U.S. patent application number 10/393638 was filed with the patent office on 2003-12-18 for modified release dosage forms.
Invention is credited to Lee, Der-Yang, Li, Shun-Por, McNally, Gerard P., McTeigue, Daniel, Parikh, Narendra, Sowden, Harry S., Wynn, David.
Application Number | 20030232082 10/393638 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2003-12-18 |
United States Patent
Application |
20030232082 |
Kind Code |
A1 |
Li, Shun-Por ; et
al. |
December 18, 2003 |
Modified release dosage forms
Abstract
A dosage form comprises: (a) at least one active ingredient; (b)
a core having an outer surface; and (c) a shell which resides upon
at least a portion of the core outer surface, wherein at least a
portion of the shell is semipermeable, such that the liquid medium
diffuses through the semipermeable shell or shell portion to the
core due to osmosis. The shell also provides for delivery of the
active ingredient to a liquid medium outside the shell after
contacting of the dosage form with the liquid medium. The dosage
form delivers one or more active ingredients in a controlled manner
upon contacting of the dosage form with a liquid medium. The dosage
form may be employed to provide a burst release of the active
ingredient, or to provide release of the active ingredient at an
ascending release rate over an extended time period upon contacting
of the dosage form with a liquid medium.
Inventors: |
Li, Shun-Por; (Lansdale,
PA) ; Lee, Der-Yang; (Flemington, NJ) ;
McNally, Gerard P.; (Berwyn, PA) ; McTeigue,
Daniel; (North Wales, PA) ; Parikh, Narendra;
(Long Valley, NJ) ; Sowden, Harry S.; (Glenside,
PA) ; 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.: |
10/393638 |
Filed: |
March 21, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10393638 |
Mar 21, 2003 |
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PCT/US02/31129 |
Sep 28, 2002 |
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10393638 |
Mar 21, 2003 |
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PCT/US02/31117 |
Sep 28, 2002 |
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10393638 |
Mar 21, 2003 |
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PCT/US02/31062 |
Sep 28, 2002 |
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10393638 |
Mar 21, 2003 |
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PCT/US02/31024 |
Sep 28, 2002 |
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10393638 |
Mar 21, 2003 |
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PCT/US02/31163 |
Sep 28, 2002 |
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PCT/US02/31163 |
Sep 28, 2002 |
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09966939 |
Sep 28, 2001 |
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PCT/US02/31163 |
Sep 28, 2002 |
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09966509 |
Sep 28, 2001 |
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PCT/US02/31163 |
Sep 28, 2002 |
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09966497 |
Sep 28, 2001 |
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PCT/US02/31163 |
Sep 28, 2002 |
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09967414 |
Sep 28, 2001 |
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PCT/US02/31163 |
Sep 28, 2002 |
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09966450 |
Sep 28, 2001 |
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Current U.S.
Class: |
424/473 |
Current CPC
Class: |
A61K 9/2031 20130101;
A61K 9/2013 20130101; A61K 9/2873 20130101; A23G 3/368 20130101;
A61J 3/005 20130101; A61K 9/0056 20130101; A61K 9/2054 20130101;
A61K 9/0004 20130101; A61K 9/2018 20130101; A61K 9/286 20130101;
A23G 1/54 20130101; A61K 9/2893 20130101; A23G 3/0029 20130101;
A61K 9/2081 20130101; A61P 43/00 20180101; A23G 3/04 20130101; A61P
11/00 20180101; A61K 9/2095 20130101; A61K 9/284 20130101; Y10T
428/1352 20150115; A23G 3/54 20130101; A61K 9/2068 20130101; B30B
11/34 20130101; B30B 15/302 20130101; A61J 3/06 20130101; A61K
9/2027 20130101; A61J 3/10 20130101; A61K 9/282 20130101; A23L
29/30 20160801; A61K 9/2072 20130101; A61K 9/2886 20130101; A61K
9/209 20130101; A61K 9/2826 20130101; A61K 9/5084 20130101; B30B
11/08 20130101 |
Class at
Publication: |
424/473 |
International
Class: |
A61K 009/24 |
Claims
The invention claimed is:
1. A dosage form comprising: (a) at least one active ingredient;
(b) a core having an outer surface; and (c) a shell which resides
upon at least a portion of the core outer surface, wherein at least
a portion of the shell is semipermeable, at least about 30% of the
cross-sectional area of the semipermeable shell portion is
non-striated, and the shell comprises means for providing the
active ingredient to a liquid medium outside the shell after
contacting of the dosage form with the liquid medium.
2. The dosage form of claim 1, in which substantially all of the
shell is semipermeable, and the shell additionally comprises at
least one passageway therein extending to the core outer
surface.
3. The dosage form of claim 1, in which at least about 50% of the
cross sectional area of the shell is non-striated.
4. The dosage form of claim 1, in which at least about 80% of the
cross sectional area of the shell is non-striated.
5. The dosage form of claim 1, in which the core comprises at least
one active ingredient.
6. The dosage form of claim 1, in which the shell comprises at
least one active ingredient.
7. The dosage form of claim 1, in which the core and the shell each
comprise at least one active ingredient.
8. The dosage form of claim 1, in which the core comprises an
osmagent.
9. The dosage form of claim 1, in which the core comprises a first
core portion and a second core portion.
10. The dosage form of claim 9, in which the shell comprises a
plurality of passageways therein extending to the core.
11. A dosage form comprising: (a) at least one active ingredient;
(b) a core having an outer surface; and (c) a shell which resides
upon at least a portion of the core outer surface, wherein the
shell comprises a first shell portion which is semipermeable to the
liquid medium, and a second shell portion which is compositionally
different than the first shell portion, the first and second shell
portions each are substantially in contact with the core outer
surface, and the shell comprises means for providing the active
ingredient to a liquid medium outside the shell after contacting of
the dosage form with the liquid medium.
12. The dosage form of claim 11, in which at least one of the first
or second shell portions has at least one passageway therein
extending to the core outer surface.
13. The dosage form of claim 11, in which the second shell portion
is diffusible.
14. The dosage form of claim 11, in which the first shell portion
has at least one passageway therein extending to the core, and the
second shell portion is impermeable to the liquid medium.
15. The dosage form of claim 11, in which the second shell portion
has at least one passageway therein extending to the core.
16. The dosage form of claim 11, in which the core comprises at
least one active ingredient.
17. The dosage form of claim 11, in which the first shell portion
comprises at least one active ingredient.
18. The dosage form of claim 11, in which the second shell portion
comprises at least one active ingredient.
19. The dosage form of claim 11, in which the core, the first shell
portion and the second shell portion each comprises at least one
active ingredient.
20. The dosage form of claim 11, in which the first shell portion
has a first thickness, and the second shell portion has a second
thickness which is different than the first shell portion
thickness.
21. The dosage form of claim 11, in which the first shell portion
has a first thickness, and the second shell portion has a second
thickness which is substantially the same as the first shell
portion thickness.
22. The dosage form of claim 11, in which the core comprises a
first core portion and a second core portion.
23. The dosage form of claim 22, in which at least one of the first
or second core portions comprises at least one active
ingredient.
24. The dosage form of claim 22, in which the first core portion
comprises a first active ingredient and the second core portion
comprises a second active ingredient which may be the same or
different than the first active ingredient.
25. A dosage form comprising: (a) at least one active ingredient;
(b) a core having an outer surface, a first core portion, a second
core portion, and a third core portion located between the first
and second core portions, wherein the third core portion comprises
an osmopolymer; and (c) a shell which resides upon at least a
portion of the core outer surface, in which the shell comprises a
first shell portion which is semipermeable to the liquid medium,
and a second shell portion which is compositionally different than
the first shell portion, the first and second shell portions each
are substantially in contact with the core outer surface, and at
least one of the first or second shell portions has at least one
passageway therein extending to the core outer surface.
26. The dosage form of claim 25, in which at least one of the first
or second core portions comprises at least one active
ingredient.
27. The dosage form of claim 25, in which the first core portion
comprises a first active ingredient and the second core portion
comprises a second active ingredient which may be the same or
different than the first active ingredient.
28. A dosage form comprising: (a) at least one active ingredient;
(b) a core having an outer surface; and (c) a shell which resides
upon at least a portion of the core outer surface, in which the
shell comprises a first shell portion which is semipermeable to the
liquid medium, and a second shell portion which is compositionally
different than the first shell portion, the first and second shell
portions each are substantially in contact with the core outer
surface, and the shell and core have a continuous cavity therein
defining an interior surface, wherein neither the first shell
portion nor the second shell portion extend substantially upon the
interior surface.
29. The dosage form of claim 28, in which the core comprises at
least one active ingredient.
30. A dosage form comprising: (a) at least one active ingredient;
(b) a core having an outer surface, a first core portion, a second
core portion, and a third core portion located between the first
and second core portions, wherein the third core portion comprises
a osmopolymer; and (c) a shell which resides upon at least a
portion of the core outer surface, in which the shell comprises a
first shell portion which is semipermeable to the liquid medium,
and a second shell portion which is compositionally different than
the first shell portion, the first and second shell portions each
are substantially in contact with the core outer surface, and the
shell and core have a continuous cavity therein defining an
interior surface, wherein neither the first shell portion nor the
second shell portion extend substantially upon the interior
surface.
31. The dosage form of claim 30, in which at least one of the first
or second core portions comprises at least one active
ingredient.
32. The dosage form of claim 30, in which the first core portion
comprises a first active ingredient and the second core portion
comprises a second active ingredient which may be the same or
different than the first active ingredient.
33. The dosage form of claims 28 or 30, in which the core erodes
upon contacting of the interior surface with a liquid medium.
34. The dosage form of claims 28 or 30, in which the diameter of
the continuous cavity is in the range of about 15 to about 90
percent of the thickness of the dosage form.
35. The dosage form of any of claims 1, 11, 25, 28 or 30, wherein
the providing of at least one active ingredient follows
substantially zero-order kinetics over a specified time
interval.
36. The dosage form of any of claims 1, 11, 25, 28 or 30, wherein
the providing of at least one active ingredient follows
square-root-of-time kinetics over a specified time interval.
37. The dosage form of any of claims 1, 11, 25, 28 or 30, wherein
the providing of at least one active ingredient follows
substantially first-order kinetics over a specified time
interval.
38. The dosage form of any of claims 9, 22, 25 or 30, wherein at
least one of the first or second core portions functions as an
eroding matrix.
39. The dosage form of claim 38, wherein the eroding matrix core
portion comprises a release-modifying compressible or moldable
excipient selected from swellable erodible hydrophilic agents,
pH-dependent polymers, and combinations thereof.
40. The dosage form of any of claims 1, 11, 25, 28 or 30, in which
the release rate of at least one active ingredient is
non-constant.
41. The dosage form of any of claims 1, 11, 25, 28 or 30, in which
the release of at least one dose of at least one active ingredient
is a burst release.
42. The dosage form of any of claims 1, 11, 25, 28 or 30, in which
the release rate of at least one active ingredient is an ascending
release rate.
43. The dosage form of any of claim 1, 11, 25, 28, or 30, which
provides an ascending blood level PK profile for at least one
active ingredient after administration to a mammal.
44. The dosage form of any of claims 1, 11, 25, 28 or 30, in which
the shell contains greater than 90 mg of at least one active
ingredient.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of PCT Application Nos.
PCT/IUS02/31129, filed Sep. 28, 2002; PCT/US02/31117, filed Sep.
28, 2002; PCT/US02/31062, filed Sep. 28, 2002; PCT/US02/31024,
filed Sep. 28, 2002; and PCT/US02/31163, filed Sep. 28, 2002, which
are each continuations-in-part of U.S. Ser. No. 09/966,939, filed
Sep. 28, 2001; U.S. Ser. No. 09/966,509, filed Sep. 28, 2001; U.S.
Ser. No. 09/966,497, filed Sep. 28, 2001; U.S. Ser. No. 09/967,414,
filed Sep. 28, 2001; and U.S. Ser. No. 09/966,450, filed September
28, the disclosures of all of the above being incorporated herein
by reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] This invention relates to modified release dosage forms such
as modified release pharmaceutical compositions, and methods of
providing predetermined active ingredient concentrations, which may
be substantially constant or substantially non-constant, over an
extended period of time, using such dosage forms. More
particularly, this invention relates to modified release dosage
forms for delivering one or more active ingredients in a controlled
or delayed manner upon contacting of the dosage form with a liquid
medium. The dosage form contains at least one active ingredient,
and has a core and a shell. At least a portion of the shell is
semipermeable to a liquid medium such as the gastro-intestinal (GI)
fluids of a patient, such that the liquid medium diffuses through
the semipermeable shell or shell portion to the core, for example
due to osmosis. The shell or shell portion also provides for
delivery of active ingredient to the liquid medium outside of the
dosage form after the dosage form is contacted with the liquid
medium.
[0004] 2. Background Information
[0005] 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 GI fluids of
a patient, especially to slow the release to provide prolonged
action of the drug in the body.
[0006] 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 GI mucosa. To be absorbed into the circulatory system
(blood), the drug must first be dissolved in the GI fluids. For
many drugs, diffusion across the GI 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.
[0007] 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.
[0008] 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.
[0009] Another particularly desirable PK profile is an "ascending
blood level" profile. This is achieved when the rate of absortion
of drug into the blood (circulation) exceeds its rate of
elimination from the blood for a period of time, producing an
increasing blood level ofer the course of the dosing interval or a
portion thereof. This type of PK profile is exemplified in PCT
Publication No. WO99/62946.
[0010] Another particularly desirable PK profile is achieved by a
dosage form that delivers a delayed release dissolution profile, in
which the release of one or more doses of drug from the dosage form
is delayed for a pre-determined time after contact with a liquid
medium, e.g. 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").
[0011] One particularly desirable type of delayed release PK
profile, is a "pulsatile" profile, in which for example, a first
dose of a first drug is delivered, followed by a delay period
during which there is substantially no release of the first drug
from the dosage form, followed by either prompt or sustained
release of a subsequent dose of the same drug. In one particularly
desirable type of pulsatile drug delivery system, the first dose is
released essentially immediately upon contacting of the dosage form
with a liquid medium. In another particularly desirable type of
pulsatile drug delivery system, the delay period corresponds
approximately to the time during which a therapeutic concentration
of the first dose is maintained in the blood. Pulsatile delivery
systems are particularly useful for applications where a continuous
release of drug is not ideal. Examples of this are drugs exhibiting
first pass metabolism by the liver, drugs that induce biological
tolerance (i.e. the therapeutic effect decreases with continuous
presence of the drug at the site of action), and drugs whose
efficacy is influenced by circadian rhythms of body functions or
diseases.
[0012] 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.
[0013] 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.
[0014] 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 (AC) of the
drug across the membrane, the partition coefficient (K) of the drug
into the membrane, and the diffusion coefficient (D) according to
the following equation:
dM/dt={ADK.DELTA.C}/1
[0015] 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.
[0016] Another common type of diffusion-controlled release system
comprises active ingredient, distributed throughout an insoluble
porous matrix through which the active ingredient must diffuse 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 according to the following equation:
M=A(DE/T(2Cp-ECs)(Cs)t).sup.1/2
[0017] 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.
[0018] 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 according to the following equation:
dM/dt=A{dx/dt}{f(C)}
[0019] 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.
[0020] 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 according to the following equation:
T.sub.1=h(dx/dt)
[0021] 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)
[0022] where dM/dt is generally described by either the
diffusion-controlled or erosion-controlled equations above, and
T.sub.1 is the lag time.
[0023] 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.
[0024] In various embodiments of this invention, the modified
release dosage forms of this invention act as osmotically
controlled drug delivery systems. As discussed, for example, in
Verma et al., "Osmotically Controlled Oral Drug Delivery," Drug
Development and Industrial Pharmacy, 26(7), pp. 695-708 (2000),
osmotically controlled drug delivery systems offer a number of
advantages over conventional controlled release delivery systems.
The basic principle of operation of osmotic drug delivery systems
employs the difference in osmotic pressure between the exterior and
interior of a dosage form which contains active ingredient. For
example, as discussed by Verna et al., in an elementary osmotic
pump (EOP) system, an active ingredient, together with a suitable
osmotic solute is contained within a core such as a compressed
tablet, which is coated at least in part with a semipermeable
membrane or shell having a small orifice therein. When this dosage
form contacts a liquid medium such as the aqueous environment of
the GI tract, the active ingredient draws liquid through the
semipermeable membrane due to the osmotic pressure gradient and
forms a saturated solution of active ingredient within the dosage
form. Hydrostatic pressure thus develops within the dosage form,
and is relieved by the flow of saturated solution through the
orifice and out of the dosage form, thereby delivering the active
ingredient to the patient until the pressures inside and outside
the dosage form are equal. Such a system is exemplified in U.S.
Pat. No. 3,845,770, which discloses (see FIG. 1 of U.S. Pat. No.
3,845,770) a device having a semipermeable wall which surrounds a
compartment containing active ingredient. A passageway communicates
with the compartment and the exterior of the device. Fluid
permeates the wall into the compartment and produces a solution of
active ingredient which is released through the passageway.
[0025] Various improvements have also been made in the design of
osmotic drug delivery systems. For example, U.S. Pat. No. 3,995,631
discloses a system in which a semipermeable membrane houses a
solution of an osmotically effective solute and a flexible bag of
relatively impervious material which contains active ingredient.
The flexible bag is provided with dispensing means for dispensing
active ingredient out of the flexible bag when liquid permeates the
membrane and exerts mechanical compressing or deflating force on
the bag.
[0026] U.S. Pat. No. 4,111,202 discloses a dosage form having a
semipermeable wall which surrounds an active ingredient compartment
and an osmagent compartment. The two compartments are separated by
a moveable film which is impermeable to the active ingredient and
osmagent. The semipermeable wall has a passageway therethrough for
delivering active ingredient from its compartment. The system
operates by having fluid imbibe through the wall into the osmagent
compartment and causing the osmagent compartment to expand in
volume and move the film, thereby diminishing the volume of the
active ingredient compartment and delivering the active ingredient
through the passageway.
[0027] U.S. Pat. No. 4,327,725 discloses a system having a
semipermeable outer wall which contains an active agent compartment
and a fluid swellable hydrogel compartment. The semipermeable wall
has a passageway therethrough for delivering active ingredient in
solution from its compartment when the hydrogel absorbs fluid
passing through the outer wall and the hydrogel swells. A
precipitate forms at the interface of the hydrogel and active
ingredient to restrict the passage of active ingredient into the
hydrogel, and to act as an in situ formed membrane to apply
pressure against the active ingredient in solution.
[0028] U.S. Pat. No. 4,449,983 discloses a system in which a
semipermeable wall contains first and second compartments which
each contain a different active ingredient. Each of the
compartments has an orifice which permits delivery of the active
ingredient from each compartment, and the two compartments are
separated by a hydrogel partition. The hydrogel absorbs fluid and
swells, causing delivery of a solution of active ingredient through
the respective compartment orifices.
[0029] U.S. Pat. No. 4,627,971 discloses a device in which a
semipermeable wall which surrounds a compartment containing a first
layer containing an active ingredient and a second layer containing
a hydrogel and means for sealing or closing a passageway by forming
a film under the influence of thermo laser energy. A first
passageway permits delivery of the active ingredient out of the
compartment, and a second passageway formed during the manufacture
of the device is adjacent to the hydrogel layer. Upon exposure of
the means to thermo laser energy, a film is formed and the second
passageway is sealed. The hydrogel absorbs fluid and swells,
causing delivery of a solution of active ingredient through the
first passageway.
[0030] U.S. Pat. No. 5,830,501 discloses a dosage form having a
semipermeable wall which surrounds an internal compartment. The
semipermeable wall contains at least one exit means such as a
passageway, and the internal compartment contains an active
ingredient, a flocculating hydrophilic polymer, a dehydrating
agent, a surfactant, a swellable hydrophilic polymer, a lubricant,
and an osmagent. When the dosage form is in a biological
environment of use, the flocculating polymer precipitates and forms
a floc containing the active ingredient. When fluid permeates the
semipermeable wall, the swellable polymer and osmagent act as a
push member to deliver the floc through the exit means. The floe
lessens the tackiness and/or irritation of the mucosal tissue of
the patient.
[0031] U.S. Pat. No. 6,342,249 discloses a dosage form having a
semipermeable wall with an exit orifice, in which the wall defines
a cavity containing an active ingredient layer adjacent to the
orifice and an expandable "push" layer remote from the orifice. The
active ingredient layer contains a liquid active ingredient
formulation absorbed in porous particles. A placebo layer to delay
onset of delivery of the active ingredient may optionally be placed
between the active ingredient layer and the exit orifice. When
fluid permeates the semipermeable wall, the push layer expands to
deliver the placebo (if employed) and particles containing active
ingredient through the orifice.
[0032] European Patent Publication No. 0384642 discloses a device
for releasing active ingredient in a pulsed manner. The device
comprises a water permeable or impermeable capsule containing an
active ingredient and a water swellable material, in which the
capsule has an opening which is closed by a water permeable plug.
When fluid permeates into the capsule, the water swellable material
expands to eject the plug and deliver the active ingredient through
the opening. If the flux of liquid through the plug is sufficient
to achieve the desired pulsed release of active ingredient, the
capsule may be made of a water impermeable material.
[0033] The modified release dosage forms of this invention employ a
core and a shell, which may optionally comprise multiple portions
having different compositions and/or functions. The dosage forms of
this invention are prepared by a novel method which enables at
least portion of the shell to be semipermeable. In contrast,
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 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
viscosity 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.
[0034] It is one object of this invention to provide a modified
release 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. It is one
feature of the dosage form of this invention that it has a
semipermeable shell or shell portion. It is another feature of this
invention that the semipermeable shell or shell portion allows the
liquid medium to diffuse through the shell or shell portion to the
core, for example due to osmosis and permeate into the core. It is
another feature of this invention that the shell provides for
delivery of liquid medium carrying active ingredient out of the
dosage form. 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
[0035] The invention provides a dosage form comprising (a) at least
one active ingredient; (b) a core having an outer surface having an
outer surface; and (c) a shell which resides upon at least a
portion of the core outer surface, wherein at least a portion of
the shell is semipermeable, at least about 30% of the
cross-sectional area of the semipermeable shell portion is
non-striated, and the shell comprises means for providing the
active ingredient to a liquid medium outside the shell after
contacting of the dosage form with the liquid medium.
[0036] The invention also provides a dosage from comprising (a) at
least one active ingredient; (b) a core having an outer surface;
and (c) a shell which resides upon at least a portion of the core
outer surface, wherein the shell comprises a first shell portion
which is semipermeable to the liquid medium, and a second shell
portion which is compositionally different than the first shell
portion, the first and second shell portions each are substantially
in contact with the core outer surface, and the shell comprises
means for providing the active ingredient to a liquid medium
outside the shell after contacting of the dosage form with the
liquid medium.
[0037] The invention further provides a dosage form comprising: (a)
at least one active ingredient; (b) a core having an outer surface,
a first core portion, a second core portion, and a third core
portion located between the first and second core portions, wherein
the third core portion comprises an osmopolymer; (c) and a shell
which resides upon at least a portion of the core outer surface, in
which the shell comprises a first shell portion which is
semipermeable to the liquid medium, and a second shell portion
which is compositionally different than the first shell portion,
the first and second shell portions each are substantially in
contact with the core outer surface, and at least one of the first
or second shell portions has at least one passageway therein
extending to the core outer surface.
[0038] The invention also provides a dosage form comprising (a) at
least one active ingredient; (b) a core having an outer surface;
(c) and a shell which resides upon at least a portion of the core
outer surface, in which the shell comprises a first shell portion
which is semipermeable to the liquid medium, and a second shell
portion which is compositionally different than the first shell
portion, the first and second shell portions each are substantially
in contact with the core outer surface, and the shell and core have
a continuous cavity therein defining an interior surface, wherein
neither the first shell portion nor the second shell portion extend
substantially upon the interior surface.
[0039] The invention further provides a dosage form comprising: (a)
at least one active ingredient; (b) a core having an outer surface,
a first core portion, a second core portion, and a third core
portion located between the first and second core portions, wherein
the third core portion comprises a osmopolymer; and (c) a shell
which resides upon at least a portion of the core outer surface, in
which the shell comprises a first shell portion which is
semipermeable to the liquid medium, and a second shell portion
which is compositionally different than the first shell portion,
the first and second shell portions each are substantially in
contact with the core outer surface, and the shell and core have a
continuous cavity therein defining an interior surface, wherein
neither the first shell portion nor the second shell portion extend
substantially upon the interior surface.
BRIEF DESCRIPTION OF THE DRAWINGS
[0040] FIG. 1A depicts a cross-sectional side view of one
embodiment of the dosage form of this invention.
[0041] FIG. 1B depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0042] FIG. 2 depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0043] FIG. 3 depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0044] FIG. 4 depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0045] FIG. 5 depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0046] FIG. 6 depicts a cross-sectional side view of another
embodiment of the dosage form of this invention.
[0047] FIGS. 7A and 7B depict cross-sectional micrographs of a
prior art coated composition.
[0048] FIGS. 8A and 8B depict cross-sectional micrographs of an
embodiment of this invention.
[0049] FIG. 9 depicts the release profile of active ingredient for
the dosage form of this invention described in Example 1
herein.
DETAILED DESCRIPTION OF THE INVENTION
[0050] 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 include 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 GI
tract of a human.
[0051] The dosage forms of this 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
shell or portion thereof, or a combination of two or more of these
parts of the dosage form.
[0052] 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
[0053] The dosage forms of the present invention are designed to
release substantially all (i.e. at least about 80%, or at least
about 90%, say at least about 95%) of the active ingredient
contained therein, within a specified amount of time. As used
herein, the total amount of time required for substantially all of
the active ingredient(s) to be released from the dosage form shall
be referred to as the "dosing interval." During the dosing
interval, the amount of drug released is typically measured at
several time points.
[0054] As used herein, the term "time interval" shall refer to
periods of time during the dosing interval, over which a periodic
rate of release may be measured. The time interval may be the
entire dosing interval, or a portion thereof.
[0055] As used herein, a drug "release rate" refers to the quantity
of drug released from a dosage form per unit time, e.g., milligrams
of drug released per hour (mg/hr). Drug release rates are
calculated under in vitro dosage form dissolution testing
conditions known in the art. As used herein, a drug release rate
obtained at a specified time "following administration" refers to
the in vitro drug release rate obtained at the specified time
following implementation of an appropriate dissolution test.
[0056] As used herein, a "periodic release rate" refers to the
quantity per unit time of drug released from a dosage form during a
specified periodic interval as determined at the end of that
specified periodic interval, i.e., at each periodic interval when a
determination is made, the quantity per unit time of drug released
represents the periodic release rate during that periodic interval.
For example, the quantity of drug released per hour (h) determined
as the difference in quantity released between t=0 and t=2h divided
by the time interval of 2 hours represents the periodic release
rate during the first two hours following administration, the
quantity of drug released per hour as determined from t=2h to t=4h
represents the periodic release rate from two to four hours
following administration, etc.
[0057] As used herein, a "constant release rate" is obtained over a
given time interval when the periodic release rates determined
during two or more portions of the time interval are substantially
the same, i.e. not more than 6% different. As used herein,
"non-constant release rate" shall mean two or more periodic release
rates are not the same, i.e. more than 6% different, over the
entire duration of the specified interval.
[0058] As used herein, an "ascending release rate" refers to a
periodic release rate that is increased over the immediately
preceding periodic release rate. For example, when the quantity of
drug released from a dosage form is measured at hourly intervals
and the quantity of drug released during the fifth hour following
administration is greater than the quantity of drug released from
the dosage form during the fourth hour following administration, an
ascending release rate from the fourth hour to the fifth hour has
occurred. It will be appreciated that the first periodic release
rate measured, e.g., the periodic release rate at t=1 hour (unless
equal to 0), will always be greater than the release rate during
the preceding period, e.g., the hour before the dosage form was
administered, and thus, the first periodic release rate always
constitutes an occurrence of an ascending release rate.
[0059] As used herein, "ascending blood level" refers to the PK
profile obtained when the rate of release of drug from the dosage
form, and also its absorption into the bloodstream, exceeds its
reate of elimination from the blood of a mammal for a period of
time, producing an increasing blood level ofer the course of the
dosing interval or a portion thereof.
[0060] As used herein, a "burst release" profile refers to a
release profile which meets immediate release criteria during a
specified interval. The specified interval may optionally follow a
pre-determined lag time.
[0061] A first embodiment of this invention is depicted in FIG. 1A,
which is a cross-sectional view of a dosage form 2 which comprises
a core 4 and a shell 5. In other embodiments of this invention,
shell 5 may reside upon a portion of core 4 without surrounding
core 4. In this embodiment of the invention, shell 5 is
semipermeable to a liquid medium, and at least about 30% of the
cross-sectional area of the semipermeable shell 5 is non-striated
as is discussed further herein. Core 4 contains at least one active
ingredient, and shell 5 may optionally contain at least one active
ingredient which may be the same or different than the active
ingredient contained within core 4. In this embodiment of the
invention, shell 5 contains passageway 12 which extends from the
outer surface of shell 5 to the outer surface of core 4, as shown.
In other embodiments of this invention, a plurality of passageways
may be employed. Accordingly, upon contacting of dosage form 2 with
a liquid medium, the liquid medium permeates shell 5, reaches core
4 (where active ingredient, and optionally osmagent or osmopolymer,
are contained), and liquid medium containing active ingredient is
osmotically "pumped" through passageway 12 and out of dosage form 2
into the surrounding liquid medium.
[0062] Another embodiment of this invention is depicted in FIG.
11B, which is a cross-sectional view of a dosage form 22 which
comprises a core 24, a first shell portion 25 and a second shell
portion 26, which in this embodiment surround core 24. In other
embodiments of this invention, first shell portion 25 or second
shell portion 26 may reside upon a portion of core 24 without
surrounding core 24. First shell portion 25 is semipermeable to a
liquid medium and second shell portion 26 is compositionally
different than first shell portion 25. In the embodiment depicted
in FIG. 1B, second shell portion 26 is diffusible. Core 24 contains
at least one active ingredient, and first shell portion 25 and/or
second shell portion 26 may optionally contain at least one active
ingredient which may be the same or different than the active
ingredient contained within core 24. Accordingly, upon contacting
of dosage form 22 with a liquid medium, the liquid medium permeates
first shell portion 25, reaches core 24 (where active ingredient is
contained), and liquid medium containing active ingredient is
osmotically "pumped" through diffusible second shell portion 26 and
out of dosage form 22 into the surrounding liquid medium. In other
embodiments, second shell portion 26 may be erodible, thereby
permitting active ingredient to be released from the core 24 as
second shell portion 26 erodes to expose core 24 to the liquid
medium.
[0063] Another 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 and a shell 206 having a first shell portion
208 which is semipermeable to the liquid medium, and a second shell
portion 210 which is compositionally different than first shell
portion 208. For example, second shell portion 210 may be
diffusible, impermeable or erodible. Core 204 contains at least one
active ingredient, and shell 206 may optionally contain at least
one active ingredient which may be the same or different than the
active ingredient contained within core 204. In this embodiment of
the invention, first shell portion 208 contains passageway 212
which extends from the outer surface of first shell portion 208 to
the outer surface of core 204, as shown. In other embodiments of
this invention, first shell portion 208 may contain a plurality of
passageways. In this embodiment, first shell portion 208 is
semipermeable, and second shell portion 210 is impermeable.
Accordingly, upon contacting of dosage form 202 with a liquid
medium, the liquid medium permeates first shell portion 208,
reaches core 204 (where active ingredient, and optionally osmagent
or osmopolymer are contained), and liquid medium containing active
ingredient is osmotically "pumped" through passageway 212 and out
of dosage form 202 into the surrounding liquid medium. In other
embodiments of this invention (not shown in FIG. 2), second shell
portion 210 may contain at least one passageway which extends from
the outer surface of second shell portion 210 to the outer surface
of core 204, or both first shell portion 208 and second shell
portion 210 may each contain at least one passageway which extends
from the outer surface of first shell portion 208 and second shell
portion 210, respectively, to the outer surface of core 204.
[0064] Another embodiment of this invention is depicted in FIG. 3,
which is a cross-sectional side view of a dosage form 302 which
comprises a core 304 having first core portion 303 and second core
portion 305, and shell 306 having a plurality of passageways 312
therein which extend from the outer surface of shell 306 to the
outer surfaces of first and second core portions 303 and 305. In
other embodiments of this invention, shell 306 may have a single
passageway. Core 304 contains at least one active ingredient, and
shell 306 may optionally contain at least one active ingredient
which may be the same or different than the active ingredient
contained within core 304. At least a portion of shell 306 is
semipermeable to a liquid medium, and at least about 30% of the
cross-sectional area of the semipermeable portion of the shell is
non-striated. Upon contacting of dosage form 302 with a liquid
medium, the liquid medium permeates shell 306, reaches first and
second core portions 303 and 305, respectively, (where active
ingredient or ingredients, and optionally osmagent or osmopolymer
are contained), and liquid medium containing active ingredient or
ingredients is osmotically "pumped" through passageways 312 and out
of dosage form 302 into the surrounding liquid medium. In one
embodiment, first core portion 303 contains a first active
ingredient and second core portion 305 contains a second active
ingredient which may be the same or different than the first active
ingredient. In another preferred embodiment, first and second core
portions 303 and 305 each contain a different dose or concentration
of first and second active ingredients, which may be the same or
different active ingredients. In another embodiment, passageways
312 in shell 306 may expose different surface areas of the
underlying core portions 303 and 305, respectively, thereby
permitting either different release rates for the first and second
active ingredients, or the same release rate for the first and
second active ingredients, if the first and second active
ingredients have different solubilities.
[0065] Another embodiment of this invention is depicted in FIG. 4,
which is a cross-sectional side view of a dosage form 402 which
comprises a core 404 having first core portion 403, second core
portion 405, and third core portion 407, and shell 406 comprising
first and second shell portions 408 and 410, respectively. A
plurality of passageways 412 extend from the outer surface of shell
406 to the outer surfaces of first and second core portions 403 and
405. In other embodiments of this invention, shell 406 may have a
single passageway located in either first shell portion 408 or
second shell portion 410. In this embodiment, first shell portion
408 and second shell portion 410 are each semipermeable to a liquid
medium. Second shell portion 410 may be compositionally different
than first shell portion 408. For example, in other embodiments
first shell portion 408 may be semipermeable, and second shell
portion 410 may be diffusible, impermeable or erodible. Core 404
contains at least one active ingredient, and shell 406 may
optionally contain at least one active ingredient which may be the
same or different than the active ingredient contained within core
404. In the embodiment depicted in FIG. 4, first core portion 403
contains a first active ingredient, second core portion 405
contains a second active ingredient which may be the same or
different than the first active ingredient, and third core portion
407 contains an osmopolymer which provides osmotic pressure upon
contact with the liquid medium to push the active ingredients
through the passageways 412 to the surface of shell 406. In the
embodiment depicted in FIG. 4, upon contacting of dosage form 402
with a liquid medium, the liquid medium permeates the first and
second shell portions 408 and 410, reaches first and second core
portions 403 and 405, respectively (where active ingredient or
ingredients are contained), as well as third core portion 407
containing the osmopolymer (which swells and compresses against
first and second core portions 403 and 405), and liquid medium
containing active ingredient is osmotically "pumped" through
passageways 412 and out of dosage form 402 into the surrounding
liquid medium. In addition, passageways 412 in first and second
shell portions 408 and 410 may expose different surface areas of
the underlying core portions 403 and 405, respectively, thereby
permitting either different release rates for the first and second
active ingredients, or the same release rate for the first and
second active ingredients, if the first and second active
ingredients have different solubilities.
[0066] Another embodiment of this invention is depicted in FIG. 5,
which is a cross-sectional side view of a dosage form 502 which
comprises a core 504 and a shell 506 having a first shell portion
508 which is semipermeable to the liquid medium, and a second shell
portion 510 which is compositionally different than first shell
portion 508. For example, second shell portion 510 may be
semipermeable, diffusible, impermeable or erodible, although in
this embodiment second shell portion 510 is semipermeable. Core 504
contains at least one active ingredient, and shell 506 may
optionally contain at least one active ingredient which may be the
same or different than the active ingredient contained within core
504. As depicted in FIG. 5, cavity 501 extends through core 504,
first shell portion 508 and second shell portion 510. The interior
surface 513 of core 504 is defined by cavity 501, and neither first
shell portion 508 nor second shell portion 510 substantially extend
upon interior surface 513, thereby permitting active ingredient
contained within core 504 to be released only through interior
surface 513. The diameter of the continuous cavity is preferably in
the range of about 15 to about 90 percent of the thickness of the
dosage form, and the diameter of the continuous cavity is
preferably in the range of about 5 to about 30 percent of the core
diameter. The length of the continuous cavity is typically about
the same as the thickness of the dosage form, and the length of the
continuous cavity is preferably about 25 to about 40 percent of the
diameter of the dosage form. Upon contacting of dosage form 502
with a liquid medium, the liquid medium permeates interior surface
513, as well as first and second shell portions 508 and 510,
reaches core 504 (where active ingredient is contained), and liquid
medium containing active ingredient passes through interior surface
513 into central cavity 501 and out of dosage form 502 into the
surrounding liquid medium. In this embodiment, the predominant
mechanism for drug release is erosion.
[0067] Another embodiment of this invention is depicted in FIG. 6,
which is a cross-sectional side view of a dosage form 602 which
comprises a core 604 having first core portion 603, second core
portion 605, and third core portion 607, and a shell 606 having a
first shell portion 608 which is semipermeable to the liquid
medium, and a second shell portion 610 which is compositionally
different than first shell portion 608. For example, second shell
portion 610 may be semipermeable, diffusible, impermeable or
erodible, although in this embodiment second shell portion 610 is
semipermeable. Core 604 contains at least one active ingredient,
and shell 606 may optionally contain at least one active ingredient
which may be the same or different than the active ingredient
contained within core 604. As depicted in FIG. 6, cavity 601
extends through core 604, first shell portion 608 and second shell
portion 610. The interior surface 613 of core 604 is defined by
cavity 601, and neither first shell portion 608 nor second shell
portion 610 substantially extend upon interior surface 613, thereby
permitting active ingredient contained within core 604 to be
released only through interior surface 613. In one embodiment,
first core portion 603 contains a first active ingredient, second
core portion 605 contains a second active ingredient which may be
the same or different than the first active ingredient, and third
core portion 607 contains a osmopolymer which provides osmotic
pressure upon contact with the liquid medium to push the active
ingredients through the interior surface 613 and into the liquid
medium. The diameter of the continuous cavity is preferably in the
range of about 15 to about 90 percent of the thickness of the
dosage form, and the diameter of the continuous cavity is
preferably in the range of about 5 to about 30 percent of the core
diameter. The length of the continuous cavity is typically about
the same as the thickness of the dosage form, and the length of the
continuous cavity is preferably about 25 to about 40 percent of the
diameter of the dosage form. Upon contacting of dosage form 602
with the liquid medium, the liquid medium permeates interior
surface 613, as well as the first and second shell portions 608 and
610, respectively, reaches first core portion and second core
portions 603 and 605, respectively, (where active ingredient or
ingredients are contained) as well as third core portion 607
containing the osmopolymer (which swells and compresses against
first core portion 603 and second core portion 605), and liquid
medium containing the active ingredient or ingredients passes
through interior surface 613 into central cavity 601 and out of
dosage form 602 into the surrounding liquid medium. In this
embodiment, the predominant mechanism for drug release is
erosion.
[0068] In embodiments of this invention in which the shell
comprises at least two shell portions, the inner surface of each
shell portion must be substantially in contact with the outer
surface of the core, as depicted, for example, in FIGS. 1B, 2, 4, 5
and 6. Accordingly, in such embodiments, the inner surface of any
shell portion does not reside upon the outer surface of any other
shell portion.
[0069] 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.
[0070] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0071] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0072] 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.
[0073] 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.
[0074] 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.
mefenamic 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 one particular 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 another 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.
[0075] 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.
[0076] 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.
[0077] The active ingredient is 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 about 2 to about 75 weight percent, for
example, the dosage form may comprise about 5 to about 50 weight
percent, say about 7 to about 25 weight percent of a combination of
one or more active ingredients. In one embodiment, the core
comprises a total of at least about 25 weight percent, e.g. about
25 to about 75 weight percent (based on the weight of the core) of
one or more active ingredients.
[0078] The active ingredient 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
embodiment, such particles are crystals having an average particle
size of about 1-300 microns. In another embodiment, the particles
ate granules or pellets having an average particle size of about
50-2000 microns, preferably about 50-1000 microns, most preferably
about 100-800 microns.
[0079] 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.
[0080] 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 one or more active ingredients are
modified: e.g. controlled, sustained, extended, retarded,
prolonged, delayed and the like. In one embodiment in which one or
more active ingredients are released in a modified manner, the
modified release active ingredient or ingredients are contained in
the core. In one particular such embodiment, the dosage form
releases one or more active ingredients contained in the core at a
substantially constant rate over a specified time interval.
[0081] 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.
[0082] In certain embodiments, the core or 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 or 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 or
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.
[0083] In certain other embodiments, the core or 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 or 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 or 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 embodiments in which a core or core portion functions as a
diffusional matrix, the release of the active ingredient from the
core or 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
or core portion preferably comprises a pore former.
[0084] In embodiments in which the core or 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 the surrounding shell or 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 or core
portion and shell or 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.
[0085] 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.
[0086] In certain 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 the
shell or 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 or 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.
[0087] The core or core portion 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 core).
[0088] 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.
[0089] 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 soluble
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.
[0090] 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.
[0091] 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.
[0092] 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.
[0093] Suitable glidants for making the core, or a portion thereof,
by compression, include colloidal silicon dioxide, and the
like.
[0094] 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.
[0095] 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 derivatives, 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
glycols 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-molecular 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.
[0096] 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, GLYCOWAX-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.
[0097] 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.
[0098] 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
[0099] In one embodiment, the core or a portion thereof comprises
at least one osmagent, an osmotically effective solute or
osmotically effective compound that can be blended homogeneously or
heterogeneously with the core constituents to form a push member,
acting as osmotically effective solutes that are soluble in liquid
medium imbibed into the core, and exhibit an osmotic pressure
gradient across the semipermeable shell or shell portion against an
exterior liquid medium. Osmagents useful in the present invention
include compounds disclosed at col. 8, lines 18-35 of U.S. Pat. No.
5,830,501, which is incorporated herein by reference.
[0100] In another embodiment, the core or a portion thereof
comprises at least one osmopolymer. The osmopolymer, if employed,
exhibits fluid absorbing and or fluid imbibing properties. The
osmopolymer comprises a hydrophilic polymer that can interact with
water and aqueous biological fluids and then swell or expand to an
equilibrium state. The osmopolymer exhibits the ability to retain a
significant portion of the imbibed or absorbed fluid. Other
osmopolymers include poly(hydroxyalkyl methacrylate) having a
molecular weight of 20,000 to 5,000,000; poly(vinylpyrrolidone)
having a molecular weight of about 10,000 to 360,000;
poly(vinylalcohol) having a low acetate content and lightly
cross-linked with glyoxal, formaldehyde, or glutaraidehyde and
having a degree of polymerization from 2,000 to 30,000;
poly(ethylene oxide) having a molecular weight from 10,000 to
7,800,000; acidic carboxy polymers known as carboxypolymethylene or
as carboxyvinyl polymers, a polymer consisting of acrylic acid
lightly cross-linked with polyallylsucrose and sold under the trade
name CARBOPOL, acidic carboxy polymer having a molecular weight of
200,000 to 6,000,000, including sodium acidic carboxyvinyl hydrogel
and potassium acidic carboxyvinyl hydrogel; CYANAMER
polyacrylamide; and the like. Representative polymers, used for the
purpose of the present invention, are known to those skilled in the
art and described, for example, in Scott & Roff, Handbook of
Common Polymers (published by the Chemical Company Cleveland,
Ohio); Ratner & Hoffman, ACS Symposium Series, No.31, pp.1 to
36, (1976) (published by the American Chemical Society); and
Schact, Recent Advances in Drug Delivery Systems, pp. 259 to 278
(published by Plenum Press, N.Y.).
[0101] In embodiments in which the core or core portion is prepared
by compression, a dry blending (i.e. direct compression), or wet
granulation process may be employed. In a dry blending (direct
compression) method, the active ingredient or ingredients, together
with the excipients, are blended in a suitable blender, than
transferred directly to a compression machine for pressing into
tablets. In a wet granulation method, the active ingredient or
ingredients, appropriate excipients, and a solution or dispersion
of a wet binder (e.g. an aqueous cooked starch paste, or solution
of polyvinyl pyrrolidone) are mixed and granulated. Alternatively a
dry binder may be included among the excipients, and the mixture
may be granulated with water or other suitable solvent. Suitable
equipment for wet granulation are known in the art, including low
shear, e.g. planetary mixers; high shear mixers; and fluid beds,
including rotary fluid beds. The resulting granulated material is
dried, and optionally dry-blended with further ingredients, e.g.
adjuvants and/or excipients such as for example lubricants,
colorants, and the like. The final dry blend is then suitable for
compression. Methods for direct compression and wet granulation
processes are known in the art, and are described in detail in, for
example, Lachman, et al., The Theory and Practice of Industrial
Pharmacy, Chapter 11 (3rd ed. 1986).
[0102] The dry-blended, or wet granulated, powder mixture is
typically compacted into tablets using a rotary compression machine
as known in the art, such as for example those commercially
available from Fette America Inc. (Rockaway, N.J.), or Manesty
Machines LTD (Liverpool, UK). In a rotary compression machine, a
metered volume of powder is filled into a die cavity, which rotates
as part of a "die table" from the filling position to a compaction
position where the powder is compacted between an upper and a lower
punch to an ejection position, where the resulting tablet is pushed
from the die cavity by the lower punch and guided to an ejection
chute by a stationary "take-off" bar.
[0103] In one particular optional embodiment, the core or core
portion may be 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.
[0104] In certain preferred embodiments of this invention, the
core, or the shell, or a portion thereof, is prepared by molding.
In particular, the core, the shell or a portion of either one may
be made by solvent-based or solvent-free molding. In such
embodiments, the core, or the shell, or a portion thereof, is made
from a flowable material optionally comprising an active
ingredient. 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 dispersed, 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.
[0105] In one embodiment, solvent-based or solvent-free molding is
performed via thermal setting molding using the 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, a core, shell, or portion
thereof is formed by injecting flowable form into a molding
chamber. The flowable material preferably comprises a thermal
setting material at a temperature above its melting point but below
the decomposition temperature of any active ingredient contained
therein. The flowable material is cooled and solidifies in the
molding chamber into a shaped form (i.e., having the shape of the
mold).
[0106] According to this method, the flowable material may comprise
solid particles suspended in a molten matrix, for example a polymer
matrix. The flowable material may be completely molten or in the
form of a paste. The flowable material may comprise an active
ingredient dissolved in a molten material in the case of
solvent-based molding. Alternatively, the flowable material may be
made by dissolving a solid in a solvent, which solvent is then
evaporated after the molding step in the case of solvent-based
molding.
[0107] In another embodiment, solvent-based or solvent-free molding
is performed by thermal cycle molding using the method and
apparatus described in copending U.S. patent application Ser. No.
09/966,497, pages 27-51, the disclosure of which is incorporated
herein by reference. Thermal cycle molding is performed by
injecting a flowable material into a heated molding chamber. The
flowable material may comprise active ingredient and a
thermoplastic material at a temperature above the set temperature
of the thermoplastic material but below the decomposition
temperature of active ingredient. The flowable material is cooled
and solidifies in the molding chamber into a shaped form (i.e.,
having the shape of the mold).
[0108] 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. 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 the temperature control system 600.
[0109] The mold units may comprise center mold assemblies 212,
upper mold assemblies 214, and lower mold assemblies 210, as shown
in FIGS. 26-28, which mate to form mold cavities having a desired
shape, for instance of a core or a shell surrounding a core. As
rotor 202 rotates, opposing center and upper mold assemblies or
opposing center and lower mold assemblies close. Flowable material,
which is heated to a flowable state in reservoir 206, is injected
into the resulting mold cavities. The temperature of the flowable
material is then decreased, hardening the flowable material. The
mold assemblies open and eject the finished product.
[0110] In a particularly preferred embodiment of the invention, the
shell is applied to the dosage form using a thermal cycle molding
apparatus of the general type shown in FIGS. 28A-C of copending
U.S. application Ser. No. 09/966,497 comprising rotatable center
mold assemblies 212, lower mold assemblies 210 and upper mold
assemblies 214. Cores are continuously fed to the mold assemblies.
Shell flowable material, which is heated to a flowable state in
reservoir 206, is injected into the mold cavities created by the
closed mold assemblies holding the cores. The temperature of the
shell flowable material is then decreased, hardening it around the
cores. The mold assemblies open and eject the finished dosage
forms. Shell coating is performed in two steps, each half of the
dosage forms being coated separately as shown in the flow diagram
of FIG. 28B of copending U.S. application Ser. No. 09/966,939 via
rotation of the center mold assembly.
[0111] A preferred method for making the shell or a shell portion
by solvent-based molding comprises: (a) preparing a flowable
dispersion of the film former, release-modifying excipient, and
other shell materials in a suitable solvent, e.g. water, organic
solvents such as alcohols or acetone, or combinations of water and
organic solvents, such as acetone; (b) injecting the flowable
dispersion (which may be heated in a heated feed tank) into a mold
cavity (at room temp or below) containing a core such that the
flowable dispersion surrounds a first portion of the core within
the mold cavity; (c) rapidly changing the temperature of the mold
cavity to induce thermal setting of the flowable dispersion around
at first portion of the core; (d) opening the mold cavity and
rotating the portion of the mold containing the core to expose a
second portion of the core; (e) closing the mold cavity; (f)
injecting heated, flowable dispersion into the mold cavity such
that the flowable dispersion surrounds the second portion of the
core within the mold cavity; (g) rapidly changing the temperature
of the mold cavity to induce thermal setting of the flowable
dispersion surrounding the second portion of the core; (h) removing
the coated core from the mold cavity; and (i) drying the coated
core to remove residual solvent. The mold may be optionally heated
to remove solvent, then cooled to set the shell materials. This is
preferred if organic solvents are used, but is not required if the
solvent used is water.
[0112] A preferred method for making the shell or a shell portion
by solvent-free molding comprises: (a) melting a thermal reversible
carrier, adding and mixing a release-modifying excipient and any
other desired ingredients for the shell into the thermal reversible
carrier to form a flowable shell material; (b) injecting the
flowable shell material (which is heated in a heated feed tank)
into a mold cavity (heated to allow the flowable shell material to
flow) containing a core such that the flowable shell material
surrounds a first portion of the core within the mold cavity; (c)
rapidly lowering the temperature of the mold cavity to induce
thermal setting of the flowable shell material surrounding the
first portion of the core; (d) opening the mold cavity and rotating
the portion of the mold containing the core to expose a second
portion of the core; (e) closing the mold cavity; (f) injecting
heated, flowable shell material into the mold cavity (also heated)
such that the flowable shell material surrounds the second portion
of the core within the mold cavity; (g) rapidly lowering the
temperature of the mold cavity to induce thermal setting of the
flowable shell material surrounding the second portion of the core;
(h) removing the coated core from the mold cavity. The mold may be
optionally rapidly heated or cooled to facilitate removal of dosage
form.
[0113] In one embodiment, the compression module of copending U.S.
patent application Ser. No. 09/966,509, pp. 16-27 may be employed
to make cores. The shell may be made applied to these cores using a
thermal cycle molding module as described above. A transfer device
as described in U.S. patent application Ser. No. 09/966,414, pp.
51-57, the disclosure of which is incorporated herein by reference,
may be used to transfer the cores from the compression module to
the thermal cycle molding module. Such a transfer device may have
the structure shown as 300 in FIG. 3 of copending U.S. application
Ser. No. 09/966,939. It comprises a plurality of transfer units 304
attached in cantilever fashion to a belt 312 as shown in FIGS. 68
and 69 of copending U.S. application Ser. No. 09/966,939. The
transfer device rotates and operates in sync with the compression
module and the thermal cycle molding module to which it is coupled.
Transfer units 304 comprise retainers 330 for holding cores as they
travel around the transfer device.
[0114] Suitable materials for use in or as the flowable material
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. Suitable dispersed components include
insoluble edible materials.
[0115] 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
derivatives, thermoplastic vinyl polymers, thermoplastic starches,
thermoplastic 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 water insoluble
cellulose derivatives 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.
[0116] 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.
[0117] 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.
[0118] 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.
[0119] 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.
[0120] 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.
[0121] 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.
[0122] One suitable polyvinyl alcohol and polyethylene glycol
copolymer is commercially available from BASF Corporation under the
tradename KOLLICOAT IR.
[0123] 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.
[0124] 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.
[0125] 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.
[0126] 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.
[0127] 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.
[0128] 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.
[0129] 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.
[0130] Suitable xanthan gums include those available from C. P.
Kelco Company under the tradenames KELTROL 1000, XANTROL 180, or
K9B310
[0131] Suitable clays include smectites such as bentonite, kaolin,
and laponite; magnesium trisilicate, magnesium aluminum silicate,
and the like, and derivatives and mixtures thereof.
[0132] "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.
[0133] "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.
[0134] 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,
GLYCOWAX-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.
[0135] 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.
[0136] 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.
[0137] 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.
[0138] 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., 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.
[0139] In certain embodiments in which the core, the shell, or
portions thereof are prepared using solvent-free molding, the core,
shell, or portions thereof 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. Solvent-free molding may be used to obtain
semipermeable, impermeable, or diffusible shells or shell
portions.
[0140] 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 certain 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):
[0141] 1. Shallow Concave.
[0142] 2. Standard Concave.
[0143] 3. Deep Concave.
[0144] 4. Extra Deep Concave.
[0145] 5. Modified Ball Concave.
[0146] 6. Standard Concave Bisect.
[0147] 7. Standard Concave Double Bisect.
[0148] 8. Standard Concave European Bisect.
[0149] 9. Standard Concave Partial Bisect.
[0150] 10. Double Radius.
[0151] 11. Bevel & Concave.
[0152] 12. Flat Plain.
[0153] 13. Flat-Faced-Beveled Edge (F.F.B.E.).
[0154] 14. F.F.B.E. Bisect.
[0155] 15. F.F.B.E. Double Bisect.
[0156] 16. Ring.
[0157] 17. Dimple.
[0158] 18. Ellipse.
[0159] 19. Oval.
[0160] 20. Capsule.
[0161] 21. Rectangle.
[0162] 22. Square.
[0163] 23. Triangle.
[0164] 24. Hexagon.
[0165] 25. Pentagon.
[0166] 26. Octagon.
[0167] 27. Diamond.
[0168] 28. Arrowhead.
[0169] 29. Bullet.
[0170] 30. Shallow Concave.
[0171] 31. Standard Concave.
[0172] 32. Deep Concave.
[0173] 33. Extra Deep Concave.
[0174] 34. Modified Ball Concave.
[0175] 35. Standard Concave Bisect.
[0176] 36. Standard Concave Double Bisect.
[0177] 37. Standard Concave European Bisect.
[0178] 38. Standard Concave Partial Bisect.
[0179] 39. Double Radius.
[0180] 40. Bevel & Concave.
[0181] 41. Flat Plain.
[0182] 42. Flat-Faced-Beveled Edge (F.F.B.E.).
[0183] 43. F.F.B.E. Bisect.
[0184] 44. F.F.B.E. Double Bisect.
[0185] 45. Ring.
[0186] 46. Dimple.
[0187] 47. Ellipse.
[0188] 48. Oval.
[0189] 49. Capsule.
[0190] 50. Rectangle.
[0191] 51. Square.
[0192] 52. Triangle.
[0193] 53. Hexagon.
[0194] 54. Pentagon.
[0195] 55. Octagon.
[0196] 56. Diamond.
[0197] 57. Arrowhead.
[0198] 58. Bullet.
[0199] 59. Barrel.
[0200] 60. Half Moon.
[0201] 61. Shield.
[0202] 62. Heart.
[0203] 63. Almond.
[0204] 64. House/Home Plate.
[0205] 65. Parallelogram.
[0206] 66. Trapezoid.
[0207] 67. FIG. 8/Bar Bell.
[0208] 68. Bow Tie.
[0209] 69. Uneven Triangle.
[0210] 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, such as the thermal cycle molding or thermal setting
molding methods described herein, and mated using various
techniques. 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.
[0211] In another embodiment of this invention, the core comprises
first, second and third portions, each comprising the same or
different active ingredient. In another embodiment, the core
comprises first, second and third portions, and the third portion
(located between the first and second portions) has a higher
concentration of active ingredient, thereby causing a particularly
desired release profile for at least one active ingredient from the
dosage form. In this embodiment, release of at least one active
ingredient from the dosage form may have a substantially constant
release rate, substantially non-constant release rate, or an
ascending release rate. In another embodiment the core comprises
first, second, and third portions, and the third portion (located
between the first and second portions) is substantially free of
active ingredient, and may contain osmagent or osmopolymer, or may
serve as a barrier to the passage of active ingredient between the
first and second core portions.
[0212] 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.
[0213] 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, a thermal-reversible carrier may be
included in the core portion and may function by dissolving and
forming pores or channels through which the active ingredient may
be liberated.
[0214] As described herein, at least a portion of the shell is
semipermeable to a liquid medium. As used herein, the term
"semipermeable" means permeable to the passage of water but not
permeable to the passage of active ingredient therethrough. The
semipermeable shell or shell portion allows water to be absorbed
therethrough and into the core of the dosage form from the
environment, such as the dissolution media or gastro-intestinal
fluids. The semipermeable shell portion functions as a barrier to
the passage of active ingredient from the underlying core portion,
forcing the active ingredient to be released from the dosage form
via a different avenue, such as an orifice or passageway, or
through a diffusible shell portion. The semipermeable shell or
shell portions are non-erodible, and they are insoluble in
fluids.
[0215] In one embodiment of this invention, the semipermeable shell
or shell portion is made using a flowable material. Suitable
dissolved or molten components for the flowable material for
forming the semi-permeable shell or shell portion may include
thermoplastic film-formers selected from cellulose esters,
cellulose ethers, and cellulose ester-ethers. These cellulosic
polymers have a degree of substitution (D.S.) on the anhydroglucose
unit, from greater than 0 up to 3 inclusive. By "degree of
substitution" as used herein it is meant the average number of
hydroxyl groups originally present on the anhydroglucose unit
comprising the cellulose polymer that are replaced by a
substituting group. Representative materials include those selected
from the group consisting of cellulose acylate, cellulose
diacylate, cellulose triacylate, cellulose acetate, cellulose
diacetate, cellulose triacetate, mono-, di-, and tricellulose
alkanylates, nono-, di-, and tricellulose aroylates, and the like.
Exemplary polymers include cellulose acetate having a D.S. up to 1
and an acetyl content up to 21%; cellulose acetate having an acetyl
content of 32 to 39.8%; cellulose acetate having a D.S. of 1 to 2
and an acetyl content of 21 to 35%; cellulose acetate having a D.S.
of 2 to 3 and an acetyl content of 35 to 44.8%, and the like. More
specific cellulosic polymers include cellulose propionate having a
D.S. of 1.8 and a propyl content of 39.2 to 45% and a hydroxyl
content of 2.8 to 5.4%; cellulose acetate butyrate having a D.S. of
1.8, an acetyl content of 13 to 15% and a butyryl content of 34 to
39%; cellulose acetate butyrate having an acetyl content of 2 to
29%, a butyryl content of 17 to 53% and a hydroxyl content of 0.5
to 4.7%; cellulose triacylates having a D.S. of 2.9 to 3, such as
cellulose trivalerate, cellulose trilaurate, cellulose
tripalmitate, cellulose trisuccinate, and cellulose trioctanoate;
cellulose diacylates having a D.S. of 2.2 to 2.6, such as cellulose
disuccinate, cellulose dipalmitate, cellulose dioctanoate,
cellulose dipentanoate, co-esters of cellulose, such as cellulose
acetate butyrate and cellulose acetate propionate.
[0216] Additional polymers useful for manufacturing the
semipermeable shell or shell portion include ethyl cellulose of
various degree of etherification with ethoxy content of from about
40 to 55%, acetaldehyde demethylcellulose acetate, cellulose
acetate ethyl carbamate, cellulose acetate methyl carbamate,
cellulose acetate diethyl aminoacetate, semipermeable polyamides;
semipermeable polyurethanes; semipermeable sulfonated polystyrenes;
semipermeable cross-linked selective polymers formed by the
coprecipitation of a polyanion and a polycation as disclosed in
U.S. Pat. Nos. 3,173,876; 3,276,586; 4,541,005; 3,541,006, and
3,546,142; semipermeable polymers as disclosed in U.S. Pat. No.
3,133,132; semipermeable lightly cross-linked poly(-sodium styrene
sulfonate); semipermeable cross-linked poly(vinylbenzyltrimethyl
ammonium chloride); semipermeable polymers exhibiting a fluid
permeability of 2.5.times.10.sup.-8 to
2.5.times.10.sup.-4(cm.sup.2/hr atm) expressed per atmosphere of
hydrostatic or osmotic pressure difference across the semipermeable
wall. The polymers are known to those skilled in the art, as set
forth in U.S. Pat. Nos. 3,845,770; 3,916,899; and 4,160,020.
[0217] In one embodiment, wherein the semipermeable shell or shell
portion functions to slow or delay the rate of passage of a fluid,
such as water or a biological fluid therethrough, the dissolved or
molten components for the flowable material for forming the
semi-permeable shell or shell portion comprise a polymer exhibiting
a 8,500 to 4,000,000 molecular weight, and is present in the shell
portion at a level from about 15 to about 85 weight percent of the
shell portion. Polymeric materials, which may be used include
non-ionic water-soluble polymers, cellulose ether nonionic with its
solutions unaffected by cations, hydroxyalkylcellulose,
hydroxyalkylalkylcellulose, hydroxypropylcellulose, phenylellulose,
benzylcellulose, nonionic cellulose ester with its solutions
unaffected by cations, benzhydrylcellulose,
hydroxyethyloctylcellulose, diphenylmethylcellulose,
hydroxyethylcellulose, tritylcellulose and polymercompositions that
delay water flux up to 7.0 hours, and more preferably, up to 4.5
hours.
[0218] In one embodiment, at least about 30% of the cross-sectional
area of the semipermeable shell or semipermeable shell portion used
in dosage forms of this invention is non-striated. In other
embodiments, at least about 50% of the cross-sectional area of the
semipermeable shell or semipermeable shell portion is non-striated.
In yet other embodiments, at least about 80% of the cross-sectional
area of the semipermeable shell or semipermeable shell portion is
non-striated. As used herein, "non-striated" means homogeneous with
respect to appearance, and with respect to the internal structure
of the shell or shell portion when viewed under any magnification
and lighting conditions. For example a cross-section of the shell
or shell portion is free of striations, and uniform with respect to
refractive properties when observed utilizing a light microscope at
a magnification of about 50 to about 400 times.
[0219] The costly and lengthy prior art method for building up a
semi-permeable coating on tablets and pharmaceutical dosage forms
by spray-coating techniques gives rise to a characteristic striated
pattern, which is visible in the cross section of such dosage forms
or their semi-permeable coatings (see for example FIGS. 7A and 7B).
These characteristic striations are indicative of the spray-coating
process consisting of multiple repetitions of the steps consisting
of: (a) application via spraying of coating solution; followed by
(b) warm air drying, to a tumbling bed of dosage forms in a
revolving coating pan such that numerous layers of coating material
are built up as each application of coating material dries to form
a layer. The thickness of typical sprayed semi-permeable coatings
is about 60 to about 150 microns. The thickness of an individual
layer is typically in the range of about 10 microns to about 13
microns.
[0220] In contrast, the shell or shell portion of the present
invention may advantageously be applied to a core directly by a
molding process, yielding a uniform and homogeneous layer in 5
minutes or less, e.g. 60 seconds or less, or 30 seconds or less, or
10 seconds or less, and in certain embodiments, say 1 second or
less. As such, at least about 30% of the cross-sectional area of
the shell or shell portion in certain embodiments of the present
invention is non-striated.
[0221] FIGS. 7A and 7B show prior art spray coated compositions
having striations which are thus distinguishable from certain
embodiments of the present invention. FIG. 7A is a micrographic
cross-section (121.times. magnification) of a prior art PROCARDIA
XL tablet (commercially available from Pfizer Labs) and FIG. 7B is
a micrographic cross-section (800.times. magnification) of the same
tablet. This prior art product clearly had striations. In contrast,
FIGS. 8A and 8B show a dosage form of this invention (at 124.times.
and 800.times. magnifications, respectively). As shown, this
embodiment of the invention had no striations.
[0222] The shell or shell portion of the present invention has a
cross-sectional area in the range of about 1 to 900 sq. mm,
preferably about 25 to 600 sq. mm, most preferably about 50 to
about 500 sq. mm.
[0223] In one particular embodiment, the shell comprises two parts
that abut one another, thereby forming a shell that completely
surrounds the core.
[0224] In certain embodiments of this invention, a portion of the
shell contains active ingredient which is released essentially
immediately upon ingestion of the dosage form. In these
embodiments, the shell or shell portion preferably comprises
materials which exhibit rapid dissolution in gastro-intestinal
fluids.
[0225] The shell or shell portion employed in this invention also
provides for delivery of active ingredient from the core or core
portion to the liquid medium outside the dosage form after the
dosage form is contacted with the liquid medium. In one embodiment,
this is accomplished by having at least one aperture or passageway
within the shell or shell portion to permit liquid medium
containing active ingredient within the dosage form to pass through
the shell or shell portion and out of the dosage form. In another
embodiment, the shell comprises a diffusible shell or shell
portion, and active ingredient diffuses therethrough to the liquid
medium outside of the dosage form. In yet another embodiment, the
shell or shell portion has at least a portion which is extremely
thin (e.g. less than about 50 microns), and internal pressure
within the shell or shell portion causes a breach or mechanical
failure of the thin shell portion, thereby delivering active
ingredient from the core to the liquid medium outside of the dosage
form. In yet another embodiment, the shell or shell portion has a
seam, and internal pressure within the shell or shell portion
causes a breach or mechanical failure of the seam, thereby
delivering active ingredient from the core to the liquid medium
outside of the dosage form.
[0226] In certain other embodiments, a portion of the shell
functions as a diffusional membrane which contains pores through
which liquid medium containing active ingredient within the dosage
form can be released through the diffusible shell portion in a
sustained, extended, prolonged or retarded manner. In these
embodiments, the rate of release of active ingredient from the
underlying core or core portion will depend upon the total pore
area in the shell or 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 or core portion
itself). In preferred embodiments in which the shell or 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 shell or
shell portion may follow zero-order, first-order, or square-root of
time kinetics. In certain such embodiments, the diffusional
membrane shell or shell portion preferably 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 or shell portion is prepared by solvent-free molding
using a thermal reversible carrier, the thermal-reversible carrier
may function by dissolving and forming pores or channels through
which the active ingredient may be liberated.
[0227] In certain other embodiments, a portion of the shell
functions as an eroding matrix from which active ingredient
dispersed in the shell portion is liberated by the dissolution of
successive layers of the shell or 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 or 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 or shell portion preferably comprises a swellable
erodible hydrophilic material.
[0228] 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. Typically, this is achieved by having at least one
passageway in the shell or shell portion to permit active
ingredient to reach the liquid medium outside the dosage form. 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 embodiments, the barrier shell portion preferably
comprises a water insoluble material such as for example a water
insoluble polymer.
[0229] In certain other embodiments, the shell or portion thereof
functions 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 or shell portion
preferably comprises a swellable erodible hydrophilic material.
[0230] In embodiments in which the shell or portion thereof
functions to modify the release of an active ingredient which is
contained in the core or the subject shell or shell portion, the
thickness of the shell or 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 the shell or one or
more shell portions function to modify the release of an active
ingredient which is contained in the core or the subject shell or
shell portion, the shell or shell portion is made by the thermal
cycle or thermal setting molding methods and apparatus described
below.
[0231] 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
or shell portion which resides upon at least a portion of the core;
and an outer coating which covers at least a portion of the shell
or shell portion. 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.
[0232] In one embodiment of the present invention, in which the
shell comprises first and second shell portions, 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.
[0233] In embodiments in which the shell or shell portion or
portions are prepared using a solvent-free molding process, the
shell or shell portions will typically comprise at least about 30
percent, e.g. at least about 45 percent by weight of a
thermal-reversible carrier. The shell or shell portion or portions
may optionally further comprise up to about 55 weight percent of a
release-modifying excipient. The shell or 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 or shell portions are prepared by
solvent-free molding, and function to delay the release of one or
more active ingredients from an underlying core or core portion,
the release modifying excipient is preferably selected from
swellable, erodible hydrophilic materials.
[0234] In embodiments in which the shell or shell portion or
portions are prepared using a solvent-based molding process, the
shell or 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 or shell portion or portions may
optionally further comprise up to about 55 weight percent of a
release-modifying excipient. The solvent-molded shell or shell
portion or portions may again also optionally further comprise up
to about 30 weight percent total of various plasticizers,
adjuvants, and excipients.
[0235] In one embodiment of this invention, the shell or 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 or 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.
[0236] Shell or shell portions may be tested for surface gloss
using an instrument available from TriCor Systems Inc. (Elgin, IL)
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.
[0237] 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.
[0238] 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.
[0239] 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.)
[0240] 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:
[0241] Rotation: 0
[0242] Depth: 0.25 inches
[0243] Gloss Threshold: 95
[0244] % Full Scale: 50%
[0245] Index of Refraction: 1.57
[0246] The average surface gloss value for the reference standard
was determined to be 269.
[0247] The total weight of the shell or shell portion or portions
is preferably about 20 percent to about 400 percent of the weight
of the core. In embodiments wherein the shell or shell portion or
portions prepared by a solvent-free molding process, the total
weight of the shell or 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 or shell portion or portions is typically from
about 20 percent to about 100 percent of the weight of the
core.
[0248] Typical shell or shell portion thicknesses which may be
employed in this invention are about 10 to about 1000 microns. In
certain preferred embodiments, the shell or shell portion has a
thickness of less than 800 microns. In embodiments wherein the
shell or shell portion is prepared by a solvent-free molding
process, the shell or 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 or shell portion is
prepared by a solvent-based molding process, the shell or shell
portion typically has a thickness of less than about 800 microns,
e.g. about 20 to about 600 microns, say about 40 to about 200
microns. The semi-permeable shell or shell portion typically has a
thickness from about 20 to about 400 microns, e.g. about 20 to
about 200 microns, say about 40 to about 100 microns.
[0249] In those embodiments in which solvent-free molding is
employed, the flowable material may comprise a thermal-reversible
carrier. Suitable thermal-reversible carriers 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 thermoplastic 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,
GLYCOWAX-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 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 thermal-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.
[0250] 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.
[0251] 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
derivatives, 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 glycols 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-molecular 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.
[0252] Suitable pH-dependent polymers for use as release-modifying
moldable excipients for making the 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.
[0253] 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, GLYCOWAX-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.
[0254] Suitable pore formers for use as release-modifying
excipients for making the molded 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.
[0255] In embodiments in which the shell or portions thereof
comprise an active ingredient intended to have immediate release
from the dosage form, the shell or 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.
[0256] In embodiments in which the shell or shell portion functions
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 or shell portion typically comprises at least
one release modifying agent as described above.
[0257] In embodiments of the invention in which the core or portion
thereof and shell or portion thereof 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.
[0258] 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.
[0259] In one particular embodiment of this invention, at least one
active ingredient contained within the dosage form exhibits a
non-constant release rate.
[0260] In another 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 preferably 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)).
[0261] 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 preferably 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 preferably
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.
[0262] 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 solvent-free molding, the
thermal-reversible carrier may function by dissolving and forming
pores or channels through which the active ingredient may be
liberated.
[0263] In embodiments in which a shell or 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 or shell portion preferably comprises a
release modifying excipient selected from swellable erodible
hydrophilic materials, insoluble edible materials, and combinations
thereof.
[0264] In embodiments in which a shell or 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 or 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.
[0265] In embodiments of the invention in which a shell or 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 or 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 or 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 or shell portion preferably comprises a
release modifying excipient selected from swellable erodible
hydrophilic materials, insoluble edible materials, and combinations
thereof.
[0266] In embodiments in which the shell or portions thereof
contain active ingredient which is released essentially immediately
upon ingestion of the dosage form, the shell or shell portion
preferably comprises materials which exhibit rapid dissolution in
gastro-intestinal fluids. For example the immediate release shell
or 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 or 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.
[0267] In one embodiment of this invention, the shell or portion
thereof additionally comprises at least one active ingredient which
may be the same or different than the active ingredient contained
in the core.
[0268] In embodiments in which the shell or portion thereof confers
sustained, extended, or retarded release of an active ingredient
contained in an underlying core or core portion, the
release-modifying agent in the shell or shell portion preferably
comprises a pore-former, and optionally a film-former. In a
particularly preferred embodiment, the shell or 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. Shells or 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.
[0269] In embodiments in which the shell or portion thereof confers
sustained, extended, or retarded release of an active ingredient
contained in the shell or first or second shell portion, the
release-modifying agent in the shell or 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.
[0270] In embodiments in which the shell or portion thereof confers
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.
The shell or shell portions which confer delayed release can be
prepared by a solvent-free method, or a solvent-based method, as
described above.
[0271] In embodiments in which the shell or portion thereof
provides a barrier to prevent release therethrough of an active
ingredient contained in the underlying core or core portion, the
shell or 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 or 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.
[0272] This invention will be illustrated by the following
examples, which are not meant to limit the invention in any
way.
EXAMPLE 1
[0273] 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.
[0274] The following ingredients were used to make the first core
portion (Osmotic layer):
1 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Polyethylene Oxide Polyox .RTM. WSR 303 Union Carbide 69 128.3 (MW
= 7,000,000) Corporation, Danbury, CT Sodium Chloride Sigma
Chemical Co. 25 46.5 St Louis, MO Hydroxypropyl Methocel E5 Dow
Chemical 5.8 10.8 Methylcellulose Company, Midland, MI Magnesium
Stearate Mallinckrodt Inc., 0.2 0.4 St. Louis, MO FD&C Yellow
#6 Trace Amount Ethanol Anhydrous (dried as solvent)
[0275] Sodium chloride, hydroxypropyl methylcellulose, polyethylene
oxide (PEO) (MW=7,000,000), and FD&C yellow # 6 were mixed in a
plastic bag for 5 minutes. This powder mixture was added into a 5
qt. bowl of a planetary mixer (available from Hobart Corp., Dayton,
Ohio). The alcohol was added to the powder mixture while mixing at
low speed. The ingredients were mixed for 3 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 put into a plastic bag.
Magnesium stearate was added to the dry granules, followed by
mixing for 5 minutes to form the first core portion.
[0276] The following ingredients were used to make the second core
portion:
2 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Pseudoephedrine BASF 15.0 65.1 HCI Crystal PharmaChemikalien GmbH
& Co. Polyethylene Oxide Polyox .RTM. WSR N-750 Union Carbide
75.0 325.5 (MW = 300,000) Corporation, Danbury, CT Hydroxypropyl
Methocel ES Dow Chemical 8.5 36.9 Methylcellulose Company, Midland,
MI Magnesium Stearate Mallinckrodt Inc., 1.5 6.5 St. Louis, MO
Alcohol USP (dried as solvent)
[0277] 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 (available from 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 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.
[0278] Cores were made from two different portions (by weight) of
the first and second core portions as follows. A model M hydraulic
Carver Laboratory Press (available from Fred S. Carver, Inc.,
Hydraulic Equipment, Summit, N.J.) was employed. A round, concave
punch and die unit having a 0.4375" diameter was used for
compression. The osmotic layer granulation (186 mg) for the first
core portion was fed into the cavity mold of the press and was
gently tapped. Then the pseudoephedrine HCl granulation (434 mg)
for the second core portion was fed into the cavity overlying the
osmotic granulation. The granulations were pressed into a solid
two-portion core using 1600 lb/sq. in. of compression force.
[0279] The shell portion was made using the following
ingredients:
3 Mg/Dosage Ingredient Trade Name Manufacturer Weight % Form
Cellulose Acetate 398-10 Eastman Chemical 80.0 27.4 Company,
Kingsport, TN Polyethylene Oxide Polyox .RTM. WSR N-80 Union
Carbide 20.0 6.8 (MW = 200,000) Corporation, Danbury, CT Acetone
(dried as solvent)
[0280] 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. PEO, which was screened
through a #40 mesh screen, was added to the cellulose acetate
solution, which was again mixed until all powder was dispersed. The
shell portion material was provided in flowable form.
[0281] A laboratory scale thermal cycle molding unit was used to
apply the first and second shell portions to the core, 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 cold stage at 5.degree. C. for 30
seconds. The 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
osmotic layer 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.
[0282] The upper mold assembly portion was next cycled to a cold
stage at 5.degree. C. for 30 seconds. The 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 pseudoephedrine HCl
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 the same shell portion, was ejected form the upper
mold cavity. The weight gain due to the shell portion, 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 12 hours to remove all residual solvent. A 0.55 mm
aperture was manually drilled on the pseudophedrine HCl layer side
of the dosage form by using a pin of diameter of 0.55 mm.
[0283] The release profile for the active ingredient contained in
the dosage form of this example is given as follow. The results are
shown in FIG. 9, which depicts the percent release of active
ingredient versus hours for the dosage form of Example 1. The curve
depicts the dissolution profile of the pseudoephedrine HCl
contained in the second core portion of the finished dosage form of
this example.
[0284] All curves were obtained using the following dissolution
apparatus: USP Type II apparatus (paddles, 50 RPM). Media: pH 6.8
phosphate buffer at 37.degree. C. Time points: Samples were removed
at 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 and 12 hours to be analyzed
for pseudoephedrine HCl. Dissolution samples were analyzed for
pseudoephedrine HCl versus a standard prepared at the theoretical
concentration for 100% released of the compound. Samples were
assayed spectrophotometrically using a Cary 50 UV-Visible
spectrophotometer at 257 nm for pseudoephedrine HCl content.
[0285] 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 the invention.
* * * * *
References