U.S. patent application number 10/476504 was filed with the patent office on 2004-10-28 for modified release dosage forms.
Invention is credited to Lee, Der-Yang, Li, Shun-Por, McTeigue, Dan, Parikh, Narendra, Sowden, Harry S., Thomas, Martin, Wynn, David.
Application Number | 20040213848 10/476504 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2004-10-28 |
United States Patent
Application |
20040213848 |
Kind Code |
A1 |
Li, Shun-Por ; et
al. |
October 28, 2004 |
Modified release dosage forms
Abstract
In one embodiment, a dosage form comprises: (a) at least one
active ingredient; (b) a molded core which is solid at room
temperature; and (c) a shell which is in contact with at least a
portion of the core, wherein the dosage form provides modified
release of the active ingredient upon contacting of the dosage form
with a liquid medium. In another embodiment of this invention, a
dosage form comprises: (a) at least one active ingredient; (b) a
molded core comprising a plurality of particles; and (c) a shell
which is in contact with at least a portion of the core, wherein
the dosage form provides modified release of the active ingredient
upon contacting of the dosage form with a liquid medium.
Inventors: |
Li, Shun-Por; (Lansdale,
PA) ; Wynn, David; (Huntingdon Valley, PA) ;
Parikh, Narendra; (Long Valley, NJ) ; McTeigue,
Dan; (North Wales, PA) ; Sowden, Harry S.;
(Glenside, PA) ; Thomas, Martin; (Lake Worth,
FL) ; Lee, Der-Yang; (Flemington, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27542311 |
Appl. No.: |
10/476504 |
Filed: |
May 17, 2004 |
PCT Filed: |
September 28, 2002 |
PCT NO: |
PCT/US02/31116 |
Related U.S. Patent Documents
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10476504 |
May 17, 2004 |
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09966939 |
Sep 28, 2001 |
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10476504 |
May 17, 2004 |
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09966509 |
Sep 28, 2001 |
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6767200 |
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10476504 |
May 17, 2004 |
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09966497 |
Sep 28, 2001 |
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10476504 |
May 17, 2004 |
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09967414 |
Sep 28, 2001 |
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6742646 |
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10476504 |
May 17, 2004 |
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09966450 |
Sep 28, 2001 |
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Current U.S.
Class: |
424/472 |
Current CPC
Class: |
A61J 3/005 20130101;
A61P 11/00 20180101; A61K 9/2018 20130101; A61K 9/282 20130101;
A61K 9/2873 20130101; Y10T 428/1352 20150115; A61K 9/5084 20130101;
A61J 3/10 20130101; A61K 9/2886 20130101; A23G 3/54 20130101; A61K
9/0056 20130101; A23L 29/30 20160801; A61K 9/284 20130101; A23G
1/54 20130101; A61K 9/2068 20130101; B30B 11/34 20130101; A61K
9/0004 20130101; A61K 9/2095 20130101; A23G 3/368 20130101; A61K
9/2031 20130101; B30B 11/08 20130101; A61K 9/286 20130101; A61K
9/2054 20130101; A61K 9/2081 20130101; A61K 9/209 20130101; A61K
9/2013 20130101; A61K 9/2826 20130101; A61P 43/00 20180101; A23G
3/0029 20130101; A23G 3/04 20130101; A61K 9/2072 20130101; A61K
9/2893 20130101; A61J 3/06 20130101; B30B 15/302 20130101; A61K
9/2027 20130101 |
Class at
Publication: |
424/472 |
International
Class: |
A61K 009/24 |
Claims
1. A dosage form comprising: (a) at least one active ingredient;
(b) a molded core which is solid at room temperature; and (c) a
shell which is in contact with at least a portion of the molded
core, wherein the dosage form provides modified release of the
active ingredient upon contacting of the dosage form with a liquid
medium.
2. The dosage form of claim 1, in which the molded core comprises
one or more active ingredients dispersed in a molded matrix.
3. The dosage form of claim 1, in which the shell is capable of
providing modified release of at least one active ingredient upon
contacting of the dosage form with a liquid medium.
4. The dosage form of claim 3, in which the shell is capable of
providing a time delay prior to the release of at least one active
ingredient upon contacting of the dosage form with a liquid
medium.
5. The dosage form of claim 4, in which the time delay is
independent of the pH of the liquid medium.
6. The dosage form of claim 1, in which the shell comprises means
for providing modified release of at least one active ingredient
upon contacting of the dosage form with a liquid medium.
7. The dosage form of claim 3, in which the shell comprises means
for releasing at least one active ingredient in a sustained manner
upon contacting of the dosage form with a liquid medium.
8. The dosage form of claim 1, wherein the shell comprises at least
about 30 percent by weight of a thermal-reversible carrier.
9. The dosage form of claim 1, wherein the shell comprises at least
one active ingredient.
10. The dosage form of claim 1, in which the core comprises a
molded matrix.
11. The dosage form of claim 1, in which the core comprises at
least one active ingredient.
12. The dosage form of claim 11, in which the core is capable of
providing modified release of at least one active ingredient upon
contacting of the dosage form with a liquid medium.
13. The dosage form of claim 11, in which the core comprises means
for providing modified release of at least one active ingredient
upon contacting of the dosage form with a liquid medium.
14. The dosage form of claim 11, in which the core comprises one or
more release-modifying excipients.
15. The dosage form of claim 14, in which the release modifying
excipient is selected from the group consisting of swellable
erodible hydrophilic materials, pH-dependent polymers, insoluble
edible materials, and pore-formers, and derivatives, copolymers,
and combinations thereof.
16. The dosage form of claim 1, in which the core comprises at
least 30% of a thermal-reversible carrier.
17. The dosage form of claim 16, in which the thermal-reversible
carrier is selected from the group consisting of polyethylene
glycol, thermoplastic polyethylene oxide, shellac, and derivatives,
copolymers, and combinations thereof.
18. The dosage form of claim 16, in which the thermal-reversible
carrier has a melting point of about 20 to about 110.degree. C.
19. The dosage form of claim 1, in which the core comprises a
plurality of particles which comprise at least one active
ingredient.
20. The dosage form of claim 19, in which at least a portion of the
particles are coated with a coating capable of providing modified
release of the active ingredient contained therein upon contacting
of the coated particles with a liquid medium.
21. The dosage form of claim 19, in which at least a portion of the
particles are coated with a coating comprising means for providing
modified release of the active ingredient contained therein upon
contacting of the dosage form with a liquid medium.
22. The dosage form of claim 19, in which at least a portion of the
particles are coated with a coating comprising 10-100wt. % of a
release-modifying polymer selected from the group consisting of
pH-dependent polymers, water-soluble polymers, water-insoluble
polymers, and copolymers and derivatives and mixtures thereof.
23. The dosage form of claim 1, in which upon contacting of the
dosage form with a liquid medium, a time delay occurs prior to
release of at least a portion the active ingredient.
24. The dosage form of claim 23, in which the portion of the active
ingredient released after the time delay is released in a sustained
manner.
25. The dosage form of claim 1, in which the dosage form comprises
first and second active ingredients which are the same or
different, and upon contacting of the dosage form with a liquid
medium, the first active ingredient is released in a sustained
manner, and a time delay precedes release of the second active
ingredient.
26. The dosage form of claim 1, in which the shell comprises a
first active ingredient and the core comprises a second active
ingredient which may be the same or different than the first active
ingredient, and upon contacting of the dosage form with a liquid
medium, immediate release of the first active ingredient occurs
followed by a time delay, followed by release of the second active
ingredient.
27. The dosage form of claim 1, in which the shell comprises a
first active ingredient and the core comprises a second active
ingredient which may be the same or different than the first active
ingredient, and upon contacting of the dosage form with a liquid
medium, immediate release of the first active ingredient occurs
followed by sustained release of the second active ingredient.
28. The dosage form of claim 1, in which the shell comprises a
first active ingredient and the core comprises particles comprising
a second active ingredient which may be the same or different than
the first active ingredient, and upon contacting of the dosage form
with a liquid medium, immediate release of the first active
ingredient occurs followed by delayed release of the second active
ingredient.
29. The dosage form of claim 1, in which the shell comprises a
first active ingredient and the core comprises particles comprising
a second active ingredient which may be the same or different than
the first active ingredient, and upon contacting of the dosage form
with a liquid medium, immediate release of the first active
ingredient occurs followed by sustained release of the second
active ingredient.
30. The dosage form of claim 2, in which the level of active
ingredient is at least about 25 weight percent of the core.
31. The dosage form of claim 2, in which the molded matrix
comprises a thermal reversible carrier having a melting point from
about 20 to about 100.degree. C.
32. The dosage form of claim 2, in which the molded matrix
comprises a thermal reversible carrier selected from the group
consisting of thermoplastic polyalkylene oxides, low melting
hydrophobic materials, thermoplastic polymers, thermoplastic
starches, and combinations thereof.
33. The dosage form of claim 2, in which the molded matrix
comprises a low-melting thermal-reversible carrier selected from
the group consisting of polycaprolactones, polyvinyl acetate,
polyalkylene glycols, and combinations thereof at a level of about
30 to about 70 weight percent of the matrix.
34. The dosage form of claim 2, in which the molded matrix
comprises a thermal-reversible carrier selected from the groups
consisting of polyethylene glycol or polyethylene oxide at a level
from about 10 to about 100 weight percent of the matrix.
35. The dosage form of claim 33, in which the molded matrix further
comprises a thermoplastic polyethylene oxide at a level of about 15
to about 25%.
36. The dosage form of claim 1, in which the shell has a thickness
from about 300 to about 2000 microns.
37. The dosage form of claim 1, in which the shell has a thickness
from about 150 to about 400 microns.
38. The dosage form of claim 1, in which the weight of the shell is
from about 50 to about 400 percent of the weight of the core.
39. The dosage form of claim 1, in which the weight of the shell is
from about 20 to about 100 percent of the weight of the core.
40. The dosage form of claim 1, in which the core is substantially
free of pores having a diameter of 0.5 to 5.0 microns.
41. The dosage form of claim 32, in which the thermal reversible
carrier is polyethylene glycol having a molecular weight from about
100 to about 8000 Daltons.
42. The dosage form of claim 2, in which the molded matrix
comprises a release-modifying excipient.
43. The dosage form of claim 42, in which the release-modifying
polymer is shellac.
44. The dosage form of claim 42, in which the release-modifying
excipient is croscarmellose sodium.
45. The dosage form of claim 2, further comprising tributyl citrate
as a plasticizer.
46. The dosage form of claim 1, in which the shell comprises a
film-former selected from the group consisting of cellulose
acetate, ammonia methacrylate copolymer type B, shellac,
hydroxypropylmethylcellulose, polyethylene oxide, and combinations
thereof.
47. The dosage form of claim 1, in which the shell comprises a
release-modifying excipient selected from swellable erodible
hydrophilic materials.
48. The dosage form of claim 47, in which the release-modifying
excipient is croscarmellose sodium.
49. The dosage form of claim 1, in which the shell comprises
triethyl citrate as a plasticizer.
50. The dosage form of claim 33, in which the thermal reversible
carrier is polyethylene glycol having a molecular weight from about
100 to about 8000 Daltons.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to modified release dosage forms such
as modified release pharmaceutical compositions. More particularly,
this invention relates to modified release dosage forms comprising
a molded core, and a shell residing upon at least a portion of the
core.
[0003] 2. Background Information
[0004] Modified release pharmaceutical dosage forms have long been
used to optimize drug delivery and enhance patient compliance,
especially by reducing the number of doses of medicine the patient
must take in a day. For this purpose, it is often desirable to
modify the rate of release of a drug (one particularly preferred
type of active ingredient) from a dosage form into the
gastrointestinal (g.i.) fluids of a patient, especially to slow the
release to provide prolonged action of the drug in the body.
[0005] The rate at which an orally delivered pharmaceutical active
ingredient reaches its site of action in the body depends on a
number of factors, including the rate and extent of drug absorption
through the g.i. mucosa. To be absorbed into the circulatory system
(blood), the drug must first be dissolved in the g.i. fluids. For
many drugs, diffusion across the g.i. membranes is relatively rapid
compared to dissolution. In these cases, the dissolution of the
active ingredient is the rate limiting step in drug absorption, and
controlling the rate of dissolution allows the formulator to
control the rate of drug absorption into the circulatory system of
a patient.
[0006] An important objective of modified release dosage forms is
to provide a desired blood concentration versus time
(pharmacokinetic, or PK) profile for the drug. Fundamentally, the
PK profile for a drug is governed by the rate of absorption of the
drug into the blood, and the rate of elimination of the drug from
the blood. The type of PK profile desired depends, among other
factors, on the particular active ingredient, and physiological
condition being treated.
[0007] One particularly desirable PK profile for a number of drugs
and conditions, is one in which the level of drug in the blood is
maintained essentially constant (i.e. the rate of drug absorption
is approximately equal to the rate of drug elimination) over a
relatively long period of time. Such systems have the benefit of
reducing the frequency of dosing, improving patient compliance, as
well as minimizing side effects while maintaining full therapeutic
efficacy. A dosage form which provides a "zero-order," or constant,
release rate of the drug is useful for this purpose. Since
zero-order release systems are difficult to achieve, systems which
approximate a constant release rate, such as for example
first-order and square root of time profiles are often used to
provide sustained (prolonged, extended, or retarded) release of a
drug.
[0008] Another particularly desirable PK profile is achieved by a
dosage form that delivers a delayed release dissolution profile, in
which the release of drug from the dosage form is delayed for a
pre-determined time after ingestion by the patient. The delay
period ("lag time") can be followed either by prompt release of the
active ingredient ("delayed burst"), or by sustained (prolonged,
extended, or retarded) release of the active ingredient ("delayed
then sustained").
[0009] 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.
[0010] One classic diffusion-controlled release system comprises a
"reservoir" containing the active ingredient, surrounded by a
"membrane" through which the active ingredient must diffuse in
order to be absorbed into the bloodstream of the patient. The rate
of drug release, (dM/dt) depends on the area (A) of the membrane,
the diffusional pathlength (l), the concentration gradient
(.DELTA.C) of the drug across the membrane, the partition
coefficient (K) of the drug into the membrane, and the diffusion
coefficient (D):
dM/dt={ADK.DELTA.C}/1
[0011] Since one or more of the above terms, particularly the
diffusional pathlength and concentration gradient tend to be
non-constant, diffusion-controlled systems generally deliver a
non-constant release rate. In general, the rate of drug release
from diffusion-controlled release systems typically follows first
order kinetics. One disadvantage of membrane-reservoir type systems
is their vulnerability to "dose dumping." The diffusional membrane
must remain intact without breach throughout the functional life of
the dosage form in order to prevent this occurrence and the
possibility of overdose along with the associated toxic side
effects. One typical type of diffusional membrane-reservoir systems
comprises a compressed tablet core which acts as the reservoir,
surrounded by a shell (or coating) which functions as the
diffusional membrane. Current core-shell systems are limited by the
available methods for manufacturing them, as well as the materials
that are suitable for use with the current methods. A shell, or
coating, which confers modified release properties is typically
applied via conventional methods, such as for example,
spray-coating in a coating pan. Pan-coating produces a single shell
which essentially surrounds the core. Defects that commonly occur
during coating, include "picking," "sticking," and "twinning," all
of which result in undesired holes in the coating, which lead to
dose dumping. The coating compositions that can be applied via
spraying are limited by their viscosity. High viscosity solutions
are difficult or impractical to pump and deliver through a spray
nozzle. Spray coating methods suffer the further limitations of
being time-intensive and costly. Several hours of spraying may be
required to spray an effective amount of coating to control the
release of an active ingredient. Coating times of 8 to 24 hours are
not uncommon.
[0012] Another common type of diffusion-controlled release system
comprises active ingredient, distributed throughout an insoluble
porous matrix through which the active ingredient must diffuse in
order to be absorbed into the bloodstream of the patient. The
amount of drug (M) released at a given time at sink conditions
(i.e. drug concentration at the matrix surface is much greater than
drug concentration in the bulk solution), depends on the area (A)
of the matrix, the diffusion coefficient (D), the porosity (E) and
tortuosity (T) of the matrix, the drug solubility (Cs) in the
dissolution medium, time (t) and the drug concentration (Cp) in the
dosage form:
M=A(DE/T(2Cp-ECs)(Cs)t).sup.1/2
[0013] It will be noted in the above relationship that the amount
of drug released is generally proportional to the square root of
time. Assuming factors such as matrix porosity and tortuosity are
constant within the dosage form, a plot of amount of drug released
versus the square root of time should be linear. One typical type
of diffusional matrix system may be prepared by compression of the
active ingredient along with a mixture of soluble and insoluble
materials designed to produce a desired porosity and tortuosity as
the soluble materials dissolve in the dissolution medium or
gastro-intestinal fluids.
[0014] A commonly used erosion-controlled release system comprises
a "matrix" throughout which the drug is distributed. The matrix
typically comprises a material which swells at the surface, and
slowly dissolves away layer by layer, liberating drug as it
dissolves. The rate of drug release, (dM/dt), in these systems
depends on the rate of erosion (dx/dt) of the matrix, the
concentration profile in the matrix, and the surface area (A) of
the system:
dM/dt=A{dx/dt} {f(C)}
[0015] Again, variation in one or more terms, such as surface area,
typically leads 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. One typical method of
preparing such eroding matrix systems is by compression of the
active ingredient blended with a mixture of compressible excipients
comprising water swellable erodible materials which create a
temporary barrier as they swell, and allow small amounts of active
ingredient to be released as the continuously receding surface
layer slowly dissolves in the dissolution medium or
gastro-intestinal fluids.
[0016] 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.l) depends on the thickness (h) of the erodible
layer, and the rate of erosion (dx/dt) of the matrix, which in turn
depends on the swelling rate and solubility of the matrix
components:
T.sub.l=h(dx/dt)
[0017] The cumulative amount of drug (M) released from these
systems at a given time generally follows the equation:
M=(dM/dt) (t-T.sub.l)
[0018] where dM/dt is generally described by either the
diffusion-controlled or erosion-controlled equations above, and
T.sub.l is the lag time.
[0019] Modified release dosage forms prepared via compression to
obtain either diffusional or eroding matrices are exemplified in
U.S. Pat. Nos. 5,738,874 and 6,294,200, and WO 99/51209. Compressed
dosage forms are limited by the achievable geometry's, as well as
the suitable materials for producing them.
[0020] WO 97/49384 describes a hot-melt extrudable mixture of a
therapeutic compound and a high molecular weight poly(ethylene
oxide). In some embodiments, the formulation further comprises
poly(ethylene glycol). The high molecular weight poly(ethylene
oxide)s employed have molecular weights ranging from about 1 to
about 10 million Daltons. The minimum ratio of high molecular
weight poly(ethylene oxide) to active ingredient is 80:20. The
dosage forms of this reference are limited in the amount of active
ingredient they can deliver. The maximum amount of active
ingredient that may be delivered in the composition is not more
that 20 weight percent of the composition. Typical hot-melt systems
are additionally limited by high processing temperatures, and are
therefore not optimal for delivering low melting, or heat labile
active ingredients. Typical hot-melt systems are additionally not
optimal for delivering coated particles of active ingredients, due
to both the high processing temperatures, and the high shear
imparted during processing through extruders or spray nozzles.
Typical hot-melt systems are additionally not optimal for applying
a coating thereon by conventional methods such as spraying,
dipping, or compression.
[0021] It would be desirable to have a versatile and cost-effective
method for preparing modified release matrix systems, which are not
susceptible to dose dumping. It would additionally be desirable to
have a method for preparing modified release matrix systems in a
variety of shapes, for either functional purposes, e.g. achieving a
desired release profile using certain advantageous geometries, or
for consumer preference purposes, such as swallowability, dosage
form elegance, and product identification and differentiation. It
would additionally be desirable to have a controlled release matrix
systems capable of delivering a relatively high level of active
ingredient in a relatively small dosage form. It would additionally
be desirable to have modified release matrix systems for delivering
low-melting or heat labile active ingredients. It would
additionally be desirable to have modified release matrix systems
capable of delivering coated particles of active ingredient. It
would additionally be desirable to have a method of applying a
shell to a molded core.
[0022] It is one object of this invention to provide a dosage form
in which at least one active ingredient contained therein exhibits
a modified release profile upon contacting of the dosage form with
a liquid medium. It is another object of this invention to provide
a dosage form in which at least one active ingredient contained
therein exhibits a modified release profile upon contacting of the
dosage form with a liquid medium. Other objects, features and
advantages of the invention will be apparent to those skilled in
the art from the detailed description set forth below.
SUMMARY OF THE INVENTION
[0023] In one embodiment, the dosage form of this invention
comprises: (a) at least one active ingredient; (b) a molded core
which is solid at room temperature; and (c) a shell which is in
contact with at least a portion of the core, wherein the dosage
form provides modified release of the active ingredient upon
contacting of the dosage form with a liquid medium.
[0024] In another embodiment, the molded core comprises one or more
active ingredients dispersed in a molded matrix.
[0025] In another embodiment, the shell is capable of providing
modified release of at least one active ingredient upon contacting
of the dosage form with a liquid medium.
[0026] In another embodiment, the shell is capable of providing a
time delay prior to the release o fat least one active ingredient
upon contacting of the dosage form with a liquid medium.
[0027] In another embodiment, the time delay is independent of the
pH of the liquid medium.
[0028] In another embodiment, the shell comprises at least about 30
percent by weight of a thermal-reversible carrier.
[0029] In another embodiment, the shell comprises at least one
active ingredient.
[0030] In another embodiment, the core comprises a molded
matrix.
[0031] In another embodiment, the core comprises at least one
active ingredient.
[0032] In another embodiment, the core is capable of providing
modified release of at least one active ingredient upon contacting
of the dosage form with a liquid medium.
[0033] In another embodiment, the core comprises one or more
release-modifying excipients.
[0034] In another embodiment, the release modifying excipient is
selected from the group consisting of swellable erodible
hydrophilic materials, pH-dependent polymers, insoluble edible
materials, and pore-formers, and derivatives, copolymers, and
combinations thereof.
[0035] In another embodiment, the core comprises at least 30% of
thermal-reversible carrier.
[0036] In another embodiment, the thermal-reversible carrier is
selected from the group consisting of polyethylene glycol,
thermoplastic polyethylene oxide, shellac, and derivatives,
copolymers, and combinations thereof.
[0037] In another embodiment, the thermal-reversible carrier has a
melting point of about 20 to about 110.degree. C.
[0038] In another embodiment, the core comprises a plurality of
particles which comprise at least one active ingredient.
[0039] In another embodiment, at least a portion of the particles
are coated with a coating capable of providing modified release of
the active ingredient contained therein upon contacting of the
coated particles with a liquid medium.
[0040] In another embodiment, at least a portion of the particles
are coated with a coating comprising 10-100 wt. % of a
release-modifying polymer selected from the group consisting of
pH-dependent polymers, water-soluble polymer, water-insoluble
polymers, and copolymers and derivatives and mixtures thereof.
[0041] In another embodiment, upon contacting of the dosage form
with a liquid medium, a time delay occurs prior to release of at
least a portion of the active ingredient.
[0042] In another embodiment, the portion of the active ingredient
released after the time delay is released in a sustained
manner.
[0043] In another embodiment, the dosage form comprises first and
second active ingredients which are the same or different, and upon
contacting of the dosage form with a liquid medium, the first
active ingredient is released in a sustained manner, and a time
delay precedes release of the second active ingredient.
[0044] In another embodiment, the shell comprises a first active
ingredient and the core comprises a second active ingredient which
may be the same or different than the first active ingredient, and
upon contacting of the dosage form with a liquid medium, immediate
release of the first active ingredient occurs followed by a time
delay, followed by release of the second active ingredient.
[0045] In another embodiment, the shell comprises a first active
ingredient and the core comprises a second active ingredient which
may be the same or different than the first active ingredient, and
upon contacting of the dosage form with a liquid medium, immediate
release of the first active ingredient occurs followed by sustained
release of the second active ingredient.
[0046] In another embodiment, the shell comprises a first active
ingredient and the core comprises particles comprising a second
active ingredient which may be the same or different than the first
active ingredient, and upon contacting of the dosage form with a
liquid medium, immediate release of the first active ingredient
occurs followed by sustained release of the second active
ingredient.
[0047] In another embodiment, the level of active ingredient is at
least about 25 weight percent of the core.
[0048] In another embodiment, the molded matrix comprises a thermal
reversible carrier having a melting point from about 20 to about
100.degree. C.
[0049] In another embodiment, the molded matrix comprises a thermal
reversible carrier selected from the group consisting of
thermoplastic polyalkalene oxides, low melting hydrophobic
materials, thermoplastic polymers, the thermoplastic starches, and
combinations thereof.
[0050] In another embodiment, the molded matrix comprises a
low-melting thermal-reversible carrier selected from the group
consisting of polycaprolactones, polyvinyl acetate, polyalkylene
glycols, and combinations thereof at a level of about 30 to about
70 weight percent of the matrix.
[0051] In another embodiment, the molded matrix comprises a
thermal-reversible carrier selected from the group consisting of
polyethylene glycol or polyethylene oxide at a level from about 10
to about 100 weight percent of the matrix.
[0052] In another embodiment, the molded matrix further comprises a
thermoplastic polyethylene oxide at a level of about 15 to about
25%.
[0053] In another embodiment, the shell has a thickness from about
300 to about 2000 microns.
[0054] In another embodiment, the shell has a thickness from about
150 to about 400 microns.
[0055] In another embodiment, the weight of the shell is from about
50 to about 400 percent of the weight of the core.
[0056] In another embodiment, the weight of the shell is from about
20 to about 100 percent of the weight of the core.
[0057] In another embodiment, the core is substantially free of
pores having a diameter of 0.5 to 5.0 microns.
[0058] In another embodiment, the thermal reversible carrier is
polyethylene glycol having a molecular weight from about 100 to
about 8000 Daltons.
[0059] In another embodiment, the molded matrix comprises a
release-modifying excipient.
[0060] In another embodiment, the release modifying polymer is
shellac.
[0061] In another embodiment, the release-modifying excipient is
croscarmellose sodium.
[0062] In another embodiment, the dosage form further comprises
tributyl citrate as a plasticizer.
[0063] In another embodiment, the shell comprises a film-former
selected from the group consisting of cellulose acetate, ammonio
methacrylate copolymer type B, shellac,
hydroxyporoylmethylcellulose, polyethylene oxide, and combinations
thereof.
[0064] In another embodiment, the shell comprises a
release-modifying excipient selected from swellable erodible
hydrophilic materials.
[0065] In another embodiment, the release-modifying excipient is
croscarmellose sodium.
[0066] In another embodiment, the shell comprises triethyl citrate
as a plasticizer.
BRIEF DESCRIPTION OF THE DRAWINGS
[0067] FIG. 1A depicts a cross-sectional side view of one
embodiment of the dosage form of this invention.
[0068] FIG. 1B depicts a cross-sectional side view of another
embodiment of the dosage from of this invention.
[0069] FIG. 2 depicts the % release of active ingredient vs. hours
measured for the dosage form of Example 1.
DETAILED DESCRIPTION OF THE INVENTION
[0070] As used herein, the term "dosage form" applies to any solid
object, semi-solid, or liquid composition designed to contain a
specific pre-determined amount (i.e. dose) of a certain ingredient,
for example an active ingredient as defined below. Suitable dosage
forms may be pharmaceutical drug delivery systems, including those
for oral administration, buccal administration, rectal
administration, topical or mucosal delivery, or subcutaneous
implants, or other implanted drug delivery systems; or compositions
for delivering minerals, vitamins and other nutraceuticals, oral
care agents, flavorants, and the like. Preferably the dosage forms
of the present invention are considered to be solid, however they
may contain liquid or semi-solid components. In a particularly
preferred embodiment, the dosage form is an orally administered
system for delivering a pharmaceutical active ingredient to the
gastro-intestinal tract of a human.
[0071] The dosage forms of the invention exhibit modified release
of one or more active ingredients contained therein. One or more
active ingredients may be found within the shell, molded matrix, or
coated or uncoated particles distributed therethrough. As used
herein, the term "modified release" shall apply to dosage forms,
matrices, particles, coatings, 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 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 shell, core, composition, or
portion thereof providing the modification; for example the
modified release active ingredient may be contained in the core,
and the modification may be provided by an 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 a portion thereof, or a combination of
these parts of the dosage form.
[0072] A first embodiment of this invention is depicted in FIG. 1A,
which is a cross-sectional side view of a dosage form 202 which
comprises a molded core 204 comprising a molded matrix and a shell
203 which is in contact with at least a portion of the core 204. In
FIG. 1A the core 204 comprises a plurality of uncoated particles
206 although this is not required in this embodiment of the
invention. The active ingredient may be contained within the
matrix, the uncoated particles (if employed), the shell; or a
combination thereof. The dosage form provides modified release of
the active ingredient upon contacting of the dosage form with a
liquid medium such as water, gastrointestinal fluid and the like.
Either the shell or the matrix or a combination thereof may provide
modified release of the active ingredient.
[0073] Another embodiment of this invention is depicted in FIG. 1B,
which is a cross-sectional side view of a dosage form 252 which
comprises a molded core 254 comprising a molded matrix and a shell
253 which is in contact with at least a portion of the core 254. In
FIG. 1B the core 254 comprises a plurality of coated particles 256.
The active ingredient may be contained within the matrix, the
coated particles, the shell, or a combination thereof. The dosage
form provides modified release of the active ingredient upon
contacting of the dosage form with a liquid medium such as water,
gastrointestinal fluid and the like. Any of the shell, the coating,
the matrix or a combination thereof may provide modified release of
the active ingredient
[0074] The active ingredient employed in the dosage forms of this
invention may be found within the core, the particles (whether
coated or uncoated), the shell or a combination thereof. Suitable
active ingredients for use in this invention include for example
pharmaceuticals, minerals, vitamins and other nutraceuticals, oral
care agents, flavorants and mixtures thereof. Suitable
pharmaceuticals include analgesics, anti-inflammatory agents,
antiarthritics, anesthetics, antihistamines, antitussives,
antibiotics, anti-infective agents, antivirals, anticoagulants,
antidepressants, antidiabetic agents, antiemetics, antiflatulents,
antifungals, antispasmodics, appetite suppressants,
bronchodilators, cardiovascular agents, central nervous system
agents, central nervous system stimulants, decongestants,
diuretics, expectorants, gastrointestinal agents, migraine
preparations, motion sickness products, mucolytics, muscle
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep-aids, urinary tract agents and mixtures
thereof.
[0075] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0076] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubble gum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0077] Examples of suitable gastrointestinal agents include
antacids such as calcium carbonate, magnesium hydroxide, magnesium
oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate,
dihydroxyaluminum sodium carbonate; stimulant laxatives, such as
bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,
castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures
thereof; H2 receptor antagonists, such as famotadine, ranitidine,
cimetadine, nizatidine; proton pump inhibitors such as omeprazole
or lansoprazole; gastrointestinal cytoprotectives, such as
sucraflate and misoprostol; gastrointestinal prokinetics, such as
prucalopride, antibiotics for H. pylori, such as clarithromycin,
amoxicillin, tetracycline, and metronidazole; antidiarrheals, such
as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such
as ondansetron, analgesics, such as mesalamine.
[0078] In one embodiment of the invention, the active ingredient or
agent may be selected from bisacodyl, famotadine, ranitidine,
cimetidine, prucalopride, diphenoxylate, loperamide, lactase,
mesalamine, bismuth, antacids, and pharmaceutically acceptable
salts, esters, isomers, and mixtures thereof.
[0079] In another embodiment, the active agent is selected from
analgesics, anti-inflammatories, and antipyretics, e.g.
non-steroidal anti-inflammatory drugs (NSAIDs), including propionic
acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the
like; acetic acid derivatives, e.g. indomethacin, diclofenac,
sulindac, tolmetin, and the like; fenamic acid derivatives, e.g.
mefanamic acid, meclofenamic acid, flufenamic acid, and the like;
biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal,
and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam,
meloxicam, and the like. In a particularly preferred embodiment,
the active agent 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.
[0080] In another embodiment of the invention, the active
ingredient may be selected from pseudoephedrine,
phenylpropanolamine, chlorpheniramine, dextromethorphan,
diphenhydramine, doxylamine, astemizole, norastemizole,
terfenadine, fexofenadine, loratadine, desloratadine, cetirizine,
mixtures thereof and pharmaceutically acceptable salts, esters,
isomers, and mixtures thereof.
[0081] 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.
[0082] The active ingredient or ingredients are present in the
dosage form in a therapeutically effective amount, which is an
amount that produces the desired therapeutic response upon oral
administration and can be readily determined by one skilled in the
art. In determining such amounts, the particular active ingredient
being administered, the bioavailability characteristics of the
active ingredient, the dose regime, the age and weight of the
patient, and other factors must be considered, as known in the art.
In a preferred embodiment the dosage form comprises one or more
active ingredient or ingredients at a combined level of more than
about 20 weight percent, e.g. at least about 25 weight percent, or
at least about 30 weight percent, or at least about 50 weight
percent of the dosage form.
[0083] The active ingredient or ingredients may be present in the
dosage form in any form. For example, the active ingredient may be
dispersed at the molecular level, e.g. melted or dissolved, within
the dosage form, or may be in the form of particles, which in turn
may be coated or uncoated. If the active ingredient is in form of
particles , the particles (whether coated or uncoated) typically
have an average particle size of about 1-2000 microns. In one
preferred embodiment, such particles are crystals having an average
particle size of about 1-300 microns. In another preferred
embodiment, the particles are granules or pellets having an average
particle size of about 50-2000 microns, preferably about 50-1000
microns, most preferably about 100-800 microns.
[0084] The molded matrix of the present invention is made by
molding, preferably using a solvent-free process. In a preferred
embodiment, the matrix comprises a flowable material. The flowable
material may be any edible material that is flowable at a
temperature between about 37.degree. C. and about 250.degree. C.,
and that is solid, semi-solid, or can form a gel at a temperature
between about -10.degree. C. and about 80.degree. C. In a preferred
embodiment, the flowable material comprises 10-100% by weight of a
thermal reversible carrier having a melting point of less than
about 100.degree. C., preferably from about 20 to about 100.degree.
C.; and optionally up to about 30 weight percent of various
adjuvants such as for example plasticizers, gelling agents,
colorants, stabilizers, preservatives, and the like as known in the
art. The matrix may optionally further comprise up to about 55
weight percent of one or more release-modifying excipients as
described below.
[0085] In embodiments of this invention in which the matrix
comprises 10-100% by weight of a thermal reversible carrier having
a melting point of less than about 100.degree. C., such low melting
materials may include, for example thermoplastic polyalkalene
oxides, low melting hydrophobic materials, thermoplastic polymers,
thermoplastic starches, and the like. Preferred low-melting
materials may be selected from thermoplastic polymers,
thermoplastic polyalkalene oxides, low melting hydrophobic
materials, and combinations thereof.
[0086] Suitable thermal-reversible carriers for making the molded
matrix include are thermoplastic materials typically having a
melting point below about 110.degree. C., more preferably between
about 20 and about 100.degree. C. Examples of suitable
thermal-reversible carriers for solvent-free molding include
thermoplastic polyalkalene glycols, thermoplastic polyalkalene
oxides, low melting hydrophobic materials, thermoplastic polymers,
thermoplastic starches, and the like. Preferred thermal-reversible
carriers include polyethylene glycol and polyethylene oxide.
Suitable thermoplastic polyalkylene glycols for use as
thermal-reversible carriers include polyethylene glycol having
molecular weight from about 100 to about 20,000, e.g. from about
100 to about 8,000, say about 1000 to about 8,000 Daltons. Suitable
thermoplastic polyalkalene oxides include polyethylene oxide having
a molecular weight from about 1,000 to about 900,000 Daltons.
Suitable low-melting hydrophobic materials for use as
thermal-reversible carriers include fats, fatty acid esters,
phospholipids, and waxes which are solid at room temperature,
fat-containing mixtures such as chocolate; and the like. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes which are solid at room temperature include carnauba wax,
spermaceti wax, beeswax, candelilla wax, shellac wax,
microcrystalline wax, and paraffin wax.
[0087] In one preferred embodiment, the matrix comprises a
low-melting thermal-reversible carrier selected from
polycaprolactones, polyvinyl acetate, polyalkylene glycols and
combinations thereof at a level of about 30 to about 70 weight
percent, e.g. about 35 to about 50 weight percent of the matrix.
The low-melting thermal-reversible polymer has a melting point of
less than about 100.degree. C. In one such embodiment, the matrix
further comprises a thermoplastic polyethylene oxide at a level of
about 15 to about 25% as a strengthening polymer. Polyethylene
oxides having suitable thermoplastic properties for use in the
present invention have a molecular weight of about 100,000 to about
900,000. In another such embodiment, the matrix is substantially
free of poly(ethylene oxide), e.g. contains less than 1%, or
contains less than 0.1 weight percent of poly(ethylene oxide).
[0088] In other embodiments of this invention in which it is not
required that the matrix comprise a material have a melting point
of less than 100.degree. C., the matrix composition may comprise
any of the materials set forth above having a melting point of less
than 100.degree. C., and the matrix composition may also comprise
other materials such as release modifying agents, various adjuvants
such as for example plasticizers, gelling agents, colorants,
stabilizers, preservatives, and the like as known in the art.
[0089] Suitable release-modifying moldible excipients for making
the molded matrix, or a portion thereof, by molding include but are
not limited to swellable erodible hydrophilic materials,
pH-dependent polymers, insoluble edible materials, and
pore-formers.
[0090] Suitable swellable erodible hydrophilic materials for use as
release-modifying excipients for making the molded matrix, or a
portion thereof, by molding include water swellable cellulose
derivatives, polyalkalene glycols, thermoplastic polyalkalene
oxides, acrylic polymers, hydrocolloids, clays, gelling starches,
and swelling cross-linked polymers, and derivatives, copolymers,
and combinations thereof. Examples of suitable water swellable
cellulose derivatives include sodium carboxymethylcellulose,
cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),
hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose,
hydroxybutylcellulose,hydroxyphenylcellulose, hydroxyethylcellulose
(HEC), hydroxypentylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples
of suitable polyalkalene glyclols include polyethylene glycol.
Examples of suitable thermoplastic polyalkalene oxides include poly
(ethylene oxide). Examples of suitable acrylic polymers include
potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, CARBOPOL (high-molceular weight
cross-linked acrylic acid homopolymers and copolymers), and the
like. Examples of suitable hydrocolloids include alginates, agar,
guar gum, locust bean gum, kappa carrageenan, iota carrageenan,
tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan. Examples of suitable
clays include smectites such as bentonite, kaolin, and laponite;
magnesium trisilicate, magnesium aluminum silicate, and the like,
and derivatives and mixtures thereof. Examples of suitable gelling
starches include acid hydrolyzed starches, swelling starches such
as sodium starch glycolate, and derivatives thereof. Examples of
suitable swelling cross-linked polymers include cross-linked
polyvinyl pyrrolidone, cross-linked agar, and cross-linked
carboxymethylcellose sodium.
[0091] Suitable pH-dependent polymers for use as release-modifying
excipients for making the molded matrix or a portion thereof by
molding include enteric cellulose derivatives, for example
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, cellulose acetate phthalate;
natural resins such as shellac and zein; enteric acetate
derivatives such as for example polyvinylacetate phthalate,
cellulose acetate phthalate, acetaldehyde dimethylcellulose
acetate; and enteric acrylate derivatives such as for example
polymethacrylate-based polymers such as poly(methacrylic acid,
methyl methacrylate) 1:2, which is commercially available from Rohm
Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic
acid, methyl methacrylate) 1:1, which is commercially available
from Rohm Pharma GmbH under the tradename EUDRAGIT L, and the like,
and derivatives, salts, copolymers, and combinations thereof.
[0092] Suitable insoluble edible materials for use as
release-modifying excipients for making the molded matrix, or a
portion thereof, by molding include water-insoluble polymers, and
low-melting hydrophobic materials. Examples of suitable
water-insoluble polymers include ethylcellulose, polyvinyl
alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate
and its derivatives, acrylates, methacrylates, acrylic acid
copolymers; and the like and derivatives, copolymers, and
combinations thereof. Suitable low-melting hydrophobic materials
include fats, fatty acid esters, phospholipids, and waxes. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes include carnauba wax, spermaceti wax, beeswax, candelilla
wax, shellac wax, microcrystalline wax, and paraffin wax;
fat-containing mixtures such as chocolate; and the like.
[0093] Suitable pore-formers for use as release-modifying
excipients for making the molded matrix or a portion thereof by
molding include water-soluble organic and inorganic materials. In
one embodiment the pore former is hydroxypropylmethylcellulose.
Examples of suitable water-soluble organic materials include water
soluble polymers including water soluble cellulose derivatives such
as hydroxypropylmethylcellulose, and hydroxypropylcellulose; water
soluble carbohydrates such as sugars, and starches; water soluble
polymers such as polyvinylpyrrolidone and polyethylene glycol, and
insoluble swelling polymers such as microcrystalline cellulose.
Examples of suitable water soluble inorganic materials include
salts such as sodium chloride and potassium chloride and the like
and/or mixtures thereof.
[0094] Suitable plasticizers for making the molded matrix, or a
portion thereof, by molding, include triacetin, acetylated
monoglyceride, rape oil, olive oil, sesame oil, acetyltributyl
citrate, glycerin sorbitol, diethyloxalate, diethylmalate, diethyl
fumarate, dibutyl succinate, diethylmalonate, dioctylphthalate,
dibutylsuccinate, triethylcitrate, tributylcitrate,
glyceroltributyrate, propylene glycol, polyethylene glycols,
hydrogenated castor oil, fatty acids, substituted triglycerides and
glycerides, and the like.
[0095] The matrix may be in a variety of different shapes. For
example, the matrix 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
matrix has one or more major faces. For example in certain
embodiments matrix surface may have two opposing major faces formed
by contact with upper and lower mold surfaces. In such embodiments
the core surface may further comprise a "belly-band" located
between the two major faces, and formed by contact with the side
walls in the mold.
[0096] In one embodiment, the matrix is prepared by thermal setting
molding using the method and apparatus described in copending U.S.
patent application Ser. No. 09/966,450, pages 57-63, the disclosure
of which is incorporated herein by reference. In this embodiment,
the matrix 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).
[0097] In another embodiment, the matrix is prepared by thermal
cycle molding using the method and apparatus described in copending
U.S. patent application Ser. No. 09/966,497, pages 27-51, the
disclosure of which is incorporated herein by reference. In this
embodiment, the matrix is formed by injecting a starting material
in flowable form into a heated molding chamber. The starting
material preferably comprises an active ingredient and a
thermoplastic material at a temperature above the set temperature
of the thermoplastic 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).
[0098] According to these methods, the starting material must be in
flowable form. For example, it may comprise solid particles
suspended in a molten matrix, for example a polymer matrix. The
starting material may be completely molten or in the form of a
paste. The starting material may comprise an active ingredient
dissolved in a molten material. Alternatively, the starting
material may be made by dissolving and/or suspending a solid in a
solvent, which solvent is then evaporated from the starting
material after it has been molded.
[0099] If particles are contained in the matrix, the particles
(whether coated or uncoated) typically have an average particle
size of about 1-2000 microns. In one preferred embodiment, the
particles are crystals of the active ingredient or ingredients, and
the average particle size is about 1-300 microns. In another
preferred embodiment, the particles are granules or pellets, and
the average particle size is about 50-2000 microns, preferably
about 50-1000 microns, most preferably about 100-800 microns.
[0100] In particular embodiments of this invention in which
uncoated particles are employed, the particles may comprise active
ingredient as described herein, or may be inactive particles
included for example to provide a visual distinction to the
appearance of the dosage form.
[0101] In particular embodiments of this invention in which coated
particles are employed, the particles may be as described herein,
and the particle coating may comprise In particular embodiments of
this invention in which coated particles are employed, the
particles may be as described herein, and the particle coating may
comprise about 10-100 weight percent (based on the weight of the
coating) of a film former; optionally up to about 50 weight percent
based on the weight of the coating of a pore former; and optionally
up to about 30 weight percent of various adjuvants or excipients
such as plasticizers etc. The particles may be coated using
conventional coating technology which is well known to those
skilled in the art including microencapsulation techniques such as
coacervation, spray-drying, and fluidized bed coating including
tangential spray rotor coating and bottom spray wurster coating.
Examples of suitable particle coating methods and materials can be
found in U.S. Pat. Nos. 5,286,497; 4,863,742; 4,173,626; 4,980,170;
4,984,240; 5,912,013; 6,270,805; and 6,322,819. Such coated
particles may provide controlled release of the active ingredient
contained therein in certain embodiments.
[0102] Suitable film formers for particle coating include, but are
not limited to, film-forming water soluble polymers, film-forming
proteins, film-forming water insoluble polymers, and film-forming
pH-dependent polymers. In one embodiment, the film-former for
particle coating may be selected from cellulose acetate, ammonio
methacrylate copolymer type B, shellac,
hydroxypropylmethylcellulose, and polyethylene oxide, and
combinations thereof.
[0103] Suitable film-forming water soluble polymers for particle
coating include water soluble vinyl polymers such as
polyvinylalcohol; water soluble polycarbohydrates such as
hydroxypropyl starch, hydroxyethyl starch, pullulan, methylethyl
starch, carboxymethyl starch, pre-gelatinized starches, and
film-forming modified starches; water swellable cellulose
derivatives such as hydroxypropyl cellulose (HPC),
hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC),
hydroxyethylmethylcellulose (HEMC), hydroxybutylmethylcellulose
(HBMC), hydroxyethylethylcellulose (HEEC), and
hydroxyethylhydroxypropylmethyl cellulose (HEMPMC); water soluble
copolymers such as methacrylic acid and methacrylate ester
copolymers, polyvinyl alcohol and polyethylene glycol copolymers,
polyethylene oxide and polyvinylpyrrolidone copolymers; and
derivatives and combinations thereof.
[0104] Suitable film-forming proteins may be natural or chemically
modified, and include gelatin, whey protein, myofibrillar proteins,
coaggulatable proteins such as albumin, casein, caseinates and
casein isolates, soy protein and soy protein isolates, zein;; and
polymers, derivatives and mixtures thereof.
[0105] In embodiments in which the particle coating confers
modified release to one or more active ingredients contained in the
particle, suitable film formers may be selected from film forming
water insoluble polymers; film forming pH-dependent polymers; and
copolymers and combinations thereof. In certain such embodiments in
which the particle coating functions as a diffusional membrane, the
release-modifying particle coating preferably comprises a pore
former.
[0106] Suitable film forming water insoluble polymers for use in
release-modifying particle coatings include for example
ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives,
acrylates, methacrylates, acrylic acid copolymers; and the like and
derivatives, copolymers, and combinations thereof.
[0107] Suitable film forming pH-dependent polymers for use in
release-modifying particle coatings include for example enteric
cellulose derivatives, such as for example hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate
succinate, cellulose acetate phthalate; natural resins, such as
shellac and zein; enteric acetate derivatives such as for example
polyvinylacetate phthalate, cellulose acetate phthalate,
acetaldehyde dimethylcellulose acetate; and enteric acrylate
derivatives such as for example polymethacrylate-based polymers
such as poly(methacrylic acid, methyl methacrylate) 1:2, which is
commercially available from Rohm Pharma GmbH under the tradename
EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1,
which is commercially available from Rohm Pharma GmbH under the
tradename EUDRAGIT L; and the like, and derivatives, salts,
copolymers, and combinations thereof.
[0108] Suitable pore formers for use in release-modifying particle
coatings include water-soluble organic and inorganic materials. In
one embodiment the pore former is selected from
hydroxypropylcellulose and hydroxypropylmethylcellulose. Examples
of suitable water-soluble organic materials include water soluble
cellulose derivatives such as hydroxypropylmethylcellulose, and
hydroxypropylcellulose; water soluble carbohydrates such as sugars,
and starches; water soluble polymers such as polyvinylpyrrolidone
and polyethylene glycol, and insoluble swelling polymers such as
microcrystalline cellulose. Examples of suitable water soluble
inorganic materials include salts such as sodium chloride and
potassium chloride and the like and/or mixtures thereof.
[0109] Examples of suitable adjuvants or excipients for particle
coatings include plasticizers, detackifiers, humectants,
surfactants, anti-foaming agents, colorants, opacifiers, and the
like. Suitable plasticizers for making the core, the shell, or a
portion thereof, by molding include, but not be limited to
polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl
citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as
castor oil, rape oil, olive oil, and sesame oil; surfactants such
as polysorbates, sodium lauryl sulfates, and dioctyl-sodium
sulfosuccinates; mono acetate of glycerol; diacetate of glycerol;
triacetate of glycerol; natural gums; triacetin; acetyltributyl
citrate; diethyloxalate; diethylmalate; diethyl fumarate;
diethylmalonate; dioctylphthalate; dibutylsuccinate;
glyceroltributyrate; hydrogenated castor oil; fatty acids;
substituted triglycerides and glycerides; and the like and/or
mixtures thereof. In one embodiment, the plasticizer is triethyl
citrate. In certain embodiments, the shell is substantially free of
plasticizers, i.e. contains less than about 1%, say less than about
0.01% of plasticizers.
[0110] In certain particularly preferred embodiments of this
invention, the dosage form releases one or more active ingredients
contained therein in a sustained, extended, prolonged, or retarded
manner, more preferably at a substantially constant rate upon
contacting of the dosage form with a liquid medium. In such
embodiments, the molded matrix may function as a diffusional matrix
or an eroding matrix. In embodiments in which the molded matrix
functions as an eroding matrix from which dispersed active
ingredient is liberated in a sustained, extended, prolonged, or
retarded manner, the molded matrix preferably comprises a
release-modifying moldable excipient selected from swellable
erodible hydrophilic materials, pH-dependent polymers, insoluble
edible materials, and combinations thereof. In embodiments in which
the molded matrix functions as a diffusional matrix through which
active ingredient contained therein is liberated in a sustained,
extended, prolonged, or retarded manner, the molded matrix
preferably comprises a release-modifying excipient selected from
combinations of insoluble edible materials and pore formers.
Alternately, in such embodiments in which the matrix 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.
[0111] In certain other preferred embodiments of this invention,
the dosage form releases at least first and second active
ingredients contained therein in a sustained, extended, prolonged,
or retarded manner. In certain such embodiments, the first and
second active ingredients have different unmodified release
characteristics; however the dosage form advantageously provides
different types of modification to the first and second active
ingredients, such that the dissolution profiles of the first and
second active ingredients from the dosage form are similar. In
certain other such embodiments, the dosage form advantageously
provides different types of modification to the first and second
active ingredients, such that the dissolution profiles of the first
and second active ingredients from the dosage form are
substantially different, e.g. the first and second active
ingredients are released from the dosage for at different rates or
times upon contacting of the dosage form with a liquid medium. In a
particularly preferred embodiment, the first and second active
ingredient are both released from the dosage form at a
substantially constant rate upon contacting of the dosage form with
a liquid medium.
[0112] In certain other embodiments of this invention, upon
contacting of the dosage form with a liquid medium, a time delay
occurs prior to release of at least a portion of one or more active
ingredients occurs followed by sustained release of the delayed
release active ingredient or ingredients. In such embodiments, the
time delay is provided by the dissolution of all or a portion of
the molded matrix, and the subsequent sustained release is provided
by one or more coatings on the particles of active ingredient. In
such embodiments, the molded matrix preferably comprises a release
modifying excipient selected from pH-dependent polymers. In such
embodiments, the particle coating preferably comprises a release
modifying excipient which may be selected from combinations of pore
formers and insoluble edible materials; swellable erodible
hydrophilic materials; pH-dependent polymers; and combinations
thereof.
[0113] In another particular embodiment of this invention, the
dosage form comprises first and second active ingredients which may
be the same or different, and upon contacting of the dosage form
with a liquid medium, sustained release of the first active
ingredient occurs, followed by sustained release of the second
active ingredient. In such embodiments, the sustained release of
first active ingredient is provided by the controlled dissolution
of all or a portion of the molded matrix, and the subsequent
sustained release of the second active ingredient is provided by
one or more coatings on the particles of active ingredient. In such
embodiments, the molded matrix preferably comprises a release
modifying excipient selected from swellable erodible hydrophilic
materials, pH-dependent polymers, insoluble edible materials, and
combinations thereof. In such embodiments, the particle coating
preferably comprises a release modifying excipient which may be
selected from combinations of pore formers and insoluble edible
materials; swellable erodible hydrophilic materials; pH-dependent
polymers, and combinations thereof.
[0114] In another particularly preferred embodiment of this
invention, the matrix comprises a first dose of active ingredient
and the particles contained therein comprise a second dose of
active ingredient which may be the same or different than the first
active ingredient, and upon contacting of the dosage form with a
liquid medium, immediate release of the first dose of active
ingredient occurs, followed by a lag time, which is in turn
followed by delayed release of the second dose active ingredient.
In such embodiments, the matrix preferably comprises materials
which exhibit rapid dissolution in gastro-intestinal fluids. For
example the immediate release shell portion or portions may
comprise readily soluble materials selected from water soluble or
water swellable thermoplastic film formers, water soluble or water
swellable thickeners, crystallizable and non-crystallizable
carbohydrates. In certain such embodiments, suitable water soluble
or water swellable thermoplastic film formers may be selected from
water swellable cellulose derivatives, thermoplastic starches,
polyalkalene glycols, polyalkalene oxides, and amorphous sugar
glass, and combinations thereof. In certain other such embodiments,
suitable film formers may be selected from film forming water
soluble polymers such as for example water soluble vinyl polymers,
water soluble polycarbohydrates, water swellable cellulose
derivatives, and water soluble copolymers; film-forming proteins,
and combinations thereof. In certain other such embodiments,
suitable thickeners may be selected from gelling polymers or
hydrocolloids; gelling starches, and crystallizable carbohydrates,
and combinations thereof. In certain other such embodiments,
suitable non-crystallizable carbohydrates may be selected from
polydextrose, starch hydrolysates, and non-crystallizable sugar
alcohols, and combinations thereof. In such embodiments, the
immediate release matrix will preferably liberate the coated
particles of delayed release active ingredient by being breached or
dissolved within 30 minutes in 900 ml water or 0.1 N HCl, or
phosphate buffer solution at 37.degree. C. with stirring by a USP
type 2 (Paddle method) at 50 or 100 rpm. In these embodiments, the
time delay is provided by a coating on the particles containing the
second dose of active ingredient. Preferably the delayed release
particle coating comprises a release-modifying excipient selected
from swellable erodible hydrophilic materials, and pH-dependent
polymers, and combinations thereof.
[0115] In another particularly preferred embodiment of this
invention, the matrix comprises a first dose of active ingredient
and the particles contained therein comprise a second dose of
active ingredient which may be the same or different than the first
dose of active ingredient, and upon contacting of the dosage form
with a liquid medium, immediate release of the first dose of active
ingredient occurs followed by sustained release of the second dose
of active ingredient. In such embodiments, the matrix preferably
comprises materials which exhibit rapid dissolution in
gastro-intestinal fluids. For example the immediate release shell
portion or portions may comprise readily soluble materials selected
from water soluble or water swellable thermoplastic film formers,
water soluble or water swellable thickeners, crystallizable and
non-crystallizable carbohydrates. In certain such embodiments,
suitable water soluble or water swellable thermoplastic film
formers may be selected from water swellable cellulose derivatives,
thermoplastic starches, polyalkalene glycols, polyalkalene oxides,
and amorphous sugar glass, and combinations thereof. In certain
other such embodiments, suitable film formers may be selected from
film forming water soluble polymers such as for example water
soluble vinyl polymers, water soluble polycarbohydrates, water
swellable cellulose derivatives, and water soluble copolymers;
film-forming proteins, and combinations thereof. In certain other
such embodiments, suitable thickeners may be selected from gelling
polymers or hydrocolloids; gelling starches, and crystallizable
carbohydrates. In certain other such embodiments, suitable
non-crystallizable carbohydrates may be selected from polydextrose,
starch hydrolysates, and non-crystallizable sugar alcohols. In such
embodiments, the immediate release matrix will preferably liberate
the coated particles of delayed release active ingredient by being
breached or dissolved within 30 minutes in 900 ml water or 0.1 N
HCl, or phosphate buffer solution at 37.degree. C. with stirring by
a USP type 2 (Paddle method) at 50 or 100 rpm. In these
embodiments, the sustained release is provided by a coating on the
particles containing the second dose of active ingredient.
Preferably the sustained release particle coating comprises a
release-modifying excipient which may be selected from combinations
of pore formers and insoluble edible materials; swellable erodible
hydrophilic materials; pH-dependent polymers.
[0116] Preferably the molded matrix of the present invention is
made by injecting the flowable material through an orifice into a
mold cavity, then solidifying the flowable material, according to
the method set forth herein, the disclosure of which is
incorporated herein by reference. In one such embodiment wherein
the dosage form comprises particles, the orifice has a diameter
greater than the diameter of the particles, e.g. from about 1000 to
about 4000 microns, say about 2000 to about 3000 microns. In
certain such embodiments the particles are introduced into the mold
cavity in the form of a flowable slurry or suspension in the matrix
material. The flowable slurry or suspension may be introduced under
pressure through the orifice. In one embodiment, the mold assembly
may be free of a valve at the injection point. In another
embodiment, the mold assembly may comprise an elastomeric plug type
valve which does not crush the particles upon closing.
[0117] Advantageously this method provides a versatile and
cost-effective process for preparing the modified release molded
matrix systems of the present invention. Advantageously, the method
of the present invention may be carried out at relatively low
processing temperatures, enabling the incorporation of low melting
active ingredients, heat labile active ingredients, and coated
particles into molded matrix dosage forms. Advantageously the
combination of methods and materials of the present invention
enable the incorporation of relatively high levels of active
ingredient into the molded matrix dosage form, and enable the
production of unique elegant dosage forms with transparent,
semi-transparent, or translucent matrices.
[0118] In certain embodiments of the invention, the shell contains
active ingredient which is released essentially immediately upon
ingestion of the dosage form. In these embodiments, the shell
preferably comprises materials which exhibit rapid dissolution in
gastro-intestinal fluids.
[0119] In certain other embodiments, the shell functions as a
diffusional membrane which contains pores through which fluids can
enter the dosage form, and dissolved active ingredient can be
released in a sustained, extended, prolonged or retarded manner. In
these embodiments, the rate of release of active ingredient from
the underlying core will depend upon the total pore area in the
shell, the pathlength of the pores, and the solubility and
diffusivity of the active ingredient (in addition to its rate of
release from the core portion itself). In preferred embodiments in
which the shell 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
may follow zero-order, first-order, or square-root of time
kinetics. In certain such embodiments, the diffusional membrane
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 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.
[0120] In certain other embodiments, the shell functions as an
eroding matrix from which active ingredient dispersed in the shell
is liberated by the dissolution of successive layers of the shell
surface. In these embodiments, the rate of active ingredient
release will depend on the dissolution rate of the matrix material
in the shell. 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 preferably comprises a swellable erodible
hydrophilic material.
[0121] In certain other embodiments, the shell functions as a
barrier to prevent release therethrough of an active ingredient
contained in the underlying core or core portion. In such
embodiments, active ingredient is typically released from a portion
of the core which is not covered by the barrier shell portion. Such
embodiments advantageously allow for control of the surface area
for release of the active ingredient. In certain particular
embodiments, for example, the surface area for release of active
ingredient can be maintained substantially constant over time. In a
particularly preferred embodiment, the release of at least one
active ingredient follows substantially zero-order kinetics. In
certain such embodiments, the barrier shell portion preferably
comprises a water insoluble material such as for example a water
insoluble polymer.
[0122] In certain other embodiments, the shell functions as a
delayed release coating to delay release of an active ingredient
which is contained in the core or a portion thereof. In these
embodiments, the lag-time for onset of active ingredient release
may be governed by erosion of the shell or diffusion through the
shell, or a combination thereof. In certain such embodiments, the
eroding matrix shell preferably comprises a swellable erodible
hydrophilic material.
[0123] In embodiments in which the shell functions to modify the
release of an active ingredient which is contained in the core or
the subject shell portion, the thickness of the shell portion is
critical to the release properties of the dosage form.
Advantageously the dosage forms of the invention can be made with
precise control over shell thickness. In a preferred embodiment in
which the shell functions to modify the release of an active
ingredient which is contained in the core or the shell, the shell
is made by the thermal cycle or thermal setting injection molding
methods and apparatus described herein.
[0124] The shell of the present invention may be prepared by
molding, using a solvent-free process, or a solvent-based process,
and depending on the method used, typically comprises a variety of
excipients which are useful for conferring desired properties to
the shell. The shell may optionally further comprise one or more
active ingredients.
[0125] In embodiments in which the shell is prepared using a
solvent-free molding process, the shell will typically comprise at
least about 30 percent, e.g. at least about 45 percent by weight of
a thermal-reversible carrier. The shell may optionally further
comprise up to about 55 weight percent of a release-modifying
excipient. The shell may optionally further comprise up to about 30
weight percent total of various plasticizers, adjuvants and
excipients. In certain embodiments in which the shell is prepared
by solvent-free molding, and functions to delay the release of one
or more active ingredients from an underlying core portion, the
release modifying excipient is preferably selected from swellable,
erodible hydrophilic materials.
[0126] In embodiments wherein the shell is prepared by a
solvent-free molding process, the shell typically has a thickness
of about 200 to about 4000 microns, e.g. about 300 to about 2000
microns.
[0127] In embodiments wherein the shell is prepared by a
solvent-free molding process, the flowable starting material may be
completely molten or in the form of a paste. The starting material
may comprise an active ingredient dissolved in a molten material.
The ingredients comprising the starting material are preferably
mixed together, and heated to a temperature above the melting
temperature of the thermal reversible carrier to produce the
flowable starting material.
[0128] In embodiments in which the shell is prepared using a
solvent-based molding process, the shell will typically comprise at
least about 10 weight percent, e.g. at least about 12 weight
percent or at least about 15 weight percent or at least about 20
weight percent or at least about 25 weight percent of a
film-former. Here, the solvent-molded shell may optionally further
comprise up to about 55 weight percent of a release-modifying
excipient. The solvent-molded shell may again also optionally
further comprise up to about 30 weight percent total of various
plasticizers, adjuvants, and excipients. 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 100 to about 600 microns, e.g. about 150 to about 400
microns.
[0129] In embodiments wherein the shell is prepared by a
solvent-based molding process, the flowable starting material may
be made by dissolving and/or suspending a solid in a solvent. The
solvent is then evaporated from the starting material after it has
been molded. The ingredients comprising the starting material are
preferably mixed together, and optionally heated, to disperse the
film former and optional other ingredients to produce the flowable
starting material.
[0130] The total weight of the shell portion or portions is
preferably about 20 percent to about 400 percent of the weight of
the core. In embodiments wherein the shell portion or portions
prepared by a solvent-free molding process, the total weight of the
shell portion or portions is typically from about 50 percent to
about 400 percent, e.g. from about 75 percent to about 400 percent,
or about 100 percent to about 200 percent of the weight of the
core. In embodiments wherein the shell portion or portions are
prepared by a solvent-based molding process, the total weight of
the shell portion or portions is typically from about 20 percent to
about 100 percent of the weight of the core.
[0131] Suitable thermal-reversible carriers for preparing the shell
by solvent-free molding typically have a melting point below about
110.degree. C., e.g. from about 20 to about 100.degree. C. Suitable
thermal-reversible carriers for preparing the shell by solvent-free
molding may be selected from the thermal-reversible carriers listed
herein for preparing the core by solvent-free molding. Particularly
preferred thermal-reversible carriers for preparing the shell by
solvent-free molding may be selected from polyethylene glycol,
thermoplastic polyethylene oxide, shellac, and combinations
thereof.
[0132] Suitable release modifying agents for making the shell
portion by solvent-free or solvent-based molding include but are
not limited to swellable erodible hydrophilic materials,
film-formers, pH dependent polymers, and pore-formers.
[0133] Suitable plasticizers for making the shell by solvent-free
or solvent-based molding include, but are not limited to
polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl
citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as
castor oil, rape oil, olive oil, and sesame oil; surfactants such
as polysorbates, sodium lauryl sulfates, and dioctyl-sodium
sulfosuccinates; mono acetate of glycerol; diacetate of glycerol;
triacetate of glycerol; natural gums; triacetin; acetyltributyl
citrate; diethyloxalate; diethylmalate; diethyl fumarate;
diethylmalonate; dioctylphthalate; dibutylsuccinate;
glyceroltributyrate; hydrogenated castor oil; fatty acids;
substituted triglycerides and glycerides; and the like and/or
mixtures thereof. In one embodiment, the plasticizer is triethyl
citrate. In certain embodiments, the shell is substantially free of
plasticizers, i.e. contains less than about 1%, say less than about
0.01% of plasticizers.
[0134] Suitable adjuvants and excipients for making the shell by
solvent-free or solvent-based molding include secondary film
formers such as for example shellac, secondary gelling agents, such
as for example cross-linked carboxymethylcellulose, cross-linked
polyvinylpyrrolidone, sodium starch glycolate, and the like, as
well as preservatives, high intensity sweeteners such as aspartame,
acesulfame potassium, sucralose, and saccharin; flavors,
antioxidants, surfactants, and coloring agents, many examples of
which are known in the art.
[0135] Suitable film-formers for preparing the shell by
solvent-based molding include, but are not limited to, film-forming
water soluble polymers, film-forming proteins, film-forming water
insoluble polymers, and film-forming pH-dependent polymers. In one
embodiment, the film-former for making the shell or portion thereof
by molding may be selected from cellulose acetate, ammonio
methacrylate copolymer type B, shellac,
hydroxypropylmethylcellulose, and polyethylene oxide, and
combinations thereof.
[0136] Suitable film-forming water soluble polymers include water
soluble vinyl polymers such as polyvinylalcohol (PVA); water
soluble polycarbohydrates such as hydroxypropyl starch,
hydroxyethyl starch, pullulan, methylethyl starch, carboxymethyl
starch, pre-gelatinized starches, and film-forming modified
starches; water swellable cellulose derivatives such as
hydroxypropyl cellulose (HPC), hydroxypropylmethyl cellulose
(HPMC), methyl cellulose (MC), hydroxyethylmethylcellulose (HEMC),
hydroxybutylmethylcellulose (HBMC), hydroxyethylethylcellulose
(HEEC), and hydroxyethylhydroxypropylmethyl cellulose (HEMPMC);
water soluble copolymers such as methacrylic acid and methacrylate
ester copolymers, polyvinyl alcohol and polyethylene glycol
copolymers, polyethylene oxide and polyvinylpyrrolidone copolymers;
and derivatives and combinations thereof.
[0137] Suitable film-forming proteins may be natural or chemically
modified, and include gelatin, whey protein, myofibrillar proteins,
coaggulatable proteins such as albumin, casein, caseinates and
casein isolates, soy protein and soy protein isolates, zein;; and
polymers, derivatives and mixtures thereof.
[0138] Suitable film-forming water insoluble polymers, include for
example ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives,
acrylates, methacrylates, acrylic acid copolymers; and the like and
derivatives, copolymers, and combinations thereof.
[0139] Suitable film-forming pH-dependent polymers include enteric
cellulose derivatives, such as for example hydroxypropyl
methylcellulose phthalate, hydroxypropyl methylcellulose acetate
succinate, cellulose acetate phthalate; natural resins, such as
shellac and zein; enteric acetate derivatives such as for example
polyvinylacetate phthalate, cellulose acetate phthalate,
acetaldehyde dimethylcellulose acetate; and enteric acrylate
derivatives such as for example polymethacrylate-based polymers
such as poly(methacrylic acid, methyl methacrylate) 1:2, which is
commercially available from Rohm Pharma GmbH under the tradename,
EUDRAGIT S, and poly(methacrylic acid, methyl methacrylate) 1:1,
which is commercially available from Rohm Pharma GmbH under the
tradename, EUDRAGIT L, and the like, and derivatives, salts,
copolymers, and combinations thereof.
[0140] One suitable hydroxypropylmethylcellulose compound for use
as a thermoplastic film-forming water soluble polymer is HPMC 2910,
which is a cellulose ether having a degree of substitution of about
1.9 and a hydroxypropyl molar substitution of 0.23, and containing,
based upon the total weight of the compound, from about 29% to
about 30% methoxyl groups and from about 7% to about 12%
hydroxylpropyl groups. HPMC 2910 is commercially available from the
Dow Chemical Company under the tradename METHOCEL E. METHOCEL E5,
which is one grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 4 to 6 cps (4 to 6
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. Similarly, METHOCEL E6, which
is another grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 5 to 7 cps (5 to 7
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. METHOCEL E15, which is
another grade of HPMC-2910 suitable for use in the present
invention, has a viscosity of about 15000 cps (15
millipascal-seconds) at 20.degree. C. in a 2% aqueous solution as
determined by a Ubbelohde viscometer. As used herein, "degree of
substitution" shall mean the average number of substituent groups
attached to a anhydroglucose ring, and "hydroxypropyl molar
substitution" shall mean the number of moles of hydroxypropyl per
mole anhydroglucose.
[0141] One suitable polyvinyl alcohol and polyethylene glycol
copolymer is commercially available from BASF Corporation under the
tradename KOLLICOAT IR.
[0142] As used herein, "modified starches" include starches that
have been modified by crosslinking, chemically modified for
improved stability or optimized performance, or physically modified
for improved solubility properties or optimized performance.
Examples of chemically-modified starches are well known in the art
and typically include those starches that have been chemically
treated to cause replacement of some of its hydroxyl groups with
either ester or ether groups. Crosslinking, as used herein, may
occur in modified starches when two hydroxyl groups on neighboring
starch molecules are chemically linked. As used herein,
"pre-gelatinized starches" or "instantized starches" refers to
modified starches that have been pre-wetted, then dried to enhance
their cold-water solubility. Suitable modified starches are
commercially available from several suppliers such as, for example,
A. E. Staley Manufacturing Company, and National Starch &
Chemical Company. One suitable film forming modified starch
includes the pre-gelatinized waxy maize derivative starches that
are commercially available from National Starch & Chemical
Company under the tradenames PURITY GUM and FILMSET, and
derivatives, copolymers, and mixtures thereof. Such waxy maize
starches typically contain, based upon the total weight of the
starch, from about 0 percent to about 18 percent of amylose and
from about 100% to about 88% of amylopectin.
[0143] Another suitable film forming modified starch includes the
hydroxypropylated starches, in which some of the hydroxyl groups of
the starch have been etherified with hydroxypropyl groups, usually
via treatment with propylene oxide. One example of a suitable
hydroxypropyl starch that possesses film-forming properties is
available from Grain Processing Company under the tradename,
PURE-COTE B790.
[0144] Suitable tapioca dextrins for use as film formers include
those available from National Starch & Chemical Company under
the tradenames CRYSTAL GUM or K-4484, and derivatives thereof such
as modified food starch derived from tapioca, which is available
from National Starch and Chemical under the tradename PURITY GUM
40, and copolymers and mixtures thereof.
[0145] In a preferred embodiment, the shell is prepared using the
molding methods and apparatuses described in copending U.S. patent
application Ser. No. 09/966,939, pages 27-51 and 57-63, which is
incorporated herein by reference in its entirety. The shell itself
may comprise at least one active ingredient.
[0146] In a preferred embodiment of the invention, the shell is
applied to the core in the form of a flowable material using the
thermal cycle method and apparatus described in copending U.S.
patent application Ser. No. 09/966,497, pages 27-51, the disclosure
of which is incorporated herein by reference. In this embodiment,
the shell is applied using a thermal cycle molding module having
the general configuration shown in FIG. 3 therein. 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 therein) for holding
shell flowable material. In addition, the thermal cycle molding
module is provided with a temperature control system for rapidly
heating and cooling the mold units. FIGS. 55 and 56 depict the
temperature control system 600.
[0147] The thermal cycle molding module is preferably of the type
shown in FIG. 28A of copending U.S. application Ser. No.
09/966,497, comprising a series of mold units 204. The mold units
204 in turn comprise upper mold assemblies 214, rotatable center
mold assemblies 212 and lower mold assemblies 210 as shown in FIG.
28C. Cores are continuously transferred to the mold assemblies,
which then close over the cores. The shell flowable material, which
is heated to a flowable state in reservoir 206, is injected into
the mold cavities created by the closed mold assemblies. The
temperature of the shell flowable material is then decreased,
hardening it. The mold assemblies open and eject the coated cores.
In one particular embodiment, coating is performed in two steps,
each half of the cores being coated separately as shown in the flow
diagram of FIG. 28B of copending U.S. application Ser. No.
09/966,497 via rotation of the center mold assembly.
[0148] In a preferred embodiment of the invention, the shell
completely surrounds the core.
[0149] In one particular embodiment of this invention, at least one
active ingredient contained within the dosage form exhibits a
delayed burst release profile. By "delayed burst release profile"
it is meant that the release of that particular active ingredient
from the dosage form is delayed for a pre-determined time after
ingestion by the patient, and the delay period ("lag time") is
followed by prompt (immediate) release of that active ingredient.
At least one shell portion of the present invention provides for
the delay period and is preferably substantially free of the active
ingredient to be released in a delayed burst manner. In such
embodiments, the delayed burst active ingredient is typically
contained within the corresponding underlying core portion. In
these embodiments, the core portion may be prepared by compression
or molding, and is formulated for immediate release, as is known in
the art, so that the core portion is readily soluble upon contact
with the dissolution medium. In such embodiments the core portion
preferably comprises a disintegrant, and optionally comprises
additional excipients such as fillers or thermoplastic materials
selected from water-soluble or low-melting materials, and
surfactants or wetting agents. In these embodiments, the
dissolution of the burst release active ingredient, after the delay
period, meets USP specifications for immediate release tablets
containing that active ingredient. For example, for acetaminophen
tablets, USP 24 specifies that in pH 5.8 phosphate buffer, using
USP apparatus 2 (paddles) at 50 rpm, at least 80% of the
acetaminophen contained in the dosage form is released therefrom
within 30 minutes after dosing, and for ibuprofen tablets, USP 24
specifies that in pH 7.2 phosphate buffer, using USP apparatus 2
(paddles) at 50 rpm, at least 80% of the ibuprofen contained in the
dosage form is released therefrom within 60 minutes after dosing.
See USP 24, 2000 Version, 19-20 and 856 (1999).
[0150] In another particular embodiment of this invention at least
one active ingredient contained within the dosage form exhibits a
delayed and sustained release profile. By "delayed then sustained
release profile" it is meant that the release of that particular
active ingredient from the dosage form is delayed for a
pre-determined time after ingestion by the patient, and the delay
period ("lag time") is followed by sustained (prolonged, extended,
or retarded) release of that active ingredient. At least one shell
portion of the present invention provides for the delay period, and
is preferably substantially free of the active ingredient to be
released in a delayed then sustained manner. In such embodiments,
the delayed then sustained release active ingredient is preferably
contained within the corresponding underlying core portion. In such
embodiments the core portion may function for example as an eroding
matrix or a diffusional matrix, or an osmotic pump. In embodiments
in which the core portion functions as a diffusional matrix through
which active ingredient is liberated in a sustained, extended,
prolonged, or retarded manner, the core portion preferably
comprises a release-modifying excipient selected from combinations
of insoluble edible materials and pore-formers. Alternately, in
such embodiments in which the core portion is prepared by molding,
the thermal-reversible carrier may function by dissolving and
forming pores or channels through which the active ingredient may
be liberated. In embodiments in which the core portion functions as
an eroding matrix from which dispersed active ingredient is
liberated in a sustained, extended, prolonged, or retarded manner,
the core portion preferably comprises a release-modifying
compressible or moldable excipient selected from swellable erodible
hydrophilic materials, pH-dependent polymers, and combinations
thereof.
[0151] In another particularly preferred embodiment of this
invention, the dosage form comprises first and second active
ingredients which may be the same or different, and upon contacting
of the dosage form with a liquid medium, delayed release of the
first active ingredient occurs followed by sustained release of the
second active ingredient.
[0152] In another particularly preferred embodiment of this
invention, the shell comprises a first active ingredient and the
core comprises a second active ingredient (for example, within the
matrix or coated or uncoated particles or a combination thereof)
which may be the same or different than the first active
ingredient, and upon contacting of the dosage form with a liquid
medium, immediate release of the first active ingredient occurs
followed by delayed release of the second active ingredient.
[0153] In another particularly preferred embodiment of this
invention, the shell comprises a first active ingredient and the
core comprises a second active ingredient (for example, within the
matrix or coated or uncoated particles or a combination thereof)
which may be the same or different than the first active
ingredient, and upon contacting of the dosage form with a liquid
medium, immediate release of the first active ingredient occurs
followed by sustained release of the second active ingredient.
[0154] In one embodiment of this invention, the core or matrix or
shell of the present invention, whether prepared by a solvent-free
molding process, or by a solvent-based molding process, are
substantially free of pores having a diameter of 0.5-5.0 microns.
As used herein, "substantially free" means that the shell portion
or portions have a pore volume of less than about 0.02 cc/g,
preferably less than about 0.01 cc/g, more preferably less than
about 0.005 cc/g in the pore diameter range of 0.5 to 5.0 microns.
In contrast, typical compressed materials have pore volumes of more
than about 0.02 cc/g in this diameter range. In another embodiment
of this invention, the core is a molded core and the core or core
portions are substantially free of pores having a diameter of
0.5-5.0 microns.
[0155] The pore volume, pore diameter and density 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.
[0156] Equipment used for pore volume measurements:
[0157] 1. Quantachrome Instruments PoreMaster 60.
[0158] 2. Analytical Balance capable of weighing to 0.0001 g.
[0159] 3. Desiccator.
[0160] Reagents used for measurements:
[0161] 1. High purity nitrogen.
[0162] 2. Triply distilled mercury.
[0163] 3. High pressure fluid (Dila AX, available from Shell
Chemical Co.).
[0164] 4. Liquid nitrogen (for Hg vapor cold trap).
[0165] 5. Isopropanol or methanol for cleaning sample cells.
[0166] 6. Liquid detergent for cell cleaning.
[0167] Procedure:
[0168] 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:
[0169] Fine Evacuation time: 1 min.
[0170] Fine Evacuation rate: 10
[0171] Coarse Evacuation time: 5 min.
[0172] 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:
[0173] Mode: Low pressure
[0174] Fine evacuation rate: 10
[0175] Fine evacuation until: 200 .mu. Hg
[0176] Coarse evacuation time: 10 min.
[0177] Fill pressure: Contact +0.1
[0178] Maximum pressure: 50
[0179] Direction: Intrusion And Extrusion
[0180] Repeat: 0
[0181] Mercury contact angle; 140
[0182] Mercury surface tension: 480
[0183] 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:
[0184] Mode: Fixed rate
[0185] Motor speed: 5
[0186] Start pressure: 20
[0187] End pressure: 60,000
[0188] Direction: Intrusion and extrusion
[0189] Repeat: 0
[0190] Oil fill length: 5
[0191] Mercury contact angle: 140
[0192] Mercury surface tension: 480
[0193] 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.
[0194] This invention will be illustrated by the following
examples, which are not meant to limit the invention in any
way.
EXAMPLE 1
[0195] Dosage forms according to the invention, comprising molded
cores with shells thereon were made as follows.
[0196] The molded cores (Example 1A) were made from the following
ingredients:
1 Tablet Trade Name Manufacturer Weight % Mg/Tablet Pseudoephedrine
BASF 22.0 130 Hydrochloride PharmaChemikalien Crystal GmbH &
Co., Ludwigshafen/Rhein. Polyethylene Carbowax .RTM. Union Carbide
45.0 267 Glycol 3350 Corporation, Danbury, CT Shellac Powder
Regular bleached Mantrose-Haeuser 7.0 42 shellac Company, Atteboro,
MA Croscarmellose Ac-Di-Sol .RTM. FINE MUSCLE 26.0 154 Sodium
COORDINATION Corporation, Newark DE
[0197] Processing Steps: A beaker was submersed in a water bath
(Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water
temperature was set at 70.degree. C. Polyethylene glycol (PEG) 3350
was added to the beaker and was mixed with a spatula until all PEG
was melted. Shellac powder, screened through a #40 mesh screen, was
added to the molten PEG and the combined ingredients were mixed
until all powder was dispersed. Croscarmellose sodium was then
added followed by mixing for 2 minutes. Pseudoephedrine
hydrochloride crystal was added, followed by mixing for 5 minutes.
570 to 610 mg of the molten mixture was added a round, concave
lower punch and die unit (0.4375 inch diameter) which was manually
joined with the upper punch to form a molded tablet core. The
molded tablet core was ejected from the die.
[0198] The shells (Example 1B) were made of the following
ingredients:
2 Shell Trade Name Manufacturer Weight % Mg/Tablet Polyethylene
Carbowax .RTM. Union Carbide 45.0 849 Glycol 3350 Corporation,
Danbury, CT Polyethylene Oxide Polyox .RTM. Union Carbide 15.0 283
(MW 200,000) WSR N-80 Corporation, Danbury, CT Shellac Powder
Regular bleached Mantrose-Haeuser 20.0 377 shellac Company,
Atteboro, MA Croscarmellose Ac-Di-Sol .RTM. FMC Corporation, 10.0
188 Sodium Newark, DE Tributyl Citrate Morflex, Inc., 10.0 188
Greensboro, NC
[0199] Processing Steps: A beaker was submersed in a water bath
(Ret digi-visc; Antal-Direct, Wayne, Pa.) where the water
temperature was set at 70.degree. C. Polyethylene glycol (PEG) 3350
was added to the beaker and was mixed with a spatula until all PEG
was melted. Shellac powder, screened through a #40 mesh screen, was
added to the molten PEG and the ingredients were mixed until all
powder was dispersed. Tributyl citrate was added to the molten PEG
mixture, followed by mixing for 1 minute. Polyethylene oxide
(MW=200,000) was then added, followed by mixing for 10 minutes.
Croscarmellose sodium was added, followed by mixing for 2
minutes.
[0200] A laboratory scale thermal cycle molding module was used to
apply the shell in two portions onto the core. A first mold
assembly comprising a cavity was cycled to hot stage at 85.degree.
C. for 30 seconds. A first portion of the shell material in
flowable form (Example 1B) was added to the cavity. A molded core
(Example 1A) was then inserted into the cavity. A blank mold
assembly that masked half the core was screwed into the first mold
assembly. The joined mold assemblies were cycled to cold stage at
5.degree. C. for 60 seconds to harden the shell on the exposed half
of the core. The blank mold assembly was removed and the molded
core coated with the first shell portion was ejected form the
cavity.
[0201] A second mold assembly comprising a second cavity was cycled
to hot stage at 85.degree. C. for 30 seconds. A second portion of
the shell material in flowable form (Example 1B) was added to the
cavity. The molded core comprising the first shell portion was
inserted into the second mold assembly in such a way that the
uncoated half of the core (without the first shell portion) was
inserted into the second mold cavity. The first mold assembly,
which was kept in cold cycle at 5.degree. C., was screwed into the
second mold assembly. The second mold assembly was cycled to cold
stage at 5.degree. C. for 60 seconds to harden a second shell
portion on the core. The first mold assembly was removed and the
dosage form, a molded core coated with the first and second shell
portions (Example 1C), was ejected from the mold assembly. The
weight gain of the dosage form due to the first and second shell
portions was recorded.
[0202] Shell material in flowable form (Example 1B) was added into
a flat faced, 0.6875 inch rubber mold and a coated core (Example
1C) was inserted into the mold. Additional shell material was added
to fill the mold. The round molded tablet core was removed from the
mold after 5 minutes of cooling in the mold. The weight gain of the
core due to the shell was recorded.
[0203] FIG. 2 depicts the % release of active ingredient vs. hours
for the dosage form of Example 1 and other dosage forms. More
particularly this figure shows the dissolution rate of three
different samples of different shell weight gain of the present
invention. Curve (a) shows the release rate of pseudoephedrine HCL
from the matrix with 314% shell weight gain of this invention.
Curve (b) shows the release rate of pseudoephedrine HCL from the
matrix with 118% shell weight gain of this invention. Curve (c)
shows the release rate of pseudoephedrine HCL from the matrix with
55% shell weight gain of this invention. All curves were derived
using the following dissolution analysis: USP Type II apparatus
(paddles, 50 RPM) in 0.1 N HCL and pH 5.6 phosphate buffer at
37.degree. C. Samples were tested at 1, 2, 3, 4, 8, 12, 16, 20, and
24 hours for pseudoephedrine HCl. Dissolution samples were analyzed
for pseudoephedrine HCl versus a standard prepared at the
theoretical concentration for 100% released of each compound.
Samples were analyzed using a HPLC equipped with a Waters.RTM. 717
Autoinjector and a Waters.RTM. 486 UV detector set at a wavelength
of 214 nm. The mobile phase was prepared using 55% acetonitrile and
45% 18 mM Potassium phosphate buffer. The injection volume was 50
.mu.L with a run time of approximately 8 minutes and a pump flow of
2.0 mL/min. The column used was a Zorbax.RTM. 300-SCX
(4.6mm.times.25 cm).
EXAMPLE 2
[0204] Dosage forms of the invention are made in a continuous
process using an apparatus comprising two thermal cycle molding
modules linked in series via a transfer device as described at
pages 14-16 of copending U.S. application Ser. No. 09/966,939, the
disclosure of which is incorporated herein by reference. The dosage
forms comprise a molded core and a shell. The core comprises the
ingredients of Example 1A, provided in flowable form as described
in Example 1. The shell comprises the ingredients of Example 1B,
provided in flowable form as described in Example 1.
[0205] The thermal cycle molding modules have the general
configuration shown in FIG. 3 of copending U.S. application Ser.
No. 09/966,497, which depicts a thermal cycle molding module 200
comprising a rotor 202 around which a plurality of mold units 204
are disposed. Each thermal cycle molding module includes its own
reservoir 206 (see FIG. 4 of copending U.S. application Ser. No.
09/966,497) for holding the core flowable material, and the shell
flowable material, respectively. In addition, each thermal cycle
molding module is provided with a temperature control system for
rapidly heating and cooling the mold units. FIGS. 55 and 56 of
copending U.S. application Ser. No. 09/966,497 depict the
temperature control system 600.
[0206] The cores are made in a first thermal cycle molding module,
which is linked via a transfer device to a second thermal cycle
molding module. The first thermal cycle molding module has the
specific configuration shown in FIG. 26A of copending U.S.
application Ser. No. 09/966,497. The first thermal cycle molding
module comprises center mold assemblies 212 and upper mold
assemblies 214 as shown in FIG. 26C, which mate to form mold
cavities having the shape of the cores. As rotor 202 rotates, the
opposing center and upper mold assemblies close. Core flowable
material, which is heated to a flowable state in reservoir 206, is
injected into the resulting mold cavities. The temperature of the
core flowable material is then decreased, hardening the core
flowable material into cores. The mold assemblies open and eject
the cores, which are received by the transfer device.
[0207] The transfer device has the structure shown as 300 in FIG. 3
and described at pages 51-57 of copending U.S. application Ser. No.
09/966,414, the disclosure of which is incorporated herein by
reference. It comprises a plurality of transfer units 304 attached
in cantilever fashion to a belt 312 as shown in FIGS. 68 and 69 of
copending U.S. application Ser. No. 09/966,414. The transfer device
rotates and operates in sync with the thermal cycle molding modules
to which it is coupled. Transfer units 304 comprise retainers 330
for holding the cores as they travel around the transfer
device.
[0208] The transfer device transfers the cores to the second
thermal cycle molding module, which applies the shell to the cores.
The second thermal cycle molding module is of the type shown in
FIG. 28A of copending U.S. application Ser. No. 09/966,497. The
mold units 204 of the second thermal cycle molding module comprise
upper mold assemblies 214, rotatable center mold assemblies 212 and
lower mold assemblies 210 as shown in FIG. 28C. Cores are
continuously transferred to the mold assemblies, which then close
over the cores. Shell material, which is heated to a flowable state
in reservoir 206, is injected into the mold cavities created by the
closed mold assemblies. The temperature of the shell material is
then decreased, hardening it. The mold assemblies open and eject
the coated cores. Coating is performed in two steps, each half of
the cores being coated separately as shown in the flow diagram of
FIG. 28B of copending U.S. application Ser. No. 09/966,939 via
rotation of the center mold assembly.
[0209] Although this invention has been illustrated by reference to
specific embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made which
clearly fall within the scope of this invention.
* * * * *