U.S. patent application number 12/049628 was filed with the patent office on 2008-12-11 for polymer composition and dosage forms comprising the same.
Invention is credited to Frank J. Bunick, Jen Chi Chen, Harry S. Sowden.
Application Number | 20080305150 12/049628 |
Document ID | / |
Family ID | 27542311 |
Filed Date | 2008-12-11 |
United States Patent
Application |
20080305150 |
Kind Code |
A1 |
Chen; Jen Chi ; et
al. |
December 11, 2008 |
Polymer Composition And Dosage Forms Comprising The Same
Abstract
A composition comprising a high molecular weight, water soluble
polymer having a cloud point from about 20 to about 90.degree. C.
and a gelling polymer is provided. The composition may be used as a
component of a pharmaceutical dosage form, such as the shell of a
dosage form, or as an edible matrix, i.e., a pharmaceutical dosage
form per se.
Inventors: |
Chen; Jen Chi; (Morrisville,
PA) ; Bunick; Frank J.; (Randolph, NJ) ;
Sowden; Harry S.; (Glenside, PA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
27542311 |
Appl. No.: |
12/049628 |
Filed: |
March 17, 2008 |
Related U.S. Patent Documents
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Application
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Filing Date |
Patent Number |
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10393764 |
Mar 21, 2003 |
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12049628 |
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PCT/US02/31129 |
Sep 28, 2002 |
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10393764 |
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PCT/US02/31117 |
Sep 28, 2002 |
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PCT/US02/31129 |
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PCT/US02/31062 |
Sep 28, 2002 |
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PCT/US02/31117 |
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PCT/US02/31024 |
Sep 28, 2002 |
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PCT/US02/31062 |
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PCT/US02/31163 |
Sep 28, 2002 |
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PCT/US02/31024 |
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09966939 |
Sep 28, 2001 |
6837696 |
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PCT/US02/31163 |
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09966509 |
Sep 28, 2001 |
6767200 |
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09966939 |
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09966497 |
Sep 28, 2001 |
7122143 |
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09966509 |
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09967414 |
Sep 28, 2001 |
6742646 |
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09966497 |
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09966450 |
Sep 28, 2001 |
6982094 |
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09967414 |
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Current U.S.
Class: |
424/439 ;
424/400; 514/772.2; 514/781 |
Current CPC
Class: |
A61K 9/284 20130101;
A61K 9/2027 20130101; A61K 9/2068 20130101; A61K 9/286 20130101;
B30B 11/08 20130101; A61K 9/2886 20130101; A61K 9/2013 20130101;
A23G 3/368 20130101; A61P 11/00 20180101; A61J 3/10 20130101; A61K
9/2081 20130101; A61K 9/2095 20130101; A61K 9/2893 20130101; A61K
9/2054 20130101; A23G 1/54 20130101; A61P 43/00 20180101; A61K
9/2826 20130101; A23G 3/54 20130101; A23G 3/0029 20130101; Y10T
428/1352 20150115; A61K 9/2031 20130101; B30B 11/34 20130101; A61K
9/0004 20130101; A61J 3/005 20130101; A61K 9/0056 20130101; A61K
9/2072 20130101; A61K 9/282 20130101; B30B 15/302 20130101; A23G
3/04 20130101; A61K 9/209 20130101; A61K 9/2018 20130101; A61K
9/2873 20130101; A61J 3/06 20130101; A23L 29/30 20160801; A61K
9/5084 20130101 |
Class at
Publication: |
424/439 ;
514/781; 514/772.2; 424/400 |
International
Class: |
A61K 47/38 20060101
A61K047/38; A61K 9/00 20060101 A61K009/00; A61K 47/30 20060101
A61K047/30; A61K 9/10 20060101 A61K009/10 |
Claims
1-43. (canceled)
44. A process for preparing a dosage form, which comprises coating
a core with an aqueous dispersion of a high molecular weight, water
soluble polymer in a gelling polymer at a temperature above the
cloud point of the high molecular weight water soluble polymer, and
then cooling the coated core.
45. The process of claim 44, wherein the high molecular weight,
water soluble polymer is selected from the group consisting of
hydroxypropylmethyl cellulose, hydroxypropyl cellulose, methyl
cellulose, polyvinyl alcohol, and mixtures thereof.
46. The process of claim 44, wherein the high molecular weight,
water soluble polymer comprises polyvinyl alcohol having a weight
average molecular weight from about 30,000 to about 200,000.
47. The process of claim 44, wherein the cloud point of the high
molecular weight, water soluble polymer is about 20.degree. C. to
about 90.degree. C.
48. The process of claim 44, wherein the gelling polymer is a high
temperature setting anionic polymer.
49. The process of claim 44, wherein the gelling polymer is
selected from the group consisting of carrageenan, agar, gellan
gum, combinations of carrageenan and locust bean gum, and mixtures
thereof.
50. The process of claim 44, wherein the aqueous dispersion
comprises about 15 to about 40 weight percent solids.
51. The process of claim 44, wherein the high molecular weight
water soluble polymer comprises about 15 to about 19 weight percent
of the total weight of the aqueous dispersion.
52. The process of claim 44, wherein the gelling polymer comprises
about 1 to about 5 weight percent of the total weight of the
aqueous dispersion.
53. The process of claim 44, wherein the aqueous dispersion further
comprises an inorganic cation.
54. The process of claim 53, wherein the inorganic cation is
selected from the group consisting of potassium cation, calcium
cation, and mixtures thereof.
55. The process of claim 44, wherein the aqueous dispersion further
comprises a water-insoluble polymer.
56. The process of claim 55, wherein the water-insoluble polymer is
selected from the group consisting of ethyl cellulose, cellulose
acetate, cellulose acetate butyrate, and mixtures thereof.
57. The process of claim 44, wherein core is coated with the
aqueous dispersion by molding.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This is a continuation-in-part of PCT Application Nos.
PCT/US02/31129, filed Sep. 28, 2002; PCT/US02/31117, filed Sep. 28,
2002; PCT/US02/31062, filed Sep. 28, 2002; PCT/US02/31024, filed
Sep. 28, 2002; and PCT/US02/31163, filed Sep. 28, 2002, which are
each continuations-in-part of U.S. Ser. No. 09/966,939, filed Sep.
28, 2001; U.S. Ser. No. 09/966,509, filed Sep. 28, 2001; U.S. Ser.
No. 09/966,497, filed Sep. 28, 2001; U.S. Ser. No. 09/967,414,
filed Sep. 28, 2001; and U.S. Ser. No. 09/966,450, filed September
28, the disclosures of all of the above being incorporated herein
by reference in their entirety.
FIELD OF THE INVENTION
[0002] This invention relates to composition comprising a high
molecular weight, water soluble polymer having a cloud point from
about 20 to about 90.degree. C., and a gelling polymer. The
composition may be used as a component of a pharmaceutical dosage
form, e.g. the shell of a dosage form or an edible matrix also
containing active ingredient.
BACKGROUND OF THE INVENTION
[0003] A variety of cellulosic polymers are known to be useful in
the preparation of dosage forms. They are often combined with other
polymers and used as coatings or shells for dosage forms. For
example, WO 01/32150 discloses an edible, hardenable coating
composition containing microcrystalline cellulose, carrageenan, and
at least one of a strengthening polymer, a plasticizer, a surface
active agent or a combination thereof. The composition provides a
prompt, i.e., immediate, release coating for solid dosage forms and
is applied by spray coating.
[0004] WO 00/40223 relates to a composition comprising
hydroxypropylcellulose and at least one anionic polymer such as
carboxymethyl ether salts of cellulose, methacrylic acid polymers
and copolymers, carboxyvinyl polymers and copolymers, methacrylic
acid polymers and copolymers, carboxyvinyl polymers and copolymers,
alginic acid salts, pectinic acid salts, pectic acid salts,
carrageenan, agar and carboxylic acid salts of polysaccharides. The
ratio of hydroxypropylcellulose to anionic polymer is from 1:20 to
20:1. The composition is used as an aqueous solution to coat
substrates.
[0005] U.S. Pat. No. 6,358,525 B1 discloses a pharmaceutical
composition containing a medicament and a blend of two components.
The first component is hydroxypropylcellulose and the second
component is at least one other polymer selected from a group that
includes carrageenan, agar, and gellan gum. The pharmaceutical
composition is formed into a tablet that may be coated with a
conventional coating material.
[0006] U.S. Pat. No. 6,245,356 B1 relates to a sustained release,
oral, solid dosage form comprising agglomerated particles of a
therapeutically active medicament in amorphous form, a gelling
agent, an ionizable gel strength enhancing agent and an inert
diluent. The gelling agent preferably comprises xanthan gum and
locust bean gum, but may alternatively comprise alginates,
carrageenan, pectin, and other compounds. The ionizable gel
strength enhancing agent may be a monovalent or multivalent metal
cation. The active medicament in amorphous form, gelling agent,
ionizable gel strength enhancing agent and an inert diluent are
mixed or granulated together and formed into a tablet.
[0007] Known compositions comprising water soluble polymers are
often difficult to use, for example in coating operations, because
their viscosity becomes too high, especially with increasing
polymer concentrations, or increasing polymer molecular weight.
Spraying and molding processes can be particularly difficult.
Accordingly, dilute solutions must be used, resulting in lengthy
processing times to build up adequate thickness.
[0008] Applicants have now discovered that a composition comprising
a combination of a high molecular weight, water soluble polymer
having a cloud point from about 20 to about 90.degree. C. and a
gelling polymer can be used as a component of a dosage form, for
example as the shell of a dosage form, or as part of an edible
matrix also containing active ingredient. The two polymers can be
dispersed in water, optionally with other ingredients, at a
temperature above the cloud point of the high molecular weight,
water soluble polymer, leaving the high molecular weight, water
soluble polymer undissolved and the viscosity of the dispersion
manageable. The dispersion flows easily, and sets quickly and
strongly at a relatively high temperature due to the presence of
the gelling polymer. Cores can advantageously be coated with this
composition, preferably by molding, removed quickly from the
coating apparatus, and processed further. Alternatively, the
ingredients of the composition can be combined with an active
ingredient and made into an edible matrix, preferably by molding.
Dosage forms comprising such a composition advantageously provide
modified release of active ingredient contained therein.
SUMMARY OF THE INVENTION
[0009] The invention provides a composition comprising 75 to 95
weight percent of a high molecular weight, water soluble polymer
having a cloud point from about 20 to about 90.degree. C., and 5 to
25 weight percent of a gelling polymer, said composition being a
solid substantially free of pores having a diameter of 0.5 to 5.0
microns.
[0010] The invention also provides an edible matrix comprising: a)
up to about 80 weight percent of at least one active ingredient; b)
about 15 to about 95 weight percent of a high molecular weight,
water soluble polymer having a cloud point from about 20 to about
90.degree. C.; and c) about 5 to about 25 weight percent of a
gelling polymer, said edible matrix being a solid substantially
free of pores having a diameter of 0.5 to 5.0 microns.
[0011] The present invention also provides a process for preparing
a dosage form, which comprises coating a core with an aqueous
dispersion of a high molecular weight, water soluble polymer in a
gelling polymer at a temperature above the cloud point of the high
molecular weight water soluble polymer, and then cooling the coated
core.
DETAILED DESCRIPTION OF THE INVENTION
[0012] As used herein, the term "dosage form" applies to any solid
object, semi-solid, or liquid composition designed to contain a
specific pre-determined amount (dose) of a certain ingredient, for
example an active ingredient as defined below. Suitable dosage
forms may be pharmaceutical drug delivery systems, including those
for oral administration, buccal administration, rectal
administration, topical or mucosal delivery, or subcutaneous
implants, or other implanted drug delivery systems; or compositions
for delivering minerals, vitamins and other nutraceuticals, oral
care agents, flavorants, and the like. Preferably the dosage forms
of the present invention are considered to be solid, however they
may contain liquid or semi-solid components. In a particularly
preferred embodiment, the dosage form is an orally administered
system for delivering a pharmaceutical active ingredient to the
gastro-intestinal tract of a human.
[0013] 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,
antifuingals, antispasmodics, appetite suppressants,
bronchodilators, cardiovascular agents, central nervous system
agents, central nervous system stimulants, decongestants, oral
contraceptives, diuretics, expectorants, gastrointestinal agents,
migraine preparations, motion sickness products, mucolytics, muscle
relaxants, osteoporosis preparations, polydimethylsiloxanes,
respiratory agents, sleep-aids, urinary tract agents and mixtures
thereof:
[0014] Suitable oral care agents include breath fresheners, tooth
whiteners, antimicrobial agents, tooth mineralizers, tooth decay
inhibitors, topical anesthetics, mucoprotectants, and the like.
[0015] Suitable flavorants include menthol, peppermint, mint
flavors, fruit flavors, chocolate, vanilla, bubblegum flavors,
coffee flavors, liqueur flavors and combinations and the like.
[0016] Examples of suitable gastrointestinal agents include
antacids such as calcium carbonate, magnesium hydroxide, magnesium
oxide, magnesium carbonate, aluminum hydroxide, sodium bicarbonate,
dlihydroxyaluminum 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.
[0017] 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.
[0018] 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 one particular embodiment, the active
ingredient is selected from propionic acid derivative NSAID, e.g.
ibuprofen, naproxen, flurbiprofen, fenbufen, fenoprofen,
indoprofen, ketoprofen, fluprofen, pirprofen, carprofen, oxaprozin,
pranoprofen, suprofen, and pharmaceutically acceptable salts,
derivatives, and combinations thereof In another particular
embodiment of the invention, the active ingredient may be selected
from acetaminophen, acetyl salicylic acid, ibuprofen, naproxen,
ketoprofen, flurbiprofen, diclofenac, cyclobenzaprine, meloxicam,
rofecoxib, celecoxib, and pharmaceutically acceptable salts,
esters, isomers, and mixtures thereof.
[0019] 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.
[0020] 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.
[0021] The active ingredient or ingredients are present in the
dosage form in a therapeutically effective amount, which is an
amount that produces the desired therapeutic response upon oral
administration and can be readily determined by one skilled in the
art. In determining such amounts, the particular active ingredient
being administered, the bioavailability characteristics of the
active ingredient, the dosing regimen, the age and weight of the
patient, and other factors must be considered, as known in the art.
Typically, the dosage form comprises at least about 1 weight
percent, preferably, the dosage form comprises at least about 5
weight percent, e.g. at least about 25 weight percent of a
combination of one or more active ingredients. In one embodiment, a
core comprises a total of at least about 50 weight percent, e.g. at
least about 70 weight percent, say at least about 80 weight percent
(based on the weight of the core) of one or more active
ingredients.
[0022] 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
embodiment, such particles are crystals having an average particle
size of about 1-300 microns. In another embodiment, the particles
are granules or pellets having an average particle size of about
50-2000 microns, for example about 50-1000 microns, say about
100-800 microns.
[0023] The composition of the invention comprises a combination of
a high molecular weight, water soluble polymer and a gelling
polymer. It is a solid and is substantially free of pores having a
diameter of 0.5 to 5.0 microns. It may be used as a component of a
pharmaceutical dosage form, such as the shell of a dosage form, a
portion of a shell of a dosage form, the core of a dosage form, a
portion of the core of a dosage form. When combined with one or
more active ingredients, it may be made into an edible matrix. Such
an edible matrix may be used as a dosage form per se, or as a
component of a pharmaceutical dosage form, such as the core of a
dosage form, a portion of the core of a dosage form, the shell of a
dosage form, or a portion of the shell of a dosage form, and may
optionally be coated with conventional coating materials, as well
known in the art.
[0024] The high molecular weight, water soluble polymer has a cloud
point from about 20 to about 90.degree. C. Preferably, the high
molecular weight, water soluble polymer has a cloud point from
about 35 to about 70.degree. C. The weight average molecular weight
of the high molecular weight, water soluble polymer may be in the
range of about 1000 to about 2,000,000 g/mole.
[0025] Examples of suitable high molecular weight, water soluble
polymers include hydroxypropylmethyl cellulose, hydroxypropyl
cellulose, methyl cellulose, polyvinyl alcohol, and mixtures
thereof.
[0026] In one embodiment, the high molecular weight, water soluble
polymer comprises hydroxypropyl cellulose having a weight average
molecular weight from about 140,000 to about 1,150,000. In another
embodiment, the high molecular weight, water soluble polymer
comprises hydroxypropyl methylcellulose having a viscosity from
about 80 to about 120,000 mPa s in 2% aqueous solution. In a
further embodiment, the high molecular weight, water soluble
polymer comprises methylcellulose having a viscosity of 4000 mPa s
in 2% aqueous solution. In yet another embodiment, the high
molecular weight, water soluble polymer comprises polyvinyl alcohol
having a weight average molecular weight from about 30,000 to about
200,000.
[0027] The gelling polymer may be for example, a high temperature
setting anionic polymer. Examples of suitable gelling polymers
include carrageenan, agar, gellan gun, combinations of carrageenan
with locust bean gum, and mixtures thereof. In one embodiment, the
gelling polymer is carrageenan.
[0028] The gelling polymer is typically present in an amount from
about 5 to about 25 percent of the composition. In one embodiment,
the weight ratio of high molecular weight, water soluble polymer to
gelling polymer in the composition is typically from about 75:25 to
about 95:5. Preferably, the weight ratio of high molecular weight,
water soluble polymer in the composition to gelling polymer is from
about 80:20 to about 90:10.
[0029] In another embodiment, active ingredient is combined with
the ingredients of the composition to form an edible matrix. When
active ingredient is present, the level of high molecular weight
water soluble polymer in the edible matrix is adjusted downward by
the amount of the active ingredient. In one particular embodiment,
the edible matrix comprises up to about 80 weight percent of at
least one active ingredient; about 15 to about 95 weight percent of
a high molecular weight, water soluble polymer having a cloud point
from about 20 to about 90.degree. C.; and about 5 to about 25
weight percent of a gelling polymer. Accordingly, in this
embodiment, the weight ratio of high molecular weight water soluble
polymer to gelling polymer may be from about 60:40 to about 95:5.
The weight ratio of active ingredient to high molecular weight
water soluble polymer may be from about 1:99 to about 82:18.
[0030] The composition or edible matrix, whether used as a shell,
portion of a shell, i.e. "shell portion," core, core portion, or as
a dosage form per se, may comprise other optional ingredients. In
one embodiment, the composition or edible matrix also comprises an
inorganic cation. Suitable inorganic cations include
pharmaceutically acceptable monovalent, divalent, and trivalent
cations. For example, the inorganic cation may be selected from the
group consisting of potassium cations, calcium cations, and
mixtures thereof
[0031] In another embodiment, the composition or edible matrix also
comprises a water-insoluble polymer. Suitable water-insoluble
polymers include of ethyl cellulose, cellulose acetate, cellulose
acetate butyrate and mixtures thereof
[0032] In one embodiment, a dosage form according to the invention
comprises a core at least partially surrounded by a shell or a
shell portion that comprises a high molecular weight, water soluble
polymer, and a gelling polymer in a weight ratio of about 75:25 to
about 95:5. In another embodiment, a dosage form according to the
invention comprises a core at least partially surrounded by a shell
that comprises 75 to 95 weight percent of a high molecular weight,
water soluble polymer, and 5 to 25 weight percent of a gelling
polymer. Such shell may comprise about 1 to about 75, or about 2 to
about 24, or about 5 to about 15, weight percent of the total
weight of the dosage form. The average thickness of the shell or
shell portion may be in the range of about 50 to about 500
microns.
[0033] The shell may completely surround the core, or only
partially surround the core. Moreover, only one shell portion may
comprise the composition or edible matrix of the invention, as
further discussed below. For example, in one embodiment a shell
comprising a first shell portion and a second shell portion
surrounds the core, and the first shell portion comprises the
composition or edible matrix of the present invention, while the
second shell portion is compositionally different from the first
shell portion. In embodiments wherein a first shell portion of a
dosage form comprises the composition or edible matrix of the
present invention, the weight of said first shell portion may be
from about 1 to about 75, e.g. about 1 to about 25, or about 1 to
about 10 percent of the weight of the dosage form.
[0034] In embodiments in which the composition or edible matrix is
employed as a first shell portion, the second shell portion may
comprise any suitable materials, and be applied by any suitable
method, for example, those disclosed in U.S. Application Serial
Nos. ______ {MCP-321, MCP-313, or MCP-311, or MCP-5001}, the
disclosures of which are incorporated herein by reference.
[0035] The core may be any solid form. The core may prepared by any
suitable method, including for example compression or molding. As
used herein, "core" refers to a material which is at least
partially enveloped or surrounded by another material. Preferably,
the core is a self-contained unitary object, such as a tablet or
capsule. Typically, the core comprises a solid, for example, the
core may be a compressed or molded tablet, hard or soft capsule,
suppository, or a confectionery form such as a lozenge, nougat,
caramel, fondant, or fat based composition. In certain other
embodiments, the core or a portion thereof may be in the form of a
semi-solid or a liquid in the finished dosage form. For example the
core may comprise a liquid filled capsule, or a semisolid fondant
material. In embodiments in which the core comprises a flowable
component, such as a plurality of granules or particles, or a
liquid, the core preferably additionally comprises an enveloping
component, such as a capsule shell, or a coating, for containing
the flowable material. In certain particular embodiments in which
the core comprises an enveloping component, the shell or shell
portions of the present invention are in direct contact with the
enveloping component of the core, which separates the shell from
the flowable component of the core,
[0036] In one embodiment the core is a compressed tablet having a
hardness from about 2 to about 30 kp/cm.sup.2, e.g. from about 6 to
about 25 kp/cm.sup.2. "Hardness" is a term used in the art to
describe the diametral breaking strength of either the core or the
coated solid dosage form as measured by conventional pharmaceutical
hardness testing equipment, such as a Schleuniger Hardness Tester.
In order to compare values across different size tablets, the
breaking strength must be normalized for the area of the break.
This normalized value, expressed in kp/cm.sup.2, is sometimes
referred in the art as tablet tensile strength. A general
discussion of tablet hardness testing is found in Leiberman et
al.,Pharmaceutical Dosage Forms--Tablets, Volume 2, 2.sup.nd ed.,
Marcel Dekker Inc., 1990, pp. 213-217, 327-329.
[0037] The core may have one of a variety of different shapes. For
example, the core may be shaped as a polyhedron, such as a cube,
pyramid, prism, or the like; or may have the geometry of a space
figure with some non-flat faces, such as a cone, truncated cone,
cylinder, sphere, torus, or the like. In certain embodiments, a
core has one or more major faces. For example, in embodiments
wherein a 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. A core may also comprise a
multilayer tablet. Exemplary core shapes that may be employed
include tablet shapes formed from compression tooling shapes
described by "The Elizabeth Companies Tablet Design Training
Manual" 30 (Elizabeth Carbide Die Co., Inc., p. 7 (McKeesport, Pa.)
(incorporated herein by reference).
[0038] The core typically comprises active ingredient and a variety
of excipients, depending on the method by which it is made.
[0039] In embodiments in which the core is made by compression,
suitable excipients include fillers, binders, disintegrants,
lubricants, glidants, and the like, as known in the art. A core
made by compression may be a single or multi-layer, for example
bi-layer, tablet.
[0040] Suitable fillers for use in making the core by compression
include water-soluble compressible carbohydrates such as sugars,
which include dextrose, sucrose, maltose, and lactose,
sugar-alcohols, which include mannitol, sorbitol, maltitol,
xylitol, starch hydrolysates, which include dextrins, and
maltodextrins, and the like, water insoluble plastically deforming
materials such as microcrystalline cellulose or other cellulosic
derivatives, water-insoluble brinttle fracture materials such as
dicalcium phosphate, tricalcium phosphate and the like and mixtures
thereof
[0041] Suitable binders for making the core by compression include
dry binders such as polyvinyl pyrrolidone,
hydroxypropylmethylcellulose, and the like; wet binders such as
water-soluble polymers, including hydrocolloids such as acacia,
alginates, agar, guar gum, locust bean, carrageenan,
carboxymethylcellulose, tara, gum arabic, tragacanth, pectin,
xanthan, gellan, gelatin, maltodextrin, galactomannan, pusstulan,
laminarin, scieroglucan, inulin, whelan, rhamsan, zooglan,
methylan, chitin, cyclodextrin, chitosan, polyvinyl pyrrolidone,
cellulosics, sucrose, starches, and the like; and derivatives and
mixtures thereof.
[0042] Suitable disintegrants for making the core by compression,
include sodium starch glycolate, cross-linked polyvinylpyrrolidone,
cross-linked carboxymethylcellulose, starches, microcrystalline
cellulose, and the like.
[0043] Suitable lubricants for making the core by compression
include long chain fatty acids and their salts, such as magnesium
stearate and stearic acid, talc, glycerides and waxes.
[0044] Suitable glidants for making the core by compression,
include colloidal silicon dioxide, and the like.
[0045] In certain embodiments, the core or a portion thereof may
optionally comprise release modifying excipients as known in the
art, for example as disclosed in commonly assigned, copending U.S.
Application Serial No. ______ [MCP 321], the disclosure of which is
incorporated by reference herein. Suitable release-modifying
excipients for making the core by compression include swellable
erodible hydrophillic materials, insoluble edible materials,
pH-dependent polymers, and the like.
[0046] Suitable pharmaceutically acceptable adjuvants for making
the cores 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.
[0047] In embodiments wherein the core is prepared by compression,
a dry blending (i.e. direct compression), or wet granulation
process may be employed, as known in the art. In a dry blending
(direct compression) method, the active ingredient or ingredients,
together with the excipients, are blended in a suitable blender,
then transferred directly to a compression machine for pressing
into tablets. In a wet granulation method, the active ingredient or
ingredients, appropriate excipients, and a solution or dispersion
of a wet binder (e.g. an aqueous cooked starch paste, or solution
of polyvinyl pyrrolidone) are mixed and granulated. Alternatively a
dry binder may be included among the excipients, and the mixture
may be granulated with water or other suitable solvent. Suitable
apparatuses for wet granulation are known in the art, including low
shear, e.g. planetary mixers; high shear mixers; and fluid beds,
including rotary fluid beds. The resulting granulated material is
dried, and optionally dry-blended with further ingredients, e.g.
adjuvants and/or excipients such as for example lubricants,
colorants, and the like. The final dry blend is then suitable for
compression. Methods for direct compression and wet granulation
processes are known in the art, and are described in detail in, for
example, Lachman, et al., The Theory and Practice of Industrial
Pharmacy, Chapter 11 (3rd ed. 1986).
[0048] The dry-blended, or wet granulated, powder mixture is
typically compacted into tablets using a rotary compression machine
as known in the art, such as for example those commercially
available from Fette America Inc., Rockaway, N.J., or Manesty
Machines LTD, Liverpool, UK. In a rotary compression machine, a
metered volume of powder is filled into a die cavity, which rotates
as part of a "die table" from the filling position to a compaction
position where the powder is compacted between an upper and a lower
punch to an ejection position where the resulting tablet is pushed
from the die cavity by the lower punch and guided to an ejection
chute by a stationary "take-off" bar.
[0049] In one optional embodiment, the core may be prepared by the
compression methods and apparatus described in copending U.S.
patent application Ser. No. 09/966,509, pages 16-27, the disclosure
of which is incorporated herein by reference. Specifically, the
core is made using a rotary compression module comprising a fill
zone, insertion zone, compression zone, ejection zone, and purge
zone in a single apparatus having a double row die construction as
shown in FIG. 6 of U.S. patent application Ser. No. 09/966,509. The
dies of the compression module are preferably filled using the
assistance of a vacuum, with filters located in or near each
die.
[0050] The shell may be substantially unitary and continuous, or
the shell may comprise multiple portions, e.g. a first shell
portion and a second shell portion. In certain embodiments, at
least one such shell portion comprises the composition or edible
matrix of the invention. In certain embodiments the shell or shell
portions are in direct contact with the core. In certain other
embodiments, the shell or shell portions are in direct contact with
a subcoating that substantially surrounds the core. In certain
embodiments, the shell or a shell portion may comprise one ore more
openings therein.
[0051] In embodiments in which the shell or shell portion is
applied to the core by molding, at least a portion of the shell
surrounds the core such that the shell inner surface resides
substantially conformally upon the core outer surface. As used
herein, the term "substantially conformally" shall mean that the
inner surface of the shell has peaks and valleys or indentations
and protrusions corresponding substantially inversely to the peaks
and valleys of the outer surface of the core. In certain such
embodiments, the indentations and protrusions typically have a
length, width, height or depth in one dimension of greater than 10
microns, say greater than 20 microns, and less than about 30,000
microns, preferably less than about 2000 microns.
[0052] In certain embodiments, the shell comprises a first shell
portion and a second shell portion that are compositionally
different. In one embodiment, a first shell portion comprises the
composition or edible matrix of the invention, and a second shell
portion is compositionally different from the first shell portion.
As used herein, the term "compositionally different" means having
features that are readily distinguishable by qualitative or
quantitative chemical analysis, physical testing, or visual
observation. For example, the first and second shell portions may
contain different ingredients, or different levels of the same
ingredients, or the first and second shell portions may have
different physical or chemical properties, different functional
properties, or be visually distinct. Examples of physical or
chemical properties that may be different include hydrophylicity,
hydrophobicity, hygroscopicity, elasticity, plasticity, tensile
strength, crystallinity, and density. Examples of functional
properties which may be different include rate and/or extent of
dissolution of the material itself or of an active ingredient
therefrom, rate of disintegration of the material, permeability to
active ingredients, permeability to water or aqueous media, and the
like. Examples of visual distinctions include size, shape,
topography, or other geometric features, color, hue, opacity, and
gloss.
[0053] In one embodiment, the dosage form of the invention
comprises: a) a core containing an active ingredient; b) an
optional subcoating that substantially covers the core; and c) a
shell comprising first and second shell portions residing on the
surface of the subcoating, the first shell portion comprising the
composition or edible matrix of the invention. As used herein,
"substantially covers" shall mean at least about 95 percent of the
surface area of the core is covered by the subcoating.
[0054] The use of subcoatings is well known in the art and
disclosed in, for example, U.S. Pat. Nos. 3,185,626, which is
incorporated by reference herein. Any composition suitable for
film-coating a tablet may be used as a subcoating according to the
present invention. Examples of suitable subcoatings are disclosed
in U.S. Pat. Nos. 4,683,256, 4,543,370, 4,643,894, 4,828,841,
4,725,441, 4,802,924, 5,630,871, and 6,274,162, which are all
incorporated by reference herein. Additional suitable subcoatings
include one or more of the following ingredients: cellulose ethers
such as hydroxypropylmethylcellulose, hydroxypropylcellulose, and
hydroxyethylcellulose; polycarbohydrates such as xanthan gum,
starch, and maltodextrin; plasticizers including for example,
glycerin, polyethylene glycol propylene glycol, dibutyl sebecate,
triethyl citrate, vegetable oils such as castor oil, surfactants
such as polysorbate-80, sodium lauryl sulfate and dioctyl-sodium
sulfosuccinate; polycarbohydrates, pigments, and opacifiers.
[0055] In one embodiment, the subcoating comprises from about 2
percent to about 8 percent, e.g. from about 4 percent to about 6
percent of a water-soluble cellulose ether and from about 0.1
percent to about 1 percent, castor oil, as disclosed in detail in
U.S. Pat. No. 5,658,589, which is incorporated by reference herein.
In another embodiment, the subcoating comprises from about 20
percent to about 50 percent, e.g., from about 25 percent to about
40 percent of HPMC; from about 45 percent to about 75 percent,
e.g., from about 50 percent to about 70 percent of maltodextrin;
and from about 1 percent to about 10 percent, e.g., from about 5
percent to about 10 percent of PEG 400.
[0056] The dried subcoating typically is present in an amount,
based upon the dry weight of the core, from about 0 percent to
about 5 percent.
[0057] In one embodiment, an aqueous dispersion of the composition
comprising the high molecular weight, water soluble polymer and the
gelling polymer is used to prepare the shell. In particular, the
high molecular weight, water soluble polymer and gelling polymer
are dispersed in water at a temperature above the cloud point of
the high molecular weight, water soluble polymer. The dispersion is
applied to a core, by for example molding, dipping, spraying, or
other means. Preferably, the dispersion is applied to the core by
molding. Spraying is least preferred. After application of the
dispersion to the core, the core is cooled, preferably at a
relatively high temperature, i.e., above the cloud point of the
high molecular weight, water soluble polymer.
[0058] The aqueous dispersion typically comprises about 15 to about
40 weight percent solids. In one embodiment, the aqueous dispersion
comprises about 15 to about 20 weight percent solids.
[0059] In one embodiment, the high molecular weight, water soluble
polymer comprises about 15 to about 19 weight percent of the total
weight of the aqueous dispersion.
[0060] In another embodiment, the gelling polymer comprises about 1
to about 5 weight percent of the total weight of the aqueous
dispersion.
[0061] The shell thickness at various locations may be measured
using a microscope, for example, an environmental scanning electron
microscope, model XL 30 ESEM LaB6, Philips Electronic Instruments
Company, Mahwah, WT. The shell thickness is measured at 6 different
locations on a single dosage form. The relative standard deviation
(RSD) is calculated as the sample standard deviation, divided by
the mean, times 100 as known in the art (i.e. the RSD is the
standard deviation expressed as a percentage of the mean). The RSD
in shell thickness provides an indication of the variation in the
thickness of the shell on a single dosage form. In certain optional
embodiments of the invention, the relative standard deviation in
shell thickness is less than about 40%, e.g less than about 30%, or
less than about 20%.
[0062] The shell itself or an outer coating thereon may optionally
contain active ingredient. In one embodiment, such active
ingredient will be released immediately from the dosage form upon
ingestion, or contacting of the dosage form with a liquid medium.
In another embodiment, such active ingredient will be released in a
controlled, sustained, prolonged, or extended fashion upon
ingestion, or contacting of the dosage form with a liquid
medium.
[0063] In certain embodiments of the invention, the core, the
shell, or the edible matrix are prepared by molding. In such
embodiments, the core, the shell, or the edible matrix is made from
a dispersion as described above optionally comprising active
ingredient. The dispersion comprises the high molecular weight
water soluble polymer dispersed in a liquid carrier comprising the
gelling agent and a liquid plasticizer at a temperature above the
cloud point of the high molecular weight polymer and above the
gelling temperature of the gelling polymer. Suitable liquid
plasticizers include water, glycerin, propylene glycol, triacetin,
triethyl citrate, polyethylene glycol, sorbitol, tribuyl citrate,
and mixtures thereof
[0064] In one embodiment, molding is performed via thermal setting
molding using the method and apparatus described in copending U.S.
patent application Ser. No. 09/966,450, pages 57-63, the disclosure
of which is incorporated herein by reference. In this embodiment, a
core, theshell, or the edible matrix is formed by injecting the
dispersion into a molding chamber. The dispersion is cooled and
solidifies in the molding chamber into a shaped form (i.e., having
the shape of the mold).
[0065] According to this method, the dispersion may comprise solid
particles of the high molecular weight water-soluble polymer
suspended in a liquid carrier comprising the gelling polymer and
the liquid plasticizer, e.g. water. Here, the gelling polymer is
dissolved in the liquid plasticizer.
[0066] In another embodiment, molding is performed by thermal cycle
molding using the method and apparatus described in copending U.S.
patent application Ser. No. 09/966,497, pages 27-51, the disclosure
of which is incorporated herein by reference. Thermal cycle molding
is performed by injecting the dispersion into a heated molding
chamber. In this embodiment, the dispersion may comprise the high
molecular weight water soluble polymer dispersed in a liquid
carrier comprising the gelling polymer and water at a temperature
above the cloud point of the high molecular weight polymer and
above the gelling temperature of the gelling polymer. The
dispersion is cooled and solidifies in the molding chamber into a
shaped form (i.e., having the shape of the mold).
[0067] 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 dispersion. In addition, the thermal cycle molding
module is provided with a temperature control system for rapidly
heating and cooling the mold units. FIGS. 55 and 56 depict the
temperature control system 600.
[0068] The mold units may comprise center mold assemblies 212,
upper mold assemblies 214, and lower mold assemblies 210, as shown
in FIGS. 26-28, which mate to form mold cavities having a desired
shape, for instance of a core or a shell surrounding one or more
cores. As rotor 202 rotates, opposing center and upper mold
assemblies or opposing center and lower mold assemblies close.
Dispersion, which is heated to a flowable state in reservoir 206,
is injected into the resulting mold cavities. The temperature of
the dispersion is then decreased, hardening the dispersion. The
mold assemblies open and eject the finished product.
[0069] In one optional embodiment of the invention, the shell is
applied to the dosage form using a thermal cycle molding apparatus
of the general type shown in FIGS. 28A-C of copending U.S.
application Ser. No. 09/966,497 comprising rotatable center mold
assemblies 212, lower mold assemblies 210 and upper mold assemblies
214. Cores are continuously fed to the mold assemblies. Dispersion
for making the shell, which is heated to a flowable state in
reservoir 206, is injected into the mold cavities created by the
closed mold assemblies holding the cores. The temperature of the
shell dispersion is then decreased, hardening it around the cores.
The mold assemblies open and eject the finished dosage forms. Shell
coating is performed in two steps, each half of the dosage forms
being coated separately as shown in the flow diagram of FIG. 28B of
copending U.S. application Ser. No. 09/966,939 via rotation of the
center mold assembly.
[0070] In one embodiment, the compression module of copending U.S.
patent application Ser. No. 09/966,509, pp. 16-27 may be employed
to make the core and the shell is applied to the core using a
thermal cycle molding module as described above. A transfer device
as described in U.S. patent application Ser. No. 09/966,414, pp.
51-57, the disclosure of which is incorporated herein by reference,
may be used to transfer the cores from the compression module to
the thermal cycle molding module. Such a transfer device may have
the structure shown as 300 in FIG. 3 of copending U.S. application
Ser. No. 09/966,939. It comprises a plurality of transfer units 304
attached in cantilever fashion to a belt 312 as shown in FIGS. 68
and 69 of copending U.S. application Ser. No. 09/966,939. The
transfer device rotates and operates in sync with the compression
module and the thermal cycle molding module to which it is coupled.
Transfer units 304 comprise retainers 330 for holding cores as they
travel around the transfer device.
[0071] In certain embodiments wherein a liquid carrier for the
dispersion is formed from a mixture of gelling polymer and liquid
plasticizer, the liquid carrier may be a thermoplastic system. For
example when the gelling polymer is melted and mixed with the
liquid plasticizer in a certain ratio, the mixture can be in a
thermoplastic state depending on temperature and pressure. In
certain other embodiments, the liquid carrier is not a
thermoplastic system.
[0072] In certain optional embodiments the shell, core, or edible
matrix of the invention may additionally comprise a water insoluble
polymer at a level of up to about 40%, e.g 15% of the weight of the
shell, core, or edible matrix. In embodiments wherein a water
insoluble polymer is employed, the weight ratio of high molecular
weight water soluble polymer to water insoluble polymer may be from
about 99:1 to about 50:50. Suitable water insoluble polymers
include ethyl cellulose, cellulose acetate, cellulose acetate
butyrate, cellulose propionate, and mixtures thereof.
[0073] The dispersion for making cores or the shell by molding may
optionally comprise adjuvants or excipients, which may comprise up
to about 30% by weight of the dispersion. Examples of suitable
adjuvants or excipients include detackifiers, humectants,
surfactants, anti-foaming agents, colorants, flavorants,
sweeteners, opacifiers, and the like.
[0074] In embodiments in which the composition or the edible
matrixis prepared by molding, the composition or edible matrix
typically is substantially free of pores in the diameter range of
0.5 to 5.0 microns, i.e. has a pore volume in the pore diameter
range of 0.5 to 5.0 microns 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. Typical compressed materials have pore volumes in
this diameter range of more than about 0.02 cc/g. Pore volume, pore
diameter and density may be determined using a Quantachrome
Instruments PoreMaster 60 mercury intrusion porosimeter and
associated computer software program known as "Porowin." The
procedure is documented in the Quantachrome Instruments PoreMaster
Operation Manual. The PoreMaster determines both pore volume and
pore diameter of a solid or powder by forced intrusion of a
non-wetting liquid (mercury), which involves evacuation of the
sample in a sample cell (penetrometer), filling the cell with
mercury to surround the sample with mercury, applying pressure to
the sample cell by: (i) compressed air (up to 50 psi maximum); and
(ii) a hydraulic (oil) pressure generator (up to 60000 psi
maximum). Intruded volume is measured by a change in the
capacitance as mercury moves from outside the sample into its pores
under applied pressure. The corresponding pore size diameter (d) at
which the intrusion takes place is calculated directly from the
so-called "Washburn Equation": d=-(4.gamma.(cos .theta.)/P) where
.gamma. is the surface tension of liquid mercury, .theta. is the
contact angle between mercury and the sample surface and P is the
applied pressure.
[0075] Equipment used for pore volume measurements: [0076] 1.
Quantachrome Instruments PoreMaster 60. [0077] 2. Analytical
Balance capable of weighing to 0.0001 g. [0078] 3. Desiccator.
[0079] Reagents used for measurements: [0080] 1. High purity
nitrogen. [0081] 2. Triply distilled mercury. [0082] 3. High
pressure fluid (Dila AX, available from Shell Chemical Co.). [0083]
4. Liquid nitrogen (for Hg vapor cold trap). [0084] 5. Isopropanol
or methanol for cleaning sample cells. [0085] 6. Liquid detergent
for cell cleaning.
[0086] Procedure:
[0087] 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:
[0088] Fine Evacuation time: 1 mm.
[0089] Fine Evacuation rate: 10
[0090] Coarse Evacuation time: 5 min.
[0091] 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: [0092] Mode: Low pressure [0093] Fine
evacuation rate: 10 [0094] Fine evacuation until: 200 .mu.Hg [0095]
Coarse evacuation time: 10 min. [0096] Fill pressure: Contact +0.1
[0097] Maximum pressure: 50 [0098] Direction: Intrusion And
Extrusion [0099] Repeat: 0 [0100] Mercury contact angle: 140 [0101]
Mercury surface tension: 480
[0102] 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: [0103] Mode:
Fixed rate [0104] Motor speed: 5 [0105] Start pressure: 20 [0106]
End pressure: 60,000 [0107] Direction: Intrusion and extrusion
[0108] Repeat: 0 [0109] Oil fill length: 5 [0110] Mercury contact
angle: 140 [0111] Mercury surface tension: 480
[0112] 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.
[0113] Dosage forms according to the invention preferably provide
modified release of at least one active ingredient contained
therein. As used herein, the term "modified release" means the
release of an active ingredient from a dosage form or a portion
thereof in other than an immediate release fashion, i.e., other
than immediately upon contact of the dosage form or portion thereof
with a liquid medium. As known in the art, types of modified
release include delayed or controlled. Types of controlled release
include prolonged, sustained, extended, retarded, and the like.
Modified release profiles that incorporate a delayed release
feature include pulsatile, repeat action, and the like. As is also
known in the art, suitable mechanisms for achieving modified
release of an active ingredient include diffusion, erosion, surface
area control via geometry and/or impermeable barriers, and other
known mechanisms known.
[0114] In one preferred embodiment, the composition and edible
matrix of the invention provide for erosion-based release of
ingredients contained therewith. Accordingly, a dosage form in
which the composition is employed as the shell may provide delayed
release of at least one active ingredient contained in the
underlying core. That is, release of the active ingredient 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").
[0115] In one embodiment, wherein the edible matrix composition of
the present invention is used as a dosage form per se, or as the
core or a portion of the core of a dosage form, the edible matrix
functions as a release modifying erodible matrix. In such
embodiments, the high molecular weight water soluble polymer
performs as a swellable erodible hydrophilic material. In this
embodiment, active ingredient dispersed in the edible matrix is
liberated by the dissolution of successive layers of the matrix
surface. In this embodiment, the rate of active ingredient release
from the dosage form, core, or core portion will depend on the
dissolution rate of the high molecular weight water soluble
polymer.
[0116] The following non-limiting example further illustrates the
invention.
EXAMPLE
[0117] A. Preparation of dispersion for making a shell:
[0118] Dosage forms of this invention are prepared as follows. A
dispersion is prepared containing 80 parts of hydroxypropyl
methylcellulose (HPMC) having a viscosity of about 4000 mPa s in 2%
aqueous solution [commercially available from Dow Chemical as
METHOCEL K4M]; and 20 parts of Kappa Carrageenan in 471 parts of
purified water. The solution has a solids concentration of 17.5%.
First, carrageenan is dispersed in room temperature water with an
electric mixer equipped with a propellor style blade to form a
liquid carrier. Next, the carrageenan/water dispersion is heated to
about 80.degree. C. with continued mixing. Next, the HPMC is
dispersed in the liquid carrier with the propellor mixer, and
mixing continued to maintain the HPMC in a suspended state.
[0119] B. Applying the shell to cores:
[0120] The dispersion from part A is applied to cores (i.e. MOTRIN
100 mg caplets, available from McNeil-PPC Inc.) using a thermal
cycle molding apparatus as described above, to obtain dosage forms
having shells residing upon the cores. First, the cores are
transferred into a molding chamber as described above. Next, the
molding chamber is heated to about 75.degree. C. Next, the
dispersion from part A is injected into the heated molding chamber.
Next, the thermal cycle molding apparatus is cycled to "cold," and
the chamber temperature drops to about 25.degree. C. As the
dispersion is cooled, the HPMC dissolves and solidifies in the
molding chamber to form a shell around the caplet core. The shell
surface takes on the inverse shape and topography of the mold
surface. The shell has excellent strength, and is easily removed
from the mold.
* * * * *