U.S. patent application number 10/432488 was filed with the patent office on 2004-04-01 for modified release dosage forms.
Invention is credited to Lee, Der-Yang, Li, Shun-Por, McTeigue, Daniel, Parikh, Narendra, Sowden, Harry S., Thomas, Martin, Wynn, David.
Application Number | 20040062804 10/432488 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2004-04-01 |
United States Patent
Application |
20040062804 |
Kind Code |
A1 |
Lee, Der-Yang ; et
al. |
April 1, 2004 |
Modified release dosage forms
Abstract
A dosage form comprises: (a) at least one active ingredient; (b)
a core; and(c) a shell which surrounds the core, wherein the shell
is substantially free of pores having a diameter of 0.5-5.0
microns, and the shell comprises a first shell portion and a second
shell portion which are compositionally different and the dosage
form provides a modified release profile of the active ingredient
upon contacting of the dosage form with a liquid medium. In another
embodiment, the dosage form comprises: (a) at least one active
ingredient; (b) a core comprising first and second core portions;
and (c) a shell which surrounds the core, wherein the shell
comprises first and second shell portions such that the first shell
portion resides upon the first core portion and the second shell
portion resides upon the second core portion, and at least one of
the first or second shell portions or first or second shell
portions provides a modified release profile of the active
ingredient upon contacting of the dosage form with a liquid
medium.
Inventors: |
Lee, Der-Yang; (Flemington,
NJ) ; Li, Shun-Por; (Lansdale, PA) ; McTeigue,
Daniel; (North Wales, PA) ; Parikh, Narendra;
(Long Valley, NJ) ; Sowden, Harry S.; (Glenside,
PA) ; Thomas, Martin; (Lake Worth, FL) ; Wynn,
David; (Abington, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27542311 |
Appl. No.: |
10/432488 |
Filed: |
October 1, 2003 |
PCT Filed: |
September 28, 2002 |
PCT NO: |
PCT/US02/31024 |
Current U.S.
Class: |
424/471 |
Current CPC
Class: |
A61K 9/2095 20130101;
A61K 9/2873 20130101; A61K 9/0004 20130101; A61K 9/2013 20130101;
A61K 9/209 20130101; A61K 9/2826 20130101; Y10T 428/1352 20150115;
A61K 9/2893 20130101; A61K 9/2886 20130101; B30B 11/08 20130101;
A23G 3/0029 20130101; A61K 9/2054 20130101; A61K 9/2072 20130101;
A23L 29/30 20160801; A61K 9/282 20130101; A61J 3/06 20130101; A61J
3/10 20130101; A61J 3/005 20130101; A61K 9/0056 20130101; A61K
9/284 20130101; A61K 9/2031 20130101; A23G 3/54 20130101; A61K
9/286 20130101; A23G 1/54 20130101; A23G 3/368 20130101; A61K
9/2081 20130101; A61K 9/5084 20130101; A61P 11/00 20180101; A61K
9/2018 20130101; B30B 15/302 20130101; A61P 43/00 20180101; B30B
11/34 20130101; A61K 9/2027 20130101; A61K 9/2068 20130101; A23G
3/04 20130101 |
Class at
Publication: |
424/471 |
International
Class: |
A61K 009/24 |
Foreign Application Data
Date |
Code |
Application Number |
Sep 28, 2001 |
US |
09966939 |
Sep 28, 2001 |
US |
09966509 |
Sep 28, 2001 |
US |
09966497 |
Sep 28, 2001 |
US |
09967414 |
Sep 28, 2001 |
US |
09966450 |
Claims
The invention claimed is:
1. A dosage form comprising: (a) at least one active ingredient;
(a) a core; and (b) a shell which resides upon at least a portion
of the core, wherein the shell is substantially free of pores
having a diameter of 0.5 to 5.0 microns; the shell comprises a
first shell portion and a second shell portion which are
compositionally different; and the dosage form provides a modified
release profile of the active ingredient upon contacting of the
dosage form with a liquid medium.
2. The dosage form of claim 1, in which at least one of the first
or second shell portions comprises means for modifying the release
profile of an active ingredient contained either in (i) the core or
(ii) the shell portion comprising the means for modifying the
release profile upon contacting of the dosage form with a liquid
medium.
3. The dosage form of claim 1 in which at least one of the first or
second shell portions comprises an active ingredient.
4. The dosage form of claim 1, in which the first and second shell
portions each comprise an active ingredient.
5. The dosage form of claim 1, in which at least one of the first
or second shell portions comprises an active ingredient which is
immediately released therefrom upon contacting of the dosage form
with a liquid medium.
6. The dosage form of claim 1, in which at least one of the first
or second shell portions provides modified release of at least one
active ingredient contained therein.
7. The dosage form of claim 1, in which at least one of the first
or second shell portions comprises at least one active ingredient,
and the release of the active ingredient contained in the shell
portion is sustained, prolonged, extended, or retarded upon
contacting of the dosage form with a liquid medium.
8. The dosage form of claim 4, in which the first and second shell
portions each provide different release profiles for the active
ingredients contained therein upon contacting of the dosage form
with a liquid medium.
9. The dosage form of claim 1, in which at least one of the first
or second shell portions provides modified release of at least one
active ingredient contained in the underlying core or portion
thereof.
10. The dosage form of claim 1, in which the core comprises
particles comprising the active material.
11. The dosage form of claim 6, in which the particles comprise a
coating capable of providing a modified release profile of the
active ingredient in the particles upon contacting of the core with
a liquid medium.
12. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, at least one core portion
comprises at least one active ingredient, and at least one active
ingredient contained in the first or second core portion exhibits a
modified release profile upon contacting of the dosage form with a
liquid medium.
13. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the first or second
core portion comprises a material which provides a modification to
the release of an active ingredient contained therein upon
contacting of the dosage form with a liquid medium.
14. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the first or second
shell portion comprises a material which provides a modification to
the release of an active ingredient contained in the underlying
core portion upon contacting of the dosage form with a liquid
medium.
15. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the release of the
active ingredient contained in the core portion is delayed upon
contacting of the dosage form with a liquid medium.
16. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, and at least one core
portion comprises at least one active ingredient, and the release
of the active ingredient contained in the core portion is
sustained, prolonged, extended, or retarded upon contacting of the
dosage form with a liquid medium.
17. The dosage form of claim 1, in which at least one of the first
or second core portions comprises an active ingredient which is
immediately released therefrom upon breach of the surrounding shell
portion and contacting of the core portion with a liquid
medium.
18. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, each core portion comprises
an active ingredient, and each of the active ingredients exhibits a
modifed release profile upon contacting of the dosage form with a
liquid medium.
19. The dosage form of claim 18, in which the release profiles of
the active ingredients in the first and second core portions are
substantially similar.
20. The dosage form of claim 18, in which the release profiles of
the first and second core portions are substantially different.
21. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion, only one of the first or
second core portions comprises an active ingredient, and the active
ingredient exhibits a modifed release profile upon contacting of
the dosage form with a liquid medium.
22. The dosage form of claim 1, in which the core is a bi-layer
tablet.
23. The dosage form of claim 1, in which at least one of the first
or second core portions comprises particles comprising at least one
active ingredient.
24. The dosage form of claim 23, in which the particles comprise a
coating capable of providing a modifed release profile of the
active ingredient in the particles upon contacting of the core with
a liquid medium.
25. The dosage form of claim 1, in which the core is substantially
free of pores having a diameter of 0.5-5.0 microns.
26. A dosage form comprising: (a) at least one active ingredient;
(b) a core comprising first and second core portions; and (c) a
shell portion which surrounds at least one of the first or second
core portions.
27. A dosage form comprising: (a) at least one active ingredient;
(b) a core comprising first and second core portions; and (c) a
shell portion which surrounds only the first core portion, wherein
the second core portion is not enclosed by a shell portion, and the
second core portion is exposed immediately to the liquid medium
upon contact of the dosage form with a liquid medium.
28. A dosage form comprising: (a) at least one active ingredient;
(b) a core comprising first and second core portions; and (c) a
shell which resides upon at least a portion of the core, wherein
the shell comprises first and second shell portions such that the
first shell portion resides upon at least a portion of the first
core portion and the second shell portion resides upon at least a
portion of the second core portion, and at least one of the first
or second core portions or first or second shell portions provides
a modified release profile of an active ingredient upon contacting
of the dosage form with a liquid medium.
29. The dosage form of claim 28, in which the first core portion
comprises a first active ingredient, and the second core portion
does not comprise an active ingredient.
30. The dosage form of claim 28, in which the first core portion
comprises a first active ingredient, and the second core portion
comprises a second active ingredient.
31. The dosage form of claim 30, in which the first shell portion
provides for modified release of the first active ingredient, and
the second shell portion provides for modified release of the
second active ingredient.
32. The dosage form of claim 30, in which the first shell portion
provides for immediate release of the first active ingredient, and
the second shell portion provides for modified release of the
second active ingredient.
33. The dosage form of claim 28, in which the first core portion
comprises a first active ingredient, the second core portion
comprises a second active ingredient, the first shell portion
comprises a third active ingredient, and the second shell portion
comprises a fourth active ingredient.
34. The dosage form of claim 1 or claim 28, wherein the dosage form
comprises means for providing an erosion controlled release profile
of at least one active ingredient.
35. The dosage form of claim 34, wherein the dosage form comprises
means for providing an erosion controlled release profile of an
active ingredient contained in the core.
36. The dosage form of claim 1 or claim 28, wherein the dosage form
comprises means for providing a diffusion controlled release
profile of at least one active ingredient.
37. The dosage form of claim 36, wherein the dosage form comprises
means for providing a diffusion controlled release profile of an
active ingredient contained in the core.
38. The dosage form of claim 1 or claim 28, wherein the dosage form
comprises means for providing an immediate release profile for an
active ingredient contained in the shell.
39. The dosage form of claim 1 or claim 28, wherein the dosage form
comprises means for providing a delayed release profile for an
active ingredient contained in the core.
40. The dosage form of claim 1 or claim 28, wherein the dosage form
comprises means for providing an immediate release profile of an
active ingredient contained in the core upon a breach of the shell
by the liquid medium.
41. The dosage form of claim 28, in which at least one of the first
or second core portions is substantially free of pores having a
diameter of 0.5-5.0 microns.
42. The dosage form of claim 28, in which at least one of the first
or second shell portions is substantially free of pores having a
diameter of 0.5-5.0 microns.
43. The dosage form of claim 1 or claim 28, wherein the dosage form
comprises means for providing a pulsatile release profile of at
least one active ingredient.
44. The dosage form of claim 1 or claim 28, wherein one or more
shell portions prevent release therethrough of an active ingredient
contained in the underlying core or core portion.
45. The dosage form of claim 1 or claim 28, wherein at least one of
the first or second shell portions comprises a thermal-reversible
carrier selected from the group consisting of polyethylene glycol,
polyethylene oxide and combinations thereof.
46. The dosage form of claim 1 or claim 28, wherein at least one of
the first or second shell portions comprises a release modifying
excipent selected from the group consisting of shellac,
hydroxypropylmethylcellulo- se, polyethylene oxide, ammonio
methacrylate copolymer type B, and combinations thereof.
47. The dosage form of claim 1 or claim 28, wherein at least one of
the first or second shell portions comprises a film-former selected
from the group consisting of cellulose acetate, ammonio
methacrylate copolymer type B, shellac,
hydroxypropylmethylcellulose, and combinations thereof.
48. The dosage form of claim 1 or claim 28, wherein at least one of
the first or second shell portions comprises a swellable erodible
hydrophilic material selected from the group consisting of selected
from cross-linked polyvinyl pyrrolidone, cross-linked agar,
cross-linked carboxymethylcellose sodium, and combinations
thereof.
49. The dosage form of claim 1 or claim 28, wherein at least one of
the first or second shell portions further comprises a
plasticizer.
50. The dosage form of claim 1 or claim 28, wherein at least one of
the first or second shell portions comprises a pore former.
51. The dosage form of claim 1 or claim 28, further comprising an
outer coating which covers at least a portion of the shell.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to modified release dosage forms such
as modified release pharmaceutical compositions. More particularly,
this invention relates to modified release dosage forms having a
two-portion shell for delivering one or more active ingredients in
a controlled or delayed manner upon contacting of the dosage form
with a liquid medium.
[0003] 2. Background Information
[0004] Modified release pharmaceutical dosage forms have long been
used to optimize drug delivery and enhance patient compliance,
especially by reducing the number of doses of medicine the patient
must take in a day. For this purpose, it is often desirable to
modify the rate of release of a drug (one particularly preferred
type of active ingredient) from a dosage form into the
gastro-intestinal (g.i.) fluids of a patient, especially to slow
the release to provide prolonged action of the drug in the
body.
[0005] The rate at which an orally delivered pharmaceutical active
ingredient reaches its site of action in the body depends on a
number of factors, including the rate and extent of drug absorption
through the g.i. mucosa. To be absorbed into the circulatory system
(blood), the drug must first be dissolved in the g.i. fluids. For
many drugs, diffusion across the g.i. membranes is relatively rapid
compared to dissolution. In these cases, the dissolution of the
active ingredient is the rate limiting step in drug absorption, and
controlling the rate of dissolution allows the formulator to
control the rate of drug absorption into the circulatory system of
a patient.
[0006] An important objective of modified release dosage forms is
to provide a desired blood concentration versus time
(pharmacokinetic, or PK) profile for the drug. Fundamentally, the
PK profile for a drug is governed by the rate of absorption of the
drug into the blood, and the rate of elimination of the drug from
the blood. The type of PK profile desired depends, among other
factors, on the particular active ingredient, and physiological
condition being treated.
[0007] A particularly desirable PK profile for a number of drugs
and conditions is one in which the level of drug in the blood is
maintained essentially constant (i.e. the rate of drug absorption
is approximately equal to the rate of drug elimination) over a
relatively long period of time. Such systems have the benefit of
reducing the frequency of dosing, improving patient compliance, as
well as minimizing side effects while maintaining full therapeutic
efficacy. A dosage form which provides a "zero-order," or constant
release rate of the drug is useful for this purpose. Since
zero-order release systems are difficult to achieve, systems which
approximate a constant release rate, such as for example
first-order and square root of time profiles are often used to
provide sustained (e.g. prolonged, extended, or retarded) release
of a drug.
[0008] Another particularly desirable PK profile is achieved by a
dosage form that delivers a delayed release dissolution profile, in
which the release of drug from the dosage form is delayed for a
pre-determined time after ingestion by the patient. The delay
period ("lag time") can be followed either by prompt release of the
active ingredient ("delayed burst"), or by sustained (prolonged,
extended, or retarded) release of the active ingredient ("delayed
then sustained").
[0009] Another particularly desirable PK profile, is a "pulsatile"
profile, in which for example, a first dose is delivered
immediately, followed by a delay corresponding approximately to the
time during which a therapeutic concentration of the first dose is
maintained in the blood, followed by either prompt or sustained
release of a subsequent dose of the same drug.
[0010] It is also particularly desirable for a pharmaceutical
dosage form to deliver more than one drug at a modified rate.
Because the onset and duration of the therapeutic efficacy of drugs
vary widely, as do their absorption, distribution, metabolism, and
elimination, it is often desirable to modify the release of
different drugs in different ways, or to have a first active
ingredient immediately released from the dosage form, while a
second drug is released in a delayed, controlled, sustained,
prolonged, extended, or retarded manner.
[0011] Well known mechanisms by which a dosage form (or drug
delivery system) can deliver drug at a controlled rate (e.g.
sustained, prolonged, extended or retarded release) include
diffusion, erosion, and osmosis.
[0012] One classic diffusion-controlled release system comprises a
"reservoir" containing the active ingredient, surrounded by a
"membrane" through which the active ingredient must diffuse to be
absorbed into the bloodstream of the patient. The rate of drug
release, dM/dt depends on the area (A) of the membrane, the
diffusional pathlength (1), the concentration gradient (.DELTA.C)
of the drug across the membrane, the partition coefficient (K) of
the drug into the membrane, and the diffusion coefficient (D):
dM/dt={ADK.DELTA.C}/1
[0013] Since one or more of the above terms, particularly the
diffusional pathlength, and concentration gradient tend to be
non-constant, diffusion-controlled systems generally deliver a
non-constant release rate. In general, the rate of drug release
from diffusion-controlled release systems typically follows first
order kinetics.
[0014] Another common type of diffusion-controlled release system
comprises active ingredient, distributed throughout an insoluble
porous matrix through which the active ingredient must diffuse in
order to be absorbed into the bloodstream of the patient. The
amount of drug release (M) at a given time at sink conditions (i.e.
drug concentration at the matrix surface is much greater than drug
concentration in the bulk solution) depends on the area (A) of the
matrix, the diffusion coefficient (D), the porosity (E) and
tortuosity (T) of the matrix, the drug solubility (Cs) in the
dissolution medium, time (t) and the drug concentration (Cp) in the
dosage form:
M=A (DE/T(2Cp-ECs)(Cs)t).sup.1/2
[0015] It will be noted in the above relationship that the amount
of drug released is generally proportional to the square root of
time. Assuming factors such as matrix porosity and tortuosity are
constant within the dosage form, a plot of amount of drug released
versus the square root of time should be linear.
[0016] A commonly used erosion-controlled release system comprises
a "matrix" throughout which the drug is distributed. The matrix
typically comprises a material which swells at the surface, and
slowly dissolves away layer by layer, liberating drug as it
dissolves. The rate of drug release (dM/dt) in these systems
depends on the rate of erosion (dx/dt) of the matrix, the
concentration profile in the matrix, and the surface area (A) of
the system:
dM/dt=A{dx/dt}{f(C)}
[0017] Again, variation in one or more terms, such as surface area,
typically lead to a non-constant release rate of drug. In general,
the rate of drug release from erosion-controlled release systems
typically follows first order kinetics.
[0018] Another type of erosion controlled delivery system employs
materials which swell and dissolve slowly by surface erosion to
provide a delayed release of pharmaceutical active ingredient.
Delayed release is useful, for example in pulsatile or repeat
action delivery systems, in which an immediate release dose is
delivered, followed by a pre-determined lag time before a
subsequent dose is delivered from the system. In these systems, the
lag time (T.sub.1) depends on the thickness (h) of the erodible
layer, and the rate of erosion (dx/dt) of the matrix, which in turn
depends on the swelling rate and solubility of the matrix
components:
T.sub.1=h (dx/dt)
[0019] The cumulative amount of drug (M) released from these
systems at a given time generally follows the equation:
M=(dM/dt)(t-T.sub.1)
[0020] where dM/dt is generally described by either the
diffusion-controlled or erosion-controlled equations above, and
T.sub.1 is the lag time.
[0021] It is often practical to design dosage forms which use a
combination of the above mechanisms to achieve a particularly
desirable release profile for a particular active ingredient. It
will be readily recognized by those skilled in the art that a
dosage form construct which offers multiple compartments, such as
for example multiple core portions and/or multiple shell portions,
is particularly advantageous for its flexibility in providing a
number of different mechanisms for controlling the release of one
or more active ingredients.
[0022] Current core-shell systems are limited by the available
methods for manufacturing them, as well as the materials that are
suitable for use with the current methods. A shell, or coating,
which confers modified release properties is typically applied via
conventional methods, such as for example, spray-coating in a
coating pan. Pan-coating produces a single shell which essentially
surrounds the core. The single shell is inherently limited in its
functionality. It is possible via pan-coating to apply multiple
concentric shells, each with a different functionality, however
such systems are limited in that the outer shell must first
dissolve before the functionality conferred by each successive
layer can be realized. It is also known, via pan coating, to
deliver a first dose of active ingredient from a coating, and a
second dose of active ingredient from a core. Dosage forms having
sprayed coatings which provide delayed release are described, for
example, in G. Maffione et al., "High-Viscosity HPMC as a
Film-Coating Agent," Drug Development and Industrial Pharmacy
(1993) 19(16), pp. 2043-2053. U.S. Pat. No. 4,576,604, for example,
discloses an osmotic device (dosage form) comprising a drug
compartment surrounded by a wall (coating) in which the coating may
comprise an immediate release dose of drug, and the inner drug
compartment may comprise a sustained release dose of drug. The
coating compositions that can be applied via spraying are limited
by their viscosity. High vicosity solutions are difficult or
impractical to pump and deliver through a spray nozzle. Spray
coating methods suffer the further limitations of being
time-intensive and costly. Several hours of spraying may be
required to spray an effective amount of coating to control the
release of an active ingredient. Coating times of 8 to 24 hours are
not uncommon.
[0023] Alternately, conventional modifed release systems may be
prepared by compression, to produce either multiple stacked layers,
or core and shell configurations. Modified release dosage forms
prepared via compression are exemplified in U.S. Pat. Nos.
5,738,874 and 6,294,200, and WO 99/51209. It is possible, via
compression-coating, to produce a 2-portion shell, which may
function as a barrier, or release delaying coating, however
compression-coated systems are limited by the shell thickness and
shell composition. Gunsel et al., "Compression-coated and layer
tablets" in Pharmaceutical Dosage Forms--Tablets, edited by H. A.
Lieberman, L. Lachman, J. B. Schwartz (2nd ed., rev. and expanded.
Marcel Dekker, Inc.) pp. 247-284, for example discloses the
thickness of compression coated shells is typically between 800 and
1200 microns. Because of these limitations, compression-coated
dosage forms are not optimal for providing certain types of
modified release, such as for example diffusion-controlled release
which is not preceded by a lag-time. U.S. Pat. No. 5,738,874,
discloses a 3-layer pharmaceutical compressed tablet capable of
liberating one or more drugs at different release rates, in which
an immediate release dose of active may be contained in a
compressed coating layer, and the compressed coating layer has a
weight which is 230% to 250% of the weight of the core, and a
sustained release dose of active ingredient is contained in the
core. Alternatively the outer compressed coating layer may function
via an erosion mechanism to delay release of an active ingredient
contained in the core. U.S. Pat. No. 5,464,633, for example,
discloses delayed-release dosage forms in which an extermal coating
layer was applied by a compression coating process. The coating
level ranged from 105 percent to 140 percent of the weight of the
core in order to yield product with the desired time delayed
profile.
[0024] It is one object of this invention to provide a dosage form
in which at least one active ingredient contained therein exhibits
a modified release profile upon contacting of the dosage form with
a liquid medium. Other objects, features and advantages of the
invention will be apparent to those skilled in the art from the
detailed description set forth below.
SUMMARY OF THE INVENTION
[0025] In one embodiment, the dosage form of this invention
comprises: (a) at least one active ingredient; (b) a core; and (c)
a shell which resides upon at least a portion of the core, wherein
the shell is substantially free of pores having a diameter of 0.5
to 5.0 microns, the shell comprises a first shell portion and a
second shell portion which are compositionally different and the
dosage form provides a modified release profile of the active
ingredient upon contacting of the dosage form with a liquid
medium.
[0026] In another embodiment, the dosage form of this invention
comprises: (a) at least one active ingredient; (b) a core
comprising first and second core portions; and (c) a shell portion
which surrounds at least one of the first or second core
portions.
[0027] In another embodiment, the dosage form of this invention
comprises: (a) at least one active ingredient; (b) a core
comprising first and second core portions; and (c) a shell portion
which surrounds only the first core portion, wherein the second
core portion is not enclosed by a shell portion, and is exposed
immediately to the liquid medium upon contact of the dosage form
with a liquid medium.
[0028] In another embodiment, the dosage form of this invention
comprises: (a) at least one active ingredient; (b) a core
comprising first and second core portions; and (c) a shell which
resides upon at least a portion of the core, wherein the shell
comprises first and second shell portions such that the first shell
portion resides upon at least a portion of the first core portion
and the second shell portion resides upon at least a portion of the
second core portion, and at least one of the first or second core
portions or first or second shell portions provides a modified
release profile of an active ingredient upon contacting of the
dosage form with a liquid medium.
[0029] In another embodiment, at least one of the first or second
shell portions comprises an active ingredient.
[0030] In another embodiment, the first and second shell portions
each comprise an active ingredient.
[0031] In another embodiment, at least one of the first or second
shell portions comprises an active ingredient which is immediately
released therefrom upon contacting of the dosage form with a liquid
medium.
[0032] In another embodiment, at least one of the first or second
shell portions provides modified release of at least one active
ingredient contained therein.
[0033] In another embodiment, at least one of the first or second
shell portions comprises at least one active ingredient, and the
release of the active ingredient contained in the shell portion is
sustained, prolonged, extended, or retarded upon contacting of the
dosage form with a liquid medium.
[0034] In another embodiment, the first and second shell portions
each provide different release profiles for the active ingredients
contained therein upon contacting of the dosage form with a liquid
medium.
[0035] In another embodiment, at least one of the first or second
shell portions provides modified release of at least one active
ingredient contained in the underlying core or portion thereof.
[0036] In another embodiment, the core comprises particles
comprising at least one active ingredient.
[0037] In another embodiment, the particles comprise a coating
capable of providing a modified release profile of the active
ingredient in the particles upon contacting of the core with a
liquid medium.
[0038] In another embodiment, the core comprises a first core
portion and a second core portion, at least one core portion
comprises at least one active ingredient, and at least one active
ingredient contained in the first or second core portion exhibits a
modified release profile upon contacting of the dosage form with a
liquid medium.
[0039] In another embodiment, the core comprises a first core
portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the materials
comprising the first or second core portion provide a modification
to the release of an active ingredient contained therein upon
contacting of the dosage form with a liquid medium.
[0040] In another embodiment, the core comprises a first core
portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the materials
comprising the first or second shell portion provide a modification
to the release of an active ingredient contained in the underlying
core portion upon contacting of the dosage form with a liquid
medium.
[0041] In another embodiment, the core comprises a first core
portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the release of the
active ingredient contained in the core portion is delayed upon
contacting of the dosage form with a liquid medium.
[0042] In another embodiment, the core comprises a first core
portion and a second core portion, at least one core portion
comprises at least one active ingredient, and the release of the
active ingredient contained in the core portion is sustained,
prolonged, extened, or retarded upon contacting of the dosage form
with a liquid medium.
[0043] In another embodiment, at least one of the first or second
core portions comprises an active ingredient which is immediately
released therefrom upon breach of the surrounding shell portion and
contacting of the core portion with a liquid medium.
[0044] In another embodiment, the core comprises a first core
portion and a second core portion, each core portion comprises an
active ingredient, and each of the active ingredients exhibits a
modified release profile upon contacting of the dosage form with a
liquid medium.
[0045] In another embodiment, the release profiles of the active
ingredients in the first and second core portions are substantially
similar.
[0046] In another embodiment, the release profiles of the first and
second core portions are substantially different.
[0047] In another embodiment, the core comprises a first core
portion and a second core portion, only one of the first or second
core portions comprises one or more active ingredients, and at
least one active ingredient exhibits a modified release profile
upon contacting of the dosage form with a liquid medium.
[0048] In another embodiment, the core is a bi-layer tablet.
[0049] In another embodiment, at least one of the first or second
core portions comprises particles comprising at least one active
ingredient.
[0050] In another embodiment, the particles comprise a coating
capable of providing a modifed release profile of the active
ingredient in the particles upon contacting of the core with a
liquid medium.
[0051] In another embodiment, the core is substantially free of
pores having a diameter of 0.5-5.0 microns.
[0052] In another embodiment, the first core portion comprises a
first active ingredient, and the second core portion does not
comprise an active ingredient.
[0053] In another embodiment, the first core portion comprises a
first active ingredient, and the second core portion comprises a
second active ingredient.
[0054] In another embodiment, the first shell portion provides for
modified release of the first active ingredient, and the second
shell portion provides for modified release of the second active
ingredient.
[0055] In another embodiment, the first shell portion provides for
immediate release of the first active ingredient, and the second
shell portion provides for modified release of the second active
ingredient.
[0056] In another embodiment, the first core portion comprises a
first active ingredient, the second core portion comprises a second
active ingredient, the first shell portion comprises a third active
ingredient, and the second shell portion comprises a fourth active
ingredient.
[0057] In another embodiment, at least one of the first or second
core portions is substantially free of pores having a diameter of
0.5-5.0 microns.
[0058] In another embodiment, at least one of the first or second
shell portions is substantially free of pores having a diameter of
0.5-5.0 microns.
[0059] In another embodiment, one or more shell portions functions
as a barrier to prevent release therethrough of an active
ingredient contained in the underlying core or core portion.
[0060] In another embodiment, at least one of the first or second
shell portions comprises a thermal-reversible carrier selected from
the group consisting of polyethylene glycol, polyethylene oxide and
combinations thereof.
[0061] In another embodiment, at least one of the first or second
shell portions comprises a release modifying excipent selected from
the group consisting of shellac, hydroxypropylmethylcellulose,
polyethylene oxide, ammonio methacrylate copolymer type B, and
combinations thereof.
[0062] In another embodiment, at least one of the first or second
shell portions comprises a film-former selected from the group
consisting of cellulose acetate, ammonio methacrylate copolymer
type B, shellac, hydroxypropylmethylcellulose, and combinations
thereof.
[0063] In another embodiment, at least one of the first or second
shell portions comprises a swellable erodible hydrophilic material
selected from the group consisting of selected from cross-linked
polyvinyl pyrrolidone, cross-linked agar, cross-linked
carboxymethylcellose sodium, and combinations thereof.
[0064] In another embodiment, at least one of the first or second
shell portions further comprises a plasticizer.
[0065] In another embodiment, at least one of the first or second
shell portions comprises a pore former.
[0066] In another embodiment, an outer coating covers at least a
portion of the shell.
[0067] In another embodiment, the shell is prepared using a
solvent-free molding process.
[0068] In another embodiment, the shell comprises at least 30% by
weight of a thermal-reversible carrier.
[0069] In another embodiment, the shell comprises up to 55% by
weight of a swellable, erodible hydrophilic material.
[0070] In another embodiment, the shell is prepared using a
solvent-based molding process.
[0071] In another embodiment, the shell comprises at least 15% by
weight of a film-former.
[0072] In another embodiment, the shell comprises at least 55% by
weight of a release-modifying agent.
BRIEF DESCRIPTION OF THE DRAWINGS
[0073] FIG. 1 depicts a cross-sectional side view of one embodiment
of the dosage form of this invention.
[0074] FIG. 2 depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0075] FIG. 3 depicts the % release of active ingredient vs. time
measured for the dosage form of Example 1.
[0076] FIG. 4 depicts the % release of active ingredient vs. time
measured for the dosage form of Example 2.
DETAILED DESCRIPTION OF THE INVENTION
[0077] As used herein, the term "dosage form" applies to any solid
object, semi-solid, or liquid composition designed to contain a
specific pre-determined amount (dose) of a certain ingredient, for
example an active ingredient as defined below. Suitable dosage
forms may be pharmaceutical drug delivery systems, including those
for oral administration, buccal administration, rectal
administration, topical or mucosal delivery, or subcutaneous
implants, or other implanted drug delivery systems; or compositions
for delivering minerals, vitamins and other nutraceuticals, oral
care agents, flavorants, and the like. Preferably the dosage forms
of the present invention are considered to be solid, however they
may contain liquid or semi-solid components. In a particularly
preferred embodiment, the dosage form is an orally administered
system for delivering a pharmaceutical active ingredient to the
gastro-intestinal tract of a human.
[0078] The dosage forms of the invention exhibit modified release
of one or more active ingredients contained therein. The active
ingredient or ingredients may be found within the core, the shell,
or a portion or combination thereof. As used herein, the term
"modified release" shall apply to dosage forms, coatings, shells,
cores, portions thereof, or compositions that alter the release of
an active ingredient in any manner. The active ingredient or
ingredients that are released in a modified manner may be contained
within the coating, shell, core, composition, or portion thereof
providing the modification. Alternatively the modified release
active ingredient may be contained in a different portion of the
dosage form from the coating, shell, core, composition, or portion
thereof providing the modification; for example the modified
release active ingredient may be contained in a core portion, and
the modification may be provided by the overlaying shell portion.
Types of modified release include controlled, prolonged, sustained,
extended, delayed, pulsatile, repeat action, and the like. Suitable
mechanisms for achieving these types of modified release include
diffusion, erosion, surface area control via geometry and/or
impermeable barriers, or other mechanisms known in the art.
Moreover, the modified release properties of the dosage form may be
achieved through design of the core or a portion thereof, or the
first shell portion, or the second shell portion, or a combination
of two or more of these parts of the dosage form.
[0079] The dissolution profile of each active ingredient from the
dosage form may be governed by a sum of contributions from the
properties of the various portions. Additionally, a single portion,
for example a core portion, may possess a combination of erosional
and diffusional properties. In any case, the dissolution rate of a
particular active ingredient from the dosage form will be the sum
of the contributions from all the various mechanisms contributed by
the various portions of the dosage form which effect the release of
that particular active ingredient, as depicted by the following
equation:
Rate.sub.total . . . = . . . X.sub.1Rate.sub.1 . . .
+X.sub.2Rate.sub.2 . . . +X.sub.3Rate.sub.3 . . .
+X.sub.nRate.sub.n
[0080] where X.sub.1, X.sub.2, X.sub.3, . . . X.sub.n are the
relative contribution fractions of to the total release rate, and
Rate.sub.1, Rate.sub.2, Rate.sub.3, . . . Rate.sub.n are the
various release rates contributed by effects of the various
portions of the dosage form on a particular active ingredient.
[0081] Suitable active ingredients for use in this invention
include for example pharmaceuticals, minerals, vitamins and other
nutraceuticals, oral care agents, flavorants and mixtures thereof.
Suitable pharmaceuticals include analgesics, anti-inflammatory
agents, antiarthritics, anesthetics, antihistamines, antitussives,
antibiotics, anti-infective agents, antivirals, anticoagulants,
antidepressants, antidiabetic agents, antiemetics, antiflatulents,
antifungals, antispasmodics, appetite suppressants,
bronchodilators, cardiovascular agents, central nervous system
agents, central nervous system stimulants, decongestants, oral
contraceptives, diuretics, expectorants, gastrointestinal agents,
migraine preparations, motion sickness products, mucolytics, muscle
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep-aids, urinary tract agents and mixtures
thereof.
[0082] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0083] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0084] Examples of suitable gastrointestinal agents include
antacids such as calcium carbonate, magnesium hydroxide, magnesium
oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate,
dihydroxyaluminum sodium carbonate; stimulant laxatives, such as
bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,
castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures
thereof; H2 receptor antagonists, such as famotadine, ranitidine,
cimetadine, nizatidine; proton pump inhibitors such as omeprazole
or lansoprazole; gastrointestinal cytoprotectives, such as
sucraflate and misoprostol; gastrointestinal prokinetics, such as
prucalopride, antibiotics for H. pylori, such as clarithromycin,
amoxicillin, tetracycline, and metronidazole; antidiarrheals, such
as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such
as ondansetron, analgesics, such as mesalamine.
[0085] In one embodiment of the invention, the active ingredient
may be selected from bisacodyl, famotadine, ranitidine, cimetidine,
prucalopride, diphenoxylate, loperamide, lactase, mesalamine,
bismuth, antacids, and pharmaceutically acceptable salts, esters,
isomers, and mixtures thereof.
[0086] In another embodiment, the active ingredient is selected
from analgesics, anti-inflammatories, and antipyretics, e.g.
non-steroidal anti-inflammatory drugs (NSAIDs), including propionic
acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the
like; acetic acid derivatives, e.g. indomethacin, diclofenac,
sulindac, tolmetin, and the like; fenamic acid derivatives, e.g.
mefanamic acid, meclofenamic acid, flufenamic acid, and the like;
biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal,
and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam,
meloxicam, and the like. In a particularly preferred embodiment,
the active ingredient is selected from propionic acid derivative
NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,
fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen,
carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically
acceptable salts, derivatives, and combinations thereof. In a
particular embodiment of the invention, the active ingredient may
be selected from acetaminophen, acetyl salicylic acid, ibuprofen,
naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine,
meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable
salts, esters, isomers, and mixtures thereof.
[0087] In another embodiment of the invention, the active
ingredient may be selected from pseudoephedrine,
phenylpropanolamine, chlorpheniramine, dextromethorphan,
diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine,
desloratadine, cetirizine, mixtures thereof and pharmaceutically
acceptable salts, esters, isomers, and mixtures thereof.
[0088] Examples of suitable polydimethylsiloxanes, which include,
but are not limited to dimethicone and simethicone, are those
disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260,
the contents of each is expressly incorporated herein by reference.
As used herein, the term "simethicone" refers to the broader class
of polydimethylsiloxanes, including but not limited to simethicone
and dimethicone.
[0089] The active ingredient or ingredients are present in the
dosage form in a therapeutically effective amount, which is an
amount that produces the desired therapeutic response upon oral
administration and can be readily determined by one skilled in the
art. In determining such amounts, the particular active ingredient
being administered, the bioavailability characteristics of the
active ingredient, the dosing regimen, the age and weight of the
patient, and other factors must be considered, as known in the art.
Typically, the dosage form comprises at least about 1 weight
percent, preferably, the dosage form comprises at least about 5
weight percent, e.g. about 20 weight percent of a combination of
one or more active ingredients. In one preferred embodiment, the
core comprises a total of at least about 25 weight percent (based
on the weight of the core) of one or more active ingredients.
[0090] The active ingredient or ingredients may be present in the
dosage form in any form. For example, the active ingredient may be
dispersed at the molecular level, e.g. melted or dissolved, within
the dosage form, or may be in the form of particles, which in turn
may be coated or uncoated. If the active ingredient is in form of
particles , the particles (whether coated or uncoated) typically
have an average particle size of about 1-2000 microns. In one
preferred embodiment, such particles are crystals having an average
particle size of about 1-300 microns. In another preferred
embodiment, the particles are granules or pellets having an average
particle size of about 50-2000 microns, preferably about 50-1000
microns, most preferably about 100-800 microns.
[0091] In embodiments where an active ingredient is contained
within the core, at least a portion of the active ingredient may be
optionally coated with a release-modifying coating, as known in the
art. This advantageously provides an additional tool for modifying
the release profile of active ingredient from the dosage form. For
example, the core may contain coated particles of one or more
active ingredients, in which the particle coating confers a release
modifying function, as is well known in the art. Examples of
suitable release modifying coatings for particles are described in
U.S. Pat. Nos. 4,173,626; 4,863,742; 4,980,170; 4,984,240;
5,286,497; 5,912,013; 6,270,805; and 6,322,819. Commercially
available modified release coated active particles may also be
employed. Accordingly, all or a portion of one or more active
ingredients in the core may be coated with a release-modifying
material.
[0092] In embodiments in which it is desired for the active
ingredient to be absorbed into the systemic circulation of an
animal, the active ingredient or ingredients are preferably capable
of dissolution upon contact with a fluid such as water, gastric
fluid, intestinal fluid or the like. In one embodiment, the
dissolution characteristics of at least one active ingredient meets
USP specifications for immediate release tablets containing the
active ingredient. For example, for acetaminophen tablets, USP 24
specifies that in pH 5.8 phosphate buffer, using USP apparatus 2
(paddles) at 50 rpm, at least 80% of the acetaminophen contained in
the dosage form is released therefrom within 30 minutes after
dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2
phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at
least 80% of the ibuprofen contained in the dosage form is released
therefrom within 60 minutes after dosing. See USP 24, 2000 Version,
19-20 and 856 (1999). In embodiments in which at least one active
ingredient is released immediately, the immediately released active
ingredient is preferably contained in the shell or on the surface
of the shell, e.g. in a further coating surrounding at least a
portion of the shell. In another embodiment, the dissolution
characteristics of one or more active ingredients are modified:
e.g. controlled, sustained, extended, retarded, prolonged, delayed
and the like. In a preferred embodiment in which one or more active
ingredients are released in a modified manner, the modified release
active or actives are preferably contained in the core.
[0093] A first embodiment of this invention is depicted in FIG. 1,
which is a cross-sectional side view of a dosage form 2 which
comprises a core 4 and first and second shell portions 6 and 8,
respectively, which in this embodiment surround the core. In other
embodiments of this invention, the first and second shell portions
6 and 8 may reside upon a portion of the core 4 without surrounding
the core 4.
[0094] A second embodiment of this invention is depicted in FIG. 2,
which is a cross-sectional side view of a dosage form 202 which
comprises a core 204 having first and second portions 203 and 205,
respectively, and first and second shell portions 206 and 208,
respectively, which in this embodiment surround the core. In other
embodiments of this invention, the first and second shell portions
206 and 208 may reside upon first and second core portions 203 and
205, respectively, without surrounding the core 204.
[0095] In certain embodiments of the invention, one or more shell
portions contain active ingredient which is released essentially
immediately upon ingestion of the dosage form. In these
embodiments, the shell portion preferably comprises materials which
exhibit rapid dissolution in gastro-intestinal fluids.
[0096] In certain other embodiments, one or more shell portions
function as a diffusional membrane which contains pores through
which fluids can enter the dosage form, and dissolved active
ingredient can be released in a sustained, extended, prolonged or
retarded manner. In these embodiments, the rate of release of
active ingredient from an underlying core portion will depend upon
the total pore area in the shell portion, the pathlength of the
pores, and the solubility and diffusivity of the active ingredient
(in addition to its rate of release from the core portion itself).
In preferred embodiments in which a shell portion functions as a
diffusional membrane, the release of the active ingredient from the
dosage form may be described as controlled, prolonged, sustained or
extended. In these embodiments, the contribution to active
ingredient dissolution from the subject shell portion may follow
zero-order, first-order, or square-root of time kinetics. In
certain such embodiments, the diffusional membrane shell portion
preferrably comprises a release-modifying excipient such as a
combination of a pore former and an insoluble edible material such
as for example a film forming water insoluble polymer. Alternately,
in such embodiments in which the shell portion is prepared by
solven-free molding, the thermal-reversible carrier may function by
dissolving and forming pores or channels through which the active
ingredient may be liberated.
[0097] In certain other embodiments, one or more shell portions
function as an eroding matrix from which active ingredient
dispersed in the shell portion is liberated by the dissolution of
successive layers of the shell portion surface. In these
embodiments, the rate of active ingredient release will depend on
the dissolution rate of the matrix material in the shell portion.
Particularly useful matrix materials for providing surface erosion
include those which first absorb liquid, then swell and/or gel
prior to dissolving. In certain such embodiments, the eroding
matrix shell portion preferably comprises a swellable erodible
hydrophilic material.
[0098] In certain other embodiments, one or more shell portions
function as a barrier to prevent release therethrough of an active
ingredient contained in the underlying core or core portion. In
such embodiments, active ingredient is typically released from a
portion of the core which is not covered by the barrier shell
portion. Such embodiments advantageously allow for control of the
surface area for release of the active ingredient. In certain
particular embodiments, for example, the surface area for release
of active ingredient can be maintained substantially constant over
time. In a particularly preferred embodiment, the release of at
least one active ingredient follows substantially zero-order
kinetics. In certain such embdiments, the barrier shell portion
preferably comprises a water insoluble material such as for example
a water insoluble polymer.
[0099] In certain other embodiments, one or more shell portions
function as a delayed release coating to delay release of an active
ingredient which is contained in the core or a portion thereof. In
these embodiments, the lag-time for onset of active ingredient
release may be governed by erosion of the coating or diffusion
through the coating or a combination thereof. In certain such
embodiments, the eroding matrix shell portion preferably comprises
a swellable erodible hydrophilic material.
[0100] In embodiments in which one or more shell portions function
to modify the release of an active ingredient which is contained in
the core or the subject shell portion, the thickness of the shell
portion is critical to the release properties of the dosage form.
Advantageously the dosage forms of the invention can be made with
precise control over shell thickness. In a preferred embodiment in
which one or more shell portions function to modify the release of
an active ingredient which is contained in the core or the subject
shell portion, the shell portion or portions are made by the
thermal cycle or thermal setting injection molding methods and
apparatus described below.
[0101] In certain embodiments of the invention, one or more core
portions function to promptly, e.g. immediately, release one or
more active ingredients contained therein upon breach of the
surrounding shell portion. In these embodiments, the core portion
preferably comprises materials which exhibit rapid dissolution in
gastro-intestinal fluids, for example the core portion may comprise
a disintegrant.
[0102] In certain other embodiments, one or more core portions
function as an eroding matrix from which dispersed active
ingredient is liberated by the dissolution of successive layers of
the matrix surface. In these embodiments, the rate of active
ingredient release from the core portion will depend on the
dissolution rate of the matrix material. Particularly useful
eroding matrix materials for providing surface erosion include
those which first absorb liquid, then swell and/or gel prior to
dissolving. In certain such embodiments, the eroding matrix core
portion preferrably comprises a swellable erodible hydrophilic
material.
[0103] In certain other embodiments, one or more core portions
function as a diffusional matrix. In these embodiments, the core
portion preferably comprises active ingredient, distributed
throughout an insoluble porous matrix, which contains pores or
channels through which fluids can enter the core portion, and the
active ingredient must diffuse to be released from the dosage form.
In these embodiments, the rate of active ingredient release from
the core portion will depend upon the area (A) of the matrix, the
diffusion coefficient (D), the porosity (E) and tortuosity (T) of
the matrix, the drug solubility (Cs) in the dissolution medium, and
the drug concentration (Cp) in the dosage form. In preferred
embodiments in which a core portion functions as a diffusional
matrix, the release of the active ingredient from the core portion
may be described as controlled, prolonged, sustained, or extended.
In these embodiments, the contribution to active ingredient
dissolution from the subject core portion may follow zero-order,
first-order, or preferably square-root of time kinetics. In certain
such embodiments, the diffusional matrix core portion preferably
comprises a pore former.
[0104] In embodiments in which a core portion functions to modify
release of an active ingredient contained therein, the release of
active ingredient may be further modified by the function of a
surrounding shell portion, as described above. In such embodiments,
the release of the active ingredient from the dosage form will be
governed by the sum of all the contributions acting upon it, e.g.
from the relevant core and shell portions, and may be described as
controlled, prolonged, sustained, extended, delayed, or pulsatile.
In these embodiments, the dissolution of active ingredient from the
dosage form may follow zero-order, first-order, or square-root of
time kinetics.
[0105] In embodiments in which the core comprises multiple
portions, the portions may comprise different materials, or be
prepared by different methods, or both. In one particular
embodiment a first core portion may be prepared by compression, and
a second core portion may be prepared by molding.
[0106] In certain preferred embodiments, the core comprises
multiple portions, which comprise different active ingredients or
have different release-modifying properties, or both; and the shell
comprises a corresponding number of multiple portions, which each
cover a specific core portion in order to modify or further modify
the release of one or more active ingredients contained within the
respective core portion. For such embodiments, it is critical to
have a manufacturing process which is capable of maintaining the
orientation of the core prior to and during the application of each
shell portion thereon. Advantageously, the orientation of the
components of the dosage forms of the present invention can be
precisely controlled, when manufactured using the thermal cycle and
thermal setting apparatus and described below. In one such
particularly preferred embodiment, the dosage form comprises a core
comprising a first core portion and a second core portion which are
compositionally different, wherein at least one of the first or
second core portions comprises an active ingredient; and a shell
which surrounds the core and comprises a first shell portion and a
second shell portion which are compositionally different, wherein
at least one of the first or second shell portions confers a
modification to the release of an active ingredient contained in
the underlying core portion.
[0107] In certain other embodiments of the invention, a further
degree of flexibility in designing the dosage forms of the present
invention can be achieved through the use of an additional outer
coating overlaying the shell or one or more portions thereof. The
additional outer coating may be applied for example by compression,
or by molding. In such embodiments, the dosage form of the
invention comprises at least one active ingredient; a core; a shell
which resides upon at least a portion of the core and comprises a
first and second shell portion which are compositionally different;
and an outer coating which covers at least a portion of the shell.
The outer coating may for example cover a portion of the first
shell portion, or the second shell portion, or both, or may
surround the entire shell. In one particularly preferred
embodiment, the outer coating comprises an active ingredient, which
is released immediately (i.e. the dissolution of the active
ingredient from the outer coating conforms to USP specifications
for immediate release dosage forms of the particular active
ingredient employed). In one such particularly preferred
embodiment, the dosage form is a pulsatile drug delivery system, in
which one or more shell portions provides for delayed release of a
second dose of active ingredient, which is contained in an
underlying core portion.
[0108] The core of the present invention may be prepared by any
suitable method, including for example compression and molding, and
depending on the method by which it is made, typically comprises
active ingredient and a variety of excipients (inactive ingredients
which may be useful for conferring desired physical properties to
the dosage core).
[0109] In embodiments in which the core, or a portion thereof, is
made by compression, suitable excipients include fillers, binders,
disintegrants, lubricants, glidants, and the like, as known in the
art. In embodiments in which the core is made by compression and
additionally confers modified release of an active ingredient
contained therein, the core preferably further comprises a
release-modifying compressible excipient.
[0110] Suitable fillers for use in making the core, or a portion
thereof, by compression include water-soluble compressible
carbohydrates such as sugars, which include dextrose, sucrose,
maltose, and lactose, sugar-alcohols, which include mannitol,
sorbitol, maltitol, xylitol, starch hydrolysates, which include
dextrins, and maltodextrins, and the like, water insoluble
plastically deforming materials such as microcrystalline cellulose
or other cellulosic derivatives, water-insoluble brittle fracture
materials such as dicalcium phosphate, tricalcium phosphate and the
like and mixtures thereof.
[0111] Suitable binders for making the core, or a portion thereof,
by compression include dry binders such as polyvinyl pyrrolidone,
hydroxypropylmethylcellulose, and the like; wet binders such as
water-soluble polymers, including hydrocolloids such as acacia,
alginates, agar, guar gum, locust bean, carrageenan,
carboxymethylcellulose, tara, gum arabic, tragacanth, pectin,
xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan,
laminarin, scleroglucan, inulin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone,
cellulosics, sucrose, starches, and the like; and derivatives and
mixtures thereof.
[0112] Suitable disintegrants for making the core, or a portion
thereof, by compression, include sodium starch glycolate,
cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starches, microcrystalline cellulose, and
the like.
[0113] Suitable lubricants for making the core, or a portion
thereof, by compression include long chain fatty acids and their
salts, such as magnesium stearate and stearic acid, talc,
glycerides and waxes.
[0114] Suitable glidants for making the core, or a portion thereof,
by compression, include colloidal silicon dioxide, and the
like.
[0115] Suitable release-modifying compressible excipients for
making the core, or a portion thereof, by compression include
swellable erodible hydrophillic materials, insoluble edible
materials, pH-dependent polymers, and the like.
[0116] Suitable swellable erodible hydrophilic materials for use as
release-modifying excipients for making the core, or a portion
thereof, by compression include: water swellable cellulose
derivatives, polyalkalene glycols, thermoplastic polyalkalene
oxides, acrylic polymers, hydrocolloids, clays, gelling starches,
and swelling cross-linked polymers, and derivitives, copolymers,
and combinations thereof. Examples of suitable water swellable
cellulose derivatives include sodium carboxymethylcellulose,
cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),
hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,
hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose
(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples
of suitable polyalkalene glyclols include polyethylene glycol.
Examples of suitable thermoplastic polyalkalene oxides include poly
(ethylene oxide). Examples of suitable acrylic polymers include
potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, CARBOPOL (high-molceular weight
cross-linked acrylic acid homopolymers and copolymers), and the
like. Examples of suitable hydrocolloids include alginates, agar,
guar gum, locust bean gum, kappa carrageenan, iota carrageenan,
tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan. Examples of suitable
clays include smectites such as bentonite, kaolin, and laponite;
magnesium trisilicate, magnesium aluminum silicate, and the like,
and derivatives and mixtures thereof. Examples of suitable gelling
starches include acid hydrolyzed starches, swelling starches such
as sodium starch glycolate, and derivatives thereof. Examples of
suitable swelling cross-linked polymers include cross-linked
polyvinyl pyrrolidone, cross-linked agar, and cross-linked
carboxymethylcellose sodium.
[0117] Suitable insoluble edible materials for use as
release-modifying excipients for making the core, or a portion
thereof, by compression include water-insoluble polymers, and
low-melting hydrophobic materials. Examples of suitable
water-insoluble polymers include ethylcellulose, polyvinyl
alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate
and its derivatives, acrylates, methacrylates, acrylic acid
copolymers; and the like and derivatives, copolymers, and
combinations thereof. Suitable low-melting hydrophobic materials
include fats, fatty acid esters, phospholipids, and waxes. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, Glyco Wax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes include camauba wax, spermaceti wax, beeswax, candelilla wax,
shellac wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate; and the like.
[0118] Suitable pH-dependent polymers for use as release-modifying
excipients for making the core, or a portion thereof, by
compression include enteric cellulose derivatives, for example
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, cellulose acetate phthalate;
natural resins such as shellac and zein; enteric acetate
derivatives such as for example polyvinylacetate phthalate,
cellulose acetate phthalate, acetaldehyde dimethylcellulose
acetate; and enteric acrylate derivatives such as for example
polymethacrylate-based polymers such as poly(methacrylic acid,
methyl methacrylate) 1:2, which is commercially available from Rohm
Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic
acid, methyl methacrylate) 1:1, which is commercially available
from Rohm Pharma GmbH under the tradename EUDRAGIT L, and the like,
and derivatives, salts, copolymers, and combinations thereof.
[0119] Suitable pharmaceutically acceptable adjuvants for making
the core, or a portion thereof, by compression include,
preservatives; high intensity sweeteners such as aspartame,
acesulfame potassium, sucralose, and saccharin; flavorants;
colorants; antioxidants; surfactants; wetting agents; and the like
and mixtures thereof.
[0120] In one embodiment, the core is prepared by the compression
methods and apparatus described in copending U.S. patent
application Ser. No. 09/966,509, pages 16-27, the disclosure of
which is incorporated herein by reference. Specifically, the core
is made using a rotary compression module comprising a fill zone,
insertion zone, compression zone, ejection zone, and purge zone in
a single apparatus having a double row die construction as shown in
FIG. 6 of U.S. patent application Ser. No. 09/966,509. The dies of
the compression module are preferably filled using the assistance
of a vacuum, with filters located in or near each die. The purge
zone of the compression module includes an optional powder recovery
system to recover excess powder from the filters and return the
powder to the dies.
[0121] In certain preferred embodiments of the invention, the core,
or the shell, or a portion thereof, is prepared by molding. In such
embodiments, the core, or the shell, or a portion thereof, is made
from a flowable material. The flowable material may be any edible
material that is flowable at a temperature between about 37.degree.
C. and 250.degree. C., and that is solid, semi-solid, or can form a
gel at a temperature between about -10.degree. C. and about
35.degree. C. When it is in the fluid or flowable state, the
flowable material may comprise a dissolved or molten component, and
optionally a solvent such as for example water or organic solvents,
or combinations thereof. The solvent may be partially or
substantially removed by drying.
[0122] Suitable flowable materials for making the core, or the
shell, or a portion thereof by molding include those comprising
thermoplastic materials; film formers; thickeners such as gelling
polymers or hydrocolloids; low melting hydrophobic materials such
as fats and waxes; non-crystallizable carbohydrates; and the like.
Suitable molten components of the flowable material include
thermoplastic materials, low melting hydrophobic materials, and the
like. Suitable dissolved components for the flowable material
include film formers, thickeners such as gelling polymers or
hydrocolloids, non-crystallizable carbohydrates, and the like.
[0123] Suitable thermoplastic materials can be molded and shaped
when heated, and include both water soluble and water insoluble
polymers that are generally linear, not crosslinked, nor strongly
hydrogen bonded to adjacent polymer chains. Examples of suitable
thermoplastic materials include: thermoplastic water swellable
cellulose derivatives, thermoplastic water insoluble cellulose
derivatrives, thermoplastic vinyl polymers, thermoplastic starches,
thermplastic polyalkalene glycols, thermoplastic polyalkalene
oxides, and amorphous sugar-glass, and the like, and derivatives,
copolymers, and combinations thereof. Examples of suitable
thermoplastic water swellable cellulose derivatives include
hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), methyl cellulose (MC). Examples of suitable thermoplastic
water insoluble cellulose derivatrives include cellulose acetate
(CA), ethyl cellulose (EC), cellulose acetate butyrate (CAB),
cellulose propionate. Examples of suitable thermoplastic vinyl
polymers include polyvinyl alcohol (PVA) and polyvinyl pyrrolidone
(PVP). Examples of suitable thermoplastic starches are disclosed
for example in U.S. Pat. No. 5,427,614. Examples of suitable
thermoplastic polyalkalene glycols include polyethylene glycol.
Examples of suitable thermoplastic polyalkalene oxides include
polyethylene oxide having a molecular weight from about 100,000 to
about 900,000 Daltons. Other suitable thermoplastic materials
include sugar in the form on an amorphous glass such as that used
to make hard candy forms.
[0124] Any film former known in the art is suitable for use in the
flowable material of the present invention. Examples of suitable
film formers include, but are not limited to, film-forming water
soluble polymers, film-forming proteins, film-forming water
insoluble polymers, and film-forming pH-dependent polymers. In one
embodiment, the film-former for making the core or shell or portion
thereof by molding may be selected from cellulose acetate, ammonio
methacrylate copolymer type B, shellac,
hydroxypropylmethylcellulose, and polyethylene oxide, and
combinations thereof.
[0125] Suitable film-forming water soluble polymers include water
soluble vinyl polymers such as polyvinylalcohol (PVA); water
soluble polycarbohydrates such as hydroxypropyl starch,
hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl
starch, pre-gelatinized starches, and film-forming modified
starches; water swellable cellulose derivatives such as
hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC),
hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose
(HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC);
water soluble copolymers such as methacrylic acid and methacrylate
ester copolymers, polyvinyl alcohol and polyethylene glycol
copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers;
and derivatives and combinations thereof.
[0126] Suitable film-forming proteins may be natural or chemically
modified, and include gelatin, whey protein, myofibrillar proteins,
coaggulatable proteins such as albumin, casein, caseinates and
casein isolates, soy protein and soy protein isolates, zein; and
polymers, derivatives and mixtures thereof.
[0127] Suitable film-forming water insoluble polymers, include for
example ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives,
acrylates, methacrylates, acrylic acid copolymers; and the like and
derivatives, copolymers, and combinations thereof.
[0128] Suitable film-forming pH-dependent polymers include enteric
cellulose derivatives, such as for example hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate
succinate, cellulose acetate phthalate; natural resins, such as
shellac and zein; enteric acetate derivatives such as for example
polyvinylacetate phthalate, cellulose acetate phthalate,
acetaldehyde dimethylcellulose acetate; and enteric acrylate
derivatives such as for example polymethacrylate-based polymers
such as poly(methacrylic acid, methyl methacrylate) 1:2, which is
commercially available from Rohm Pharma GmbH under the tradename,
EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1,
which is commercially available from Rohm Pharma GmbH under the
tradename, EUDRAGIT L, and the like, and derivatives, salts,
copolymers, and combinations thereof.
[0129] One suitable hydroxypropylmethylcellulose compound for use
as a thermoplastic film-forming water soluble polymer is "HPMC
2910", which is a cellulose ether having a degree of substitution
of about 1.9 and a hydroxypropyl molar substitution of 0.23, and
containing, based upon the total weight of the compound, from about
29% to about 30% methoxyl groups and from about 7% to about 12%
hydroxylpropyl groups. HPMC 2910 is commercially available from the
Dow Chemical Company under the tradename METHOCEL E. METHOCEL E5,
which is one grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 4 to 6 cps (4 to 6
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which
is another grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 5 to 7 cps (5 to 7
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. METHOCEL E15, which is
another grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 15000 cps (15
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. As used herein, "degree of
substitution" shall mean the average number of substituent groups
attached to a anhydroglucose ring, and "hydroxypropyl molar
substitution" shall mean the number of moles of hydroxypropyl per
mole anhydroglucose.
[0130] One suitable polyvinyl alcohol and polyethylene glycol
copolymer is commercially available from BASF Corporation under the
tradename KOLLICOAT IR.
[0131] As used herein, "modified starches" include starches that
have been modified by crosslinking, chemically modified for
improved stability or optimized performance, or physically modified
for improved solubility properties or optimized performance.
Examples of chemically-modified starches are well known in the art
and typically include those starches that have been chemically
treated to cause replacement of some of its hydroxyl groups with
either ester or ether groups. Crosslinking, as used herein, may
occur in modified starches when two hydroxyl groups on neighboring
starch molecules are chemically linked. As used herein,
"pre-gelatinized starches" or "instantized starches" refers to
modified starches that have been pre-wetted, then dried to enhance
their cold-water solubility. Suitable modified starches are
commercially available from several suppliers such as, for example,
A. E. Staley Manufacturing Company, and National Starch &
Chemical Company. One suitable film forming modified starch
includes the pre-gelatinized waxy maize derivative starches that
are commercially available from National Starch & Chemical
Company under the tradenames PURITY GUM and FILMSET, and
derivatives, copolymers, and mixtures thereof Such waxy maize
starches typically contain, based upon the total weight of the
starch, from about 0 percent to about 18 percent of amylose and
from about 100% to about 88% of amylopectin.
[0132] Another suitable film forming modified starch includes the
hydroxypropylated starches, in which some of the hydroxyl groups of
the starch have been etherified with hydroxypropyl groups, usually
via treatment with propylene oxide. One example of a suitable
hydroxypropyl starch that possesses film-forming properties is
available from Grain Processing Company under the tradename,
PURE-COTE B790.
[0133] Suitable tapioca dextrins for use as film formers include
those available from National Starch & Chemical Company under
the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such
as modified food starch derived from tapioca, which is available
from National Starch and Chemical under the tradename PURITY GUM
40, and copolymers and mixtures thereof.
[0134] Any thickener known in the art is suitable for use in the
flowable material of the present invention. Examples of such
thickeners include but are not limited to hydrocolloids (also
referred to herein as gelling polymers), clays, gelling starches,
and crystallizable carbohydrates, and derivatives, copolymers and
mixtures thereof.
[0135] Examples of suitable hydrocolloids (also referred to herein
as gelling polymers) such as alginates, agar, guar gum, locust
bean, carrageenan, tara, gum arabic, tragacanth, pectin, xanthan,
gellan, maltodextrin, galactomannan, pusstulan, laminarin,
scleroglucan, gum arabic, inulin, pectin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan. Examples of suitable
clays include smectites such as bentonite, kaolin, and laponite;
magnesium trisilicate, magnesium aluminum silicate, and the like,
and derivatives and mixtures thereof. Examples of suitable gelling
starches include acid hydrolyzed starches, and derivatives and
mixtures thereof. Additional suitable thickening hydrocolloids
include low-moisture polymer solutions such as mixtures of gelatin
and other hydrocolloids at water contents up to about 30%, such as
for example those used to make "gummi" confection forms.
[0136] Additional suitable thickeners include crystallizable
carbohydrates, and the like, and derivatives and combinations
thereof. Suitable crystallizable carbohydrates include the
monosaccharides and the oligosaccharides. Of the monosaccharides,
the aldohexoses e.g., the D and L isomers of allose, altrose,
glucose, mannose, gulose, idose, galactose, talose, and the
ketohexoses e.g., the D and L isomers of fructose and sorbose along
with their hydrogenated analogs: e.g., glucitol (sorbitol), and
mannitol are preferred. Of the oligosaccharides, the
1,2-disaccharides sucrose and trehalose, the 1,4-disaccharides
maltose, lactose, and cellobiose, and the 1,6-disaccharides
gentiobiose and melibiose, as well as the trisaccharide raffinose
are preferred along with the isomerized form of sucrose known as
isomaltulose and its hydrogenated analog isomalt. Other
hydrogenated forms of reducing disaccharides (such as maltose and
lactose), for example, maltitol and lactitol are also preferred.
Additionally, the hydrogenated forms of the aldopentoses: e.g., D
and L ribose, arabinose, xylose, and lyxose and the hydrogenated
forms of the aldotetroses: e.g., D and L erythrose and threose are
preferred and are exemplified by xylitol and erythritol,
respectively.
[0137] In one embodiment of the invention, the flowable material
comprises gelatin as a gelling polymer. Gelatin is a natural,
thermogelling polymer. It is a tasteless and colorless mixture of
derived proteins of the albuminous class which is ordinarily
soluble in warm water. Two types of gelatin--Type A and Type B--are
commonly used. Type A gelatin is a derivative of acid-treated raw
materials. Type B gelatin is a derivative of alkali-treated raw
materials. The moisture content of gelatin, as well as its Bloom
strength, composition and original gelatin processing conditions,
determine its transition temperature between liquid and solid.
Bloom is a standard measure of the strength of a gelatin gel, and
is roughly correlated with molecular weight. Bloom is defined as
the weight in grams required to move a half-inch diameter plastic
plunger 4 mm into a 6.67% gelatin gel that has been held at
10.degree. C. for 17 hours. In a preferred embodiment, the flowable
material is an aqueous solution comprising 20% 275 Bloom pork skin
gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60%
water.
[0138] Suitable xanthan gums include those available from C. P.
Kelco Company under the tradenames KELTROL 1000, XANTROL 180, or
K9B310.
[0139] Suitable clays include smectites such as bentonite, kaolin,
and laponite; magnesium trisilicate, magnesium aluminum silicate,
and the like, and derivatives and mixtures thereof.
[0140] "Acid-hydrolyzed starch," as used herein, is one type of
modified starch that results from treating a starch suspension with
dilute acid at a temperature below the gelatinization point of the
starch. During the acid hydrolysis, the granular form of the starch
is maintained in the starch suspension, and the hydrolysis reaction
is ended by neutralization, filtration and drying once the desired
degree of hydrolysis is reached. As a result, the average molecular
size of the starch polymers is reduced. Acid-hydrolyzed starches
(also known as "thin boiling starches") tend to have a much lower
hot viscosity than the same native starch as well as a strong
tendency to gel when cooled.
[0141] "Gelling starches," as used herein, include those starches
that, when combined with water and heated to a temperature
sufficient to form a solution, thereafter form a gel upon cooling
to a temperature below the gelation point of the starch. Examples
of gelling starches include, but are not limited to, acid
hydrolyzed starches such as that available from Grain Processing
Corporation under the tradename PURE-SET B950; hydroxypropyl
distarch phosphate such as that available from Grain Processing
Corporation under the tradename, PURE-GEL B990, and mixtures
thereof.
[0142] Suitable low-melting hydrophobic materials include fats,
fatty acid esters, phospholipids, and waxes. Examples of suitable
fats include hydrogenated vegetable oils such as for example cocoa
butter, hydrogenated palm kernel oil, hydrogenated cottonseed oil,
hydrogenated sunflower oil, and hydrogenated soybean oil; and free
fatty acids and their salts. Examples of suitable fatty acid esters
include sucrose fatty acid esters, mono, di, and triglycerides,
glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate,
glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate,
Glyco Wax-932, lauroyl macrogol-32 glycerides, and stearoyl
macrogol-32 glycerides. Examples of suitable phospholipids include
phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol,
and phosphotidic acid. Examples of suitable waxes include carnauba
wax, spermaceti wax, beeswax, candelilla wax, shellac wax,
microcrystalline wax, and paraffin wax; fat-containing mixtures
such as chocolate; and the like.
[0143] Suitable non-crystallizable carbohydrates include
non-crystallizable sugars such as polydextrose, and starch
hydrolysates, e.g. glucose syrup, corn syrup, and high fructose
corn syrup; and non-crystallizable sugar-alcohols such as maltitol
syrup.
[0144] Suitable solvents for optional use as components of the
flowable material for making the core, or the shell, or a portion
thereof by molding include water; polar organic solvents such as
methanol, ethanol, isopropanol, acetone, and the like; and
non-polar organic solvents such as methylene chloride, and the
like; and mixtures thereof.
[0145] The flowable material for making the core or the shell or a
portion thereof by molding may optionally comprise adjuvants or
excipients, which may comprise up to about 30% by weight of the
flowable material. Examples of suitable adjuvants or excipients
include plasticizers, detackifiers, humectants, surfactants,
anti-foaming agents, colorants, flavorants, sweeteners, opacifiers,
and the like. Suitable plasticizers for making the core, the shell,
or a portion thereof, by molding include, but not be limited to
polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl
citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as
castor oil, rape oil, olive oil, and sesame oil; surfactants such
as polysorbates, sodium lauryl sulfates, and dioctyl-sodium
sulfosuccinates; mono acetate of glycerol; diacetate of glycerol;
triacetate of glycerol; natural gums; triacetin; acetyltributyl
citrate; diethyloxalate; diethylmalate; diethyl fumarate;
diethylmalonate; dioctylphthalate; dibutylsuccinate;
glyceroltributyrate; hydrogenated castor oil; fatty acids;
substituted triglycerides and glycerides; and the like and/or
mixtures thereof. In one embodiment, the plasticizer is triethyl
citrate. In certain embodiments, the shell is substantially free of
plasticizers, i.e. contains less than about 1%, say less than about
0.01% of plasticizers.
[0146] In one preferred embodiment, the flowable material comprises
less than 5% humectants, or alternately is substantially free of
humectants, such as glycerin, sorbitol, maltitol, xylitol, or
propylene glycol. Humectants have traditionally been included in
pre-formed films employed in enrobing processes, such as that
disclosed in U.S. Pat. Nos. 5,146,730 and 5,459,983, assigned to
Banner Gelatin Products Corp., in order to ensure adequate
flexibility or plasticity and bondability of the film during
processing. Humectants function by binding water and retaining it
in the film. Pre-formed films used in enrobing processes can
typically comprise up to 45% water. Disadvantageously, the presence
of humectant prolongs the drying process, and can adversely affect
the stability of the finished dosage form.
[0147] In certain embodiments, the core, the shell, or portions
thereof may be molded using a solvent-free process. In such
embodiments, the core may comprise active ingredient contained
within an excipient matrix. The matrix, or the core, or the shell,
or portions thereof typically comprises at least about 30 percent,
e.g. at least about 45 weight percent of a thermal-reversible
carrier, and optionally up to about 30 weight percent of various
adjuvants such as for example plasticizers, gelling agents,
strengthening agents, colorants, stabilizers, preservatives, and
the like as known in the art. The matrix or the core, or the shell,
or portions thereof may optionally further comprise up to about 55
weight percent of one or more release-modifying moldable excipients
as described below.
[0148] The core may be in a variety of different shapes. For
example, the core may be shaped as a polyhedron, such as a cube,
pyramid, prism, or the like; or may have the geometry of a space
figure with some non-flat faces, such as a cone, truncated cone,
cylinder, sphere, torus, or the like. In cetrain embodiments, the
core has one or more major faces. For example in embodiments
wherein the core is a compressed tablet, the core surface typically
has two opposing major faces formed by contact with the upper and
lower punch faces in the compression machine. In such embodiments
the core surface typically further comprises a "belly-band" located
between the two major faces, and formed by contact with the die
walls in the compression machine. Exemplary core shapes which may
be employed include tablet shapes formed from compression tooling
shapes described by "The Elizabeth Companies Tablet Design Training
Manual" (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.)
(incorporated herein by reference) as follows (the tablet shape
corresponds inversely to the shape of the compression tooling):
1 1. Shallow Concave. 2. Standard Concave. 3. Deep Concave. 4.
Extra Deep Concave. 5. Modified Ball Concave. 6. Standard Concave
Bisect. 7. Standard Concave Double Bisect. 8. Standard Concave
European Bisect. 9. Standard Concave Partial Bisect. 10. Double
Radius. 11. Bevel & Concave. 12. Flat Plain. 13.
Flat-Faced-Beveled Edge (F.F.B.E.). 14. F.F.B.E. Bisect. 15.
F.F.B.E. Double Bisect. 16. Ring. 17. Dimple. 18. Ellipse. 19.
Oval. 20. Capsule. 21. Rectangle. 22. Square. 23. Triangle. 24.
Hexagon. 25. Pentagon. 26. Octagon. 27. Diamond. 28. Arrowhead. 29.
Bullet. 30. Shallow Concave. 31. Standard Concave. 32. Deep
Concave. 33. Extra Deep Concave. 34. Modified Ball Concave. 35.
Standard Concave Bisect. 36. Standard Concave Double Bisect. 37.
Standard Concave European Bisect. 38. Standard Concave Partial
Bisect. 39. Double Radius. 40. Bevel & Concave. 41. Flat Plain.
42. Flat-Faced-Beveled Edge (F.F.B.E.). 43. F.F.B.E. Bisect. 44.
F.F.B.E. Double Bisect. 45. Ring. 46. Dimple. 47. Ellipse. 48.
Oval. 49. Capsule. 50. Rectangle. 51. Square. 52. Triangle. 53.
Hexagon. 54. Pentagon. 55. Octagon. 56. Diamond. 57. Arrowhead. 58.
Bullet. 59. Barrel. 60. Half Moon. 61. Shield. 62. Heart. 63.
Almond. 64. House/Home Plate. 65. Parallelogram. 66. Trapezoid. 67.
FIG. 8/Bar Bell. 68. Bow Tie. 69. Uneven Triangle.
[0149] In one embodiment of the invention, the core comprises
multiple portions, for example a first portion and a second
portion. The portions may be prepared by the same or different
methods and mated using various techniques, such as the thermal
cycle molding and thermal setting molding methods described herein.
For example, the first and second portions may both be made by
compression, or both may be made by molding. Or one portion may be
made by compression and the other by molding. The same or different
active ingredient may be present in the first and second portions
of the core. Alternately, one or more core portions may be
substantially free of active ingredients.
[0150] In certain embodiments of the invention, the core or a
portion thereof may function to confer modified release properties
to at least one active ingredient contained therein. In such
embodiments, wherein the core or core portion is made by
compression, as previously noted, the core preferably comprises a
release-modifying compressible excipient. In such embodiments,
wherein the core or core portion is made by molding, as previously
noted, the core preferably comprises a release-modifying moldable
excipient. In embodiments in which one or more core portions
function as an eroding matrix from which dispersed active
ingredient is liberated in a sustained, extended, prolonged, or
retarded manner, the core portion preferably comprises a
release-modifying compressible or moldable excipient selected from
swellable erodible hydrophilic agents, pH-dependent polymers, and
combinations thereof.
[0151] In embodiments in which one or more core portions function
as a diffusional matrix through which active ingredient is
liberated in a sustained, extended, prolonged, or retarded manner,
the core portion preferably comprises a release-modifying excipient
selected from combinations of insoluble edible materials and pore
formers. Alternately, in such embodiments in which the core portion
is prepared by molding, the thermal-reversible carrier may function
by dissolving and forming pores or channels through which the
active ingredient may be liberated.
[0152] The shell of the present invention comprises and first shell
portion and a second shell portion that are compositionally
different. For example the first and second shell portions may
comprise different ingredients, or the first and second shell
portions may comprise different levels of the same ingredients,
e.g. colorants, opacifiers, film-formers, etc. In one such
embodiment, the first and second shell portions may be visually
distinct from one another, for example the visually distinct
portions may be of different colors, hues, glosses, reflective
qualities, brightness, depth, shades, chroma, opacity, etc. For
example, the shell may have a red portion and a yellow portion, or
a flat finish portion and a glossy portion, or an opaque portion
and a translucent portion. Alternatively, the first and second
shell portions may have different thickness. The first and second
shell portions may have different functionalities. For example, the
first and second shell portions may confer different release
properties to an active ingredient contained in either the subject
shell portion, or in a corresponding underlying core portion. In
one particular embodiment, the first shell portion may function as
a diffusional membrane which contains pores through which fluids
can enter the dosage form, and dissolved active ingredient can be
released from an underlying core portion; and the second shell
portion, may function as an eroding matrix from which active
ingredient dispersed in the second shell portion is liberated by
the dissolution of successive layers of the shell portion
surface.
[0153] The shell portions of the present invention may be prepared
by molding, using a solvent-free process, or a solvent-based
process, and depending on the method used, typically comprise a
variety of excipients which are useful for conferring desired
properties to the shell portions. The shell portions may optionally
further comprise one or more active ingredients.
[0154] In embodiments in which the shell portion or portions are
prepared using a solvent-free molding process, the shell will
typically comprise at least about 30 percent, e.g. at least about
45 percent by weight of a thermal-reversible carrier. The shell
portion or portions may optionally further comprise up to about 55
weight percent of a release-modifying excipient. The shell portion
or portions may optionally further comprise up to about 30 weight
percent total of various plasticizers, adjuvants and excipients. In
certain embodiments in which the shell portion is prepared by
solvent-free molding, and functions to delay the release of one or
more active ingredients from an underlying core portion, the
release modifying excipient is preferrably selected from swellable,
erodible hydrophilic materials.
[0155] In embodiments in which the shell portion or portions are
prepared using a solvent-based molding process, the shell portion
or portions will typically comprise at least about 10 weight
percent, e.g. at least about 12 weight percent or at least about 15
weight percent or at least about 20 weight percent or at least
about 25 weight percent of a film-former. Here, the solvent-molded
shell portion or portions may optionally further comprise up to
about 55 weight percent of a release-modifying excipient. The
solvent-molded shell portion or portions may again also optionally
further comprise up to about 30 weight percent total of various
plasticizers, adjuvants, and excipients.
[0156] In one embodiment of this invention, the shell portion or
portions of the present invention, whether prepared by a
solvent-free molding process, or by a solvent-based molding
process, are substantially free of pores having a diameter of
0.5-5.0 microns. As used herein, "substantially free" means that
the shell portion or portions have a pore volume of less than about
0.02 cc/g, preferably less than about 0.01 cc/g, more preferably
less than about 0.005 cc/g in the pore diameter range of 0.5 to 5.0
microns. In contrast, typical compressed materials have pore
volumes of more than about 0.02 cc/g in this diameter range. In
another embodiment of this invention, the core is a molded core and
the core or core portions are substantially free of pores having a
diameter of 0.5-5.0 microns.
[0157] The pore volume, pore diameter and density of the shell
portions of this invention may be determined using a Quantachrome
Instruments PoreMaster 60 mercury intrusion porosimeter and
associated computer software program known as "Porowin." The
procedure is documented in the Quantachrome Instruments PoreMaster
Operation Manual. The PoreMaster determines both pore volume and
pore diameter of a solid or powder by forced intrusion of a
non-wetting liquid (mercury), which involves evacuation of the
sample in a sample cell (penetrometer), filling the cell with
mercury to surround the sample with mercury, applying pressure to
the sample cell by: (i) compressed air (up to 50 psi maximum); and
(ii) a hydraulic (oil) pressure generator (up to 60000 psi
maximum). Intruded volume is measured by a change in the
capacitance as mercury moves from outside the sample into its pores
under applied pressure. The corresponding pore size diameter (d) at
which the intrusion takes place is calculated directly from the
so-called "Washburn Equation": d=-(4.gamma.(cos .theta.))/P where
.gamma. is the surface tension of liquid mercury, .theta. is the
contact angle between mercury and the sample surface and P is the
applied pressure.
[0158] Equipment used for pore volume measurements:
[0159] 1. Quantachrome Instruments PoreMaster 60.
[0160] 2. Analytical Balance capable of weighing to 0.0001 g.
[0161] 3. Desiccator.
[0162] Reagents used for measurements:
[0163] 1. High purity nitrogen.
[0164] 2. Triply distilled mercury.
[0165] 3. High pressure fluid (Dila AX, available from Shell
Chemical Co.).
[0166] 4. Liquid nitrogen (for Hg vapor cold trap).
[0167] 5. Isopropanol or methanol for cleaning sample cells.
[0168] 6. Liquid detergent for cell cleaning.
[0169] Procedure:
[0170] The samples remain in sealed packages or as received in the
dessicator until analysis. The vacuum pump is switched on, the
mercury vapor cold trap is filled with liquid nitrogen, the
compressed gas supply is regulated at 55 psi., and the instrument
is turned on and allowed a warm up time of at least 30 minutes. The
empty penetrometer cell is assembled as described in the instrument
manual and its weight is recorded. The cell is installed in the low
pressure station and "evacuation and fill only" is selected from
the analysis menu, and the following settings are employed:
[0171] Fine Evacuation time: 1 min.
[0172] Fine Evacuation rate: 10
[0173] Coarse Evacuation time: 5 min.
[0174] The cell (filled with mercury) is then removed and weighed.
The cell is then emptied into the mercury reservoir, and two
tablets from each sample are placed in the cell and the cell is
reassembled. The weight of the cell and sample are then recorded.
The cell is then installed in the low-pressure station, the
low-pressure option is selected from the menu, and the following
parameters are set:
[0175] Mode: Low pressure
[0176] Fine evacuation rate: 10
[0177] Fine evacuation until: 200 .mu.Hg
[0178] Coarse evacuation time: 10 min.
[0179] Fill pressure: Contact +0.1
[0180] Maximum pressure: 50
[0181] Direction: Intrusion And Extrusion
[0182] Repeat: 0
[0183] Mercury contact angle; 140
[0184] Mercury surface tension: 480
[0185] Data acquisition is then begun. The pressure vs. cumulative
volume-intruded plot is displayed on the screen. After low-pressure
analysis is complete, the cell is removed from the low-pressure
station and reweighed. The space above the mercury is filled with
hydraulic oil, and the cell is assembled and installed in the
high-pressure cavity. The following settings are used:
[0186] Mode: Fixed rate
[0187] Motor speed: 5
[0188] Start pressure: 20
[0189] End pressure: 60,000
[0190] Direction: Intrusion and extrusion
[0191] Repeat: 0
[0192] Oil fill length: 5
[0193] Mercury contact angle: 140
[0194] Mercury surface tension: 480
[0195] Data acquisition is then begun and graphic plot pressure vs.
intruded volume is displayed on the screen. After the high pressure
run is complete, the low-and high-pressure data files of the same
sample are merged.
[0196] The shell portion or portions of the present invention,
whether prepared by a solvent-free molding process, or by a
solvent-based molding process, typically has a surface gloss of at
least about 150 gloss units, e.g. at least about 175 gloss units,
or at least about 190 gloss units, when measured according to the
method set forth below. In contrast, typical sprayed coatings have
gloss values of less than about 150 gloss units. Dosage forms with
high surface gloss are preferred by consumers due to their
aesthetic elegance and perceived swallowability. The surface gloss
of the shell depends upon a number of factors, including the shell
composition, the method of forming the shell, and, if a mold is
used, the surface finish on the mold.
[0197] Shell or shell portions may be tested for surface gloss
using an instrument available from TriCor Systems Inc. (Elgin,
Ill.) under the tradename TRI-COR MODEL 805A/806H SURFACE ANALYSIS
SYSTEM and generally in accordance with the procedure described in
"TriCor Systems WGLOSS 3.4 Model 805A/806H Surface Analysis System
Reference Manual" (1996), which is incorporated by reference
herein, except as modified below.
[0198] This instrument uses a CCD camera detector, a flat diffuse
light source, compares tablet samples to a reference standard, and
determines average gloss values at a 60 degree incident angle.
During its operation, the instrument generates a gray-scale image,
wherein the occurrence of brighter pixels indicates the presence of
more gloss at that given location.
[0199] The instrument also incorporates software that uses a
grouping method to quantify gloss: i.e., pixels with similar
brightness which are grouped together for averaging purposes.
[0200] The "percent full scale" or "percent ideal" setting (also
referred to as the "percent sample group" setting), is specified by
the user to designate the portion of the brightest pixels above the
threshold that will be considered as one group and averaged within
that group. "Threshold," as used herein, is defined as the maximum
gloss value that will not be included in the average gloss value
calculation. Thus, the background, or the non-glossy areas of a
sample are excluded from the average gloss value calculations. The
method disclosed in K. Fegley and C. Vesey, "The Effect of Tablet
Shape on the Perception of High Gloss Film Coating Systems," which
is available at www.colorcon.com as of Mar. 18, 2002 and
incorporated by reference herein, is used to minimize the effects
resulting from different tablet shapes, and to report a metric that
was comparable across the industry. (The 50% sample group setting
is selected as the setting which best approximates analogous data
from tablet surface roughness measurements.)
[0201] After initially calibrating the instrument using a
calibration reference plate (190-228; 294 degree standard; no mask,
rotation 0, depth 0), a standard surface gloss measurement is
created. For example, a standard surface gloss was obtained using
gel-coated caplets available from McNEIL-PPC, Inc. under the
tradename, EXTRA STRENGTH TYLENOL GELCAPS. The average gloss value
for a sample of 112 of such gel-coated caplets was then determined,
while employing the 25 mm full view mask (190-280), and configuring
the instrument to the following settings:
[0202] Rotation: 0
[0203] Depth: 0.25 inches
[0204] Gloss Threshold: 95
[0205] % Full Scale: 50%
[0206] Index of Refraction: 1.57
[0207] The average surface gloss value for the reference standard
was determined to be 269.
[0208] The total weight of the shell portion or portions is
preferably about 20 percent to about 400 percent of the weight of
the core. In embodiments wherein the shell portion or portions
prepared by a solvent-free molding process, the total weight of the
shell portion or portions is typically from about 50 percent to
about 400 percent, e.g. from about 75 percent to about 400 percent,
or about 100 percent to about 200 percent of the weight of the
core. In embodiments wherein the shell portion or portions are
prepared by a solvent-based molding process, the total weight of
the shell portion or portions is typically from about 20 percent to
about 100 percent of the weight of the core.
[0209] Typical shell portion thicknesses which may be employed in
this invention are about 50 to about 4000 microns. In certain
preferred embodiments, the shell has a thickness of less than 800
microns. In embodiments wherein the shell portion is prepared by a
solvent-free molding process, the shell portion typically has a
thickness of about 500 to about 4000 microns, e.g. about 500 to
about 2000 microns, say about 500 to about 800 microns, or about
800 to about 1200 microns. In embodiments wherein the shell portion
is prepared by a solvent-based molding process, the shell portion
typically has a thickness of less than about 800 microns, e.g.
about 100 to about 600 microns, say about 150 to about 400 microns.
In a particularly preferred embodiment the dosage form comprises
first and second core portions and first and second shell portions,
and at least one of the shell portions has a thickness of less than
about 800 microns, e.g. about 100 to about 600 microns, e.g. about
150 to about 400 microns
[0210] Suitable thermal-reversible carriers for making the core, or
the shell, or a portion thereof, by molding are thermoplastic
materials typically having a melting point below about 110.degree.
C., more preferably between about 20 and about 100.degree. C.
Examples of suitable thermal-reversible carriers for solvent-free
molding include thermplastic polyalkalene glycols, thermoplastic
polyalkalene oxides, low melting hydrophobic materials,
thermoplastic polymers, thermoplastic starches, and the like.
Preferred thermal-reversible carriers include polyethylene glycol
and polyethylene oxide. Suitable thermoplastic polyalkylene glycols
for use as thermal-reversible carriers include polyethylene glycol
having molecular weight from about 100 to about 20,000, e.g. from
about 100 to about 8,000 Daltons. Suitable thermoplastic
polyalkalene oxides include polyethylene oxide having a molecular
weight from about 100,000 to about 900,000 Daltons. Suitable
low-melting hydrophobic materials for use as thermal-reversible
carriers include fats, fatty acid esters, phospholipids, and waxes
which are solid at room temperature, fat-containing mixtures such
as chocolate; and the like. Examples of suitable fats include
hydrogenated vegetable oils such as for example cocoa butter,
hydrogenated palm kernel oil, hydrogenated cottonseed oil,
hydrogenated sunflower oil, and hydrogenated soybean oil; and free
fatty acids and their salts. Examples of suitable fatty acid esters
include sucrose fatty acid esters, mono, di, and triglycerides,
glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate,
glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate,
Glyco Wax-932, lauroyl macrogol-32 glycerides, and stearoyl
macrogol-32 glycerides. Examples of suitable phospholipids include
phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol,
and phosphotidic acid. Examples of suitable waxes which are solid
at room temperature include carnauba wax, spermaceti wax, beeswax,
candelilla wax, shellac wax, microcrystalline wax, and paraffin
wax. Suitable thermoplastic polymers for use as thermal-reversible
carriers include thermoplastic water swellable cellulose
derivatives, thermoplastic water insoluble polymers, thermoplastic
vinyl polymers, thermoplastic starches, and thermoplastic resins,
and combinations thereof. Suitable thermoplastic water swellable
cellulose derivatives include include hydroxypropylmethyl cellulose
(HPMC), methyl cellulose (MC), carboxymethylcellulose (CMC),
cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),
hydroxybutylcellulose (HBC), hydroxyethylcellulose (HEC),
hydroxypropylethylcellulose, hydroxypropylbutylcellulose,
hydroxypropylethylcellulose, and salts, derivatives, copolymers,
and combinations thereof. Suitable thermoplastic water insoluble
polymers include ethylcellulose, polyvinyl alcohols, polyvinyl
acetate, polycaprolactones, cellulose acetate and its derivatives,
acrylates, methacrylates, acrylic acid copolymers, and the like and
derivatives, copolymers, and combinations thereof. Suitable
thermoplastic vinyl polymers include polyvinylacetate, polyvinyl
alcohol, and polyvinyl pyrrolidone (PVP). Examples of suitable
thermoplastic starches for use as thermal-reversible carriers are
disclosed for example in U.S. Pat. No. 5,427,614. ______. Examples
of suitable thermoplastic resins for use as themal-reversible
carriers include dammars, mastic, rosin, shellac, sandarac, and
glcerol ester of rosin. In one embodiment, the thermal-reversible
carrier for making the core, or a portion thereof, by molding is
selected from polyalkylene glycols, polyalkaline oxides, and
combinations thereof.
[0211] Suitable release-modifying excipients for making the core,
or the shell, or a portion thereof, by solvent free or solvent
based molding include but are not limited to swellable erodible
hydrophilic materials, pH-dependent polymers, pore formers, and
insoluble edible materials. In one embodiment, suitable
release-modifying excipients for making the core, or the shell, or
a portion thereof, by molding include hydroxypropylmethylcellulose,
polyethylene oxide, ammonio methacrylate copolymer type B, and
shellac, and combinations thereof.
[0212] Suitable swellable erodible hydrophilic materials for use as
release-modifying excipients for making the core, or the shell, or
a portion thereof by a solvent-free molding process include water
swellable cellulose derivatives, polyalkalene glycols,
thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids,
clays, gelling starches, and swelling cross-linked polymers, and
derivitives, copolymers, and combinations thereof. Examples of
suitable water swellable cellulose derivatives include sodium
carboxymethylcellulose, cross-linked hydroxypropylcellulose,
hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC),
hydroxyisopropylcellulose,
hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose
(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples
of suitable polyalkalene glyclols include polyethylene glycol.
Examples of suitable thermoplastic polyalkalene oxides include poly
(ethylene oxide). Examples of suitable acrylic polymers include
potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, CARBOPOL (high-molceular weight
cross-linked acrylic acid homopolymers and copolymers), and the
like. Examples of suitable hydrocolloids include alginates, agar,
guar gum, locust bean gum, kappa carrageenan, iota carrageenan,
tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan. Examples of suitable
clays include smectites such as bentonite, kaolin, and laponite;
magnesium trisilicate, magnesium aluminum silicate, and the like,
and derivatives and mixtures thereof. Examples of suitable gelling
starches include acid hydrolyzed starches, swelling starches such
as sodium starch glycolate, and derivatives thereof. Examples of
suitable swelling cross-linked polymers include cross-linked
polyvinyl pyrrolidone, cross-linked agar, and cross-linked
carboxymethylcellose sodium.
[0213] Suitable pH-dependent polymers for use as release-modifying
moldable excipients for making the molded matrix or molded core or
molded shell or a portion thereof by molding include enteric
cellulose derivatives, for example hydroxypropyl methylcellulose
phthalate, hydroxypropyl methylcellulose acetate succinate,
cellulose acetate phthalate; natural resins such as shellac and
zein; enteric acetate derivatives such as for example
polyvinylacetate phthalate, cellulose acetate phthalate,
acetaldehyde dimethylcellulose acetate; and enteric acrylate
derivatives such as for example polymethacrylate-based polymers
such as poly(methacrylic acid, methyl methacrylate) 1:2, which is
commercially available from Rohm Pharma GmbH under the tradename
EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1,
which is commercially available from Rohm Pharma GmbH under the
tradename EUDRAGIT L, and the like, and derivatives, salts,
copolymers, and combinations thereof.
[0214] Suitable insoluble edible materials for use as
release-modifying excipients making the core, or the shell, or a
portion thereof by molding, include water-insoluble polymers, and
low-melting hydrophobic materials. Examples of suitable
water-insoluble polymers include ethylcellulose, polyvinyl
alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate
and its derivatives, acrylates, methacrylates, acrylic acid
copolymers; and the like and derivatives, copolymers, and
combinations thereof. Suitable low-melting hydrophobic materials
include fats, fatty acid esters, phospholipids, and waxes. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, Glyco Wax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes include carnauba wax, spermaceti wax, beeswax, candelilla
wax, shellac wax, microcrystalline wax, and paraffin wax;
fat-containing mixtures such as chocolate; and the like.
[0215] Suitable pore formers for use as release-modifying
excipients for making the molded matrix, the core, the shell, or a
portion thereof by molding include water-soluble organic and
inorganic materials. In one embodiment the pore former is
hydroxypropylmethylcellulose. Examples of suitable water-soluble
organic materials include water soluble polymers including water
soluble cellulose derivatives such as hydroxypropylmethylcellulose,
and hydroxypropylcellulose; water soluble carbohydrates such as
sugars, and starches; water soluble polymers such as
polyvinylpyrrolidone and polyethylene glycol, and insoluble
swelling polymers such as microcrystalline cellulose. Examples of
suitable water soluble inorganic materials include salts such as
sodium chloride and potassium chloride and the like and/or mixtures
thereof.
[0216] In embodiments in which the first or second shell portion
comprises an active ingredient intended to have immediate release
from the dosage form, the shell portion is preferably prepared via
the solvent-free molding method described above. In such
embodiments the thermal-reversible carrier is preferably selected
from polyethylene glycol with weight average molecular weight from
about 1450 to about 20000, polyethylene oxide with weight average
molecular weight from about 100,000 to about 900,000, and the
like.
[0217] In embodiments in which at least one of the first or second
shell portions function to confer modified release properties to at
least one active ingredient contained within the dosage form, in
the core, the shell or both, the shell portion typically comprises
at least one release modifying agent as described above.
[0218] In embodiments of the invention in which the core portions
and shell portions each comprise a dose of active ingredient, the
dosage form may function for example as a multi-compartment, e.g. a
four-compartment pulsatile release delivery system. In one such
embodiment, each of the compartments may comprise a dose of the
same active ingredient, to be release at a desired time or rate. In
another such embodiment, the corresponding first core portion and
first shell portions may comprise a dose of the same first active
ingredient to be released at a desired time or rate, while the
second core portion and second shell portion may comprise a dose of
the same second active ingredient to be released at a desired time
or rate. In such embodiments, each compartment comprises inactive
materials which enable the desired functionality of that particular
core portion or shell portion.
[0219] In certain such embodiments, the dosage form may further
comprise a water-impermeable barrier layer between the first and
second core portions. The water-impermeable barrier layer may be
made by any method, for example compression or molding, and
preferably comprises at least one water-insoluble material selected
from water-insoluble polymers, insoluble edible materials,
pH-dependent polymers, and mixtures thereof.
[0220] In one particular embodiment of this invention, at least one
active ingredient contained within the dosage form exhibits a
delayed burst release profile. By "delayed burst release profile"
it is meant that the release of that particular active ingredient
from the dosage form is delayed for a pre-determined time after
ingestion by the patient, and the delay period ("lag time") is
followed by prompt (immediate) release of that active ingredient.
At least one shell portion of the present invention provides for
the delay period and is preferraby substantially free of the active
ingredient to be released in a delayed burst manner. In such
embodiments, the delayed burst active ingredient is typically
contained within the corresponding underlying core portion. In
these embodiments, the core portion may be prepared by compression
or molding, and is formulated for immediate release, as is known in
the art, so that the core portion is readily soluble upon contact
with the dissolution medium. In such embodiments the core portion
preferably comprises a disintegrant, and optionally comprises
additional excipients such as fillers or thermoplastic materials
selected from water-soluble or low-melting materials, and
surfactants or wetting agents. In these embodiments, the
dissolution of the burst release active ingredient, after the delay
period, meets USP specifications for immediate release tablets
containing that active ingredient. For example, for acetaminophen
tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using
USP apparatus 2 (paddles) at 50 rpm, at least 80% of the
acetaminophen contained in the dosage form is released therefrom
within 30 minutes after dosing, and for ibuprofen tablets, USP 24
specifies that in pH 7.2 phosphate buffer, using USP apparatus 2
(paddles) at 50 rpm, at least 80% of the ibuprofen contained in the
dosage form is released therefrom within 60 minutes after dosing.
See USP 24, 2000 Version, 19-20 and 856 (1999).
[0221] In another particular embodiment of this invention at least
one active ingredient contained within the dosage form exhibits a
delayed and sustained release profile. By "delayed then sustained
release profile" it is meant that the release of that particular
active ingredient from the dosage form is delayed for a
pre-determined time after ingestion by the patient, and the delay
period ("lag time") is followed by sustained (prolonged, extended,
or retarded) release of that active ingredient. At least one shell
portion of the present invention provides for the delay period, and
is preferraby substantially free of the active ingredient to be
released in a delayed then sustained manner. In such embodiments,
the delayed then sustained release active ingredient is preferrably
contained within the corresponding underlying core portion. In such
embodiments the core portion may function for example as an eroding
matrix or a diffusional matrix, or an osmotic pump. In embodiments
in which the core portion functions as a diffusional matrix through
which active ingredient is liberated in a sustained, extended,
prolonged, or retarded manner, the core portion preferably
comprises a release-modifying excipient selected from combinations
of insoluble edible materials and pore-formers. Alternately, in
such embodiments in which the core portion is prepared by molding,
the thermal-reversible carrier may function by dissolving and
forming pores or channels through which the active ingredient may
be liberated. In embodiments in which the core portion functions as
an eroding matrix from which dispersed active ingredient is
liberated in a sustained, extended, prolonged, or retarded manner,
the core portion preferably comprises a release-modifying
compressible or moldable excipient selected from swellable erodible
hydrophilic materials, pH-dependent polymers, and combinations
thereof.
[0222] In embodiments in which one or more core portions function
as a diffusional matrix through which active ingredient contained
therein is liberated in a sustained, extended, prolonged, or
retarded manner, the core portion preferably comprises a
release-modifying excipient selected from combinations of insoluble
edible materials and pore formers. Alternately, in such embodiments
in which the core portion is prepared by solven-free molding, the
thermal-reversible carrier may function by dissolving and forming
pores or channels through which the active ingredient may be
liberated.
[0223] In embodiments in which the core or a portion thereof
functions as an eroding matrix from which dispersed active
ingredient is liberated in a sustained, extended, prolonged, or
retarded manner, the core portion preferably comprises a
release-modifying compressible or moldable excipient selected from
swellable erodible hydrophilic materials, pH-dependent polymers,
insoluble edible materials, and combinations thereof. In such
embodiments, the overlaying shell portion will typically be
breached or dissolved prior to onset of erosion of the underlying
core portion, and release of active ingredient therefrom.
[0224] In embodiments in which a shell portion functions by an
erosion-based mechanism to provide a time delay for the release of
an active ingredient from an underlying core portion, the
release-delaying shell portion preferably comprises a release
modifying excipient selected from swellable erodible hydrophilic
materials, insoluble edible materials, and combinations
thereof.
[0225] In embodiments in which a shell portion functions as an
eroding matrix from which active ingredient dispersed therein is
liberated in a sustained, extended, prolonged, or retarded manner,
the shell portion preferably comprises a release-modifying
compressible or moldable excipient selected from swellable erodible
hydrophilic materials, pH-dependent polymers, insoluble edible
materials, and combinations thereof.
[0226] In embodiments of the invention, in which a shell portion
functions to confer a delay to the release of one or more active
ingredients contained in an underlying core portion, the
release-delaying shell portion preferably provides a delay of
greater than one hour, for example at least about 3 hours, or at
least about 4 hours, or at least about 6 hours, or at least about
12 hours to the onset of dissolution of the active ingredient upon
contacting of the dosage form with a liquid medium such as water,
gastrointestinal fluid or the like. The delay period is typically
controlled by the shell portion thickness, composition, or a
combination thereof. In one embodiment the delay period is
independent of the pH of the dissolution media or fluid
environment. For example, the average lag-time for dissolution of
active ingredient in 0.1 N HCl is not substantially different (i.e.
within about 30 minutes, preferably within about 15 minutes) from
the average lag-time for the dissolution of active ingredient in pH
5.6 buffer system. In certain such embodiments, the
release-delaying shell portion prefarably comprises a release
modifying excipient selected from swellable erodible hydrophilic
materials, insoluble edible materials, and combinations
thereof.
[0227] In embodiments in which one or more shell portions contain
active ingredient which is released essentially immediately upon
ingestion of the dosage form, the shell portion preferably
comprises materials which exhibit rapid dissolution in
gastro-intestinal fluids. For example the immediate release shell
portion or portions may comprise readily soluble materials selected
from water soluble or water swellable thermoplastic film formers,
water soluble or water swellable thickeners, crystallizable and
non-crystallizable carbohydrates. In certain such embodiments,
suitable water soluble or water swellable thermoplastic film
formers may be selected from water swellable cellulose derivatives,
thermoplastic starches, polyalkalene glycols, polyalkalene oxides,
and amorphous sugar glass, and combinations thereof. In certain
other such embodiments, suitable film formers may be selected from
film forming water soluble polymers such as for example water
soluble vinyl polymers, water soluble polycarbohydrates, water
swellable cellulose derivatives, and water soluble copolymers;
film-forming proteins, and combinations thereof. In certain other
such embodiments, suitable thickeners may be selected from gelling
polymers or hydrocolloids; gelling starches, and crystallizable
carbohydrates. In certain other such embodiments, suitable
non-crystallizable carbohydrates may be selected from polydextrose,
starch hydrolysates, and non-crystallizable sugar alcohols. In such
embodiments, the immediate release shell portion will preferably be
breached or dissolved within 30 minutes in 900 ml water or 0.1 N
HCl, or phosphate buffer solution at 37.degree. C. with stirring by
a USP type 2 (Paddle method) at 50 or 100 rpm.
[0228] In one embodiment of the invention, the shell portion or
portions additionally comprise at least one active ingredient which
may be the same or different than the active ingredient contained
in the core.
[0229] In embodiments in which the first or second shell portions
confer sustained, extended, or retarded release of an active
ingredient contained in an underlying core or core portion, the
release-modifying agent in said shell portion preferably comprises
a pore-former, and optionally a film-former. In a particularly
preferred embodiment, the shell portion functions as a diffusional
membrane. In some such embodiments, the dissolution of the active
ingredient may follow "diffusion-controlled" release kinetics, as
described for example in Example 1 of U.S. Pat. No. 5,286,497.
Shell portions which confer sustained, extended, or retarded
release and/or function as diffusional membranes can be prepared by
a solvent-free method, or a solvent-based method, as described
above.
[0230] In embodiments in which the first or second shell portions
confer sustained, extended, or retarded release of an active
ingredient contained in said first or second shell portion, the
release-modifying agent in said shell portion preferably comprises
a swellable erodible hydrophilic material, and may optionally
comprise a secondary gelling agent such as for example cross-linked
carboxymethylcellulose, cross-linked polyvinylpyrrolidone, or
sodium starch glycolate.
[0231] In embodiments in which the first or second shell portions
confer a delayed release to an active ingredient contained in an
underlying core or core portion, the release-modifying agent is
preferably selected from swellable erodible hydrophilic materials.
Shell portions which confer delayed release can be prepared by a
solvent-free method, or a solvent-based method, as described
above.
[0232] In embodiments in which the first or second shell portions
provide a barrier to prevent release therethrough of an active
ingredient contained in the underlying core or core portion, the
shell portion is preferably prepared via a solvent-free molding
method, as described above. In such embodiments, the
thermal-reversible carrier is preferably selected from waxes, such
as for example camuba wax, spermaceti wax, beeswax, candelilla wax,
shellac wax, microcrystalline wax, and paraffin wax; hydrogenated
vegetable oils such as for example cocoa butter, hydrogenated
castor oil; other waxy materials such as for example glyceryl
behenate, glyceryl palmitostearate, glyceryl monostearate, glyceryl
tristearate, glyceryl trilaurylate, glyceryl myristate;
thermal-reversible polymers such as for example polycaprolactones
and polyvinyl acetate. In certain embodiments, an impermeable
barrier can be formed which consists essentially of the thermal
reversible carrier. In such embodiments, an additional
release-modifying agent is not necessary. In certain other
embodiments, the release-modifying agent is preferably selected
from water insoluble polymers such as cellulose acetate, acrylates,
acrylic acid copolymers, cellulose acetate, cellulose acetate
propionate, cellulose acetate propionate, cellulose propionate,
cellulose acetate butyrate, cellulose acetate phthalate,
acetaldehyde dimethylcellulose acetate, cellulose acetate ethyl
carbamate, cellulose acetate methyl carbamate, cellulose acetate
diethyl aminoacetate, ethylcellulose, methacrylates, polyvinyl
alcohols, polyvinyl acetate, polycaprolactones, and the like, and
mixtures thereof. In such embodiments, the shell portion may
optionally further comprise a liquid carrier such as for example
mineral oil, propylene glycol, low molecular weight polyethylene
glycol, glycerin, and the like.
[0233] In one embodiment of the invention, the core, the shell, a
core portion, or a shell portion is made by the thermal setting
molding method and apparatus described in copending U.S. patent
application Ser. No. 09/966,450, pages 57-63, the disclosure of
which is incorporated herein by reference. In this embodiment, the
core, the shell, or a portion thereof is formed by injecting a
starting material in flowable form into a molding chamber. The
starting material preferably comprises an active ingredient and a
thermal setting material at a temperature above the melting point
of the thermal setting material but below the decomposition
temperature of the active ingredient. The starting material is
cooled and solidifies in the molding chamber into a shaped form
(i.e., having the shape of the mold).
[0234] According to this method, the starting material must be in
flowable form. For example, it may comprise solid particles
suspended in a molten matrix, for example a polymer matrix. The
starting material may be completely molten or in the form of a
paste. The starting material may comprise an active ingredient
dissolved in a molten material. Alternatively, the starting
material may be made by dissolving a solid in a solvent, which
solvent is then evaporated from the starting material after it has
been molded.
[0235] The starting material may comprise any edible material which
is desirable to incorporate into a shaped form, including active
ingredients, nutritionals, vitamins, minerals, flavors, sweeteners,
and the like. Preferably, the starting material comprises an active
ingredient and a thermal setting material. The thermal setting
material may be any edible material that is flowable at a
temperature between about 37 and about 120.degree. C., and that is
a solid at a temperature between about 0 and about 35.degree. C.
Preferred thermal setting materials include water-soluble polymers
such as polyalkylene glycols, polyethylene oxides and derivatives,
and sucrose esters; fats such as cocoa butter, hydrogenated
vegetable oil such as palm kernel oil, cottonseed oil, sunflower
oil, and soybean oil; mono-, di-, and triglycerides, phospholipids,
waxes such as camuba wax, spermaceti wax, beeswax, candelilla wax,
shellac wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate; sugar in the form on an amorphous glass
such as that used to make hard candy forms, sugar in a
supersaturated solution such as that used to make fondant forms;
low-moisture polymer solutions such as mixtures of gelatin and
other hydrocolloids at water contents up to about 30% such as those
used to make "gummi" confection forms. In a particularly preferred
embodiment, the thermal setting material is a water-soluble polymer
such as polyethylene glycol.
[0236] In another embodiment of the invention, the core, the shell,
a core portion, or a shell portion is make using the thermal cycle
molding method and apparatus described in copending U.S. patent
application Ser. No. 09/966,497, pages 27-51, the disclosure of
which is also incorporated herein by reference. In the thermal
cycle molding method and apparatus of U.S. patent application Ser.
No. 09/966,497, a thermal cycle molding module having the general
configuration shown in FIG. 3 therein is employed. The thermal
cycle molding module 200 comprises a rotor 202 around which a
plurality of mold units 204 are disposed. The thermal cycle molding
module includes a reservoir 206 (see FIG. 4) for holding flowable
material to make the core, the shell, a core portion, or a shell
portioncore. In addition, the thermal cycle molding module is
provided with a temperature control system for rapidly heating and
cooling the mold units. FIGS. 55 and 56 depict such a temperature
control system 600.
[0237] This invention will be illustrated by the following
examples, which are not meant to limit the invention in any
way.
EXAMPLE 1
[0238] Dosage forms according to the invention comprising a core
within a shell comprising a first shell portion and a second shell
portion were prepared as follows.
[0239] The following ingredients were used to make the cores:
2 Mg/dosage Ingredient Trade Name Manufacturer Weight % Form
Verapamil HCL Extended Verelan PM 300 mg Schwarz Pharma, Inc., 22.0
131 Release Pellets capsules Gainesville, GA Polyethylene Glycol
3350 Carbowax .RTM. Union Carbide 47.0 279 Corporation, Danbury, CT
Shellac Powder Mantrose-Haeuser 10.0 59 Company, Atteboro, MA
Croscarmellose Sodium Ac-Di-Sol .RTM. FMC Corporation, 21.0 125
Newark, DE
[0240] The cores were prepared as follows: a beaker was submersed
in a 70.degree. C. water bath (Ret digi-visc; Antal-Direct, Wayne,
Pa.). The polyethylene glycol (PEG) was added to the beaker and
mixed with a spatula until melted. The shellac powder was screened
through a #40 mesh screen, and then added to the molten PEG. The
combined ingredients were mixed until all the powder was dispersed.
Croscarmellose sodium was added next and the beaker contents were
mixed for an additional two minutes. The verapamil HCL pellets were
then added, and the contents were mixed for five more minutes.
Cores were made by dispensing 620 to 640 mg of the resulting molten
mixture into an open stainless steel mold (round, 0.4455 inch
diameter) and closing the mold. The finished cores were ejected
from the mold.
[0241] The first shell portion was made using the following
ingredients:
3 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Pseudoephedrine HCl Crystal BASF 30.0 53 PharmaChemikalien GmbH
& Co. Ludwigshafen/Rhein. Polyethylene Glycol 3350 Carbowax
.RTM. Union Carbide 50.0 89 Corporation, Danbury, CT Polyethylene
Oxide (MW Polyox .RTM. WSR N-80 Union Carbide 15.0 27 200,000)
Corporation, Danbury, CT Triethyl Citrate Morflex, Inc., 5.0 9
Greensboro, NC
[0242] The first shell portion material was prepared by first
submersing a beaker in a 70.degree. C. water bath (Ret digi-visc;
Antal-Direct, Wayne, Pa.). The polyethylene glycol (PEG) was added
to the beaker and mixed with a spatula until melted. The triethyl
citrate was then added to the molten PEG and the mixture was mixed
for one minute. The polyethylene oxide (PEO) was added thereto, and
the ingredients were mixed for 10 additional minutes. The
pseudoephedrine hydrochloride was added, and the ingredients were
mixed for two more minutes. The first shell portion material was
provided in flowable form.
[0243] The second shell portion was made using the following
ingredients:
4 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Dextromethorphan HBr Roche Chemical 10.0 16 Co., Belvidere, NJ
Polyethylene Glycol 3350 Carbowax .RTM. Union Carbide 50.0 77
Corporation, Danbury, CT Polyethylene Oxide (MW Polyox .RTM. WSR
N-80 Union Carbide 15.0 23 200,000) Corporation, Danbury, CT
Shellac Powder Mantrose-Haeuser 10.0 16 Company, Atteboro, MA
Croscarmellose Sodium Ac-Di-Sol .RTM. FMC Corporation, 5.0 8
Newark, DE Triethyl Citrate Morflex, Inc., 10.0 16 Greensboro,
NC
[0244] The second shell portion material was prepared by first
submersing a beaker in a 70.degree. C. water bath (Ret digi-visc;
Antal-Direct, Wayne, Pa.). PEG was added to the beaker and mixed
with a spatula until melted. The shellac powder was screened
through a #40 mesh screen, and then added to the molten PEG. The
combined ingredients were mixed until all powder was dispersed. The
triethyl citrate was added next and the beaker contents were mixed
for one minute. PEO was added to the beaker and the mixture was
mixed for 10 minutes. Croscarmellose sodium was then added and the
contents of the beaker were mixed for two additional minutes.
Finally, dextromethorphan HBr was added to the beaker and the
ingredients were mixed for two more minutes. The second shell
portion material was provided in flowable form.
[0245] A laboratory scale thermal cycle molding unit was used to
apply the first and second shell portions to the cores, and
comprised a single mold assembly made from an upper mold assembly
portion comprising an upper mold cavity, and a lower mold assembly
portion comprising a lower mold cavity. The lower mold assembly
portion was first cycled to a hot stage at 85.degree. C. for 30
seconds. The first shell portion material of Example 1 was
introduced into the lower mold cavity. A core prepared as described
above was then inserted into the cavity. A blank upper mold
assembly portion was mated with the lower mold assembly portion.
The mold assembly was then cycled to a cold stage at 5.degree. C.
for 60 seconds to harden the first shell portion. The blank mold
assembly portion was removed from the lower mold assembly portion,
and the half-coated core was ejected from the lower mold cavity.
The "weight gain" due to the first shell portion (i.e. the
difference in weight between the half-coated core and the uncoated
core) was recorded.
[0246] The upper mold assembly portion was cycled to a hot stage at
85.degree. C. for 30 seconds. The second shell portion material was
added to the upper mold cavity. The half-coated core was then
inserted into the upper mold cavity such that the uncoated portion
of the core rested within the upper mold cavity. The lower mold
assembly portion, which had been maintained at 5.degree. C., was
then mated with the upper mold assembly portion. The upper mold
assembly portion was then cycled to a cold stage at 5.degree. C.
for 60 seconds to harden the second shell portion. The lower mold
assembly portion was then removed and the finished dosage form, a
molded core coated with two different shell portions, was ejected
from the upper mold cavity. The weight gain due to the second shell
portion (i.e. the difference in weight between the finished dosage
form, and the half-coated core) was recorded.
[0247] The release profiles for the three active ingredients
contained in the dosage form of Example 1 were compared with those
of other dosage forms containing the same active ingredients. The
results are shown in FIG. 3, which depicts the percent release of
active ingredient versus hours for the dosage form of Example 1 and
the other dosage forms. Curve (a) depicts the dissolution profile
of the verapamil HCL contained in the core of the dosage form of
this example. Curve (b) depicts the dissolution of verapamil from
commercially available, sustained release capsules (Verelan.RTM. PM
300 mg). Curve (c) shows the dissolution of dextromethorphan HBr
contained in the second shell portion of the dosage form of this
example. Curve (d) shows the dissolution profile of pseudoephedrine
HCl contained in the first shell portion of the dosage form of this
example. Curve (e) depicts the dissolution profile of
pseudoephedrine HCl from commercially available immediate release
tablets (Sudafed.RTM.). Curve (f) depicts the dissolution profile
of dextromethorphan HBr from commercially available immediate
release coated tablets (Tylenol.RTM. Cold caplets).
[0248] All curves were derived using the following dissolution
apparatus: USP Type II apparatus (paddles, 50 RPM). Media: pH 7.2
phosphate buffer at 37.degree. C. Time points: Samples were removed
at 0.5, 1, 2, 4, 8, 12, 16, 20, and 24 hours to be analyzed for
pseudoephedrine HCl, dextromethorphan HBr, and verapamil HCl.
Dissolution samples were analyzed for these three active
ingredients versus a standard prepared at the theoretical
concentration for 100% released of each compound. Samples were
analyzed using an HPLC equipped with a Waters.RTM. 717 Autoinjector
and a Waters.RTM. 486 UV detector set at a wavelength of 214 nm.
The mobile phase was prepared using 55% acetonitrile and 45% 18 mM
Potassium phosphate buffer. The injection volume was 50 .mu.L with
a run time of approximately 8 minutes an a pump flow of 2.0 mL/min.
A Zorbax.RTM. 300-SCX (4.6 m.times.25 cm) column was used.
[0249] The curves depicted in FIG. 3 demonstrate that the verapamil
HCl was released from the dosage form of the present example in a
sustained manner. The dextromethorphan HBr was released from the
dosage form of the present example in a delayed manner. The
pseudoephedrine HCl was immediately released from the dosage form
of the present example.
EXAMPLE 2
[0250] Dosage forms according to the invention comprising a core
having a first core portion and a second core portion within a
shell having a first shell portion and a second shell portion were
prepared as follows.
[0251] The following ingredients were used to make the first core
portion:
5 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Pseudoephedrine HCl Crystal BASF 15.0 48 PharmaChemikalien GmbH
& Co. Ludwigshafen/Rhein. Polyethylene Oxide Polyox .RTM. WSR
N-750 Union Carbide 75.0 239 (MW 300,000) Corporation, Danbury, CT
Hydroxypropyl Methocel E5 Dow Chemical 8.5 27 Methylcellulose
Company, Midland, MI Magnesium Stearate Mallinckrodt Inc., 1.5 5
St. Louis, MO Alcohol USP (dried as solvent)
[0252] The pseudoephedrine HCl crystal, hydroxypropyl
methylcellulose, and PEO (MW=300,000), were first mixed in a
plastic bag for 1-2 minutes. This powder mixture was added into the
(5 qt) bowl of a planetary mixer (Hobart Corp., Dayton, Ohio). The
alcohol was added to the powder mixture while mixing at low speed.
The ingredients were mixed for 10 minutes. The resulting
granulation was removed from the bowl and dried at room temperature
for 12 to 16 hours to remove all residual solvent. The granulation
was screened through a #20 mesh screen and were put into a plastic
bag. Magnesium stearate was added to the dry granules, followed by
mixing for 3 minutes to form the first core portion.
[0253] The following ingredients were used to make the second core
portion:
6 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Dextromethorphan HBr Roche Chemical Co. 15.1 48 Belvidere, NJ
Polyethylene Oxide Polyox .RTM. WSR N-750 Union Carbide 75.4 240
(MW 300,000) Corporation, Danbury, CT Hydroxypropyl Methylcellulose
Methocel E5 Dow Chemical 8.5 27 Company, Midland, MI Magnesium
Stearate Mallinckrodt Inc., 1.0 3 St. Louis, MO D&C Yellow #10
Trace Amount Ethanol Anhydrous (dried as solvent)
[0254] Dextromethorphan HBr, hydroxypropyl methylcellulose, PEO
(MW=300,000), and D&C yellow #10 were mixed in a plastic bag
for 1-2 minutes. This powder mixture was added into the (5 qt) bowl
of a planetary mixer (Hobart Corp., Dayton, Ohio). The alcohol was
added to the powder mixture while mixing at low speed. The
ingredients were mixed for 10 minutes. The resulting granulation
was removed from the bowl and dried at room temperature for 12 to
16 hours to remove all residual solvent. The granulation was
screened through a #20 mesh screen and were put into a plastic bag.
Magnesium stearate was added to the dry granules, followed by
mixing for 3 minutes to form the second core portion.
[0255] Cores were made from equal portions (by weight) of the first
and second core portions as follows. A model M hydraulic Carver
Laboratory Press (Fred S. Carver, Inc., Hydraulic Equipment,
Summit, N.J.) was employed. A round, concave punch and die unit
having 0.4455" diameter was used for compression. The
pseudoephedrine granulation for the first core portion was fed into
the cavity mold of the press and was gently tapped. Then the
dextromethorphan granulation for the second core portion was fed
into the cavity overlying the pseudoephedrine granulation. The
granulations were pressed into a solid two-portion core using 1500
lb/sq. in. of compression force.
[0256] The first shell portion was made using the following
ingredients:
7 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Cellulose Acetate 398-10 Eastman Chemical 60.0 12.9 Company,
Kingsport, TN Polyethylene Oxide Polyox .RTM. WSR N-80 Union
Carbide 20.0 4.3 (MW 200,000) Corporation, Danbury, CT
Hydroxypropyl Methocel E5 Dow Chemical Company, 20.0 4.3
Methylcellulose Midland, MI Acetone (dried as solvent)
[0257] The cellulose acetate was added to a beaker containing
acetone and mixed using a mixer until all powder was dissolved. An
agitating speed of 500 rpm was used. Hydroxypropyl methylcellulose
and PEO, which were screened through a #40 mesh screen, were added
to the cellulose acetate solution, which was again mixed until all
powder was dispersed. The first shell portion material was provided
in flowable form.
[0258] The second shell portion was made using the following
ingredients:
8 Mg/Dosaage Ingredient Trade Name Manufacturer Weight % Form
Cellulose Acetate 398-10 Eastman Chemical 56.0 12.0 Company,
Kingsport, TN Ammonio Methacrylate Eudragit .RTM. RS 100 Roehm
America 24.0 5.2 Copolymer Type B Inc., Somerset, NJ Polyethylene
Oxide Polyox .RTM. WSR N-80 Union Carbide 20.0 4.3 (MW 200,000)
Corporation, Danbury, CT Acetone (dried as solvent)
[0259] The cellulose acetate was added into a beaker containing
acetone and was mixed using a mixer until all powder was dissolved.
An agitating speed of 500 rpm was used. Ammonio methacrylate
copolymer and PEO, which were screened through a #40 mesh screen,
were added to the cellulose acetate solution, which was then mixed
until all powder was dispersed. The second shell portion was
provided in flowable form.
[0260] A thermal cycle molding module as described in Example 1 was
used to apply the first and second shell portions onto the core.
The lower mold assembly portion was first cycled to a cold stage at
25.degree. C. for 30 seconds. The first shell portion material was
added to the lower mold cavity. A two-portion core as described
above was inserted into the lower mold cavity such that the first
core portion, containing pseudoephedrine HCl sustained release
granules, was inserted into the lower mold cavity. A blank upper
mold assembly portion was mated the lower mold assembly portion.
The mold assembly was then cycled to a hot stage at 85.degree. C.
for 2 minutes. Next, the assembly was cycled to a cold stage at
5.degree. C. for 1 minute to harden the first shell portion. The
blank upper mold assembly portion was then removed from the lower
mold assembly portion.
[0261] The upper mold assembly portion was next cycled to a cold
stage at 25.degree. C. for 30 seconds. The second shell portion
material was added to the upper mold cavity. The half-coated core,
with the first shell portion, was inserted into the upper mold
cavity such that the uncoated core portion containing
dextromethorphan HBr sustained release granules rested within the
upper mold cavity. The lower mold assembly portion, which had been
maintained at 5.degree. C., was then mated with the upper mold
assembly portion. The upper mold assembly portion was then cycled
to a hot stage at 85.degree. C. for 2 minutes, followed by a cold
stage at 5.degree. C. for 1 minute to harden the second shell
portion. The lower mold assembly portion was removed and the
finished dosage form, a two-portion core coated with two different
shell portions, was ejected form the upper mold cavity. The weight
gain due to the first and second shell portions, i.e. the
difference in weights of the finished dosage form and the uncoated
core, was recorded. The finished dosage form was dried at room
temperature for 24 hours to remove all residual solvent.
[0262] The release profiles for the two active ingredients
contained in the dosage form of this example were compared with
those of other dosage forms containing the same active ingredients.
The results are shown in FIG. 4, which depicts the percent release
of active ingredient versus hours for the dosage form of Example 2
and other dosage forms. Curve (a) depicts the dissolution profile
of the dextromethorphan HBr contained in the second core portion of
the finished dosage form of this example. Curve (b) depicts the
dissolution profile of the dextromethorphan HBr from the uncoated
core prepared according to this example, but without the second
shell portion. Curve (c) shows the dissolution profile of
pseudoephedrine HCl contained in the first core portion of the
finished dosage form of this Example. Curve (d) shows the
dissolution profile of pseudoephedrine HCl from the uncoated core
prepared according to this example, but without the first shell
portion.
[0263] All curves were derived using the following dissolution
apparatus: USP Type II apparatus (paddles, 50 RPM). Media: pH 7.2
phosphate buffer at 37.degree. C. Time points: Samples were removed
at 0.5, 1, 2, 4, 8, 12, 16, 20, and 24 hours to be analyzed for
pseudoephedrine HCl, and dextromethorphan HBr. Dissolution samples
were analyzed for these two active ingredients versus a standard
prepared at the theoretical concentration for 100% released of each
compound. Samples were analyzed using an HPLC equipped with a
Waters.RTM. 717 Autoinjector and a Waters.RTM. 486 UV detector set
at a wavelength of 214 nm. The mobile phase was prepared using 55%
acetonitrile and 45% 18 mM Potassium phosphate buffer. The
injection volume was 50 .mu.L with a run time of approximately 8
minutes an a pump flow of 2.0 mL/min. A Zorbax.RTM. 300-SCX (4.6
m.times.25 cm) column was used.
EXAMPLE 3
[0264] Dosage forms of the invention are made in a continuous
process using an apparatus comprising two thermal cycle molding
modules linked in series via a transfer device as described at
pages 14-16 of copending U.S. application Ser. No. 09/966,939, the
disclosure of which is incorporated herein by reference. The dosage
forms comprise a core coated with a shell comprising a first
portion and a second portion.
[0265] The core is made of a core flowable material comprising the
following ingredients:
9 Mg/dosage Ingredient Trade Name Manufacturer Weight % Form
Verapamil HCL Extended Verelan PM 300 mg Schwarz Pharma, Inc., 22.0
131 Release Pellets capsules Gainesville, GA Polyethylene Glycol
3350 Carbowax .RTM. Union Carbide 47.0 279 Corporation, Danbury, CT
Shellac Powder Mantrose-Haeuser 10.0 59 Company, Atteboro, MA
Croscarmellose Sodium Ac-Di-Sol .RTM. FMC Corporation, 21.0 125
Newark, DE
[0266] PEG is heated to 70.degree. C. and mixed until melted. The
shellac powder is screened through a #40 mesh screen, and then
added to the molten PEG. The combined ingredients are mixed until
all the powder is dispersed. Croscarmellose sodium is added next
and the ingredients are mixed for an additional two minutes. The
verapamil HCL pellets are then added, and the ingredients are mixed
for five more minutes.
[0267] The first shell portion is made of a first shell portion
flowable material comprising the following ingredients:
10 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Pseudoephedrine HCl Crystal BASF 30.0 53 PharmaChemikalien GmbH
& Co. Ludwigshafen/Rhein. Polyethylene Glycol 3350 Carbowax
.RTM. Union Carbide 50.0 89 Corporation, Danbury, CT Polyethylene
Oxide Polyox .RTM. WSR N-80 Union Carbide 15.0 27 (MW 200,000)
Corporation, Danbury, CT Triethyl Citrate Morflex, Inc., 5.0 9
Greensboro, NC
[0268] The PEG is heated to 70.degree. C. and mixed until melted.
The triethyl citrate is then added to the molten PEG and the
mixture is mixed for one minute. The PEO is added thereto, and the
ingredients are mixed for 10 additional minutes. The
pseudoephedrine hydrochloride is added, and the ingredients are
mixed for two more minutes.
[0269] The second shell portion is made of a second shell portion
flowable material comprising the following ingredients:
11 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Dextromethorphan HBr Roche Chemical 10.0 16 Co., Belvidere, NJ
Polyethylene Glycol 3350 Carbowax .RTM. Union Carbide 50.0 77
Corporation, Danbury, CT Polyethylene Oxide Polyox .RTM. WSR N-80
Union Carbide 15.0 23 (MW 200,000) Corporation, Danbury, CT Shellac
Powder Mantrose-Haeuser 10.0 16 Company, Atteboro, MA
Croscarmellose Sodium Ac-Di-Sol .RTM. FMC Corporation, 5.0 8
Newark, DE Triethyl Citrate Morflex, Inc., 10.0 16 Greensboro,
NC
[0270] The PEG is heated to 70.degree. C. and mixed until melted.
The shellac powder is screened through a #40 mesh screen, and then
added to the molten PEG. The combined ingredients are mixed until
all powder is dispersed. The triethyl citrate is added next and the
ingredients are mixed for one minute. PEO is added to the mixture
and the ingredients are again mixed for 10 minutes. Croscarmellose
sodium is then added followed by mixing for two additional minutes.
Finally, dextromethorphan HBr is added and the ingredients are
mixed for two more minutes.
[0271] The thermal cycle molding modules have the general
configuration shown in FIG. 3 and pages 27-51 of copending U.S.
application Ser. No. 09/966,497, which depicts a thermal cycle
molding module 200 comprising a rotor 202 around which a plurality
of mold units 204 are disposed. The thermal cycle molding modules
include reservoirs 206 (see FIG. 4) for holding the core flowable
material, the first shell portion flowable material, and the second
shell portion flowable material. In addition, each thermal cycle
molding module is provided with a temperature control system for
rapidly heating and cooling the mold units. FIGS. 55 and 56 of
pending U.S. application Ser. No. 09/966,497 depict the temperature
control system 600.
[0272] The cores are made in a first thermal cycle molding module,
which is linked via a transfer device to a second thermal cycle
molding module. The first thermal cycle molding module has the
specific configuration shown in FIG. 26A of copending U.S.
application Ser. No. 09/966,497. The first thermal cycle molding
module comprises center mold assemblies 212 and upper mold
assemblies 214 as shown in FIG. 26C of copending U.S. application
Ser. No. 09/966,497, which mate to form mold cavities having a
tablet shape. As rotor 202 rotates, the opposing center and upper
mold assemblies close. Core flowable material, which is heated to a
flowable state in reservoir 206, is injected into the resulting
mold cavities. The temperature of the core flowable material is
then decreased, hardening the core flowable material into
tablet-shaped cores. The mold assemblies open and eject the cores,
which are received by the first transfer device.
[0273] The transfer device has the structure shown as 300 in FIG. 3
and described on pages 51-57 of copending U.S. application Ser. No.
09/966,414, the disclosure of which is incorporated by reference.
It comprises a plurality of transfer units 304 attached in
cantilever fashion to a belt 312 as shown in FIGS. 68 and 69. The
transfer device rotates and operates in sync with the thermal cycle
molding modules to which it is coupled. Transfer units 304 comprise
retainers 330 for holding the cores as they travel around the
transfer device.
[0274] The transfer device transfers the cores to the second
thermal cycle molding module, which applies the shell to the cores.
The second thermal cycle molding module is of the type shown in
FIG. 28A of copending U.S. application Ser. No. 09/966,497. The
mold units 204 of the second thermal cycle molding module comprise
upper mold assemblies 214, rotatable center mold assemblies 212 and
lower mold assemblies 210 as shown in FIG. 28C. Cores are
continuously transferred to the mold assemblies, which then close
over the cores.
[0275] Coating is performed in two steps, the first and second
shell portions being applied separately as shown in the flow
diagram of FIG. 28B of copending U.S. application Ser. No.
09/966,497. In a first step, first shell portion flowable material,
heated to a flowable state in reservoir 206, is injected into the
mold cavities created by the closed mold assemblies. The
temperature of the first shell portion flowable material is then
decreased, hardening it over half the core. The mold assemblies
separate, the center mold assembly rotates, and then the mold
assemblies again close. In a second step, second shell portion
flowable material, heated to a flowable state in reservoir 206, is
injected into the mold cavities. The temperature of the second
shell portion flowable material is then decreased, hardening it
over the other half of the core. The mold assemblies separate, and
the finished dosage forms are ejected from the apparatus.
[0276] Although this invention has been illustrated by reference to
specific embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made which
clearly fall within the scope of this invention.
* * * * *
References