U.S. patent application number 15/965357 was filed with the patent office on 2018-10-25 for abuse resistant drug formulation.
The applicant listed for this patent is CIMA LABS INC.. Invention is credited to Walid A. Habib, Ehab Hamed, Manuel A. Vega Zepeda.
Application Number | 20180303826 15/965357 |
Document ID | / |
Family ID | 40132565 |
Filed Date | 2018-10-25 |
United States Patent
Application |
20180303826 |
Kind Code |
A1 |
Habib; Walid A. ; et
al. |
October 25, 2018 |
ABUSE RESISTANT DRUG FORMULATION
Abstract
A pharmaceutical composition may include a coated particulate
which may include at least one active pharmaceutical ingredient,
particularly one susceptible to abuse by an individual. The coated
particles may include a fat/wax and have improved controlled
release and/or crush resistance. Method of making these coated
particulate and dosage forms therewith are also described.
Inventors: |
Habib; Walid A.; (Riyadh,
SA) ; Hamed; Ehab; (Concord, MA) ; Vega
Zepeda; Manuel A.; (Minnetonka, MN) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
CIMA LABS INC. |
Brooklyn Park |
MN |
US |
|
|
Family ID: |
40132565 |
Appl. No.: |
15/965357 |
Filed: |
April 27, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14714942 |
May 18, 2015 |
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15965357 |
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13728801 |
Dec 27, 2012 |
9572803 |
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14714942 |
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12075543 |
Mar 12, 2008 |
8445018 |
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13728801 |
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11900851 |
Sep 13, 2007 |
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12075543 |
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60850456 |
Oct 10, 2006 |
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60845151 |
Sep 15, 2006 |
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60845128 |
Sep 15, 2006 |
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60845127 |
Sep 15, 2006 |
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60845126 |
Sep 15, 2006 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2081 20130101;
A61K 9/5047 20130101; A61K 9/1652 20130101; A61K 9/2054 20130101;
A61K 9/14 20130101; A61K 47/44 20130101; A61K 9/1694 20130101; A61K
9/2077 20130101; A61K 9/2013 20130101; A61K 9/5042 20130101; A61K
31/485 20130101; A61K 9/2018 20130101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/50 20060101 A61K009/50; A61K 9/20 20060101
A61K009/20; A61K 9/14 20060101 A61K009/14; A61K 9/16 20060101
A61K009/16; A61K 47/44 20060101 A61K047/44 |
Claims
1. A pharmaceutical composition comprising: a solid Granulate
consisting of: an opioid or a salt thereof in an amount of about
1-80% by weight of the granulate; a first material that is a
natural or synthetic starch, a natural or synthetic cellulose, an
acrylic, a vinylic, or a resin; and a second material that is
hydroxypropylmethylcellulose; and, a coating on the granulate;
wherein the first material and second material together are
provided in an amount from about 0.1 to about 90 percent by weight
of the formulation.
2. The composition of claim 1, wherein the opioid is selected from
oxycodone, hydrocodone and salts thereof.
3. The composition of claim 2, wherein the opioid is oxycodone, or
a salt thereof.
4. The composition of claim 3, wherein the formulation,
post-administration, extends release of the oxycodone or salt
thereof to a period of from at least about 6 hours to about 24
hours.
5. The composition of claim 2, wherein the opioid is hydrocodone,
or a salt thereof.
6. The composition of claim 2, wherein the first material is
provided in an amount from about 0.1 wt % to about 40 wt %, based
on the total weight percent of the formulation.
7. The composition of claim 2, wherein the second material is
provided in an amount from about 1 wt % to about 50 wt %, based on
the total weight percent of the formulation.
8. The composition of claim 1, wherein the coating is selected from
the group consisting of cellulose polymers, methacrylate ester
copolymers, methacrylic acid copolymers, and shellac.
9. The composition of claim 8, wherein the coating is
ethylcellulose.
10. The composition of claim 8, wherein the coating further
comprises a fat/wax.
11. The composition of claim 9, wherein the fat/wax is provided in
an amount between about 5 and about 40% based on the weight of the
coated granulate.
12. An extended release particle, consisting of: an opioid or a
salt thereof in an amount of about 1-80% by weight of the particle;
a first material that is a natural or synthetic starch, a natural
or synthetic cellulose, an acrylic, a vinylic, or a resin; and a
second material that is hydroxypropylmethylcellulose; and, a
coating on the particle; wherein the first material and second
material together are provided in an amount from about 0.1 to about
90 percent by weight of the particle.
13. The particle of claim 12, wherein the opioid is selected from
oxycodone, hydrocodone, and salts thereof.
14. The particle of claim 12, wherein the first material is
provided in an amount from about 0.1 wt % to about 40 wt %, based
on the total weight percent of the particle.
15. The particle of claim 12, wherein the second material is
provided in an amount from about 1 wt % to about 50 wt %, based on
the total weight of the particle.
16. The particle of claim 13, wherein the opioid is hydroxycodone
or a salt thereof.
17. The composition according to claim 1, wherein the first
material is at least partially soluble in an alcohol.
18. The composition according to claim 17, wherein the first
material is at least partially soluble in ethanol.
19. The particle according to claim 12, wherein the first material
is at least partially soluble in an alcohol.
20. The composition according to claim 19, wherein the first
material is at least partially soluble in ethanol.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. Ser. No.
14/714,942, filed on May 18, 2015, which is a continuation of U.S.
Ser. No. 13/728,801, filed Dec. 27, 2012 (now U.S. Pat. No.
9,572,803, issued Feb. 21, 2017), which is a continuation of U.S.
Ser. No. 12/075,543, filed Mar. 12, 2008 (now U.S. Pat. No.
8,445,018, issued May 21, 2013), which is a continuation-in-part of
U.S. Ser. No. 11/900,851, filed Sep. 13, 2007 (now abandoned),
which claims benefit of U.S. provisional patent application Nos.
60/845,128, filed Sep. 15, 2006, 60/845,127, filed Sep. 15, 2006,
60/845,126, filed Sep. 15, 2006, 60/845,151, filed Sep. 15, 2006,
and 60/850,456, filed Oct. 10, 2006, the entire disclosures of each
of which are hereby incorporated herein by reference.
BACKGROUND OF THE INVENTION
[0002] Certain drugs (referred to herein as Active Pharmaceutical
Ingredients or "API") such as, for example, the opioid oxycodone,
are administered to patients to reduce pain. Successful pain
management in many of these patients requires maintenance of
certain blood levels of the opioid throughout the day. One way of
obtaining acceptable blood levels, used commonly in the
pharmaceutical industry, is providing a dose which contains far
more drug than is necessary to obtain the desired blood level.
Blood levels shortly after the tablet is ingested reach a maximum
or C.sub.max in a relatively short time, often within hours of
ingestion (T.sub.max) and thereafter, as the body uses, processes
and excretes drug from the blood system, the blood level drops. If
the C.sub.max attained is sufficiently high, and the body's
clearance of the drug is sufficiently slow, the blood levels may
not fall to subtherapeutic levels for 4-12 hours or even longer.
However, with drugs like oxycodone and indeed for many other drugs,
this is an impractical and inefficient dosing system. In addition,
there is a risk to the patient in that such high initial API levels
can cause significant side effects.
[0003] Another method of administering drugs involves the use of an
extended release mechanism. An extended release can be achieved in
many different ways and there are many different release profiles
that can be attained. For exemplification only, a granulate
material can be produced with a material that when exposed to the
digestive tract, swells with available fluids and either slowly
erodes or slows the wetting and diffusion of API drug materials
contained within the granulate, thus providing a much lower
C.sub.max and often a much longer T.sub.max. Ideally, a zero order
release is obtained whereby a constant release rate and a constant
blood level is attained throughout an extended period of time often
six hours or more, more preferably twelve hours or more, and most
preferably over about 24 hours. Not only could this strategy reduce
the number of doses that need to be taken in a day, it also may
prevent one from being exposed to the side effects which can come
from unnecessarily high initial blood levels.
[0004] Those who seek to abuse these types of products to "get
high" can be frustrated by such extended and indeed other
controlled release strategies. These strategies actively prevent
one from obtaining high blood levels of the drug which can cause
the euphoria or other physiologic effects which they are actually
seeking, but which normal patients would consider an undesirable or
even dangerous side effect. Such prescription drug abusers have
learned to circumvent controlled release mechanisms by various
administrative abuse means including simply chewing extended
release tablets or crushing them using a mortar and a pestle for
injection or the like. This can cause the rupture or otherwise
compromise the API particle and/or controlled release coating,
exposing more of the API to digestion and absorption more quickly,
allowing the abuser to achieve much higher blood levels.
[0005] Such abuse can have rather far ranging consequences. First,
it facilitates drug abuse by individuals which can lead to
significant health consequences and even death for the abuser. The
consequences of such abuse reach far beyond the abuser and his or
her immediate family. Indeed, they can be societal as well. Useful
drugs necessary for cancer patients, patients with post-operative
or pre-operative pain, chronic pains from arthritis or back
injuries need to have available products to allow them to cope.
However, the potential for abuse is a constant concern to
regulators and law enforcement as these often prescription drugs
may be more freely obtainable than truly illegal illicit
substances. There are also the societal problems relating to drug
use, which includes the cost of their health care, the cost of
their rehabilitation, the increase in crime which may come from
supporting their drug habit and the like.
[0006] Ways of making a dosage form more crush resistant/abuse
resistant include those disclosed in U.S. Patent App. Pub. No.
2006/0104909 and 2006/0193914. Coating pharmaceuticals or particles
with various materials, which may include a fat/wax, to achieve
other objectives, such as taste-masking, extended release, easier
swallowing, etc. are also known. See, for example, U.S. Pat. Nos.
5,178,878; 5,607,697; 6,024,981; 6,280,770; 6,368,625; 6,692,771;
6,740,341; 2003/0180362; 2005/0163839; and 2007/0003617. See also
U.S. Pat. No. 6,740,341, which discloses, inter alia, granulates
coated with a dual layer coating one of which can include ethyl
cellulose and HPMC.
[0007] Another way to circumvent controlled release coatings is to
attempt to dissolve the dosage form in a solvent such as water or
ethanol. The latter can be particularly dangerous as many
prescription drugs should not be taken with alcohol. Depending upon
the coating material used, the ethanol or water may act as a
solvent, dissolving or eroding the coating and circumventing the
intended controlled release. The resulting material can then be
administered generally, orally, or in a syringe by a drug
abuser.
[0008] There are several techniques which have been developed to
deter this type of solvent abuse. One abuse deterrent system for
oral opioid compounds is described in U.S. Published Application
No. 2006/0177380. This disclosure describes a composition
containing a gel forming polymer forming an obstacle to syringe
uptake, and nasal/mucosal irritant that causes discomfort when
excessive amounts of the active compound are inhaled. Such
abuse-deterring systems often are designed for the nasal or
parenteral abuse routes. See also U.S. Patent Application
Publication Nos. 2006/0193914, 2006/0188447, 2006/0193782,
2006/0204573, 2002/0110595, WO 2006/079550, WO 2007/087452A2, U.S.
Pat. Nos. 6,607,751 and 7,090,867. Uses of fax/waxes more generally
are also described in US 2004/0116352. U.S. Pat. No. 5,500,227
discloses, the use of, inter alia, waxes and fatty alcohols in a
coating to provide sustained release.
SUMMARY OF THE INVENTION
[0009] In one embodiment, the present invention comprises a
particle which is coated and which provides advantages in terms of
a controlled release of any active pharmaceutical ingredient
("API") contained therein or abuse resistance and, in particular,
resistance to crushing. This is accomplished, at least in part, by
the addition of a fat/wax to the particle, to the coating, or
both.
[0010] In another embodiment, a particle of the invention
containing a fat/wax in the core, in the coating, or both, is
blended with and in other aspects, formulated into a dosage form
with, other particles of fat/wax which may be the same or
different. Not only can these pharmaceutical compositions and
dosage forms produced therefrom provide benefits in terms of
controlled release and/or crush resistance, they also may provide,
in certain instances, solvent resistance thereby providing an abuse
resistant, controlled release dosage form with reduced exposure to
abuse by exposure to solvents and/or physical forces such as
crushing.
[0011] In another embodiment, the present invention includes coated
particles comprising: controlled release API-containing particles
comprising an API in an amount of at least about 0.1%, and a
fat/wax in an amount of between about 5 and about 40% based on the
weight of the particles, and a crush resistant coating containing
between about 5 and about 30% of a fat/wax based on the weight of
the coated particles. In some aspects of this embodiment, the
coating is present in an amount of between about 20 and about 75%
by weight based on the weight of the coated particles. The coated
particles of this embodiment exhibit at least one of greater crush
resistance or longer API release when compared to identical coated
particles that do not include a fat/wax in both the particle and
the coating.
[0012] In other aspects of this embodiment, the coated particles
are wet granulates comprising an API in an amount of between about
0.1 to about 90 percent by weight of the granulate. In some aspects
of this embodiment, the API is granulated with a first material
that is at most slightly soluble in water but is at least slightly
soluble in alcohol and is present in an amount between about 1 to
about 90 percent by weight of the granulate. In addition to or
instead of the first material just described, the API can be
granulated with a second material that is at most slightly soluble
in alcohol but at least slightly soluble in water and is present in
an amount between about 1 and about 90 percent by weight of the
granulate. When the particle is a wet granulate, it is preferably
granulated in the presence of water and alcohol. In one aspect, the
first material is ethylcellulose and the second material is
HPMC.
[0013] The coating on the particles further comprises a material
selected from the group consisting of cellulose polymers,
methacrylate ester copolymers, methacrylic acid copolymers and
shellac, said coating material deposited on the particles using an
alcohol based solvent. In one embodiment, this coating material is
ethylcellulose and the coating is deposited on the particle using
substantially anhydrous ethanol. In some embodiments, at least one
of the particles and coated particles is cured. Preferred APIs are
opiates with fentanyl, oxycodone and hydromorphone, and salts
thereof being particularly preferred.
[0014] In another embodiment, the present invention contemplates a
pharmaceutical composition comprising: a matrix including particles
of a fat/wax in an amount of between about 5 and about 40% by
weight of the composition and any of the API-containing particles
described above. In some instances, the use of these fat/waxes in
the matrix may provide solvent resistance, and may also affect
release rate and/or crushing.
[0015] These compositions may include a pharmaceutical dosage forms
comprising: a matrix including particles of a fat/wax selected from
the group consisting of waxes, fatty acids and fatty acid esters
present in an amount of between about 5 and about 30% by weight of
the dosage form and an amount of API-containing particles
sufficient to provide an effective amount of the API. The
API-containing particles, in some aspects, comprise an API and a
fat/wax. In some aspects of this embodiment, the fat/wax is
selected from the group consisting of waxes, fatty acids and fatty
acid esters and is present in an amount of between about 5 and
about 40% based on the weight of the API-containing particles. In
some aspects of this embodiment, the present invention includes a
crush resistant coating containing between about 5 and about 40% of
a fat/wax. In some further aspects, the fat/wax is selected from
the group consisting of waxes, fatty acids and fatty acid esters,
based on the weight of the coated particles, and the coating is
present in an amount of between about 20 and about 75% by weight of
the coated particles. One or more excipients or additional
ingredients may also be present in the dosage form.
[0016] In some aspects of this embodiment, the dosage form further
comprises a first material that is at most slightly soluble in
water but is at least slightly soluble in alcohol and is present in
an amount between about 1 to about 90 percent by weight of the
particle. In still other aspects, it comprises a second material
that is at most slightly soluble in alcohol but at least slightly
soluble in water present in an amount between about 1 and about 90
percent by weight of the particle. When the particle is a wet
granulate comprising the API, the first and the second material, it
is often granulated with a solvent system of water and alcohol. In
some aspects of this embodiment, the coating further comprises a
coating material selected from the group consisting of cellulose
polymers, methacrylate ester copolymers, methacrylic acid
copolymers and shellac, said coating material deposited on the
granulate using an alcohol based solvent. Again, in some aspects,
the coated particles are present in the dosage form in an amount
sufficient to provide of between about 10 micrograms and about 2000
milligrams of API per dosage form, more preferably 10 micrograms to
1000 milligrams.
[0017] In one aspect, the first material is ethylcellulose and the
second material is HPMC. In another, the coating material is
ethylcellulose and the coating is deposited on the particle using
substantially anhydrous ethanol. The particles and/or the coated
particles may be cured.
[0018] Another embodiment of the invention is a method of producing
a dosage form providing longer release and enhanced crush
resistance release dosage form comprising: granulating, in the
presence of water and alcohol, an API with a first material that is
at most slightly soluble in water but is at least slightly soluble
in alcohol. In some aspects, this first material is present in an
amount between about 1 to about 90 percent by weight of the
granulate. Granulation may instead, or in addition, include a
second material that is at most slightly soluble in alcohol but at
least slightly soluble in water. In some aspects, this second
material is present in an amount between about 1 and about 90
percent by weight of the granulate. The granulate may, in some
embodiments, also includes a fat/wax present in an amount of about
5 and about 40% based on the weight of the granulate. After
granulation and optional drying and/or curing, the granulate is
coated with a coating comprising a material selected from the group
consisting of cellulose polymers, methacrylate ester copolymers,
methacrylic acid copolymers and shellac, said coating material
deposited on said granulate using an alcohol based solvent and, in
some embodiments, further comprising a fat/wax in an amount of
between about 5 and about 40% based on the weight of the coated
granulate. The coating is provided in an amount of between about
20% and about 75% by weight base on the weight of the coated
particle. This coated granulate may optionally be dried and/or
cured. The coated granulate is next mixed with at least one
excipient to form a blend; and individual dosage forms are formed
from the blend. This can include packets of the coated particles,
capsules filled with particles, or tablets compressed using the
coated granulate particles. In some embodiments, the fat/wax is
added to said granulate and/or in a solid, non-molten form.
[0019] Another embodiment of the invention is a method wherein the
blend includes particles of fat/wax. In some embodiments, these
additional fat/wax particles are provided in an amount which is
sufficient to provide at least one of additional crush resistance,
longer release of the API or additional solvent resistance. The
fat/wax is often selected from the group consisting of waxes, fatty
acids and fatty acid esters.
BRIEF DESCRIPTION OF THE DRAWINGS
[0020] FIG. 1 illustrates comparative dissolution results for
granules coated with and without a crush resistant coating in
accordance with Examples 1 and 2 of the present invention.
[0021] FIG. 2 illustrates comparative dissolution profiles for
various coated granules with and without a crush resistant coating
in accordance with Examples 1 and 2 of the present invention after
crushing.
[0022] FIG. 3 illustrates the dissolution profiles of CR coated
granulates of Examples 1 and 5 of the invention containing
different levels of polymer in the granulate.
[0023] FIG. 4 illustrates the dissolution profiles of CR coated
granulates of Examples 1 and 5 of the invention containing
different levels of polymer in the granulate after crushing.
[0024] FIG. 5 illustrates comparative dissolution results for
various coated granulates with and without barrier beads in variant
proportions. The line formed by the triangles represents coated
granules alone; the line formed by the diamonds represents a 50:50
mixture of celpheres and coated granulate produced in Example 6;
the line formed by the "x"s represents a 75:25 mixture of celpheres
to the coated granules; and the line formed by the squares
represents a 25:75 mixture of celpheres to the coated granules of
Example 6.
[0025] FIG. 6 illustrates a comparative test undertaken with the
materials described in Example 7.
[0026] FIG. 7 is a chart showing the comparative dissolution
profiles as described in Example 11 for oxycodone HCl (10 mg)
tablets prepared according to one embodiment of the invention.
[0027] FIG. 8 is a chart showing the comparative dissolution
profiles as described in Example 13 for oxycodone HCl (80 mg)
tablets prepared according to one embodiment of the invention.
[0028] FIG. 9 is a chart showing the comparative dissolution
profiles of CR coated granulates of Examples 14 through 16 of the
invention containing different percentages of coated granulate.
[0029] FIG. 10 illustrates the effect of curing coated granules
with Compritol in the coat only on hydromorphone HCl release in
comparison to coated granules without Compritol or curing.
[0030] FIG. 11 illustrates the effect of curing coated granules
with Compritol in the core only on hydromorphone HCl release in
comparison to coated granules without Compritol or curing.
[0031] FIG. 12 illustrates the effect of adding compritol in the
core with no curing on hydromorphone HCl release from coated
granules (50% coat with no compritol or curing) where the shaded
diamonds represent lot 3766-06B (no compritol) and the open squares
represent lot 3766-33 (20% compritol).
[0032] FIG. 13 illustrates the effect of adding compritol in the
core with no curing on hydromorphone HCl release from crushed
coated granules (50% coat with no compritol or curing) where the
shaded diamonds represent lot 3766-06B (no compritol) and the open
squares represent lot 3766-33 (20% compritol).
[0033] FIG. 14 illustrates the effect of adding compritol in the
core with curing on hydromorphone HCl release from coated granules
(50% coat with no compritol or curing) where the shaded diamonds
represent lot 3766-06B (no compritol) and the open squares
represent lot 3766-38 (20% compritol and cured).
[0034] FIG. 15 illustrates the effect of adding compritol in the
core with curing on hydromorphone HCl release from crushed coated
granules (50% coat with no compritol or curing) where the shaded
diamonds represent lot 3766-06B (no compritol) and the open squares
represent lot 3766-38 (20% compritol and cured).
[0035] FIG. 16 illustrates the effect of compritol level in the
core on hydromorphone HCl release from coated granules (50% coat
with compritol and curing) where the shaded diamonds represent lot
4002-31B (10% compritol, cured granules cured coating) and the open
squares represent lot 4002-21 (20% compritol, cured granules cured
coating).
[0036] FIG. 17 illustrates the effect of compritol level in the
core on hydromorphone HCl release from crushed coated granules (50%
coat with compritol and curing) where the shaded diamonds represent
lot 4002-31B (10% compritol, cured granules cured coating) and the
open squares represent lot 4002-21 (20% compritol, cured granules
cured coating).
[0037] FIG. 18 illustrates the effect of adding compritol in the
coat (replacing magnesium stearate) with no curing on hydromorphone
HCl release from coated granules (50% coat) where the shaded
diamonds represent lot 3766-06B (no compritol) and the open squares
represent lot 3766-27A (compritol).
[0038] FIG. 19 illustrates the effect of adding compritol in the
coat (replacing magnesium stearate) with no curing on hydromorphone
HCl release from crushed coated granules (50% coat) where the
shaded diamonds represent lot 3766-06B (no compritol) and the open
squares represent lot 3766-27A (compritol).
[0039] FIG. 20 illustrates the effect of adding compritol in the
coat (replacing magnesium stearate) with curing on hydromorphone
HCl release from coated granules (50% coat) where the shaded
diamonds represent lot 3766-06B (no compritol) and the open squares
represent lot 3766-27B (compritol and curing).
[0040] FIG. 21 illustrates the effect of adding compritol in the
coat (replacing magnesium stearate) with curing on hydromorphone
HCl release from crushed coated granules (50% coat) where the
shaded diamonds represent lot 3766-06B (no compritol) and the open
squares represent lot 3766-27B (compritol and curing).
[0041] FIG. 22 illustrates the effect of adding compritol in the
core (20%) and the coat with no curing of either on hydromorphone
HCl release from coated granules (50% coat) where the shaded
diamonds represent lot 3766-06B (no compritol in core nor in coat,
not cured) and the open squares represent lot 4002-40A (compritol
in core and coat, not cured).
[0042] FIG. 23 illustrates the effect of adding compritol in the
core (20%) and the coat with no curing of either on hydromorphone
HCl release from crushed coated granules (50% coat) where the
shaded diamonds represent lot 3766-06B (no compritol in core nor in
coat, not cured) and the open squares represent lot 4002-40A
(compritol in core and coat, not cured).
[0043] FIG. 24 illustrates the effect of adding compritol in the
core (20%) and the coat with no curing of either on release from
coated granules in comparison to adding compritol in the core only
with no curing (50% coat) where the shaded diamonds represent lot
3766-33 (compritol in core not in coat, not cured) and the open
squares represent lot 4002-40A (compritol in core and coat, not
cured).
[0044] FIG. 25 illustrates the effect of adding compritol in the
core (20%) and the coat with no curing of either on release from
crushed coated granules in comparison to adding compritol in the
core only with no curing (50% coat) where the shaded diamonds
represent lot 3766-33 (compritol in core not in coat, not cured)
and the open squares represent lot 4002-40A (compritol in core and
coat, not cured).
[0045] FIG. 26 illustrates the effect of adding compritol in the
core (20%) and the coat with no curing of either on release from
coated granules in comparison to adding compritol in the coat only
with no curing (50% coat) where the shaded diamonds represent lot
3766-27A (compritol in coat not in core, not cured) and the open
squares represent lot 4002-40A (compritol in core and coat, not
cured).
[0046] FIG. 27 illustrates the effect of adding compritol in the
core (20%) and the coat with no curing of either on release from
crushed coated granules in comparison to adding compritol in the
coat only with no curing (50% coat) where the shaded diamonds
represent lot 3766-27A (compritol in coat not in core, not cured)
and the open squares represent lot 4002-40A (compritol in core and
coat, not cured).
[0047] FIG. 28 illustrates the effect of adding compritol in the
core only (20%) with no curing on release from coated granules in
comparison to adding compritol in the coat only with no curing (50%
coat) where the shaded diamonds represent lot 3766-33 (compritol in
core not in coat, not cured) and the open squares represent lot
3766-27A (compritol in coat not in core, not cured).
[0048] FIG. 29 illustrates the effect of adding compritol in the
core only (20%) with no curing on release from crushed coated
granules in comparison to adding compritol in the coat only with no
curing (50% coat) where the shaded diamonds represent lot 3766-33
(compritol in core not in coat, not cured) and the open squares
represent lot 3766-27A (compritol in coat not in core, not
cured).
[0049] FIG. 30 illustrates the effect of adding compritol in the
core (20%) and the coat with curing of both on hydromorphone HCl
release from coated granules (50% coat) where the shaded diamonds
represent lot 3766-06B (no compritol in core nor in coat, not
cured) and the open squares represent lot 4002-21 (compritol in
core and coat, cured).
[0050] FIG. 31 illustrates the effect of adding compritol in the
core (20%) and the coat with curing of both on hydromorphone HCl
release from crushed coated granules (50% coat) where the shaded
diamonds represent lot 3766-06B (no compritol in core nor in coat,
not cured) and the open squares represent lot 4002-21 (compritol in
core and coat, cured).
[0051] FIG. 32 illustrates the effect of adding compritol in the
core (20%) and the coat with curing of both on release from coated
granules in comparison to adding compritol in the core only with
curing (50% coat) where the shaded diamonds represent lot 3766-38
(compritol in core not in coat, cured) and the open squares
represent lot 4002-21 (compritol in core and coat, cured).
[0052] FIG. 33 illustrates the effect of adding compritol in the
core (20%) and the coat with curing of both on release from crushed
coated granules in comparison to adding compritol in the core only
with curing (50% coat) where the shaded diamonds represent lot
3766-38 (compritol in core not in coat, cured) and the open squares
represent lot 4002-21 (compritol in core and coat, cured).
[0053] FIG. 34 illustrates the effect of adding compritol in the
core (20%) and the coat with curing of both on release from coated
granules in comparison to adding compritol in the coat only with
curing (50% coat) where the shaded diamonds represent lot 3766-27B
(compritol in coat not in core, cured) and the open squares
represent lot 4002-21 (compritol in core and coat, cured).
[0054] FIG. 35 illustrates the effect of adding compritol in the
core (20%) and the coat with curing of both on release from crushed
coated granules in comparison to adding compritol in the coat only
with curing (50% coat) where the shaded diamonds represent lot
3766-27B (compritol in coat not in core, cured) and the open
squares represent lot 4002-21 (compritol in core and coat,
cured).
[0055] FIG. 36 illustrates the effect of adding compritol in the
core only (20%) and curing in comparison to adding compritol in the
coat only with curing (50% coat), normal dissolution where the
shaded diamonds represent lot 3766-38 (compritol in core not in
coat, cured) and the open squares represent lot 3766-27B (compritol
in coat not in cure, cured).
[0056] FIG. 37 illustrates the effect of adding compritol in the
core only (20%) and curing in comparison to adding compritol in the
coat only with curing (50% coat), crushed dissolution where the
shaded diamonds represent lot 3766-38 (compritol in core not in
coat, cured) and the open squares represent lot 3766-27B (compritol
in coat not in cure, cured).
[0057] FIG. 38 illustrates the effect of curing on hydromorphone
HCl release from coated granules with 20% compritol in core and no
compritol in coat (50% coat) where the shaded diamonds represent
lot 3766-33 (compritol in core not in coat, not cured) and the open
squares represent lot 3766-38 (compritol in core not in coat,
cured).
[0058] FIG. 39 illustrates the effect of curing on hydromorphone
HCl release from crushed coated granules with 20% compritol in core
and no compritol in coat (50% coat) where the shaded diamonds
represent lot 3766-33 (compritol in core not in coat, not cured)
and the open squares represent lot 3766-38 (compritol in core not
in coat, cured).
[0059] FIG. 40 illustrates the effect of curing on hydromorphone
HCl release from coated granules with no compritol in core but
compritol in coat (50% coat) where the shaded diamonds represent
lot 3766-27A (compritol in coat not in core, not cured) and the
open squares represent lot 3766-27B (compritol in coat not in core,
cured).
[0060] FIG. 41 illustrates the effect of curing on hydromorphone
HCl release from crushed coated granules with no compritol in core
but compritol in coat (50% coat) where the shaded diamonds
represent lot 3766-27A (compritol in coat not in core, not cured)
and the open squares represent lot 3766-27B (compritol in coat not
in core, cured).
[0061] FIG. 42 illustrates the effect of curing on hydromorphone
HCl release from coated granules with compritol in core (20%) and
compritol in coat (50% coat) where the shaded diamonds represent
lot 4002-40A (compritol in core and coat, not cured) and the open
squares represent lot 4002-21 (compritol in core and coat,
cured).
[0062] FIG. 43 illustrates the effect of curing on hydromorphone
HCl release from crushed coated granules with compritol in core
(20%) and compritol in coat (50% coat) where the shaded diamonds
represent lot 4002-40A (compritol in core and coat, not cured) and
the open squares represent lot 4002-21 (compritol in core and coat,
cured).
[0063] FIG. 44 illustrates the effect of curing on hydromorphone
HCl release from coated granules with compritol in core (10%) and
compritol in coat (40% coat) where the shaded diamonds represent
lot 4002-54 (compritol in core and coat, not cured) and the open
squares represent lot 4002-46 (compritol in core and coat,
cured).
[0064] FIG. 45 illustrates the effect of curing on hydromorphone
HCl release from crushed coated granules with compritol in core
(10%) and compritol in coat (50% coat) where the shaded diamonds
represent lot 4002-54 (compritol in core and coat, not cured) and
the open squares represent lot 4002-46 (compritol in core and coat,
cured).
[0065] FIG. 46 illustrates the comparison of normal dissolution
results on hydromorphone coated granules, lots LB4002-73, 76, 79
where the shaded diamonds represent lot LB4002-73 (with carnuba wax
in core and coat, not cured), the x's represent lot LB4002-54 (with
Compritol in core and coat, not cured), the shaded squares
represent lot LB4002-76 (with gelucire 50/13 in core and coat, not
cured), the *'s represent lot LB3766-33 (with Compritol in core not
in coat, not cured) and the shaded triangles represent lot
LB4002-79 (with gelucire 33/01 in core not in coat, not cured).
[0066] FIG. 47 illustrates the comparison of crushed dissolution
results on hydromorphone coated granules, lots LB4002-73, 76, 79
where the shaded black diamonds represent lot LB4002-73 (with
carnuba wax in core and coat, not cured), the x's represent lot
LB4002-54 (with Compritol in core and coat, not cured), the shaded
squares represent lot LB4002-76 (with gelucire 50/13 in core and
coat, not cured), the *'s represent lot LB3766-33 (with Compritol
in core not in coat, not cured) and the shaded triangles represent
lot LB4002-79 (with gelucire 33/01 in core not in coat, not
cured).
DETAILED DESCRIPTION
[0067] While the specification concludes with the claims
particularly pointing and distinctly claiming the invention, it is
believed that the present invention will be better understood from
the following description. All percentages and ratios used herein
are by weight of the total dosage form, or coated particle, as the
context requires, unless otherwise designated. All measurements
made are at 25.degree. C. and normal pressure unless otherwise
designated. All temperatures are in Degrees Celsius unless
specified otherwise. The present invention can comprise or consist
essentially of the components of the present invention as well as
other ingredients or elements described herein. As used herein,
"comprising" means the elements recited, or their equivalent in
structure or function, plus any other element or elements which are
not recited. The terms "having" and "including" are also to be
construed as open ended unless the context suggests otherwise. As
used herein, "consisting essentially of" means that the invention
may include ingredients in addition to those recited in the claim,
but only if the additional ingredients do not materially alter the
basic and novel characteristics of the claimed invention.
Preferably, such additives will not be present at all or only in
trace amounts. However, it may be possible to include up to about
10% by weight of materials that could materially alter the basic
and novel characteristics of the invention as long as the utility
of the compounds (as opposed to the degree of utility) is
maintained. All ranges recited herein include the endpoints,
including those that recite a range "between" two values. Terms
such as "about," "generally," "substantially," and the like are to
be construed as modifying a term or value such that it is not an
absolute, but does not read on the prior art. Such terms will be
defined by the circumstances and the terms that they modify as
those terms are understood by those of skill in the art. This
includes, at very least, the degree of expected experimental error,
technique error and instrument error for a given technique used to
measure a value.
[0068] Note that while the specification and claims may refer to a
tablet or other dosage form of the invention as, for example,
containing particles having a certain particle size or
distribution, or a certain type of, for example, nondirect
compression sugar, it may be difficult to tell from the final
dosage form that the recitation is satisfied. However, such a
recitation may be satisfied if the materials used prior to final
blending and tablet formulation, for example, meet that recitation.
In another example, while it might be difficult to know the weight
gain of a coated active pharmaceutical ingredient
("API")-containing granule as it actually exists in a finished
tablet, if it is determined that the coated API-containing
granulate used to make the tablet, prior to a final blending and
compression step, did exhibit the desired coating level, that is
sufficient. Indeed, as to any property of a dosage form which
cannot be ascertained from the dosage form directly, it is
sufficient if that property resides in the formulation just prior
to producing a dosage form therefrom.
[0069] In one embodiment, the present invention embraces coated
particles wherein one of the particles or the coating comprises a
fat/wax. It has been discovered that the presence of the fat/wax
within the coating or the particles provide enhanced pharmaceutical
delivery properties and, in particular, extending the release time
an API and/or providing additional crush resistance. This is
compared to an otherwise identically constructed coated particle
not containing the fat/wax as described herein.
[0070] In another embodiment, coated particles in accordance with
the present invention may include a fat/wax in both the particle
and the coating. In this embodiment, the coated particles will
exhibit at least one of enhanced crush resistance or longer API
release when compared to an identical coated particle that does not
include a fat/wax in both the particle and the coating. In another
embodiment, the present invention may be a particle which is a
granulate, comprising at least one API, particularly one
susceptible to abuse by an individual, in an amount between about
0.1 to about 90 percent by weight of the granulate. This API is
granulated with at least one material, the API and the at least one
material being granulated in the presence of a water and alcohol
mixed solvent system. In still another embodiment, the particle is
granulated of API and two discrete materials with different
solubility behavior in water and alcohol. These granulates may also
include a fat/wax.
[0071] The term "particle" is meant to be interpreted broadly so as
to include, without limitation, powders, crystals, amorphous solid,
cores, granules, microcrystals, microganuals, microparticles,
minitablets, and the like.
[0072] The term "coating" is meant to encompass a material which
substantially surrounds the particles and provides some additional
function, such as, without limitation, taste masking, storage
stability, reduced reactivity, controlled release, and/or abuse
resistance. The term "controlled release" encompasses both an
extended release which extends/or patterns the release of an API
over time, as well as a delayed release such as enteric release.
Controlled release, or "CR" coated particles, in one embodiment,
extends the release of the API over a period of release from a
normal immediate release dosage form to about 6 hours or more, more
preferably 12 to about 24 hours or more. Preferred delayed release
coated particles include preventing the release until the dosage
form or coated particles enter the intestines.
[0073] "Abuse resistance" in the context of the invention generally
refers to reducing the amount of API which would be released
prematurely after application of either physical forces (crushing,
for example) or solvent.
[0074] Particles can be composed of the API alone, the API coated
onto a sphere or nonpareil, a mixture of nondrug/API particles, or
a wet or dry granulate. These particles may include a fat/wax as
described herein. In a preferred embodiment, the API-containing
particle is a wet granulate that aids in providing crush
resistance, controlled release or both. A wet granulate is an
agglomerate formed by wet granulation, which is a process by which
particles, often smaller particles, are bound together in a
granulator.
[0075] When the API is used as the particle per se then it
comprises 100% by weight of the particles. When the particle is a
mixture, is coated onto a core, or is a granulate, the API
generally constitutes about between about 0.1% and about 90% by
weight of the particles. This weight is based on the dried weight
of the particles. For a specific example, the API can be between
about 0.1 and about 90% by weight of the granulate with the balance
being binders, other particles, granulating excipients, and the
like. In another embodiment, the API is present in an amount of
between about 1 and about 80, more preferably between about 20 and
about 60% by weight of the particles. This is based on the uncoated
granules formulation, not the coated particles.
[0076] When the particles are wet granulated, they can be formed
using any solvent and/or binder which can be added separately or
together. However, it has been discovered that crush resistance can
be obtained or augmented by using certain binders applied and/or
granulated with a solvent system of water and alcohol. In one
embodiment, the amount of water in the solvent mixture ranges from
about 5 to about 50 percent by weight, more preferably from about
10 to about 40 percent by weight, and most preferably between about
20 to about 30 percent by weight of the solvent. Any alcohol as
defined herein may be used, but C.sub.1-C.sub.6 linear alcohols are
preferred and most preferred is ethanol.
[0077] Alcohol or alcohol based solvents in accordance with the
present invention generally means that the material includes at
least about 90% of a C.sub.1-C.sub.7 alcohol more preferably
C.sub.2-C.sub.6 alcohol and at most about 10% water by volume. More
preferably, the alcohol is ethanol which is at least about 95%
alcohol by volume with the balance being water. Absolute ethanol
may also be used which contains greater than about 99% ethanol by
volume.
[0078] In one embodiment, the granulate includes at least one other
material, sometimes referred to as the "first material." In one
embodiment, this first material is a polymer, which is at least
slightly soluble, preferably, soluble in alcohol and at most
slightly soluble in water. Generally this first material is
selected from natural and synthetic starches, natural and synthetic
celluloses, acrylics, vinylics and resins. More preferably, the
first material is selected from ethylcellulose, Eudragit RS, RL, E,
NE, L, S, and shellac. Most preferably, the first material is
ethylcellulose This first material could be added as a solid, could
be dissolved in the solvent, or could be added to the granulation
process in both forms.
[0079] The granulate can also include a "second material" which is
at least slightly soluble, preferably, soluble in water and at most
slightly soluble in alcohol. This second material, like the first
material, could be added as a solid, could be dissolved in the
solvent, or could be added to the granulation process in both
forms. One such second material is HPMC.
[0080] Other second materials may be selected from the same general
categories as the first material; namely, natural and synthetic
starches, natural and synthetic celluloses, acrylates, and
polyalkylene oxides. Natural and synthetic celluloses are preferred
for both the first and second slightly soluble materials. In a
particularly preferred embodiment, the second material, which can
also be called a second gelable material, is a modified celluloses
such as hydroxypropymethylcellulose (HPMC), hydroxypropylcellulose
(HPC) hydroxymethylcellulose (HMC), methylcellulose (MC),
hydroxyethylcellulose (HEC), carboxymethylcellulose (CMC). However,
the second material and are generally water soluble and generally
insoluble in alcohols C.sub.1-C.sub.6 alcohols as discussed
above.
[0081] As noted above, in some embodiments, the particle includes a
first material that is at most "slightly soluble" in water but is
at least slightly soluble in alcohol, and a second material that is
at most "slightly soluble" in alcohol but is at least sparingly
slightly in water, and an API. By "slightly soluble" it is meant
that the material is generally soluble in one of the solvents
requiring between about 100 and 1000 parts of solvent to solubilize
a single part of the material in question. The material may be
dissolvable or dispersible in larger volumes. Sparingly soluble
means it requires 30-100 parts of solvent to dissolve one part of
the solute. In another embodiment, however, the gap in solubility
of the first and second materials between water and alcohol is
greater. Thus, in one embodiment, the first material is only
sightly soluble in water but it is at least sparingly soluble (more
soluble than just slightly soluble) in alcohols. The reverse is
true for the second material which remains only slightly soluble,
at most, in alcohol, but is at least sparingly soluble in
water.
[0082] In a particularly preferred embodiment, the first material
is ethylcellulose. Ethylcellulose is an inert, hydrophobic polymer
and is essentially tasteless, odorless, colorless, non-caloric, and
physiologically inert. There are many types of ethylcellulose which
can be used, as long as they meet the other requirements, such as
alcohol solubility, discussed herein. The ethylcellulose used can
have different ethoxy content such as 48.0-49.5% described as
N-type; 49.6-51.5% described as T-type; 50.5-52.5% described as
X-type; all available from Aqualon, Hercules Research center,
Wilmington, Del.
[0083] The ethylcellulose used can have different molecular weights
such as including EC polymers of the N-type that form 5% w/w
solution in toluene:ethanol (80:20) that have viscosity ranges of
5.6-8.0 centipoise (cps) described as N7; 8.0-11 cps described as
N10; 12-16 cps described as N14; 18-24 cps described as N22; 40-52
cps described as N50; 80-105 cps described as N100.
[0084] Finally, the ethylcellulose can include different degrees of
substitution of ethoxy groups per anhydroglucose unit, such as
2.65-2.81 for the X-type. N-type has values of 2.46-2.58.
[0085] When HPMC is used in the granulate as the second material,
the HPMC used can have different methyl to hydroxypropyl
substitution percent ratios ranging from 30:0 in the A-type, 29:8.5
for the E-type, 28:5 in the F-type, 22:8 for the K-type all
available from DOW Chemical Company, Midland, Mich. or any other
HPMC polymers available from other suppliers such as Aqualon.
[0086] The HPMC used can have different molecular weights such as
including HPMC polymers that form 2% w/w aqueous solution at
20.degree. C. that have viscosity ranges of 15-4000 mPas for the
A-type, 3-10,000 for the E-type, 50-4000 for the F-type and
3-100,000 for the K-type.
[0087] Before coating, the API containing particles preferably have
an average particle size of about 100 to about 600 microns, and
more preferably about 150 to about 500 microns, and most preferably
about 200 to about 400 microns when tested by a sieve-shaking
method. In another preferred embodiment, the pre-coated API
containing particles preferably have a particle size distribution
wherein no more than about 10% are less than 50 microns, and no
more than 10% are larger than 700 microns. Of course, overs and
unders could be discarded. These particle sizes are determined by a
seive shaking method based on weight.
[0088] Some of the particles in accordance with the present
invention can provide abuse resistance in terms of crush
resistance, solvent resistance, or both. One particularly preferred
type of particle that accomplishes those goals is the
API-containing granulate with ethylcellulose and HPMC granulated
from a solvent system of water and ethanol as previously
described.
[0089] Readily available solvents which can be utilized to dissolve
dosage forms safely are few. Water is certainly one. Ethanol, while
dangerous, is second. Other solvents may be available, but they are
often inconvenient to obtain and/or can have debilitating,
permanent side effects, which even an addict cannot ignore. For
example, methanol or wood alcohol, is easy to find. However, it can
cause blindness. This embodiment of the present invention utilizes
two materials which, when exposed to a limited volume of alcohol,
water, or a mixture thereof, forms a noninjectable mass ranging
from an insoluble mass, to a gel, to a viscous slurry. It might
also retard dissolution in these solvents.
[0090] By "limited volume" it will be appreciated that a small
amount of a material that is, for example, at most slightly soluble
in water (but at least slightly soluble in, for example, ethanol,
such as ethylcellulose), could nonetheless be dissolved, dispersed
or at least diluted sufficiently that it could not form a
noninjectable mass, given enough solvent. Thus, for example, while
a tablet in accordance with the present invention could, once
dissolved, form insoluble mass, a gel, or otherwise raise the
viscosity of 20 mL of water sufficiently to retard injection, it
would do little to change the properties of, for example, one liter
of water or more. Of course, it would be difficult in such
circumstances to inject that liter into the body to obtain the
desired "high."
[0091] The second material found within the granulate is a second
slightly soluble material. This material is at most slightly
soluble in alcohol but is at often soluble in the same volume of
water. Like the first slightly soluble material, any material that
is safe for ingestion or injection and can form a noninjectable
mass under the specified condition is contemplated. The amount of
the second slightly soluble material present in the granulate will
depend on the same criteria as previously described in connection
with the first gelable material.
[0092] Generally, a limited volume in accordance with the present
invention is defined as 50 milliliters or less, more preferably 20
milliliters or less and even more preferably 10 milliliters or less
and most preferably 5 milliliters or less (volumes which could be
injected). Thus, the first slightly soluble material used in the
dosage form must be of a type and available in an amount which is
sufficient to allow it to form a noninjectable mass and the second
slightly soluble material must be capable of doing the same when
the dosage form containing both is dissolved (which includes
partially dissolved or where an attempt is made to make it
dissolve) in a limited volume of water, alcohol or both.
[0093] Generally, both the first material and the second material
are provided within the granulate in an amount of between about 1%
to about 90% by weight of the granulate, each, depending upon the
desired properties, the API used, and the like. However, generally,
the amount of first material in the granulate will range from
between about 1 to about 90% by weight of the uncoated granulate.
In another embodiment, the first material is present in an amount
of from between about 5 to about 75% by weight of the granulate,
and in yet another embodiment about 10 to about 40%. For the second
material, in one embodiment it ranges from between about 10 to
about 75% by weight of the granulate, and in another embodiment
between about 15 to about 50% by weight of the granulate. In terms
of all excipients (everything other than the API, the total amount
in the uncoated particles can range from about 10 to about 99.9% by
weight of the coated granulate. If stated as a percentage of the
coated granulate, the amount generally ranges from between about
60% to about 90% by weight.
[0094] There are no specific particle size limitations with regard
to the first or second slightly soluble materials in accordance
with the present invention. However, the materials should be
sufficiently small so as to enhance their ability to rapidly form a
noninjectable mass.
[0095] As described above, the granulate comprises a first slightly
soluble material and a second slightly soluble material. However,
the granulate may include more than one material that is at most
slightly soluble in water and is at least slightly soluble in
alcohol and/or more than one second material that is at most
slightly soluble in alcohol but is at least slightly soluble in
water. In addition, a third or more slightly soluble material(s)
may be added to provide a similar level of solvent abuse resistance
as needed. Other conventional granulation excipients may also be
present.
[0096] In addition to an API, the coated particles include a
fat/wax which may, in some embodiments, be part of the particle
instead of, or in addition to the coating. The fat/wax could be
granulated with the API, with or without other additional
ingredients. However, preferably, it is granulated with a first
material and even more preferably a first and second material as
described already herein. Of course, these materials could be
merely mixed together and/or dry granulated together, or the
particles and API could be embedded within or on discrete particles
of fat/wax.
[0097] When present within the API-containing particles, the
fat/wax generally makes up between about 5% to about 40% by weight
of the particle, more preferably between about 5% to about 30% by
weight of the uncoated particle. Those percentages may, however,
vary depending upon the number of additional materials contained
within the particle. Thus, for example, the fat/wax may make up a
larger percentage by weight of the a granulate that uses only a
first material and one which includes both, for example,
ethylcellulose and HPMC.
[0098] The fat/wax preferably used in the particles (also referred
to as cores) and coatings of the present invention, and indeed in
the matrix or excipients in compositions and dosage forms, are
hydrophobic and solid at room temperature (25.degree. C.). Fats are
fatty acid based compounds generally having a
hydrophilic/lipophilic balance (HLB) of about 6 or less, more
preferably 4 or less, and most preferably 2 or less, and also have
a melting point which is preferably 30.degree. C. or more, more
preferably 40.degree. C. and even more preferably 50.degree. C. In
one embodiment, the fat has an HLB of about 6 or less and a melting
point of about 30.degree. C. or more. In another embodiment, it has
an HLB of about 4 or less and a melting point of about 40.degree.
C. or more. In another embodiment, the fat has an HLB of about 2 or
less and a melting point of about 50.degree. C. or more. Fats,
including fatty acids and fatty esters in accordance with the
present invention may be substituted or unsubstituted, saturated or
unsaturated. However, generally they have a chain length of at
least about 14. The esters in question may include fatty acid
groups bound to alcohols, glycols, and in particularly preferred
embodiment, glycerol. With regard to glyercols, for example, mono-,
di-, and tri-fatty substituted glycerols are contemplated as are
mixtures thereof. Thixotropic fats/waxes can also be used.
[0099] Suitable fat ingredients include, without limitation,
glycerol fatty esters, fatty glyceride derivatives, waxes and fatty
alcohols such as, for example, glycerol behenate (COMPRITOL.RTM.),
glycerol palmitostearate (PRECIROL.RTM.), stearoyl macroglycerides
(GELUCIRE.RTM.50/13). A particularly preferred material useful in
accordance with the present invention is glycerol behenate.
[0100] Waxes are very complex and difficult to classify. See
Kirk-Othmer, Encyclopedia of Chemical Technology (4th ed. 1998)
Vol. 25 pp. 614-26, the text of which is incorporated by reference.
They often meet the criteria described previously for fats (e.g.,
HLB of about 6 or less and melting point of 30.degree. C. or more,
HLB of about 4 or less and melting point of about 40.degree. C. or
more, HLB of about 2 or less and melting point of about 50.degree.
C. or more), but waxes that do not meet these criteria may also be
used. Waxes include, without limitation, insect and animal waxes,
vegetable waxes, mineral waxes, petroleum waxes, and synthetic
waxes. Particularly preferred are beeswax, carnauba wax, condelilla
wax, montan wax, ouricury wax, rice-bran wax, jojoba wax,
microcrystalline wax, cetyl ester wax, anionic emulsifying wax,
nonionic emulsifying wax and paraffin wax. In one embodiment, the
fat/wax is a fatty acid ester of glycerol. In another, the fatty
acid ester of glycerol is glycerol behenate.
[0101] As illustrated in FIGS. 46 and 47, coated granules were
prepared using different fat/waxes including carnuba wax (Strath
and Pitsch, West Babylon, N.Y., lot#21293/07), Gelucire 50-13 and
Gelucire 33-01 (both from Gattefosse, Paramus, N.J., Lot #s 106058
and 102590 respectively). Gelucire 50-13 has a melting range of
around 50.degree. C. and an HLB of 13. Gelucire 33-01 has a melting
range of about 33.degree. C. and an HLB of 1. The formulations
tested were prepared in accordance with examples 8, 44, and 45.
Note that Gelucire 50-13 was used in both the core and the coating
whereas the Gelucire 33-01 particles used the fat/wax only in the
core and not in the coating.
[0102] Reviewing the figures, it is clear that carnuba wax and
Gelucire 33-01 performed well. Carnuba wax is a wax and Gelucire
33/01 is fatty acid esters of glycerol--a substituted fatty ester.
Gelucire 50-13 provided inferior results. While it is a fatty ester
derivative and has a desirable melting point of 50.degree. C. or
more, its HLB of 13 which makes it far too hydrophilic. As noted
previously, not all fat materials which would structurally fall
within the scope of the materials described will perform
adequately. It has been found that only those with both a melting
point of about 30.degree. C. or more and an HLB of less than 6 will
perform adequately. More preferably, the fat will have a melting
point of about 40.degree. C. or above, and an HLB of about 4 and
below, and most preferably will have a melting point of about
50.degree. C. or above and an HLB of about 2 and below. Compritol
ATO 888 (generally used in the examples), for example, has a
melting point of about 65.degree. C. or above and an HLB of 2.
[0103] Gelucire 33-01, despite being very difficult to work with
and being located only in the core, and carnuba wax, performed very
well. Its generally lower melting point may make it more difficult
to work with on a commercial scale. However, Gelucire 33-01
demonstrates that even materials with a melting point approaching
the endpoints discussed herein may in fact provide successful
particles and formulations.
[0104] More preferably, these materials are also listed in one or
more compendia, meaning they have been recognized for use in oral
pharmaceutical products.
[0105] Fat/waxes used in accordance with the present invention may
be used in a molten form. However, it has been discovered that even
when used as a generally solid, non-molten form such as relatively
small particles at room temperature, they can provide some, if not
all of the advantages as molten materials. Any usable particle size
which allows for proper formation of the particles, coating or in
the matrix and which provides the desired properties of the
invention may be used. However, in one embodiment, for the
compritol materials used in the examples, the average particle size
ranged from between about 30 to about 60 microns with less than 10%
larger than about 100 microns, all measured by volume using laser
diffraction. However, a broader range is certainly contemplated
thus particles having an average particle size between about 10 and
about 100 microns are contemplated for the fat/wax as measured by
laser diffraction. Carnuba wax used in the examples had a particle
size of at least 65% passing through sieves with holes of 75 micron
and at least 40% passing through sieves with holes of 44 micron.
This would also meet the particle size range measured by laser
diffraction.
[0106] In general, the binder used in granulation may be formed in
situ (adding a solvent to a dry material that, when wetted, serves
as a binder) or may be sprayed on or mixed with a solvent. In some
instances, the solvent itself may serve as a binder. Moreover, one
or more of the ingredients to be contained within the granulate can
be introduced as part of the binder and/or as part of a solvent
system. Thus, for example, the API could be dissolved, dispersed,
suspended, or mixed with the solvent and/or with the binder and
applied to the surface of the particulate of the first and/or
second slightly soluble materials or some other component of the
granulate. This is also true for the excipients described
previously. The fat/wax, when present, is added as a dry
particulate into the granulation. In the coating, it is dispersed
in the coating solution.
[0107] Excipients which may be used in accordance with the present
invention to form granulates include those which are traditionally
used in oral dosage forms. In a preferred embodiment, the granulate
may include any excipients as desired, which are then measured into
a granulator.
[0108] It has been discovered that producing granulates in
accordance with the present invention can provide advantages in
terms of enhanced crush resistance and also provide adequate
controlled release. However, in particular, by including a fat/wax
in the particle/granulate as described herein it was unexpectedly
found that one can attain further enhancements. For example, one
may attain a further enhancement in the length of API release when
compared to a similar particle produced without the fat/wax. As
discussed in more detail herein, and as shown in Table 13, in one
instance, otherwise identical formulations with and without
compritol 888 (glyceryl behenate) in a tableted coated granulate
were compared.
TABLE-US-00001 TABLE 13 Tablet Data The table has been modified to
reflect the exact data Sim'd Oral Time of .gtoreq.90% Tampering
Tablet Lot # release (30 min) LB3766-57 16 hr (90%) 36% LB3766-69 8
hr (96%) NA LB3766-70 20 hr (91%) NA LB3766-72 20 hr (93%) 28%
LB3766-73 16 hrs (94%) 64% LB3766-87 16 (90%) 38% LB3766-88 55N 16
hr (93%) 52 LB3766-88 74N 16 hr (90%) 50% LB3766-89 8 hr (99%)
51%
The time necessary to obtain a release of greater than 90% was 8
hours (96%) in for the granulate without fat/wax. It was 16 hours
(90%) for a compritol-containing granulate.
[0109] Therefore, in accordance with one aspect of the present
invention, the fat/wax is selected of a type and used in an amount,
in the particle, the core or both, such that the dosage form or
coated particles provide at least a 10% increase in the length of
time needed to achieve greater than 90% release of API contained
within the particles when compared to an otherwise identical
particulate without the fat/wax. If a granulate without a fat/wax
released >90% after 14 hours, the granulate of the invention
would release >90% after at least 15.4 hours. In another
embodiment, the minimum increase is 25% and in yet still another
embodiment, a 40% increase is realized.
[0110] Also, as illustrated in Table 13, the presence of a fat/wax
in the core may provide advantages in terms of abuse resistance, in
this instance due to the application of physical forces such as
crushing force. Identical granules were produced with compritol and
without compritol in the granulate, coated with a
non-fat/wax-containing coating, and tableted. The granules prepared
with compritol achieved a greater than 90% release in 20 hours
(93%), whereas the granules without compritol only required 16
hours to reach a greater than 90% release (94%).
[0111] Tampering was simulated using a mortar and pestle as
described herein and the release from those particles was measured,
and was based on percent release of the API at 30 minutes. The
granulate containing compritol ATO 888 released only 28% at 30
minutes, while the granulates without compritol ATO 888 released
63%. Thus, the use of a fat/wax in a coated particle, and in this
case particles where the fat/wax was disposed only in the core,
provided both better performance in terms of extended release
properties and crush resistance.
[0112] During production of the particles, where solvent is used,
it is not necessary that the material be actively dried in, for
example, an oven, tray or other device. It may be left to air dry.
The granulate can be coated after drying. When a coating is applied
in a fluidized bed, the processes can go on nearly simultaneously.
The coated particles are then mixed with at least one excipient as
described herein and preferably compressed into tablets filled into
capsules or measured into other dose based forms or packages.
[0113] The crush-resistance of these particles, coatings, coated
particles and compositions of the invention can be measured by
crushing a defined amount of coated API-containing particles (or a
dosage form) with a mortar and pestle, placing the crushed
materials in a solution, such as water, and assaying the resultant
solution to determine the amount of API released, compared to that
of an identical amount of API-containing particles coated with the
same amount of the same coating, or dosage form, without the
fat/wax. Crush resistant as described herein is defined as the
resistance of drug (API) release from the coated particles (or
dosage form) to enhancement under the influence of mechanical
stresses. Drug release from the coated particle is determined in
accordance with the methods and apparatus used to measure
dissolution and drug release as described in the latest version of
United States Pharmacopoeia (Chapter <711>2008), with or
without modifications. To assess crushing resistance, drug release
from the coated particles is initially measured by placing the
particles (or dosage form) in a suitable dissolution media in the
USP apparatus and measuring how much drug is released over a
certain period of time. After subjecting the coated particles (or
dosage form) to mechanical stresses the drug release from the
stressed or tampered protected particles is then measured as
described above. The enhancement of release is calculated as the
difference in drug release from the coated particles at certain
time points before and after applying the mechanical stress. The
lower the enhancement the better the crushing resistance. Examples
of mechanical stress include, but not limited to, applying
compression and/or shear forces onto the particles by using mortar
and pestles or any other suitable configuration (ex. pistons and
cylinders, ball mills). The severity of stress can be controlled by
controlling the force applied, the time period when the particles
are exposed to stress (number of hits inflicted by the
pestle/piston, duration of running in the mill) and the materials
of construction of the mortar and pestle (or any other equipment).
For one aspect of this invention, the coated particles were
subjected to mechanical stress by using 130 mm OD Porcelain mortar
and 1-pound pestle. In summary, the particles are placed in a
ceramic mortar (13 cm outer diameter) then by using a pestle and
applying force vertically downward, the coated granules or tablets
are crushed by 360.degree. C. circular motion. Each full circle
motion constitutes 1 stroke. Each sample is crushed by applying 12
strokes as described above. The crushed samples are then analyzed
using USP apparatus number 2 and the dissoluation data at 30
minutes was considered.
[0114] The coating in accordance with the present invention
comprises any polymeric material which would be acceptable for use
in the pharmaceutical industry and whose solubility can be
characterized as the following: the successful polymeric material
will be at least slightly, preferably sparingly soluble in alcohol.
In contrast, the successful material will generally be no more than
slightly soluble in water. Often it is virtually insoluble in
water. A sparingly soluble polymer is a polymer that requires 30 to
100 parts of a solvent to dissolve one part of the polymer. A
slightly soluble polymer requires from about 100 to about 1000
parts of the solvent to dissolve one part of the polymer. Note,
however, that these are general requirements. If the manufacturer's
literature of a particular material indicates that it is, for
example, at least slightly/sparingly soluble in alcohol based
solutions, then it can be a candidate for use in a coating, even if
when measured by certain tests, its solubility would not fall into
the ranges discussed above. Particularly preferred materials
include those previously identified as the first material for use
in a granulate. Most preferred is ethylcellulose.
[0115] These materials when dissolved or dispersed in an
alcohol-based solvent as described herein may impart surprising
properties, including added crush resistance in comparison to an
identical coating applied with water alone, or a high water content
solvent with less than about 90% alcohol by volume. They may
instead, or also, provide a favorably enhanced (lengthened) release
time. Generally, the polymer to solvent ratio in a coating before
it is applied is about 1:100 to 1:10, and most preferably about
1:15 to 1:7. Some amount of solvent may be detected in the
resulting dosage form once the coating is dried. However it is
preferred that the dosage form contains little if any residual
solvent.
[0116] It has been discovered that including a fat/wax in the
coating can also have additional advantages over the use of a
coating without a fat/wax. Moreover, the combination of the use of
a fat/wax in a coating along with a fat/wax in the core or particle
can, in some instances, provide even greater advantages than would
be realized from their use in only one or the other.
[0117] In particular, as shown in Table 14, formulations including
a fat/wax performed better in terms of, for example, abuse
resistant when compared to coatings without the fat/wax.
TABLE-US-00002 TABLE 14 Granules Data Hydromorphone Granulations
Sim'd Oral Time of >90% Tampering Process Description release
(30 min) 50% coat (06B) 8 hr (95%) 44% 50% coat, compritol in * 21%
coating solution, not cured (27A) 50% coat, compritol in 20 hr
(90%) 15% coating solution, cured (27B) 50% coat, compritol in *
28% granulation, not cured (-33) 50% coat, compritol in 24 hr (90%)
29% granulation, cured (-38) * did not release 100% after 24
hours
[0118] Again, this was measured by the relative release of API
detected after 30 minutes with the lower degree of release
generally indicating better crush resistance. In addition, the use
of a fat/wax-containing coating may provide some additional benefit
in terms of the release of the API contained therein. Note that the
first entry above is illustrated in FIG. 11 by the triangle, the
fourth entry in Table 14 is illustrated in FIG. 11 as a diamond,
and the last entry is illustrated in FIG. 11 with a square.
[0119] The fat/waxes used in the coating can be the same or
different as those used in a particle. However, they should meet
all of the same criteria and thus all of the materials previously
identified as possible fat/waxes in connection with the particles
may be used as such in the coatings as well. When used in the
coating, the amount of fat/wax generally ranges from between about
5 to about 40, more preferably from about 10 to 30% by weight and
most preferably 20-30%. This is based on the weight of the coated
particle. Alternatively, the amount of fat/wax can be determined by
its concentration or content in the coating liquid and the amount
of coating liquid applied in the weight gain of the particles. The
coating mixture or solution can contain between about 1 and about
10% by weight of a fat/wax. One exemplary formulation used in the
examples included 10% ethylcellulose by weight, 5% fat/wax by
weight and the balance was ethanol (commercial).
[0120] Generally, it is preferred that the controlled release
material is ethylcellulose, meaning that it must be used in an
amount that is capable of providing controlled release and crush
resistance and should be applied from an alcohol based solvent. For
controlled release, generally the amount of control release polymer
coating material used in a coating is about 10 to 60, and more
preferably about 20 to 50, and most preferably about 25 to 40. In
addition, the API-containing particle may itself provide some
measure of controlled release. For example, a wet granulate can be
made from HPMC and ethylcellulose formulated using a water and
alcohol solvent system. This material may itself provide some
measure of crush resistance and/or controlled release.
[0121] In one embodiment, the use of the fat/wax containing coated
particle the present invention will provide not more than about a
25% increase in API release measured at 5 minutes in a USP
dissolution test as identified herein compared to an unstressed
particle or dosage form which is of otherwise similar construction
without the fat/wax. Note that this need not be limited to
materials which can be applied from an alcohol base solvent or
solution as described herein with regard to the crush resistant
materials. Thus, for example, a layer of HPMC may be used to coat
the API material followed by a coating layer of, for example,
ethylcellulose. These may be applied from the same or from
different solvent systems and may include the same or different
additives.
[0122] As previously noted in connection with the particles,
fat/waxes in coatings can be used in molten form. However,
preferably, the fat/wax can be mixed into the coating material and
applied, without applying molten material. When this practice is
utilized, the fat/wax is generally added in a form of a solid,
non-molten, particulate material having the same particle size
ranges as for fat/waxes in the cores, namely particle sizes ranging
from about 10 to about 100, more preferably from about 20 to about
80, most preferably about 30 to about 70 microns. This is measured
by volume using a laser diffractometer. The fat/wax may be
dissolved, suspended and/or dispersed in the coating material.
Coatings may be applied by any known process, including but not
limited to, spraying, dipping, pouring, spray drying, etc. It is
also contemplated that the coating may be a single layer or
multiple layers, having varying, or uniform crush-resistance
layers.
[0123] The coating is ideally applied to the particles so as to
substantially completely coat the particles with coating material.
Of course, in practice, without checking each particle, one can not
know that all particles are coated, that they are all coated to a
specific thickness, and/or to a specific degree. Thus the degree of
coating is inferred from analysis of the processes or resulting
material in bulk.
[0124] Generally, however, it is preferred that the coating has a
thickness resulting in an average weight gain of a particle of
about 30% to about 300%, and more preferably about 50% to about
200%, and most preferably about 65% to about 150%. These numbers
reflect any coating additives as part of the coating. These average
weight gain values correspond to the coating material being present
in an amount of between about 20 and about 75% by weight of coated
particle or granulate, and more preferably 30 to 60% by weight of
the coated particle or granulate.
[0125] Once coated with the coating, it is generally preferred that
the coated API containing particles have an average particle size
of about 300 to about 1200 microns, and more preferably about 400
to about 1000 microns, and most preferably about 500 to about 800
microns when tested by a sieve-shaking method by weight. In another
preferred embodiment, the coated API containing particles
preferably have a particle size distribution wherein no more than
about 10% are less than 75 microns, and no more than 10% are larger
than 1400 microns. Again, overs and unders could be discarded
[0126] In one aspect of the products and processes of the present
invention, the coated particles may be cured. Indeed, the particles
themselves may be cured, then coated, and cured again.
Alternatively, the particles may be cured, coated and not cured
again, or the particles may be uncured, coated, and thereafter the
coated particle cured. Preferably, however, two discrete curing
steps take place. By "curing" it is understood that merely drying
the particles or coated particles is generally insufficient. Curing
transcends the application of energy at levels and times merely
necessary to substantially remove surface water (generally to an
amount less than 10%, more preferably less than about 5% by
weight). Instead, curing is defined herein may be accomplished by
heating the particles or coated particles in a fluidized bed until
the temperature reaches melting point or range of the fat/wax used.
Then the temperature is maintained at the fat/wax melting
point/range +/-5.degree. C. for at least 15 minutes. In the
examples using compritol, 30 minutes at 70.degree. C. was used,
unless otherwise specified.
[0127] As can be shown from Table 14, for otherwise identical
formulations, curing can, in some instances, provide additional
benefits in terms of the relative length of API release and/or
crush resistance. The first three compositions in Table 14 were
granulates coated to a 50% coat with a coating material (this means
that 100% weight percent of coating material was added relative to
the weight of the uncoated granulate). The particles in the first
entry used a coating with no compritol (magnesium stearate instead)
and no curing. The second entry was a coated granulate with
compritol and no curing. The third entry in Table 14 was the same
coated granulate as in entry 2, however, the coated particle was
cured. No curing was done on the uncoated only.
[0128] All three formulations included identical particles (46.6%
hydromorphone HCl, 36.4% HPMC, 17.0% EC) and a 50% coat of 2:1 to
ethylcellulose:(magnesium stearate or compritol 888) applied with
an ethanol solvent (10% EC, 5% compritol, 85% ethanol (commercial).
The coating without compritol or curing resulted in greater than
90% release in 8 hours (95%) while the uncured compritol coated
granulate released 84% at 12 hours. The cured version improved
release releasing 90% in 20 hours.
[0129] In addition, the release at 30 minutes following simulated
tampering went from 44% to 21% to a low of 15% respectively. Thus,
the cured compritol coated granulate provided the longest release
and lowest release upon tampering--better than that resulting from
a compritol containing coating without curing and about twice as
good as the material without a fat/wax in either structure. In some
instances, curing the particle and curing the coating may provide
cumulative benefits. In other times, not. Note that when compritol
was used in the granulate and not in the coating, there appeared to
be no significant difference whether or not the core was cured
(both released about 90% at 24 hours). However, the coated
granulates both gave even longer release, and improved tamper
performance over a core and coating without a fat/wax.
[0130] Table 15 provides data from the 11 lots of granulated/coated
materials graphed in FIGS. 12-45 whose formulations are described
in the examples. The same 11 lots of materials were used in all of
the figures, although they were arranged differently for purposes
of providing additional perspectives on the effect of the addition
of a fat/wax to a core, coating or both, with and without curing.
All of the cores were identical except that where indicated, cores
included either 10 or 20 percent compritol 888 (Glyceryl behenate
from Gattefosse (Paramus, N.J., USA).
TABLE-US-00003 TABLE 15 4/8/16 hr 30 min abuse Lot No. Description
release release 3766-06B Core* -No 88%/95%/97% 44% compritol and
not cured** - Coating*** - No compritol and not cured 3766-33 Core
- 35%/54%/79% 28% 20% compritol and not cured- Coating - no
compritol and not cured 3766-38 Core - 24%/47%/78% 29% 20%
compritol and cured- Coating - no compritol and not cured 4002-40A
Core - 23%/43%/67% 7% 20% compritol and not cured- Coating -
compritol and not cured 3766-27A Core-No 66%/80%/87% 21% compritol
and not cured - Coating - compritol and not cured 3766-27B Core-No
44%/71%/87% 15% compritol and not cured - Coating - compritol and
cured 4002-31B Core - 10% 13%/34%/61% 6% compritol and cured -
Coating (50%) - compritol and cured 4002-31A Core - 10% 41%/70%/91%
15% compritol and cured - Coating (40%) - compritol and cured
4002-21 Core -20% 12%/27%/51% 9% compritol and cured Coating
compritol and cured 4002-54 Core - 10% 60%/84%/97% 23% compritol
and not cured - Coating - 40% of compritol containing coating and
not cured 4002-46 Core - 10% 39%/65%/87% 17% compritol and cured -
Coating - 40% of compritol containing coating and cured *Cores were
all particles of the invention which were wet granulates. Their
compositions are in the examples. Percent compritol is reported by
weight of the uncoated core. **See examples. ***Note that all
coatings in this table include 10% ethylcellulose, 5% of either
compritol (where an entry says "compritol" in the coating), or
magnesium stearate (otherwise) and 85% by weight ethanol when
applied. All coatings were applied such that they made up about 50%
by weight of the final weight of the coated particles (when dried)
(about 100% weight gain based on the weight of the uncoated
particles), except for 4002-46 and 4002-54 which were applied at a
40% coating level.
[0131] As can be seen from the above summarized data, some general
trends can be observed. Curing slows the normal release no matter
where the fat/wax is distributed. Its effect, however, can vary
widely.
[0132] When a fat/wax is in the core or the coat only, curing tends
to provide significant reductions in the release following
simulated tampering by crushing. However, when a fat/wax is in both
the core and the coating, curing does not appear to have as
dramatic an effect on abuse resistance. Without a fat/wax in the
core or the coating, performance of the granules included the
highest level of release following simulated abuse testing at 30
minutes and an almost complete release by four hours. See lot
3766-06B. Adding a fat/wax to the core at a level of 20% provided
significant improvement, not only in terms of a longer overall
release, but in terms of a reduction in the amount of release at 30
minutes following simulated abuse testing. See lot 3766-33, 3766-38
(note that 4002-40A had Compritol in core and coat). Compritol
alone in the coating, not in the core (cores coated to a 100%
weight gain with a solution/suspension of 10% ethylcellulose, 5%
compritol in 85% ethanol by weight) did not provide significant
improvement in terms of release. See lots 3766-27A and 3766-27B.
However, addition of the compritol to the coating, in this
particular instance, generally provided significant improvement in
terms of abuse resistance. Comparing lots 4002-40A and 3766-27B, it
is clear that having a fat/wax in both the core and the coating is
advantageous.
[0133] Indeed, even having a lower amount of compritol in the core
can be advantageous. Lot 4002-31B included 10% compritol in the
granulate which was cured and coated with a compritol containing
coating which was also cured. However, as illustrated by lot
4002-21, 20% compritol in the core coupled with a coating with a
fat/wax which was cured provided perhaps the best performance in
terms of long term release and very similar 30 minute abuse
resistance numbers when compared to a lesser amount of compritol in
the core. The remaining lots 4002-54 and 4002-46 included a
slightly lower amount of coating material and, in addition, lot
4002-46 had a cured granule and a cured coating.
[0134] It will be appreciated that in designing a particular dosage
form for a particular API, it may not be desirable to maximize the
length of release and/or crush or solvent resistance. Each product
may need to meet unique criteria. Adding a fat/wax to both the core
and coating and curing, while in some instances maximizing release
and abuse resistance may be undesirable. However, the discoveries
embodied in the present invention give the formulator much greater
control and may allow for tailoring of a particular formulation
without having to adjust other excipients or add additional
structures. If the release is too long, one can remove the curing.
If that is not sufficient, one can remove the fat/wax from either
the particle or the coat. If thereafter the release performance is
okay, but abuse resistance is insufficient, curing of the core
could be used. And, fat/wax can also be added to the matrix or
excipients blended with the coated particulate to improve
characteristics as well. Similarly, the addition of a fat/wax to
the matrix may provide solvent resistance. In some instances,
however, an increase in one property may come at the expense of
another. However, a balance of overall properties may be
achieved.
[0135] The degree to which any particular change or combination of
changes will affect any given formulation will need to be evaluated
on a case-by-case basis. However, the present invention allows for
relatively simple adjustments which can be quickly and decisively
evaluated for any given active inexpensively and using standard
equipment so as to arrive at an optimal balance of release and
abuse resistance.
[0136] The coating may also, optionally, include one or more of the
following: 1) channeling agents; 2) plasticizers; 3) antitacking
agents); 4) antifoaming agents; 5) colorant; and 6) viscosity
modifiers.
[0137] Channeling agents, also called pore formers, can be added
into the coating by being either dissolved or dispersed in the
solvent and preferably are inert and will not chemically alter the
polymer used in the coating. They are intended to leach out from
the coat upon exposure to aqueous media (stomach content/intestine)
creating channels within the coat to facilitate the drug release
process. This term and mechanism are well recognized, but may not
reflect an accurate description of what is taking place.
Nonetheless, these materials are known as channeling agents. When
properly used, by whatever name or mechanism, they can alter API
release.
[0138] Examples of channeling agents include salts like sodium
chloride, sodium carbonates, bicarbonate, citrate, calcium
phosphates, potassium chlorides etc, sugars like sucrose, glucose,
lactose, mannitol, sorbitol, polymers like HPMC, MC, HPC, CMC,
polyethylene glycol, poloxamer, PVP, polyacrylic acid, polyvinyl
alcohol and graft or block copolymers of such polymers, and
preferably poloxamers. These can be included at levels of 0-50%
based on of the dry polymer weight of the coating material, more
preferred 1-40% and most preferred 5-30%.
[0139] Antitacking agents, also called antiadherent or glidants or
separating agents, are used to reduce tackiness and agglomeration
during the coating process and may be used herein. Examples of
these materials include: magnesium stearate, calcium stearate,
stearic acid, talc, kaolin, and stearyltrimethyl ammonium chloride.
When used, they may be used at levels of 0-100% based on the dry
polymer weight of the coating materials, more preferred 20-80%,
most preferred 20-50%. Preferred is magnesium stearate.
[0140] Plasticizers may also be used in the coating to lower the
glass transition temperature of the polymer to improve the film
formation process during coating or subsequent heat treatment. They
also impart flexibility. They are added to the coating by being
either dissolved or dispersed in the solvent. Examples of
plasticizers include triethyl citrate, triacetin, polyethylene
glycols, propylene glycol, acetyl triethyl citrate, acetyl tributyl
citrate, dibutyl phthalate, diethyl phthalate, tributyl citrate,
dibutyl sebacate, diethyl sebacate, castor oil, Myvacet 9-40,
Glyceryl tributyrate. These may be used at levels of 0-150% based
on the dry polymer weight of the coating, more preferred 1-50%,
most preferred 5-30%.
[0141] Antifoaming agents in the coat may be used to reduce foam
formation during coating solution/dispersion preparation process.
Examples include silicon based antifoaming agent like Antifoam
FG-10 made by Dow Corning. Antifoaming agents may be used at levels
of 0-10% based on the polymer dry weight of the coating, 0.1-5% and
0.5-5%.
[0142] For product differentiation and aesthetic purposes,
colorants may be used. Examples include FD&C and D&C lakes,
titanium dioxide, magnesium carbonate, talc, pyrogenic silica, iron
oxides, channel black, natural colorants and insoluble dyes.
Colorants which may be used in an amount of 0-25% of the polymer
dry weight of the coating, 0.5-10, 1-5%.
[0143] To reduce the polymer solution/dispersion viscosity while
maintaining high polymer content to facilitate the coating process,
viscosity modifiers may be used. Their level must be carefully
selected to reduce the viscosity without any detrimental phase
separation. Examples of these materials include salts with high
order in the hofmeister's series including sodium citrate and
sodium chloride which may be used at levels of 0-0.1 mol/liter of
the coating solution/dispersion, more preferred 0.001-0.05, most
preferred 0.005-0.03 mol/L, based on the weight of the coating.
[0144] The compositions and dosage forms of the invention may be
used therapeutically alone or with additional excipients. These can
be taken as a powder, sprinkled on food such as apple sauce, loaded
into capsules, or compressed into a tablet dosage form. However, it
has been found that the addition of a fat/wax to a dosage form
which also includes a fat/wax-containing coated particle of the
present invention can provide additional benefits in terms of
release and/or abuse resistance. In particular, the use of a
fat/wax in the blended with the coated particles of the invention
can provide solvent resistance. However, it may in addition or
instead provide advantages in crush resistance and/or controlled
release.
[0145] The fat/wax may be used alone as the matrix or, along with
other excipients, may comprise the matrix which makes up the
balance of any composition or dosage form (over and above the
coated particulate of the invention). In this context, "matrix"
broadly means the balance of the composition or dosage form. The
fat/wax may be used in any form, but in some instances may be used
in the form of a second particulate.
[0146] The second particle containing the fat/wax material can be
provided in an amount of from about 1% to about 50% per dosage form
unit (e.g., tablet). Preferably, the dosage form unit can contain
from about 2.5% to about 30% fat/wax-containing particles per unit,
most preferably from about 5% to about 25%, per total dosage form
unit. These weight percentages are also for the weight percentage
in the pre-dosage form composition, which would contain weight
percentages equal to the final dosage form. The fat/wax particles
in the matrix may be selected from the same materials identified
for the fat/wax found in the coated particles and may have the same
particle sizes.
[0147] It may be possible to modify the active-to-fat/wax ratio to
provide the optimal effect with regard to the potential chemical
solvent resistance properties of the dosage form. Balancing
chemical or solvent resistance versus desired delayed release
parameters of the dosage form should also be considered.
Accordingly, two general factors may be involved: first, the
thickness and type of coating material employed; and second, the
amount of fat/wax particles in the dosage form. In other words,
release of active ingredient could be controlled by modifying the
coating/extended release material in combination with the dual
particle system which might create a tortuous path that delays the
chemical or solvent access to the first active particle hence drug
diffusion. Variations in these factors affect the chemical
resistance and delayed release parameters, in addition to physical
tampering/crush resistance.
[0148] The first particles containing the API and fat/wax and the
second particle containing the fat/wax material can be combined to
form mixtures of particulate prior to forming the resulting dosage
form. Additional or secondary ingredients or excipients can be
combined as part of the process of preparing the resultant dosage
form, e.g., tablet. For example, the dosage form formulation can
include spray-dried lactose and EMCOMPRESS (dibasic calcium
phosphate dihydrate).
[0149] Dosage forms of this aspect of the invention can be prepared
according to any process. In one embodiment, however, the following
process is used. To prepare the first particle of the composition
of the invention, the API and fat/wax can be mixed with polymers in
a granulator first as a dry mix. Then, a polymer solution can be
added to the mix, and the process continues while adding the
solution until granulation is achieved. The resulting granules can
be partially dried until the desired loss of drying value is
reached for the given formulation. The granules can then be milled
in a granular mill and then dried to a LOD of less than 5%, for
example. These particles may, instead or in addition, be cured.
[0150] Next, the granules can then be coated (with ethylcellulose
in ethanol solution, for example) and with magnesium stearate or
Compritol in a bottom spray fluid bed, until the desired coat level
is obtained. The granules can then dried and optionally cured and
can be mixed together with the second particles of fat/wax and
other excipients to form a common blend. This can then be metered
or measured into discrete amounts and packaged, filled, and/or
tableted.
[0151] While at least one API is required, it is contemplated that
multiple APIs may also be used. "API", or Active Pharmaceutical
Ingredient, in accordance with the present invention include
materials capable of being particles, materials likely to be abused
by people, or otherwise useful in the present invention. Such
active ingredients may include systematically distributable
pharmaceutical ingredients, vitamins, minerals, dietary
supplements, as well as non-systemically distributable drugs. A
combination or mixture of any of the foregoing is also contemplated
by the present invention. Pharmaceutical ingredients may include,
without limitation, antacids, analgesics, stimulants, sleep aids,
hypnotics, antipyretics, antimicrobials, anxiolytics, laxatives,
antidepressants, antidiuretics, antiflatuants, antispasmodics,
anti-inflammatory, antibiotics, diuretics, anorexics,
antihistamines, antiasthmatics, antidiuretics, antiflatuents,
antimigraine agents, antispasmodics, sedatives, antihyperactives,
antihypertensives, tranquilizers, decongestants,
immunosuppressants, anticancers, antivirals, antiparasitics,
antifungals, antiemetics, antidepressants, antiepileptics, local
anesthetics, vasoactive agents, antiasthmatics, skeletal muscle
relaxants, drugs for parkinsonism, antipsychotics, hematopoietic
growth factors, antihyperlipidemics, anticoagulants, fibrinolytics,
antithrombotics, hormones, therapeutic proteins and peptides,
antiarrhythmia, antiangina, beta blockers and combinations thereof.
Also included as API's in accordance with the present invention are
the drugs and pharmaceutically active ingredients described in
Mantelle, U.S. Pat. No. 5,234,957, in columns 18 through 21. That
text of Mantelle is hereby incorporated by reference. In one
embodiment in accordance with the present invention, the APIs are
preferably pharmaceutical agents having a high likelihood of abuse
by people. In another preferred embodiment of the present
invention, the API is a pain medication such as an a narcotic or
non-narcotic analgesic as listed on pages THER-2 and THER-3 of The
Merck Index, 13th Ed., Published by Merck & Co., Inc., of
Whitehouse Station, N.J., copyright 2001, which is hereby
incorporated by reference. The narcotic analgesics include, but are
not limited to, analgesics, pain relievers, opioids such as
oxycodone, codeine, hydrocodone, morphine, hydromorphone,
oxymorphone, methadone, propoxyphene, meperidine, fentanyl,
buprenorphine, butorphanol, dezocine, levomethadyl acetate,
levorphanol, nalbuphine, pentazocine, remifentanil, sufentanil,
tramadol; Stimulants like amphetamine, methamphetamine,
dexamphetamine, methylphenidate, dexmethylphenidate, pemoline;
Sedative and hypnotics including barbiturates as amobarbital,
aprobarbital, butabarbital, mephobarbital, phenobarbital,
secobarbital; benzodiazepines such as alprazolam, clonazepam,
diazepam, estazolam, flurazepam, halazepam, lorazepam, midazolam,
quazepam, temazepam, triazolam, prazepam, oxazepam, other drug
classes include modafinil and armodafinil. Particularly preferred
APIs include oxycodone, fentanyl and hydromorphone. Salts of all of
the API's are also contemplated as are their stereogenic isomers,
polymorphs and solvates.
[0152] As used in this disclosure, the term "vitamin" refers to
trace organic substances that are required in the diet. For the
purposes of the present invention, vitamin(s) include, without
limitation, thiamin, riboflavin, nicotinic acid, pantothenic acid,
pyridoxine, biotin, folic acid, vitamin B12, lipoic acid, ascorbic
acid, vitamin A, vitamin D, vitamin E and vitamin K. Also included
within the term vitamin are the coenzymes thereof. Coenzymes are
specific chemical forms of vitamins. Coenzymes that may be useful
in the present invention include thiamine pyrophosphates (TPP),
flavin mononucleotide (FMM), flavin adenine dinucleotive (FAD),
Nicotinamide adenine dinucleotide (AND), Nicotinamide adenine
dinucleotide phosphate (NADP) Coenzyme A (CoA) pyridoxal phosphate,
biocytin, tetrahydrofolic acid, coenzyme B12, lipoyllysine,
11-cis-retinal, and 1,25-dihydroxycholecalciferol. The term
vitamin(s) also includes choline, carnitine, and alpha, beta, and
gamma carotenes.
[0153] As used in this disclosure, the term "mineral" refers to
inorganic substances, metals, and the like required in the human
diet. Thus, the term "mineral" as used herein includes, without
limitation, calcium, iron, zinc, selenium, copper, iodine,
magnesium, phosphorus, chromium and the like, and mixtures
thereof.
[0154] The term "dietary supplement" as used herein means a
substance which has an appreciable nutritional effect when
administered in small amounts. Dietary supplements include, without
limitation, such ingredients as bee pollen, bran, wheat germ, kelp,
cod liver oil, ginseng, and fish oils, amino-acids, proteins and
mixtures thereof. As will be appreciated, dietary supplements may
incorporate vitamins and minerals.
[0155] The amount of API in the composition can vary greatly. In
terms of the proportion of the uncoated particle that is API, that
can range from about 0.1% to about 90% by weight of the uncoated
particle or granulate, and more preferably in an amount of about 1%
to about 80% by weight, and most preferably in an amount of about
20% to about 60% by weight of the uncoated particle. In terms of
the proportion of the coated particle, the amount of the drug can
range from about 0.1% to about 75% by weight of the coated
particle, and more preferably in an amount of about % to about 607%
by weight, and most preferably in an amount of about 10% to about
40% by weight of the coated particle.
[0156] The amount of granulates and/or coated particles within a
dosage form can vary greatly and can depend upon, among other
things, the type and properties of the API, the density,
friability, hardness, etc. of the API particles, the condition it
is intended to treat or prevent, the size, weight, age, and
condition of the patient, the amount and size of other ingredients,
the size of the coated particles, the overall composition, the size
and nature of the dosage form, the number of dosage forms per dose,
whether or not more than one API is to be delivered from the dosage
form, etc. It is preferred that the dosage form provide a
therapeutically effective amount of at least one API to a patient
in need thereof. The coated particles are preferably present in one
or more dosage forms in an amount sufficient to provide a
therapeutically effective amount the at least one API. A
"therapeutically effective amount" is the amount or quantity of an
API or active ingredient which is sufficient to elicit the required
or desired therapeutic response, or in other words, the amount
which is sufficient to elicit an appreciable biological response
when administered to a patient. The dosage need not be optimal, nor
even provide a cure or symptomatic relief. Generally, the total
amount of coated particles for any individual dosage form is an
amount which is capable of providing between about 10 micrograms
and about 2 grams of API per dosage form, more preferably from
about 0.1 milligram and about 1 gram of API per dosage form and
even more preferably from about 1 milligram to about 800 milligrams
per dosage form. Therefore, an amount of coated particulate
sufficient to provide that amount of API per dosage form will be
necessary. Understandably that amount will vary because of the
factors discussed previously. As a nonlimiting example, twice as
much of a particulate having a 25% by weight API load would be
needed to provide the same amount of API, in an otherwise identical
tablet, having particles with a 50% load of API.
[0157] As used with reference to a vitamin or mineral, the term
"effective amount" means an amount at least about 10% of the United
States Recommended Daily Allowance ("RDA") of that particular
ingredient for a patient. For example, if an intended ingredient is
vitamin C, then an effective amount of vitamin C would include an
amount of vitamin C sufficient to provide 10% or more of the
RDA.
[0158] It is contemplated that the composition of the present
invention may also include at least one other ingredient or
excipient in addition to the API-containing coated particle and
optionally any fat/wax in the extra-particulate matrix. The other
ingredient or excipient may include, but are not limited to, other
APIs, taste masking agents, binders, fillers, sugars, artificial
sweeteners, polymers, flavoring agents, coloring agents,
lubricants, glidants, bio- or muco-adhesives, viscosity modifiers,
surfactants, buffers, disintegrants etc. The amount of any one or
more of these ingredients will vary with the amount of CR coating
(including ethylcellulose), additional polymers, API, API particle
size, and shape of the dosage form, form of the dosage form, how
many ingredients are used, which ingredients are used, the number
of dosage forms that will make-up a dose, the amount of API per
dose and the like. Any combination or amounts are contemplated
sufficient to allow the creation of a crush-resistant,
solvent-resistant, storable dosage form in accordance with the
present invention.
[0159] "Taste masking agent(s)" in accordance with the present
invention include anything known to be used as a taste masking
agents in this art. Preferred taste masking agents in accordance
with the present invention may include Eudragit E-100,
ethylcellulose, hydroxypropylmethylcellulose, hydroxypropyl
cellulose, methylcellulose, Hydroxyethylcellulose,
carboxymethylcellulose, shellac, zein, carbomers, fats, waxes,
glycerol mono-, di-, tri-glycerides, Compritol, Precirol,
gelucires, poloxamers, modified chitosans, carrageenans, cellulose
acetate trimellitate, hydroxypropyl methylcellulose phthalate,
hydroxypropylmethylcellulose acetate succinate, methacrylic acid
copolymers including Eudragit L 100, S 100, L30D-55,
polyvinylacetate phthalate (PVAP). Taste masking agents can be used
in conventional amounts and preferably in an amount of about 0 to
about 50% by weight of the total dosage form, and more preferably
in an amount of about 5% to about 40% by weight of the total dosage
form, and most preferably in an amount of about 10% to about 30% by
weight of the total dosage form.
[0160] Binders can be anything known to be used as binders. These
materials are used to add cohesiveness to powders and provide the
necessary bonding to form granules that can be compressed into hard
tablets that have acceptable mechanical strength to withstand
subsequent processing or shipping and handling. Some binders that
may be useful in the present invention include acacia, tragacanth,
gelatin, starch (both modified or unmodified), cellulose materials
such as methylcellulose, ethylcellulose,
hydroxypropylmethylcellulose, hydroxypropyl cellulose,
Hydroxyethylcellulose and sodium carboxy methylcellulose, alginic
acids and salts thereof, magnesium aluminum silicate, polyethylene
glycol, guar gum, polysaccharide acids, bentonites, sugars, invert
sugars, and the like, fats, waxes, polyvinylpyrrolidone,
polymethacrylate and other acrylic and vinyl-based polymers.
Binders can be used in conventional amounts and preferably in an
amount of about 0 by weight to about 50 and more preferably about 2
to about 10 percent by weight of the total dosage form.
[0161] Fillers can be anything known to be used as fillers. Some
fillers that may be useful in the present invention include
mannitol, dextrose, sorbitol, lactose, sucrose, and calcium
carbonate. Fillers can be used in conventional amounts and
preferably in an amount of about 0 to about 90, and more preferably
about 10 to about 50.
[0162] A particularly preferred type of filler which may be used is
sugars. Sugars that may be used in the present invention include
sugar, sugar alcohols, ketoses, saccharides, polysaccharides,
oligosaccharides and the like, as well as celluloses and modified
celluloses.
[0163] Sugars may also include direct compression and/or nondirect
compression sugars. Particularly preferred nondirect compression
sugars include, without limitation, dextrose, mannitol, sorbitol,
trehalose, lactose and sucrose. Of course, these sugars generally
exist as either a direct compression sugar, i.e., a sugar which has
been modified to increase its compressibility and/or flow, or a
nondirect compression sugar which does not have sufficient
flowability and/or compressibility to allow it to be used in high
speed processing and multi-tablet presses without some sort of
augmentation such as, without limitation, a glidant to increase
flow, granulation to increase flow and/or compressibility and the
like. Of course, techniques like granulation can also be used to
convert something which initially has sufficient flow and
compressibility to be considered a direct compression sugar before
processing into a nondirect compression sugar as well. This can be
measured by directly compressing tablets made only from a sugar and
comparing the flow and compressibility both before and after
processing. If flow and/or compressibility are reduced after
processing the material is likely to have become a nondirect
compression sugar. It will be appreciated however, that whether or
not the reduction in properties are sufficient to require
augmentation or further processing before the sugar is used in a
commercial process will depend on a number of factors including the
amount used, the type of processing equipment used, and the overall
formulation. Generally, however, some further processing or
augmentation is required. While not definitive, sometimes a
nondirect compression sugar will have at least about 90% of its
particles smaller than about 200 microns, and more preferably 80%
smaller than about 150 microns.
[0164] The amount of total sugar can range from about 0 to about
90. More preferably, the amount of sugar will range from about 5 to
about 75, and even more preferably between about 10 and 50. Other
non-carbohydrate diluents and fillers which may be used in
accordance with the present invention include for example
dihydrated or anhydrous dibasic calcium phosphate, tricalcium
phosphate, calcium carbonate, anhydrous or hydrated calcium
sulphate, and calcium lactate trihydrate. When used these are
present in an amount of ranging from 0 to about 90, more preferably
from about 5 to about 75 and most preferably from about 10 to about
50% by weight of the dosage form.
[0165] Artificial sweeteners can be anything known to be used as
artificial sweeteners. Some artificial sweeteners that may be
useful in the present invention without limitation include
saccharin, aspartame, sucralose, neotame, and acesulfame potassium.
Artificial sweeteners may be used in conventional amounts, and
preferably in an amount ranging from about 0.1 to about 2.
[0166] Flavoring agents can be anything known to be used as
flavoring agents. Flavoring agents that may be useful in the
present invention may include synthetic flavor oils and flavoring
aromatics and/or natural oils, extracts from plants, leaves,
flowers, fruits and so forth and combinations thereof. These may
include cinnamon oil, oil of wintergreen, peppermint oils, clove
oil, bay oil, anise oil, eucalyptus, thyme oil, cedar leave oil,
oil of nutmeg, oil of sage, oil of bitter almonds and cassia oil.
Also useful as flavoring agents are vanilla, citrus oil, including
lemon, orange, banana, grape, lime and grapefruit, and fruit
essences, including apple, pear, peach, strawberry, raspberry,
cherry, plum, pineapple, apricot and so forth.
[0167] Flavoring agents may be used in conventional amounts, and
preferably in an amount ranging from about 0.01% to about 3% by
weight of the dosage form, and more preferably from about 0.1% to
about 2.5% by weight of the dosage form, and most preferably from
about 0.25% to about 2% by weight of the dosage form.
[0168] Coloring agents can be anything known to be used as a
coloring agent. Coloring agents useful in the present invention may
include titanium dioxide, and dyes suitable for food such as those
known as F.D.& C. dyes and natural coloring agents such as
grape skin extract, beet red powder, beta-carotene, annatto,
carmine, turmeric, paprika, etc. Coloring agents may be used in
conventional amounts, and preferably in an amount ranging from
about 0.001% to about 1% by weight of the dosage form.
[0169] Lubricants can be anything known to be used as a lubricant.
Lubricants that may be useful in the present invention may include
intrinsic or extrinsic lubricants. Intrinsic lubricants may include
magnesium, calcium, zinc salts of stearic acid, hydrogenated and
partially hydrogenated vegetable oils, animal fats, polyethylene
glycol, polyoxyethylene monostearate, talc, light mineral oils,
sodium benzoate, sodium lauryl sulphate, magnesium oxide and the
like. Lubricants may be used in conventional amounts, and
preferably in an amount from about 0.1% to about 5% by weight of
the dosage form, more preferably from about 0.25 to about 2.5 and
most preferably from 0.5 to 2%.
[0170] Viscosity modifiers can be anything known to used as a
viscosity modifier. Some viscosity modifiers that may be useful in
the present invention include, without limitation, sodium alginate,
hydroxypropyl methylcellulose (HPMC), hydroxyethylcellulose (HEC),
sodium carboxymethycellulose (sodium CMC), polyvinylpyrrolidone
(PVP), Konjac flour, carrageenan, xanthan gum, other hydrophilic
polymers, or mixtures thereof. Viscosity modifiers can be used in
conventional amounts and preferably in an amount of about 1 to
about 40, and more preferably in an amount of about 2 to about 20
by weight of the dosage form.
[0171] Surfactants can be anything known to be used as surfactants.
Some surfactants that may be useful in the present invention
include, without limitation, various grades of the following
commercial products: Arlacel.RTM., Tween.RTM., Capmul.RTM.,
Centrophase.RTM., Cremophor.RTM., Labrafac.RTM., Labrafil.RTM.,
Labrasol.RTM., Myverol.RTM., Tagat.RTM., and any non-toxic short
and medium chain alcohols. Surfactants can be used in conventional
amounts and preferably in an amount of about 0.01 to about 5, and
more preferably in an amount of about 0.1 to about 2 by weight of
the dosage form.
[0172] Buffers can be anything known to be used as a buffer. Some
buffers that may be useful in the present invention include any
weak acid or weak base or, preferably, any buffer system that is
not harmful to the gastrointestinal mucosa. These include, but are
not limited to, sodium carbonate, potassium carbonate, potassium
carbonate, disodium hydrogen phosphate, sodium dihydrogen
phosphate, and the equivalent potassium salts. Buffers can be used
in conventional amounts and preferably in an amount of about 0.1 to
about 10, and more preferably in an amount of about 1 to about 5 by
weight of the dosage form.
[0173] Disintegrants which may be used include starch, cellulose,
modified starch, microcrystalline cellulose, alginic acid, clays,
veegum and super disintegrants including, without limitation,
cross-linked PVP, croscaramellose salts such as croscaramellose
sodium, starch derivatives like sodium starch glycolate.
[0174] Where such super disintegrants are used, they are
traditionally found in an amount of between about 1 and about 20%,
more preferably between about 2 and about 10%, and most preferably
between about 2 and about 5% by weight of the finished dosage form.
In addition to, instead of any portion of, or instead of any super
disintegrant, the dosage forms in accordance with the present
invention may include at least one effervescent couple or
disintegrant.
[0175] Effervescent couples are made from a reaction of a soluble
acid source and a metal carbonate or bicarbonate. The acid sources
or acid may be any which are safe for human consumption and may
generally include food acids, acid anhydrides and acid salts. Food
acids include citric acid, tartaric acid, malic acid, fumaric acid,
adipic acid, and succinic acids etc. Because these acids are
directly ingested, their overall solubility in water is less
important than it would be if the effervescent tablet formulations
of the present invention were intended to be dissolved in a glass
of water. Acid anhydrides and acid salts of the above described
acids may also be used. Acid salts may include sodium, dihydrogen
phosphate, disodium dihydrogen pyrophosphate, acid citrate salts
and sodium acid sulfite.
[0176] Carbonate sources include dry solid carbonate and
bicarbonate salts such as sodium bicarbonate, sodium carbonate,
potassium bicarbonate and potassium carbonate, magnesium carbonate
and sodium sesquicarbonate, sodium glycine carbonate, L-lysine
carbonate, arginine carbonate and amorphous calcium carbonate.
These effervescent couples may be provided in an amount of between
about 3% and about 50% by weight of the dosage form, more
preferably between about 3% and about 25% by weight.
[0177] Nonlimiting examples of such noneffervescent disintegration
agents include: microcrystalline, cellulose, starches, corn starch,
potato starch and modified starches thereof, clays, such as
bentonite, alginates, gums such as agar, guar, locust bean, karaya,
pecitin and tragacanth. These disintegrants may comprise up to
about 20 weight percent and preferably between about 2% and about
10% of the total weight of the dosage form.
[0178] If desired the dosage form may also contain minor amounts of
nontoxic substances such as wetting or emulsifying agents, pH
buffering agents and the like, for example, sodium acetate,
sorbitan monolaurate, triethanolamine, sodium acetate,
triethanolamine oleate, sodium lauryl sulfate, dioctyl sodium
sulfosuccinate, polyoxyethylene sorbitan fatty acid esters.
[0179] A "dosage form" in accordance with the present invention is
a tablet, capsule, caplet, sachet, powder or other solid known for
the administration of medicines orally. It is generally made from a
mixture as defined herein and is either formed (as in a tablet) or
packaged (as in a capsule, powder, or sachet) into a form for use
by a doctor or patient for administration. A tablet can be an
ALKA-SELTZER.RTM.-like tablet which is dropped into a glass of a
liquid and dissolved prior to ingestion, a dosage form which is
orally disintegrable/dissolvable on a patient's tongue, a dosage
form which is to be administered gingivally, buccally or
sublingually, or a traditional dosage form which is to be swallowed
as a dispersion, suspension or slurry. An orally
disintegrable/dissolvable dosage form is one which is placed on the
tongue and which dissolves/disintegrates in the mouth generally in
about 90 seconds or less, more often in about 60 seconds or less.
Thereafter, the resulting suspension, solution or slurry is
swallowed. In buccal, gingival and sublingual dosage forms, the
active ingredient is typically transferred through the oral mucosa.
A dosage form could be prepared by metering powder or slugged cores
into a hard gelatin capsule for oral ingestion or provided as a
powder to be taken directly, to be sprinkled onto food, or mixed
with a beverage prior to ingestion are also contemplated.
[0180] Dosage forms as contemplated by the present invention may be
provided in a range of shapes and sizes. In a preferred embodiment,
the dosage form is in a size capable of oral administration and
provides a therapeutic amount of the API therein. Generally, such
dosage forms will be less than 1.5 inches in any one direction,
more preferably less than 1 inch and most preferably less than 0.75
inch. Shapes include but not limited to round with both flat or
convex face, capsule shape (caplets), diamond shape, triangular,
rectangular, hexagonal, pentagonal, heart-shaped, animal shaped
tablets like rabbits, elephants etc. Dosage forms can be any size
and shape, but preferable of a size and shape to avoid crushing or
abuse.
[0181] The frequency of dosing depends on various factors including
the amount of active ingredient present in the dosage form, the
size of the dosage form, the weight of the patient, the number of
dosage form per dose, the condition of the patient, side effects of
the active ingredient, etc. The administration of multiple dosage
forms and multiple frequency of dosing is contemplated depending
upon the above factors as well as duration of the patient's
condition, how long the active ingredient stays in a patient's
system, etc., however, dosage 4 times per day of fewer are
desirable. Most preferably, dosing is 1, 2, 3, or at least 4 times
per day.
[0182] In some embodiments tablets the invention often have a
hardness of about 20 Newtons or less, and in other embodiments
20-250 Newtons. In one embodiment, hardness is about 20 to about 40
Newtons and a friability of less than 1% as measured by the U.S.P.
method as of the filing date.
[0183] Tablets can either be manufactured by direct compression,
wet granulation, dry granulation or any other tablet manufacturing
technique. See, e.g., U.S. Pat. Nos. 5,178,878, 5,223,264 and
6,024,981 which are incorporated by reference herein.
[0184] In another aspect, the present invention comprises an abuse
resistant dosage form in accordance with the present invention and
one or more indicia indicating that it is abuse resistant. In one
embodiment, the dosage form itself includes the indicia. The
indicia could be, for example, one or more letters such as "AR,"
one or more words such as "abuse" and/or "resistant" or a picture
or symbol. These can be printed onto the surface of the dosage
form, imbedded as a relief or as a raised structure. Instead, or in
addition, the abuse resistant dosage forms of the present invention
may be packaged in one or more blister packs, or in multi-tablet
openable and reclosable containers, such as a bottle. The
packaging, or any associated product label or package insert could
also include one or more letters, words, pictures or symbols which
indicate that the dosage forms were abuse resistant.
[0185] Such indicia could provide additional assistance in reducing
abuse in a number of ways. For one thing, a patient who is informed
of the abuse-resistant feature and insists on another form of the
drug could alert a pharmacist that the patient could have a
problem. Second, knowing that the dosage forms are abuse resistant
could reduce their theft or their illegal resale as they would be
less desirable to abusers.
EXAMPLES
Example 1 Coated Granules Lot 2926-76C
[0186] The present invention can be illustrated by producing
controlled release coated particles with wet granules as API
particles.
TABLE-US-00004 TABLE 1 Granules Formulation Component % (w/w)
Oxycodone Hydrochloride 27.8 Hydroxypropyl methylcellulose 844 46.3
Ethylcellulose 25.9
TABLE-US-00005 TABLE 2 Coated Granules Formulation Component %
(w/w) Oxycodone Granules 50.0 Ethylcellulose 33.3 Magnesium
Stearate 16.7
[0187] Granules were manufactured in a high shear granulator where
oxycodone hydrochloride, HPMC 844 and 71% of the total amount of
ethylcellulose were dry mixed for 2 minutes. Then, a 10%
hydro-ethanolic (30:70) solution of ethylcellulose was slowly added
while maintaining the granulator impeller and chopper speeds at
pre-selected values to provide enough shear for granule formation
and growth. Solution addition was continued until the
aforementioned percentage of ethylcellulose was realized. The
granules were subsequently dried in a fluid bed to a level that
renders them suitable for milling. The granules were then milled in
a granumill and finally dried.
[0188] The prepared granules were then coated in a bottom spray
fluid bed using a 15% alcoholic suspension of ethycellulose and
magnesium stearate (2:1). Average particle size was determined by a
sieve shaking method, and equaled about 630 microns. This is the
geometric mean diameter, the number 630 was obtained by manually
plotting the cumulative % frequency against the particle size on a
Log-probability paper. The dissolution profile of these coated
granulates were tested (FIG. 1).
[0189] Aliquots of a sample were crushed using a mortar and pestle,
crushing in 12 circular strokes of the pestle. The aliquots were
pooled and then divided into aliquots each contains a drug amount
equivalent to a single dose. The aliquots are tested for
dissolution in 500 mL of medium (0.1N HCl). At specified time
points, 5 mL aliquots were pulled from each vessel and analyzed via
HPLC versus a standard. The results are shown in FIG. 1 for the
uncrushed coated particles and FIG. 2 for the "crushed" coated
particles and in both plots, the dark squares indicate the measured
data points.
Example 2 Coated Granules Lot 2926-76B
[0190] The methods of making coated particles, described above in
Example 1 were employed again except the formulation was coated
with the aqueous EC dispersion.
TABLE-US-00006 TABLE 3 Granules Formulation Component % (w/w)
Oxycodone Hydrochloride 27.8 Hydroxypropyl methylcellulose 844 46.3
Ethylcellulose 25.9
TABLE-US-00007 TABLE 4 Coated Granules Formulation Component %
(w/w) Oxycodone Granules 50.0 Surelease .RTM. (25% Solid) 50.0
[0191] The coating used was a SURELEASE aqueous dispersion
(Commercial Aqueous dispersion of EC from Colorcon Manufacturer Lot
#1N509251) The dissolution results of uncrushed (FIG. 1) and
crushed (FIG. 2) particles from the aqueous coating are shown in
plots using diamonds indicating the measured data points.
Example 3
TABLE-US-00008 [0192] TABLE 5 Granules Formulation Component %
(w/w) Oxycodone Hydrochloride 46.1 Hydroxypropyl methylcellulose
844 36.9 Ethylcellulose 17.0
TABLE-US-00009 TABLE 6 Coated Granules Formulation Component %
(w/w) Oxycodone Granules 50.0 Ethylcellulose 33.3 Magnesium
Stearate 16.6
[0193] The same manufacturing method as used in Example 1 can be
used except only 54% of EC is dry mixed with other ingredients
instead of 71%.
Example 4 Coated Granules Lot 3531-18
TABLE-US-00010 [0194] TABLE 7 Granules Formulation Component %
(w/w) Oxycodone Hydrochloride 46.1 Hydroxypropyl methylcellulose
844 36.9 Ethylcellulose 17.0
TABLE-US-00011 TABLE 8 Coated Granules Formulation Component %
(w/w) Oxycodone Granules 50.0 Ethylcellulose 32.3 Lutrol F127 1.6
Magnesium Stearate 16.1
[0195] The same manufacturing method as in Example 1 may be used
except only 54% of EC is mixed dry with other ingredients (instead
of 71). Also the coating dispersion contained EC and additives,
namely: magnesium stearate:Lutrol:Ethanol ratio of
10:5:0.5:84.5.
Example 5 Coated Granules Lot 3070-70
TABLE-US-00012 [0196] TABLE 9 Granules Formulation Component %
(w/w) Oxycodone Hydrochloride 65.6 Hydroxypropyl methylcellulose
844 22.5 Ethylcellulose 11.9
TABLE-US-00013 TABLE 10 Coated Granules Formulation Component %
(w/w) Oxycodone Granules 50.0 Ethylcellulose 33.3 Magnesium
Stearate 16.7
[0197] The same manufacturing method used as in Example 1 was
employed here except only 47% of EC was dry mixed with other
ingredients instead of 71% in the granulate core. FIGS. 3 and 4
provide dissolution profiles in 0.1N HCl for 50% coated granules
with different levels of polymers in the granule portion of the
coated granule. FIG. 3 illustrates a comparison between the
dissolution profiles of the granules in Example 1, which contained
approximately 72.2% polymer, coated in an ethanol based EC coating,
with the coated particles produced in accordance with this example
(Example 5) where the granulate (the uncoated granulate) contained
approximately 34.4% polymer, coated with the same ethanolic based
EC coating. FIG. 4 demonstrates the dissolution profiles of the
same materials after they have been crushed as described in Example
1. In FIG. 3, the unshaded triangles represent the data plotted for
the granulate of Example 1 and the shaded diamonds for the coated
granulate of Example 5. In FIG. 4, the shaded diamonds provide the
data for the coated granulate of Example 1 and the asterisks
provide the data for the coated granulate of Example 5. It will be
noted from FIG. 4 that the higher level of polymer content in the
core (72.2% as opposed to 34.4%) provided relatively better crush
resistance.
Example 6
[0198] The same manufacturing method as in Example 1 was employed
here except that here the API particles were mixed with barrier
beads as discussed herein.
TABLE-US-00014 TABLE 11 Granules Formulation Component % (w/w)
Oxycodone Hydrochloride 27.8 Hydroxypropyl methylcellulose 844 46.3
Ethylcellulose 25.9
TABLE-US-00015 TABLE 12 Coated Granules Formulation Component %
(w/w) Oxycodone Granules 50.00 Ethylcellulose 33.33 Magnesium
Stearate 16.67
[0199] The coated granulates and barrier beads are then mixed in
different proportions. Microcrystalline cellulose particles
commercially available as Celphere CP-507 were used. Specifically,
the coated particles were mixed with CP-507 at 25:75, 50:50 and
75:25. Published size information for the CP-507 was at least about
75% within range of 500-710 microns. The mixtures were subjected to
mechanical stress by using 130 mm OD Porcelain mortar and 1-pound
pestle. In summary, the particles are placed in a ceramic mortar
(13 cm outer diameter) then by using the pestle and applying force
vertically down word, the coated granules are crushed by
360.degree. C. circular motion. Each full circle motion constitutes
1 stroke. Each sample is crushed by applying 12 strokes as
described above. Oxycodone release from the stressed granules was
measured in USP Dissolution apparatus 2 using 0.1 N HCl as release
medium. The release profiles from non-stressed as well as stressed
mixtures of oxycodone coated granules and Celpheres are presented
in FIG. 5.
[0200] Note that at 75:25 barrier bead:API particle ratio,
additional protection was obtained against stress. In other
instances, the ratio needed to provide additional protection when
compared to a formulation without barrier beads will differ. It is
also important to note that this improvement was realized using
protected particles which were themselves designed to be crush
resistant. Indeed, granulates made with certain celluloses from an
aqueous/alcoholic solution as a binder are believed to provide
crush resistance when compared to an identical granulate made using
water without alcohol as the binder. Similarly, a particle coated
with a cellulose from an aqueous/alcoholic solution has been found
to independently provide crush resistance when compared to an
identically coated particle made using water without alcohol for
the coating. Thus, the example demonstrates improvements resulting
from the use of barrier beads can be obtained even when combined
with other crush resistant technology. Indeed, improvement was
realized here even where the average particle size of the barrier
beads was considered to be less than that of the protected
particles.
Example 7
[0201] The coated oxycodone granules described in Example 6 above
were also mixed in a 50:50 mixture with isomalt granules
manufactured in Fluid bed granulator as barrier beads. The granules
mixture was stressed in a mortar and pestle as described in example
6 above. The release profiles from nonstressed as well as stressed
mixtures of oxycodone coated granules and isomalt granules are
presented in FIG. 6.
Example 8 Coated Granules Lot 4002-79 (Gelucire 33/01 in Core Only
not Cured)
[0202] Using a process similar to that described above in Examples
17 and 45, but with using 82% of EC for dry mixing together with
20% Gelucire 33/01 with other ingredients, the following
formulation was prepared, which differs from Example 17 in the
amounts of each component used. Before granulation, Gelucire 33/01
was first broken into small pieces (about 1 cm in diameter) using a
hand-held extruder. Gelucire 33/01 pieces were then mixed by hand
with HPMC and EC and hand screened through a 16-mesh screen.
Hydromorphone HCl was then screened through the same screen and the
mixture was then granulated. The wet granules were not partially
dried prior to milling.
TABLE-US-00016 TABLE 87 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Gelucire 33/01 20.0 Total 100.0
TABLE-US-00017 TABLE 88 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Magnesium Stearate 16.7 Total 100.00
Example 9 Coated Granules Lot 3375-51
[0203] Granules can be manufactured using a high shear granulator
wherein oxycodone hydrochloride, hydroxymethylcellulose HPMC 844,
and from about 47% to about 54% of the total amount of
ethylcellulose to be used are dry mixed for a period of 2 minutes.
Then, a 10% hydro-ethanolic (30:70) solution of ethylcellulose can
be slowly added while maintaining the granulator impeller and
chopper speeds at pre-selected values sufficient to provide shear
for granule formation and growth. The solution can be added until
the desired percentage ethylcellulose is obtained. The granules can
then be dried in a fluid bed to a level rendering them suitable for
milling. The granules can then be milled in a mill and dried.
[0204] Using a process similar to that described hereinabove and
using 54% of the total amount of ethylcellulose, the following
uncoated granulate composition was prepared:
TABLE-US-00018 TABLE 16 Uncoated Oxycodone Granule Amount
Ingredient (% w/w) Oxycodone HCl 46.1 Hydroxypropyl methylcellulose
36.9 (HPMC) Ethylcellulose 17.0 Total 100.0
[0205] The prepared granules can then be coated in a bottom spray
fluid bed using a 15% alcoholic suspension of ethylcellulose and
magnesium stearate (2:1). After coating, about 40% of the coated
granules based on weight can be composed of the coating materials.
Using this process, the following coated granule formulation was
prepared:
TABLE-US-00019 TABLE 17 Coated Oxycodone Granule Amount Ingredient
(% w/w) Oxycodone granules 60.00 (oxycodone HCl, HPMC,
ethylcellulose of Table 16) Ethylcellulose 26.67 Magnesium stearate
13.33 Total 100.00
Example 10 Tablet Lot 3375-59
[0206] Coated granules prepared as described herein above can be
formed into solid dosage form, e.g., tablet. The coated granules
can be mixed with EMCOMPRESS (dibasic calcium phosphate dihydrate),
lactose (FAST-FLO, spray-dried), COMPRITOL ATO 888 (glyceryl
behenate) in a V-blender for a period of about 30 minutes. The
blended mixture can then be compressed in a rotary tablet press to
form tablets. Tablet weight can vary from about 110 mg for a 10 mg
oxycodone HCl active ingredient to about 880 mg for an 80 mg
oxycodone HCl tablet. Using this process, the following tablet was
prepared:
TABLE-US-00020 TABLE 18 Oxycodone HCl (10 mg) Tablet Formulation
Amount Amount Component (% w/w) (mg) Oxycodone 38.82 42.70 coated
granules (Table 17) EMCOMPRESS 33.18 36.50 Lactose 23.00 25.30
COMPRITOL 5.00 5.50 (glyceryl behenate) Total 100.00 110.00 mg
[0207] The above calculations account for the fact that the actual
potency of the coated granules made were less than the theoretical
amount. Thus, 110.00 mg of the prepared tablet contained 10 mg
oxycodone HCl.
[0208] Various tablet shapes and sizes can be employed with the
invention. Furthermore, the same process above can be used except
the second particle fat/wax with a low melting point is melted and
poured into a capsule shell and combined, or pre-combined, and the
suspension can then be poured into a capsule shell.
Example 11
[0209] 10 mg oxycodone HCl tablets prepared according to the
invention were dissolved in two dissolution medium: acid/water
medium (normal) and water/alcohol (alcohol) medium in order to
measure the percent active ingredient released over time and
compare the results.
[0210] Using compressed tablets prepared using the 10 mg
oxycodone-containing composition prepared according to Example 10
with the formulation of Table 18, the normal dissolution of the
active ingredient in dissolution medium was measured. Starting with
500 ml 0.1 N HCl (in water) as a release (dissolution) medium at a
temperature of 37.degree. C. in a USP Dissolution apparatus (2
paddles at a rate of rpm 50), granules (equivalent to 10 mg
oxycodone HCl) were added to the dissolution medium. Samples were
withdrawn at intervals 5 min, 15 min, 30 min, 45 min, 60 min, 120
min. Each sample was tested for solubilized oxycodone content using
HPLC method, and the values described in percentage terms and
plotted against time to establish release profiles. The data
appears in the following table:
TABLE-US-00021 TABLE 19 Percent (%) Oxycodone Released per Time in
HCl/ Water Dissolution Medium Percent (%) Release Time Oxycodone
(min) HCl 0 0 5 2 15 10 30 22 45 33 60 44 120 82
[0211] The normal dissolution data as plotted appears in FIG.
7.
[0212] Normal dissolution was compared to dissolution conditions
representative of solvent (alcohol)-accelerated dose dumping abuse
and tampering conduct. The procedure above was repeated except the
dissolution medium contained water:ethanol in 60:40 volume ratio
simulating a combination of the tablet with alcohol. Samples were
taken at 5, 15, 30, 45, 60 and 120 minute intervals, and measured
again for oxycodone content. The results were plotted against time
and appear in the following table:
TABLE-US-00022 TABLE 20 Percent (%) Oxycodone Released per Time in
Alcohol and Water Dissolution Medium Time Percent (%) Release (min)
Oxycodone HCl 0 0 5 0 15 0 30 14 45 22 60 32 120 60
[0213] The data as plotted appears in the chart of FIG. 7
(Dissolution Profiles).
[0214] As can be seen from the figure, the ability to accelerate
the release of active ingredients (e.g., oxycodone HCl) from tablet
dosage forms prepared according to the invention, using alcohol as
a solvent, is limited. The measured amounts of oxycodone active
release in alcohol-containing dissolution medium is comparable to
that amount measured in the acidic water-containing (normal)
dissolution medium.
Example 12 Tablet Lot 3070-98
[0215] Using a process similar to that described above in Example 9
and using 54% of the total amount of ethylcellulose, the following
uncoated granulate composition was prepared:
TABLE-US-00023 TABLE 21 Uncoated Oxycodone Granule Amount
Ingredient (% w/w) Oxycodone HCl 65.61 Hydroxypropyl 22.49
methylcellulose (HPMC) Ethylcellulose 11.90 Total 100.00
[0216] Using a process similar to that described above in Example
9, the following coated granule composition was prepared:
TABLE-US-00024 TABLE 22 Coated Oxycodone Granule Amount Ingredient
(% w/w) Oxycodone granules 50.00 (oxycodone HCl, HPMC,
ethylcellulose of Table 21) Ethylcellulose 33.33 Magnesium stearate
16.67 Total 100.00
[0217] Using a process similar to that described above in Example
10, the following formulation was prepared:
TABLE-US-00025 TABLE 23 Oxycodone HCl (80 mg) Tablet Formulation
Amount Amount Ingredient (% w/w) (mg) Oxycodone 39.02 243.90 coated
granules (of Table 22) EMCOMPRESS 30.59 191.20 Lactose 20.38 127.40
COMPRITOL 10.00 62.50 (glyceryl behenate) Total 100.00 625.00
mg
Example 13
[0218] 80 mg oxycodone HCl tablets prepared according to the
invention and as formulated in Table 23, were dissolved in two
dissolution medium: acid/water medium (normal) and water/alcohol
(alcohol) medium in order to measure the percent active ingredient
released over time and compare the results.
[0219] Using compressed tablets prepared using the 80 mg
oxycodone-containing composition prepared according to Example 12
with the formulation of Table 23, the normal dissolution of the
active ingredient in solution medium was measured. Starting with
500 ml 0.1 N HCl (in water) as a release (dissolution) medium at a
temperature of 37.degree. C. in a USP Dissolution apparatus (2
paddles at a rate of rpm 50), granules (equivalent to 80 mg
oxycodone HCl) were added to the dissolution medium. Samples were
withdrawn at intervals 5 min, 15 min, 30 min, 45 min, 60 min, 120
min. Each sample was tested for solubilized oxycodone content using
HPLC method, and the values described in percentage terms and
plotted against time to establish release profiles. The data
appears in the following table:
TABLE-US-00026 TABLE 24 Percent (%) Oxycodone Released per Time in
Acid/ Water Dissolution Medium Percent Time (%) Release (min)
oxycodone HCl 0 0 5 1 15 2 30 4 45 6 60 8 120 18
[0220] The normal dissolution data as plotted appears in FIG.
8.
[0221] Normal dissolution was compared to dissolution conditions
representative of solvent (alcohol)-accelerated dose dumping abuse
and tampering conduct. The procedure above was repeated except the
dissolution medium contained water:ethanol in 60:40 volume ratio
simulating a combination of the tablet with alcohol. Samples were
taken at 5, 15, 30, 45, 60, and 120 minute intervals, and measured
again for oxycodone content. The results were plotted against time
and appear in the following table:
TABLE-US-00027 TABLE 25 Percent (%) Oxycodone Released per Time in
Water/ Alcohol Dissolution Medium Percent Time (%) Release (min)
Oxycodone HCl 0 0 5 0 15 2 30 6 45 10 60 15 120 27
[0222] The alcohol dissolution data as plotted appears in FIG. 8.
As can be seen from the chart of FIG. 8, the ability to accelerate
the release of active ingredients (e.g., oxycodone HCl) from tablet
dosage forms prepared according to the invention, using alcohol as
a solvent, is limited. The measured amounts of oxycodone active
release in alcohol-containing dissolution medium is at least
comparable to that amount measured in the acidic water-containing
(normal) dissolution medium.
Example 14 Coated Granules Lot 770300
[0223] The present invention can be illustrated by producing a
composition including CR coated particles with wet granules as API
particles.
[0224] Using a process similar to that described above in Example
1, except 53% of EC is dry mixed with other ingredients instead of
71%, the following formulation was prepared, which differs from
Example 1 in the amounts of each component used
TABLE-US-00028 TABLE 26 Granules Formulations Amount Ingredient (%
w/w) Oxycodone HCl 46.1 Hydroxypropyl 36.9 methylcellulose (HPMC)
Ethylcellulose 17.0 Total 100.00
TABLE-US-00029 TABLE 27 Coated Granules Formulation Amount
Ingredient (% w/w) Oxycodone granules 60.00 (oxycodone HCl, HPMC,
ethylcellulose) Ethylcellulose 26.67 Magnesium stearate 13.33 Total
100.00
[0225] Using a process similar to that described above in Example
10, the following formulation was prepared using different amounts
and components than in Example 10:
TABLE-US-00030 TABLE 28 Oxycodone HCl (80 mg) Tablet Formulation
Amount Component (% w/w) Amount (mg) Oxycodone 33.98 288.8 coated
granules Lactose 56.02 476.2 Monohydrate (fast Flo) COMPRITOL 10.00
85.0 (glyceryl behenate) Total 100.00 850.0 mg
[0226] While COMPRITOL is always kept at 10% of the total weight of
the dosage form (tablet), any change in the actual assay amount,
from theoretical values, is accounted for by changing the amount of
lactose and coated granules to maintain the amount of Oxycodone HCl
at 80 mg per tablet. The average tablet weight is 850 mg, and has
an average hardness of between 140 and 155 N. The tablet dimensions
are 0.3125''.times.0.5625.''
[0227] Using a process similar to that of Example 11, the following
data was obtained using the above formulation:
TABLE-US-00031 TABLE 29 Percent (%) Oxycodone Released per Time in
HCl/Water Dissolution Medium Percent (%) Release Time Oxycodone
(min) HCl 0 0 30 11 60 28 120 62 240 95 360 97 480 98 600 98 720
99
TABLE-US-00032 TABLE 30 Percent (%) Oxycodone Released per Time in
Alcohol and Water Dissolution Medium Percent (%) Release Time
Oxycodone (min) HCl 0 0 5 0 15 3 30 7 45 11 60 14 120 31
TABLE-US-00033 TABLE 31 Percent (%) Oxycodone Released per Time in
HCl/Water Dissolution Medium after crushing Percent (%) Release
Time (min) Oxycodone HCl 0 0 5 8 15 34 30 69 45 86 60 94 120 98
[0228] The data of Table 29 is illustrated in FIG. 9 as the upper
curve with shaded squares and "X"s.
Example 15 Coated Granules Lot 770299
[0229] Using a process similar to that described above in Example
14, again dry mixing only 53% of EC with other ingredients, the
following formulation was prepared, which differs from Example 14
in the amounts of each component used:
TABLE-US-00034 TABLE 32 Granules Formulations Ingredient Amount (%
w/w) Oxycodone HCl 46.1 Hydroxypropyl methylcellulose 36.9 (HPMC)
Ethylcellulose 17.0 Total 100.00
TABLE-US-00035 TABLE 33 Coated Granules Formulation Ingredient
Amount (% w/w) Oxycodone granules (oxycodone 52.5 HCl, HPMC,
ethylcellulose) Ethylcellulose 31.7 Magnesium stearate 15.8 Total
100.00
[0230] Using a process similar to that described in Example 14, the
following formulation was prepared using different amounts than in
Example 14:
TABLE-US-00036 TABLE 34 Oxycodone HCl (80 mg) Tablet Formulation
Component Amount (% w/w) Amount (mg) Oxycodone coated 38.89 330.6
granules Lactose Monohydrate 51.11 434.4 (fast Flo) COMPRITOL
(glyceryl 10.00 85.0 behenate) Total 100.00 850.0 mg
[0231] While COMPRITOL is always kept at 10% of the total weight of
the dosage form (tablet), any change in the actual assay amount,
from theoretical values, is accounted for by changing the amount of
lactose and coated granules to maintain the amount of Oxycodone HCl
at 80 mg per tablet. The average tablet weight is 850 mg, and has
an average hardness of between 140 and 155 N. The tablet dimensions
are 0.3125''.times.0.5625''.
[0232] Using a process similar to that of Example 14, the following
data was obtained using the above formulation:
TABLE-US-00037 TABLE 35 Percent (%) Oxycodone Released per Time in
HCl/Water Dissolution Medium Percent (%) Release Time (min)
Oxycodone HCl 0 0 30 5 60 15 120 37 240 74 360 90 480 97 600 98 720
99
TABLE-US-00038 TABLE 36 Percent (%) Oxycodone Released per Time in
Alcohol and Water Dissolution Medium Percent (%) Release Time (min)
Oxycodone HCl 0 0 5 0 15 2 30 6 45 9 60 12 120 25
TABLE-US-00039 TABLE 37 Percent (%) Oxycodone Released per Time in
HCl/Water Dissolution Medium after crushing Percent (%) Release
Time (min) Oxycodone HCl 0 0 5 4 15 15 30 42 45 63 60 78 120 95
[0233] The data of Table 35 is illustrated in FIG. 9 as the shaded
triangles.
Example 16 Coated Granules Lot 770298
[0234] Using a process similar to that described above in Example
15, again using only 53% of EC for dry mixing with other
ingredients, the following formulation was prepared, which differs
from Example 15 in the amounts of each component used:
TABLE-US-00040 TABLE 38 Granules Formulations Ingredient Amount (%
w/w) Oxycodone HCl 46.1 Hydroxypropyl methylcellulose 36.9 (HPMC)
Ethylcellulose 17.0 Total 100.00
TABLE-US-00041 TABLE 39 Coated Granules Formulation Ingredient
Amount (% w/w) Oxycodone granules (oxycodone 50.0 HCl, HPMC,
ethylcellulose) Ethylcellulose 33.3 Magnesium stearate 16.7 Total
100.00
[0235] Using a process similar to that described above in Example
15, the following formulation was prepared using different amounts
than in Example 15:
TABLE-US-00042 TABLE 40 Oxycodone HCl (80 mg) Tablet Formulation
Component Amount (% w/w) Amount (mg) Oxycodone coated 40.74 346.3
granules Lactose Monohydrate 49.26 418.7 (fast Flo) COMPRITOL
(glyceryl 10.00 85.0 behenate) Total 100.00 850.0 mg
[0236] While COMPRITOL is always kept at 10% of the tablet weight,
any change in the actual assay amount, from theoretical values, is
accounted for by changing the amount of lactose and coated granules
to maintain the amount of Oxycodone HCl at 80 mg. The average
tablet weight is 850 mg, and has an average hardness of between 139
and 155 N. The tablet dimensions are 0.3125''.times.0.5625''.
[0237] Using a process similar to that of Example 15, the following
data was obtained using the above formulation:
TABLE-US-00043 TABLE 41 Percent (%) Oxycodone Released per Time in
HCl/Water Dissolution Medium Percent (%) Release Time (min)
Oxycodone HCl 0 0 30 5 60 11 120 25 240 52 360 74 480 87 600 94 720
98
TABLE-US-00044 TABLE 42 Percent (%) Oxycodone Released per Time in
Alcohol and Water Dissolution Medium Percent (%) Release Time (min)
Oxycodone HCl 0 0 5 1 15 2 30 6 45 8 60 11 120 23
TABLE-US-00045 TABLE 43 Percent (%) Oxycodone Released per Time in
HCl/Water Dissolution Medium after crushing Percent (%) Release
Time (min) Oxycodone HCl 0 0 5 5 15 13 30 29 45 44 60 57 120 85
[0238] The data of Table 41 is illustrated in FIG. 9 as the lower
curve with shaded squares.
Example 17 Coated Granules Lots #3766-06B and 3766-80
[0239] Using a process similar to that described above in Example
3, again using only 53% of EC for dry mixing with other ingredients
instead of 54%, the following formulation was prepared, which
differs from Example 3 in the amounts of each component used and
the drug used:
TABLE-US-00046 TABLE 44 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 36.4
(HPMC) Ethylcellulose 17.0 Total 100.00
TABLE-US-00047 TABLE 45 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Magnesium stearate 16.7 Total 100.00
[0240] In this example, Hydromorphone HCl was substituted for
Oxycodone HCl. However, the same process steps may be used for
various types of API's.
Example 18 Coated Granules Lot #3766-06C
[0241] Using a process similar to that described above in Example
17, again using only 53% of EC for dry mixing with other
ingredients, the following formulation was prepared, which differs
from Example 17 in the amounts of each component used:
TABLE-US-00048 TABLE 46 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 36.4
(HPMC) Ethylcellulose 17.0 Total 100.00
TABLE-US-00049 TABLE 47 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 40.0 Ethylcellulose 40.0
Magnesium stearate 20.0 Total 100.00
[0242] As in Example 17, Hydromorphone HCl replaced Oxycodone HCl
as the API.
Example 19 Coated Granules Lot #3766-06A
[0243] Using a process similar to that described above in Example
18, again using only 53% of EC for dry mixing with other
ingredients, the following formulation was prepared, which differs
from Example 18 in the amounts of each component used:
TABLE-US-00050 TABLE 48 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 36.4
(HPMC) Ethylcellulose 17.0 Total 100.00
TABLE-US-00051 TABLE 49 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 60.0 Ethylcellulose 26.7
Magnesium stearate 13.3 Total 100.00
[0244] As in Example 18, Hydromorphone HCl replaced Oxycodone HCl
as the API.
[0245] [Start with Example 20 and FIG. 10 and Table 50]
Example 20 Coated Granules Lot#3766-27A (Compritol in the Coat Only
and not Cured)
[0246] Using a process similar to that described above in Example
17, again using only 53% of EC for dry mixing with other
ingredients, the following formulation was prepared, which differs
from Example 17 in the amounts of each component used.
TABLE-US-00052 TABLE 50 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 36.4
(HPMC) Ethylcellulose 17.0 Total 100.00
TABLE-US-00053 TABLE 51 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Glycerol Behenate (Compritol 16.7 888 Ato) Total 100.00
Example 21 Coated Granules Lot#3766-27B (Compritol in the Coat Only
and Cured)
[0247] Using a process similar to that described above in Example
17, again using only 53% of EC for dry mixing with other
ingredients, the following formulation was prepared, which differs
from Example 17 in the amounts of each component used.
TABLE-US-00054 TABLE 52 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 36.4
(HPMC) Ethylcellulose 17.0 Total 100.00
TABLE-US-00055 TABLE 53 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Glycerol Behenate (Compritol 16.7 888 Ato) Total 100.00
[0248] After the right amount of coating has been sprayed into the
granules, the coated granules were further cured by suspending them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 60.degree. C. for 40 minutes.
Example 22 Coated Granules Lot#3766-33 (Compritol in the Core Only
and not Cured)
[0249] Using a process similar to that described above in Example
17, but with using 72% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used.
TABLE-US-00056 TABLE 54 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 20.0 Total 100.0
TABLE-US-00057 TABLE 55 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Magnesium stearate 16.7 Total 100.00
Example 23 Coated Granules Lot#3766-38 (Compritol in the Core Only
and Cured)
[0250] Using a process similar to that described above in Example
17, but with using 72% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The uncoated granules were further cured by
suspended them in the fluid bed while increasing the inlet air
temperature. Curing was considered complete when the bed
temperature was maintained above 60.degree. C. for 40 minutes and
above 70.degree. C. for 20 minutes.
TABLE-US-00058 TABLE 56 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 20.0 Total 100.0
TABLE-US-00059 TABLE 57 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Magnesium stearate 16.7 Total 100.00
Example 24 Coated Granules Lot#4002-21 (Compritol in the Core and
Cured and in the Coat and Cured)
[0251] Using a process similar to that described above in Example
17, but with using 72% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling. The uncoated granules were further cured by suspended them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 60.degree. C. for 30 minutes.
TABLE-US-00060 TABLE 58 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 20.0 Total 100.0
TABLE-US-00061 TABLE 59 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Glycerol Behenate (Compritol 16.7 888 Ato) Total 100.00
[0252] After the right amount of coating has been sprayed into the
granules, the coated granules were further cured by suspending them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 60.degree. C. for 30 minutes.
Example 25 Coated Granules Lot#4002-31B (Compritol in the Core and
Cured and in the Coat and Cured, 50% Coat)
[0253] Using a process similar to that described above in Example
17, but with using 61% of EC for dry mixing together with 10%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling. The uncoated granules were further cured by suspended them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 65.degree. C. for 30 minutes.
TABLE-US-00062 TABLE 60 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.7 Hydroxypropyl methylcellulose 26.5
(HPMC) Ethylcellulose 16.8 Glycerol behenate 10.0 Total 100.0
TABLE-US-00063 TABLE 61 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Glycerol Behenate (Compritol 16.7 888 Ato) Total 100.00
[0254] After the right amount of coating has been sprayed into the
granules, the coated granules were further cured by suspending them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 65.degree. C. for 30 minutes.
Example 26 Coated Granules Lot#4002-31A (Compritol in the Core and
Cured and in the Coat and Cured, 40% Coat)
[0255] Using a process similar to that described above in Example
17, but with using 61% of EC for dry mixing together with 10%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling. The uncoated granules were further cured by suspended them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 65.degree. C. for 30 minutes.
TABLE-US-00064 TABLE 62 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.7 Hydroxypropyl methylcellulose 26.5
(HPMC) Ethylcellulose 16.8 Glycerol behenate 10.0 Total 100.0
TABLE-US-00065 TABLE 63 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 60.0 Ethylcellulose 26.7
Glycerol Behenate (Compritol 13.3 888 Ato) Total 100.00
[0256] After the right amount of coating has been sprayed into the
granules in the fluid bed, the coated granules were further cured
by placing them in an oven set at temperature of 70.degree. C. for
30 minutes.
Example 27 Coated Granules Lot#4002-40A (Compritol in the Core and
not Cured and in the Coat and not Cured, 50% Coat)
[0257] Using a process similar to that described above in Example
17, but with using 72% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling.
TABLE-US-00066 TABLE 64 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 20.0 Total 100.0
TABLE-US-00067 TABLE 65 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 50.0 Ethylcellulose 33.3
Glycerol Behenate (Compritol 16.7 888 Ato) Total 100.00
Example 28 Coated Granules Lot#4002-40B (Compritol in the Core and
not Cured and in the Coat and not Cured, 55% Coat)
[0258] Using a process similar to that described above in Example
17, but with using 72% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling.
TABLE-US-00068 TABLE 66 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 20.0 Total 100.0
TABLE-US-00069 TABLE 67 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 45.0 Ethylcellulose 36.7
Glycerol Behenate (Compritol 18.3 888 Ato) Total 100.00
Example 29 Coated Granules Lot#4002-40C (Compritol in the Core and
not Cured and in the Coat and not Cured, 60% Coat)
[0259] Using a process similar to that described above in Example
17, but with using 72% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling.
TABLE-US-00070 TABLE 68 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 16.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 20.0 Total 100.0
TABLE-US-00071 TABLE 69 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 40.0 Ethylcellulose 40.0
Glycerol Behenate (Compritol 20.0 888 Ato) Total 100.00
Example 30 Coated Granules Lot#4002-46 (Compritol in the Core and
Cured and in the Coat and Cured, 40% Coat)
[0260] Using a process similar to that described above in Example
17, but with using 61% of EC for dry mixing together with 10%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling. The uncoated granules were further cured by suspended them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 65.degree. C. for 30 minutes.
TABLE-US-00072 TABLE 70 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.7 Hydroxypropyl methylcellulose 26.5
(HPMC) Ethylcellulose 16.8 Glycerol behenate 10.0 Total 100.0
TABLE-US-00073 TABLE 71 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 60.0 Ethylcellulose 26.7
Glycerol Behenate (Compritol 13.3 888 Ato) Total 100.00
[0261] After the right amount of coating has been sprayed into the
granules, the coated granules were further cured by suspending them
in the fluid bed while increasing the inlet air temperature. Curing
was considered complete when the bed temperature was maintained
above 65.degree. C. for 30 minutes.
Example 31 Coated Granules Lot#4002-54 (Compritol in the Core and
not Cured and in the Coat and not Cured, 40% Coat)
[0262] Using a process similar to that described above in Example
17, but with using 62% of EC for dry mixing together with 20%
glycerol behenate with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling.
TABLE-US-00074 TABLE 72 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 26.4
(HPMC) Ethylcellulose 17.0 Glycerol behenate 10.0 Total 100.0
TABLE-US-00075 TABLE 73 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 60.0 Ethylcellulose 26.7
Glycerol Behenate (Compritol 13.3 888 Ato) Total 100.00
Example 32 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-69
[0263] Coated granules prepared as described herein above can be
formed into solid dosage form, e.g., tablet. The coated granules
can be mixed with EMCOMPRESS (dibasic calcium phosphate dihydrate),
lactose (FAST-FLO, spray-dried), COMPRITOL ATO 888 (glyceryl
behenate) in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00076 TABLE 74 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 36.9
granules (Example 17, Table 45) EMCOMPRESS 15.0 Lactose 37.1
COMPRITOL (glyceryl 10.00 behenate) Magnesium Stearate 1.0 Total
100.00
[0264] The above calculation is based on the actual rather than the
theoretical potency of the coated granules
Example 33 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-70
[0265] The coated granules can be mixed with EMCOMPRESS (dibasic
calcium phosphate dihydrate), lactose (FAST-FLO, spray-dried),
COMPRITOL ATO 888 (glyceryl behenate) in a V-blender for a period
of about 30 minutes. Magnesium stearate is then added to the blend
and mixed for additional 5 minutes. The blended mixture can then be
compressed in a rotary tablet press to form 400 mg round shaped
tablets with diameter of 3/8''. Using this process, the following
tablet was prepared:
TABLE-US-00077 TABLE 75 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 39.0
granules (Example 22, Table 55) EMCOMPRESS 15.0 Lactose 35.0
COMPRITOL (glyceryl 10.0 behenate) Magnesium Stearate 1.0 Total
100.00
[0266] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 34 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-72
[0267] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), COMPRITOL ATO 888 (glyceryl behenate), Benecel MP844
(Hypromellose) in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00078 TABLE 76 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 39.0
granules (Example 22, Table 55) Benecel MP844 10.0 (Hypromellose)
Lactose 40.0 COMPRITOL (glyceryl 10.0 behenate) Magnesium Stearate
1.0 Total 100.00
[0268] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 35 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-73
[0269] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), COMPRITOL ATO 888 (glyceryl behenate), Benecel MP844
(Hypromellose) in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00079 TABLE 77 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 36.9
granules (Example 17, Table 45) Benecel MP844 10.0 (Hypromellose)
Lactose 42.1 COMPRITOL (glyceryl 10.0 behenate) Magnesium Stearate
1.0 Total 100.00
[0270] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 36 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-87
[0271] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), COMPRITOL ATO 888 (glyceryl behenate), Benecel MP844
(Hypromellose) in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00080 TABLE 78 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 38.7
granules (Example 17, Table 45) Benecel MP844 20.0 (Hypromellose)
Lactose 30.3 COMPRITOL (glyceryl 10.0 behenate) Magnesium Stearate
1.0 Total 100.00
[0272] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 37 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-88
[0273] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), Benecel MP844 (Hypromellose) in a V-blender for a
period of about 30 minutes. Magnesium stearate is then added to the
blend and mixed for additional 5 minutes. The blended mixture can
then be compressed in a rotary tablet press to form 400 mg round
shaped tablets with diameter of 3/8''. Using this process, the
following tablet was prepared:
TABLE-US-00081 TABLE 79 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 38.7
granules (Example 17, Table 45) Benecel MP844 20.0 (Hypromellose)
Lactose 40.3 Magnesium Stearate 1.0 Total 100.00
[0274] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 38 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-89
[0275] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), ethyl cellulose NT 10, COMPRITOL (glycerol behenate)
in a V-blender for a period of about 30 minutes. Magnesium stearate
is then added to the blend and mixed for additional 5 minutes. The
blended mixture can then be compressed in a rotary tablet press to
form 400 mg round shaped tablets with diameter of 3/8''. Using this
process, the following tablet was prepared:
TABLE-US-00082 TABLE 80 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 38.7
granules (Example 17, Table 45) Ethyl Cellulose NT 10 50.3
COMPRITOL (glyceryl 10.0 behenate) Magnesium Stearate 1.0 Total
100.00
[0276] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 39 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#3766-57
[0277] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), COMPRITOL (glyceryl behenate) in a V-blender for a
period of about 30 minutes. The blended mixture can then be
compressed in a rotary tablet press to form 400 mg round shaped
tablets with diameter of 3/8''. Using this process, the following
tablet was prepared:
TABLE-US-00083 TABLE 81 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 39.0
granules (Example 21, Table 55) Lactose 51.0 COMPRITOL (glyceryl
10.0 behenate) Total 100.00
[0278] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 40 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#4002-57
[0279] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00084 TABLE 82 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 27.8
granules (Example 30, Table 71) lactose 71.2 Magnesium Stearate 1.0
Total 100.00
[0280] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 41 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#4002-60
[0281] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), Benecel MP844 (Hypromellose) in a V-blender for a
period of about 30 minutes. Magnesium stearate is then added to the
blend and mixed for additional 5 minutes. The blended mixture can
then be compressed in a rotary tablet press to form 400 mg round
shaped tablets with diameter of 3/8''. Using this process, the
following tablet was prepared:
TABLE-US-00085 TABLE 83 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 27.8
granules (Example 30, Table 71) Benecel MP844 10.0 (Hypromellose)
Lactose 61.2 Magnesium Stearate 1.0 Total 100.00
[0282] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 42 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#4002-61
[0283] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), COMPRITOL ATO 888 (glyceryl behenate), Benecel MP844
(Hypromellose) in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00086 TABLE 84 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 27.8
granules (Example 30, Table 71) Benecel MP844 10.0 (Hypromellose)
Lactose 51.2 COMPRITOL (glyceryl 10.0 behenate) Magnesium Stearate
1.0 Total 100.00
[0284] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 43 Hydromorphone HCl (32 mg) Tablet Formulations Lot
#4002-58
[0285] The coated granules can be mixed with lactose (FAST-FLO,
spray-dried), in a V-blender for a period of about 30 minutes.
Magnesium stearate is then added to the blend and mixed for
additional 5 minutes. The blended mixture can then be compressed in
a rotary tablet press to form 400 mg round shaped tablets with
diameter of 3/8''. Using this process, the following tablet was
prepared:
TABLE-US-00087 TABLE 85 Hydromorphone HCl (32 mg) Tablet
Formulations Component Amount (% w/w) Hydromorphone coated 28.0
granules (Example 31, Table 73) lactose 71.0 Magnesium Stearate 1.0
Total 100.00
[0286] The above calculation is based on the actual rather than the
theoretical potency of the coated granules.
Example 44 Coated Granules Lot 4002-73 (Carnauba Wax in Core and
Coat, No Curing)
[0287] Using a process similar to that described above in Example
17, but with using 62% of EC for dry mixing together with 10%
carnauba wax with other ingredients, the following formulation was
prepared, which differs from Example 17 in the amounts of each
component used. The wet granules were not partially dried prior to
milling.
TABLE-US-00088 TABLE 86 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.6 Hydroxypropyl methylcellulose 26.4
(HPMC) Ethylcellulose 17.0 Carnauba Wax 10.0 Total 100.0
TABLE-US-00089 TABLE 89 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 60.0 Ethylcellulose 26.7
Carnauba Wax 13.3 Total 100.00
Example 45 Coated Granules Lot 4002-76 (Gelucire 50/13 in Core and
Coat, not Cured)
[0288] Using a process similar to that described above in Example
17, but with using 64% of EC for dry mixing together with 10.1%
Gelucire 50/13 with other ingredients, the following formulation
was prepared, which differs from Example 17 in the amounts of each
component used. Before granulation, Gelucire 50/13 was first milled
and sieved through a 30 mesh screen prior to mixing with other
materials. The wet granules were not partially dried prior to
milling.
TABLE-US-00090 TABLE 90 Granules Formulations Ingredient Amount (%
w/w) Hydromorphone HCl 46.8 Hydroxypropyl methylcellulose 26.5
(HPMC) Ethylcellulose 16.6 Gelucire 50/13 10.1 Total 100.0
[0289] Before coating, Gelucire 50/13 was first milled and sieved
through a 200-mesh screen prior to adding to the ethanolic EC
solution.
TABLE-US-00091 TABLE 91 Coated Granules Formulation Ingredient
Amount (% w/w) Hydromorphone granules 60.0 Ethylcellulose 26.7
Gelucire 50/13 13.3 Total 100.00
Example 46
[0290] A number of lots of tablets including the coated granules of
the present invention were produced as shown in Table 92 below.
TABLE-US-00092 TABLE 92 Tablet Average Coated Gran. Tablet Lots
Hardness (N) 3766-06 3766-69 50 3766-73 40 3766-80 3766-87 47
3766-88A, B 55, 74 3766-89 38 3766-33 3766-57 52 3766-70 45 3766-72
40 4002-46 4002-57 80 4002-60 70-80 4002-61 48 4002-54 4002-58
80
[0291] The tablet lot numbers are indicated in the second column
and the coated granulates used (whose production were described
earlier) are indicated in the first column. The third column
provides the average tablet hardness. Details of the manufacturing
process can be found in the pertaining example sections.
[0292] Tables 93, 94 and 95 identify the tablet lot to the left and
provide dissolution information at various times for each lot. Lot
3766-57, for example, were 400 milligram tablets having a hardness
of 52 Newtons, which were round and 3/4 of an inch. These tablets
included coated granulate lot 3766-33, whose production was
described in example 22. As shown in Table 93, these tablets when
tested using the USP dissolution apparatus number 2 using 500 ml of
0.1 N HCl (normal dissolution) or 40% etahnolic solution (dose
dumping dissolution) as the dissolution medium. Simulated oral
tampering testing was conducted by crushing the tablets using
ceramic mortars and pestles. Each tablet was placed in a ceramic
mortar (13 cm outer diameter) then by using a pestle and applying
force vertically downward, the tablets are crushed by 360.degree.
C. circular motion. Each full circle motion constitutes 1 stroke.
Each table is crushed by applying 12 strokes as described above.
The crushed powder are then analyzed using USP apparatus number 2
and the dissoluation data at 30 minutes was considered. This lot
exhibited a 29% release at four hours, a 58% release at 8 hours and
a 90% release at 16 hours. As shown in Table 94, the same lot
released 51% within two hours upon exposure to ethanol. This is
compared to a 13% release under normal conditions. In this
particular instance, such a discrepancy was not considered
sucessful in terms of solvent resistance. According to Table 95,
the same tablet lot showed a release of 36% at 30 minutes after
simulated tampering as described herein.
TABLE-US-00093 TABLE 93 Hydromorphone Tablets (32 mg) Normal
Dissolution % Released in Time (hrs) Lot # 0 1 2 4 8 12 16 20 24
3766-57 0 8 13 29 58 81 90 94 96 3766-69 0 24 53 88 96 98 98 99 99
3766-70 0 8 13 30 60 80 88 91 92 3766-72 0 5 8 18 42 64 81 93 98
3766-73 0 9 21 41 67 83 94 99 102 3766-87 0 4 11 29 57 76 90 99 104
3766-88A 0 6 17 36 62 79 90 95 98 3766-88B 0 6 16 36 64 82 93 99
101 3766-89 0 3 11 54 99 102 103 103 104 4002-57 0 7 26 67 95 102
105 107 108 4002-58 0 8 28 62 86 94 97 98 100 4002-60 0 2 8 24 54
76 90 96 98 4002-61 0 2 5 17 46 72 90 101 105
TABLE-US-00094 TABLE 94 Dose Dumping Dissolution % Released in Time
(min) Normal Dissolution Lot# 0 15 30 45 60 120 release in 2 hr
3766-57 0 2 4 7 13 51 13 3766-69 0 2 6 12 16 33 53 3766-70 0 2 3 5
9 24 13 3766-72 0 1 2 3 4 14 8 3766-73 0 1 3 5 8 19 21 3766-87 0 1
2 2 4 14 11 3766-88A 0 1 2 3 5 14 17 3766-88B 0 1 2 3 5 16 16
3766-89 0 3 38 67 83 98 11 4002-57 0 3 16 46 72 96 26 4002-58 0 3
20 47 71 94 28 4002-60 0 1 3 8 14 29 8 4002-61 0 1 2 6 11 25 5
TABLE-US-00095 TABLE 95 Simulated Oral Tampering Dissolution %
Released in Time (min) Lot # 0 15 30 45 60 120 3766-57 0 24 36 44
48 57 3766-72 0 19 28 36 42 55 3766-73 0 31 63 75 84 94 3766-87 0
19 38 53 64 87 3766-88A 0 32 50 66 74 88 3766-88B 0 38 52 66 75 89
3766-89 0 29 51 65 73 88 4002-57 0 13 23 29 36 54 4002-58 0 20 34
44 52 69 4002-60 0 19 31 39 46 66 4002-61 0 13 27 40 50 67
[0293] Although the invention herein has been described with
reference to particular embodiments, it is to be understood that
these embodiments are merely illustrative of the principles and
applications of the present invention. It is therefore to be
understood that numerous modifications may be made to the
illustrative embodiments and that other arrangements may be devised
without departing from the spirit and scope of the present
invention as defined by the appended claims.
* * * * *