U.S. patent application number 10/435013 was filed with the patent office on 2003-10-30 for multiplex drug delivery system suitable for oral administration.
This patent application is currently assigned to IMPAX Pharmaceuticals, Inc.. Invention is credited to Hsiao, Charles, Ting, Richard.
Application Number | 20030203028 10/435013 |
Document ID | / |
Family ID | 22595418 |
Filed Date | 2003-10-30 |
United States Patent
Application |
20030203028 |
Kind Code |
A1 |
Ting, Richard ; et
al. |
October 30, 2003 |
Multiplex drug delivery system suitable for oral administration
Abstract
A multiplex drug delivery system suitable for oral
administration containing at least two distinct drug dosage
packages, which exhibit equivalent dissolution profiles for an
active agent when compare to one another and when compared to that
of the entire multiplex drug delivery unit, and substantially
enveloped by a scored film coating that allows the separation of
the multiplex drug delivery system into individual drug dosage
packages can provide a convenient and cost effective drug delivery
unit, particularly for patients with a regimen of prescribed
dosages that varies during their treatment period.
Inventors: |
Ting, Richard; (Danville,
CA) ; Hsiao, Charles; (Livermore, CA) |
Correspondence
Address: |
FLESHNER & KIM, LLP
P.O. Box 221200
Chantilly
VA
20153-1200
US
|
Assignee: |
IMPAX Pharmaceuticals, Inc.
|
Family ID: |
22595418 |
Appl. No.: |
10/435013 |
Filed: |
May 12, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10435013 |
May 12, 2003 |
|
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09164642 |
Sep 29, 1998 |
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6602521 |
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Current U.S.
Class: |
424/471 ;
514/211.07; 514/262.1; 514/470 |
Current CPC
Class: |
A61K 9/2072 20130101;
A61J 3/10 20130101; A61K 9/209 20130101 |
Class at
Publication: |
424/471 ;
514/211.07; 514/262.1; 514/470 |
International
Class: |
A61K 031/554; A61K
031/519; A61K 009/24 |
Claims
What is claimed is:
1. A multiplex drug delivery system suitable for oral
administration comprising at least two immediate-release
compartments substantially enveloped by a scored extended-release
compartment, which facilitates separation of said multiplex drug
delivery system into individual drug dosage packages.
2. The multiplex drug delivery system of claim 1, wherein each of
said immediate-release compartments further comprises an effective
amount of an active agent, or a pharmaceutically acceptable salt
thereof, and wherein said scored extended-release compartment
further comprises an effective amount of an active agent, or a
pharmaceutically acceptable salt thereof, in a compressed blend
with a combination of a hydrophilic polymer and a hydrophobic
material, and wherein each of said individual drug dosage packages
exhibits an equivalent release profile for said active agent when
compared to one another or when compared to said multiplex drug
delivery system in its entirety.
3. The multiplex drug delivery system of claim 1, wherein each of
said immediate-release compartments further comprises an effective
amount of an active agent, or a pharmaceutically acceptable salt
thereof, in a compressed blend with a polymer.
4. The multiplex drug delivery system of claim 1, wherein said
scored extended-release compartment further comprises an effective
amount of an active agent, or a pharmaceutically acceptable salt
thereof, in a compressed blend with a combination of a hydrophilic
polymer and a hydrophobic material.
5. The multiplex drug delivery system of claim 2, wherein said
active agent is a drug.
6. The multiplex drug delivery system of claim 5, wherein said drug
is a therapeutic drug.
7. The multiplex drug delivery system of claim 5, wherein said drug
is a prophylactic drug.
8. The multiplex drug delivery system of claim 5, wherein said drug
is selected from the group consisting of diltiazem, trapidil,
urapidil, benziodarone, dipyridamole, isosorbide mononitrate, and
lidoflazine.
9. The multiplex drug delivery system of claim 5, wherein said drug
is selected from the group consisting of non-steroidal
antiinflammatory drugs (NSAIDs) and steroidal antiinflammatory
drugs.
10. The multiplex drug delivery system of claim 9, wherein said
steroidal antiinflammatory drug is selected from the group
consisting of diclofenac sodium, ibuprofen, ketoprofen, diflunisal,
piroxicam, motrin, and naproxen.
11. The multiplex drug delivery system of claim 5, wherein said
drug is selected from the group consisting of acetaminophen,
aldosterone, alprenolol, amitryptyline, aspirin, beclomethasone,
diproprionate, bromocriptine, butorphanol tartrate,
chlormethiazole, chlorpheniramine, chlorpromazine HCl, cimetidine,
codeine, cortisone, cyclobenzamine HCl, desmethylimipramine,
dextropropoxyphene, dihydroergotamine, diltiazem HCl, dobutamine
HCl, domperidone, dopamine HCl, doxepin HCl, epinephrine, ergoloid
mesylates, ergotamine tartrate estradiol, ethinylestradiol,
flunisolide, fluorouracil, flurazepam HCl,
5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide,
glyceryl trinitrate, guanethidine sulfate, hydralazine HCl,
imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate,
isoprenaline, isoproterenol sulfate, isosorbide dinitrate,
levallorphan tartrate, levodopa, lidocaine HCl, lignocaine,
lorcainide, meperidine HCl, 6-mercaptopurine, metaproterenol
sulfate, methoxamine HCl, methylphenidate, methylpreonisolone,
methyltestosterone mesylate, metoclopramide, metoprolol tartrate,
morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine,
nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate,
norethindrone, nortriptylene HCl, oxprenolol, oxyphenbutazone,
penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital,
petnidine, phenacetin, phentolamine HCl, phentolamine mesylate,
phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal,
prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene
napsylate, propranolol HCl, quinidine, reserpine, ritodrine HCl,
salicylamide, salbutamol, secobarbital, testosterone, terbutaline,
timolol maleate, tolbutamide, and verapamil HCl.
12. The multiplex drug delivery system of claim 5, wherein said
active agent is isosorbide-5-mononitrate.
13. The multiplex drug delivery system of claim 2, wherein said
active agent exhibits the following in vitro dissolution profile
when measured in a type 2 dissolution apparatus (paddle) according
to U.S. Pharmacopeia XXII at 37.degree. C..+-.0.5.degree. C. in
deionized water at 75 rotations per minute: (a) from about 0% to
about 90% of said active agent is released between 1 hour and 16
hours of measurement in said apparatus; and (b) from about 0% to
about 100% of said active agent is released between 1.5 hours and
28 hours after measurement in said apparatus.
14. The multiplex drug delivery system of claim 13, wherein said
active agent exhibits the following in vitro dissolution profile
when measured in a type 2 dissolution apparatus (paddle) according
to U.S. Pharmacopeia XXII at 37.degree. C..+-.0.5.degree. C. in
deionized water at 75 rotations per minute: (a) from about 10% to
about 75% of said active agent is released between 1 hour and 5
hours of measurement in said apparatus; and (b) no less than about
90% of said active agent is released after 6 hours of measurement
in said apparatus.
15. The multiplex drug delivery system of claim 14, wherein said
active agent is isosorbide-5-mononitrate.
16. The multiplex drug delivery system of claim 3, wherein said
polymer is selected from the group consisting of alginic acid,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
colloidal silicon dioxide, guar gum, magnesium aluminum silicate,
methylcellulose, microcrystalline cellulose, cellulose,
pregelatinized starch, sodium alginate, starch, ethylcellulose,
gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polymethacrylates, povidone,
shellac, and zein.
17. The multiplex drug delivery system of claim 16, wherein said
polymer is selected from the group consisting of colloidal silicon
dioxide, microcrystalline cellulose, and hydroxypropyl
methylcellulose.
18. The multiplex drug delivery system of claim 2, wherein said
hydrophilic polymer is selected from the group consisting of
carboxymethylcellulose, guar gum, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, and povidone.
19. The multiplex drug delivery system of claim 18, wherein said
hydrophilic polymer is hydroxypropyl methylcellulose.
20. The multiplex drug delivery system of claim 2, wherein said
hydrophobic material is selected from the group consisting of
carnauba wax, ethylcellulose, glyceryl palmitostearate,
hydrogenated castor oil, hydrogenated vegetable oil,
microcrystalline wax, polymethacrylates, and stearic acid.
21. The multiplex drug delivery system of claim 20, wherein said
hydrophobic material is hydrogenated vegetable oil.
22. A method for preparing a multiplex drug delivery system
suitable for oral administration comprising the steps of: (a)
combining an effective amount of an active agent, or a
pharmaceutically acceptable salt thereof, and a polymer to form at
least two immediate-release compartments; (b) combining an
effective amount of an active agent, or a pharmaceutically
acceptable salt thereof, and a hydrophilic polymer and a
hydrophobic material to form an extended-release compartment; (c)
press coating said extended-release compartment to substantially
envelop said at least two immediate-release compartments, and (d)
scoring said extended-release compartment such that said
immediate-release compartments are separable.
23. The method of claim 22, wherein said combining is selected from
the group consisting of blending, perforated pan coating, fluidized
particle coating, wet granulation, fluid-bed granulation, and dry
granulation.
24. The method of claim 22, wherein said active agent is a
drug.
25. The method of claim 24, wherein said drug is a therapeutic
drug.
26. The method of claim 24, wherein said drug is a prophylactic
drug.
27. The method of claim 24, wherein said drug is selected from the
group consisting of diltiazem, trapidil, urapidil, benziodarone,
dipyridamole, isosorbide mononitrate, and lidoflazine.
28. The method of claim 24, wherein said drug is selected from the
group consisting of non-steroidal antiinflammatory drugs (NSAIDs)
and steroidal antiinflammatory drugs.
29. The method of claim 28, wherein said steroidal antiinflammatory
drug is selected from the group consisting of diclofenac sodium,
ibuprofen, ketoprofen, diflunisal, piroxicam, motrin, and
naproxen.
30. The method of claim 24, wherein said drug is selected from the
group consisting of acetaminophen, aldosterone, alprenolol,
amitryptyline, aspirin, beclomethasone, diproprionate,
bromocriptine, butorphanol tartrate, chlormethiazole,
chlorpheniramine, chlorpromazine HCl, cimetidine, codeine,
cortisone, cyclobenzamine HCl, desmethylimipramine,
dextropropoxyphene, dihydroergotamine, diltiazem HCl, dobutamine
HCl, domperidone, dopamine HCl, doxepin HCl, epinephrine, ergoloid
mesylates, ergotamine tartrate estradiol, ethinylestradiol,
flunisolide, fluorouracil, flurazepam HCl,
5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide,
glyceryl trinitrate, guanethidine sulfate, hydralazine HCl,
imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate,
isoprenaline, isoproterenol sulfate, isosorbide dinitrate,
levallorphan tartrate, levodopa, lidocaine HCl, lignocaine,
lorcainide, meperidine HCl, 6-mercaptopurine, metaproterenol
sulfate, methoxamine HCl, methylphenidate, methylpreonisolone,
methyltestosterone mesylate, metoclopramide, metoprolol tartrate,
morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine,
nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate,
norethindrone, nortriptylene HCl, oxprenolol, oxyphenbutazone,
penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital,
petnidine, phenacetin, phentolamine HCl, phentolamine mesylate,
phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal,
prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene
napsylate, propranolol HCl, quinidine, reserpine, ritodrine HCl,
salicylamide, salbutamol, secobarbital, testosterone, terbutaline,
timolol maleate, tolbutamide, and verapamil HCl.
31. The method of claim 24, wherein said active agent is
isosorbide-5-mononitrate.
32. The method of claim 24, wherein said polymer is selected from
the group consisting of alginic acid, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, colloidal silicon dioxide,
guar gum, magnesium aluminum silicate, methylcellulose,
microcrystalline cellulose, cellulose, pregelatinized starch,
sodium alginate, starch, ethylcellulose, gelatin, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polymethacrylates, povidone, shellac, and zein.
33. The method of claim 32, wherein said polymer is selected from
the group consisting of colloidal silicon dioxide, croscarmellose
sodium, microcrystalline cellulose, and hydroxypropyl
methylcellulose.
34. The method of claim 24, wherein said hydrophilic polymer is
selected from the group consisting of carboxymethylcellulose, guar
gum, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl
methylcellulose, methylcellulose, and povidone.
35. The method of claim 34, wherein said hydrophilic polymer is
hydroxypropyl methylcellulose.
36. The method of claim 24, wherein said hydrophobic material is
selected from the group consisting of carnauba wax, ethylcellulose,
glyceryl palmitostearate, hydrogenated castor oil, hydrogenated
vegetable oil, microcrystalline wax, polymethacrylates, and stearic
acid.
37. The method of claim 36, wherein said hydrophobic material is
hydrogenated vegetable oil.
Description
FIELD OF THE INVENTION
[0001] The present invention relates to a single drug delivery unit
suitable for oral administration containing at least two distinct
drug dosage packages. This multiplex system contains at least two
immediate-release compartments substantially enveloped by a scored
extended-release compartment. The scored nature of the
extended-release compartment facilitates the separation by the
patient of the multiplex drug delivery system into individual drug
dosage packages for oral administration of the prescribed dosage.
Upon separation, each individual drug dosage package can exhibit an
equivalent, and preferably identical, release profile for the
active agent as compared to one another and to that of the entire
multiplex system. Accordingly, in a preferred embodiment, the
separability of the multiplex drug delivery system enables its use
throughout the entire course of a varying dosage regimen, and thus,
facilitates cost effective patient compliance.
BACKGROUND OF THE INVENTION
[0002] Drug efficacy depends upon the maintenance of the proper
therapeutic levels of the drug over the required treatment period.
With respect to orally administered drugs, the effectiveness of
treatment depends, in part or sometimes in whole, on patient
compliance with the prescribed dosage regimen. Particularly where
the prescribed dosage increases or decreases during the treatment
period, patient compliance can suffer because of the unavailability
of, or inconvenience in obtaining, the appropriate dosage of the
prescribed medication at different times.
[0003] It would therefore be beneficial for patients to have one
drug delivery unit that allows patients themselves to regulate the
amount of drug to administer. Such a capability would enable
patients to use the same drug delivery unit throughout their entire
treatment period even where their prescribed dosage changes during
that time. Patients in such circumstances would have the
convenience and cost effectiveness of obtaining in one unit and at
the same time the different dosages of their prescribed drug that
would be needed during their treatment period.
[0004] A valuable contribution to the art therefore would be the
development of a multiplex drug delivery system suitable for oral
administration containing at least two immediate-release
compartments substantially enveloped by a scored extended-release
compartment that facilitates the separation of the multiplex drug
delivery system into individual drug dosage packages for oral
administration of the prescribed dosage, each of which can exhibit
an equivalent, and preferably identical, release profile for the
active agent as compared to one another and to that of the entire
multiplex system.
SUMMARY OF THE INVENTION
[0005] Accordingly, an objective of the present invention is a
single drug delivery unit suitable for oral administration that
patients could separate into individual drug dosage packages. These
individual drug dosage packages can exhibit an equivalent, and
preferably identical, release profile for the active agent when
compared to one another or when compared to the entire, intact
multiplex drug delivery system.
[0006] The present invention accomplishes this objective through a
multiplex drug delivery system suitable for oral administration
containing at least two immediate-release compartments. The scored
extended-release compartment of the invention allows the separation
of the multiplex drug delivery system into individual drug dosage
packages for oral administration of the prescribed dosage, each of
which can exhibit an equivalent, and preferably identical, release
profile for the active agent as compared to one another and to that
of the entire multiplex system.
[0007] One preferred embodiment of the claimed invention is a
multiplex drug delivery system suitable for oral administration
comprising at least two immediate-release compartments
substantially enveloped by a scored extended-release compartment.
The extended-release compartment can comprise a combination of a
hydrophilic and a hydrophobic material. In such an embodiment, the
hydrophilic polymer(s) dissolves away to weaken the
extended-release compartment, while the hydrophobic material
retards the water, thus helping to preserve the integrity of the
drug delivery system. Where the immediate-release compartments are
inert (i.e., do not comprise an active agent), they can facilitate
a bursting effect, which can disrupt any remaining integrity of the
extended-release compartment.
[0008] In another preferred embodiment of the claimed invention,
each immediate-release compartment further comprises an effective
amount of an active agent, or a pharmaceutically acceptable salt
thereof and the scored extended-release compartment further
comprises an effective amount of an active agent, or a
pharmaceutically acceptable salt thereof, in a compressed blend
with the combination of a hydrophilic polymer and a hydrophobic
material.
[0009] In a further preferred embodiment, each immediate-release
compartment further comprises an effective amount of an active
agent, or a pharmaceutically acceptable salt thereof, in a
compressed blend with a polymer. In one other preferred embodiment,
the scored extended-release compartment further comprises an
effective amount of an active agent, or a pharmaceutically
acceptable salt thereof, in a compressed blend with the combination
of a hydrophilic polymer and a hydrophobic material. By varying the
composition of the polymer(s) in the immediate-release compartments
and/or the relative composition of the hydrophilic polymer and
hydrophobic material in the extended-release compartment, the
respective time periods for the dissolution of the active agent or
the bursting effect can be adjusted.
[0010] In a preferred embodiment of the claimed invention, the
active agent contained in the multiplex drug delivery system can be
a drug. In other embodiments, that drug can be a therapeutic or a
prophylactic drug.
[0011] In one preferred embodiment of the claimed invention, the
drug of the multiplex drug delivery system can be diltiazem,
trapidil, urapidil, benziodarone, dipyridamole, isosorbide
mononitrate, or lidoflazine. In another embodiment, the drug can be
a non-steroidal antiinflammatory drug (NSAID) or steroidal
antiinflammatory drug. In an embodiment, the steroidal
antiinflammatory drug can be diclofenac sodium, ibuprofen,
ketoprofen, diflunisal, piroxicam, motrin, or naproxen. In yet
another embodiment, the drug can be acetaminophen, aldosterone,
alprenolol, amitryptyline, aspirin, beclomethasone, diproprionate,
bromocriptine, butorphanol tartrate, chlormethiazole,
chlorpheniramine, chlorpromazine HCl, cimetidine, codeine,
cortisone, cyclobenzamine HCl, desmethylimipramine,
dextropropoxyphene, dihydroergotamine, diltiazem HCl, dobutamine
HCl, domperidone, dopamine HCl, doxepin HCl, epinephrine, ergoloid
mesylates, ergotamine tartrate estradiol, ethinylestradiol,
flunisolide, fluorouracil, flurazepam HCl,
5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide,
glyceryl trinitrate, guanethidine sulfate, hydralazine HCl,
imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate,
isoprenaline, isoproterenol sulfate, isosorbide dinitrate,
levallorphan tartrate, levodopa, lidocaine HCl, lignocaine,
lorcainide, meperidine HCl, 6-mercaptopurine, metaproterenol
sulfate, methoxamine HCl, methylphenidate, methylpreonisolone,
methyltestosterone mesylate, metoclopramide, metoprolol tartrate,
morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine,
nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate,
norethindrone, nortriptylene HCl, oxprenolol, oxyphenbutazone,
penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital,
petnidine, phenacetin, phentolamine HCl, phentolamine mesylate,
phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal,
prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene
napsylate, propranolol HCl, quinidine, reserpine, ritodrine HCl,
salicylamide, salbutamol, secobarbital, testosterone, terbutaline,
timolol maleate, tolbutamide, or verapamil HCl.
[0012] In one other preferred embodiment of the claimed invention,
the active agent can preferably be isosorbide-5-mononitrate.
[0013] In a preferred embodiment, the active agent of the multiplex
drug delivery system can exhibit the following in vitro dissolution
profile when measured in a type 2 dissolution apparatus (paddle)
according to U.S. Pharmacopeia XXII at 37.degree. C..+-.0.5.degree.
C. in deionized water at 75 rotations per minute:
[0014] from about 0% to about 90% of said active agent is released
between 1 hour and 16 hours of measurement in said apparatus;
and
[0015] from about 0% to about 100% of said active agent is released
between 1.5 hours and 28 hours after measurement in said
apparatus.
[0016] In such a preferred embodiment, the active agent of the
multiplex drug delivery system can be isosorbide-5-mononitrate.
[0017] In still another preferred embodiment, the active agent of
the multiplex drug delivery system can exhibit the following in
vitro dissolution profile when measured in a type 2 dissolution
apparatus (paddle) according to U.S. Pharmacopeia XXII at
37.degree. C..+-.0.5.degree. C. in deionized water at 75 rotations
per minute:
[0018] from about 10% to about 75% of said active agent is released
between 1 hour and 5 hours of measurement in said apparatus;
and
[0019] no less than about 90% of said active agent is released
after 6 hours of measurement in said apparatus.
[0020] In one preferred embodiment of the claimed invention, the
polymer of the multiplex drug delivery system can be alginic acid,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
colloidal silicon dioxide, guar gum, magnesium aluminum silicate,
methylcellulose, microcrystalline cellulose, cellulose,
pregelatinized starch, sodium alginate, starch, ethylcellulose,
gelatin, hydroxyethyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polymethacrylates, povidone,
shellac, or zein, and preferably hydroxypropyl methylcellulose.
[0021] In yet another preferred embodiment, the hydrophilic polymer
of the multiplex drug delivery system can be
carboxymethylcellulose, guar gum, hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, or povidone, and preferably hydroxypropyl
methylcellulose.
[0022] In a preferred embodiment of the claimed invention, the
hydrophobic material of the multiplex drug delivery system can be
carnauba wax, ethylcellulose, glyceryl palmitostearate,
hydrogenated castor oil, hydrogenated vegetable oil,
microcrystalline wax, polymethacrylates, or stearic acid, and
preferably hydrogenated vegetable oil.
[0023] The present invention also accomplishes these and other
objectives through a method for preparing a multiplex drug delivery
system suitable for oral administration comprising the steps of:
combining an effective amount of an active agent, or a
pharmaceutically acceptable salt thereof, and a polymer to form at
least two immediate-release compartments; combining an effective
amount of an active agent, or a pharmaceutically acceptable salt
thereof, and a hydrophilic polymer and a hydrophobic material to
form an extended-release compartment; press coating the
extended-release compartment to substantially envelop the at least
two immediate-release compartments, and scoring the
extended-release compartment such that the immediate-release
compartments are separable.
[0024] In a preferred embodiment, the method for preparing a
multiplex drug delivery system suitable for oral administration can
include combining by blending, perforated pan coating, fluidized
particle coating, wet granulation, fluid-bed granulation, or dry
granulation according to methods recognized in the art.
[0025] Other objects, features and advantages of the present
invention will become apparent from the following detailed
description. The detailed description and the specific examples,
however, indicate only preferred embodiments of the invention.
Various changes and modifications within the spirit and scope of
the invention will become apparent to those skilled in the art from
this detailed description.
DESCRIPTION OF DRAWINGS
[0026] FIG. 1 is a schematic of one preferred embodiment of the
multiplex drug delivery system suitable for oral administration,
which contains two immediate-release compartments substantially
enveloped by a scored extended-release compartment. The scored
extended-release compartment of the invention allows the separation
of the multiplex drug delivery system into individual drug dosage
packages for oral administration of the prescribed dosage, each of
which can exhibit an equivalent, and preferably identical, release
profile for the active agent as compared to one another and to that
of the entire multiplex system.
[0027] In this preferred embodiment, the multiplex system consists
of an oblong tablet scored in the middle to allow for easy breaking
of the tablet. Each half of the tablet contains an
immediate-release compartment located concentrically within the
round tablet edges, allowing for a slightly thicker wall from the
center edge when the tablet is broken in half. The distance between
immediate-release compartments need not be greater than twice the
distance between the interface of the immediate-release and
extended-release compartments and that of the extended-release
compartment and the outer surface or optional cosmetic compartment,
so long as once separated, each individual drug dosage package can
exhibit an equivalent, and preferably identical, release profile
for the active agent as compared to one another and to that of the
entire multiplex system.
[0028] FIG. 2 is a graph showing the in vitro dissolution profile
(% dissolved versus time) of isosorbide mononitrate extended
release tablets (Lots 127-19A and 127-19B), according to an
embodiment of the present invention, in deionized water using a
type 2 dissolution apparatus (paddle method) at 37.+-.0.5.degree.
C. at 75 rotations per minute (rpm). See U.S. Pharmacopeia XXII
<711> Dissolution.
[0029] FIG. 3 is a graph showing the in vitro dissolution profiles
(% dissolved versus time) of an entire multiplex drug delivery
system containing two immediate-release compartments (each
comprising the active agent isosorbide mononitrate) (Lot 127-19A
"whole tablet"), and an individual drug dosage package thereof
after separation (Lot 127-19A "half tablet"), according to
respective embodiments of the present invention, in deionized water
using a type 2 dissolution apparatus (paddle method) at
37.+-.0.5.degree. C. at 75 rotations per minute (rpm). See U.S.
Pharmacopeia XXII <711> Dissolution.
DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS
[0030] In accordance with the present invention, the term "active
agent" includes one or more drugs, their pharmaceutically
acceptable salts, pro-drug forms, metabolites, and derivatives.
[0031] Active agents include therapeutic or prophylactic compounds
as described in the Physicians' Desk Reference, most preferably
including (but not limited to) those prescribed for the prevention
and/or treatment of angina and hypertension: diltiazem, trapidil,
urapidil, benziodarone, dipyridamole, isosorbide mononitrate, and
lidoflazine; and those prescribed for the prevention and/or
treatment of rheumatic diseases such as rheumatoid arthritis:
non-steroidal antiinflammatory drugs (NSAIDs) and steroidal
antiinflammatory drugs such as diclofenac sodium, ibuprofen,
ketoprofen, diflunisal, piroxicam, motrin, and naproxen, and
combinations thereof.
[0032] The active agent of the present invention also preferably
includes drugs that are subject to the first pass effect. Various
examples of such drugs include (but are not limited to)
acetaminophen, aldosterone, alprenolol, amitryptyline, aspirin,
beclomethasone, diproprionate, bromocriptine, butorphanol tartrate,
chlormethiazole, chlorpheniramine, chlorpromazine HCl, cimetidine,
codeine, cortisone, cyclobenzamine HCl, desmethylimipramine,
dextropropoxyphene, dihydroergotamine, diltiazem HCl, dobutamine
HCl, domperidone, dopamine HCl, doxepin HCl, epinephrine, ergoloid
mesylates, ergotamine tartrate estradiol, ethinylestradiol,
flunisolide, fluorouracil, flurazepam HCl,
5-fluoro-21-deoxyuridine, furosemide, glipizide, glyburide,
glyceryl trinitrate, guanethidine sulfate, hydralazine HCl,
imipramine HCl, indoramin, isoethorine HCl, isoethrine mesylate,
isoprenaline, isoproterenol sulfate, isosorbide dinitrate,
levallorphan tartrate, levodopa, lidocaine HCl, lignocaine,
lorcainide, meperidine HCl, 6-mercaptopurine, metaproterenol
sulfate, methoxamine HCl, methylphenidate, methylpreonisolone,
methyltestosterone mesylate, metoclopramide, metoprolol tartrate,
morphine sulfate, nalbuphine HCl, naloxone HCl, neostigmine,
nifedipine, nitrendipine, nitroglycerin, norepinephrine bitartrate,
norethindrone, nortriptylene HCl, oxprenolol, oxyphenbutazone,
penicillamine, pentazocine HCl, pentazocine lactate, pentobarbital,
petnidine, phenacetin, phentolamine HCl, phentolamine mesylate,
phenylephrine HCl, phenylephrine bitartrate, phenytoin, pindolal,
prazosin, prednisone, progesterone, propoxyphene HCl, propoxyphene
napsylate, propranolol HCl, quinidine, reserpine, ritodrine HCl,
salicylamide, salbutamol, secobarbital, testosterone, terbutaline,
timolol maleate, tolbutamide, and verapamil HCl.
[0033] In a preferred embodiment of the present invention, the
active agent may include the drug, isosorbide-5-mononitrate, an
organic nitrate, which is a vasodilator with effects on both
arteries and veins. The empirical formula is C.sub.6H.sub.9NO.sub.6
and the molecular weight is 191.14. The chemical name for
isosorbide mononitrate is 1,4:3,6-dianhydro-D-glucitrol
5-nitrate.
[0034] Isosorbide mononitrate is the major active metabolite of
isosorbide dinitrate and most of the clinical activity of the
dinitrate can be attributable to the mononitrate. A principal
pharmacological action of isosorbide mononitrate is relaxation of
vascular smooth muscle and consequent dilatation of peripheral
arteries and veins, especially the latter. Dilatation of the veins
is known to promote peripheral pooling of blood and decrease venous
return to the heart, thereby reducing left ventricular and
diastolic pressure and pulmonary capillary wedge pressure
(preload). Arteriolar relaxation reduces systemic vascular
resistance, systolic arterial pressure, and mean arterial pressure
(afterload). Dilation of the coronary arteries also occurs. The
relative importance of preload reduction, afterload reduction, and
coronary dilatation remains undefined. The mechanism by which
isosorbide mononitrate relieves angina pecteria is not fully
understood.
[0035] Isosorbide mononitrate is rapidly and completely absorbed
from the gastrointestinal tract. In humans, isosorbide mononitrate
is not subject to first pass metabolism in the liver. The overall
elimination half-life of isosorbide mononitrate is about 6 hours.
The rate of clearance is the same in healthy young adults, and in
patients with various degrees of renal, hepatic, or cardiac
dysfunction.
[0036] In accordance with the present invention, the term "polymer"
includes single or multiple polymeric substances, which can swell,
gel, degrade or erode on contact with an aqueous environment (e.g.,
water), such as one or more of alginic acid, carboxymethylcellulose
calcium, carboxymethylcellulose sodium, colloidal silicon dioxide,
guar gum, magnesium aluminum silicate, methylcellulose,
microcrystalline cellulose, cellulose, pregelatinized starch,
sodium alginate, starch, ethylcellulose, gelatin, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
polymethacrylates, povidone, pregelatinized starch, shellac, and
zein, and combinations thereof.
[0037] The "hydrophilic polymers" of the present invention include
one or more of carboxymethylcellulose, guar gum, hydroxyethyl
cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose,
methylcellulose, and povidone. The "hydrophobic materials" of the
present invention include one or more of carnauba wax,
ethylcellulose, glyceryl palmitostearate, hydrogenated castor oil,
hydrogenated vegetable oil, microcrystalline wax,
polymethacrylates, and stearic acid.
[0038] Without further elaboration, it is believed that one skilled
in the art, using the preceding description, can practice the
present invention to the fullest extent. The following examples are
illustrative only, and not limiting of the remainder of the
disclosure in any way whatsoever.
EXAMPLES
[0039] The method below was employed to obtain a multiplex drug
delivery system, the composition of which is set forth in the
tables immediately following in Table 1:
[0040] Immediate-Release Compartment. Isosorbide mononitrate was
first mixed with silicon dioxide in a Patterson-Kelley V-blender
together with microcrystalline cellulose, croscarmellulose sodium,
and magnesium stearate for 15 minutes. The powder blend was then
compressed using a Manesty Dry-cota with a {fraction (3/16)}"
diameter, round, flat-face punch and die set. The hardness of the
tablets were maintained at 4.+-.2 kp.
[0041] Immediate-Release Compartment Plus Extended-Release
Compartment Isosorbide mononitrate was mixed with silicon dioxide
in a Patterson-Kelley V-blender together with hydroxypropyl
methylcellulose 2208, microcrystalline cellulose, hydrogenated
vegetable oil, and magnesium stearate for 15 minutes. The core
tablets were press-coated using a Korsch Core Coater {fraction
(5/16)}".times.3/4" capsule shape punches. The hardness of the
tablets were maintained at 12.+-.4 kp.
[0042] In addition, the formulation of respective release
compartments can occur by appropriate granulation methods. In wet
granulation, solutions of the binding agent (polymer) are added
with stirring to the mixed powders. The powder mass is wetted with
the binding solution until the mass has the consistency of damp
snow or brown sugar. The wet granulated material is forced through
a sieving device. Moist material from the milling step is dried by
placing it in a temperature controlled container. After drying, the
granulated material is reduced in particle size by passing through
a sieving device. Lubricant is added, and the final blend is then
compressed.
[0043] In fluid-bed granulation, particles of inert material and/or
active agent are suspended in a vertical column with a rising air
stream. While the particles are suspended, the common granulating
materials in solution are sprayed into the column. There is a
gradual particle buildup under a controlled set of conditions
resulting in tablet granulation. Following drying and the addition
of lubricant, the granulated material is ready for compression.
[0044] In dry-granulation, the active agent, diluent, and lubricant
are blended and compressed into large tablets. The compressed large
tablets are comminuted through the desirable mesh screen by sieving
equipment. Some more lubricant is added to the granulated material
and blended gently. The material is then compressed into
tablets.
1 TABLE 1 QUANTITY/TABLET Example #1 Example #2 Immediate-Release
(IR) Compartment Lot 127-13 Lot 127-13 Isosorbide-5-mononitrate 80%
w/lactose 25.0 mg 25.0 mg Croscarmellose sodium 1.1 mg 1.1 mg
Microcrystalline cellulose 28.2 mg 28.2 mg Colloidal silicon
dioxide 0.2 mg 0.2 mg Magnesium stearate 0.5 mg 0.5 mg Total: 55.0
mg 55.0 mg IR Compartment Plus Extended-Release (ER) Compartment
Lot 127-19A Lot 127-19B IR Compartment (two cores) 110.0 mg 110.0
mg Isosorbide-5-mononitrate 80% w/lactose 37.5 mg 37.5 mg
Hydroxypropyl methylcellulose, type 2208 201.6 mg 288.0 mg
Microcrystalline cellulose 245.5 mg 245.5 mg Hydrogenated vegetable
oil, type 1 223.2 mg 136.8 mg Colloidal silicon dioxide 3.6 mg 3.6
mg Magnesium stearate 7.2 mg 7.2 mg Blue dye 1.4 mg 1.4 mg Total:
830.0 mg 830.0 mg
[0045] The invention has been disclosed broadly and illustrated in
reference to representative embodiments described above. Those
skilled in the art will recognize that various modifications can be
made to the present invention without departing from the spirit and
scope thereof.
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