U.S. patent application number 10/393765 was filed with the patent office on 2004-01-29 for delayed release dosage forms.
Invention is credited to Parikh, Narendra, Wynn, David.
Application Number | 20040018327 10/393765 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2004-01-29 |
United States Patent
Application |
20040018327 |
Kind Code |
A1 |
Wynn, David ; et
al. |
January 29, 2004 |
Delayed release dosage forms
Abstract
A dosage form comprises: (a) a core having an outer surface,
wherein the core comprises at least one active ingredient and at
least one disintegrant; and (b) a shell comprising at least a first
shell portion which resides upon at least a portion of the core
outer surface, wherein the shell comprises (i) at least one water
insoluble film forming polymer, and (ii) at least one water
insoluble lipid, and the weight ratio of film forming polymer to
lipid is in the range of about 40:60 to about 60:40. A method of
providing a delayed burst release of an active ingredient from a
dosage form comprises contacting the dosage form of this invention
with a liquid medium such as gastrointestinal fluid.
Inventors: |
Wynn, David; (Abington,
PA) ; Parikh, Narendra; (Long Valley, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27542311 |
Appl. No.: |
10/393765 |
Filed: |
March 21, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10393765 |
Mar 21, 2003 |
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PCT/US02/31129 |
Sep 28, 2002 |
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10393765 |
Mar 21, 2003 |
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PCT/US02/31117 |
Sep 28, 2002 |
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10393765 |
Mar 21, 2003 |
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PCT/US02/31062 |
Sep 28, 2002 |
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10393765 |
Mar 21, 2003 |
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PCT/US02/31024 |
Sep 28, 2002 |
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10393765 |
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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09966939 |
Sep 28, 2001 |
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09966509 |
Sep 28, 2001 |
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09966509 |
Sep 28, 2001 |
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09966497 |
Sep 28, 2001 |
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09966497 |
Sep 28, 2001 |
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09967414 |
Sep 28, 2001 |
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09966497 |
Sep 28, 2001 |
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09966450 |
Sep 28, 2001 |
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Current U.S.
Class: |
428/35.7 |
Current CPC
Class: |
A61K 9/2018 20130101;
A61J 3/06 20130101; B30B 11/08 20130101; A23L 29/30 20160801; A61K
9/2095 20130101; A61K 9/2013 20130101; A61P 43/00 20180101; A61K
9/0004 20130101; B30B 15/302 20130101; Y10T 428/1352 20150115; A61P
11/00 20180101; A61K 9/2054 20130101; A61K 9/2027 20130101; B30B
11/34 20130101; A23G 3/54 20130101; A61K 9/209 20130101; A23G 1/54
20130101; A23G 3/368 20130101; A61K 9/284 20130101; A61K 9/2031
20130101; A61K 9/2873 20130101; A61K 9/5084 20130101; A61K 9/282
20130101; A61K 9/2068 20130101; A61K 9/2072 20130101; A23G 3/0029
20130101; A61J 3/10 20130101; A61K 9/0056 20130101; A61K 9/2081
20130101; A23G 3/04 20130101; A61J 3/005 20130101; A61K 9/2826
20130101; A61K 9/286 20130101; A61K 9/2893 20130101; A61K 9/2886
20130101 |
Class at
Publication: |
428/35.7 |
International
Class: |
B65D 001/00 |
Claims
The invention claimed is:
1. A dosage form comprising: (a) a core having an outer surface,
wherein the core comprises at least one active ingredient and at
least one disintegrant; and (b) a shell which resides upon at least
a portion of the core outer surface, wherein the shell comprises at
least a first shell portion comprising (i) at least one water
insoluble film forming polymer, and (ii) at least one water
insoluble lipid, and the weight ratio of film forming polymer to
lipid is in the range of about 40:60 to about 60:40.
2. The dosage form of claim 1, in which the disintegrant is
selected from the group consisting of sodium starch glycolate,
cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starches, microcrystalline cellulose, and
the like and mixtures thereof.
3. The dosage form of claim 1, in which the shell or first shell
portion weight is about 10% to about 30% of the total weight of the
dosage form.
4. The dosage form of claim 1, in which the film forming polymer is
selected from the group consisting of ethylcellulose, cellulose
acetate, polymethacrylic acid, methyl methacrylate, cellulose
acetate butyrate, cellulose acetate propionate, polyvinyl alcohol,
polyvinyl acetate, polycaprolactone, and mixtures thereof.
5. The dosage form of claim 1, in which at least a portion of at
least one active ingredient is released from the dosage form in a
delayed manner upon contacting of the dosage form with a liquid
medium.
6. The dosage form of claim 1, in which the lipid is selected from
the group consisting of glyceryl behenate, fats, waxes, cocoa
butter, hydrogenated vegetable oils, palm kernel oil, cottonseed
oil, sunflower oil, soybean oil, long chain fatty acids having a
chain length of about C.sub.10-C.sub.40, fatty acid esters having a
fatty acid chain length of about C.sub.10-C.sub.40, and mixtures
thereof.
7. The dosage form of claim 1, in which the shell or first shell
portion is a single layer in contact with the core outer
surface.
8. The dosage form of claim 1, in which the release profile of at
least one active ingredient upon contacting of the dosage form with
a liquid medium is a delayed burst release.
9. The dosage form of claim 1, in which the release profile of at
least one active ingredient upon contacting of the dosage form with
a liquid medium is a delayed then sustained release.
10. The dosage form of claim 8 or 9 in which the delay time prior
to the release of at least one active ingredient is independent of
the pH of the liquid medium.
11. The dosage form of claim 8 or 9, in which a first dose of at
least one active ingredient is released essentially immediately
upon contacting of the dosage form with a liquid medium.
12. The dosage form of claim 1, in which the shell or first shell
portion additionally comprises up to about 20% by weight of the
shell or shell portion of at least one additional component
selected from the group consisting of a water soluble polymer, a
water soluble crystalline material, a water swellable material, and
mixtures thereof.
13. The dosage form of claim 12, in which the additional component
is a water soluble polymer selected from the group consisting of
hydroxypropyl methylcellulose, polyvinyl pyrrolidone and mixtures
thereof.
14. The dosage form of claim 13, in which the additional component
is a crystalline material selected from the group consisting of
sugars, water soluble inorganic salts, polyhedric alcohols, and
mixtures thereof.
15. The dosage form of claim 14, in which the additional component
is a water swellable material selected from the group consisting of
water swellable cellulose derivatives, polyalkalene glycols,
polyalkalene oxides, acrylic polymers, hydrocolloids, gelling
starches, swelling cross-linked polymers, and derivatives,
copolymers, and combinations thereof.
16. The dosage form of claim 15, in which the additional component
is a pore former.
17. A method of providing a delayed burst release of an active
ingredient from a dosage form, wherein the method comprises: (I)
providing a dosage form comprising: (a) a core having an outer
surface, wherein the core comprises at least one active ingredient
and at least one disintegrant, and (b) a shell comprising at least
a first shell portion which resides upon at least a portion of the
core outer surface, wherein the shell or first shell portion
comprises (i) at least one water insoluble film forming polymer,
and (ii) at least one water insoluble lipid, and the weight ratio
of film forming polymer to lipid is in the range of about 40:60 to
about 60:40; and (II) contacting the dosage form with a liquid
medium.
18. The method of claim 17, in which at least a portion of at least
one active ingredient is released from the dosage form in a delayed
manner upon contacting of the dosage form with a liquid medium.
19. The dosage form of claim 1 wherein the shell comprises first
and second shell portions that are compositionally different and in
contact with each other at an interface.
20. The dosage form of claim 19, wherein the shell substantially
surrounds the core.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of PCT Application Nos.
PCT/US02/31129, 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 Sept.
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 delayed release or pulsatile
release dosage forms such as delayed release or pulsatile release
pharmaceutical compositions, and methods of providing predetermined
active ingredient concentrations in a delayed or pulsatile release
manner using such dosage forms. More particularly, this invention
relates to dosage forms for delivering one or more active
ingredients in a delayed or pulsatile release manner upon
contacting of the dosage form with a liquid medium such as
gastrointestinal (GI) fluid. In a preferred embodiment, the dosage
form provides a delayed or pulsatile release profile for one or
more active ingredients contained therein, i.e. contact of the
dosage form with a liquid medium is followed by a programmed time
delay, followed by a prompt release of one or more doses (portions)
of one or more active ingredients. The dosage form comprises a core
containing at least one active ingredient and a disintegrant, and a
shell comprising at least a first shell portion which resides upon
at least a portion of the core. The shell or first shell portion
comprises at least one water insoluble film forming polymer and at
least one water insoluble lipid in a weight ratio of about 40:60 to
60:40.
[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. In some instances, it is particularly desirable
for a dosage form to deliver more than one dose of one or more
drugs at different rates or predetermined times. 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 dose of active ingredient (e.g.
drug) immediately released from the dosage form, while a second
dose of the same or a different drug is released in a modified
(e.g. delayed, pulsatile, repeat action, controlled, sustained,
prolonged, extended, or retarded) manner.
[0006] An important objective of modified release dosage forms is
to provide a desired blood concentration versus time
(pharmacokinetic, or PK) profile for each 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. To be absorbed into the blood (circulatory system), the
drug must first be dissolved in the GI fluids. For those relatively
rapidly absorbed drugs whose dissolution in GI fluids is the rate
limiting step in drug absorption, controlling the rate of
dissolution (i.e. drug release from the dosage form) allows the
formulator to control the rate of drug absorption into the
circulatory system of a patient. The type of PK profile desired
depends, among other factors, on the particular active ingredient
or ingredients, and physiological condition being treated.
[0007] One 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 of the dosage
form by a liquid medium, such as for example, after ingestion by
the patient. The delay period ("lag time") can be followed either
by prompt release of the active ingredient ("delayed burst"), or by
sustained (prolonged, extended, or retarded) release of the active
ingredient ("delayed then sustained"). U.S. Pat. No. 5,464,633, for
example, discloses delayed-release dosage forms in which an
external coating layer was applied by a compression coating
process. The coating level ranged from 105 percent to 140 percent
of the weight of the core in order to yield product with the
desired time delayed profile.
[0008] 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. One typical pulsatile dosage form design contains the
first dose of drug in an exterior coating, or shell, while
subsequent doses of drug are contained in underlying layers of
subcoatings, or a central core. PCT publication No. WO99/62496, for
example, discloses a dosage form comprising an immediate-release
dose of drug contained within an overcoat applied onto the surface
of the semipermeable membrane of an osmotic dosage form. U.S. Pat.
Nos. 4,857,330 and 4,801,461 disclose dosage forms comprising an
exterior drug coat that surrounds a semipermeable wall, which in
turn surrounds an internal compartment containing a second dose of
drug, and comprises exit means for connecting the interior of the
dosage form with the exterior environment of use. These dosage
forms are designed to release drug immediately from the exterior
coating, followed by a relatively short delay period, followed by a
sustained release of drug from the internal compartment.
[0009] Another design for a pulsatile delivery system is
exemplified in U.S. Pat. No. 4,865,849, which describes a tablet
able to release active substances at successive times, comprising a
first layer containing a portion of the active substance, a water
soluble or water gellable barrier layer which is interposed between
the first layer and a third layer containing the remaining portion
of active substance, and the barrier layer and third layer are
housed in an insoluble, impermeable casing. The casing can be
applied by various methods such as spraying, compression, or
immersion, or the tablet parts can be inserted into a pre-formed
casing. Multilayer compressed tablets in stacked layer
configurations necessarily require an impermeable partial coating
(casing) to provide a pulsatile release profile. These systems
suffer from the complexity and high cost of assembling multiple,
separate compartments comprising multiple, different
compositions.
[0010] 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. 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.
[0011] To date, erosion has been the primary mechanism for delaying
release of active from a portion of a dosage form for a period of
time.
[0012] A commonly used erosion-controlled release system comprises
a "matrix" throughout which one or more drugs are 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)}
[0013] 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.
[0014] 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)
[0015] 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)
[0016] where dM/dt is generally described by either the
diffusion-controlled or erosion-controlled equations above, and
T.sub.1 is the lag time.
[0017] Delayed release dosage forms are known in the art. For
example, U.S. Pat. No. 6,143,327 discloses a delayed release coated
tablet. The coated tablet comprises: a core having glyceryl
behenate and the antidepressant drug bupropion hydrochloride
contained therein; a first coating containing a water insoluble,
water permeable film forming polymer, a plasticizer and a water
soluble polymer; and a second coating containing a methacrylic
polymer and a plasticizer. WO98/30208 discloses a delayed release
coated tablet comprising: a core having bupropion hydrochloride
contained therein; a first barrier layer which coats a first face
of the core; and an optional second barrier layer which coats the
opposite face of the core. The barrier layer or layers contain a
polymeric material which shows a high degree of swelling and
gelling in an aqueous medium, or non-swellable wax or polymeric
material which is aqueous media. The composition of the present
invention advantageously accomplishes its function in a single
coating layer.
[0018] The delayed or pulsatile release dosage forms of this
invention employ a core containing at least one active ingredient
and a shell which surrounds the core. The shell comprises at least
a first shell portion which comprises a novel composition which
enables the shell to provide a delay in release of one or more
active ingredients contained in the underlying core or core
portion. The time period of the delay in release is independent of
the pH of the surrounding liquid medium (e.g. GI fluid). The delay
period may be followed by a burst or immediate release of active
ingredient, or alternatively, the delay period may be followed by a
controlled release of active ingredient.
[0019] 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 delayed release properties is typically
applied via conventional methods, such as for example by
compression, to produce either multiple stacked layers, or core and
shell configurations. In one such system, the outer compressed
coating layer may function via an erosion mechanism to delay
release of an active ingredient contained in the core. U.S. Pat.
No. 5,464,633, for example, discloses delayed-release dosage forms
in which an external coating layer was applied by a compression
coating process. The coating level ranged from 105 percent to 140
percent of the weight of the core in order to yield product with
the desired time delayed profile. Additional modified release
dosage forms prepared via compression are exemplified in U.S. Pat.
Nos. 5,738,874 and 6,294,200, and WO99/51209. It is possible, via
compression-coating, to produce a 2-portion shell, which may
function as a barrier, or release delaying coating, however
compression-coated systems are limited by the shell thickness and
shell composition. Gunsel et al., "Compression-coated and layer
tablets" in Pharmaceutical Dosage Forms--Tablets, edited by H. A.
Lieberman, L. Lachlnan, J. B. Schwartz (2 nd ed., rev. and
expanded. Marcel Dekker, Inc.) pp. 247-284, for example, discloses
the thickness of compression coated shells is typically between 800
and 1200 microns. U.S. Pat. No. 5,738,874, discloses a 3-layer
pharmaceutical compressed tablet capable of liberating one or more
drugs at different release rates, in which an immediate release
dose of active may be contained in a compressed coating layer, and
the compressed coating layer has a weight which is 230% to 250% of
the weight of the core, and a sustained release dose of active
ingredient is contained in the core. Spraying methods have not
traditionally been found to be optimal for applying a
delayed-release coating, due to the preference of formulators for
using water-swellable materials to achieve an erosion mechanism for
dissolution of the release-delaying coating. Water swellable
materials typically swell irreversibly in the coating dispersion,
accordingly losing their swellability in the finished dosage form.
The present invention advantageously provides a sprayable
formulation for forming a release-delaying coating, optionally
without the use of water-swellable materials, and which retains its
release delaying properties when formed into a coating on a
substrate, whether by spraying or by molding.
[0020] It is one object of this invention to provide a dosage form
in which at least one active ingredient contained therein exhibits
a delayed or pulsatile release profile upon contacting of the
dosage form with a liquid medium. It is one feature of the dosage
form of this invention that the core contains at least one active
ingredient and at least one disintegrant. It is another feature of
the dosage form of this invention that the shell comprises at least
a first shell portion which contains at least one water insoluble
film forming polymer and at least one water insoluble lipid. It is
another feature of the dosage form of this invention that the
weight ratio of film forming polymer:lipid in the shell or first
shell portion is in the range of about 40:60 to 60:40. It is
another feature of the dosage form of this invention that the time
period of delay prior to the release of the active ingredient or
ingredients is independent of the pH of the liquid medium
contacting the dosage form. It is yet another feature of the dosage
form of this invention that the shell may contain an additional
optional component which promotes permeation of the liquid medium
through the shell into the core.
[0021] It is another object of this invention to provide a method
for providing a delayed or pulsatile release of an active
ingredient from the dosage form of this invention upon contacting
the dosage form with a liquid medium. It is a feature of the dosage
form of this invention that the delay time period prior to the
release of the active ingredient or ingredients may be controlled
by the shell weight as compared to the total weight of the dosage
form. It is another feature of the dosage form of this invention
that the time period of delay prior to the release of the active
ingredient or ingredients is independent of the pH of the liquid
medium contacting the dosage form. Other objects, features and
advantages of this invention will be apparent to those skilled in
the art from the detailed description set forth below.
SUMMARY OF THE INVENTION
[0022] The present invention provides a dosage form comprising: a)
a core having an outer surface, wherein the core comprises at least
one active ingredient and at least one disintegrant; and b) a shell
which resides upon at least a portion of the core outer surface,
wherein the shell comprises at least a first shell portion
comprising (i) at least one water insoluble film forming polymer,
and (ii) at least one water insoluble lipid, and the weight ratio
of film forming polymer to lipid is in the range of about 40:60 to
about 60:40.
[0023] The present invention also provides a method of providing a
delayed burst release of an active ingredient from a dosage form,
wherein the method comprises: (I) providing a dosage form
comprising: a) a core having an outer surface, wherein the core
comprises at least one active ingredient and at least one
disintegrant, and b) a shell comprising at least a first shell
portion which resides upon at least a portion of the core outer
surface, wherein the shell or first shell portion comprises (i) at
least one water insoluble film forming polymer, and (ii) at least
one water insoluble lipid, and the weight ratio of film forming
polymer to lipid is in the range of about 40:60 to about 60:40; and
(II) contacting the dosage form with a liquid medium.
BRIEF DESCRIPTION OF THE DRAWINGS
[0024] FIG. 1 depicts a cross sectional side view of one embodiment
of the dosage form of this invention.
[0025] FIG. 2 depicts the dissolution profile of active ingredient
from the dosage form of Example 1.
DETAILED DESCRIPTION OF THE INVENTION
[0026] As used herein, the term "dosage form" applies to any solid,
semi-solid, or liquid composition designed to contain a specific
pre-determined amount (dose) of a certain ingredient, for example
an active ingredient as defined below. Suitable dosage forms may be
pharmaceutical drug delivery systems, including those for oral
administration, buccal administration, rectal administration,
topical or mucosal delivery, or subcutaneous implants, or other
implanted drug delivery systems; or compositions for delivering
minerals, vitamins and other nutraceuticals, oral care agents,
flavorants, and the like. Preferably the dosage forms of the
present invention are considered to be solid, however they may
contain liquid or semi-solid components. In a particularly
preferred embodiment, the dosage form is an orally administered
system for delivering a pharmaceutical active ingredient to the GI
tract of a human.
[0027] At least one active ingredient contained within the dosage
form of this invention exhibits a delayed release profile. As used
herein, a delayed release profile for a certain active ingredient
means the dissolution of that active ingredient from the dosage
form is delayed for a predetermined period of time (lag time). The
delay period may be preceded by a period of release for a prior
dose of the same or another active ingredient, or the delay period
may begin upon contacting of the dosage form with a liquid medium,
such as suitable in vitro dissolution media or GI fluids.
[0028] In a preferred embodiment, at least one active ingredient
contained within the dosage form of this invention exhibits a
delayed burst release profile. 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 predetermined lag time. By "delayed burst
release profile" it is meant that the release of at least a
portion, or dose, of that particular active ingredient from the
dosage form is delayed for a pre-determined time after contact with
a liquid medium, such as after ingestion by the patient, and the
delay period ("lag time") is followed by prompt (i.e. immediate)
release of that dose of active ingredient. The shell or first shell
portion provides for the delay period and is substantially free of
the portion of active ingredient to be released in a delayed burst
manner. The delayed burst active ingredient is typically contained
within the corresponding underlying core portion. The core may be
prepared by any method, for example compression or molding, and is
formulated for immediate release, as is known in the art, so that
the core is readily soluble upon contact with the dissolution
medium. The core 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. As used herein, "core" refers to a
material which is at least partially enveloped or surrounded by
another material. Preferably, the core is a self-contained unitary
object, such as a tablet or capsule. Typically, the core comprises
a solid, for example, the core may be a compressed or molded
tablet, hard or soft capsule, suppository, or a confectionery form
such as a lozenge, nougat, caramel, fondant, or fat based
composition. In certain other embodiments, the core or a portion
thereof may be in the form of a semi-solid or a liquid in the
finished dosage form. For example the core may comprise a liquid
filled capsule, or a semisolid fondant material. In embodiments in
which the core comprises a flowable component, such as a plurality
of granules or particles, or a liquid, the core preferably
additionally comprises an enveloping component, such as a capsule
shell, or a coating, for containing the flowable material. In
certain particular embodiments in which the core comprises an
enveloping component, the shell or shell portions of the present
invention are in direct contact with the enveloping component of
the core, which separates the shell from the flowable component of
the core.
[0029] In one embodiment the core is a compressed tablet having a
hardness from about 2to about 30 kp/cm.sup.2, e.g. from about 6 to
about 25 kp/cm.sup.2. "Hardness" is a term used in the art to
describe the diametral breaking strength of either the core or the
coated solid dosage form as measured by conventional pharmaceutical
hardness testing equipment, such as a Schleuniger Hardness Tester.
In order to compare values across different size tablets, the
breaking strength must be normalized for the area of the break.
This normalized value, expressed in kp/cm.sup.2, is sometimes
referred in the art as tablet tensile strength. A general
discussion of tablet hardness testing is found in Leiberman et al.,
Pharmaceutical Dosage Forms--Tablets, Volume 2, 2.sup.nd ed.,
Marcel Dekker Inc., 1990, pp. 213-217, 327-329.
[0030] In embodiments wherein the dosage form provides a delayed
burst profile, the dissolution of the burst release portion of
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)).
[0031] The shell or first shell portion functions to confer a delay
of the release of one or more active ingredients contained in the
underlying core or portion thereof, and 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,
GI fluid or the like. The delay period is typically controlled by
erosion of the shell or portion thereof, diffusion through the
shell or portion thereof, or a combination thereof. The delay
period may also be controlled by the shell composition, e.g., for
example, the relative amounts of the water insoluble film forming
polymer and water insoluble lipid. The delay period is essentially
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.
[0032] In addition to delaying the release of at least one active
ingredient, the dosage forms of this invention may optionally
further exhibit modified release of one or more active ingredients
contained therein. Additionally, the dosage forms of this invention
may optionally further exhibit immediate 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.
[0033] The dosage forms of this 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 or
ingredients 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.
[0034] 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.
[0035] As used herein, the "release rate" of an active ingredient
(e.g., drug) refers to the quantity of active ingredient released
from a dosage form per unit time, e.g., milligrams of active
ingredient released per hour (mg/hr). Active ingredient rates are
calculated under in vitro dosage form dissolution testing
conditions known in the art. As used herein, an active ingredient
rate obtained at a specified time "following administration" refers
to the in vitro active ingredient release rate obtained at the
specified time following implementation of an appropriate
dissolution test.
[0036] In this invention, the core comprises at least one
disintegrant such as sodium starch glycolate, cross-linked
polyvinylpyrrolidone, cross-linked carboxymethylcellulose,
starches, microcrystalline cellulose, effervescent compounds,
effervescent mixtures, and the like, and combinations thereof. As
used herein, "effervescent" is meant to include inorganic salts of
carbonic acid, inorganic bicarbonate salts, acid/base pairs that
react to liberate gases, and the like. In one embodiment, the
disintegrant is a "superdisintegrant", selected from sodium starch
glycolate, cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, and combinations thereof.
[0037] The shell or first shell portion resides upon at least a
portion of the outer surface of the core. In one embodiment, the
shell is a single layer in contact with the outer layer of the
core. In another embodiment, the shell comprises first and second
shell portions which each are in contact with the outer layer of
the core. The shell or first shell portion comprises at least one
water insoluble film forming polymer and at least one water
insoluble lipid. The weight ratio of total water insoluble film
forming polymer: total weight of water insoluble lipid must be in
the range of about 40:60 to about 60:40.
[0038] In one embodiment, the water insoluble film forming polymer
may be at least one of ethylcellulose, cellulose acetate,
polymethacrylic acid, methyl methacrylate, cellulose acetate
butyrate, cellulose acetate propionate, polyvinyl alcohol,
polyvinyl acetate, polycaprolactone, or mixtures thereof.
[0039] In one embodiment, the water insoluble lipid may be at least
one of fatty acid esters, which 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 glyceride;. fats
such as mono-, di-, and tri-glycerides having chain lengths of
about C.sub.10-C.sub.40, waxes such as include carnauba wax,
spermaceti wax, beeswax, candelilla wax, shellac wax,
microcrystalline wax, and paraffin wax and the like, cocoa butter,
hydrogenated vegetable oils, palm kernel oil, cottonseed oil,
sunflower oil, soybean oil, long chain fatty acids such as those
having a fatty acid chain length of about C.sub.10-C.sub.40, fatty
acid esters such as those having a fatty acid chain length of about
C.sub.10-C.sub.40, or mixtures thereof.
[0040] Without wishing to be bound by any one theory, it is
believed that the water insoluble film forming polymer forms a
water insoluble film around the core or core portion (thereby
providing for the delay of release of active ingredient), and the
water insoluble lipid acts as an insoluble barrier within the
shell, which gradually erodes away to weaken the film, which aids
in the eventual rupture or failure of the shell or first shell
portion (thereby providing the immediate release of active
ingredient from the core).
[0041] The weight ratio of water insoluble film forming polymer to
water insoluble lipid in the shell or first shell portion is
critical to this invention. If excess film forming polymer is used,
the shell or first shell portion will not rupture to release active
ingredient from the core. If excess lipid is used, the shell or
first shell portion will lack sufficient mechanical strength, and
the shell or first shell portion will rupture too quickly to
provide the desired delay prior to release of active ingredient
from the core.
[0042] In one embodiment, the shell weight is about 10% to about
30% of the total weight of the dosage form.
[0043] In another embodiment, the shell or first shell portion may
additionally contain up to about 20% of its weight of at least one
of a water soluble polymer, a water soluble crystalline material, a
water swellable material, or mixtures thereof.
[0044] In one embodiment, the water soluble polymer may be at least
one of hydroxypropyl methylcellulose (HPMC), polyvinyl pyrrolidone
(PVP) or mixtures thereof.
[0045] In one embodiment, the water-soluble crystalline material
may be at least one of sugars such as mono- or di-saccharides
(e.g., sucrose, glucose, fructose, lactose, mannose, or maltose),
polyhedric alcohols (e.g., mannitol, sorbitol, maltitol,
erythritol, xylitol, or lactitol), water soluble inorganic salts
(e.g., NaCl, KCl, Nal, KI, CaCl.sub.2 and the like), or
combinations thereof.
[0046] In one embodiment, the water swellable material may be at
least one of water swellable cellulose derivatives, polyalkalene
glycols, polyalkalene oxides, acrylic polymers, hydrocolloids,
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)
such as those available from Dow Chemical Company under the
tradenames METHOCEL K4M, METHOCEL K15M, and METHOCEL K100M,
hydroxyisopropylcellulose, hydroxybutylcellulose,
hydroxyphenylcellulose, hydroxyethylcellulose (HEC),
hydroxypentylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples
of suitable polyalkalene glycols include polyethylene glycol.
Examples of suitable polyalkalene oxides include poly (ethylene
oxide). Examples of suitable acrylic polymers include potassium
methacrylatedivinylbenzene copolymer, polymethylmethacrylate,
synthetic high-molecular weight acrylic acid homopolymers and
copolymers crosslinked with allyl sucrose or allyl ethers of
pentaerythritol, such as those available under the tradename
CARBOPOL, 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, and chitosan. 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.
[0047] Without wishing to be bound by any one theory, it is
believed that the water soluble polymer, water soluble crystalline
material or water swellable material acts as a pore former to
promote permeation of liquid medium through the shell or first
shell portion into the core. Accordingly, the additional water
soluble polymer, water soluble crystalline material or water
swellable material may also be employed to control the time period
of delay or lag-time prior to release of active ingredient from the
core.
[0048] A first embodiment of the dosage form of this invention is
depicted in FIG. 1, which is a cross-sectional view of a dosage
form 2 having a core 4 and a shell 6, which in this embodiment
resides upon the outer surface of core 4 and completely surrounds
core 4. Core 4 contains at least one active ingredient and at least
one disintegrant. Shell 6 contains at least one water insoluble
film forming polymer, and at least one water insoluble lipid. The
weight ratio of film forming polymer to lipid in the shell is in
the range of about 40:60 to about 60:40.
[0049] 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, antihistames, antitussives,
antibiotics, anti-infective agents, antivirals, anticoagulants,
antidepressants, antidiabetic agents, antiemetics, antiflatulents,
anti fungals, antispasmodics, appetite suppressants,
bronchodilators, cardiovascular agents, central nervous system
agents, central nervous system stimulants, decongestants, oral
contraceptives, diuretics, expectorants, GI agents, migraine
preparations, motion sickness products, mucolytics, muscle
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep-aids, urinary tract agents and mixtures
thereof.
[0050] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0051] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0052] Examples of suitable GI 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
sticraflate 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.
[0053] 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.
[0054] 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 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 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.
[0055] 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.
[0056] 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.
[0057] 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 at least about 1 weight percent, preferably,
the dosage form comprises at least about 5 weight percent, e.g.
about 20 weight percent of a combination of one or more active
ingredients.
[0058] 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
preferred embodiment, such particles are crystals having an average
particle size of about 1-300 microns. In another embodiment, the
particles are granules or pellets having an average particle size
of about 50-2000 microns, preferably about 50-1000 microns, most
preferably about 100-800 microns.
[0059] 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.
[0060] 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.
[0061] 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 a
particular 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.
[0062] In another embodiment, the dissolution characteristics of at
least one active ingredient contained in the dosage form meets USP
specifications for immediate release tablets containing the active
ingredient. In certain such embodiments, the immediately released
active ingredient or ingredients are contained in a further
coating, which resides upon at least a portion of the shell of the
present invention. In certain other such embodiments, the
dissolution characteristics of a delayed release dose, or portion,
of active ingredient meet immediate release criteria following the
delay period (i.e. lag time). In these embodiments, the delayed
release dose, or portion of active ingredient is preferably
contained within the core. 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 appraratus 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).
[0063] In one embodiment of the invention, the core comprises
multiple portions, for example a first portion and a second
portion. The portions may be prepared by the same or different
methods and mated using various techniques, such as the thermal
cycle molding and thermal setting molding methods described herein.
For example, the first and second portions may both be made by
compression, or both may be made by molding. Or one portion may be
made by compression and the other by molding. The same or different
active ingredient may be present in the first and second portions
of the core. Alternately, one or more core portions may be
substantially free of active ingredients.
[0064] In certain other embodiments, a portion of the core may
optionally 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 eroding matrix 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 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.
[0065] In certain other embodiments, a portion of the core may
function as a diffusional matrix. In these embodiments, the
diffusional matrix core portion comprises active ingredient
distributed throughout an insoluble porous matrix, which contains
pores or channels through which fluids can enter the core portion,
and the active ingredient must diffuse to be released from the
dosage form. In these embodiments, the rate of active ingredient
release from the diffusional matrix 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 portion functions
as a diffusional matrix, the release of active ingredient from the
diffusional matrix core portion may be described as controlled,
prolonged, sustained, or extended. In these embodiments, the
contribution to active ingredient dissolution from the diffusional
matrix core portion may follow zero-order, first-order, or
preferably square-root of time kinetics. In these embodiments, the
diffusional matrix core portion preferably comprises a pore
former.
[0066] In embodiments in which one or more core portions function
as a diffusional matrix through which active ingredient is
liberated in a sustained, extended, prolonged, or retarded manner,
the core portion preferably comprises a release-modifying excipient
selected from combinations of insoluble edible materials and pore
formers. Alternately, in such embodiments in which the core portion
is prepared by molding, the thermal-reversible carrier may function
by dissolving and forming pores or channels through which the
active ingredient may be liberated.
[0067] In embodiments in which a core portion functions to modify
release of an active ingredient contained therein, the release of
active ingredient may be further modified by the function of the
surrounding shell, as described above. In such embodiments, the
release of the active ingredient from the dosage form will be
governed by the sum of all the contributions acting upon it, e.g.
from the relevant core and shell, 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. In another embodiment, the core portion functions to
modify release of an active ingredient contained therein, and the
core is surrounded by separate shell portions.
[0068] In certain other 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 molded multiple portions, which
each cover a specific core portion 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 and thermal setting apparatus and described below. In
one such 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 the first shell portion confers a delay to the release of
an active ingredient contained in the underlying first core
portion, and the second shell portion may confer a modification to
the release of an active ingredient contained in the underlying
second core portion.
[0069] The core of the present invention may be prepared by any
suitable method, including for example compression and molding, and
depending on the method by which it is made, typically comprises
active ingredient and a variety of excipients (inactive ingredients
which may be useful for conferring desired physical properties to
the core).
[0070] 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.
[0071] Suitable fillers for use in making the core, or a portion
thereof, by compression include water-soluble compressible
carbohydrates such as sugars, which include dextrose, sucrose,
maltose, and lactose, sugar-alcohols, which include mannitol,
sorbitol, maltitol, xylitol, starch hydrolysates, which include
dextrins, and maltodextrins, and the like, water insoluble
plastically deforming materials such as microcrystalline cellulose
or other cellulosic derivatives, water-insoluble brittle fracture
materials such as dicalcium phosphate, tricalcium phosphate and the
like and mixtures thereof.
[0072] 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.
[0073] 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,
effervescent compounds, effervescent mixtures, and the like, and
combinations thereof. As used herein, "effervescent" is meant to
include inorganic salts of carbonic acid, inorganic bicarbonate
salts, acid/base pairs that react to liberate gases, and the like.
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.
[0074] Suitable glidants for making the core, or a portion thereof,
by compression, include colloidal silicon dioxide, and the
like.
[0075] 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.
[0076] In certain embodiments of this invention, the core comprises
a first core portion which comprises an immediate release
formulation, and an optional second core portion. In these
embodiments, one or more active ingredients contained in the first
core portion may be released from the dosage form in a delayed
burst manner upon contacting of the dosage form with a liquid
medium. In embodiments wherein the second core portion functions as
a modified release matrix, for example an erodible matrix, suitable
release-modifying excipients for making the second core portion by
compression include swellable erodible hydrophilic materials known
in the art such as those disclosed in commonly assigned, copending
U.S. application Ser. No. ______[MCP-321].
[0077] 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.
[0078] In embodiments in which the core 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).
[0079] 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.
[0080] In one particular embodiment, the core 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.
[0081] In certain optional embodiments of this invention, the core,
or the shell, or a portion thereof, may be prepared by molding. In
such embodiments, the core, or the shell, or a portion thereof, is
made from a flowable material. In embodiments in which the first
shell portion of the present invention is prepared by molding, the
flowable material preferably comprises least one water insoluble
film forming polymer, and (ii) at least one water insoluble lipid,
which may be dispersed in a suitable liquid carrier, or may be
melted to form a flowable material. The water insoluble materials
may be in solid particulate form, suspended in the liquid carrier,
or may be dissolved in the liquid carrier. Suitable liquid carriers
may comprise a solvent, such as water, alcohols, or organic
solvents and mixtures thereof, or other suitable materials that are
liquid at or above room temperature. The liquid carrier, or
solvent, if present may optionally be partially or substantially
removed by drying.
[0082] 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.
[0083] 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.
[0084] 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 or first shell portion
is substantially free of plasticizers, i.e. contains less than
about 1%, say less than about 0.01% of plasticizers.
[0085] In one 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.
[0086] 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):
1 1. Shallow Concave. 2. Standard Concave. 3. Deep Concave. 4.
Extra Deep Concave. 5. Modified Ball Concave. 6. Standard Concave
Bisect. 7. Standard Concave Double Bisect. 8. Standard Concave
European Bisect. 9. Standard Concave Partial Bisect. 10. Double
Radius. 11. Bevel & Concave. 12. Flat Plain. 13.
Flat-Faced-Beveled Edge (F.F.B.E.). 14. F.F.B.E. Bisect. 15.
F.F.B.E. Double Bisect. 16. Ring. 17. Dimple. 18. Ellipse. 19.
Oval. 20. Capsule. 21. Rectangle. 22. Square. 23. Triangle. 24.
Hexagon. 25. Pentagon. 26. Octagon. 27. Diamond. 28. Arrowhead. 29.
Bullet. 30. Shallow Concave. 31. Standard Concave. 32. Deep
Concave. 33. Extra Deep Concave. 34. Modified Ball Concave. 35.
Standard Concave Bisect. 36. Standard Concave Double Bisect. 37.
Standard Concave European Bisect. 38. Standard Concave Partial
Bisect. 39. Double Radius. 40. Bevel & Concave. 41. Flat Plain.
42. Flat-Faced-Beveled Edge (F.F.B.E.). 43. F.F.B.E. Bisect. 44.
F.F.B.E. Double Bisect. 45. Ring. 46. Dimple. 47. Ellipse. 48.
Oval. 49. Capsule. 50. Rectangle. 51. Square. 52. Triangle. 53.
Hexagon. 54. Pentagon. 55. Octagon. 56. Diamond. 57. Arrowhead. 58.
Bullet. 59. Barrel. 60. Half Moon. 61. Shield. 62. Heart. 63.
Almond. 64. House/Home Plate. 65. Parallelogram. 66. Trapezoid. 67.
Figure 8/Bar Bell. 68. Bow Tie. 69. Uneven Triangle.
[0087] The shell or first 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 shell or first shell portion typically
comprise the water insoluble film forming polymer and water
insoluble lipid described previously.
[0088] In a preferred embodiment, the shell or first shell portion
is applied to a core directly by a spraying process, comprising the
steps of: a.) preparing a dispersion of the insoluble film forming
polymer and water insoluble lipid, and optionally suitable
adjuvants and excipients in a suitable solvent such as water,
organic solvents, or combinations thereof; b.) applying the
dispersion to the cores via spraying using suitable equipment as
known in the art, including for example coating pans, fluidized bed
coaters, and the like; c.) drying to remove the solvent.
[0089] In another embodiment, the shell or first shell portion 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.
[0090] One suitable method for making the shell or shell portion of
this invention comprises: (a) preparing a dispersion of the
insoluble film forming polymer and water insoluble lipid, and other
shell materials in a suitable solvent, e.g. acetone or water or
combinations thereof; (b) injecting the dispersion (the dispersion
may be heated in a heated feed tank) into a mold cavity (at room
temp or below) containing the core such that the 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 dispersion 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 dispersion
into the mold cavity such that the 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
dispersion surrounding the second portion of the core; (h) removing
the coated core from the mold cavity; and (i) drying to remove
residual solvent. If the solvent-based process is employed, the
mold may be optionally heated to remove solvent, then cooled to set
the shell materials. This optional heating step is preferred if
organic solvents are used, but is not required if the solvent used
is water.
[0091] In embodiments where the solvent comprises water, suitable
other shell materials preferably include a gelling agent, such as
gellan gum, carrageenan, agar, gelatin, locust bean gum,
thermoplastic starch, and the like, and mixtures thereof.
[0092] In embodiments wherein the solvent is an organic solvent,
the flowable material is preferrably injected cold and cycled to
hot after injection.
[0093] One suitable method for preparing the flowable shell
material is to disperse the materials in a suitable solvent, such
as water, organic solvents such as alcohols or acetone, or
combinations of water and organic solvents.
[0094] The shell of the present invention has a cross-sectional
area in the range of about 1 to 900 sq. mm, preferably about 25 to
400 sq. mm, most preferably about 50 to about 200 sq. mm.
[0095] 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 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, the thermal-reversible
carrier may function by dissolving and forming pores or channels
through which the active ingredient may be liberated.
[0096] 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.
[0097] In embodiments in which a second shell portion 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 one
embodiment in which a second shell portions function to modify the
release of an active ingredient which is contained in the core or
the second shell portion, the second shell portion is made by the
thermal cycle or thermal setting injection molding methods and
apparatus described below.
[0098] In certain preferred embodiments of the invention, an
immediate release dose of one or more active ingredients 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.
[0099] In one embodiment of this invention, wherein the shell or
first shell portion is prepared by molding, the shell or first
shell portion is substantially free of pores having a diameter of
0.5-5.0 microns. As used herein, "substantially free" means that
the shell or first shell portion has 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.
[0100] The pore volume, pore diameter and density of the shell may
be determined using a Quantachrome Instruments PoreMaster 60
mercury intrusion porosimeter and associated computer software
program known as "Porowin." The procedure is documented in the
Quantachrome Instruments PoreMaster Operation Manual. The
PoreMaster determines both pore volume and pore diameter of a solid
or powder by forced intrusion of a non-wetting liquid (mercury),
which involves evacuation of the sample in a sample cell
(penetrometer), filling the cell with mercury to surround the
sample with mercury, applying pressure to the sample cell by: (i)
compressed air (up to 50 psi maximum); and (ii) a hydraulic (oil)
pressure generator (up to 60000 psi maximum). Intruded volume is
measured by a change in the capacitance as mercury moves from
outside the sample into its pores under applied pressure. The
corresponding pore size diameter (d) at which the intrusion takes
place is calculated directly from the so-called "Washburn
Equation": d=-(4.gamma.(cos .theta.))/P where .gamma. is the
surface tension of liquid mercury, .theta. is the contact angle
between mercury and the sample surface and P is the applied
pressure.
[0101] Equipment used for pore volume measurements:
[0102] 1. Quantachrome Instruments PoreMaster 60.
[0103] 2. Analytical Balance capable of weighing to 0.0001 g.
[0104] 3. Desiccator.
[0105] Reagents used for measurements:
[0106] 1. High purity nitrogen.
[0107] 2. Triply distilled mercury.
[0108] 3. High pressure fluid (Dila AX, available from Shell
Chemical Co.).
[0109] 4. Liquid nitrogen (for Hg vapor cold trap).
[0110] 5. Isopropanol or methanol for cleaning sample cells.
[0111] 6. Liquid detergent for cell cleaning.
[0112] Procedure: the samples remain in sealed packages or as
received in the dessicator until analysis. The vacuum pump is
switched on, the mercury vapor cold trap is filled with liquid
nitrogen, the compressed gas supply is regulated at 55 psi., and
the instrument is turned on and allowed a warm up time of at least
30 minutes. The empty penetrometer cell is assembled as described
in the instrument manual and its weight is recorded. The cell is
installed in the low pressure station and "evacuation and fill
only" is selected from the analysis menu, and the following
settings are employed:
[0113] Fine Evacuation time: 1 min.
[0114] Fine Evacuation rate: 10
[0115] Coarse Evacuation time: 5 min.
[0116] The cell (filled with mercury) is then removed and weighed.
The cell is then emptied into the mercury reservoir, and two
tablets from each sample are placed in the cell and the cell is
reassembled. The weight of the cell and sample are then recorded.
The cell is then installed in the low-pressure station, the
low-pressure option is selected from the menu, and the following
parameters are set:
[0117] Mode: Low pressure
[0118] Fine evacuation rate: 10
[0119] Fine evacuation until: 200.mu. Hg
[0120] Coarse evacuation time: 10 min.
[0121] Fill pressure: Contact+0.1
[0122] Maximum pressure: 50
[0123] Direction: Intrusion And Extrusion
[0124] Repeat: 0
[0125] Mercury contact angle: 140
[0126] Mercury surface tension: 480
[0127] Data acquisition is then begun. The pressure vs. cumulative
volume-intruded plot is displayed on the screen. After low-pressure
analysis is complete,the cell is removed from the low-pressure
station and reweighed. The space above the mercury is filled with
hydraulic oil, and the cell is assembled and installed in the
high-pressure cavity. The following settings are used:
[0128] Mode: Fixed rate
[0129] Motor speed: 5
[0130] Start pressure: 20
[0131] End pressure: 60,000
[0132] Direction: Intrusion and extrusion
[0133] Repeat: 0
[0134] Oil fill length: 5
[0135] Mercury contact angle: 140
[0136] Mercury surface tension: 480
[0137] Data acquisition is then begun and graphic plot pressure vs.
intruded volume is displayed on the screen. After the high pressure
run is complete, the low-and high-pressure data files of the same
sample are merged.
[0138] Typical shell thicknesses which may be employed in this
invention are about 20 to about 2000 microns. In certain preferred
embodiments, the shell has a thickness of less than 800 microns. In
embodiments wherein the shell is prepared by a solvent-based
molding process, the shell 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.
[0139] In embodiments in which a first shell portion comprises the
release-delaying composition of the invention, the core, or a
portion thereof, or a second shell portion, may optionally comprise
one or more release-modifying excipients. Suitable
release-modifying excipients for making the core, or a portion
thereof, or a second shell portion by 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. Suitable release-modifying excipients are known in the
art, and disclosed for example in commonly assigned, copending U.S.
application Ser. No. ______[MCP321].
[0140] 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. The shell or first
shell portion of the present invention provides for the delay
period, and is 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 contained
within the corresponding underlying core. In such embodiments the
core may function for example as an eroding matrix or a diffusional
matrix, or an osmotic pump. In embodiments in which the core
functions as a diffusional matrix through which active ingredient
is liberated in a sustained, extended, prolonged, or retarded
manner, the core preferably comprises a release-modifying excipient
selected from combinations of insoluble edible materials and
pore-formers. Alternately, in such embodiments in which the core 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
functions as an eroding matrix from which dispersed active
ingredient is liberated in a sustained, extended, prolonged, or
retarded manner, the core preferably comprises a release-modifying
compressible or moldable excipient selected from swellable erodible
hydrophilic materials, pH-dependent polymers, and combinations
thereof.
[0141] In embodiments in which the core functions as a diffusional
matrix through which active ingredient contained therein is
liberated in a sustained, extended, prolonged, or retarded manner,
the core preferably comprises a release-modifying excipient
selected from combinations of insoluble edible materials and pore
formers. Alternately, in such embodiments in which the core 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.
[0142] In embodiments in which a second shell portion confers
sustained, extended, or retarded release of an active ingredient
contained in the underlying core, the release-modifying agent in
the shell preferably comprises a pore-former, and optionally a
film-former. In a particularly preferred embodiment, the second
shell portion functions as a diffusional membrane. In some such
embodiments, the dissolution of the active ingredient may follow
"diffusion-controlled" release kinetics, as described for example
in Example 1 of U.S. Pat. No. 5,286,497. Shell portions which
confer sustained, extended, or retarded release and/or function as
diffusional membranes can be prepared by a solvent-free method, or
a solvent-based method, as described above.
[0143] In one embodiment of the invention, the core and/or the
shell or a portion thereof is made by the thermal setting molding
method and apparatus described in copending U.S. patent application
Ser. No. 09/966,450, pages 57-63, the disclosure of which is
incorporated herein by reference. In this embodiment, the core
and/or the shell or a portion thereof is formed by injecting a
starting material in flowable form into a molding chamber. The
starting material preferably comprises an active ingredient and a
thermal setting material at a temperature above the melting point
of the thermal setting material but below the decomposition
temperature of the active ingredient. The starting material is
cooled and solidifies in the molding chamber into a shaped form
(i.e., having the shape of the mold).
[0144] In another embodiment of the invention, the core and/or the
shell or a portion thereof is made using the thermal cycle molding
method and apparatus described in copending U.S. patent application
Ser. No. 09/966,497, pages 27-51, the disclosure of which is also
incorporated herein by reference. In the thermal cycle molding
method and apparatus of U.S. patent application Ser. No.
09/966,497, a thermal cycle molding module having the general
configuration shown in FIG. 3 therein is employed. The thermal
cycle molding module 200 comprises a rotor 202 around which a
plurality of mold units 204 are disposed. The thermal cycle molding
module includes a reservoir 206 (see FIG. 4) for holding flowable
material to make the core, the shell, a core portion, or a shell
portion. In addition, the thermal cycle molding module is provided
with a temperature control system for rapidly heating and cooling
the mold units. FIGS. 55 and 56 depict such a temperature control
system 600.
[0145] This invention will be illustrated by the following
examples, which are not meant to limit the invention in any
way.
[0146] Example 1
[0147] Dosage forms of this invention were prepared as follows. A
coating solution was prepared containing 13.24 g of glyceryl
behenate (COMPRITOL 888, available from Gattefosse Inc.) and 13.24
g of ethylcellulose. The solution had a concentration of 10% solids
in ethanol. The solution was applied to cores (i.e. MOTRIN 100 mg
caplets, available from McNeil-PPC, Inc.) using a bottom spray
fluid bed available from Glatt. A 150 g charge of solution was
provided at a spray rate of 7 g/minute. A coating of 15% by weight
was applied to the cores to obtain dosage forms having shells
residing upon the cores.
[0148] The dosage forms were dissolved in pH 0.1 N HCl for 2 hours,
then switched to pH 5.6 acetate buffer solution for an additional 2
hours using USP Method I with baskets at 100 RPM. The resulting
dissolution profile is depicted in FIG. 2. The dosage forms
exhibited a burst release of active ingredient after 4 hours.
[0149] 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.
* * * * *