U.S. patent application number 15/700842 was filed with the patent office on 2018-07-05 for misuse preventative, controlled release formulation.
The applicant listed for this patent is Paladin Labs (Barbados) Inc., Paladin Labs Europe Limited, Paladin Labs Inc.. Invention is credited to Ali Bichara, Bobby-Ernst Boursiquot, Frederic Duffayet, Ali El-Jammal, Angela Ferrada, Sonia Gervais, Jean-Michel Ndong, Miloud Rahmouni, Shams Rustom, Vinayak Sant, Damon Smith, Fouzia Soulhi.
Application Number | 20180185292 15/700842 |
Document ID | / |
Family ID | 40795147 |
Filed Date | 2018-07-05 |
United States Patent
Application |
20180185292 |
Kind Code |
A1 |
Rahmouni; Miloud ; et
al. |
July 5, 2018 |
MISUSE PREVENTATIVE, CONTROLLED RELEASE FORMULATION
Abstract
Disclosed is a misuse preventative, controlled release
formulation comprising a core comprising a superabsorbent material
(for example, polycarbophil), a controlled release coat surrounding
the core, and a plurality of controlled release microparticles
having a pharmaceutically active agent (for example, an opioid
analgesic) disposed within the core, the coat, or both the core and
the coat. When crushed, either intentionally or accidentally, and
exposed to an aqueous medium, the superabsorbent material present
in the core swells to encapsulate the microparticles, which remain
substantially intact thereby retarding the release of the
pharmaceutically active agent from the formulation. Also disclosed
is a method of using the misuse preventative, controlled release
formulation to deliver a pharmaceutically active agent to a mammal,
for example, a human, in need thereof.
Inventors: |
Rahmouni; Miloud;
(Pierrefonds, CA) ; Ferrada; Angela; (Montreal,
CA) ; Soulhi; Fouzia; (Dollar-Des-Ormeaux, CA)
; Gervais; Sonia; (Laval, CA) ; Sant; Vinayak;
(Pittsburgh, PA) ; Smith; Damon; (Saint-Laurent,
CA) ; Duffayet; Frederic; (Montreal, CA) ;
Rustom; Shams; (Saint-Laurent, CA) ; El-Jammal;
Ali; (Beaconsfield, CA) ; Ndong; Jean-Michel;
(Repentigny, CA) ; Boursiquot; Bobby-Ernst;
(Laval, CA) ; Bichara; Ali; (Ste-Therese,
CA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Paladin Labs Inc.
Paladin Labs (Barbados) Inc.
Paladin Labs Europe Limited |
Montreal
Hastings
Dublin |
|
CA
BB
IE |
|
|
Family ID: |
40795147 |
Appl. No.: |
15/700842 |
Filed: |
September 11, 2017 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15004471 |
Jan 22, 2016 |
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15700842 |
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14560886 |
Dec 4, 2014 |
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15004471 |
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14195813 |
Mar 3, 2014 |
8920833 |
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14560886 |
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13919476 |
Jun 17, 2013 |
8691270 |
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14195813 |
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12336495 |
Dec 16, 2008 |
8486448 |
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13919476 |
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61014296 |
Dec 17, 2007 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/2009 20130101;
A61K 9/2077 20130101; A61K 9/28 20130101; A61K 9/209 20130101; A61P
11/00 20180101; A61K 31/485 20130101; A61K 9/286 20130101; A61K
9/2813 20130101; A61K 9/2054 20130101; A61K 9/2013 20130101; A61K
9/2031 20130101; A61P 25/20 20180101; A61P 25/22 20180101; A61K
9/14 20130101; A61K 9/282 20130101; A61K 9/50 20130101; A61K 31/135
20130101; A61K 31/137 20130101; A61K 9/2866 20130101; A61P 25/04
20180101; A61K 9/20 20130101; A61K 9/2846 20130101; A61K 31/167
20130101; A61K 9/284 20130101; A61K 9/2027 20130101; A61K 9/205
20130101; A61K 31/00 20130101; A61P 43/00 20180101; A61K 9/2081
20130101 |
International
Class: |
A61K 9/20 20060101
A61K009/20; A61K 31/485 20060101 A61K031/485; A61K 9/14 20060101
A61K009/14; A61K 31/137 20060101 A61K031/137; A61K 31/135 20060101
A61K031/135; A61K 31/00 20060101 A61K031/00; A61K 9/50 20060101
A61K009/50; A61K 9/28 20060101 A61K009/28; A61K 9/24 20060101
A61K009/24; A61K 31/167 20060101 A61K031/167 |
Claims
1. A controlled release formulation, comprising: (a) a core
comprising a superabsorbent material; (b) a controlled release coat
surrounding the core; and (c) a plurality of controlled release
microparticles having a pharmaceutically active agent disposed
therein, wherein the microparticles are disposed within the core,
the coat, or both the core and the coat, and wherein the
formulation (i) when intact and exposed to an aqueous environment,
the pharmaceutically active agent is released from the formulation
over a prolonged period of time, and (ii) when crushed to break the
controlled release coat and expose the core, and exposed to an
aqueous environment, the superabsorbent material swells to create a
hard gel that traps the microparticles, and the microparticles
provide controlled release of the pharmaceutically active
agent.
2-51. (canceled)
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/004,471, filed Jan. 22, 2016, which is a
continuation of U.S. patent application Ser. No. 14/560,886, filed
Dec. 4, 2014, which is a continuation of U.S. patent application
Ser. No. 14/195,813, filed Mar. 3, 2014, now U.S. Pat. No.
8,920,883, which is a continuation of U.S. patent application Ser.
No. 13/919,476, filed Jun. 17, 2013, now U.S. Pat. No. 8,691,270,
which is a continuation of U.S. patent application Ser. No.
12/336,495, filed Dec. 16, 2008, now U.S. Pat. No. 8,486,448, which
claims the benefit of and priority to U.S. Provisional Patent
Application No. 61/014,296, filed Dec. 17, 2007, the entire
contents of each of which are incorporated by reference herein.
FIELD OF THE INVENTION
[0002] The present invention relates generally to a controlled
release formulation for the delivery of at least one
pharmaceutically active agent, and more specifically, the invention
relates to a misuse preventative, controlled release formulation,
which maintains its controlled release properties for at least one
pharmaceutically active agent even when bisected or crushed and
exposed to various media.
BACKGROUND OF THE INVENTION
[0003] Although significant developments have been made in the
field of drug delivery, concerns remain for drugs (for example,
opioid analgesics) that are subject to abuse. Furthermore, the
numbers of legitimate patients misusing such drugs, either
deliberately or accidentally, represents a serious medical problem.
In particular, patient risk can be heightened when controlled
release formulations are used because larger amounts of the
pharmaceutically active agent typically are incorporated into these
formulations to facilitate reduced dosing-frequency. However, while
controlled release formulations may offer greater convenience and
an improved adverse event profile, serious problems can occur if
the control release mechanism is compromised in any way, for
example, by accidental chewing or grinding of, or other damage to,
the tablet, or co-ingestion with alcohol. Under these scenarios,
immediate release of the pharmaceutically active agent followed by
rapid absorption of up to a total daily dose of the pharmaceutical
agent can have potentially fatal consequences.
[0004] While a number of approaches have been tried to address the
abuse and misuse of certain drugs, no effective approach has yet
been commercialized. To date, the approaches employed include, for
example, deterrent formulations, agonist/antagonist formulations,
and prodrug formulations.
[0005] Deterrent formulations are formulations that contain a
noxious substance, such as, capsaicin, an emetic, or niacin. The
aim is to prevent deliberate abuse by inflicting a painful or
otherwise unpleasant reaction should the formulation be crushed or
otherwise damaged prior to ingestion. For example, U.S. Patent
Publication Nos. 2003/0068370, 2003/0068392 and 2007/0020188
describe incorporation of aversive agents (e.g., a bitter agent, an
irritant, or an emetic agent) into a dosage containing an opioid
analgesic. The aversive agents discourage an abuser from tampering
with the dosage form and thereafter inhaling or injecting the
tampered dosage. The potential risk of such additives to the
legitimate user who accidentally damages the tablet is not
addressed by such formulations.
[0006] Antagonist formulations contain inhibitors (antagonists) of
the therapeutic drug. When the formulation is crushed, the
inhibitors are intended to prohibit or reverse the action of the
pharmaceutically active agent thereby reducing or eliminating any
benefit for non-medical use. For example, naloxone is combined with
pentazocine (Talwin.RTM., sold by Sanofi-Winthrop) to deter
parenteral abuse of pentazocine. Naloxone is intended to block the
binding of pentazocine to opioid receptors. Similarly, naloxone is
added to a buprenorphine-containing formulation (Temgesic.RTM.,
sold by Reckitt & Colman). It is understood, however, that this
approach, can expose legitimate patients to unnecessary drugs, and
can potentially inhibit effective therapy because the inhibitors
may be released during normal passage through the gastrointestinal
tract. These formulations also assume that effective inhibition can
be achieved (i.e., that the bioavailability, pharmacokinetics and
relative affinities of the agonist and antagonist can be matched so
as to elicit effective inhibition in the intended recipient). U.S.
Pat. Nos. 3,773,955 and 3,966,940, for example, describe
formulations containing combinations of opioid agonists and
antagonists, in which the antagonist does not block the therapeutic
effect when the mixture is administered orally but blocks
analgesia, euphoria or physical dependence when administered
parenterally in a crushed form by an abuser.
[0007] Prodrug formulations rely on in vivo metabolic conversion of
the prodrug into the active drug by enzymes found, for example, in
the gastrointestinal tract. While these formulations may prevent
euphoria via intravenous or nasal administration of the drug, they
do not address the problems associated with potential intoxication
(for example, alcohol intoxication) post oral administration.
[0008] Because of such limitations with existing technologies,
there exists an ongoing need for misuse preventative, controlled
release formulations that can reduce the risk of intentional abuse
and accidental misuse of formulations containing a pharmaceutically
active agent.
SUMMARY OF THE INVENTION
[0009] The invention is based, in part, upon the discovery that it
is possible to create a drug delivery platform that permits the
controlled release of a pharmaceutically active agent disposed
within the formulation even after being sectioned (for example,
bisected) or crushed. The platform is particularly useful for the
administration of pharmaceutically active agents that are capable
of abuse and/or that have a narrow therapeutic index. Agents
capable of abuse, include, for example, analgesics (for example,
opioid analgesics), hypnotic agents, anxiolytic agents, central
nervous system (CNS) and respiratory stimulating agents, and agents
having a narrow therapeutic index.
[0010] In one aspect, the invention provides a controlled release
formulation, comprising: (a) a core comprising a superabsorbent
material (for example, polycarbophil); (b) a controlled release
coat surrounding the core; and (c) a plurality of controlled
release microparticles having a pharmaceutically active agent
disposed therein, wherein the microparticles are disposed within
the core, the coat, or both the core and the coat. As a result, the
formulations are designed to have two controlled release mechanisms
(the coat and the microparticles), which work together in an intact
formulation. However, when crushed to compromise the coating, the
microparticles remain substantially intact to control the release
of the pharmaceutically active agent and prevent dose dumping.
[0011] If exposed to an aqueous environment, at least one
pharmaceutically active agent is released from the intact
formulation over a prolonged period of time (for example, for at
least 6 hours, at least 8 hours, at least 12 hours, at least 18
hours, or at least 24 hours). In certain embodiments, at least 50%,
preferably 60%, more preferably 70%, and even more preferably 80%
of at least one pharmaceutically active agent is prevented from
being released substantially immediately (for example, within 30
minutes) from the intact formulation.
[0012] If the formulation is crushed to break the controlled
release coat and expose the core, and then exposed to an aqueous
environment, the superabsorbent material swells to create a hard,
rigid gel that traps the microparticles, which remain substantially
intact. The hard gel creates an unpleasant experience if the
crushed formulation is snorted up the nose and absorbs the nasal
secretions that would otherwise permit absorption via this route.
Furthermore, once the hard gel has formed following exposure to an
extraction media, the resulting gel cannot be pushed through a
needle of a syringe. Although the controlled release properties of
the coating may be compromised by crushing, the microparticles
still permit the controlled release of the pharmaceutically active
agent and prevent the agent from being released substantially
immediately from the formulation. In certain embodiments, at least
50%, preferably 60%, more preferably 70%, and even more preferably
80% of at least one pharmaceutically active agent is prevented from
being released substantially immediately (for example, within 30
minutes) from the formulation. As a result, the formulations of the
invention reduce or eliminate the potential for dose dumping in
water, alcohol (for example, ethanol), and other media of various
pH even if the formulations have been broken or crushed.
[0013] It is understood that in certain embodiments, the controlled
release microparticles can be disposed within the core or the coat.
In other embodiments, the controlled release microparticles (which
can be the same or different) are disposed within both the core and
the coat. It is understood that the choice of location of the
particles will depend upon the release profile desired for the
formulation. For example, if release over 8 hours is desired, then
the particles may be located within the coat. On the other hand, if
release over 24 hours is desired, then the particles may be located
within the core, or within both the core and the coat.
[0014] In certain embodiments, the core is monolithic. The
monolithic core optionally comprises microparticles disposed
therein. It is understood, however, that under certain
circumstances the core can comprise a plurality of different
release matrices, which can be, for example, in the form of a
bilayer or a multilayer that contains two, three or more layers. In
one bilayer embodiment, a first layer contains the drug containing
microparticles and a second layer contains free drug (i.e., drug
not present in or associated with microparticles). As a result,
drug is released faster from the second layer that lacks the
microparticles than from the first layer that contains the
microparticles. Furthermore, it is contemplated that, depending
upon the desired release profiles, one layer of the bilayer can
contain one set of microparticles having one set of release
kinetics and the other layer of the bilayer can contain a second,
different set of microparticles having a second, different set of
release kinetics.
[0015] In certain embodiments, the superabsorbent material is
present such that it constitutes about 10% (w/w) to about 70% (w/w)
of the core. In other embodiments, the superabsorbent material
constitutes about 30% (w/w) to about 50% (w/w) of the core. In
addition, relative to the intact formulation, in certain
embodiments, the volume of the core constitutes about 5% to about
40% of the intact formulation, about 10% to about 30% of the intact
formulation, or about 15% to about 20% of the intact formulation.
In certain embodiments, the volume of the core constitutes at least
30%, at least 20%, or at least 15% of the final volume of the
resulting intact formulation.
[0016] The controlled release microparticles comprise a controlled
release medium (for example, cross-linked high amylose starch sold
under the Tradename CONTRAMID.RTM. from Labopharm, Inc., Laval,
Canada) that controls the release of the pharmaceutically active
agent disposed therein and/or a controlled release coating or film.
The microparticles have an average diameter in the range from about
1 .mu.m to about 1000 .mu.m. The microparticles, due to their small
size and high radius of curvature, resist crushing when the
formulation is crushed, for example, with a conventional pill
crusher or between spoons or in a pestle and mortar. In one
embodiment, the microparticles have an average diameter in the
range from about of 200 .mu.m to about 900 .mu.m, or from about 300
.mu.m to about 800 .mu.m. The microparticles under certain
circumstances have an average diameter of about 700 .mu.m. In
another embodiment, the controlled release microparticles have an
average diameter in the range of from about 1 .mu.m to about 400
.mu.m, from about 5 .mu.m to about 300 .mu.m, or from about 10
.mu.m to about 200 .mu.m. The microparticles can have an average
diameter of about 100 .mu.m.
[0017] In addition, it is understood that the formulations can
contain microparticles that contain the same pharmaceutically
active agent or the same combination of two or more
pharmaceutically active agents. Alternatively, the formulations can
contain microparticles where one population of microparticles
contain one agent and another population of microparticles contain
a second, different agent.
[0018] In another aspect, the invention provides a method of
providing controlled release of a pharmaceutically active agent to
a mammal, for example, a human. The method comprises orally
administering to an individual in need of the pharmaceutically
active agent one or more of the controlled release formulations
described herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The foregoing and other objects, features and advantages of
the invention will become apparent from the following description
of preferred embodiments, as illustrated in the accompanying
drawings. Like referenced elements identify common features in the
corresponding drawings. The drawings are not necessarily to scale,
with emphasis instead being placed on illustrating the principles
of the present invention, in which:
[0020] FIGS. 1A-1F show schematic representations of exemplary
misuse preventative, controlled release formulations where
controlled release microparticles containing an agent of interest
are disposed within the coat (FIGS. 1A and 1D), the core (FIGS. 1B
and 1E), or within both the core and the coat (FIGS. 1C and 1F),
wherein, in FIGS. 1A-1C, the core is monolithic and in FIGS. 1D-1F,
the core is a bilayer;
[0021] FIG. 2 is a graph showing the in vitro dissolution profile
of Tramadol HCl from an intact, exemplary controlled release
formulation of the invention in a U.S.P. Type I Apparatus in
phosphate buffer pH 6.8;
[0022] FIG. 3 is a graph showing the in vitro dissolution profile
of Tramadol HCl from an intact, exemplary controlled release
formulation of the invention in a U.S.P. Type I Apparatus where the
solvent is water (-.quadrature.-), 20% ethanol (-.box-solid.-), 40%
ethanol (-.DELTA.-), 60% ethanol (--), 80% ethanol
(-.smallcircle.-) or 100% ethanol (-.cndot.-);
[0023] FIG. 4 is a graph showing the in vitro dissolution profile
of Tramadol HCl from an intact, exemplary controlled release
formulation of the invention in a U.S.P. Type I Apparatus as a
function of pH where the solvent is water (-.box-solid.-), buffer
at pH 1.2 (-.cndot.-), buffer at pH 3.0 (-.smallcircle.-), buffer
at pH 5.0 (--), or buffer at pH 6.8 (-4-);
[0024] FIG. 5 is a graph showing the in vitro dissolution profile
of Tramadol HCl from an intact, exemplary controlled release tablet
of the invention (-.cndot.-) or from half a tablet (a bisected
tablet) of the invention where the release values have been
normalized relative to the intact tablet (-.box-solid.-) using a
U.S.P. Type I Apparatus with phosphate buffer pH 6.8;
[0025] FIG. 6 is a photograph showing five vials, where the first
vial contains 2 mL of water and the second through the fifth vials
(inverted) contain different tablets of controlled release
formulations of the invention each of which had been crushed in a
pill crusher and exposed to 2 mL of water to produce a hard gel
that remained at the bottom of each vial even when inverted;
[0026] FIG. 7 is a photograph showing seven inverted vials each
containing crushed tablets of the invention that had been exposed
to 10 mL of (i) water at room temperature for 15 minutes with
agitation (vial 1), (ii) water at 50.degree. C. for 15 minutes with
agitation (vial 2), (iii) water at 75.degree. C. for 15 minutes
with agitation (vial 3), (iv) water at 100.degree. C. for 15
minutes with agitation (vial 4), (v) acidic media (pH 1.2) at room
temperature for 15 minutes with agitation (vial 5), (vi) basic
media (pH 7.5) at room temperature for 15 minutes with agitation
(vial 6), and (vii) 40% ethanol in water at room temperature for 15
minutes with agitation (vial 7);
[0027] FIG. 8 is a bar chart showing the effect of different
ethanol concentrations on Tramadol release from crushed tablets of
the invention (bars with light shading) or Ultram ER (bar in dark
shading) after incubation in 900 mL of extraction media for 30
minutes at 37.degree. C. in a U.S.P. Type I Apparatus;
[0028] FIG. 9 is a bar chart showing the effect of pH on Tramadol
release from crushed tablets of the invention (bars with light
shading) or Ultram ER (bar in dark shading) after incubation in 900
mL of extraction media of various pH for 30 minutes at 37.degree.
C. in a U.S.P. Type I Apparatus.
[0029] FIGS. 10A and 10B are graphs showing the mean plasma
concentration of Tramadol released from an exemplary 100 mg tablet
following single-dose administration to adult humans under fasting
conditions (FIG. 10A) or under fed conditions (FIG. 10B);
[0030] FIGS. 11A AND 11B are graphs showing the in vitro
dissolution profiles of an embodiment containing 40 mg oxycodone
HCl in a U.S.P. Type I Apparatus at 100 rpm for twelve hours from
either an intact tablet (FIG. 11A) or a crushed tablet (FIG. 11B)
in phosphate buffer pH 6.8 (-.cndot.-) or buffer containing 40%
ethanol (-.quadrature.-);
[0031] FIG. 12 is a graph showing the in vitro dissolution profiles
of an embodiment containing 40 mg oxycodone HCl in a U.S.P. Type I
Apparatus at 100 rpm for twelve hours from either an intact tablet
in phosphate buffer pH 6.8 (-.cndot.-), or a bisected tablet in
phosphate buffer pH 6.8 (-.DELTA.-);
[0032] FIG. 13 is a graph showing the in vitro dissolution profile
of a coated bilayer embodiment containing 20 mg oxycodone HCl/650
mg acetaminophen, where the release of oxycodone was measured in a
U.S.P. Type I Apparatus at 100 rpm in acid at pH 1.2 for 1 hour and
then in a phosphate buffer at pH 6.8 for 11 hours;
[0033] FIGS. 14A and 14B are graphs showing the in vitro
dissolution profiles of an embodiment containing 150 mg Tramadol
HCl in a U.S.P. Type I Apparatus at 100 rpm in phosphate buffer pH
6.8 from three different lots of intact tablets (FIG. 14A) or from
crushed tablets (FIG. 14B);
[0034] FIGS. 15A and 15B are graphs showing the in vitro
dissolution profiles of an embodiment containing 150 mg Tramadol
HCl in a U.S.P. Type I Apparatus at 100 rpm in water containing 60%
ethanol from three different lots of intact tablets (FIG. 15A) or
from crushed tablets (FIG. 15B);
[0035] FIGS. 16A and 16B are graphs showing the in vitro
dissolution profiles of an embodiment containing 200 mg Tramadol
HCl in a U.S.P. Type I Apparatus at 100 rpm in phosphate buffer pH
6.8 or water from either intact tablets (FIG. 16A) or from crushed
tablets (FIG. 16B);
[0036] FIGS. 17A and 17B are graphs showing the in vitro
dissolution profiles of an embodiment containing 200 mg Tramadol
HCl in a U.S.P. Type I Apparatus at 100 rpm in phosphate buffer pH
6.8 alone (-.cndot.-) or water containing 20% ethanol
(-.tangle-solidup.-), 40% ethanol (-.box-solid.-), or 60% ethanol
(--) either from intact tablets (FIG. 17A) or from crushed tablets
(FIG. 17B); and
[0037] FIGS. 18A and 18B are graphs showing the in vitro
dissolution profiles of an embodiment containing 30 mg hydrocodone
in a U.S.P. Type I Apparatus at 100 rpm in phosphate buffer pH 6.8
(-.cndot.-) or acid pH 1.2 (-.tangle-solidup.-) either from intact
tablets (FIG. 18A) or from crushed tablets (FIG. 18B).
DETAILED DESCRIPTION OF THE INVENTION
[0038] The invention is based, in part, upon the discovery that it
is possible to produce a controlled release platform that provides
pharmaceutical formulations less susceptible to intentional abuse
and accidental misuse than other controlled release formulations
and is free from noxious additives, active ingredient antagonists,
prodrugs, and the like. The formulations maintain their controlled
release properties when sectioned (for example, bisected) as can
happen, for example, when a subject breaks a tablet in half to make
it easier to swallow. Furthermore, even when crushed, the
formulations of the invention prevent dose dumping because the
microparticles contained within the formulation remain
substantially intact and retain their controlled release
properties.
[0039] The invention provides a controlled release formulation,
comprising: (a) a core comprising a superabsorbent material (for
example, polycarbophil); (b) a controlled release coat surrounding
the core; and (c) a plurality of controlled release microparticles
having a pharmaceutically active agent disposed therein, wherein
the microparticles are disposed within the core, the coat, or both
the core and the coat. The formulations have two controlled release
mechanisms (the coat and the microparticles), which work together
in an intact formulation. However, even when crushed to compromise
the coating, the microparticles remain substantially intact to
control the release of the pharmaceutically active agent and
prevent dose dumping. As used herein, the term "dose dumping" is
understood to mean an uncontrolled release of a pharmaceutically
active agent where at least 80% of the pharmaceutically active
agent in the formulation is released within 30 minutes (a
specification that can be used to characterize a formulation as an
immediate release formulation).
[0040] FIG. 1 shows certain embodiments (FIGS. 1A-1F) of the
formulation of the invention. Each formulation 10 contains a core
20 and a coat 30. In FIGS. 1A and 1D, formulation 10 contains
controlled release microparticles 40 located within coat 30. In
FIGS. 1B and 1E, formulation 10 contains controlled release
microparticles 40 located within core 20. In FIGS. 1C and 1F,
formulation 10 contains controlled release microparticles 40
located within both core 20 and coat 30. In FIGS. 1A-1C, the core
is monolithic. In FIGS. 1D-1F, the core is shown to be a bilayer
having a first layer 50 and a second, different layer 60. It is
understood, however, that the core can comprise a multilayer having
two or more (for example, three, four or more) layers of different
materials. In each of the embodiments shown in FIG. 1, the
microparticles control the release of the active ingredient
irrespective of whether the tablet is intact or compromised (for
example, by bisection or crushing).
[0041] Under normal use, coat 30 protects core 20 from exposure to
the solvent thereby preventing the swelling of the superabsorbent
material in the core. As a result, the pharmaceutically active
agent is released steadily from the formulation. If drug containing
controlled release microparticles are located within coat 30, then
the drug is released from coat 30 as the solvent permeates the
coat. If drug containing controlled release microparticles are
located within both coat 30 and core 20, then the drug initially is
released from the microparticles in the coat. Over time, as the
solvent gradually permeates through the coat and then accesses core
20, the drug is released from the microparticles located within the
core. The formulations are designed so that coat 30 maintains
sufficient integrity (for example, the coat acts like a rigid or
semi-rigid net) such that the superabsorbent material in core 20 is
prevented from swelling and disrupting the integrity of the
tablet.
[0042] It is contemplated that the compositions described herein
can be used for the delivery of one or more (for example, two,
three, four or more) pharmaceutically active agents. For example,
the microparticles disposed in the core can contain a first
pharmaceutically active agent and microparticles disposed in the
coat can contain a second, different pharmaceutically active agent.
Alternatively, the microparticles disposed in the core and/or the
coat can contain two or more different pharmaceutically active
agents. Furthermore, it is contemplated that the core and/or the
coat can comprise two or more different populations of microspheres
where each population contains the same or a different
pharmaceutically active agent. It is understood that the excipients
present in each layer may vary. Furthermore, depending upon the
release kinetics desired, a pharmaceutically active agent can be
disposed in the core and/or the coat but not present within the
microparticles. For example, a first pharmaceutically active agent
disposed within microparticles can be present in the coat but the
same or different pharmaceutically active agent not present in
microparticles can be present in the core. Conversely, a first
pharmaceutically active agent not present in microparticles can be
present in coat but the same or different pharmaceutically active
agent disposed in microparticles can be present in the core.
[0043] In certain embodiments, the core is monolithic (see, FIGS.
1A-1C). The monolithic core optionally can comprise microparticles
disposed therein. It is understood, however, that under certain
circumstances the core can comprise a plurality of different
release matrices, which can be, for example, in the form of a
bilayer or a multilayer that contains two, three or more layers
(see, FIGS. 1D-1F). One of the layers can act can as an immediate
release layer and another layer can act as a controlled release
layer. Alternatively, at least two of the layers can have
controlled release properties. In one embodiment, one layer can
release one pharmaceutically active agent and another layer can
release a different pharmaceutically active agent, which can be
released at the same or at different rates. In another embodiment,
one layer can release one pharmaceutically active agent at one rate
and another layer can release the same pharmaceutically active
agent at a different rate (i.e., faster or slower than the first
layer). In one bilayer embodiment, a first layer contains drug
containing microparticles and a second layer contains free drug
(i.e., not contained within in or associated with microparticles).
As a result, the drug is released faster from the second layer that
lacks the microparticles than from the first layer that contains
the microparticles. Furthermore, it is contemplated that, depending
upon the desired release profiles, one layer of the bilayer can
contain one population of microparticles having one set of first
release kinetics and the other layer of the bilayer can contain a
second, different population of microparticles having a second,
different set of release kinetics.
[0044] In the case of an intact formulation, when exposed to an
aqueous environment (for example, a solution containing at least
10% (v/v) water), at least one pharmaceutically active agent is
released from the intact formulation over a prolonged period of
time (for example, for at least 8 hours, at least 12 hours, at
least 18 hours, or at least 24 hours). In certain embodiments, at
least 50%, preferably 60%, more preferably 70%, and even more
preferably 80% of at least one pharmaceutically active agent is
prevented from being released substantially immediately (for
example, within 30 minutes) from the formulation when exposed to an
extraction medium, for example, water, aqueous solutions ranging in
pH from 1.2 to 6.8, and different ethanolic media (for example,
water containing 20% ethanol, 40% ethanol, 60% ethanol, or 80%
ethanol and 100% ethanol). These features are shown, for example,
in FIGS. 2-4, which are discussed in more detail in Example 2.
[0045] When the formulation is bisected, for example, axially
bisected, as can happen when a patient breaks a tablet in half to
make it easier to swallow, the controlled release coating becomes
compromised. However, the combination of the residual coat
surrounding the core, partial swelling of the core and the
controlled release properties of the microparticles permit the
formulations to have a release profile of the pharmaceutically
active agent substantially the same as the intact tablet.
Furthermore, even when bisected, the formulations of the invention
permit the release of the pharmaceutically active agent over at
least 12 hours, at least 18 hours, or over at least 24 hours. In
certain embodiments, at least 50%, preferably 60%, more preferably
70%, and even more preferably 80% of at least one pharmaceutically
active agent is prevented from being released substantially
immediately (for example, within 30 minutes) from the formulation
when exposed to an extraction medium, for example, water, aqueous
solutions ranging in pH from 1.2 to 6.8, and different ethanolic
media (for example, water containing 20% ethanol, 40% ethanol, 60%
ethanol, or 80% ethanol and 100% ethanol). These features are
shown, for example, in FIG. 5 and in FIG. 12.
[0046] When the formulation is crushed (for example, with a
commercially available pill crusher to break formulation into at
least 10 particles or more) to break the controlled release coat
and expose the core, and then exposed to an aqueous environment,
the superabsorbent material swells rapidly (for example, within
about 30 seconds) to create a hard gel that traps the
microparticles. Based in part upon their small size (high radius of
curvature), the microparticles resist the crushing process and
remain substantially intact. The hard gel provides an unpleasant
experience if the crushed formulation is snorted up a nostril and
gel formation occurs within the nostril. This process has the
advantage that the nasal secretions needed for absorption of the
active ingredient into the blood-stream are absorbed by the
superabsorbent material preventing intoxication via this route.
Similarly, if the formulation is crushed and exposed to an aqueous
environment to extract the pharmaceutically active agent, the
superabsorbant material in the core can absorb the extraction
medium leaving little or no extraction medium to administer (see,
FIGS. 6 and 7, which are discussed in Example 4). In addition, the
hard gel that is formed during this process is difficult to draw or
push though a syringe needle.
[0047] Although the controlled release properties of the coating
are compromised by crushing, the microparticles still permit the
controlled release of the pharmaceutically active agent and prevent
the agent from being released substantially immediately from the
formulation (i.e., the microparticles provide controlled release of
the pharmaceutically active agent). For example, at least 50%,
preferably 60%, more preferably 70%, and even more preferably 80%
of at least one pharmaceutically active agent is prevented from
being released substantially immediately (for example, within 30
minutes) from the formulation (see, FIG. 8, which is discussed in
Example 4). As a result, the formulations of the invention prevent
dose dumping in water, 20% ethanol, 40% ethanol, and 60% ethanol
even if the formulations have been broken or crushed.
[0048] In certain embodiments, the formulation of the invention,
when crushed and exposed to 900 mL of water in a U.S.P. Type I
Apparatus with stirring at 100 rpm for 30 minutes at 37.degree. C.,
less than about 50%, less than about 45%, less than about 40%, less
than about 35%, less than about 30%, less than about 25%, or less
than about 20% by weight of at least one pharmaceutically active
agent originally present in the formulation before it was crushed
broken is released into the water. In certain other embodiments,
when the formulation of the invention is crushed and exposed to 900
mL of an aqueous solution containing 60% (v/v) ethanol in a U.S.P.
Type I Apparatus with stirring at 100 rpm for 30 minutes at
37.degree. C., less than about 50%, less than about 45%, less than
about 40%, less than about 35%, less than about 30%, less than
about 25%, or less than about 20% by weight of at least one
pharmaceutically active agent originally present in the formulation
before it was broken is released into the aqueous solution.
[0049] Each of the components of the formulation of the invention
are discussed in the following sections.
[0050] A. Considerations for the Core
[0051] The core comprises a superabsorbent material, which
constitutes an important feature of the invention. The term
"superabsorbent material," as used herein is understood to mean any
material that absorbs solvent, for example, 1 gram of material
absorbs at least 30 mL, more preferably 50 mL of solvent, which,
upon absorption of the solvent, swells to produce a hydrated gel
(hydrogel). In general, useful superabsorbent materials, when
exposed to an aqueous medium (for example, water) absorb in excess
of 10-15 times, such as at least greater than 30 times, more
preferably 50 times, of water based on its own weight. In certain
embodiments, the superabsorbent material is a polymer.
[0052] Superabsorbent materials can be manufactured from
polysaccharide derivatives or cross-linked polyelectrolytes.
Polysaccharide superabsorbents include, but are not limited to, a
starch graft copolymer, a crosslinked carboxymethylcellulose
derivative, a cross-linked hydroxypropyl distarch phosphate, a
hydrolyzed starch-acrylonitrile graft copolymer and a neutralized
starch-acrylic acid graft copolymer. Cross-linked polyelectrolytes
can contain functional groups such as carboxyl, sulfonate,
sulphate, sulfite, phosphate, amine, imine, amide, quaternary
ammonium or a mixture thereof. Examples of polyelectrolyte polymers
include, but are not limited to, salts or partial salts of
polyacrylic acid, polyacrylamido methylpropane sulfonic acid,
polyvinyl acetic acid, polyvinyl phosphonic acid, polyvinyl
sulfonic acid, an isobutylene-maleic anhydride copolymer,
carboxymethyl cellulose, alginic acid, carrageenan, polyaspartic
acid, polyglutamic acid, polyvinyl amine, polydiallyl dimethyl
ammonium hydroxide, polyacrylamidopropyl trimethyl ammonium
hydroxide, polyamino propanol vinyl ether, polyallylamine,
chitosan, polylysine, polyglutamine and copolymers or mixtures
thereof.
[0053] Exemplary superabsorbent materials can include a polymer
selected from the group consisting of polycarbophil,
polycarbophilic calcium, polymethacrylic acid, polyacrylic acid,
and mixtures thereof. Polycarbophil is a superabsorbent polymer is
capable of absorbing and retaining large quantities of water.
Polycarbophil is a high molecular weight acrylic acid polymer
cross-linked with divinyl glycol, and is sold under the tradename,
NOVEON.RTM. AA-1, by Lubrizol Corporation Ohio, USA. It is
understood that 1 gram of polycarbophil can absorb about 62 grams
of water. Polycarbophil is stable and does not undergo hydrolysis
or oxidation under normal conditions. Calcium salts of
polycarbophil (polycarbophilic calcium) can be used and are
available commercially under the tradename NOVEON.RTM. CA-1 or CA-2
from Lubrizol Corporation Ohio, USA. Other exemplary superabsorbent
materials include, for example, Carbopol.RTM. 71G, Carbopol.RTM.
971P, Carbopol.RTM. 974 available from Lubrizol Corporation, Ohio,
USA.
[0054] The superabsorbent material provides two functions. First,
when the formulation containing the superabsorbent material (for
example, polycarbophil) is crushed and combined with solvent (for
example, water) for parenteral injection, the superabsorbent
material rapidly absorbs the water, swells and forms a hard gel
thus preventing injection. In addition, depending upon the amount
of solvent added, all of the solvent may be absorbed leaving no
residual solvent that can be administered. Second, if the
formulation is crushed and snorted into a nostril the
superabsorbent material absorbs the liquid in the nostril causing
the superabsorbent material to swell. Not only does the swelling
cause discomfort but also prevents the drug disposed within the
formulation from being rapidly released (for example, within less
than 30 minutes).
[0055] In general, the proportion of the superabsorbent material in
the core varies from about 10% (w/w) to about 70% (w/w) of the
core, more preferably from about 30% (w/w) to about 50% (w/w) of
the core. Furthermore, the superabsorbent material in the core
varies from about 2% (w/w) to about 20% (w/w) of the final intact
formulation, more preferably from about 4% to about 14% of the
final intact formulation, more preferably from about 6% to about
12% of the final intact formulation.
[0056] In addition, relative to the intact formulation, the volume
of the core constitutes from about 5% to about 40% of the intact
formulation, from about 10% to about 30% of the intact formulation,
or from about 15% to about 20% of the intact formulation. In
certain embodiments, the volume of the core constitutes at least
30%, at least 20%, or at least 15% of the final volume of the
resulting intact formulation.
[0057] In addition to the superabsorbent material, the core can
comprise other excipients and manufacturing aids including, for
example, one or more of granulation aids (for example, xanthan gum,
polyethylene oxide, polyvinylpyrollidone, cellulose and sucrose
derivatives, and mixtures thereof), a lubricant (for example,
magnesium stearyl fumarate, magnesium stearate, and stearic acid),
a glidant (for example, colloidal silicon dioxide and talc), a dye
(for example, iron oxide), and a filler (for example,
microcrystalline starch).
[0058] In addition, the core can comprise controlled release
microparticles containing a pharmaceutically active agent of
interest. Compositions of exemplary controlled release
microparticles and methods for their manufacture are described in
Section C below.
[0059] In certain embodiments, the core is monolithic, and
optionally comprises microparticles disposed therein. It is
understood, however, that under certain circumstances the core can
comprise a plurality of different release matrices, which can be,
for example, in the form of a bilayer or a multilayer that contains
two, three or more layers. One of the layers can act can as an
immediate release layer and another layer can act as a controlled
release layer. Alternatively, at least two of the layers can have
controlled release properties. In one embodiment, one layer can
release one pharmaceutically active agent and another layer can
release a different pharmaceutically active agent, which can be
released at the same or at different rates. In another embodiment,
one layer can release one pharmaceutically active agent at one rate
and another layer can release the same pharmaceutically active
agent at a different rate (i.e., faster or slower than the first
layer).
[0060] B. Considerations for the Coat
[0061] The coat, when present, performs an important function in
the operation of the formulation of the invention. The coat
provides a hard outer shell that (i) resists damage by crushing or
chewing, (ii) resists the release of drug as the pH of the
extraction media varies (for example, when the formulations are
combined with conventional carbonated beverages), (iii) resists the
release of drug in the presence of alcohol in the extraction media
even at levels that exceed the alcohol content of alcoholic
beverages, and (iv) permits permeation by solvent to permit the
release of drug disposed within microparticles located in the core
and/or the coat. Under normal use, the coat still provides a rigid
net-like structure that encapsulates the core and prevents the
superabsorbent material in the core from swelling.
[0062] In certain embodiments, the coat comprises a controlled
release agent. Alternatively, or in addition, the coat is a
controlled release coating. Exemplary controlled release agents and
coatings can be selected from the group consisting of acetate
succinate, a polyvinyl derivative (for example, polyvinyl alcohol,
polyvinyl acetate, polyvinyl acetate phthalate, a copolymer of
vinyl acetate and vinyl pyrrolidone, a copolymer of vinyl acetate
and crotonic acid, polyvinylpyrollidone), polyethylene oxide,
polyacrylic acid, polysaccharides (for example, modified starch,
cross-linked high amylose starch, hydroxypropyl starch,
hydroxypropyl methylcellulose phthalate, cellulose and cellulose
derivatives (for example, microcrystalline cellulose,
carboxymethylethyl cellulose, cellulose acetate, methylcellulose,
ethylcellulose, hydroxypropyl cellulose, hydroxypropylmethyl
cellulose, cellulose phthalate, cellulose acetate, cellulose
acetate phthalate, cellulose acetate propionate, cellulose-acetate
succinate, cellulose acetate butyrate, cellulose-acetate
trimellitate)), poloxamer, povidone, alginic acid, sodium alginate,
polyethylene glycol, polyethylene glycol alginate, gums (for
example, xanthan gum), polymethacrylates (including, for example, a
copolymer of methacrylic acid and methyl-methacrylate, and a
copolymer of methacrylic acid and ethyl acrylate), a copolymer of
methacrylic acid and ethyl acrylate, a copolymer of polymethyl
vinyl ether and malonic acid anhydride, a copolymer of polymethyl
vinyl ether and malonic acid or the ethyl-, isopropyl-,
n-butylesters thereof, zein, and mixtures of the foregoing.
[0063] Further examples of controlled release film-coating polymers
include, but are not limited to, methylcellulose, ethylcellulose
(for example, Aquacoat.RTM. type from FMC Corp.),
methylhydroxyethylcellulose, methylhydroxypropylcellulose (for
example, Pharmacoat.RTM. type from Shin Etsu Corp.),
ethylhydroxyethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, carboxymethylcellulose or
methylcarboxymethylcellulose, acrylic polymers, polyvinylacetates,
polyvinyl chlorides, polymethylmetacrylates or a terpolymer of
vinylchloride, vinylalcohol and vinylacetate,
hydroxypropylmethylcellulose phthalate (for example, HP type from
Shin Etsu), hydroxypropylmethylcellulose acetate succinate (for
example, Aqoat from Shin Etsu), cellulose acetate phthalate (for
example, Aquacoat CPD from FMC Corp. or C-A-P NF from Eastman
Chemical), polyvinyl acetate phthalate (for example, Sureteric from
Colorcon), carboxymethylethylcellulose, and co-polymerized
methacrylic acid/methacrylic acid methyl esters (for example,
Eudragit from Degussa/Evonik Industries or Kollicoat from BASF or
Acryl-Eze from Colorcon or Eastacryl from Eastman Chemical).
[0064] In one embodiment, Kollidon.RTM. SR (a powder consisting of
polyvinyl acetate (8 parts, w/w) and polyvinyl pyrrolidone (2
parts, w/w)) is used in combination with xanthan gum. Kollidon.RTM.
SR is available from BASF, ON, Canada. In another embodiment, the
coat can be, for example, Eudragit.RTM. L30D 55, available from
Degussa/Evonik Industries, N.J., USA. Furthermore, it is understood
that, depending upon the release kinetics desired, the same
controlled release agents and coatings can be disposed within or
can coat the microparticles described below in Section C.
[0065] In addition, the coat can comprise one or more of a
viscosity increasing agent (for example, xanthan gum, polyethylene
oxide, polyvinylpyrollidone, cellulose and sucrose derivatives), a
lubricant (for example, sodium stearyl fumarate, magnesium stearate
and stearic acid), a glidant (for example, colloidal silicon
dioxide and talc), and a dye (for example, iron oxide).
[0066] In some embodiments, the coat may comprise a plasticizer.
Examples of plasticizers include, but are not limited to, cetanol,
triacetin, citric acid esters, phthalic acid esters, dibutyl
succinate, acetylated monoglyceride, acetyltributyl, acetyltributyl
citrate, acetyltriethyl citrate, benzyl benzoate, calcium stearate,
castor oil, cetanol, chlorebutanol, colloidal silica dioxide,
dibutyl phthalate, dibutyl sebacate, diethyl oxalate, diethyl
malate, diethyl maleate, diethyl malonate, diethyl fumarate,
diethyl phthalate, diethyl sebacate, diethyl succinate,
dimethylphthalate, dioctyl phthalate, glycerin,
glyceroltributyrate, glyceroltriacetate, glyceryl behanate,
glyceryl monostearate, hydrogenated vegetable oil, lecithin,
leucine, magnesium silicate, magnesium stearate, polyethylene
glycol, propylene, glycol, polysorbate, silicone, stearic acid,
talc, titanium dioxide, triacetin, tributyl citrate, triethyl
citrate, zinc stearate, PEG (polyethylene glycol), and the
like.
[0067] In one embodiment, the coat contains Kollidon.RTM. SR and
xanthan gum as release controlling agents, colloidal silicon
dioxide as a glidant, and sodium stearyl fumarate as a lubricant.
Incorporation of Kollidon.RTM. SR and xanthan gum into the coat
helps provide a controlled-release of the pharmaceutically active
agent (for example, tramadol HCl), and significantly increases the
mechanical strength of the resulting formulations making them
harder to crush.
[0068] In addition, the coat can comprise controlled release
microparticles containing a pharmaceutically active agent of
interest. Compositions of exemplary controlled release
microparticles and methods for their manufacture are described in
the following section.
[0069] C. Considerations for the Controlled Release
Microparticles
[0070] As shown in FIG. 1, the formulations of the invention
comprises controlled release microparticles disposed within the
coat (FIGS. 1A and 1D), the core (FIGS. 1B and 1E), or within both
the core and the coat (FIGS. 1C and 1F). The controlled release
microparticles contain pharmaceutically active agent and facilitate
the controlled release of the pharmaceutically active agent
disposed therein. Depending upon the configuration chosen, the
formulations can release the pharmaceutically active agent over a
prolonged period of time, for example, at least 6 hours, at least 8
hours, at least 12 hours, at least 18 hours, or at least 24
hours.
[0071] Although the controlled release particles may take a variety
of forms, they have a number of features in common, which include
(i) they have controlled release properties and (ii) they are of a
size that makes them hard to crush even when the formulations are
crushed with a conventional pill crusher. The microparticles may
have a core and a coat, where either or both provide controlled
release properties.
[0072] The core of the microparticles can comprise the
pharmaceutically active agent and a variety of excipients, which
include, for example, one or more of, a spheronizing agent, a
plasticizer, and a controlled release agent. Exemplary spheronizing
agents include, for example, microcrystalline cellulose, ethyl
cellulose, low substituted hydroxypropylcellulose and dicalcium
phosphate dihydate. Microcrystalline cellulose is preferred and is
available commercially under the tradename Avicel.RTM. PH101 from
FMC BioPolymer, DE, USA. Microcrystalline cellulose forms a plastic
and cohesive mass upon wetting, which is desirable for the
successful production of spherical granules. Microcrystalline
cellulose is considered to aid the spheronization process by
absorbing water like a molecular sponge and helps in the binding
and lubrication of the moistened powder mass during extrusion.
During the spheronization process, moisture trapped in the
microcrystalline cellulose microfibrils adds plasticity to the
extrudate and helps convert short round extrudates obtained by
extrusion into spherical pellets. Different grades of
microcrystalline cellulose are commercially available, and a
preferred grade suitable for extrusion-spheronization is
Avicel.RTM. PH 101, because of its small particle size, low packing
density and high water retentive capacity.
[0073] In addition, the core of the microparticles can contain a
plasticizer. Exemplary plasticizers include, for example, Plasacryl
available from IMTech, Pa., USA, and triethyl citrate available
from Morflex, N.C., USA.
[0074] In addition, the core of the microparticles optionally can
contain a controlled release agent that controls the release of the
pharmaceutically active agent. Exemplary controlled release agents
can be selected from the group consisting of starch, starch
derivatives, cellulose derivatives, xanthan gum, polyethylene
glycol, polyvinyl acetate, polyvinyl alcohol, and mixtures thereof.
In a preferred embodiment, the controlled release excipient
includes a starch derivative that is a cross-linked high amylose
starch, which provides the controlled release of the
pharmaceutically active agent for at least 12 hours, for at least
18 hours, or for at least 24 hours. The cross-linked high amylose
starch can be cross-linked with phosphorus oxychloride and/or can
contain hydroxypropyl side chains. In certain embodiments, a
suitable controlled release agent is commercially available from
Labopharm, Inc., Laval, Canada, under the trademark CONTRAMID.RTM..
The synthesis of the CONTRAMID.RTM. excipient is described in U.S.
Pat. No. 6,607,748.
[0075] The core of the microparticles containing a pharmaceutically
active agent can be prepared by a variety of methods, including,
for example, wet granulation and extrusion-spheronization. During
wet granulation, microparticles are prepared using, for example, a
fluid bed rotor granulator. The wet granulation process comprises,
for example, (i) wetting the powder to form wet granules; (ii)
exposing the wet granules to tumbling or spheronization, and (iii)
drying the product of step (ii). Alternatively, the pellets can be
produced by extrusion-spheronization, which has the advantage of
being highly reproducible, easy to scale up, cost effective, and
produces substantially perfect spherical microparticles.
Extrusion-spheronization comprises, for example, (i) wetting the
powder blend with an aqueous or organic solution generally
containing a binder to form a wet homogeneous mass suitable for wet
extrusion, (ii) extruding the wet mass to form cylindrical
extrudates of uniform shape and size, and (iii) spheronizing the
wet extrudates using a spheronizer, where, for example, a fast
spinning disc, breaks the extrudates into smaller microparticles
and rounds them to form spheres.
[0076] The cores of the microparticles can be coated with a
controlled-release coating that is sufficiently flexible to be
deformed under compression during tablet formation without
undergoing fracture. Suitable controlled release agents are
described in the previous section. In one embodiment, the
controlled release coating comprises polymethacrylate (e.g.,
Eudragit.RTM. RS, available from Degussa/Evonik Industries, N.J.,
USA). Eudragit.RTM. RS30D grade, which is particularly useful is an
aqueous dispersion (30% w/w) of a polymeric mixture of ethyl
acrylate, methyl methacrylate, and trimethylammonioethyl
methacrylate at a ratio of 1:2:0.1 (w/w). The Eudragit.RTM. RS
grade is designed to form water-insoluble film coats for sustained
release formulations. The Eudragit.RTM. RS grade forms a highly
flexible film coat with low permeability. Another useful coating
material includes Eudagrit.RTM. L30D 55, available from
Degussa/Evonik Industries, N.J., USA. Another controlled release
coating comprises ethyl cellulose sold under the tradename
Surelease.RTM.. Another controlled release coating includes
Kollicoat SR, available from BASF Fine Chemicals. In one approach,
the core of the microparticles is coated using a fluid bed coater
equipped with a bottom spray.
[0077] The resulting particles, depending upon their composition
and method of fabrication have an average diameter in the range of
from about 1 .mu.m to about 1000 .mu.m. In certain embodiments, the
microparticles have an average diameter of from about of 200 .mu.m
to about 900 .mu.m, or from about 300 .mu.m to about 800 .mu.m. In
certain embodiments, the resulting microparticles have an average
diameter of about 700 .mu.m. In certain other embodiments the
microparticles have an average diameter of from about 1 .mu.m to
about 400 .mu.m, from about of 5 .mu.m to about 300 .mu.m, or from
about 10 .mu.m to about 200 .mu.m. In certain embodiments, the
resulting microparticles have an average diameter of about 100
.mu.m.
[0078] D. Pharmaceutically Active Agents
[0079] It is understood that the compositions described herein can
be used for the delivery of one or more pharmaceutically active
agents. In certain embodiments, the controlled release
microparticles can contain one or more pharmaceutically active
agents. In addition, it is understood that the formulations of the
invention can contain a number of different microparticles, with
one population of microparticles containing one pharmaceutically
active agent and another population of microparticles containing a
second, different pharmaceutically active agent.
[0080] Many pharmaceutically active agents can benefit from being
delivered using the formulations described herein. The Controlled
Substances Act (CSA), Title II of the Comprehensive Drug Abuse
Prevention and Control Act of 1970, places all substances that are
regulated under existing Federal Law into one of five schedules
based upon the substance's medicinal value, harmfulness, and
potential for abuse or addiction. The formulations of the invention
are preferably used to deliver those drugs classified as Schedule
II, III, IV and V drugs. Similarly, although any drug in which
there is a benefit in having controlled release of the drug can be
incorporated into formulations of the invention, the formulations
described herein are particularly useful in the delivery of, for
example, CNS and respiratory stimulant agents, analgesics (for
example, opioid analgesics), hypnotic agents, anxiolytic agents,
and agents with a narrow therapeutic index. For purposes of this
invention, pharmaceutically active agents are intended to encompass
salts, esters, and the prodrugs of the pharmaceutically active
agents.
[0081] Exemplary opioid analgesics include, for example,
alfentanil, buprenorphine, butorphanol, carefentanil, codeine,
dezocine, diacetylmorphine, dihydrocodeine, dihydromorphine,
diprenorphine, etorphine, fentanyl, hydrocodone, hydromorphone,
.beta.-hydroxy-3-methylfentanyl, levo .alpha.-acetylmethadol,
levorphanol, lofentanil, meperidine, methadone, morphine,
nalbuphine, oxycodone, oxymorphone, pentazocine, pethidine,
propoxyphene, remifentanil, sufentanil, tilidine, tramadol
hydrochloride, or a mixture thereof.
[0082] Exemplary hypnotics include, for example, benzodiazepines
and non-benzodiazepines. Exemplary benzodiazepines include, but are
not limited to, alprazolam, diazepam, flurazepam, loprazolam
mexazolam, nitrazepam, and the like. Exemplary non-benzodiazepines
include, but are not limited to, barbiturates (for example,
butobarbitone, phenobarbitone, or amylobarbitone) chlormethiazole,
eszopiclone, ramelteon, zaleplon, zopiclone, zolpidem, and the
like.
[0083] Exemplary anxiolytic agents include, but are not limited to,
amphetamine, buspirone, barbiturates, benzodiazepines (for example,
alprazolan, bromazepam, brotizolam, camazepam, chlordiazepoxide,
clobazam, clonazepam, desalkylflurazepam, diazepam, flunitrazepam,
flurazepam, lorazepam, lometazepam, medazepam, metaclazepam,
midazolam, nitrazepam, nordazepam, oxazepam, pentylenetetrazole,
prazepam, temazepam, tetrazepam, and triazolam) and the like.
[0084] Exemplary CNS and respiratory stimulatory agents include,
but are not limited to xanthines (for example, caffeine and
theophylline), amphetamines (for example, amphetamine,
benzphetamine hydrochloride, dextroamphetamine, dextroamphetamine
sulfate, levamphetamine, levamphetamine hydrochloride,
methamphetamine, and methamphetamine hydrochloride), and
miscellaneous stimulants such as methylphenidate, methylphenidate
hydrochloride, modafinil, pemoline, sibutramine, and sibutramine
hydrochloride.
[0085] Pharmaceutically active agents with a narrow therapeutic
index include, for example, amiodarone, amphotericin, cabamazepine,
clozapine, digoxin, disopyramide, lithium carbonate, minoxidil,
phenytoin, primidone, procainamide, quinidine, theophylline,
valproic acid, and warfarin.
[0086] It will be appreciated that the amount of the
pharmaceutically active agent present in the abuse-resistant
formulation depends upon the therapeutic dose required in
conventional tablets. In generally, each pharmaceutically active
agent is present in an amount ranging from about 0.5 mg to about
900 mg by weight, from about 1 mg to about 700 mg by weight, from
about 1 mg to about 600 mg by weight, from about 1 mg to about 500
mg, from about 1 mg to about 400 mg, from about 1 mg to about 300
mg, from about 1 mg to about 200 mg, and from about 10 mg to about
200 mg. It is understood, however, that the actual dosage will
depend upon the particular pharmaceutically active ingredient and
its proposed use.
[0087] The invention also provides a solid dosage form for the
controlled release of a pharmaceutically active agent disposed
therein. The solid dosage form comprises an admixture of a
superabsorbent material (for example, polycarbophil) and a
plurality of controlled release microparticles having a
pharmaceutically active agent disposed therein. When the solid
dosage form is exposed intact to an aqueous environment, the
pharmaceutically active agent is released from the solid dosage
form over a prolonged period of time. However, when the solid
dosage form is crushed to expose the interior of the core and
exposed to an aqueous environment, the superabsorbent material
swells to create a hard gel that traps the microparticles, and the
microparticles provide controlled release of the pharmaceutically
active agent. The solid dosage form can be coated or uncoated.
Accordingly, it is understood that the features and components of
the coated formulations described hereinabove are also applicable
to the solid dosage form.
[0088] It is understood that the intact compositions described
herein can be produced using techniques known to those in a
formulary arts. An exemplary protocol for producing controlled
release tablets is described in Example 1. It is understood,
however, that other approaches can be used to make formulations of
the invention. The formulations of the invention preferably have a
hardness in the range of from about 100 N to about 500 N, or from
about 150 N to about 400N, or from about 200 N to about 400N, or
from about 300 N to about 400 N, with a target hardness of at least
200 N. Furthermore, the formulations of the invention may take the
form of capsules, caplets, tablets, or pills.
[0089] The formulations of the invention can be used to administer
a pharmaceutically active agent to a mammal, for example, a human,
in need of the pharmaceutically active agent (for example, an
opioid analgesic for pain management). It is understood that the
exact dosage will vary depending on the symptoms, age, body weight,
severity of the disease to be treated and can be optimized through
routine experimentation known to those of skill in the art.
EXAMPLES
[0090] Practice of the invention will be more fully understood from
the foregoing examples, which are presented herein for illustrative
purposes only, and should not be construed as limiting the
invention in any way.
Example 1--Preparation of Exemplary Tramadol Containing Controlled
Release Formulation
[0091] This Example describes an exemplary misuse preventative
tablet and how it can be made. The formulation contains tramadol,
an opioid drug used for the treatment of moderate to moderately
severe pain, which is capable of being abused and for which over
exposure via misuse can lead to harmful side effects. The misuse
preventative tablet described in this Example contains 100 mg of
tramadol HCl which, as can be seen from Example 2, is released from
the intact tablets over 24 hours The formulation of the complete
tablet is set forth in Table 1, and the manufacture of each of the
components for the formulation appear in the following sections of
this Example.
TABLE-US-00001 TABLE 1 Mg/Tablet Component Core blend Coat blend
Tramadol HCl 25.0 75.0 Avicel PH 101 30.6 30.0 Contramid 0.7 2.1
Polycarbophil (Noveon AA-1) 62.9 -- Xanthan gum 20.6 241.6 Kollidon
SR -- 120.5 Eudragit RS 30D 5.7 17.1 Triethyl citrate 0.6 1.7
Plasacryl 0.9 2.6 Colloidal silicon dioxide 0.75 2.5 Sodium stearyl
fumarate 1.5 5.0 FD&C Blue #1 Aluminium lake 11-13 0.08 --
Opadry white 0.67 21.3
[0092] The formulation of Table 1 was prepared by a multi-step
process, which is outlined below in subsections A-D.
[0093] A. Manufacture of Tramadol Containing Controlled Release
Microparticles
[0094] The formulation of uncoated microparticles is set forth in
Table 2, and the uncoated microparticles were produced as follows.
The various components were mixed in a mixer for 3 minutes under
low shear conditions. The dry blend then was wetted under agitation
in the same mixer by gradually adding water until a homogeneous wet
mass suitable for extrusion was produced. The wet mass then was
extruded at a constant speed (45 rpm) using a Laboratory
Multigranulator extruder model MG-55 from LCI, Inc., N.C., USA
equipped with a dome die having a 0.6 mm diameter hole and a fixed
extrusion gap. The extrudes then were spheronized at a constant
speed (1800 rpm) using a Marumerzier Model QJ-230T from LCI, Inc.,
N.C., USA. The wet microparticles were dried at 45.degree. C. in a
fluid bed until a moisture content of about 2% was achieved.
TABLE-US-00002 TABLE 2 % by Weight in Uncoated Weight (g)
Components Microparticles in Batch Tramadol HCl 70.0 2,800.0 Avicel
PH-101 28.0 1,120.0 Contramid 2.0 80.0 Water -- 600.0 Total 100.0
4000.0
[0095] The resulting microparticles then were coated with a
controlled release coating and an Opadry II White containing film
as described in Table 3. The microparticles were coated in a fluid
bed coater. The microparticles were film coated to a weight gain of
between 7% and 15% using an aqueous solution of Eudragid RS30C
containing Plasacryl and triethyl citrate (TEC). Afterwards, a
curing solution containing Opadry II White was added to provide a
film around the Eudragit containing coat to reduce the likelihood
of the microparticles sticking together.
TABLE-US-00003 TABLE 3 Dry Quantity Components substance (g)
weighed (g) Coating Solution for Microparticles Uncoated pellets --
1000.0 Eudragit RS 30D 160.0 533.3 TEC 24.0 24.0 Plasacryl 16.0
80.0 Curing Solution for Microparticles Opadry II White 18.0
18.0
[0096] The resulting controlled released microparticles had a mean
diameter of about 700 .mu.m as measured by an optical
microscope.
[0097] B. Manufacture of Core Composition
[0098] In addition to the controlled release microparticles, the
core contained polycarbophil as well as several other components.
The remaining excipients for the core are set forth in Table 4, and
were mixed and subjected dry granulation in a roller compactor
(Vector Corp.) under a roll speed of 5 rpm, a screw speed of 19
rpm, and a pressure of 800 psi.
TABLE-US-00004 TABLE 4 % by Weight in Quantity Components Core
Granulation Weighed (g) Polycarbophil 59.80 1794.0 Avicel PH-101
19.85 595.5 Xanthan Gum 19.85 595.5 Colloidal silicon dioxide 0.25
7.5 Sodium stearyl fumarate 0.25 7.5 Total 100.0 3000.0
[0099] The tramadol containing microparticles then were mixed with
the remaining granulated core excipients to produce the formulation
of the core, which is set forth in Table 5.
TABLE-US-00005 TABLE 5 Formulation Composition Mg/ Granu- % of Core
Blend Tablet lation (mg) Core g/batch Tramadol Containing 43.5 0
29.00 464.0 Microparticles Granulated Polycarbophil 104.7 62.58
69.79 1116.6 Excipients Xanthan gum 20.72 Avicel PH 101 20.82
Colloidal 0.26 silicon dioxide Sodium stearyl 0.26 fumarate
Colloidal silicon dioxide 0.5 0.33 5.3 Sodium stearyl fumarate 1.2
0.83 13.3 FD&C Blue #1 Aluminium 0.1 0.05 0.8 Lake 11-13 Total
150.0 100.00 1600
[0100] C. Manufacture of Coat Composition
[0101] In addition to the controlled release microparticles, the
coat contained Kollidon.RTM. SR and xanthan gum as well as several
other components. The remaining excipients for the coat are set
forth in Table 6, and were mixed and subjected to dry granulation
in a roller compactor (Vector Corp.) under a roll speed of 5 rpm, a
screw speed of 19 rpm, and a pressure of 800 psi.
TABLE-US-00006 TABLE 6 % by Weight in Quantity Components Coat
Granulation Weighed (g) Crospovidone (Kollidon .RTM. SR) 33.17
995.1 Xanthan gum 66.33 1989.9 Colloidal silicon dioxide 0.25 7.5
Sodium stearyl fumarate 0.25 7.5 Total 100.00 3000.0
[0102] The tramadol containing microparticles then were mixed with
the remaining granulated coat excipients to produce the formulation
of the coat, which is set forth in Table 7.
TABLE-US-00007 TABLE 7 Formulation Composition Mg/ Granu- % of Coat
blend tablet lation (Mg) Coat g/batch Tramadol Containing 130.5 0
26.10 1409.4 Microparticles Granulated Kollidon .RTM. SR 363.8
120.46 72.75 3928.3 Excipients Xanthan gum 240.88 Colloidal 0.91
silicon dioxide Sodium stearyl 0.91 fumarate Colloidal silicon
dioxide 1.6 0.32 17.3 Sodium stearyl fumarate 4.2 0.83 44.9 Total
500.0 100.00 5400.0
[0103] D. Tablet Manufacture
[0104] Dry-coated tablets then were prepared using a Dry-Cota
16-Station tablet press from Manesty, UK. The core formulation was
added to a first hopper in the tablet press and compressed into a
core tablet. The coat formulation then was added to a second hopper
in the tablet press and the core and the coat were compressed
together to form the dry coated tablet. The resulting dry coated
tablets then were film coated with a solution of Opadry II using a
fully perforated pan coating machine (O'Hara, Mississauga, ON, CA).
The formulation of film coated tablets is set forth in Table 8.
TABLE-US-00008 TABLE 8 Quantity Components weighed (g) Dry Coated
Tablets 2000.0 Opadry II White solution (20%) 60.0
[0105] The resulting tablets had a hardness in the range of from
about 300 N to about 400 N. with a target hardness of about 350
N.
Example 2--Release Properties of Intact Tablets
[0106] The release kinetics of the intact tablets produced in
Example 1 were studied in this Example. In addition, the release
kinetics were studied when alcohol was included in the extraction
media and also when the pH of the extraction media was varied.
[0107] Initially, tramadol release was measured using the rotating
basket method (U.S.P. Type I Apparatus) as described in U.S.P. 30
at 100 rounds per minute, at 37.+-.0.5.degree. C., in 900 mL of
potassium phosphate monobasic pH 6.8 solution (buffer stage) during
24 hours. The results from three experiments are summarized in FIG.
2. As can be seen from FIG. 2, the tablets produced in Example 1
release tramadol over a 24 hour period with kinetics summarized in
Table 9.
TABLE-US-00009 TABLE 9 Time % Tramadol Standard (hours) Release
Deviation 0.5 4 0.4 1.0 8 0.7 2.0 17 1.6 4.0 31 2.6 7.0 46 2.9 9.0
55 2.8 12.0 64 2.3 16.0 73 1.8 20.0 80 1.2 24.0 85 1.0
[0108] From the release kinetics presented in FIG. 2 and summarized
in Table 9, the tablets produced in Example 1, under the conditions
tested, released Tramadol over 24 hours with quasi-zero order
release kinetics.
[0109] In addition, the effect of alcohol on the release kinetics
were studied under the same conditions as before except the
extraction solvent was varied to include water, 20% ethanol in
water, 40% ethanol in water, 60% ethanol in water, 80% ethanol in
water and 100% ethanol. The results are set forth in FIG. 3, which
shows that over 6 hours, less than about 30% of the tramadol was
released when the extraction solvent contained up to 60% ethanol.
The tablets performed similarly when exposed to water, 20% ethanol,
40% ethanol and 60% ethanol. However, about 50% of the tramadol was
released over 6 hours when the tablets were exposed to extraction
solvents containing 80% and 100% ethanol.
[0110] The results set forth in FIG. 3 demonstrate that the
controlled release properties of the tablets produced in Example 1
was maintained in extraction solvents containing 100% water or 100%
ethanol. In some cases, for example, in the presence of 20%
ethanol, the release rate was even slower than in water.
Furthermore, under the conditions tested, less than 20% of the
Tramadol was released from the intact tablets in 30 minutes when
placed in water, 20% ethanol, 40% ethanol, 60% ethanol, 80%
ethanol, or 100% ethanol. Accordingly, it appears that the
formulations of the invention are compatible with conventional
alcoholic beverages.
[0111] In addition, the effect of pH on the release kinetics were
studied under the same conditions as before except the extraction
solvent was varied to include water, phosphate buffer at pH 6.8,
phosphate buffer at pH 5.0, phosphate buffer at pH 3.0, and
acidified water at pH 1.2. The results are set forth in FIG. 4,
which shows that the controlled release properties of the tablets
produced in Example 1 were maintained as pH was reduced to 1.2. It
appears, however, that the rate of release increased as pH
decreased from 6.8 to 1.2. Accordingly, it appears that the
formulations of the invention are compatible with various common
beverages (for example, carbonated drinks) that have a pH of about
3.5.
Example 3--Release Properties of Bisected Tablets
[0112] This Example demonstrates that, under the conditions tested,
the tablets produced in Example 1 can be bisected without
destroying the controlled release properties of the tablet. In
other words, dose dumping did not occur when the tablets were
broken in half.
[0113] Briefly, tablets produced in Example 1 were bisected in
half. The release kinetics of the intact tablets and the halves of
the bisected tablets were measured in a U.S.P. Type I Apparatus.
The results were normalized for the bisected tablets and are
summarized in FIG. 5. The kinetics of tramadol release from an
intact tablet and a bisected tablet in a Type I Apparatus are
summarized in Table 10 and Table 11, respectively.
TABLE-US-00010 TABLE 10 Time % Tramadol Standard (hours) Release
Deviation 0.5 4 0.4 1.0 9 0.9 2.0 20 1.2 4.0 38 1.6 7.0 55 2.7 9.0
64 3.5 12.0 72 4.0 16.0 79 4.4 20.0 84 4.8 24.0 90 6.6
TABLE-US-00011 TABLE 11 Time % Tramadol Standard (hours) Release
Deviation 0.5 9 1.5 1.0 16 2.4 2.0 29 3.7 4.0 48 5.6 7.0 68 7.4 9.0
76 9.5 12.0 88 7.4 16.0 94 7.8 20.0 98 8.2 24.0 100 8.5
[0114] FIG. 5 demonstrates that both the intact tablet and the
bisected tablet maintain their controlled release properties and
release tramadol over 20-24 hours. The release profile for the
bisected tablets was similar to that of the intact tablets,
however, it appeared that the bisected tablets released the
tramadol slightly faster than the intact tablets. For example, at
the 12 hour time point, the bisected tablet released 80-90% of the
starting amount of tramadol whereas the intact tablets released
65-75% of the tramadol.
Example 4--Release Properties of Crushed Tablets
[0115] This Example describes the performance of the tablets made
in Example 1 after crushing with a conventional pill crusher. In
particular, the performance of the crushed tablets was measured
after being exposed to a number of extraction solvents under
different conditions.
[0116] Initially, the tablets produced in Example 1 were crushed
with a pill crusher and combined in a glass vial with 2 mL of water
(a volume typical for intravenous drug abuse and greater than the
volume typically available if the crushed tablet is mixed with
food). The experiment was performed using 4 different lots of
tablets. Once the crushed tablet was combined with 2 mL of water, a
hard gel was created within 20-30 seconds at the bottom of each
leaving no available liquid that could be drawn into a syringe. As
shown in FIG. 6, the vials could be inverted and the hard gels
remained at the bottom of each vial. In FIG. 6, the first vial
contained 2 mL of water and vials 2-5 (inverted) contained crushed
tablets from four separate lots (denoted Lots 1-4) each combined
with 2 mL of water. In each case, the gel produced was rigid enough
to remain at the bottom of the vial even when inverted.
[0117] In addition, the ability to extract tramadol from the
tablets produced in Example 1 was tested under different conditions
after each tablet had been crushed with a pill crusher. Briefly,
the crushed tablet was combined with 10 mL of extraction media
(water, acid, base, or alcohol containing solvent) in a vial. The
solution was heated to the specified temperature (room temperature
(RT), 50.degree. C., 75.degree. C., or 100.degree. C.) and agitated
mechanically for 15 minutes using a wrist action Burrell agitator.
It was found, however, than no residual supernatant was produced.
FIG. 7 shows seven inverted vials, each containing a hard gel
produced after a tablet prepared in Example 1 had been crushed in a
pill crusher and exposed to 10 mL of extraction media and incubated
under various conditions, which included (1) water at room
temperature for 15 minutes (Vial 1, FIG. 7), (2) water at
50.degree. C. for 15 minutes (Vial 2, FIG. 7), (3) water at
75.degree. C. for 15 minutes (Vial 3, FIG. 7), (4) water at
100.degree. C. for 15 minutes (Vial 4, FIG. 7), (5) acidic media
(acidified water) at room temperature for 15 minutes (Vial 5, FIG.
7), (6) basic media (sodium hydroxide pH 10) at room temperature
for 15 minutes (Vial 6, FIG. 7), and (7) 40% ethanol at room
temperature for 15 minutes (Vial 7, FIG. 7). As can be seen in FIG.
7, all of the conditions tested resulted in formation of hard gels
that remained at the bottom of each vial upon inversion. There was
no residual supernatant produced by this process and so it was not
possible to measure how much tramadol, if any, had been released
from the formulation.
[0118] In another experiment, the release of tramadol was measured
from tablets produced according to Example 1 after they had been
crushed and exposed to solutions containing different
concentrations of ethanol (20%, 40% and 60% ethanol). Briefly, the
tablets were crushed and the amount of drug release into 900 mL of
extraction media in a U.S.P. Type I Apparatus with stirring at 100
rpm at 37.degree. C. over 30 minutes. The results are summarized in
the bar chart appearing in FIG. 8. In addition, the extraction of
tramadol from commercially available Ultram ER was measured once
the Ultram ER had been crushed and exposed to water under the same
conditions as those used for the tablets produced in Example 1.
[0119] The results summarized in FIG. 8 show what there is no dose
dumping of tramadol from the tablets of the invention when exposed
to 900 mL of water, 20% ethanol, 40% ethanol or 60% ethanol. Under
the conditions tested, less than 20% of the tramadol was released
after 30 minutes. In contrast, when commercially available Ultram
ER was tested under the same conditions using water as the
extraction media, approximately 80% of the tramadol was
released.
[0120] In another experiment, the release of tramadol was measured
from tablets produced according to Example 1 after they had been
crushed and exposed to extraction media having different pH values,
which included water, phosphate buffer at pH 6.8, phosphate buffer
at pH 5, phosphate buffer at pH 3, and acidified water at pH 1.2.
The tablets were crushed and the amount of drug release into 900 mL
of extraction media in a U.S.P. Type I Apparatus with stirring at
100 rpm at 37.degree. C. over 30 minutes. The results are
summarized in the bar chart appearing in FIG. 9. In addition, the
extraction of tramadol from commercially available Ultram ER was
measured once the Ultram ER had been crushed and exposed to water
under the same conditions as those used for the tablets produced in
Example 1.
[0121] The results summarized in FIG. 9 show that, under the
conditions tested, there was no dose dumping of tramadol when
incubated in 900 mL of extraction media (including water, phosphate
buffer at pH 6.8, pH 5.0 or pH 3.0, and acidified water at pH 1.2).
It is noted, however, that, under the conditions tested, as pH
decreased the amount of released tramadol increased. For example,
in water, less than 20% of the tramadol was released. In contrast,
when commercially available Ultram ER was tested under the same
conditions using water as the extraction media, approximately 100%
of the tramadol was released. In phosphate buffer at pH 6.8, 5, and
3, approximately 30-35% of the tramadol was released from the
tablets of the invention, and in acidified water at pH 1.2
approximately 65% of the tramadol was released.
Example 5--Pharmacokinetic Properties of Tramadol Tablets
[0122] The pharmacokinetic properties of the 100 mg tablets
prepared in Example 1 were assessed in a single dose, randomized,
crossover study in 18 healthy adults under both fasting conditions
and fed conditions. After administration, plasma samples were
harvested periodically, and the concentration of tramadol present
in the plasma was measured via liquid chromatography-tandem mass
spectrometry.
[0123] The results were plotted in FIG. 10, where the mean plasma
concentrations of tramadol present in the plasma under fasting
conditions is shown in FIG. 10A and the mean plasma concentrations
of tramadol present in the plasma under fed conditions is shown in
FIG. 10B. The median T.sub.max (hours) was 6.0 hours for both the
fed and fasted conditions. The C.sub.max (ng/mL) was 120.+-.32
ng/mL and 154.+-.41 ng/mL under fasted and fed conditions,
respectively. The T.sub.1/2 (hours) was 8.4.+-.2.9 hours and
6.8.+-.2.1 hours following fasted and fed administration,
respectively. The AUC.sub.0-t (ngh/mL) was 2556.+-.1026 and
2746.+-.1057 for the fasted and fed states, respectively, and the
AUC.sub.0-.infin. (ngh/mL) was 2703.+-.1109 and 2829.+-.1119 for
the fasted and fed states, respectively.
Example 6--Exemplary Oxycodone Tablet
[0124] This Example describes the manufacture and testing of 40 mg
oxycodone HCl tablet (BID) having a core and a controlled release
coating. The coat comprises microparticles that provide controlled
release properties and reduce misuse of the oxycodone disposed
within the microparticles.
[0125] The microparticles were produced by extrusion
spheronization, which produces the microparticles, and then were
coated by fluidized bed coating. The resulting coated
microparticles were blended with the coat matrix excipients and
then compressed around a pre-formed polycarbophyl core.
[0126] The composition of the oxycodone containing microparticles
are set forth in Table 12.
TABLE-US-00012 TABLE 12 Ingredients Mg/tablet Avicel PH 101 72.000
Contramid 2.297 Eudragit RS 30D 9.136 Triethyl citrate 1.365
Plasacryl 0.906 Oxycodone HCl 40.000
[0127] The resulting microparticles then were coated in a fluid bed
coater equipped with a bottom spray. The microparticles were film
coated to a weight gain of 7% to 15% using an aqueous solution of
Eudragid RS30C containing Plasacryl and triethyl citrate (TEC).
Afterwards, a curing solution containing Opadry II White was added
to provide a film around the Eudragit containing coat to reduce the
likelihood of the microparticles sticking together.
[0128] The composition of the core and the coat is set forth in
Table 13.
TABLE-US-00013 TABLE 13 Mg/tablet Ingredients Core blend Coat blend
Total Oxycodone HCl (provided -- 125.704 125.704 as microparticles)
Avicel PH 101 13.749 -- 13.749 Contramid -- 2.297 2.297
Polycarbophil (Noveon AA-1) 41.420 -- 41.420 Xanthan gum 13.749
34.451 48.200 Kollidon .RTM. SR -- 68.908 68.908 Colloidal silicon
dioxide 0.349 1.440 1.789 Sodium stearyl fumarate 0.698 2.610 3.308
FD&C Yellow #6 Aluminium lake 0.035 -- 0.035 Total 70.000
233.113 303.113
[0129] The dry-coated tablets were prepared using a Dry-Cota
16-Station tablet press from Manesty, UK. The core formulation was
added to a first hopper in the tablet press and compressed into a
core tablet. The coat formulation then was added to a second hopper
in the tablet press and the core and the coat were compressed
together to form the dry coated tablet. The resulting dry coated
tablets then were film coated with a solution of Opadry II using a
fully perforated pan coating machine (O'Hara, Mississauga, ON,
CA).
[0130] The in vitro release properties of the resulting tablets
were measured in a U.S.P. Type I Apparatus in phosphate buffer pH
6.8 or water containing 40% ethanol. The release kinetics were
measured on intact tablets (see, FIG. 11A) or crushed tablets (see,
FIG. 11B), which had been crushed by using a conventional pill
crusher. FIG. 11B also shows the release of oxycodone over time
from Oxycontin tablets available commercially from Purdue Pharma.
In addition, the release kinetics were measured for intact tablets
in the presence of phosphate buffer pH 6.8, and for bisected
tablets (half tablets) in the presence of phosphate buffer pH 6.8
(see, FIG. 12). As shown in FIG. 12, the release profiles were
substantially the same for the intact tablets and the bisected
tablets.
[0131] The intact tablets provided controlled release over 12 hours
and the release was not materially affected by the presence of 40%
ethanol. In contrast to the crushed Oxycontin tablets, neither the
crushed nor the bisected tablets (half tablets) produced in
accordance with the invention released oxycodone by dose dumping,
and no dose dumping was seen in the presence of 40% ethanol.
Example 7--Exemplary Oxycodone HCl/Acetaminophen Tablet
[0132] This Example describes the manufacture and testing of a
twice a day tablet (BID) containing 20 mg oxycodone HCl and 650 mg
of acetaminophen. The tablet comprises a core surrounded by an
enteric, controlled release coating (namely, Eudragit L30D55),
where the core is in the form of a bilayer.
[0133] The composition of the microparticles is set forth in Table
14.
TABLE-US-00014 TABLE 14 Ingredients Mg/Tablet Pellet composition
(%) Oxycodone HCl 20.0 11.51 Cellulose microcrystalline 37.3 21.49
(Avicel PH101) Contramid 2.7 1.53 Lactose monohydrate 73.4 42.22
Eudragit NE 30D 20.0 11.51 Talc 20.0 11.51 Colloidal silicon
dioxide 0.4 0.23 Total 173.8 100.00
[0134] The microparticles were produced by mixing the components
set forth in Table 14 (except for the Eudragit NE 30D and Talc).
The resulting mixture was subjected to extrusion and
spheronization, and the resulting microparticles were coated with
the Eudragit NE 30D and talc in a fluid bed coater equipped with a
bottom spray. The core of the tablet was a bilayer. The oxycodone
containing microparticles were incorporated in the slow release
layer of the bilayer whereas the acetaminophen, as COMPAP.RTM.
which was in free form and not incorporated into microparticles,
was present in both the rapid release layer and the slow release
layer.
[0135] The composition of the bilayer core is set forth in Table
15.
TABLE-US-00015 TABLE 15 Tablet composition Ingredients (Mg) (%)
First layer (rapid release) COMPAP .RTM. (which includes
acetaminophen) 288.89 89.72 Microcrystalline Cellulose PH102 19.77
6.14 Croscaramellose sodium AcDiSol 6.70 2.08 Colloidal silicon
dioxide (Cab O sil) 1.68 0.52 Sodium stearyl fumarate (Pruv) 4.83
1.50 FD&C Yellow #6 0.13 0.04 Total 322.00 100.00 Second layer
(slow release) Oxycodone (provided as oxycodone microparticles)
173.79 24.72 COMPAP .RTM. (which includes acetaminophen) 433.33
61.64 Carbopol 71 G 42.02 5.98 Xanthan gum 80 mesh 42.02 5.98
Colloidal silicon dioxide (Cab O sil) 2.95 0.42 Sodium stearyl
fumarate (Pruv) 8.86 1.26 Total 703.00 100.00
[0136] The bilayer core was prepared by mixing the components of
each layer and then compressing the materials in a Piccola.TM.
bilayer tablet press (SMI Inc., N.J., USA). The bilayer tablets had
a hardness in the range of 190 to 230 Newtons. The resulting
bilayer core was then coated with Eudragit L30D 55 by using a fully
perforated pan coating machine (O'Hara, Mississauga, ON, CA). The
resulting coating contained 82 mg of Eudragit L30D 55, which
accounted for 8% of the weight of the tablet.
[0137] The in vitro release kinetics of the resulting tablet were
measured in a U.S.P. Type III Apparatus at 20 dpm after incubation
in 0.1M hydrochloric acid at pH 1.2 for 1 hour followed by
incubation in phosphate buffer pH 6.8 for 11 hours. The results
shown in FIG. 13 indicate that no oxycodone was released from the
tablet for about one hour when the tablet was in 0.1 M HCl. Once
the pH was raised after one hour, the oxycodone was released with
controlled release kinetics.
Example 8--Exemplary Once-a-Day 150 mg Tramadol Tablet
[0138] This Example describes the manufacture and testing of an
exemplary once-a-day 150 mg tramadol HCl tablet, where the tablets
have a monolithic core and a controlled release coating. The core
comprises a super absorbent polycarbophil and the controlled
release coat comprises xanthan gum and Kollidon. Tramadol
containing microparticles are disposed within both the core and the
coat.
[0139] The composition of the microparticles is set forth in Table
16.
TABLE-US-00016 TABLE 16 Ingredients % composition Tramadol HCl
57.38 MCC Avicel PH 101 24.60 Eudragit RS30D .RTM. + Plasacryl
.RTM. + Triethyl citrate 16.39 Opadry II .RTM. white 1.63 Total
100.00
[0140] Uncoated microparticles were produced as follows. Tramadol
and Avicel PH 101 were mixed in a mixer for 3 minutes under low
shear conditions. The dry blend then was wetted under agitation in
the same mixer by gradually adding water until a homogeneous wet
mass suitable for extrusion was produced. The wet mass then was
extruded at a constant speed (45 rpm) using a Laboratory
Multigranulator extruder model MG-55 from LCI, Inc., N.C., USA
equipped with a dome die having a 0.6 mm diameter hole and a fixed
extrusion gap. The extrudates then were spheronized at a constant
speed (1,800 rpm) using a Marumerzier Model QJ-230T from LCI, Inc.,
N.C., USA. The wet microparticles were dried at 45.degree. C. in a
fluid bed until a moisture content of about 2% was achieved.
[0141] A portion of the resulting microparticles were coated with
an aqueous solution containing Eudragit RS 30D using a fluid bed
coater. The microparticles were film coated to a weight gain of
between 7% and 15%. Afterwards, a curing solution containing Opadry
II White was added to provide a film around the Eudragit containing
coat to reduce the likelihood of the microparticles sticking
together.
[0142] The composition of the core granules is set forth in Table
17.
TABLE-US-00017 TABLE 17 Ingredients % Composition Polycarbophilic
acid (Noveon AA-1) 80.00 MCC PH-101 19.50 Colloidal silicon dioxide
0.25 Sodium stearyl fumarate 0.25 Total 100.00
[0143] In addition to the controlled release microparticles, the
core contained polycarbophil as well as several other components.
The remaining excipients for the core were mixed and subjected dry
granulation in a roller compactor (Vector Corp.) under a roll speed
of 5 rpm, a screw speed of 19 rpm, and a pressure of 800 psi. Then,
uncoated microparticles were mixed with the granulated core
excipients to produce the core formulation.
[0144] The composition of the coat granules is set forth in Table
18.
TABLE-US-00018 TABLE 18 Ingredients % Composition Kollidon SR 49.75
Xanthan gum 49.75 Colloidal silicon dioxide 0.25 Sodium stearyl
fumarate 0.25 Total 100.00
[0145] The remaining excipients for the coat were mixed and
subjected to dry granulation in a roller compactor (Vector Corp.)
under a roll speed of 5 rpm, a screw speed of 19 rpm, and a
pressure of 800 psi. Then, coated microparticles were mixed with
the granulated coat excipients to produce the coat formulation.
[0146] The composition of the tablet is set forth in Table 19.
TABLE-US-00019 TABLE 19 Composition Ingredients % Mg/tablet Core
formulation Tramadol HCl microparticles 36.31 65.36 Core granules
62.44 112.39 Colloidal silicon dioxide 0.50 0.90 Sodium stearyl
fumarate 0.75 1.35 Total 100 180 Coat formulation Tramadol HCl
microparticles (film coated) 35.98 196.09 Coat granules 63.02
343.46 Colloidal silicon dioxide 0.25 1.36 Sodium stearyl fumarate
0.75 4.09 Total 100 545
[0147] Dry-coated tablets then were prepared using a Dry-Cota
16-Station tablet press from Manesty, UK. The core formulation was
added to a first hopper in the tablet press and compressed into a
core tablet. The coat formulation then was added to a second hopper
in the tablet press and the core and the coat were compressed
together to form the dry coated tablet. The resulting dry coated
tablets then were film coated with a solution of Opadry II using a
fully perforated pan coating machine (O'Hara, Mississauga, ON,
CA).
[0148] The in vitro release properties of the resulting tablets
(both intact and crushed) were measured in a U.S.P. Type I
Apparatus in phosphate buffer pH 6.8. Three separate batches were
tested. The results of in vitro release from the intact tablets is
shown in FIG. 14A and from crushed tablets is shown in FIG. 14B.
The tablets were crushed using a pill crusher. The results show
that the intact tablets of the invention demonstrated a controlled
release of tramadol over 24 hours in phosphate buffer pH 6.8.
Moreover, there was no dose dumping of tramadol from the crushed
tablets when exposed to the same dissolution conditions. Under the
conditions tested, less than 50% of the tramadol was released
within 60 minutes.
[0149] In addition, the in vitro release properties of the
resulting tablets (both intact and crushed) were measured in a
U.S.P. Type I Apparatus in water or water containing 20% ethanol,
40% ethanol and 60% ethanol. The same three batches were tested.
The results of in vitro release from the intact tablets in water
containing 60% ethanol is shown in FIG. 15A and from crushed
tablets in water containing 60% ethanol is shown in FIG. 15B.
Similar results were obtained when the water contained either 20%
or 40% ethanol. The results show that alcohol concentrations up to
at least 60% have little or no effect on the release profiles. With
respect to the crushed tablets, and as shown in FIG. 15B, less than
25% of the Tramadol was released at 60 minutes in water containing
60% ethanol.
Example 9--Exemplary Once-a-Day 200 mg Tramadol Tablet
[0150] This Example describes the manufacture and testing of an
exemplary once-a-day 200 mg tramadol HCl tablet, where the tablets
have a monolithic core and a controlled release coating. The core
comprises super absorbent polycarbophil and the controlled release
coat comprises xanthan gum and Kollidon. Tramadol containing
microparticles are disposed within the core and the coat.
[0151] The composition of four different lots of microparticles are
set forth in Table 20.
TABLE-US-00020 TABLE 20 % composition Ingredients LOT 1 LOT 2 LOT 3
LOT 4 Tramadol HCl 58.3 57.4 69.6 69.6 MCC Avicel PH 101 25.0 24.6
17.4 17.4 Eudragit RS30D .RTM. + 16.7 16.4 13.0 13.0 Plasacryl
.RTM. + Triethyl citrate Opadry II white -- 1.6 -- -- Total 100.0
100.0 100.0 100.0
[0152] The formulations of uncoated microparticles were produced as
follows. Tramadol and Avicel PH 101 were mixed in a mixer for 3
minutes under low shear conditions. The dry blend then was wetted
under agitation in the same mixer by gradually adding water until a
homogeneous wet mass suitable for extrusion was produced. The wet
mass then was extruded at a constant speed (45 rpm) using a
Laboratory Multigranulator extruder model MG-55 from LCI, Inc.,
N.C., USA equipped with a dome die having a 0.6 mm diameter hole
and a fixed extrusion gap. The extrudates then were spheronized at
a constant speed (1,800 rpm) using a Marumerzier Model QJ-230T from
LCI, Inc., N.C., USA. The wet microparticles were dried at
45.degree. C. in a fluid bed until a moisture content of about 2%
was achieved.
[0153] The resulting microparticles then were coated with an
aqueous solution containing Eudragit RS 30D using a fluid bed
coater. The microparticles were film coated to a weight gain of
between 7% and 15%. Afterwards, for Lot 2 only, a curing solution
containing Opadry II White was added to provide a film around the
Eudragit containing coat.
[0154] The composition of the core granules is set forth in Table
21.
TABLE-US-00021 TABLE 21 Ingredients % Composition Polycarbophil
(Noveon AA-1) 80.00 MCC PH-101 19.50 Colloidal silicon dioxide 0.25
Sodium stearyl fumarate 0.25 Total 100.00
[0155] In addition to the controlled release microparticles, the
core contained polycarbophilic acid as well as several other
components. The remaining excipients for the core were mixed and
subjected dry granulation in a roller compactor (Vector Corp.)
under a roll speed of 5 rpm, a screw speed of 19 rpm, and a
pressure of 800 psi. Then, the coated microparticles were mixed
with the granulated core excipients to produce the core
formulation.
[0156] The composition of the coat granules is set forth in Table
22.
TABLE-US-00022 TABLE 22 Ingredients % Composition Kollidon SR 33.2
Xanthan gum 66.3 Colloidal silicon dioxide 0.25 Sodium stearyl
fumarate 0.25 Total 100.0
[0157] The remaining excipients for the coat were mixed and
subjected to dry granulation in a roller compactor (Vector Corp.)
under a roll speed of 5 rpm, a screw speed of 19 rpm, and a
pressure of 800 psi. Then, coated microparticles were mixed with
the granulated coat excipients to produce the coat formulation.
[0158] The composition of four different lots of tablets is set
forth in Table 23.
TABLE-US-00023 TABLE 23 LOT 1 LOT 2 LOT 3 LOT 4 Ingredients %
Mg/tab % Mg/tab % Mg/tab % Mg/tab Core Compositions Coated Tramadol
HCl 47.62 85.72 45.87 87.15 37.84 71.90 47.92 71.88 microparticles
(50 mg Tramadol) Core granules 51.13 92.03 52.81 100.34 60.91
115.73 50.83 76.25 Colloidal silicon 0.50 0.90 0.50 0.95 0.50 0.95
0.50 0.75 dioxide Sodium stearyl 0.75 1.35 0.75 1.43 0.75 1.43 0.75
1.13 fumarate Total Core 100 180 100 190 100 190 100 150 Coat
Compositions Coated Tramadol HCl 47.18 257.13 46.68 261.41 38.50
215.60 35.94 215.64 microparticles (150 mg Tramadol) Coat granules
51.82 282.42 52.32 292.99 52.15 292.04 63.06 378.36 Xanthan gum --
-- -- -- 8.35 46.76 -- -- Colloidal silicon 0.25 1.36 0.25 1.40
0.25 1.40 0.25 1.50 dioxide Sodium stearyl 0.75 4.09 0.75 4.20 0.75
4.20 0.75 4.50 fumarate Total Coat 100 545 100 560 100 560 100 600
Tablet Weight 725 750 750 750
[0159] Dry-coated tablets then were prepared using a Dry-Cota
16-Station tablet press from Manesty, UK. The core formulation was
added to a first hopper in the tablet press and compressed into a
core tablet. The coat formulation then was added to a second hopper
in the tablet press and the core and the coat were compressed
together to form the dry coated tablet. The resulting dry coated
tablets then were film coated with a solution of Opadry II using a
fully perforated pan coating machine (O'Hara, Mississauga, ON,
CA).
[0160] The in vitro release properties of the resulting tablets
(both intact and crushed) were measured in a U.S.P. Type I
Apparatus in phosphate buffer pH 6.8 or water. The results of in
vitro release from intact tablets are shown in FIG. 16A and from
crushed tablets is shown in FIG. 16B. The tablets were crushed
using a pill crusher. The results show that the intact tablets of
the invention demonstrated a controlled release of tramadol over 24
hours in phosphate buffer pH 6.8. Moreover, there was no dose
dumping of tramadol from the crushed tablets when exposed to the
same dissolution conditions. Under the conditions tested, less than
50% of the tramadol was released within 60 minutes.
[0161] In addition, the in vitro release properties of the
resulting tablets from Lot 4 (both intact and crushed) were
measured in a U.S.P. Type I Apparatus in phosphate buffer pH 6.8 or
water containing 20% ethanol, 40% ethanol and 60% ethanol. The
results of in vitro release from the intact tablets in buffer are
shown in FIG. 17A and from crushed tablets are shown in FIG. 17B.
The results show that alcohol concentrations up to at least 60%
have little or no effect on the release profiles. With respect to
the crushed tablets, less than 15% of the tramadol was released at
60 minutes in water containing 60% ethanol.
Example 10--Exemplary Twelve Hour 30 mg Hydrocodone Bitartrate
Tablet
[0162] This Example describes the manufacture and testing of an
exemplary twelve hour tablet containing 30 mg of Hydrocodone
bitartrate. The tablets have a monolithic core and a controlled
release coating. The core comprises super absorbent polycarbophil
and the controlled release coat comprises xanthan gum and Kollidon.
Hydrocodone containing microparticles are disposed within the coat.
No active ingredient was disposed within the core.
[0163] The composition of the hydrocodone containing microparticles
is set forth in Table 24.
TABLE-US-00024 TABLE 24 Ingredients % Composition Hydrocodone
bitartrate 31.82 MCC Avicel PH 101 59.09 Eudragit RS30D .RTM. +
Plasacryl .RTM. + Triethyl citrate 9.09 Total 100.00
[0164] The microparticles were produced as follows. Hydrocodone
bitartrate and Avicel PH 101 were mixed in a mixer for 3 minutes
under low shear conditions. The dry blend then was wetted under
agitation in the same mixer by gradually adding water until a
homogeneous wet mass suitable for extrusion was produced. The wet
mass then was extruded at a constant speed (45 rpm) using a
Laboratory Multigranulator extruder model MG-55 from LCI, Inc.,
N.C., USA equipped with a dome die having a 0.6 mm diameter hole
and a fixed extrusion gap. The extrudes then were spheronized at a
constant speed (1,800 rpm) using a Marumerzier Model QJ-230T from
LCI, Inc., N.C., USA. The wet microparticles were dried at
45.degree. C. in a fluid bed until a moisture content of about 2%
was achieved.
[0165] The resulting microparticles were coated with an aqueous
solution containing Eudragit RS 30D using a fluid bed coater. The
microparticles were film coated to a weight gain of between 7% and
15%.
[0166] The composition of the core granules is set forth in Table
25.
TABLE-US-00025 TABLE 25 Ingredients % Composition Polycarbophil
(Noveon AA-1) 80.00 MCC PH-101 19.50 Colloidal silicon dioxide 0.25
Sodium stearyl fumarate 0.25 Total 100.00
[0167] The core contained polycarbophil as well as several other
components. These excipients were mixed and subjected dry
granulation in a roller compactor (Vector Corp.) under a roll speed
of 5 rpm, a screw speed of 19 rpm, and a pressure of 800 psi.
[0168] The composition of the coat granules is set forth in Table
26.
TABLE-US-00026 TABLE 26 Ingredients % Composition Kollidon SR 33.17
Xanthan gum 66.33 Colloidal silicon dioxide 0.25 Sodium stearyl
fumarate 0.25 Total 100.00
[0169] The remaining excipients for the coat were mixed and
subjected to dry granulation in a roller compactor (Vector Corp.)
under a roll speed of 5 rpm, a screw speed of 19 rpm, and a
pressure of 800 psi. Then, the microparticles were mixed with the
granulated coat excipients to produce the coat formulation.
[0170] The composition of intact tablets is set forth in Table
27.
TABLE-US-00027 TABLE 27 Composition Ingredients % Mg/tab Core
Formulation Hydrocodone bitartrate microparticles -- -- Core
granules 45.80 77.86 Klucel HF 52.95 90.02 Colloidal silicon
dioxide 0.50 0.85 Sodium stearyl fumarate 0.75 1.28 Total 100.00
170.00 Coat Formulation Hydrocodone bitartrate microparticles 21.93
94.30 Coat granules 53.81 231.38 Avicel PH 102 23.26 100.02
Colloidal silicon dioxide 0.25 1.08 Sodium stearyl fumarate 0.75
3.23 Total 100.00 430.00
[0171] Dry-coated tablets then were prepared using a Dry-Cota
16-Station tablet press from Manesty, UK. The core formulation was
added to a first hopper in the tablet press and compressed into a
core tablet. The coat formulation then was added to a second hopper
in the tablet press and the core and the coat were compressed
together to form the dry coated tablet. The resulting dry coated
tablets then were film coated with a solution of Opadry II using a
fully perforated pan coating machine (O'Hara, Mississauga, ON,
CA).
[0172] The in vitro release properties of the resulting tablets
(both intact and crushed) were measured in a U.S.P. Type I
Apparatus in phosphate buffer pH 6.8 or 0.1M hydrochloric acid pH
1.2. The results of in vitro release from the intact tablets are
shown in FIG. 18A and from crushed tablets are shown in FIG. 18B.
The tablets were crushed by using a pill crusher. The results show
that the intact tablets demonstrated a controlled release of
Hydrocodone bitartrate over 12 hours in phosphate buffer pH 6.8 and
in acid pH 1.2. However, the drug release rate in the acid was
slightly higher than the release in phosphate buffer pH 6.8.
Furthermore, there was no dose dumping of hydrocodone bitartrate
from the crushed tablets when exposed to the same dissolution
conditions. Under the conditions tested, less than 30%, and 55% of
hydrocodone was released within 60 minutes in phosphate buffer pH
6.8 and in acid pH 1.2, respectively.
INCORPORATION BY REFERENCE
[0173] The entire disclosure of each of the patent and scientific
documents referred to herein is incorporated by reference for all
purposes.
EQUIVALENTS
[0174] Although the present invention has been illustrated by means
of preferred embodiments thereof, it is understood that the
invention intends to cover broad aspects thereof without departing
from the spirit and scope of the invention as defined in the
appended claims.
* * * * *