enteric Coating
36TABLE 34 Coating Formulation Material Based On Weight EUDRAGIT
.TM. L30D-55 88.9 gm Triethyl Citrate (TEC) 15%, dry weight polymer
4.00 gm Imwitor .RTM. 900 5%, dry weight polymer 1.3 gm Water Total
solids to be 15% 92.5 gm Total Suspension Weight 186.7 gm
[0479] Calculation:
[0480] For an 8.2% weight gain of polymer (x is dry weight of
polymer) x/(300+x)=0.08 where x is 26.7 gm and is provided by 88.9
gm of 30% polymer suspension.
[0481] Procedure:
[0482] 1. The TEC, Imwitor.RTM. 90, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGIT.TM. L30D-55.
[0483] 2. The final coating dispersion is allowed to mix for at
least 30 minutes prior to application.
37TABLE 35 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 40/31 65 20 2.4
40/32 66 80 2.5 41/30 70
[0484] Beads were immediately coated with a 0.2% Imwitor.RTM. 900
top coat to prevent sticking during drying and storage.
[0485] 0.2% GMS Top Coat
38TABLE 36 Coating Formulation Material Based On Weight Imwitor
.RTM. 900 0.66 gm Water Total solids to be 2% 32.54 gm Total
Suspension Weight 33.20 gm
[0486] Calculation:
[0487] For an 0.2% weight gain of polymer (x is dry weight of
polymer) x/(332+x)=0.002 where x is 0.66 gm. Here, the coating
charge is increased due to the weight gain of solid material from
the previous spray applications.
[0488] Procedure:
[0489] 1. The Imwitor.RTM. 900 and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes.
39TABLE 37 Spray Process Time Temperature (.degree. C.) (min) Spray
Rate (g/min) In/Out Air Volume (M.sup.3/H) 5 0 43/33 70 15 2.0
40/32 70 25 0 40/40 70
[0490] Curing:
[0491] 1. Coated beads were collected and spread evenly onto
aluminum sheets.
[0492] 2. Final product was cured at 40.degree. C. for 2 hours and
then at room temperature overnight.
[0493] Colonic Coating
40TABLE 38 Coating Formulation Material Based On Weight EUDRAGIT
.TM. 4110D 88.9 gm Triethyl Citrate (TEC) 5%, dry weight polymer
1.3 gm Imwitor .RTM. 900 5%, dry weight polymer 1.3 gm Water Total
solids to be 15% 95.2 gm Total Suspension Weight 186.7 gm
[0494] Calculation:
[0495] For an 8.2% weight gain of polymer (x is dry weight of
polymer) x/(300+x)=0.08 where x is 26.7 gm and is provided by 88.9
gm of 30% polymer suspension.
[0496] Procedure:
[0497] 1. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30.degree. C. before adding to the EUDRAGIT.TM. 4110D.
[0498] 2. The final dispersion is allowed to mix for at least 30
minutes prior to application.
41TABLE 39 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 5 0 35/33 70 15 2.0
36/29 70 65 2.5 37/26 70
[0499] Beads were immediately coated with a 0.2% Imwitor.RTM. 900
top coat to prevent sticking during drying and storage.
[0500] 0.2% GMS Top Coat
42TABLE 40 Coating Formulation Material Based On Weight Imwitor
.RTM. 900 0.66 gm Water Total solids to be 2% 32.34 gm Total
Suspension Weight 33.00 gm
[0501] Calculation:
[0502] For an 0.2% weight gain of polymer (x is dry weight of
polymer) x/(329+x)=0.02 where x is 0.66 gm. Here, the coating
charge is increased due to the weight gain of solid material from
the previous spray applications.
[0503] Procedure:
[0504] 1. The Imwitor.RTM. 900 and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes.
43TABLE 41 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 5 0 43/33 70 15 2.0
40/32 70 25 0 40/40 70
[0505] Curing:
[0506] 1. Coated beads were collected and spread evenly onto
aluminum sheets.
[0507] 2. Final product was allowed to dry at room temperature
overnight.
[0508] The poor adhesion of the EUDRAGIT.TM. used (L30D-55 and
4110D) to the wax containing pellet resulted in poor protection of
the core when exposed to an acidic medium. When the pellets are
coated with a 2% to 3% weight gain of Opadry.RTM. II prior to
coating with the EUDRAGIT, protection of the pellets to the acidic
medium will be provided. The EUDRAGIT.TM. polymers used here
demonstrated enhanced adhesion to the Opadry.RTM. subcoat. The
dissolution profiles of these pellet formulations represented by
the two lower profiles in FIG. 19 provide the expected profile
where a subcoat of Opadry.RTM. II is included.
EXAMPLE 17
Extended Release Coating
[0509] These pellets did not include a sub-coating. They were
coated with AQUA COAT.RTM. containing the Methacel, a coating of
EUDRAGIT.TM. 4110D was then applied.
44TABLE 42 Coating Formulation Material Based On Weight AQUA-COAT
.TM. .RTM. 111.11 gm ECD Methocel .RTM. K4M 3.33 gm Triethyl
Citrate (TEC) 20%, dry weight polymer 6.00 gm AQUA-COAT .TM. .RTM.
ECD Water Total solids to be 10% w/w 212.86 gm Total Suspension
Weight 333.30 gm
[0510] (See FIG. 20 for data)
[0511] Calculation:
[0512] For a 10% weight gain of polymer (x is dry weight of
polymer) x/(300+x)=0.10 where x is 33.3 gm and is provided by
111.10 gm of 27% aqueous ethylcellulose polymer suspension and
hydroxypropyl methylcellulose in a ratio of 9:1.
[0513] Procedure:
[0514] 1. The TEC and AQUA-COAT.TM..RTM. -ECD were allowed to mix
for at least thirty minutes before combining with the HPMC
solution.
[0515] 2. The HPMC was dispersed in hot water ({fraction (1/3)} of
water for addition) and then diluted ({fraction (2/3)} of water for
addition). The HPMC was allowed to hydrate and form a cool solution
prior to addition to the AQUA-COAT.TM..RTM. ECD dispersion.
[0516] 3. The final dispersion was stirred for at least 30 minutes
prior to application.
45TABLE 43 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 5 0 60/35 70 140
2.1-2.4 60/44 70 15 0 60/44 70
[0517] Curing:
[0518] 1. Coated beads were dried in situ for 15 minutes with the
filter screen in place in preparation for the next application.
[0519] Colonic Coating of Extended Release Pellets
46TABLE 44 Coating Formulation Material Based On Weight EUDRAGIT
.TM. 4110D 90.49 gm Triethyl Citrate (TEC) 5%, dry weight polymer
1.36 gm Imwitor .RTM. 900 5%, dry weight polymer 1.36 gm Water
Total solids to be 15% 98.80 gm Total Suspension Weight 191.01
gm
[0520] Calculation:
[0521] For an 7.4% weight gain of polymer (x is dry weight of
polymer) x/(339+x)=0.074 where x is 27.15 gm and is provided by
90.49 gm of 30% polymer suspension. Here, the coating charge is
increased due to the weight gain of solid material from the
previous spray application.
[0522] Procedure:
[0523] 1. The TEC, Imwitor.RTM. 900, and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes. The resultant dispersion is then allowed to cool to less
than 30C before adding to the EUDRAGIT.TM. 4110D dispersion.
[0524] 2. The final dispersion is allowed to stir for at least 30
minutes prior to application.
47TABLE 45 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 5 0 50/41 70 63 2.1-2.5
39/29 70
[0525] Beads were immediately coated with a 0.2% Imwitor.RTM. 900
top coat to prevent sticking during drying and storage.
[0526] 0.2% GMS Top Coat
48TABLE 46 Coating Formulation Material Based On Weight Imwitor
.RTM. 900 0.74 gm Water Total solids to be 2% 36.16 gm Total
Suspension Weight 36.84 gm
[0527] Calculation:
[0528] For an 0.2% weight gain of polymer (x is dry weight of
polymer) x/(369+x)=0.002 where x is 0.74 gm. Here, the coating
charge is increased due to the weight gain of solid material from
the previous spray applications.
[0529] Procedure:
[0530] 1. The Imwitor.RTM. 900 and water are heated to
approximately 65.degree. C. and then homogenized at 4000 rpm for 15
minutes.
49TABLE 47 Spray Process Temperature (.degree. C.) Air Volume Time
(min) Spray Rate (g/min) In/Out (M.sup.3/H) 3 0 39/33 70 15 2.1-2.5
39/30 70 10 0 40/40 70
[0531] Curing:
[0532] 1. Coated beads were collected and spread evenly onto
aluminum sheets.
[0533] 2. Final product dried at 40.degree. C. overnight.
[0534] VI. Dissolution Testing
[0535] Apparatus
[0536] 1. Testing was done using the USP Method I, rotating basket
procedure.
[0537] 2. All testing was done at 37.degree. C. and 100 rpm shaft
speed.
[0538] 3. Various dissolution media was used to approximate the in
vivo conditions that the pellets may experience.
[0539] 4. Three milliliter samples were drawn at set time points,
and blank dissolution media was added to maintain a constant
dissolution volume
[0540] 5. Final dissolution volumes were 500 ml.
[0541] 6. Initial media was 0.1 N HCL and, if needed, aliquots of
0.2 M sodium phosphate tribasic was added to increase the pH. At pH
changes after the addition of the 0.2 M sodium phosphate, the pH of
the individual kettles was adjusted with 2 N NaOH prior to
sampling.
[0542] 7. Dissolution samples were filtered with a 0.45 .mu.m PTFE
filter prior to analysis.
50TABLE 48 Dissolution Time and Media Product Time Media pH
Uncoated Pellets 0-180 min 0.1 N HCl 1.0 0.05 M Phosphate 7.4 500
ml EUDRAGIT .TM. 0-120 min 0.1 N HCl 1.0 L30D-55 375 ml 120-240 min
+125 ml 6.8 0.2 M NaPO.sub.4 EUDRAGIT .TM. 0-120 min 0.1 N HCl 1.0
4110D 375 ml 120-240 min +125 ml 6.8 0.2 M NaPO.sub.4 AQUA-COAT
.TM. .RTM. 0-120 min 0.1 N HCl 1.0 ECD + 375 ml EUDRAGIT .TM. 4110D
120-240 min +125 ml 6.8 0.2 M NaPO.sub.4 240-480 min Adjust to pH
7.4
[0543] As demonstrated in FIG. 20, retardation of drug release in
an acidic (0.1 N HCl) was attained at pH 6.8, the EURDRAGIT.TM.
4110D dissolved and during the next 2 hours, the drug diffused
through the pores in the AQUA-COAT.TM. film.
[0544] VII. Drug Content
[0545] Procedure:
[0546] 1. An aliquot of pellets was ground with a porcelain mortar
and pestle.
[0547] 2. Approximately 500 mg aliquot of the ground material was
transferred to a 250 ml volumetric flask and brought to {fraction
(3/4)} volume with 0.1 N HCl.
[0548] 3. The flasks were then sonicated for 20 minutes and allowed
to cool to room temperature before bringing up to volume with
distilled water.
[0549] 4. Sample aliquots were filtered with a 0.45 .mu.m filter
prior to analysis.
[0550] VIII. Drug Analysis
51 HPLC Conditions Column: Alltech Platinum EPS .TM. C18, ODS-1, 5
.mu.m Mobile Phase: 1.1 mM Sodium Dodecyl Sulfate in 20/80 v/v
Acetonitrile/0.05 M NaPO.sub.4 (pH = 2.3) Flow Rate: 1.0 ml/min
Detection: 210 nm Injection Volume: 50 .mu.l Retention Time: 4.2
minutes
EXAMPLE 18
[0551] Multi-layered Matrix Tablet
[0552] The present example is provided to demonstrate the utility
of the present invention as a multi-layered tablet that includes a
core of a matrix containing DFMO, and a slow release material. Such
slow release materials include by way of example, Klucel.TM., HPMC,
carbomer, Polyox, and other cellulosic and hydrophilic polymers,
proteins and polysaccharides.
[0553] In some embodiments, the tablet will include a core pellet
of DFMO in a matrix. An exemplary matrix retardant used in the
present example is Klucel. This core tablet will then have a first
coat of a colonic protective material, such as EUDRAGIT.TM. S100.
This first coat is then covered with an Opadry.RTM. solution of
HPMC or similar rapidly dissolving or freely permeable material,
also containing DFMO (2nd coat). Over this, a third coat of an acid
resistant polymer (e.g. EUDRAGIT.TM. L, CAP, CAT, PVAP, HPMCP,
HPMCAS, or similar enteric polymer is applied over the second coat.
Then, a fourth coat of an immediate release material (e.g.
Opadry.RTM.) containing DFMO is applied.
[0554] The matrix tablet may be prepared by blending the DFMO (45%)
with Klucel HF (25%), spray dried lactose (24%) and Starch 1500
(5%) in a suitable blender for 10 minutes. The magnesium stearate
(0.5%) and Cabosil M5P (0.5%) are added to the powders. This is
blended for an additional 5 minutes. The powder blend is then
compressed into tablets in the 8-10 kg range in the 200-400 mg
range. The tablets are then coated as described above.
52 Exemplary Weight Gain for Pellet Coatings Coat 1 EUDRAGIT .TM.
S100 8% weight gain Coat 3 L30 D-55 8% weight gain Coat 2, Coat 4
HPMC E5:DFMO 10% weight gain (ratio 5:1)
[0555] Other chemical synthetic techniques well known to those of
skill in the art may be used such as that described in the attached
list of references which are hereby incorporated in their
entirety.
[0556] The above is a detailed description of a particular
embodiment of the invention. It is recognized that departures from
the disclosed embodiment may be made within the scope of the
invention and that obvious modifications will occur to a person
skilled in the art. The full scope of the invention is set out in
the claims that follow and their equivalents. Accordingly, the
claims and specification should not be construed to unduly narrow
the full scope of protection to which the invention is
entitled.
[0557] Those of skill in the art should, in light of the present
disclosure, appreciate that many changes can be made in the
specific embodiments where are disclosed herein and still obtain a
like or similar result without departing from the spirit and scope
of the invention. All of the compositions and methods disclosed and
claimed herein can be made and executed without undue
experimentation in light of the present disclosure. It will be
apparent that certain compounds which are both physiologically and
chemically related may be substituted for the therapeutic compound
described herein while the same or similar results are
achieved.
REFERENCES
[0558] The following references, to the extent that they provide
exemplary procedural or other details supplementary to those set
forth herein, are specifically incorporated herein by
reference.
[0559] S. G. Eckhardt, D. Dai, K. K. Davidson, B. J. Forseth, G. M.
Wahl, D. D. Von Hoff, Proc. Nat'l. Acad. Sci., USA, 1994, 91,
6674-6679.
[0560] Controlled Drug Delivery: Fundamentals and Applications, 2nd
ed. (Joseph R. Robinson and Vincent H. L. Lee, eds., Marcel Dekker,
Inc., NY; 1987) ISBN 0-8247-7588-0
[0561] Aqueous Polymeric Coatings for Pharmaceutical Dosage Forms
(James W. McGinity, ed.; Marcel Dekker, Inc., NY; 1989) ISBN
0-8247-7907-X
[0562] Pharmaceutical Dosage Forms: Tablets, Vol. 3 (Herbert A.
Lieberman, Leon Lachman and Joseph B. Schwartz, eds.; Marcel
Dekker, Inc., NY; 1990) ISBN 0-8247-8300-X
[0563] Pharmaceutical Dosage Forms and Drug Delivery Systems, 6th
Ed. (Howard C. Ansel, Nicholas G. Popovich and Lloyd V. Allen, Jr.,
eds.; Williams & Wilkins, Baltimore; 1995) ISBN
0-683-00193-0
[0564] Development of Difluoromethylornithine as a Chemoprevention
Agent for the Management of Colon Cancer, Meyskens, Frank L., Jr.;
Gemer, Eugene W. J., J. Cell. Biochem. (1995) (Suppl. 22),
126-31
[0565] Dose De-Escalation Chemoprevention Trial of
Alpha-Difluoromethylomi- thine in Patients with Colon Polyps.
(Meyakens, F. L., Jr; Emerson, S. S; Pelot, D.; Meshkinpour, H.;
Shassetz, L. R.; Einspahr J; Alberts, D. S,; Gerner, E. W. 1994 Aug
3) Journal of the National Cancer Institute, (1994 Aug 3) 86 (15)
1122-30.
[0566] Cancer Chemoprevention. (Lippman S. M.; Benner S. E.; Waun
Ki Hong J. Clin. Oncol., (1994) 12/4 (851-873).
[0567] Alpha-Difluoromethylornithine (DFMO) as a Potential
Chemopreventive Agent: Toxicology, Pharmacokinetics and
Pharmacodynamics of Chronic Oral Administration in Humans (Meeting
abstract); Creaven, P. J.; Pendyala, L.; Porter, C. W.; Murphy, M.
J. Non-serial, (1993). CCPC-93: Second International Cancer Chemo
Prevention Conference. April 28-30, 1993, Berlin, Germany, p.
53.
[0568] Randomized Phase I Chemoprevention Dose-Seeking Study of
Alpha-Difluoromethylornithine; Love, R. R.; Carbone, P. P.; Verma,
A. K.; Gilmore, D.; Carey, P.; Tutsch, K. D.; Pomplun, M.; Wilding,
G., Journal of the National Cancer Institute, (1993 May 5), 85 (9)
732-7.
[0569] Urinary and Erythrocyte Polyamines During the Evaluation of
Oral Alpha-Difluoromethylornithine in a Phase I Chemoprevention
Clinical Trial; Pendyala, L.; Creaven, P. J.; Porter, C. W., CANCER
EPIDEMIOLOGY, BIOMARKERS AND PREVENTION, (1993 May-June) pg.
235-41.
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