U.S. patent application number 10/476238 was filed with the patent office on 2004-12-02 for modified release dosage forms.
Invention is credited to Lee, Der-Yang, Li, Shun-Por, Parikh, Narendra, Sowden, Harry S, Thomas, Martin, Wynn, David.
Application Number | 20040241236 10/476238 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2004-12-02 |
United States Patent
Application |
20040241236 |
Kind Code |
A1 |
Li, Shun-Por ; et
al. |
December 2, 2004 |
Modified release dosage forms
Abstract
A dosage form comprises: (a) a core comprising at least one
active ingredient; and (b) a molded shell which surrounds the core,
wherein the shell provides a predetermined time delay of greater
than one hour for the onset of dissolution of the active ingredient
upon contacting of the dosage form with a liquid medium and the
delay is independent of the pH of the liquid medium. The weight of
the shell may be at least 50 percent of the weight of the core, and
the shell may have a thickness of about 500-4000 microns, or be
substantially free of pores having a diameter of 0.5 to 5
microns.
Inventors: |
Li, Shun-Por; (Lansdale,
PA) ; Sowden, Harry S; (Glenside, PA) ; Wynn,
David; (Glenside, PA) ; Parikh, Narendra;
(Long Valley, NJ) ; Lee, Der-Yang; (Flemington,
NJ) ; Thomas, Martin; (Flemington, NJ) |
Correspondence
Address: |
PHILIP S. JOHNSON
JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27542311 |
Appl. No.: |
10/476238 |
Filed: |
May 28, 2004 |
PCT Filed: |
September 28, 2002 |
PCT NO: |
PCT/US02/31062 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
10476238 |
May 28, 2004 |
|
|
|
09966939 |
Sep 28, 2001 |
|
|
|
10476238 |
May 28, 2004 |
|
|
|
09966509 |
Sep 28, 2001 |
|
|
|
6767200 |
|
|
|
|
10476238 |
May 28, 2004 |
|
|
|
09966497 |
Sep 28, 2001 |
|
|
|
10476238 |
May 28, 2004 |
|
|
|
09967414 |
Sep 28, 2001 |
|
|
|
6742646 |
|
|
|
|
10476238 |
May 28, 2004 |
|
|
|
09966450 |
Sep 28, 2001 |
|
|
|
Current U.S.
Class: |
424/471 |
Current CPC
Class: |
A61J 3/06 20130101; A61K
9/2081 20130101; A61P 11/00 20180101; A61K 9/2873 20130101; A61K
9/286 20130101; A61K 9/0056 20130101; A61K 9/2095 20130101; A61K
9/2893 20130101; B30B 15/302 20130101; A23G 3/0029 20130101; A23L
29/30 20160801; A61K 9/0004 20130101; A23G 3/04 20130101; A61P
43/00 20180101; A61J 3/005 20130101; A61K 9/2054 20130101; A61K
9/209 20130101; A61K 9/2072 20130101; A61K 9/282 20130101; A61K
9/5084 20130101; A23G 3/54 20130101; B30B 11/08 20130101; B30B
11/34 20130101; A23G 1/54 20130101; A61K 9/2018 20130101; Y10T
428/1352 20150115; A61J 3/10 20130101; A61K 9/2013 20130101; A61K
9/2027 20130101; A61K 9/2068 20130101; A61K 9/2826 20130101; A61K
9/2886 20130101; A23G 3/368 20130101; A61K 9/2031 20130101; A61K
9/284 20130101 |
Class at
Publication: |
424/471 |
International
Class: |
A61K 009/24 |
Claims
The invention claimed is:
1. A dosage form comprising: (a) a core comprising at least one
active ingredient; and (b) a molded shell which surrounds the core,
wherein the shell provides a predetermined time delay of greater
than one hour for the onset of dissolution of the active ingredient
upon contacting of the dosage form with a liquid medium and the
delay is independent of the pH of the liquid medium.
2. The dosage form of claim 1, in which the shell comprises means
for delaying the onset of dissolution of the active ingredient for
greater than one hour upon contacting of the dosage form with a
liquid medium, and the delay is independent of the pH of the liquid
medium.
3. The dosage form of claim 1, wherein the weight of the shell is
at least 50 percent of the weight of the core.
4. The dosage form of claim 1, wherein the shell has a thickness
from about 500 to about 4000 microns.
5. The dosage form of claim 1, wherein the shell has a thickness
from about 100 to 600 microns.
6. The dosage form of claim 1, wherein the shell is substantially
free of pores having a diameter of 0.5 to 5.0 microns.
7. The dosage form of claim 1, wherein the shell comprises at least
about 30% of a thermal reversible carrier.
8. The dosage form of claim 1, wherein the shell comprises at least
about 10% of a film-former.
9. The dosage form of claim 1, in which the shell additionally
comprises at least one active ingredient which may be the same or
different than the active ingredient contained in the core.
10. The dosage form of claim 1, which additionally comprises an
outer coating which covers at least a portion of the shell, and the
outer coating comprises at least one active ingredient which may be
the same or different than the active ingredient contained in the
core.
11. The dosage form of claim 1, in which the core is a compressed
tablet.
12. The dosage form of claim 1, in which the core comprises coated
particles of at least one active ingredient.
13. The dosage form of claim 1, in which the core is prepared by
molding.
14. 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.
15. The dosage form of claim 1, in which the core comprises at
least about 30 weight percent of a thermal-reversible carrier.
16. The dosage form of claim 1, in which the core comprises a
release-modifying excipient.
17. The dosage form of claim 1, in which the shell is not a
compression coating applied to the core.
18. The dosage form of claim 1, which provides an immediate release
of at least one active ingredient, followed by a delay of at least
about 1 hour, followed by a burst release of at least one active
ingredient.
19. The dosage form of claim 1, wherein the shell is prepared using
a solvent-free molding process.
20. The dosage form of claim 1, wherein the shell comprises at
least 30% by weight of a thermal-reversible carrier.
21. The dosage form of claim 1, wherein the shell comprises up to
55% by weight of a swellable, erodible hydrophilic material.
22. The dosage form of claim 1, wherein the shell is prepared using
a solvent-based molding process.
23. The dosage form of claim 1, wherein the shell comprises at
least 10% by weight of a film-former.
24. The dosage form of claim 1, wherein the shell comprises at
least 55% by weight of a release-modifying excipient.
25. The dosage form of claim 1, wherein the dosage form comprises
means for providing a delayed burst release profile of the active
ingredient.
26. The dosage form of claim 1, wherein the dosage form comprises
means for providing a delayed and sustained release profile of the
active ingredient.
27. The dosage form of claim 1, wherein the dosage form comprises
means for providing a pulsatile release profile of the active
ingredient.
28. The dosage form of claim 1, wherein the core or portion thereof
further comprises shellac at a level of about 5 to about 15 weight
percent of the core or portion thereof.
29. The dosage form of claim 1, wherein the shell or portion
thereof further comprises shellac at a level of about 5 to about 15
weight percent of the shell or portion thereof.
30. The dosage form of claim 20, wherein the thermal reversible
carrier is selected from the group consisting of polyethylene
glycol, polyethylene oxide and copolymers and combinations
thereof.
31. The dosage form of claim 23, wherein the film former is
polyethylene oxide.
32. The dosage form of claim 24, wherein the release-modifying
excipient is a swelling cross-linked polymer.
33. The dosage form of claim 32, wherein the swelling cross-linked
polymer is croscarmellose sodium.
34. The dosage form of claim 1, wherein the shell further comprises
a plasticizer.
35. The dosage form of claim 34, wherein the plasticizer is
tributyl citrate.
36. The dosage form of claim 22, wherein the weight of the shell is
from about 10 percent to about 60 percent of the weight of the
core.
Description
BACKGROUND OF THE INVENTION
[0001] 1. Field of the Invention
[0002] This invention relates to modified release dosage forms such
as modified release pharmaceutical compositions. More particularly,
this invention relates to modified release dosage forms having a
core containing at least one active ingredient and a shell
surrounding the core, in which the shell provides a delay of
greater than one hour for the onset of dissolution of the active
ingredient upon contacting of the dosage form with a liquid medium
such as water or gastrointestinal fluids, and the delay is
independent of the pH of the liquid medium.
[0003] 2. Background Information
[0004] Modified release pharmaceutical dosage forms have long been
used to optimize drug delivery and enhance patient compliance,
especially by reducing the number of doses of medicine the patient
must take in a day. For this purpose, it is often desirable to
modify the rate of release of a drug (one particularly preferred
type of active ingredient) from a dosage form into the
gastro-intestinal (g.i.) fluids of a patient, especially to slow
the release in order 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 gastro-intestinal (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 desirable PK profile for a number of drugs and
conditions, 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").
[0008] A particularly desirable type of delayed release PK profile
is a "pulsatile" profile, in which for example, a first dose is
delivered immediately, followed by a delay corresponding
approximately to the time during which a therapeutic concentration
of the first dose is maintained in the blood, followed by either
prompt or sustained release of a subsequent dose of the same
drug.
[0009] A particularly challenging aspect of the design of delayed
release systems involves the predictability and repeatability of
the lag time in vivo. Physiological systems, e.g. the human g.i.
tract, have a high degree of inter- and intra-subject variability,
for example in intestinal motility and pH. For the purpose of
repeatability and predictability, it is desirable to have a delayed
release mechanism that is independent of the pH of the environment
in which the dosage form must release drug.
[0010] Well known mechanisms by which a dosage form (or drug
delivery system) can deliver drug at a modified rate (e.g. delayed,
pulsatile, sustained, prolonged, extended or retarded release)
include diffusion, erosion, and osmosis.
[0011] One classic diffusion-controlled release system comprises
active ingredient, distributed throughout an insoluble porous
matrix through which the active ingredient must diffuse in order to
be absorbed into the bloodstream of the patient. The amount of drug
release (M) at a given time at sink conditions (i.e. drug
concentration at the matrix surface is much greater than drug
concentration in the bulk solution) depends on the area (A) of the
matrix, the diffusion coefficient (D), the porosity (E) and
tortuosity (T) of the matrix, the drug solubility (Cs) in the
dissolution medium, time (t) and the drug concentration (Cp) in the
dosage form:
M=A(DE/T(2Cp-ECs)(Cs)t).sup.1/2
[0012] 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.
[0013] 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)}
[0014] Again, variation in one or more terms, such as surface area,
typically lead to a non-constant release rate of drug. In general,
the rate of drug release from erosion-controlled release systems
typically follows first order kinetics.
[0015] Another type of erosion controlled delivery system utilizes
materials which swell and dissolve slowly by surface erosion are
additionally useful for providing a delayed release of
pharmaceutical active ingredient. Delayed release is useful, for
example in pulsatile or repeat action delivery systems, in which an
immediate release dose is delivered, followed by a pre-determined
lag time before a subsequent dose is delivered from the system. In
these systems, the lag time (T.sub.1) depends on the thickness (h)
of the erodible layer, and the rate of erosion (dx/dt) of the
matrix, which in turn depends on the swelling rate and solubility
of the matrix components:
T.sub.1=h(dx/dt)
[0016] The cumulative amount of drug (M) released from these
systems at a given time generally follows the equation:
M=(dM/dt)(t-T.sub.1)
[0017] where dM/dt is generally described by either the
diffusion-controlled or erosion-controlled equations above, and
T.sub.1 is the lag time.
[0018] It is often practical to design dosage forms that use a
combination of the above mechanisms to achieve a particularly
desirable release profile for a particular active ingredient.
[0019] Current delayed-release systems are limited by the available
methods for manufacturing them, as well as the materials that are
suitable for use with the current methods. A shell, or coating,
which confers modified release properties, is typically applied via
conventional methods, such as for example, spray-coating in a
coating pan. Pan-coating produces a single shell which essentially
surrounds the core. The single shell is inherently limited in its
functionality. It is possible via pan-coating to apply multiple
concentric shells, each with a different functionality, however
such systems are limited in that the outer shell must first
dissolve before the functionality conferred by each successive
layer can be realized. Additionally, the coating compositions that
can be applied via spraying are limited by their viscosity.
Spray-coating methods suffer the further limitations of being
time-intensive and costly. One well-known and commonly used design
for providing delayed release of a drug employs an enteric coating
material, either on particles containing the drug or on the surface
of a dosage form. Enteric materials are generally selected from
polymer systems which are soluble only in fluid environments with a
certain pH range, higher than that of typical gastric fluid, for
example pH greater than 5.5, greater than pH 6.0, or greater than
pH 7.0. While these systems may be useful for protecting certain
acid-labile active ingredients from gastric fluids, or for
protecting the stomach lining from damage by certain active
ingredients, they are limited in their applicability to programmed
time-delay systems due to variability in gastrointestinal pH and
motility.
[0020] The pH-independent delay of drug release has been achieved
by conventional spray-coating methods. For example, G. Maffione et
al., "High-Viscosity HPMC as a Film-Coating Agent," Drug
Development and Industrial Pharmacy (1993) 19(16), pp. 2043-2053,
describes a core or tablet matrix, surrounded by a shell or
coating, which provides a delayed burst dissolution profile.
Coating levels were 12.5-25% of the weight of the core. A preferred
coating formula employs a swellable film-former dispersed in
non-aqueous solvent. Low polymer concentrations (5-10%), and the
use of ethanol as a "non-solvent" were required for
sprayability.
[0021] It is also known, via pan coating, to deliver a first dose
of active ingredient from a coating, and a second dose of active
ingredient from a core. U.S. Pat. No. 4,576,604, for example,
discloses an osmotic device (dosage form) comprising a drug
compartment surrounded by a wall (coating) in which the coating may
comprise an immediate release dose of drug, and the inner drug
compartment may comprise a sustained release dose of drug.
[0022] Alternately, conventional controlled release systems may be
prepared by compression, to produce either multiple stacked layers,
or core and shell configurations. Modified release dosage forms
prepared via compression are exemplified in U.S. Pat. Nos.
5,738,874 and 6,294,200, and WO 99/51209.
[0023] It is possible via compression-coating to produce a
pH-independent time delayed drug release. U.S. Pat. No. 5,464,633
discloses delayed-release dosage forms in which an external coating
layer was applied by a compression coating process. The coating
level ranged from 105 percent to 140 percent of the weight of the
core in order to yield product with the desired time delayed
profile.
[0024] Compression-coated dosage forms are limited by the shell
thickness and shell composition. Gunsel et al., "Compression-coated
and layer tablets" in Pharmaceutical Dosage Forms--Tablets, edited
by H. A. Lieberman, L. Lachman, and J. B. Schwartz, (2nd ed., rev.
and expanded Marcel Dekker) Inc., p. 247-284, for example,
discloses the thickness of compression coated shells is typically
between 800 and 1200 microns.
[0025] It is one object of this invention to provide a dosage form
having a core which contains at least one active ingredient and a
shell surrounding the core, in which the shell has a weight of at
least 50 percent of the weight of the core, the shell provides a
delay of greater than one hour for the onset of dissolution of the
active ingredient upon contacting of the dosage form with a liquid
medium, and the delay is independent of the pH of the liquid
medium. Other objects, features and advantages of this invention
will be apparent to those skilled in the art from the following
detailed description of the invention.
SUMMARY OF THE INVENTION
[0026] The dosage form of this invention comprises:
[0027] (a) a core comprising at least one active ingredient;
and
[0028] (b) a molded shell which surrounds the core, wherein the
shell provides a predetermined time delay of greater than one hour
for the onset of dissolution of the active ingredient upon
contacting of the dosage form with a liquid medium and the delay is
independent of the pH of the liquid medium.
[0029] In one embodiment, the weight of the shell is at least 50
percent of the weight of the core.
[0030] In another embodiment, the shell has a thickness from about
500 to about 4000 microns.
[0031] In another embodiment, the shell has a thickness from about
100 to 600 microns.
[0032] In another embodiment, the shell has a surface gloss of at
least about 150 gloss units.
[0033] In another embodiment, the shell is substantially free of
pores having a diameter of 0.5 to 5.0 microns.
[0034] In another embodiment, the shell comprises at least 30% of a
thermal reversible carrier.
[0035] In another embodiment, the shell comprises at least about
10% of a film-former.
[0036] In another embodiment, the shell additionally comprises at
least one active ingredient which may be the same or different than
the active ingredient contained in the core.
[0037] In another embodiment, the dosage form additionally
comprises an outer coating which covers at least a portion of the
shell, and the outer coating comprises at least one active
ingredient which may be the same or different than the active
ingredient contained in the core.
[0038] In another embodiment, the core is a compressed tablet.
[0039] In another embodiment, the core comprises coated particles
of at least one active ingredient.
[0040] In another embodiment, the core is made by molding.
[0041] In another embodiment, the core is substantially free of
pores having a diameter of 0.5 to 5.0 microns.
[0042] In another embodiment, the core comprises at least about 30
weight percent of a thermal-reversible carrier.
[0043] In another embodiment, the core comprises a
release-modifying excipient.
[0044] In another embodiment, the shell is not a compression
coating applied to the core.
[0045] In another embodiment, the dosage form provides an immediate
release of at least one active ingredient, followed by a delay of
at least about 1 hour, followed by a burst release of at least one
active ingredient.
[0046] In another embodiment, the shell is prepared using a
solvent-free molding process.
[0047] In another embodiment, the shell comprises at least 30% by
weight of a thermal-reversible carrier.
[0048] In another embodiment, the shell comprises up to 55% by
weight of a swellable, erodible hydrophilic material.
[0049] In another embodiment, the shell is prepared using a
solvent-based molding process.
[0050] In another embodiment, the shell comprises at least 10% by
weight of a film-former.
[0051] In another embodiment, the shell comprises up to 55% by
weight of a release-modifying excipient.
[0052] In another embodiment, the dosage form provides a delayed
burst release profile of the active ingredient.
[0053] In another embodiment, the dosage form provides a delayed
and sustained release profile of the active ingredient.
[0054] In another embodiment, the dosage form provides a pulsatile
release profile of the active ingredient.
[0055] In another embodiment, the core or portion thereof further
comprises shellac at a level of about 5 to about 15 weight percent
of the core or portion thereof.
[0056] In another embodiment, the shell or portion thereof further
comprises shellac at a level of about 5 to about 15 weight percent
of the shell or portion thereof.
[0057] In another embodiment, the thermal reversible carrier is
selected from the group consisting of polyethylene glycol,
polyethylene oxide and copolymers and combinations thereof.
[0058] In another embodiment, the film former is polyethylene
oxide.
[0059] In another embodiment, the release-modifying excipient is a
swelling cross-linked polymer.
[0060] In another embodiment, the swelling cross-linked polymer is
croscarmellose sodium.
[0061] In another embodiment, the shell further comprises a
plasticizer.
[0062] In another embodiment, the plasticizer is tributyl
citrate.
[0063] In another embodiment, the shell is prepared using a
solvent-based molding process, and the weight of the shell is from
about 10 percent to about 60 percent of the weight of the core.
BRIEF DESCRIPTION OF THE DRAWINGS
[0064] FIG. 1 depicts a cross-sectional view of one embodiment of
this invention.
[0065] FIG. 2 depicts the percent release of active ingredient vs.
hours for the dosage form of Example 1.
[0066] FIG. 3 depicts the percent release of active ingredient vs.
hours for the dosage form of Example 2.
[0067] FIG. 4 depicts the percent release of active ingredient vs.
hours for the dosage form of Example 3.
DETAILED DESCRIPTION OF THE INVENTION
[0068] 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.
[0069] The active ingredient employed in the dosage forms of this
invention may be found within the core, 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, oral contraceptives,
polydimethylsiloxanes, respiratory agents, sleep-aids, urinary
tract agents and mixtures thereof.
[0070] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0071] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0072] Examples of suitable gastrointestinal agents include
antacids such as calcium carbonate, magnesium hydroxide, magnesium
oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate,
dihydroxyaluminum sodium carbonate; stimulant laxatives, such as
bisacodyl, cascara sagrada, danthron, senna, phenolphthalein, aloe,
castor oil, ricinoleic acid, and dehydrocholic acid, and mixtures
thereof; H2 receptor antagonists, such as famotadine, ranitidine,
cimetadine, nizatidine; proton pump inhibitors such as omeprazole
or lansoprazole; gastrointestinal cytoprotectives, such as
sucraflate and misoprostol; gastrointestinal prokinetics, such as
prucalopride, antibiotics for H. pylori, such as clarithromycin,
amoxicillin, tetracycline, and metronidazole; antidiarrheals, such
as diphenoxylate and loperamide; glycopyrrolate; antiemetics, such
as ondansetron, analgesics, such as mesalamine.
[0073] In one embodiment of the invention, the active ingredient
may be selected from bisacodyl, famotadine, ranitidine, cimetidine,
prucalopride, diphenoxylate, loperamide, lactase, mesalamine,
bismuth, antacids, and pharmaceutically acceptable salts, esters,
isomers, and mixtures thereof.
[0074] In another embodiment, the active ingredient is selected
from analgesics, anti-inflammatories, and antipyretics, e.g.
non-steroidal anti-inflammatory drugs (NSAIDs), including propionic
acid derivatives, e.g. ibuprofen, naproxen, ketoprofen and the
like; acetic acid derivatives, e.g. indomethacin, diclofenac,
sulindac, tolmetin, and the like; fenamic acid derivatives, e.g.
mefanamic acid, meclofenamic acid, flufenamic acid, and the like;
biphenylcarbodylic acid derivatives, e.g. diflunisal, flufenisal,
and the like; and oxicams, e.g. piroxicam, sudoxicam, isoxicam,
meloxicam, and the like. In a particularly preferred embodiment,
the active ingredient is selected from propionic acid derivative
NSAID, e.g. ibuprofen, naproxen, flurbiprofen, fenbufen,
fenoprofen, indoprofen, ketoprofen, fluprofen, pirprofen,
carprofen, oxaprozin, pranoprofen, suprofen, and pharmaceutically
acceptable salts, derivatives, and combinations thereof. In a
particular embodiment of the invention, the active ingredient may
be selected from acetaminophen, acetyl salicylic acid, ibuprofen,
naproxen, ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine,
meloxicam, rofecoxib, celecoxib, and pharmaceutically acceptable
salts, esters, isomers, and mixtures thereof.
[0075] In another embodiment of the invention, the active
ingredient may be selected from pseudoephedrine,
phenylpropanolamine, chlorpheniramine, dextromethorphan,
diphenhydramine, astemizole, terfenadine, fexofenadine, loratadine,
desloratadine, cetirizine, mixtures thereof and pharmaceutically
acceptable salts, esters, isomers, and mixtures thereof.
[0076] Examples of suitable polydimethylsiloxanes, which include,
but are not limited to dimethicone and simethicone, are those
disclosed in U.S. Pat. Nos. 4,906,478, 5,275,822, and 6,103,260,
the contents of each is expressly incorporated herein by reference.
As used herein, the term "simethicone" refers to the broader class
of polydimethylsiloxanes, including but not limited to simethicone
and dimethicone.
[0077] The active ingredient 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.
Typically, the dosage form comprises at least about 5 weight
percent, preferably, the dosage form comprises at least about 20
weight percent of the active ingredient. In one preferred
embodiment, the core comprises at least about 25 weight percent
(based on the weight of the core) of the active ingredient.
[0078] 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.
[0079] In certain embodiments of the invention, at least a portion
of the active ingredient may be coated with a release-modifying
coating, as known in the art. This advantageously provides an
additional tool for optimizing the release profile of the active
ingredient from the dosage form Examples of suitable release
modifying coatings are described in U.S. Pat. Nos. 4,173,626;
4,863,742; 4,980,170; 4,984,240;5,286,497, 5,912,013; 6,270,805;
and 6,322,819. Commercially available modified release coated
active particles may also be employed. Accordingly, all or a
portion of one or more active ingredients may be coated with a
release-modifying material.
[0080] In certain other embodiments of the invention, a further
degree of flexibility in designing the dosage forms of the present
invention can be achieved through the use of an additional outer
coating overlaying the shell. The additional outer coating may be
applied by known methods, for example by spraying, dipping,
printing, roller coating, compression, or by molding. In such
embodiments, the dosage form of the invention comprises a core
containing at least one active ingredient; a molded shell which
surrounds the core, wherein the shell provides a predetermined time
delay of greater than one hour for the onset of dissolution of the
active ingredient upon contacting of the dosage form with a liquid
medium and the delay is independent of the pH of the liquid medium;
and an outer coating which covers at least a portion of the shell.
In one particularly preferred embodiment, the dosage form is a
pulsatile drug delivery system, in which the outer coating
comprises an active ingredient, which is released immediately (i.e.
the dissolution of the active ingredient from the outer coating
conforms to USP specifications for immediate release dosage forms
of the particular active ingredient employed).
[0081] In embodiments in which it is desired for the active
ingredient to be absorbed into the systemic circulation of an
animal, the active ingredient or ingredients are preferably capable
of dissolution upon contact with a fluid such as water, stomach
acid, intestinal fluid or the like. In one embodiment, the
dissolution characteristics of at least one active ingredient meets
USP specifications for immediate release tablets containing the
active ingredient. For example, for acetaminophen tablets, USP 24
specifies that in pH 5.8 phosphate buffer, using USP apparatus 2
(paddles) at 50 rpm, at least 80% of the acetaminophen contained in
the dosage form is released therefrom within 30 minutes after
dosing, and for ibuprofen tablets, USP 24 specifies that in pH 7.2
phosphate buffer, using USP apparatus 2 (paddles) at 50 rpm, at
least 80% of the ibuprofen contained in the dosage form is released
therefrom within 60 minutes after dosing. See USP 24, 2000 Version,
19-20 and 856 (1999). In embodiments in which at least one active
ingredient is released immediately, the immediately released active
ingredient is preferrably contained in the shell or on the surface
of the shell, e.g. in a further coating residing upon at least a
portion of the shell. In another embodiment, the dissolution
characteristics of at least one active ingredient are modified:
e.g. controlled, sustained, extended, retarded, prolonged, delayed
and the like. In embodiments in which at least one active
ingredient is released in a modified manner, the modified release
active ingredient is preferably contained in the core.
[0082] FIG. 1 depicts a cross-sectional view of one embodiment of
this invention. In FIG. 1, a core 2 comprises an active ingredient.
The core 2 is surrounded by a shell 4 which provides a delay of
greater than one hour to the onset of dissolution of the active
ingredient upon contacting of the dosage form with a liquid medium.
The delay of the onset of dissolution is independent of the pH of
the liquid medium. The weight of the shell material is at least 50
percent of the weight of the core material.
[0083] The core of the present invention may be prepared by any
suitable method, including for example compression, or molding, and
depending on the method by which it is made, typically comprises
active ingredient and a variety of excipients (inactive ingredients
which may be useful for conferring desired physical properties to
the core).
[0084] In one embodiment, the core is prepared by the compression
methods and apparatus described in copending U.S. patent
application Ser. No. 09/966,509, pages 16-27, the disclosure of
which is incorporated herein by reference. Specifically, the core
is made using a rotary compression module comprising a fill zone,
insertion zone, compression zone, ejection zone, and purge zone in
a single apparatus having a double row die construction as shown in
FIG. 6 of U.S. patent application Ser. No. 09/966,509. The dies of
the compression module are preferably filled using the assistance
of a vacuum, with filters located in or near each die. The purge
zone of the compression module includes an optional powder recovery
system to recover excess powder from the filters and return the
powder to the dies.
[0085] In embodiments in which the core or a portion thereof is
made by compression, suitable excipients include fillers, binders,
disintegrants, lubricants, glidants, and the like, as known in the
art. In embodiments in which the core is made by compression and
additionally confers modified release of an active ingredient
contained therein, the core preferably further comprises a
release-modifying excipient for compression.
[0086] Suitable fillers for use in making the core, or a portion
thereof, by compression include water-soluble compressible
carbohydrates such as sugars, which include dextrose, sucrose,
maltose, and lactose, sugar-alcohols, which include mannitol,
sorbitol, maltitol, xylitol, starch hydrolysates, which include
dextrins, and maltodextrins, and the like, water insoluble
plasticly deforming materials such as microcrystalline cellulose or
other cellulosic derivatives, water-insoluble brittle fracture
materials such as dicalcium phosphate, tricalcium phosphate and the
like and mixtures thereof.
[0087] Suitable binders for making the core, or a portion thereof,
by compression include dry binders such as polyvinyl pyrrolidone,
hydroxypropylmethylcellulose, and the like; wet binders such as
water-soluble polymers, including hydrocolloids such as alginates,
agar, guar gum, locust bean, carrageenan, tara, gum arabic,
tragacanth, pectin, xanthan, gellan, maltodextrin, galactomannan,
pusstulan, laminarin, scleroglucan, gum arabic, inulin, pectin,
whelan, rhamsan, zooglan, methylan, chitin, cyclodextrin, chitosan,
polyvinyl pyrrolidone, cellulosics, starches, and the like; and
derivatives and mixtures thereof.
[0088] Suitable disintegrants for making the core, or a portion
thereof, by compression include sodium starch glycolate,
cross-linked polyvinylpyrrolidone, cross-linked
carboxymethylcellulose, starches, microcrystalline cellulose, and
the like.
[0089] Suitable lubricants for making the core, or a portion
thereof, by compression include long chain fatty acids and their
salts, such as magnesium stearate and stearic acid, talc, and
waxes.
[0090] Suitable glidants for making the core, or a portion thereof,
by compression include colloidal silicon dioxide, and the like.
[0091] Suitable release-modifying excipients for making the core,
or a portion thereof, by compression include swellable erodible
hydrophilic materials, insoluble edible materials, pH-dependent
polymers, and the like.
[0092] Suitable swellable erodible hydrophilic materials for use as
release-modifying excipients for making the core, or a portion
thereof, by compression, include water swellable cellulose
derivatives, polyalkalene glycols, thermoplastic polyalkalene
oxides, acrylic polymers, hydrocolloids, clays, gelling starches,
and swelling cross-linked polymers, and derivitives, copolymers,
and combinations thereof. Examples of suitable water swellable
cellulose derivatives include sodium carboxymethylcellulose,
cross-linked hydroxypropylcellulose, hydroxypropyl cellulose (HPC),
hydroxypropylmethylcellulose (HPMC) such as those available from
Dow Chemical Company under the tradename METHOCEL K4M, METHOCEL
K15M, and METHOCEL K100M, hydroxyisopropylcellulose,
hydroxybutylcellulose,hydroxyp- henylcellulose,
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.
[0093] Suitable insoluble edible materials for use as
release-modifying excipients for making the core, or a portion
thereof, by compression include water-insoluble polymers, and
low-melting hydrophobic materials. Examples of suitable
water-insoluble polymers include ethylcellulose, polyvinyl
alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate
and its derivatives, acrylates, methacrylates, acrylic acid
copolymers; and the like and derivatives, copolymers, and
combinations thereof. Suitable low-melting hydrophobic materials
include fats, fatty acid esters, phospholipids, and waxes. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes include carnauba wax, spermaceti wax, beeswax, candelilla
wax, shellac wax, microcrystalline wax, and paraffin wax;
fat-containing mixtures such as chocolate; and the like.
[0094] Suitable pH-dependent polymers for use as release-modifying
excipients for making the core, or a portion thereof, by
compression include enteric cellulose derivatives, for example
hydroxypropyl methylcellulose phthalate, hydroxypropyl
methylcellulose acetate succinate, cellulose acetate phthalate;
natural resins such as shellac and zein; enteric acetate
derivatives such as for example polyvinylacetate phthalate,
cellulose acetate phthalate, acetaldehyde dimethylcellulose
acetate; and enteric acrylate derivatives such as for example
polymethacrylate-based polymers such as poly(methacrylic acid,
methyl methacrylate) 1:2, which is commercially available from Rohm
Pharma GmbH under the tradename EUDRAGIT S, and poly(methacrylic
acid, methyl methacrylate) 1:1, which is commercially available
from Rohm Pharma GmbH under the tradename EUDRAGIT L and the like,
and derivatives, salts, copolymers, and combinations thereof.
[0095] Suitable pharmaceutically acceptable adjuvants for making
the core, or a portion thereof, by compression include,
preservatives; high intensity sweeteners such as aspartame,
acesulfame potassium, sucralose, and saccharin; flavorants;
colorants; antioxidants; surfactants; wetting agents; and the like
and mixtures thereof.
[0096] In certain preferred embodiments of the invention, the core,
or the shell, or a portion thereof, is prepared by molding. In such
embodiments, the core, or the shell, or a portion thereof, is made
from a flowable material. The flowable material may be any edible
material that is flowable at a temperature between about 37.degree.
C. and 250.degree. C., and that is solid, semi-solid, or can form a
gel at a temperature between about -10.degree. C. and about
80.degree. C., e.g. between about -10.degree. C. and about
55.degree. C., or between about -10.degree. C. and about 35.degree.
C. When it is in the fluid or flowable state, the flowable material
may comprise a dissolved or molten component, and optionally a
solvent such as for example water or organic solvents, or
combinations thereof. The solvent may be partially or substantially
removed by drying.
[0097] Suitable flowable materials for making the core, or the
shell, or a portion thereof by molding include those comprising
thermoplastic materials; film formers; thickeners such as gelling
polymers or hydrocolloids; low melting hydrophobic materials;
non-crystallizable carbohydrates; and the like. Suitable molten
components of the flowable material include thermoplastic
materials, low melting hydrophobic materials, and the like.
Suitable dissolved components for the flowable material include
film formers, thickeners such as gelling polymers or hydrocolloids,
non-crystallizable carbohydrates, and the like.
[0098] Suitable thermoplastic materials for use as components of
the flowable material for making the core or the shell or a portion
thereof by molding can be molded and shaped when heated, and
include both water soluble and water insoluble polymers that are
generally linear, not crosslinked, nor strongly hydrogen bonded to
adjacent polymer chains. Examples of suitable thermoplastic
materials include thermoplastic water swellable cellulose
derivatives, thermoplastic water insoluble cellulose derivatrives,
thermoplastic vinyl polymers, thermoplastic starches, thermplastic
polyalkalene glycols, thermoplastic polyalkalene oxides, and
amorphous sugar-glass, and the like, and derivatives, copolymers,
and combinations thereof. Examples of suitable thermoplastic water
swellable cellulose derivatives include hydroxypropyl cellulose
(HPC), hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC).
Examples of suitable thermoplastic water insoluble cellulose
derivatrives include cellulose acetate (CA), ethyl cellulose (EC),
cellulose acetate butyrate (CAB), cellulose propionate. Examples of
suitable thermoplastic vinyl polymers include, polyvinyl alcohol,
polyvinyl acetate (PVA) and polyvinyl pyrrolidone (PVP). Examples
of suitable thermoplastic starches are disclosed for example in
U.S. Pat. No. 5,427,614, which is incorporated herein by reference.
Examples of suitable thermoplastic polyalkalene glycols include
polyethylene glycol; Examples of suitable thermoplastic
polyalkalene oxides include polyethylene oxide having a molecular
weight from about 100,000 to about 900,000 Daltons. Other suitable
thermoplastic materials include sugar in the form on an amorphous
glass such as that used to make hard candy forms.
[0099] Any film former known in the art is suitable for use in the
flowable material of the present invention. Examples of suitable
film formers include, but are not limited to, film-forming water
soluble polymers, film-forming proteins, film-forming water
insoluble polymers, and film-forming pH-dependent polymers.
Suitable film-forming water soluble polymers include water soluble
vinyl polymers such as polyvinylalcohol, polyvinylacetate (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. 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. 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. 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.
[0100] 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.
[0101] One suitable polyvinyl alcohol and polyethylene glycol
copolymer is commercially available from BASF Corporation under the
tradename KOLLICOAT IR.
[0102] 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.
[0103] 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.
[0104] 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.
[0105] Any thickener known in the art is suitable for use in the
flowable material. Examples of such thickeners include but are not
limited to hydrocolloids (also referred to herein as gelling
polymers), clays, gelling starches, and crystallizable
carbohydrates, and derivatives, copolymers and mixtures thereof.
Examples of suitable hydrocolloids (also referred to herein as
gelling polymers) such as alginates, agar, guar gum, locust bean,
carrageenan, tara, gum arabic, tragacanth, pectin, xanthan, gellan,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, whelan, rhamsan, zooglan, methyl an,
chitin, cyclodextrin, chitosan. Examples of suitable clays include
smectites such as bentonite, kaolin, and laponite; magnesium
trisilicate, magnesium aluminum silicate, and the like, and
derivatives and mixtures thereof. Examples of suitable gelling
starches include acid hydrolyzed starches, and derivatives and
mixtures thereof. Additional suitable thickening hydrocolloids
include low-moisture polymer solutions such as mixtures of gelatin
and other hydrocolloids at water contents up to about 30%, such as
for example those used to make "gummi" confection forms. Suitable
crystallizable carbohydrates include the monosaccharides and the
oligosaccharides. Of the monosaccharides, the aldohexoses e.g., the
D and L isomers of allose, altrose, glucose, mannose, gulose,
idose, galactose, talose, and the ketohexoses e.g., the D and L
isomers of fructose and sorbose along with their hydrogenated
analogs: e.g., glucitol (sorbitol), and mannitol are preferred. Of
the oligosaccharides, the 1,2-disaccharides sucrose and trehalose,
the 1,4-disaccharides maltose, lactose, and cellobiose, and the
1,6-disaccharides gentiobiose and melibiose, as well as the
trisaccharide raffinose are preferred along with the isomerized
form of sucrose known as isomaltulose and its hydrogenated analog
isomalt. Other hydrogenated forms of reducing disaccharides (such
as maltose and lactose), for example, maltitol and lactitol are
also preferred. Additionally, the hydrogenated forms of the
aldopentoses: e.g., D and L ribose, arabinose, xylose, and lyxose
and the hydrogenated forms of the aldotetroses: e.g., D and L
erythrose and threose are preferred and are exemplified by xylitol
and erythritol, respectively.
[0106] In one embodiment of the invention, the flowable material
comprises gelatin as a gelling polymer. Gelatin is a natural,
thermogelling polymer. It is a tasteless and colorless mixture of
derived proteins of the albuminous class which is ordinarily
soluble in warm water. Two types of gelatin--Type A and Type B--are
commonly used. Type A gelatin is a derivative of acid-treated raw
materials. Type B gelatin is a derivative of alkali-treated raw
materials. The moisture content of gelatin, as well as its Bloom
strength, composition and original gelatin processing conditions,
determine its transition temperature between liquid and solid.
Bloom is a standard measure of the strength of a gelatin gel, and
is roughly correlated with molecular weight. Bloom is defined as
the weight in grams required to move a half-inch diameter plastic
plunger 4 mm into a 6.67% gelatin gel that has been held at
10.degree. C. for 17 hours. In a preferred embodiment, the flowable
material is an aqueous solution comprising 20% 275 Bloom pork skin
gelatin, 20% 250 Bloom Bone Gelatin, and approximately 60%
water.
[0107] Suitable xanthan gums include those available from C. P.
Kelco Company under the tradenames KELTROL 1000, XANTROL 180, or
K9B310.
[0108] "Acid-hydrolyzed starch," as used herein, is one type of
modified starch that results from treating a starch suspension with
dilute acid at a temperature below the gelatinization point of the
starch. During the acid hydrolysis, the granular form of the starch
is maintained in the starch suspension, and the hydrolysis reaction
is ended by neutralization, filtration and drying once the desired
degree of hydrolysis is reached. As a result, the average molecular
size of the starch polymers is reduced. Acid-hydrolyzed starches
(also known as "thin boiling starches") tend to have a much lower
hot viscosity than the same native starch as well as a strong
tendency to gel when cooled.
[0109] "Gelling starches," as used herein, include those starches
that, when combined with water and heated to a temperature
sufficient to form a solution, thereafter form a gel upon cooling
to a temperature below the gelation point of the starch. Examples
of gelling starches include, but are not limited to, acid
hydrolyzed starches such as that available from Grain Processing
Corporation under the tradename PURE-SET B950; hydroxypropyl
distarch phosphate such as that available from Grain Processing
Corporation under the tradename, PURE-GEL B990, and mixtures
thereof.
[0110] Suitable low-melting hydrophobic materials for use as
components of the flowable material for making the core, or the
shell, or a portion thereof by molding include fats, fatty acid
esters, phospholipids, and waxes. Examples of suitable fats include
hydrogenated vegetable oils such as for example cocoa butter,
hydrogenated palm kernel oil, hydrogenated cottonseed oil,
hydrogenated sunflower oil, and hydrogenated soybean oil; and free
fatty acids and their salts. Examples of suitable fatty acid esters
include sucrose fatty acid esters, mono, di, and triglycerides,
glyceryl behenate, glyceryl palmitostearate, glyceryl monostearate,
glyceryl tristearate, glyceryl trilaurylate, glyceryl myristate,
GlycoWax-932, lauroyl macrogol-32 glycerides, and stearoyl
macrogol-32 glycerides. Examples of suitable phospholipids include
phosphotidyl choline, phosphotidyl serene, phosphotidyl enositol,
and phosphotidic acid. Examples of suitable waxes include camauba
wax, spernaceti wax, beeswax, candelilla wax, shellac wax,
microcrystalline wax, and paraffin wax; fat-containing mixtures
such as chocolate; and the like.
[0111] Suitable non-crystallizable carbohydrates for use as
components of the flowable material for making the core, or the
shell, or a portion thereof by molding include non-crystallizable
sugars such as polydextrose, and starch hydrolysates, e.g. glucose
syrup, corn syrup, and high fructose corn syrup; and
non-crystallizable sugar-alcohols such as maltitol syrup.
[0112] Suitable solvents for optional use as components of the
flowable material for making the core, or the shell, or a portion
thereof by molding include water; polar organic solvents such as
methanol, ethanol, isopropanol, acetone, and the like; and
non-polar organic solvents such as methylene chloride, and the
like; and mixtures thereof.
[0113] The flowable material for making the core or the shell or a
portion thereof by molding may optionally comprise adjuvants or
excipients, which may comprise up to about 30% by weight of the
flowable material. Examples of suitable adjuvants or excipients
include plasticizers, detackifiers, humectants, surfactants,
anti-foaming agents, colorants, flavorants, sweeteners, opacifiers,
and the like. Suitable plasticizers for making the core, the shell,
or a portion thereof, by molding include, but not be limited to
polyethylene glycol; propylene glycol; glycerin; sorbitol; triethyl
citrate; tribuyl citrate; dibutyl sebecate; vegetable oils such as
castor oil, rape oil, olive oil, and sesame oil; surfactants such
as polysorbates, sodium lauryl sulfates, and dioctyl-sodium
sulfosuccinates; mono acetate of glycerol; diacetate of glycerol;
triacetate of glycerol; natural gums; triacetin; acetyltributyl
citrate; diethyloxalate; diethylmalate; diethyl fumarate;
diethylmalonate; dioctylphthalate; dibutylsuccinate;
glyceroltributyrate; hydrogenated castor oil; fatty acids;
substituted triglycerides and glycerides; and the like and/or
mixtures thereof. In certain embodiments, the shell is
substantially free of plasticizers, i.e. contains less than about
1%, say less than about 0.01% of plasticizers.
[0114] In one preferred embodiment, the flowable material comprises
less than 5% humectants, or alternately is substantially free of
humectants, such as glycerin, sorbitol, maltitol, xylitol, or
propylene glycol. Humectants have traditionally been included in
pre-formed films employed in enrobing processes, such as that
disclosed in U.S. Pat. Nos. 5,146,730 and 5,459,983, assigned to
Banner Gelatin Products Corp., in order to ensure adequate
flexibility or plasticity and bondability of the film during
processing. Humectants function by binding water and retaining it
in the film. Pre-formed films used in enrobing processes can
typically comprise up to 45% water. Disadvantageously, the presence
of humectant prolongs the drying process, and can adversely affect
the stability of the finished dosage form.
[0115] In one embodiment of the invention, the core, the shell, or
a portion thereof is made by the thermal setting molding method and
apparatus described in copending U.S. patent application Ser. No.
09/966,450, pages 57-63, the disclosure of which is incorporated
herein by reference. In this embodiment, the core, the shell, or a
portion thereof is formed by injecting a starting material in
flowable form into a molding chamber. The starting material
preferably comprises an active ingredient and a thermal setting
material at a temperature above the melting point of the thermal
setting material but below the decomposition temperature of the
active ingredient. The starting material is cooled and solidifies
in the molding chamber into a shaped form (i.e., having the shape
of the mold).
[0116] According to this method, the starting material must be in
flowable form. For example, it may comprise solid particles
suspended in a molten matrix, for example a polymer matrix. The
starting material may be completely molten or in the form of a
paste. The starting material may comprise an active ingredient
dissolved in a molten material. Alternatively, the starting
material may be made by dissolving a solid in a solvent, which
solvent is then evaporated from the starting material after it has
been molded.
[0117] The starting material may comprise any edible material which
is desirable to incorporate into a shaped form, including active
ingredients, nutritionals, vitamins, minerals, flavors, sweeteners,
and the like. Preferably, the starting material comprises an active
ingredient and a thermal setting material. The thermal setting
material may be any edible material that is flowable at a
temperature between about 37 and about 120.degree. C., and that is
a solid at a temperature between about 0 and about 35.degree. C.
Preferred thermal setting materials include water-soluble polymers
such as polyalkylene glycols, polyethylene oxides and derivatives,
and sucrose esters; fats such as cocoa butter, hydrogenated
vegetable oil such as palm kernel oil, cottonseed oil, sunflower
oil, and soybean oil; mono-, di-, and triglycerides, phospholipids,
waxes such as carnuba wax, spermaceti wax, beeswax, candelilla wax,
shellac wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate; sugar in the form on an amorphous glass
such as that used to make hard candy forms, sugar in a
supersaturated solution such as that used to make fondant forms;
low-moisture polymer solutions such as mixtures of gelatin and
other hydrocolloids at water contents up to about 30% such as those
used to make "gummi" confection forms. In a particularly preferred
embodiment, the thermal setting material is a water-soluble polymer
such as polyethylene glycol.
[0118] In another embodiment of the invention, the core, the shell,
or a portion thereof is make using the thermal cycle molding method
and apparatus described in copending U.S. patent application Ser.
No. 09/966,497, pages 27-51, the disclosure of which is also
incorporated herein by reference. In the thermal cycle molding
method and apparatus of U.S. patent application Ser. No.
09/966,497, a thermal cycle molding module having the general
configuration shown in FIG. 3 therein is employed. The thermal
cycle molding module 200 comprises a rotor 202 around which a
plurality of mold units 204 are disposed. The thermal cycle molding
module includes a reservoir 206 (see FIG. 4) for holding flowable
material to make the core. In addition, the thermal cycle molding
module is provided with a temperature control system for rapidly
heating and cooling the mold units. FIGS. 55 and 56 depict such a
temperature control system 600.
[0119] In certain embodiments the core or portions thereof may be
molded using a solvent-free process. In such embodiments, the core
may comprise active ingredient contained within an excipient
matrix. The matrix typically comprises at least about 30 percent,
e.g. at least about 45 weight percent of a thermal-reversible
carrier, and optionally up to about 30 weight percent of various
adjuvants such as for example plasticizers, gelling agents,
strengthening agents, colorants, stabilizers, preservatives, and
the like as known in the art. The matrix may optionally further
comprise up to about 55 weight percent of one or more
release-modifying moldable excipients as described below.
[0120] The core may be in a variety of different shapes. For
example, the core may be shaped as a polyhedron, such as a cube,
pyramid, prism, or the like; or may have the geometry of a space
figure with some non-flat faces, such as a cone, truncated cone,
cylinder, sphere, torus, or the like. In cetrain embodiments, the
core has one or more major faces. For example in embodiments
wherein the core is a compressed tablet, the core surface typically
has two opposing major faces formed by contact with the upper and
lower punch faces in the compression machine. In such embodiments
the core surface typically further comprises a "belly-band" located
between the two major faces, and formed by contact with the die
walls in the compression machine. Exemplary core shapes which may
be employed include tablet shapes formed from compression tooling
shapes described by "The Elizabeth Companies Tablet Design Training
Manual," (Elizabeth Carbide Die Co., Inc., p.7 (McKeesport, Pa.)
(incorporated herein by reference) as follows (the tablet shape
corresponds inversely to the shape of the compression tooling):
[0121] 1. Shallow Concave.
[0122] 2. Standard Concave.
[0123] 3. Deep Concave.
[0124] 4. Extra Deep Concave.
[0125] 5. Modified Ball Concave.
[0126] 6. Standard Concave Bisect.
[0127] 7. Standard Concave Double Bisect.
[0128] 8. Standard Concave European Bisect.
[0129] 9. Standard Concave Partial Bisect.
[0130] 10. Double Radius.
[0131] 11. Bevel & Concave.
[0132] 12. Flat Plain.
[0133] 13. Flat-Faced-Beveled Edge (F.F.B.E.).
[0134] 14. F.F.B.E. Bisect.
[0135] 15. F.F.B.E. Double Bisect.
[0136] 16. Ring.
[0137] 17. Dimple.
[0138] 18. Ellipse.
[0139] 19. Oval.
[0140] 20. Capsule.
[0141] 21. Rectangle.
[0142] 22. Square.
[0143] 23. Triangle.
[0144] 24. Hexagon.
[0145] 25. Pentagon.
[0146] 26. Octagon.
[0147] 27. Diamond.
[0148] 28. Arrowhead.
[0149] 29. Bullet.
[0150] 30. Barrel.
[0151] 31. Half Moon.
[0152] 32. Shield.
[0153] 33. Heart.
[0154] 34. Almond.
[0155] 35. House/Home Plate.
[0156] 36. Parallelogram.
[0157] 37. Trapezoid.
[0158] 38. FIG. 8/Bar Bell.
[0159] 39. Bow Tie.
[0160] 40. Uneven Triangle.
[0161] In one embodiment of the invention, the core comprises
multiple portions, for example a first portion and a second
portion. The portions may be prepared by the same or different
methods and mated using various techniques, such as thermal cycle
molding and thermal setting molding methods described herein. For
example, the first and second portions may both be made by
compression, or both may be made by molding. Or one portion may be
made by compression and the other by molding. The same or different
active ingredient may be present in the first and second portions
of the core. Alternately, one or more core portions may be
substantially free of active ingredients.
[0162] In certain embodiments of the invention, the core or a
portion thereof may function to confer modified release properties
to at least one active ingredient contained therein. In such
embodiments, wherein the core or core portion is made by
compression, as previously noted, the core preferably comprises a
release-modifying excipient for compression. In such embodiments,
wherein the core or core portion is made by molding, as previously
noted, the core preferably comprises a release-modifying moldable
excipient.
[0163] In embodiments in which the core or a portion thereof
functions as an eroding matrix from which dispersed active
ingredient is liberated in a sustained, extended, prolonged, or
retarded manner, the core portion preferably comprises a
release-modifying compressible or moldable excipient selected from
swellable erodible hydrophilic materials, pH-dependent polymers,
and combinations thereof.
[0164] In embodiments in which the core or a portion thereof
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.
[0165] 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 by which it is made, 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.
[0166] 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, the release modifying excipient is
preferrably selected from swellable, erodible hydrophilic
materials.
[0167] 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 portions may again also
optionally further comprise up to about 30 weight percent total of
various plasticizers, adjuvants, and excipients.
[0168] Suitable thermal-reversible carriers for making the core, or
the shell, or a portion thereof, by solvent-free molding are
thermoplastic materials typically having a melting point below
about 11.degree. C., more preferably between about 20 and about
100.degree. C. Examples of suitable thermal-reversible carriers for
solvent-free molding include thermplastic polyalkalene glycols,
thermoplastic polyalkalene oxides, low melting hydrophobic
materials, thermoplastic polymers, thermoplastic starches, and the
like. 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 from about 1000 to about 8,000 Daltons.
Suitable thermoplastic polyalkalene oxides include polyethylene
oxide having a molecular weight from about 100,000 to about 900,000
Daltons. Suitable low-melting hydrophobic materials for use as
thermal-reversible carriers include fats, fatty acid esters,
phospholipids, and waxes which are solid at room temperature,
fat-containing mixtures such as chocolate; and the like. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes that are solid at room temperature include camauba wax,
spermaceti wax, beeswax, candelilla wax, shellac wax,
microcrystalline wax, and paraffin wax. Suitable thermoplastic
polymers for use as thermal-reversible carriers include
thermoplastic water swellable cellulose derivatives, thermoplastic
water insoluble polymers, thermoplastic vinyl polymers. Suitable
thermoplastic water swellable cellulose derivatives include include
hydroxypropylmethyl cellulose (HPMC), methyl cellulose (MC),
carboxymethylcellulose (CMC), cross-linked hydroxypropylcellulose,
hydroxypropyl cellulose (HPC), hydroxybutylcellulose (HBC),
hydroxyethylcellulose (HEC), hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, hydroxypropylethylcellulose, and
salts, derivatives, copolymers, and combinations thereof. Suitable
thermoplastic water insoluble polymers include ethylcellulose,
polyvinyl alcohols, polyvinyl acetate, polycaprolactones, cellulose
acetate and its derivatives, acrylates, methacrylates, acrylic acid
copolymers, and the like and derivatives, copolymers, and
combinations thereof. Suitable thermoplastic vinyl polymers include
polyvinylacetate, polyvinyl alcohol, and polyvinyl pyrrolidone
(PVP). Examples of suitable thermoplastic starches for use as
thermal-reversible carriers include those disclosed in U.S. Pat.
No. 5,427,614, which is incorporated herein by reference.
[0169] In one embodiment, the thermal-reversible carrier for making
the core or the shell, or a portion thereof, by solvent-free
molding is selected from polyalkylene glycols, polyalkaline oxides,
and combinations thereof. In one particular such embodiment, the
core or shell or portion thereof further comprises shellac as a
strengthening adjuvant. Advantageously, shellac may be employed as
a strengthening agent in the molded core or shell or portions
thereof at a level from about 5 to about 15 weight percent of the
molded portion, without imparting pH-dependency to the dissolution
of the molded portion.
[0170] Suitable release-modifying moldable excipients for making
the core, or a portion thereof, by solvent-free or sovent based
molding include but are not limited to swellable erodible
hydrophilic materials, pH-dependent polymers, pore formers, and
insoluble edible materials.
[0171] In embodiments of the present invention wherein the shell is
prepared by a solvent-free or solvent-based molding process,
suitable release-modifying excipients are preferably selected from
swellable erodible hydrophilic materials, pH dependent polymers,
and insoluble edible materials.
[0172] Suitable swellable erodible hydrophilic materials for use as
release-modifying excipients for making the core, or the shell, or
a portion thereof by a solvent-free molding process include water
swellable cellulose derivatives, polyalkalene glycols,
thermoplastic polyalkalene oxides, acrylic polymers, hydrocolloids,
clays, gelling starches, and swelling cross-linked polymers, and
derivitives, copolymers, and combinations thereof. Examples of
suitable water swellable cellulose derivatives include sodium
carboxymethylcellulose, cross-linked hydroxypropylcellulose,
hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC),
hydroxyisopropylcellulose, hydroxybutylcellulose,
hydroxyphenylcellulose, hydroxyethylcellulose (HEC),
hydroxypentylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose, hydroxypropylethylcellulose. Examples
of suitable polyalkalene glyclols include polyethylene glycol.
Examples of suitable thermoplastic polyalkalene oxides include poly
(ethylene oxide). Examples of suitable acrylic polymers include
potassium methacrylatedivinylbenzene copolymer,
polymethylmethacrylate, CARBOPOL (high-molceular weight
cross-linked acrylic acid homopolymers and copolymers), and the
like. Examples of suitable hydrocolloids include alginates, agar,
guar gum, locust bean gum, kappa carrageenan, iota carrageenan,
tara, gum arabic, tragacanth, pectin, xanthan gum, gellan gum,
maltodextrin, galactomannan, pusstulan, laminarin, scleroglucan,
gum arabic, inulin, pectin, gelatin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan. Examples of suitable
clays include smectites such as bentonite, kaolin, and laponite;
magnesium trisilicate, magnesium aluminum silicate, and the like,
and derivatives and mixtures thereof. Examples of suitable gelling
starches include acid hydrolyzed starches, swelling starches such
as sodium starch glycolate, and derivatives thereof. Examples of
suitable swelling cross-linked polymers include cross-linked
polyvinyl pyrrolidone, cross-linked agar, and cross-linked
carboxymethylcellose sodium.
[0173] Suitable pH-dependent polymers for use as release-modifying
moldable excipients for making the molded matrix or molded core or
molded shell or a portion thereof by molding include enteric
cellulose derivatives, for example hydroxypropyl methylcellulose
phthalate, hydroxypropyl methylcellulose acetate succinate,
cellulose acetate phthalate; natural resins such as shellac and
zein; enteric acetate derivatives such as for example
polyvinylacetate phthalate, cellulose acetate phthalate,
acetaldehyde dimethylcellulose acetate; and enteric acrylate
derivatives such as for example polymethacrylate-based polymers
such as poly(methacrylic acid, methyl methacrylate) 1:2, which is
commercially available from Rohm Pharma GmbH under the tradename
EUDRAGIT S and poly(methacrylic acid, methyl methacrylate) 1:1,
which is commercially available from Rohm Pharma GmbH under the
tradename EUDRAGIT L and the like, and derivatives, salts,
copolymers, and combinations thereof.
[0174] Suitable pore formers for use as release-modifying
excipients for making the molded matrix, the core, the shell, or a
portion thereof by molding include water-soluble organic and
inorganic materials. 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.
[0175] Suitable insoluble edible materials for use as
release-modifying moldable excipients for making the core, or the
shell, or a portion thereof, by molding, include water-insoluble
polymers, and low-melting hydrophobic materials. Examples of
suitable water-insoluble polymers include ethylcellulose, polyvinyl
alcohols, polyvinyl acetate, polycaprolactones, cellulose acetate
and its derivatives, acrylates, methacrylates, acrylic acid
copolymers; and the like and derivatives, copolymers, and
combinations thereof. Suitable low-melting hydrophobic materials
include fats, fatty acid esters, phospholipids, and waxes. Examples
of suitable fats include hydrogenated vegetable oils such as for
example cocoa butter, hydrogenated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated
soybean oil; and free fatty acids and their salts. Examples of
suitable fatty acid esters include sucrose fatty acid esters, mono,
di, and triglycerides, glyceryl behenate, glyceryl palmitostearate,
glyceryl monostearate, glyceryl tristearate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides,
and stearoyl macrogol-32 glycerides. Examples of suitable
phospholipids include phosphotidyl choline, phosphotidyl serene,
phosphotidyl enositol, and phosphotidic acid. Examples of suitable
waxes include carnauba wax, spermaceti wax, beeswax, candelilla
wax, shellac wax, microcrystalline wax, and paraffin wax;
fat-containing mixtures such as chocolate; and the like.
[0176] In a preferred embodiment, the shell of the present
invention, whether prepared by a solvent-free molding process, or
by a solvent-based molding process, is substantially free of pores
having a diameter of 0.5-5.0 microns. As used herein,
"substantially free" means that the shell has a pore volume of less
than about 0.02 cc/g, preferably less than about 0.01 cc/g, more
preferably less than about 0.005 cc/g in the pore diameter range of
0.5 to 5.0 microns. In contrast, typical compressed materials have
pore volumes of more than about 0.02 cc/g in this diameter
range.
[0177] The pore volume, pore diameter and density of the shells
used in this invention may be determined using a Quantachrome
Instruments PoreMaster 60 mercury intrusion porosimeter and
associated computer software program known as "Porowin." The
procedure is documented in the Quantachrome Instruments PoreMaster
Operation Manual. The PoreMaster determines both pore volume and
pore diameter of a solid or powder by forced intrusion of a
non-wetting liquid (mercury), which involves evacuation of the
sample in a sample cell (penetrometer), filling the cell with
mercury to surround the sample with mercury, applying pressure to
the sample cell by: (i) compressed air (up to 50 psi maximum); and
(ii) a hydraulic (oil) pressure generator (up to 60000 psi
maximum). Intruded volume is measured by a change in the
capacitance as mercury moves from outside the sample into its pores
under applied pressure. The corresponding pore size diameter (d) at
which the intrusion takes place is calculated directly from the
so-called "Washburn Equation": d=-(4.gamma.(cos .theta.))/P where
.gamma. is the surface tension of liquid mercury, .theta. is the
contact angle between mercury and the sample surface and P is the
applied pressure.
[0178] Equipment used for pore volume measurements:
[0179] (1) Quantachrome Instruments PoreMaster 60.
[0180] (2) Analytical Balance capable of weighing to 0.0001 g.
[0181] (3) Desiccator.
[0182] Reagents used for measurements:
[0183] (1) High purity nitrogen.
[0184] (2) Triply distilled mercury.
[0185] (3) High pressure fluid (Dila AX, available from Shell
Chemical Co.).
[0186] (4) Liquid nitrogen (for Hg vapor cold trap).
[0187] (5) Isopropanol or methanol for cleaning sample cells.
[0188] (6) Liquid detergent for cell cleaning.
[0189] Procedure:
[0190] 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:
[0191] Fine Evacuation time: 1 min.
[0192] Fine Evacuation rate: 10
[0193] Coarse Evacuation time: 5 min.
[0194] 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:
[0195] Mode: Low pressure
[0196] Fine evacuation rate: 10
[0197] Fine evacuation until: 2001 .mu.Hg
[0198] Coarse evacuation time: 10 min.
[0199] Fill pressure: Contact+0.1
[0200] Maximum pressure: 50
[0201] Direction: Intrusion And Extrusion
[0202] Repeat: 0
[0203] Mercury contact angle; 140
[0204] Mercury surface tension: 480
[0205] 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:
[0206] Mode: Fixed rate
[0207] Motor speed: 5
[0208] Start pressure: 20
[0209] End pressure: 60,000
[0210] Direction: Intrusion and extrusion
[0211] Repeat: 0
[0212] Oil fill length: 5
[0213] Mercury contact angle: 140
[0214] Mercury surface tension: 480
[0215] 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.
[0216] The shell of the present invention, whether prepared by a
solvent-free molding process, or by a solvent-based molding
process, typically has a surface gloss of at least about 150 gloss
units, e.g. at least about 175 gloss units, or at least about 190
gloss units, when measured according to the method set forth in
Example 6 herein. In contrast, typical sprayed coatings have gloss
values of less than about 150 gloss units.
[0217] Dosage forms with high surface gloss are preferred by
consumers due to their aesthetic elegance and perceived
swallowability. The surface gloss of the shell depends upon a
number of factors, including the shell composition, the method of
forming the shell, and, if a mold is used, the surface finish on
the mold.
[0218] Shells of this invention may be tested for surface gloss
using an instrument available from TriCor Systems Inc. (Elgin,
Ill.) under the tradename TRI-COR MODEL 805A/806H SURFACE ANALYSIS
SYSTEM and generally in accordance with the procedure described in
"TriCor Systems WGLOSS 3.4 Model 805A/806H Surface Analysis System
Reference Manual" (1996), which is incorporated by reference
herein, except as modified below.
[0219] This instrument utilizes a CCD camera detector, employs a
flat diffuse light source, compares samples to a reference
standard, and determines average gloss values at a 60 degree
incident angle. During its operation, the instrument generates a
gray-scale image, wherein the occurrence of brighter pixels
indicates the presence of more gloss at that given location.
[0220] The instrument also incorporates software that utilizes a
grouping method to quantify gloss, i.e., pixels with similar
brightness are grouped together for averaging purposes.
[0221] The "percent full scale" or "percent ideal" setting (also
referred to as the "percent sample group" setting), is specified by
the user to designate the portion of the brightest pixels above the
threshold that will be considered as one group and averaged within
that group. "Threshold," as used herein, is defined as the maximum
gloss value that will not be included in the average gloss value
calculation. Thus, the background, or the non-glossy areas of a
sample are excluded from the average gloss value calculations. The
method disclosed in K. Fegley and C. Vesey, "The Effect of Tablet
Shape on the Perception of High Gloss Film Coating Systems," which
is available at www.colorcon.com as of 18 Mar. 2002 and
incorporated by reference herein, is used to minimize the effects
resulting from different shell shapes, and to report a metric that
is comparable across the industry. (The 50% sample group setting is
selected as the setting which best approximates analogous data from
surface roughness measurements.)
[0222] After initially calibrating the instrument using a
calibration reference plate (190-228; 294 degree standard; no mask,
rotation 0, depth 0), a standard surface gloss measurement may be
created using gel-coated caplets available from McNeil-PPC, Inc.
under the tradename Extra Strength TYLENOL Gelcaps. The average
gloss value for a sample of such gel-coated caplets may be
determined, while employing the 25 mm full view mask (190-280), and
configuring the instrument to the following settings:
[0223] Rotation: 0
[0224] Depth: 0.25 inches
[0225] Gloss Threshold: 95
[0226] % Full Scale: 50%
[0227] Index of Refraction: 1.57
[0228] The average surface gloss value for the reference standard
is then determined.
[0229] Each shell sample may then be independently tested in
accordance with the same procedure.
[0230] The weight of the shell is preferably about 10 to about 400%
of the weight of the core. In embodiments wherein the shell is
prepared by a solvent-free molding process, the weight of the shell
is typically from about 50 to about 400%, e.g. from about 75 to
about 400%, or about 100 to about 200% percent of the weight of the
core. In embodiments wherein the shell is prepared by a
solvent-based molding process, the weight of the shell is typically
from about 10 to about 100 percent, preferably from about 10 to
about 60 percent of the weight of the core.
[0231] The shell provides a delay of greater than one hour, for
example at least about 3 hours, or at least about 4 hours, or at
least about 6 hours, or at least about 12 hours to the onset of
dissolution of the active ingredient upon contacting of the dosage
form with a liquid medium such as water, gastrointestinal fluid or
the like. The delay period is typically controlled by the shell
thickness, composition, or a combination thereof. In one embodiment
the delay period is independent of the pH of the dissolution media
or fluid environment. For example, the average lag-time for
dissolution of active ingredient in 0.1 N HCl is not substantially
different (i.e. within about 30 minutes, preferably within about 15
minutes) from the average lag-time for the dissolution of active
ingredient in pH 5.6 buffer system.
[0232] Typical shell thicknesses which may be employed in this
invention are about 50 to about 4000 microns. In embodiments
wherein the shell is prepared by a solvent-free molding process,
the shell typically has a thickness of about 500 to about 4000
microns, e.g. about 500 to about 2000 microns, say about 800 to
about 1200 microns. In embodiments wherein the shell is prepared by
a solvent-based molding process, the shell typically has a
thickness of less than about 800 microns, e.g. about 100 to about
600 microns, say about 150 to about 400 microns.
[0233] In one embodiment of the invention, the shell additionally
comprises at least one active ingredient which may be the same or
different than the active ingredient contained in the core.
[0234] In another 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.
The shell of the present invention provides for the delay period
and is preferaby 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
core or a portion thereof. In these embodiments, the core may be
prepared by compression or molding, and is formulated for immediate
release, as is known in the art, so that the core is readily
soluble upon contact with the dissolution medium. In such
embodiments the core 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).
[0235] In another embodiment of this invention at least one active
ingredient contained within the dosage form exhibits a delayed and
sustained release profile. By "delayed then sustained release
profile" it is meant that the release of that particular active
ingredient from the dosage form is delayed for a pre-determined
time after ingestion by the patient, and the delay period ("lag
time") is followed by sustained (prolonged, extended, or retarded)
release of that active ingredient. The shell of the present
invention provides for the delay period, and is preferraby
substantially free of the active to be released in a delayed then
sustained manner. In such embodiments, the delayed then sustained
release active ingredient is preferrably contained within the core.
In such embodiments the core may function for example as an eroding
matrix or a diffusional matrix, or an osmotic pump. In embodiments
in which the core or a portion thereof 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 or a
portion thereof functions as an eroding matrix from which dispersed
active ingredient is liberated in a sustained, extended, prolonged,
or retarded manner, the core portion preferably comprises a
release-modifying compressible or moldable excipient selected from
swellable erodible hydrophilic materials, pH-dependent polymers,
and combinations thereof.
[0236] In one embodiment, the shell is not a compression coating
applied to the core.
[0237] This invention will be illustrated by the following
examples, which are not meant to limit the invention in any
way.
EXAMPLE 1
[0238] Dosage forms according to the invention, comprising a core
within a shell, were prepared as follows.
[0239] The following ingredients were used to make the shells:
1TABLE A Weight Mg/ Shell Trade Name Manufacturer percent Tablet
Polyethylene Carbowax .RTM. Union Carbide 45.0 250 Glycol 3350
Corporation, Danbury, CT Polyethylene Polyox .RTM. Union Carbide
15.0 83 Oxide WSR N-80 Corporation, (MW 200,000) Danbury, CT
Shellac Powder Regular Mantrose-Haeuser 20.0 111 bleached Company,
shellac Atteboro, MA Triethyl Citrate Morflex, Inc., 10.0 56
Greensboro, NC Croscarmellose Ac-Di-Sol .RTM. FMC Corporation, 10.0
56 Sodium Newark, DE
[0240] The shell material was prepared as follows: a beaker was
submersed in a 70.degree. C. water bath (Ret digi-visc;
Antal-Direct, Wayne, Pa.). Polyethylene glycol (PEG) 3350 was added
to the beaker and was mixed with a spatula until all PEG was
melted. Shellac powder, which was screened through 40-mesh screen,
was added to the molten PEG and was mixed until all powder was
dispersed. Triethyl citrate was added to the molten PEG and was
mixed for 1 minute. Polyethylene oxide (PEO) (MW=200,000) was added
and was mixed for 10 minutes. Croscarmellose sodium was added and
was mixed for 2 minutes. The shell material was provided in
flowable form.
[0241] The following commercially available product was used as the
core:
2TABLE B Weight Tablet Trade Name Manufacturer percent Mg/Tablet
Pseudoephedrine Nasal CVS Pharmacy, 23.0 165 HCL core tablet
decongestant Inc., Woonsocket, tablet 30 mg RI
[0242] The shell was molded according to the following process: a
laboratory scale (round, tablet-shaped, 0.4375" diameter) stainless
steel mold assembly was used to apply the shells to the cores. The
mold assembly comprised a lower mold portion and an upper mold
portion, with no temperature control. 350 to 450 mg of the molten
shell material was introduced into the mold cavity formed by the
lower mold portion. A pseudoephedrine HCL core tablet (Table B) was
then inserted into the mold cavity. Additional molten shell
material was added to fill the mold cavity and the upper mold
portion was manually applied to form a molded tablet. After 10
seconds, the upper mold portion was removed, and the molded dosage
form was ejected from the lower mold portion.
EXAMPLE 2
[0243] Dosage forms according to the invention, comprising a core
within a shell, were prepared as follows.
[0244] The following ingredients were used to make the shells:
3TABLE C Trade Weight Mg/ Shell Name Manufacturer percent Tablet
Lauroyl Macrogol-32 Gelucire Gattefosse Corp., 70.0 751 Glycerides
50/13 Westwood, NJ Lauroyl Macrogol-32 Gelucire Gattefosse Corp.,
30.0 322 Glycerides 44/14 Westwood, NJ
[0245] The shell material was prepared in the following manner: 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.
Lauroyl Macrogol-32 glycerides were added to the beaker and were
mixed with a spatula until all the glycerides were melted. The
shell material was provided in flowable form.
[0246] The shell material was applied to the cores of Example 1,
using the laboratory scale mold assembly of Example 1, in the
following manner: 700 to 800 mg of the molten shell material (Table
C) was introduced into the mold cavity formed by the lower mold
portion. A pseudoephedrine HCL core tablet (Example 1) was then
inserted into the mold cavity. Additional molten mixture was added
to fill the mold cavity and the upper mold portion was manually
applied to form a molded tablet. After 10 seconds, the upper mold
portion was removed, and the molded dosage form was ejected from
the lower mold portion.
EXAMPLE 3
[0247] Dosage forms according to the invention, comprising a core
within a shell, were prepared as follows.
[0248] The following ingredients were used to make the shells:
4TABLE D Weight Mg/ Shell Trade Name Manufacturer percent Tablet
Polyethylene Carbowax .RTM. Union Carbide 65.0 430 Glycol 3350
Corporation, Danbury, CT Hydroxypropyl Methocel Dow Chemical 25.0
165 Methylcellulose K4M Perm Co., Midland, CR MI
Hydroxpropylcellulose Klucel Hercules 10.0 66 EXAF Incorporated,
Pharm Wilmington, DE
[0249] The shell material was prepared in the following manner: 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.
PEG 3350 was added to the beaker and was mixed with a spatula until
all PEG was melted. Hydroxypropyl methylcellulose and
hydroxpropylcellulose were added to the molten PEG and mixed for 10
minutes. The shell material was provided in flowable form.
[0250] The following ingredients were used to make the cores:
5TABLE E Weight Mg/ Granulation Trade Name Manufacturer percent
Tablet Ibuprofen Albemarle Corp., 93.24 200 Orangeburg, SC Sodium
Starch Explotab Mendell, A Penwest 5.59 12 Glycolate Co.,
Patterson, NY Colloidal Silicon Cab-O-Sil Cabot Corp., 0.23 0.5
Dioxide Tuscola, IL Magnesium Mallinckrodt Inc., 0.93 2 Stearate
St. Louis, MO
[0251] The cores were made in the following manner: Ibuprofen was
screened through a #20 mesh screen and was added to a plastic bag.
Sodium starch glycolate was screened through a #30 mesh screen and
was added to the plastic bag. The powder was blended by manual
shaking for 2 minutes. Half of the powder was removed from the
first plastic bag and was added to a second plastic bag containing
colloidal silicon dioxide and magnesium stearate. The powder in the
second bag was then blended by manual shaking for 1 minute and was
passed a #20 mesh screen. The resultant powder blend was added to
the first bag and further blended by manual shaking for 1 minute.
The blend was then compressed into tablets using a Manesty
Beta-press (Thomas Engineering, Inc., Hoffman Estates, Ill.) fitted
with round, concave punch and die unit having 0.3125" diameter.
[0252] The shell material was applied to the cores, using a
laboratory scale metal mold assembly (0.5065", round), made from a
lower mold assembly portion comprising a lower mold cavity, and an
upper mold assembly portion comprising an upper mold cavity. The
dosage form was prepared in the following manner 400 to 450 mg of
the molten shell material (Table D) was introduced into the lower
mold cavity formed by the lower mold assembly. An ibuprofen core
tablet as described above was then inserted into the lower mold
cavity. Additional molten shell material was then introduced into
the upper mold cavity formed by the upper mold assembly. The upper
mold assembly was mated with the lower mold assembly to form a
dosage form. After 60 seconds, the upper and lower mold assemblies
were separated, and the dosage form was removed from the mold.
EXAMPLE 4
[0253] The release profiles for the active ingredients contained in
the dosage forms of Examples 1-3 were compared with those of the
same active ingredients from other dosage forms. Results are shown
in FIGS. 2-4.
[0254] All dissolution testing was performed according to the
following method:
[0255] Apparatus: USP Type I apparatus (Basket, 100 RPM).
[0256] Media: 0.1 N HCL and pH 5.6 phosphate buffer at 37.degree.
C. The pH of the buffer was switched from 0.1N HCL to pH 5.6
phosphate buffer at the 2 hour time point.
[0257] Time points: Samples were tested at 0.5, 1, 2, 3, 4, 6, and
8 hours for pseudoephedrine HCL.
[0258] Analysis: Dissolution samples were analyzed for
pseudoephedrine HCL versus a standard prepared at the theoretical
concentration for 100 percent 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 percent
acetonitrile and 45 percent 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 (4.6 mm.times.25 cm).
[0259] FIG. 2 depicts the percent release of active ingredient
(pseudoephedrine HCL) vs. time (hours) for the dosage form of
Example 1, as well as the percent release of pseudoephedrine vs.
time (hours) for a commercially available immediate release dosage
form (Nasal decongestant tablet made by CVS Pharmacy, Inc.-- Table
B). Curve (a) shows the release of pseudoephedrine HCl from the
dosage form of Example 1. Curve (b) shows the release of
pseudoephedrine HCl from the immediate release comparitor tablet.
As shown in FIG. 2, the dosage form of Example 1 exhibited a delay
of about 3 hours to the onset of release of active ingredient.
[0260] FIG. 3 depicts the percent release of active ingredient
(pseudoephedrine HCL) vs. time (hours) from the dosage form of
Example 2, as well as the percent release of pseudoephedrine vs.
time (hours) from a commercially available immediate release tablet
(Sudafed.RTM.). As shown in FIG. 3, the dosage form of Example 2
exhibited a delay of about 4 hours to the onset of release of
active ingredient. Curve (a) shows the release rate of
pseudoephedrine HCL of this invention. Curve (d) was derived from
the commercially immediate release dosage forms of Sudafed.RTM.
tablet (containing pseudoephedrine HCL).
[0261] FIG. 4 depicts the percent release of active ingredient
(Ibuprofen) vs. time (hours) for the dosage form of Example 3. As
shown in FIG. 4, the dosage form of Example 3 exhibited a delay of
about 8 hours to the onset of release of active ingredient.
EXAMPLE 5
[0262] Dosage forms according to the invention, comprising a
compressed core within a molded shell, are made in a continuous
process using an apparatus comprising a compression module and a
thermal cycle molding module 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 shells are made of a shell flowable material
comprising the ingredients shown in Table D above and prepared in
flowable form as described in Example 3. The cores are made of the
ingredients shown in Table E above and prepared as a powder as
described in Example 3. The cores are first compressed on a
compression module as described in copending U.S. application Ser.
No. 09/966,509 at pages 16-27. The compression module is a double
row, rotary apparatus, comprising a fill zone, insertion zone,
compression zone, ejection zone, and purge zone as shown in FIG. 6
of U.S. application Ser. No. 09/966,509. The dies of the
compression module are filled using vacuum assistance, with mesh
screen filters located in die wall ports of each die.
[0263] The cores are transferred from the compression module to the
thermal cycle molding module via a transfer device. The transfer
device has the structure shown as 300 in FIG. 3 and described on
pages 51-57 of copending U.S. application Ser. No. 09/966,414, the
disclosure of which is incorporated by reference. It comprises a
plurality of transfer units 304 attached in cantilever fashion to a
belt 312 as shown in FIGS. 68 and 69. The transfer device rotates
and operates in sync with the compression and 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.
[0264] The thermal cycle molding module has the general
configuration shown in FIG. 3 and pages 27-51 of copending U.S.
application Ser. No. 09/966,497, which depicts a thermal cycle
molding module 200 comprising a rotor 202 around which a plurality
of mold units 204 are disposed. The thermal cycle molding module
includes reservoir 206 (see FIG. 4) for holding the 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 of pending U.S. application Ser.
No. 09/966,497 depict the temperature control system 600.
[0265] The 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 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.
[0266] Coating is performed in two steps, first and second portions
of the shell portions being applied separately as shown in the flow
diagram of FIG. 28B of copending U.S. application Ser. No.
09/966,497. In a first step, a first portion of shell flowable
material, heated to a flowable state in reservoir 206, is injected
into the mold cavities created by the closed mold assemblies. The
temperature of the first portion is then decreased, hardening it
over half the core. The mold assemblies separate, the center mold
assembly rotates, and then the mold assemblies again close. In a
second step, the second portion of the shell flowable material,
heated to a flowable state in reservoir 206, is injected into the
mold cavities. The temperature of the second portion is then
decreased, hardening it over the other half of the core. The mold
assemblies separate, and the finished dosage forms are ejected from
the apparatus.
[0267] Although this invention has been illustrated by reference to
specific embodiments, it will be apparent to those skilled in the
art that various changes and modifications may be made which
clearly fall within the scope of this invention.
* * * * *
References