U.S. patent number RE45,822 [Application Number 13/923,362] was granted by the patent office on 2015-12-22 for oral dosage form comprising a therapeutic agent and an adverse-effect agent.
This patent grant is currently assigned to Purdue Pharma L.P.. The grantee listed for this patent is Purdue Pharma L.P.. Invention is credited to Anthony E. Carpanzano, Curtis Wright, IV.
United States Patent |
RE45,822 |
Wright, IV , et al. |
December 22, 2015 |
Oral dosage form comprising a therapeutic agent and an
adverse-effect agent
Abstract
The present invention provides an oral dosage form comprising a
first composition and a second composition. The first composition
comprises an effective amount of a therapeutic agent and the second
composition comprises an effective amount of an adverse-effect
agent. The adverse-effect agent is covered with a coating that is
substantially insoluble in the gastrointestinal tract. In one
embodiment, the adverse-effect agent is coated with an outer
base-soluble layer and an inner acid-soluble layer. The therapeutic
agent can be uncoated or can be coated with a coating having an
outer acid-soluble layer and an inner base-soluble layer. The
dosage form discourages administration of the therapeutic agent by
other than oral administration.
Inventors: |
Wright, IV; Curtis (Rockport,
MA), Carpanzano; Anthony E. (Sherman, CT) |
Applicant: |
Name |
City |
State |
Country |
Type |
Purdue Pharma L.P. |
Stamford |
CT |
US |
|
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Assignee: |
Purdue Pharma L.P. (Stamford,
CT)
|
Family
ID: |
23199688 |
Appl.
No.: |
13/923,362 |
Filed: |
October 28, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
Issue Date |
|
|
10208817 |
Aug 1, 2002 |
|
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|
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60309791 |
Aug 6, 2001 |
|
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Reissue of: |
10948575 |
Sep 23, 2004 |
7384653 |
Jun 10, 2008 |
|
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P
25/00 (20180101); A61K 45/06 (20130101); A61P
25/36 (20180101); A61K 31/485 (20130101); A61P
43/00 (20180101); A61K 9/5084 (20130101); A61P
25/04 (20180101); A61P 29/00 (20180101); A61K
9/2081 (20130101); A61K 9/5073 (20130101); A61K
9/1694 (20130101); A61K 31/485 (20130101); A61K
2300/00 (20130101); A61K 9/209 (20130101); A61K
9/1635 (20130101); A61K 9/5026 (20130101); A61K
9/1623 (20130101) |
Current International
Class: |
A61K
9/14 (20060101); A61K 9/16 (20060101); A61K
9/22 (20060101); A61K 9/26 (20060101); A61K
9/48 (20060101) |
References Cited
[Referenced By]
U.S. Patent Documents
Foreign Patent Documents
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754452 |
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Jan 1997 |
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EP |
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759303 |
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Feb 1997 |
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EP |
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0759303 |
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Feb 1997 |
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EP |
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S59-51223 |
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Mar 1984 |
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JP |
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7-10745 |
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Jan 1995 |
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JP |
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9-87169 |
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Mar 1997 |
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JP |
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H10-338634 |
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Dec 1998 |
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JP |
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95/28963 |
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Nov 1995 |
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WO |
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99/32119 |
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Jul 1999 |
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WO |
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99/32120 |
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Jul 1999 |
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WO |
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00/44353 |
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Aug 2000 |
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WO |
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2001-58447 |
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Aug 2001 |
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WO |
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Primary Examiner: Tran; Susan
Attorney, Agent or Firm: Lowenstein Sandler LLP
Parent Case Text
This application .Iadd.is a reissue of U.S. Pat. No. 7,384,653,
issued on Jun. 10, 2008 which issued from U.S. patent application
Ser. No. 10/948,575, filed on Sep. 23, 2004, which is a
continuation of U.S. patent application Ser. No. 10/208,817, filed
on Aug. 1, 2002, now abandoned, which .Iaddend.claims the benefit
of U.S. Provisional .Iadd.Patent .Iaddend.Application No.
60/309,791, filed Aug. 6, 2001, the disclosure of which is
incorporated by reference herein in its entirety.
Claims
What is claimed is:
1. An oral dosage form comprising a first composition and a second
composition, wherein the first composition comprises an effective
amount of a therapeutic agent and is coated with an inner
base-soluble layer and an outer acid-soluble layer and the second
composition comprises an effective amount of an adverse-effect
agent and is coated with an inner acid-soluble layer and an outer
base-soluble layer.
2. The oral dosage form of claim 1, wherein the first composition
and the second composition are in the form of powders, granules, or
beads contained within a capsule.
3. The oral dosage form of claim 1, wherein the first composition
and the second composition are in the form of granules or a powder
dispersed in a pharmaceutically acceptable matrix.
4. The oral dosage form of claim 1 in the form of a two-layer
tablet having a first layer comprising the first composition and a
second layer comprising the second composition.
5. The oral dosage form of claim 4, wherein the two-layer tablet is
further coated with a coating that dissolves in the stomach.
6. The oral dosage form of claim 1 in the form of a tablet
comprising a core coated with an inner-base soluble layer and an
outer acid soluble layer, wherein the core comprises the second
composition coated with an inner acid-soluble layer and an outer
base-soluble layer dispersed within the therapeutic agent.
7. The oral dosage form of claim 1 in the form of a tablet
comprising a core of the second composition coated with an inner
acid-soluble layer, an outer base-soluble layer, a coating of the
first composition, an inner-base-soluble layer, and an outer
acid-soluble layer.
8. The oral dosage form of claim 1, wherein the adverse-effect
agent is an antagonist of the therapeutic agent.
9. The oral dosage form of claim 1, wherein the adverse-effect
agent is laxative.
10. The oral dosage form of claim 1, wherein each acid-soluble
layer is soluble at a pH value of less than about 5.0 and
substantially insoluble at a pH value of greater than about
5.5.
11. The oral dosage form of claim 1, wherein each base-soluble
layer is soluble at a pH value of greater than about 5.5 but
substantially insoluble at a pH value of less than about 5.0.
12. The oral dosage form of claim 1, wherein each acid-soluble
layer comprises a cationic polymer with dimethylaminoethyl ammonium
functionalities.
13. The oral dosage form of claim 1, wherein each base-soluble
layer comprises an anionic polymer of methacrylic acid or a
methacrylate with carboxylic acid functionalities.
14. The oral dosage form of claim 1, wherein the first composition
is a controlled-release dosage form.
15. The oral dosage form of claim 14, wherein the first composition
is coated with an inner-most sustained-release coating.
16. The oral dosage form of claim 15, wherein the sustained-release
coating is selected from the group consisting of a wax, fatty
alcohol, shellac, zein, hydrogenated vegetable oil, water insoluble
cellulose, polymers of acrylic acid, polymers of methacrylic acid,
copolymers of acrylic acid and methacrylic acid, and mixtures
thereof.
17. The oral dosage form of claim 14, wherein the first composition
is dispersed in a controlled-release matrix.
18. The oral dosage form of claim 1, wherein the therapeutic agent
is selected from a group consisting of analgesics,
anti-inflammatory agents, anthelmintics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anti-fungal
agents, anti-gout agents, anti-hypertensive agents, anti-malarials,
anti-migraine agents, anti-muscarinic agents, anti-neoplastic
agents, erectile dysfunction improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-Blockers, cardiac ionotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastrointestinal agents,
histamine receptor antagonists, keratolytics, lipid regulating
agents, anti-anginal agents, cox-2-inhibitors, leukotriene
inhibitors, macrolides, muscle relaxants, nutritional agents,
opioid analgesics, protease inhibitors, sex hormones, stimulants,
muscle relaxants, anti-osteoporosis agents, anti-obesity agents,
cognition enhancers, anti-urinary incontinence agents, nutritional
oils, anti-benign prostate hypertrophy agents, essential fatty
acids, non-essential fatty acids, and mixtures thereof.
19. The oral dosage form of claim 1, wherein the therapeutic agent
is an agent having a potential for abuse.
20. The oral dosage form of claim 19, wherein the therapeutic agent
is an opioid, benzodiazepine, barbiturate, or a stimulant.
21. The oral dosage form of claim 20, wherein the therapeutic agent
is an opioid and the adverse-effect agent is an opioid
antagonist.
22. The oral dosage form of claim 21, wherein the opioid is
selected from the group consisting of alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide,
buprenorphine, butorphanol, clonitazene, codeine, desomorphine,
dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,
dihydroetorphine, fentanyl, hydrocodone, hydromorphone,
hydromorphodone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol, metazocine, methadone, metopon, morphine, myrophine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, papaveretum, paregoric, pentazocine, phenadoxone,
phendimetrazine, phendimetrazone, phenomorphan, phenazocine,
phenoperidine, piminodine, piritramide, propheptazine, promedol,
properidine, propoxyphene, propylhexedrine, sufentanil, tilidine,
tramadol, pharmaceutically acceptable salts thereof, and mixtures
thereof.
23. The oral dosage form of claim 22, wherein the opioid selected
from the group consisting of hydrocodone, morphine, hydromorphone,
oxycodone, codeine, levorphanol, meperidine, methadone,
oxymorphone, buprenorphine, fentanyl and derivatives thereof,
dipipanone, heroin, tramadol, etorphine, dihydroetorphine,
butorphanol, levorphanol, pharmaceutically acceptable salts
thereof, and mixtures thereof.
24. The oral dosage form of claim 23, wherein the opioid is
oxycodone or hydrocodone.
25. The oral dosage form of claim 21, wherein the adverse-effect
agent is selected from the group consisting of naloxone,
naltrexone, nalmefene, cyclazacine, and levallorphan.
26. The oral dosage form of claim 21, wherein the adverse-effect
agent is naloxone or naltrexone.
27. The oral dosage form of claim 20, wherein the therapeutic agent
is a benzodiazepine and the adverse-effect agent is a
benzodiazepine antagonist.
28. The oral dosage form of claim 27, wherein the benzodiazepine is
selected from the group consisting of alprazolam, bromazepam,
chlordiazepoxied, clorazepate, diazepam, estazolam, flurazepan,
halazepam, ketazolam, lorazepam, nitrazepam, oxazepam, prazepam,
quazepam, temazepam, triazolam, pharmaceutically acceptable salts
thereof, and mixtures thereof.
29. The oral dosage form of claim 27, wherein the benzodiazepine
antagonist is flumazenil.
30. The oral dosage form of claim 20, wherein the therapeutic agent
is a barbiturate and the adverse-effect agent is a barbiturate
antagonist.
31. The oral dosage form of claim 30, wherein the barbiturate is
selected from the group consisting of amobarbital, aprobarbotal,
butabarbital, butalbital, methohexital, mephobarbital, metharbital,
pentobarbital, phenobarbital, secobarbital, pharmaceutically
acceptable salts thereof, and mixture thereof.
32. The oral dosage form of claim 20, wherein the barbiturate
antagonist is a stimulant.
33. The oral dosage form of claim 20, wherein the therapeutic agent
is a stimulant and the adverse-effect agent is a stimulant
antagonist.
34. The oral dosage form of claim 33, wherein the amphetamine is
selected from the group consisting of amphetamine, amphetamine and
dextroamphetamine resin complex, dextroamphetamine,
methamphetamine, methylphenidate, a pharmaceutically acceptable
salt thereof, and mixtures thereof.
35. The oral dosage form of claim 33, wherein the stimulant
antagonist is a benzodiazepine.
36. The oral dosage form of claim 20, wherein the therapeutic agent
is selected from a group consisting of dronabinol, glutethimide,
methylphenidate, nabilone, anabolic steroids, methylprylon,
ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline,
levomethadyl, benzphetamine, chlorphentermine, diethylpropion,
phentermine, mebutamate, chlortermine, phenylacetone, dronabinol,
nabilone, benphetamine, chloral hydrate, ethclorovynol,
paraldehyde, midazolam, detropropoxyphene, pharmaceutically
acceptable salts thereof, and mixtures thereof.
37. The oral dosage form of claim 1, wherein the therapeutic agent
is selected from the group consisting of 5-ASA, steroids,
laxatives, octreotide, cisapride, anticholinergics, calcium channel
blockers, DNA for delivery to the cells of the colon, glucosamine,
thromboxane A.sub.2 synthetase inhibitor, 5HT3-antagonists,
antibodies against infectious bacteria, antiviral agents, heparins,
insulin, calcitonins, human growth hormone, growth hormone
releasing hormon, interferons, somatostatin and analogues thereof,
erythropoietin, granulocyte colony stimulating factor, parathyroid
hormone, luteinising hormone releasing hormone and analogues
thereof, atrial natriuretic factor, vasopressin, desmopressin,
calcitonin gene related peptide, and analgesics.
38. The oral dosage form of claim 1, wherein the ratio of
therapeutic agent to adverse-effect agent is from about 1:1 to
50:1.
39. A method for treating pain, comprising administering to a
patient in need thereof the oral dosage form of claim 1.
Description
1. FIELD OF THE INVENTION
This invention relates generally to an oral dosage form comprising
a therapeutic agent and an adverse-effect agent.
2. BACKGROUND OF THE INVENTION
Many therapeutic agents are highly effective for improving quality
of life but, because of their abuse potential, may attract drug
abusers. For example, opioids are excellent analgesic agents that
can control severe and/or chronic pain, such as cancer pain and
post-operative pain, but are also subject to abuse by drug
users.
Opioids, also known as opioid agonists, are a group of drugs that
exhibit opium- or morphine-like properties. Opioids are employed
primarily as moderate to strong analgesic agents, but provide other
pharmacological effects as well.
There have been previous attempts in the art to control the
potential for abuse of opioid analgesics. For example, sustained
release forms enable an active ingredient to work over many hours,
and such slow release tends to deter illicit use of opioids because
abusers tend to prefer the quick euphoric rush, also known as the
"burst," provided by immediate release opioids. Drug abusers,
however, can defeat the controlled release design by crushing or
dissolving the original drug form, for example a tablet, giving
them access to snortable and/or injectable opioids that provide the
burst. Accordingly, there is an important need for more effective
methods of deterring opioid abuse while still keeping orally
administered opioids available to patients who have a legitimate
need for them.
Prior art approaches to this problem have involved combining an
opioid with an opioid antagonist. When administered orally, these
combinations provide the pharmacologic action of the opioid with
minimal action of the antagonist. When administered parenterally,
however, the antagonist can be-profoundly antagonistic to the
opioid. Particular examples of such combinations include
compositions comprising naloxone and morphine or oxymorphone (U.S.
Pat. No. 3,493,657 to Lewenstein et al.); methadone and naloxone
(U.S. Pat. No. 3,773,955 to Pachter et al.); methadol or acetyl
methadol and naloxone (U.S. Pat. No. 3,966,940 to Pachter et al.);
oxycodone and naloxone (U.S. Pat. No. 4,457,933 to Gordon et al.);
and buprenorphine and naloxone (U.S. Pat. No. 4,582,835 to Lewis et
al.). Also, the combination of pentazocine hydrochloride and
naloxone has been marketed in the United States as TALWIN NX
(Sanofi-Winthrop); VALORON N, a combination of tilidine and
naloxone, has been available in Germany for the management of
severe pain since 1978; and TEMGESIC NX, a combination of
buprenorphine and naloxone, has been available in New Zealand since
1991.
U.S. Pat. No. 6,228,863 to Palermo et al. discloses an oral dosage
form of an opioid agonist and an opioid antagonist that reduces the
abuse potential of the opioid by combining the agonist and
antagonist such that at least two steps are required to separate
them.
U.S. Pat. No. 5,935,975 to Rose et al. discloses a method for
treating drug dependency by the combined administration of the drug
or an agonist of the drug and an antagonist of the drug.
There remains, however, a clear need in the art for more advanced
oral dosage forms that are effective for preventing abuse and
useful for delivering a therapeutic agent.
3. SUMMARY OF THE INVENTION
The present invention relates to an oral dosage form comprising a
first composition and a second composition, wherein the first
composition comprises a therapeutic agent and the second
composition comprises an adverse-effect agent, wherein the second
composition is coated with an inner acid-soluble layer and an outer
base-soluble layer.
The invention further relates to an oral dosage form comprising a
first composition and a second composition, wherein the first
composition comprises a therapeutic agent and is coated with an
inner base-soluble layer and an outer acid-soluble layer and the
second composition comprises an adverse-effect agent and is coated
with an inner acid-soluble layer and an outer base-soluble
layer.
The invention further relates to a method for treating or
preventing pain, comprising administering to a patient in need
thereof the oral dosage form of the invention. In one embodiment
the method comprises administering to a patient in need thereof an
oral dosage form comprising a first composition and a second
composition, wherein the first composition comprises an effective
amount of a therapeutic agent; the second composition comprises an
effective amount of an adverse-effect agent; an effective amount of
the therapeutic agent is released in the patient's small intestine;
and less than an effective amount of the adverse-effect agent is
released in the patient's gastrointestinal tract.
The invention still further relates to a method for preparing an
oral dosage form comprising a first composition and a second
composition, wherein the first composition comprises a therapeutic
agent and the second composition comprises an adverse-effect agent,
wherein the second composition is coated with an inner acid-soluble
layer and an outer base-soluble layer, the method comprising the
step of preparing the oral dosage form as set forth herein.
The invention still further relates to a method for preparing an
oral dosage form comprising a first composition and a second
composition, wherein the first composition comprises a therapeutic
agent and is coated with an inner base-soluble layer and an outer
acid-soluble layer and the second composition comprises an
adverse-effect agent and is coated with an inner acid-soluble layer
and an outer base-soluble layer, the method comprising the step of
preparing the oral dosage form as set forth herein.
4. BRIEF DESCRIPTION OF THE DRAWINGS
FIG. 1 shows a cross-sectional view of a coated granule of a first
composition useful in the oral dosage forms of the invention.
FIG. 2 shows a cross-sectional view of a coated granule of a second
composition useful in the oral dosage forms of the invention.
FIG. 3 shows a cross-sectional view of a first embodiment of the
invention, which is a capsule containing coated granules of a first
composition and coated granules of a second composition.
FIG. 4 shows a cross-sectional view of a second embodiment of the
invention, which is a two-layer tablet.
FIG. 5 shows a cross-sectional view of a third embodiment of the
invention, which is a tablet containing coated granules of a first
composition and coated granules of a second composition.
FIG. 6 shows a cross-sectional view of a fourth embodiment of the
invention, which is a coated tablet containing a first composition,
with granules of a coated second composition dispersed throughout
the first composition.
FIG. 7 shows a cross-sectional view of a fifth embodiment of the
invention, which is a tablet wherein a coated composition of the
adverse-effect agent is further coated with the therapeutic agent
and then the therapeutic agent is coated.
5. DETAILED DESCRIPTION OF THE INVENTION
The oral dosage form of the present invention comprises a first
composition and a second composition. The first composition
comprises a therapeutic agent, and the second composition comprises
an adverse-effect agent.
The term "therapeutic agent," as used herein, means any drug
intended to have a beneficial effect when administered to a
patient.
The term "adverse-effect agent," as used herein, means an agent
that (A) reduces or eliminates one or more pharmacological effects
of the therapeutic agent, such as a euphoric or toxic effect or (B)
causes an undesired physiological reaction, such as emesis.
In a first embodiment of the oral dosage form of the invention, the
second composition is coated with a layer that is substantially
insoluble in the gastrointestinal tract. Thus, when the oral dosage
form of the present invention is orally administered to a patient
as intended, only the therapeutic agent is released in the
gastrointestinal tract of the patient, and the adverse-effect agent
is not released. If the oral dosage form is tampered with so that
the coating on the second composition is damaged, however, then not
only the therapeutic agent but also the adverse-effect agent are
released upon administration.
In a second embodiment the second composition is coated with an
outer base-soluble layer and an inner acid-soluble layer, which is
not dissolved when orally administered to a patient.
In a third embodiment of the oral dosage form of the invention,
both the first composition and second composition have a coating
comprising at least two layers, an acid-soluble layer and a
base-soluble layer, but the order of the layers in the coating on
the first composition is different from that of the layers in the
coating on the second composition. The coating covering the first
composition comprises an outer acid-soluble layer and an inner
base-soluble layer, which are dissolved when orally administered to
a patient. On the other hand, the coating covering the second
composition comprises an outer base-soluble layer, which gets
dissolved when orally administered, and an inner acid-soluble
layer, which does not get dissolved when orally administered to a
patient.
When orally administered to a patient, the oral dosage form passes
through the stomach first, where its acidic environment dissolves
the first composition's outer acid-soluble layer, and then passes
into the small intestine, where its basic environment dissolves the
first composition's inner base-soluble layer. Here, the therapeutic
agent can be absorbed by the body. In contrast, the second
composition is coated with an outer base-soluble layer, which is
substantially insoluble in the stomach's acidic environment.
Therefore, the second composition passes through the stomach with
both the outer base-soluble layer and the inner acid-soluble layer
intact. When the second composition enters the small intestine, the
outer base-soluble layer dissolves, exposing the inner acid-soluble
layer, which is substantially insoluble in the small intestine's
basic environment, so that the adverse-effect agent cannot be
absorbed by the body. Thus, when the oral dosage form of the
present invention is orally administered to a patient, for example
a human, as intended, only the therapeutic agent is released in the
gastrointestinal tract and absorbed by the patient; the
adverse-effect agent is not released and, therefore, not available
for absorption into the body. Here, the therapeutic agent works as
if it were administered alone without the adverse-effect agent,
since only the therapeutic agent is available for absorption by the
body.
However, if the oral dosage form of the present invention is
tampered with, e.g., chewed, crushed, ground or dissolved,
particularly in a solvent with heat (e.g., greater than about
45.degree. C. to about 50.degree. C.), then not only the
therapeutic agent but also the adverse-effect agent becomes
available for absorption into the body. The adverse-effect agent
can then exert its effect by either reducing the effect of the
therapeutic agent or eliciting an unpleasant effect in the patient.
Thus, where the adverse-effect agent is an antagonist of the
therapeutic agent, the effects of the therapeutic agent are
drastically diminished or even eliminated by the effects of the
adverse-effect agent. For example, where the therapeutic agent is
an opioid agonist and the adverse-effect agent is an opioid
antagonist, and the oral dosage form is tampered with, the opioid
antagonist becomes bioavailable, interfering with opioid-receptor
binding and reducing the opioid antagonist's pharmacological
effects. Accordingly, only patients who take the dosage form of the
present invention as intended, i.e, orally as an intact dosage
form, can experience the full pharmacological effects of the
therapeutic agent. Where the adverse-effect agent is an emetic
agent and the oral dosage form is tampered with, the emetic agent
induces vomiting which discourages the user from tampering with the
dosage form. Moreover, where the adverse-effect agent causes
vomiting the oral dosage form of the invention not only discourages
users from tampering with it, but can also be effective to remove
the therapeutic agent from subject's body. Abusing the therapeutic
agent becomes less desirable when present in the oral dosage form
of the present invention because, when tampered with, the
adverse-effect agent exerts its undesirable effects.
In one embodiment of the present invention, the first composition
is intended to be released slowly after it is orally administered
to the subject. This prevents the burst, which some abusers seek.
The first composition can be formulated as a slow release
formulation, for example, by further coating the first composition
with a sustained-release coating that slowly dissolves so that all
the therapeutic agent is not released at once. In the embodiments
where the first composition is coated with an outer acid-soluble
layer and an inner base-soluble layer, the sustained-release
coating is an innermost layer. In another embodiment the first
composition can be formulated as a slow release formulation by
incorporating the therapeutic agent into a matrix that slowly
releases the therapeutic agent over time. Therapeutic agents
intended to be released slowly, when orally administered to a
subject, may have side effects if released all at once, rather than
slowly. The coated second composition prevents tampering, which
would result in immediate release of the therapeutic agent.
FIG. 1 shows a cross-sectional view of an embodiment of the coated
first composition 10. A first composition 14 is covered with an
innermost sustained-release coating 13 (optional), an inner
base-soluble layer 12, and an outer acid-soluble layer 11.
FIG. 2 shows a cross-sectional view of an embodiment of the coated
second composition 20. A second composition 24 is covered with an
inner acid-soluble layer 23, an outer base-soluble layer 22 and an
outermost layer that is substantially insoluble in the
gastrointestinal tract 21 (optional).
5.1 Therapeutic Agent
Any kind of therapeutic agent can be used in the oral dosage forms
of the present invention. In one embodiment the oral dosage from is
used in situations where there is a potential toxicity or overdose
associated with the uncontrolled release of the drug due to
tampering with the dosage form. Examples of useful therapeutic
agents include, but are not limited to, analgesics,
anti-inflammatory agents, anthelmintics, anti-arrhythmic agents,
anti-bacterial agents, anti-viral agents, anti-coagulants,
anti-depressants, anti-diabetics, anti-epileptics, anti-fungal
agents, anti-gout agents, anti-hypertensive agents, anti-malarials,
anti-migraine agents, anti-muscarinic agents, anti-neoplastic
agents, erectile-dysfunction-improvement agents,
immunosuppressants, anti-protozoal agents, anti-thyroid agents,
anxiolytic agents, sedatives, hypnotics, neuroleptics,
.beta.-blockers, cardiac ionotropic agents, corticosteroids,
diuretics, anti-parkinsonian agents, gastrointestinal agents,
histamine receptor antagonists, keratolytics, lipid regulating
agents, anti-anginal agents, cox-2-inhibitors, leukotriene
inhibitors, macrolides, muscle relaxants, nutritional agents,
opioid analgesics, protease inhibitors, sex hormones, stimulants,
muscle relaxants, anti-osteoporosis agents, anti-obesity agents,
cognition enhancers, anti-urinary incontinence agents, nutritional
oils, anti-benign prostate hypertrophy agents, essential fatty
acids, and non-essential fatty acids. The first composition can
comprise more than one therapeutic agent.
The phrase "therapeutic agent" is also meant to encompass all
pharmaceutically acceptable salts of the therapeutic agent.
Pharmaceutically acceptable salts include, but are not limited to,
metal salts, such as sodium salts, potassium salts, and lithium
salts; alkaline earth metals, such as calcium salts, magnesium
salts, and the like; organic amine salts, such as triethylamine
salts, pyridine salts, picoline salts, ethanolamine salts,
triethanolamine salts, dicyclohexylamine salts,
N,N'-dibenzylethylenediamine salts, and the like; inorganic acid
salts such as hydrochloride salts, hydrobromide salts, sulfate
salts, phosphate salts, and the like; organic acid salts such as
formate salts, acetate salts, trifluoroacetate salts, maleate
salts, tartrate salts, and the like; sulfonate salts such as
methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate
salts, and the like; and amino acid salts, such as arginate salts,
asparginate salts, glutamate salts, and the like.
In another embodiment the therapeutic agent has potential for
abuse. The abuse potential of a drug is established by many
factors, which may include the following: (1) the capacity of the
drug to produce the kind of physical dependence in which drug
withdrawal causes sufficient distress to bring about drug-seeking
behavior; (2) the ability to suppress withdrawal symptoms caused by
withdrawal from the drug; and (3) the degree to which the drug
induces euphoria similar to that produced by morphine and other
opioids. The term "a therapeutic agent having abuse potential," as
used herein, refers to a therapeutic agent having at least one of
the above-identified factors. Examples of therapeutic agents having
abuse potential include, but are not limited to, opioids,
benzodiazepines, barbiturates, and stimulants, such as
methylphenidate and amphetamines.
The term "opioid" refers to a substance that binds, optionally
stereo-specifically, to any of several subspecies of opioid
receptors and produces an agonist action. Opioids include, but are
not limited to, alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, desomorphine, dextromoramide,
dezocine, diampromide, diamorphone, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, etorphine,
dihydroetorphine, fentanyl, hydrocodone, hydromorphone,
hydromorphodone, hydroxypethidine, isomethadone, ketobemidone,
levorphanol, levophenacylmorphan, lofentanil, meperidine,
meptazinol, metazocine, methadone, metopon, morphine, myrophine,
narceine, nicomorphine, norlevorphanol, normethadone, nalorphine,
nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, PANTOPON, papaveretum, paregoric, pentazocine,
phenadoxone, phendimetrazine, phendimetrazone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propoxyphene, propylhexedrine, sufentanil,
tilidine, tramadol, pharmaceutically acceptable salts thereof, and
mixtures thereof.
In certain embodiments, the opioid agonist is selected from the
group consisting of hydrocodone, morphine, hydromorphone,
oxycodone, codeine, levorphanol, meperidine, methadone,
oxymorphone, buprenorphine, fentanyl and derivatives thereof,
dipipanone, heroin, tramadol, etorphine, dihydroetorphine,
butorphanol, levorphanol, pharmaceutically acceptable salts
thereof, and mixtures thereof. In one embodiment the opioid agonist
is oxycodone or hydrocodone.
The term "benzodiazepines" refers to drugs that are derivatives of
benzodiazepine and are able to depress the central nervous system.
Benzodiazepines include, but are not limited to, alprazolam,
bromazepam, chlordiazepoxied, clorazepate, diazepam, estazolam,
flurazepam, halazepam, ketazolam, lorazepam, nitrazepam, oxazepam,
prazepam, quazepam, temazepam, triazolam, methylphenidate,
pharmaceutically acceptable salts thereof, and mixture thereof.
Barbiturates refer to sedative-hypnotic drugs derived from
barbituric acid (2,4,6,-trioxohexahydropyrimidine). Barbiturates
include, but are not limited to, amobarbital, aprobarbotal,
butabarbital, butalbital, methohexital, mephobarbital, metharbital,
pentobarbital, phenobarbital, secobarbital, pharmaceutically
acceptable salts thereof, and mixtures thereof.
Stimulants refer to drugs that stimulate the central nervous
system. Stimulants include, but are not limited to, amphetamines,
such as amphetamine, amphetamine, dextroamphetamine resin complex,
dextroamphetamine, methamphetamine, methylphenidate,
pharmaceutically acceptable salts thereof and mixtures thereof.
Other examples of therapeutic agent having potential for abuse
include, but are not limited to, dronabinol, glutethimide,
methylphenidate, nabilone, anabolic steroids, methylprylon,
ethchlorovynol, ethinamate, fenfluramine, meprobamate, pemoline,
levomethadyl, benzphetamine, chlorphentermine, diethylpropion,
phentermine, mebutamate, chlortermine, phenylacetone, dronabinol,
nabilone, benphetamine, chloral hydrate, ethclorovynol,
paraldehyde, midazolam, and detropropoxyphene.
The therapeutic agent may also be an agent intended for delivery to
the colon. Therapeutic agents intended for delivery to the colon
include, but are not limited to, agents that act locally in the
colonic region to treat a colon diseases such as irritable bowel
syndrome, irritable bowel disease, Crohns disease, constipation,
post operative atony, gastrointestinal infections, and therapeutic
agents that deliver antigenic material to the lymphoid tissue.
Agents for the treatment of colon disease, include, but are not
limited to 5-ASA; steroids, such as hydrocortisone and budesonide;
laxatives; octreotide; cisapride; anticholinergics; opioids;
calcium channel blockers; DNA for delivery to the cells of the
colon; glucosamine; thromboxane A.sub.2 synthetase inhibitors, such
as Ridogrel; 5HT3-antagonists, such as ondansetron; antibodies
against infectious bacteria, such as Clostridium difficile; and
antiviral agents, for example, for the prophylaxis of HIV.
Alternatively, the therapeutic agent can be an agent that is
systemically active and for which absorption is improved in the
colon region. Such drugs include polar compounds such as: heparins;
insulin; calcitonins; human growth hormone (HGH); growth hormone
releasing hormone (GHRH); interferons; somatostatin and analogues
such as octreotide and vapreotide; erythropoietin (EPO);
granulocyte colony stimulating factor (GCSF); parathyroid hormone
(PTH); luteinising hormone releasing hormone (LHRH) and analogues
thereof; atrial natriuretic factor (ANF); vasopressin;
desmopressin; calcitonin gene related peptide (CGRP); and
analgesics.
5.2 Adverse-Effect Agent
The adverse-effect agent can be an agent that reduces or eliminates
the therapeutic agent's pharmacological activities including, but
not limited to: (1) the capacity of the drug to produce the kind of
physical dependence in which drug withdrawal causes sufficient
distress to bring about drug-seeking behavior; (2) the ability to
suppress withdrawal symptoms caused by withdrawal from the drug;
and (3) the induction of euphoria similar to that produced by
morphine and other opioids. Adverse-effect agents that reduce or
eliminate the pharmacological effects of the therapeutic agent
include, but are not limited to, antagonists of the therapeutic
agent agonist. When an opioid agonist is used as the therapeutic
agent in the oral dosage form of the present invention, an opioid
antagonist can be used as the adverse-effect agent. Likewise, when
a benzodiazepine is used as the therapeutic agent in the oral
dosage form of the present invention, a benzodiazepine antagonist
can be used as the adverse-effect agent. When a barbiturate is used
as a therapeutic agent in the oral dosage form of the present
invention, a barbiturate antagonist can be used as the
adverse-effect agent. When an amphetamine is used as a therapeutic
agent in the oral dosage form of the present invention, an
amphetamine antagonist can be used as the adverse-effect agent.
When the therapeutic agent is toxic when dosed above its normal
therapeutic range, i.e., there is a potential for an overdose, then
an antidote of the toxic therapeutic agent can be used as the
adverse-effect agent.
The phrase "adverse-effect agent" is also meant to encompass all
pharmaceutically acceptable salts of the adverse-effect agent.
Pharmaceutically acceptable salts include, but are not limited to,
metal salts, such as sodium salts, potassium salts, and lithium
salts; alkaline earth metals, such as calcium salts, magnesium
salts, and the like; organic amine salts, such as triethylamine
salts, pyridine salts, picoline salts, ethanolamine salts,
triethanolamine salts, dicyclohexylamine salts,
N,N'-dibenzylethylenediamine salts, and the like; inorganic acid
salts such as hydrochloride salts, hydrobromide salts, sulfate
salts, phosphate salts, and the like; organic acid salts such as
formate salts, acetate salts, trifluoroacetate salts, maleate
salts, tartrate salts, and the like; sulfonate salts such as
methanesulfonate salts, benzenesulfonate salts, p-toluenesulfonate
salts, and the like; and amino acid salts, such as arginate salts,
asparginate salts, glutamate salts, and the like.
Opioid antagonists that can be used as the adverse-effect agent of
the present invention include, but are not limited to, naloxone,
naltrexone, nalmefene, cyclazacine, levallorphan, and mixtures
thereof. In certain embodiments, the opioid antagonist is naloxone
or naltrexone.
Benzodiazepine antagonists that can be used as the adverse-effect
agent of the present invention include, but are not limited to,
flumazenil.
Barbiturate antagonist which can be used as the adverse-effect
agent of the present invention include, but are not limited to,
amphetamines, described herein.
Stimulant antagonists that can be used as the adverse-effect agent
of the present invention include, but are not limited to,
benzodiazepines, described herein.
In another embodiment of the present invention, the adverse-effect
agent is an agent that causes an undesired physiological reaction,
such as emesis. This type of adverse-effect agent can be used with
any kind of therapeutic agent including an opioid, a
benzodiazepine, a barbiturate, and a stimulant. Examples of emetic
agents suitable for use as the adverse-effect agent in the present
invention includes any drug that safely and effectively induces
vomiting after administration including, but not limited to, ipecac
and apomorphine.
5.4 Coatings
5.4.1. Coatings Insoluble in the Gastrointestinal Tract
Examples of useful coatings that are substantially insoluble in the
gastrointestinal tract include, but are not limited to, coatings
comprising a hydrophobic material. In one embodiment the coating
that is substantially insoluble in the gastrointestinal tract
comprises a cellulose polymer. In certain embodiments, the
cellulose polymer is a cellulose ether, a cellulose ester, or a
cellulose ester ether. In one embodiment, the cellulose polymers
have a degree of substitution, D.S., on the anhydroglucose unit of
from zero up to and including 3. By "degree of substitution" is
meant the average number of hydroxyl groups present on the
anhydroglucose-unit of the cellulose polymer that are replaced by a
substituting group. Representative cellulose polymers include, but
are not limited to, polymers selected from cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate,
cellulose diacetate, cellulose triacetate, mono, di, and
tricellulose alkanylates, mono, di, and tricellulose aroylates, and
mono, di, and tricellulose alkenylates. Exemplary cellulose
polymers include cellulose acetate having an acetyl content up to
about 21%; cellulose acetate having an acetyl content up to about
32 to 39.8%; cellulose acetate having a D.S. of about 1 to 2 and an
acetyl content of about 21 to 35%; and cellulose acetate having a
D.S. of about 2 to 3 and an acetyl content of about 35 to 44.8%. In
one embodiment, the cellulose polymer is ethylcellulose, cellulose
acetate, cellulose propionate (low, medium, or high molecular
weight), cellulose acetate propionate, cellulose acetate butyrate,
cellulose acetate phthalate, or cellulose triacetate. In one
embodiment, the ethylcellulose has an ethoxy content of about 44 to
55%.
More specific cellulose polymers include cellulose propionate
having a D.S. of about 1.8 and a propyl content of about 39.2 to
45% and a hydroxyl content of about 2.8 to 5.4%; cellulose acetate
butyrate having a D.S. of about 1.8, an acetyl content of about 13
to 15%, and a butyryl content of about 34 to 39%; cellulose acetate
butyrate having an acetyl content of about 2 to 29%, a butyryl
content of about 17 to 53%, and a hydroxyl content of about 0.5 to
4.7%; cellulose triacylate having a D.S. of about 2.9 to 3 such as
cellulose triacetate, cellulose trivalerate, cellulose trilaurate,
cellulose tripatmitate, cellulose trisuccinate, and cellulose
trioctanoate; cellulose diacylates having a D.S. of about 2.2 to
2.6 such as cellulose disuccinate, cellulose dipalmitate, cellulose
dioctanoate, cellulose dipentanoate, and coesters of cellulose such
as cellulose acetate butyrate, cellulose acetate octanoate
butyrate, and cellulose acetate propionate.
Additional cellulose polymers useful for coating the second
composition with a coating that is substantially insoluble in the
gastrointestinal tract include, but are not limited to,
acetaldehyde dimethyl cellulose acetate, cellulose acetate
ethylcarbamate, cellulose acetate methylcarbamate, and cellulose
acetate dimethylaminocellulose acetate.
Acrylic polymers are also useful for coating the second composition
with a coating that is substantially insoluble in the
gastrointestinal tract. Acrylic polymers include, but are not
limited to, acrylic resins comprising copolymers synthesized from
acrylic and methacrylic acid esters (e.g., the copolymer of acrylic
acid lower alkyl ester and methacrylic acid lower alkyl ester)
containing about 0.02 to 0.03 moles of a tri (lower alkyl) ammonium
group per mole of acrylic and methacrylic monomer. In one
embodiment, the acrylic resin is Eudragit RS 30 D manufactured by
Rohm Tech Inc. of Fitchburg, Mass. Eudragit RS 30 D is a water
insoluble copolymer of ethyl acrylate (EA), methyl methacrylate
(MM) and trimethylammonioethyl methacrylate chloride (TAM) in which
the molar ratio of TAM to the remaining components (EA and MM) is
1:40. Aqueous suspensions of acrylic resins such as EUDRAGIT RS can
be used to coat the adverse-effect agent of the invention.
In certain embodiments of the invention, the acrylic polymer is
selected from acrylic acid and methacrylic acid copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylates, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymers, poly(methyl methacrylate),
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic
acid anhydride), and glycidyl methacrylate copolymers.
When a cellulose polymer or an acrylic polymer is used as a coating
that is substantially insoluble in the gastrointestinal tract,
suitable plasticizers, e.g., acetyl triethyl citrate and/or acetyl
tributyl citrate, may also be admixed with the polymer. The coating
that is substantially insoluble in the gastrointestinal tract may
also contain additives such as coloring agents, talc, and/or
magnesium stearate, which are well known in the coating art.
Polymers useful for coating the second composition with a coating
that is substantially insoluble in the gastrointestinal tract also
include, but not limited to, poly(lactic/glycolic acid) ("PLGA")
copolymers, polylactides, polyglycolides, polyanhydrides,
polyorthoesters, polycaprolactones, polyphosphazenes,
polysaccharides, proteinaceous polymers, polyesters, polydioxanone,
polygluconate, polylactic-acid polyethylene oxide copolymers,
poly(hydroxybutyrate), polyphosphoesters, and mixtures thereof.
In certain embodiments, the polymer comprises a
poly(lactic/glycolic acid) copolymer, a copolymer of lactic and
glycolic acid, having a molecular weight of about 2,000 to about
500,000 daltons. The ratio of lactic acid to glycolic acid is from
about 100:0 to about 25:75, in one embodiment from about 65:35.
Poly(lactic/glycolic acid) may be prepared by the procedure set
forth in U.S. Pat. No. 4,293,539 to Ludwig et al., the disclosure
of which is expressly incorporated herein by reference thereto.
The coating that is substantially insoluble in the gastrointestinal
tract is of sufficient thickness to prevent release of the
adverse-effect agent from the second composition while it is in the
gastrointestinal tract. Many of the coatings that are substantially
insoluble in the gastrointestinal tract are slowly biodegraded or
dissolved in an aqueous environment and, after sufficient time,
will eventually release the adverse-effect agent. Accordingly, the
coating should be of a sufficient thickness that does not permit
the adverse effect agent to be released during the time that the
adverse-effect agent is present in the gastrointestinal tract. The
thickness of the coating will depend on the characteristics of the
coating composition being used.
5.4.2 Acid-Soluble Layer
In various embodiments, the coating useful in the present invention
comprises an acid-soluble layer. The term "acid-soluble layer"
refers to a layer that is substantially soluble at a pH of less
than about pH 5.0, but substantially insoluble at a pH of greater
than about pH 5.5. In one embodiment, the acid-soluble layer is
substantially soluble at a pH of less than about pH 4.0, but
substantially insoluble at a pH of greater than about pH 4.5. In
another embodiment, the acid-soluble layer is substantially soluble
at a pH of less than about pH 3.0, but substantially insoluble at a
pH of greater than about pH 3.5. The acid-soluble layer typically
comprises an acid-soluble polymer.
As used herein, the phrase "substantially soluble," when used to
describe a layer, means soluble to a degree that a portion of that
which the layer covers, for example, an acid-soluble layer, a
base-soluble layer, a first composition, or a second composition,
is made available to the environment of the gastrointestinal tract
in an effective amount.
As used herein, the phrase "substantially insoluble," when used to
describe a layer, means that the layer does not dissolve or does so
only to a degree that a portion of that which the layer covers, for
example, an acid-soluble layer, a base-soluble layer, a first
composition, or a second composition, is not made available to the
environment of the gastrointestinal tract or is made available to
the environment of the gastrointestinal tract in less than an
effective amount.
In one embodiment, the acid-soluble polymer has a
dimethylaminoethyl ammonium functionality. Such a polymer is
commercially available as EUDRAGIT E 100 or Eudragit E PO from Rohm
Pharma GmbH, Weiterstat, Germany. Examples of other suitable
acid-soluble polymers can be found in "Materials Used in
Pharmaceutical Formulations," edited by A. T. Florence, Society of
Chemical Industries, 1984.
5.4.3 Base-Soluble Layer
In various embodiments, the coating of the present invention
comprises a base-soluble layer. The term "base-soluble layer"
refers to a layer that is substantially soluble at a pH of greater
than about pH 5.5, but substantially insoluble at a pH of less than
about 5.0. In one embodiment, the base-soluble layer is
substantially soluble at a pH of greater than about pH 6.5, but
substantially insoluble at a pH of less than about 6.0. In another
embodiment, the base-soluble layer is substantially soluble at a pH
of greater than about pH 7.5, but substantially insoluble at a pH
of less than about 7.0. The base-soluble layer generally comprises
a base-soluble polymer. In one embodiment, the base-soluble polymer
is an anionic copolymer of methacrylic acid and methacrylates
having carboxylic acid functionalities. Such a polymer is
commercially available as EUDRAGIT L 100-55, EUDRAGIT L 30D-55,
EUDRAGIT L, or EUDRAGIT S 100 (commercially available from Rohm
Pharma GmbH, Weiterstat, Germany). Examples of other suitable
base-soluble polymers can be found in "Materials Used in
Pharmaceutical Formulations," edited by A. T. Florence, Society of
Chemical Industries, 1984.
5.4.4 Slow-Release Formulations
In one embodiment, the therapeutic agent is released slowly over
time. Suitable controlled-release formulations known to those of
ordinary skill in the art, including those described herein, can be
readily selected for use with the oral dosage forms of the
invention. Single unit dosage forms suitable for oral
administration, such as tablets, capsules, gelcaps, caplets, and
the like, that are adapted for controlled-release are encompassed
by the present invention.
The controlled release of the therapeutic agent from the first
composition can be stimulated by various inducers, for example pH,
temperature, enzymes, water, or other physiological conditions or
compounds. The controlled release of the therapeutic agent can be
achieved, for example by coating or admixing the therapeutic agent
with a controlled-release component. The term "controlled-release
component" in the context of the present invention is defined
herein as a compound or mixture of compounds, including polymers,
polymer matrices, gels, permeable membranes, liposomes,
microspheres, or the like, or a combination thereof, that
facilitates the controlled-release of the therapeutic agent from
the first composition of the oral dosage form of the invention.
As discussed above, in one embodiment of the invention the
therapeutic agent is formulated for controlled release by coating
the therapeutic agent with a sustained-release coating. The term
"sustained-release coating" refers to a coating made of one or more
materials that allows for the slow release of the drug over time.
In one embodiment, the sustained-release coating is a
pH-independent layer, i.e., a coating that has a defined
permeability that is not influenced by pH. The term "pH-independent
layer" means that the difference, at any given time, between the
amount of drug released at, e.g., pH 1.6, and the amount released
at any other pH, e.g., pH 7.2, when measured using a specific
method, such as, for example, the USP Paddle Method at 100 rpm in
900 ml aqueous buffer, is 10% (by weight) or less.
Any sustained-release coating known to those of ordinary skill in
the art can be used in the oral dosage form of the invention.
Sustained-release coatings are well known in the art (See, e.g.,
Remingtons Pharmaceutical Sciences, 18.sup.th ed. Mack Publishing
Co., Easton, Pa., 1990, p. 1670). Typically, the sustained-release
coating comprises a water-insoluble material, such as a wax or a
wax-like substance, fatty alcohol, shellac, zein, hydrogenated
vegetable oil, water insoluble cellulose, polymer of acrylic and/or
methacrylic acid, or any other slowly digestible or dissolvable
solid known in the art. The coating formulations useful in the
present invention should be capable of producing a strong,
continuous film that is smooth and elegant, capable of supporting
pigments and other coating additives, non-toxic, inert, and
tack-free. Generally, the film coat is applied to the first
composition, for example when in the form of a tablet or a granule,
to achieve a weight gain level from about 2 to about 25 percent.
However, the film coat may be lesser or greater depending upon the
physical properties of the therapeutic agent included in the
formulation and the desired release rate.
In one embodiment, the sustained-release coating comprises a
hydrophobic polymer. In another embodiment, the hydrophobic polymer
comprises a water-insoluble cellulosic polymer, such as an
alkylcellulose, for example ethylcellulose; an acrylic polymer; or
mixtures thereof.
In another embodiment, the sustained-release coating comprises an
acrylic polymer. Any acrylic polymer that is pharmaceutically
acceptable can be used. For example, the acrylic polymer can be an
acrylate or methacrylate, formed from one or more of acrylic acid,
methacrylic acid, acrylic acid esters, and methacrylic acid esters.
These polymers can be cationic, anionic, or non-ionic, so that it
is possible to obtain polymers that are soluble in, or resistant to
dissolution, over a wide range of pH values. Some acrylic polymers
useful for the purposes of the present invention are those that are
marketed under the trade name EUDRAGIT (commercially available from
Rohm Pharma GmbH, Weiterstat, Germany). Examples of suitable
acrylic polymers include, but are not limited to, acrylic acid and
methacrylic acid copolymers, methyl methacrylate polymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates polymers,
cyanoethyl methacrylate polymers, aminoalkyl methacrylate
copolymers, poly(acrylic acid), poly(methacrylic acid), methacrylic
acid alkylamine copolymers, poly(methyl methacrylate),
poly(methacrylic acid)(anhydride), polymethacrylate,
polyacrylamide, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers.
The acrylic polymer can comprise one or more ammonio methacrylate
copolymers. Ammonio methacrylate copolymers are well known in the
art, and are fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups. In order to obtain a desirable dissolution profile for a
given therapeutic agent, it might be necessary to incorporate two
or more ammonio methacrylate copolymers having differing physical
properties. For example, it is known that by changing the molar
ratio of the quaternary ammonium groups to neutral (meth)acrylic
esters, the permeability properties of the resultant coating can be
modified. One of ordinary skill in the art will readily know how to
combine monomers to provide a copolymer that releases the
therapeutic agent at the desired release rate. Copolymers of
acrylate and methacrylate having a quaternary ammonium group
functionality are commercially available as EUDRAGIT RS and
EUDRAGIT RL from Rohm Pharma GmbH, Weiterstat, Germany.
Other polymers suitable for use in the invention include, but are
not limited to, hydroxyalkylcelluloses; poly(lactic/glycolic acid)
("PLGA"); polylactide; polyglycolide; polyanhydrides;
polyorthoesters; polycaprolactone; polyphosphazenes;
polysaccharides; proteinaceous polymers; polyesters; polydioxanone;
polygluconate; polylactic-acid polyethylene oxide copolymers;
poly(hydroxybutyrate) polyphosphoesters; or mixtures thereof.
The inclusion of an effective amount of a plasticizer in the
aqueous dispersion of hydrophobic polymer can further improve the
physical properties of the film. For example, because
ethylcellulose has a relatively high glass-transition temperature
("Tg") and does not form flexible films under normal coating
conditions, it is often necessary to plasticize the ethylcellulose
before using it as a coating material.
The suitability of a plasticizer may relate to its affinity or
solvating power for the polymer and its effectiveness for
interfering with polymer-polymer attachments. Such activity imparts
a desired flexibility to the polymer by relieving molecular
rigidity. An important parameter in determining the suitability of
a plasticizer for a polymer is related to the Tg of the polymer.
The Tg is related to the temperature or temperature range where
there is a fundamental change in the physical properties of the
polymer. This change does not reflect a change in state, but rather
a change in the macromolecular mobility of the polymer. Below the
Tg, polymer chain mobility is severely restricted. Thus, for a
given polymer, if the Tg is above room temperature, the polymer
will behave as a glass at room temperature, being hard,
non-pliable, and rather brittle: properties that are restrictive
for a film coating since the coated dosage form may be subjected to
a certain amount of external stress. Incorporation of suitable
plasticizers into the polymer matrix effectively reduces the Tg, so
that under ambient conditions the films are softer, more pliable
and often stronger, and, thus, better able to resist mechanical
stress. Other aspects of suitable plasticizers include their
ability to act as a good "swelling agent," especially for
ethylcellulose, and to improve the solubility profile of the
coating in water.
Examples of suitable plasticizers for ethylcellulose include
dibutyl sebacate, diethyl phthalate, triethyl citrate, and tributyl
citrate, although other plasticizers (such as acetylated
monoglycerides, phthalate esters and castor oil) can be used. In
one embodiment, triethyl citrate is a plasticizer for the aqueous
dispersions of ethyl cellulose.
Examples of suitable plasticizers for the acrylic polymers useful
in the present invention include, but are not limited to, citric
acid esters such as triethyl citrate, tributyl citrate, dibutyl
phthalate, and 1,2-propylene glycol. Other plasticizers suitable
for enhancing the elasticity of the films formed from acrylic
films, such as EUDRAGIT RL/RS lacquer solutions, include
polyethylene glycols, propylene glycol, diethyl phthalate, castor
oil, and triacetin. The plasticizer is typically added to a
solution of the polymer in an aqueous or non-aqueous solvent that
is used to coat the first composition.
Generally, the amount of plasticizer included in a coating solution
is based on the concentration of the coating. In one embodiment,
the amount of plasticizer included in a coating solution of
ethylcellulose is from about 1 to about 50 percent by weight of the
ethylcellulose. In another embodiment, the amount of plasticizer
included in a coating solution of an aqueous dispersion of acrylic
polymer is about 20%. The necessary concentration of the
plasticizer for a particular coating solution and method of
application can be readily determined by one of ordinary skill in
the art without undue experimentation.
A commercially available aqueous dispersion of ethylcellulose
suitable for use in the invention is AQUACOAT (commercially
available from FMC Corp., Philadelphia, Pa., U.S.A.). AQUACOAT is
prepared by dissolving ethylcellulose in a water-immiscible organic
solvent and then emulsifying the organic solvent in water in the
presence of a surfactant and a stabilizer. After homogenization to
generate submicron droplets, the organic solvent is evaporated
under vacuum to form a pseudolatex. Plasticizer is not incorporated
in the pseudolatex during the manufacturing phase; therefore, prior
to using the pseudolatex as a coating, it is necessary to
intimately mix the AQUACOAT with a suitable plasticizer.
Another commercially available aqueous dispersion of ethylcellulose
suitable for use in the invention is SURELEASE (commercially
available from Colorcon, Inc., West Point, Pa., U.S.A.).
In one embodiment, the acrylic coating comprises an acrylic resin
lacquer used in the form of an aqueous dispersion, such as
EUDRAGIT. In further embodiments, the acrylic coating comprises a
mixture of two acrylic resin lacquers commercially available from
Rohm Pharma GmbH, Weiterstat, Germany under the tradenames EUDRAGIT
RL 30 D and EUDRAGIT RS 30 D. These materials are copolymers of
acrylic and methacrylic esters having a low content of quaternary
ammonium groups, the molar ratio of ammonium groups to the
remaining neutral (meth)acrylic esters being 1:20 in EUDRAGIT RL 30
D and 1:40 in EUDRAGIT RS 30 D. The mean molecular weight of these
materials is about 150,000. The code designations RL (high
permeability) and RS (low permeability) refer to the permeability
properties of these agents. EUDRAGIT RL/RS mixtures are
substantially insoluble in water and in digestive fluids. However,
coatings formed from the same are swellable and permeable in
aqueous solutions and digestive fluids. The EUDRAGIT RL/RS
dispersions useful in the present invention can be mixed together
in any desired ratio in order to ultimately obtain a
controlled-release formulation having a desirable dissolution
profile. Desirable controlled-release formulations can be obtained,
for instance, from a coating derived from 100% EUDRAGIT RL; 50%
EUDRAGIT RL, 50% EUDRAGIT RS; and 10% EUDRAGIT RL, 90% Eudragit RS
(each commercially available from Rohm Pharma GmbH, Weiterstat,
Germany).
The sustained-release coating can also comprise a mixture of a
hydrophobic material and a hydrophilic material. The ratio of
hydrophobic material to hydrophilic material is determined by,
among other factors, the required release rate of the therapeutic
agent and the solubility characteristics of the materials selected.
Hydrophilic materials include, but are not limited to,
polyvinylpyrrolidone and water soluble celluloses, such as
hydroxypropylmethyl cellulose. Examples of combinations of
hydrophobic material and hydrophilic material useful for the
sustained-release coating include, but are not limited, to a
combination of shellac and polyvinylpyrrolidone and a combination
of ethyl cellulose and hydroxypropylmethyl cellulose.
Alternatively, the therapeutic agent can be dispersed in a
controlled-release matrix. The phrase "controlled-release matrix,"
as used herein means a matrix that slowly releases the therapeutic
agent over time. Any controlled-release matrix can be used in the
oral dosage form of the invention. Certain controlled-release
matrices are known for oral formulations (See, e.g., Remingtons
Pharmaceutical Sciences, 18.sup.th ed. Mack Publishing Co., Easton,
Pa., 1990, p. 1684-1685). Other examples of useful
controlled-release matrices are described in U.S. Pat. Nos.
6,143,328 to Heafield et al.; U.S. Pat. No. 6,063,405 to Drizen et
al.; U.S. Pat. No. 5,462,747 to Radebaugh et al.; U.S. Pat. No.
5,451,409 to Rencher et al.; U.S. Pat. No. 5,334,392 to Cuine et
al.; and 5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351,
5,356,467, and 5,472,712, each to Oshlack et al., the contents of
which are expressly incorporated herein by reference thereto.
Particularly useful controlled-release matrices for opioids are
described in U.S. Pat. No. 6,143,328 to Heafield et al. and U.S.
Pat. Nos. 5,266,331, 5,549,912, 5,508,042, 5,656,295, 5,324,351,
5,356,467, and 5,472,712, each to Oshlack et al.
The controlled-release matrix can be a fusible hydrophobic
material, optionally combined with a hydrophilic material. The
hydrophobic fusible material can be, for example, a hydrophobic
polymer or a natural or synthetic wax or oil, such as hydrogenated
vegetable oil or hydrogenated castor oil, which in one embodiment
has a melting point of from about 35 to 100.degree. C., and in
another embodiment from about 45 to 90.degree. C. The hydrophilic
material can be a hydrophilic polymer; a water soluble fusible
material, such as polyethylene glycol; or a water soluble
particulate material, such as dicalcium phosphate or lactose.
The therapeutic agent dispersed in a controlled-release matrix can
be prepared by formulating, e.g., using dry or wet granulation or
by blending, the therapeutic agent with a component other than the
fusible component. Suitable non-fusible materials for inclusion in
a controlled release matrix include, but are not limited to:
(a) hydrophilic or hydrophobic polymers, such as gums, cellulose
ethers, protein-derived materials, nylon, acrylic resins,
polylactic acid, polyvinylchloride, starches,
polyvinylpyrrolidones, and cellulose acetate phthalate. Of these
polymers, cellulose ethers, for example substituted cellulose
ethers such as alkylcelluloses (e.g., ethylcellulose),
C.sub.1-C.sub.6 hydroxyalkylcelluloses (e.g.,
hydroxypropylcellulose and hydroxyethyl cellulose), and acrylic
resins (e.g., methacrylates such as methacrylic acid copolymers)
are used in one embodiment. The controlled-release matrix can
conveniently contain between 1% and 80% (by weight) of the
hydrophobic and/or hydrophilic polymer.
(b) digestible, long chain (C.sub.8-C.sub.50, in one embodiment
C.sub.8-C.sub.40) substituted or unsubstituted hydrocarbons, such
as fatty acids; hydrogenated vegetable oils; fatty alcohols, such
as lauryl, myristyl, stearyl, cetyl or, in one embodiment
cetostearyl alcohol; glyceryl esters of fatty acids, for example,
glyceryl monostearate; mineral oils; and waxes, such as beeswax,
glycowax, castor wax, and carnauba wax. Hydrocarbons having a
melting point of between about 25.degree. C. and 90.degree. C. are
used in one embodiment. Of these long chain hydrocarbon materials,
fatty (aliphatic) alcohols are useful in one embodiment. The
controlled-release matrix may contain up to 60% (by weight) of at
least one digestible, long chain hydrocarbon.
(c) Polyalkylene glycols. The controlled-release matrix may contain
up to 60% (by weight) of at least one polyalkylene glycol.
A suitable controlled-release matrix for use in the oral dosage
form of the invention comprises one or more cellulose ethers or
acrylic resins, one or more C.sub.12-C.sub.36, in one embodiment
C.sub.12-C.sub.22, aliphatic alcohols, and/or one or more
hydrogenated vegetable oils. A particular suitable matrix comprises
one or more alkylcelluloses, one or more C.sub.12-C.sub.36, in one
embodiment C.sub.12-C.sub.22, aliphatic alcohols, and optionally
one or more polyalkylene glycols. In another embodiment the matrix
contains between about 0.5% and 60%, and in another embodiment,
between 1% and 50% (by weight) of the cellulose ether.
The acrylic resin is for example a methacrylate such as methacrylic
acid copolymer USNF Type A (EUDRAGIT L), Type B (EUDRAGIT S,), Type
C (EUDRAGIT L 100-55), EUDRAGIT NE 30 D, EUDRAGIT E, EUDRAGIT RL,
or EUDRAGIT RS (commercially available from Rohm Pharma GmbH,
Weiterstat, Germany). In one embodiment the matrix contains between
about 0.5% and 60% by weight, and in another embodiment between 1%
and 50% by weight of the acrylic resin.
In the absence of polyalkylene glycol, the matrix in one embodiment
contains between about 1% and 40%, in another embodiment between
about 2% and 36% (by weight) of the aliphatic alcohol. When
polyalkylene glycol is present in the oral dosage form, then the
combined weight of the aliphatic alcohol and the polyalkylene
glycol in one embodiment constitutes between about 2% and 40%, in
another embodiment between about 2 and 36% (by weight) of the
matrix.
The polyalkylene glycol may be, for example, polypropylene glycol
or, in one embodiment, polyethylene glycol. The number average
molecular weight of the at least one polyalkylene glycol is in one
embodiment between 200 and 15,000, and in another embodiment
between 400 and 12,000.
The controlled-release matrix containing the therapeutic agent can
readily be prepared by dispersing the therapeutic agent in the
components of the matrix using conventional pharmaceutical
techniques including, but not limited to, melt granulation, wet
granulation, dry blending, dry granulation, and
co-precipitation.
The controlled-release formulations slowly release the therapeutic
agent when ingested and exposed to gastric and/or intestinal
fluids.
5.4.5 Coating Process
In one embodiment the first and second compositions are solids,
such as, but not limited to, granules, fine granules, pills, beads,
capsules, tablets, or powders. Methods for preparing these solids
are well known in the art. The compositions can additionally
comprise any conventional pharmaceutically acceptable excipient
such as a binding agent (e.g., pregelatinised maize starch,
polyvinylpyrrolidone or hydroxypropyl methylcellulose); filler
(e.g., lactose, microcrystalline cellulose or calcium hydrogen
phosphate); lubricant (e.g., magnesium stearate, talc or silica);
disintegrant (e.g., potato starch or sodium starch glycolate); or
wetting agent (e.g., sodium lauryl sulphate). Such compositions, if
desired, can also contain a minor amount of an emulsifying agent or
a pH-buffering agent. In one embodiment, the first and/or second
composition comprises a hydrophobic material to provide the
composition with a sustained-release property. Examples of useful
hydrophobic material are disclosed in section 5.4.4, supra. Solid
compositions can be prepared by using conventional methods known in
the art, for example, wet granulation, melt extrusion, and
tableting by compression.
The solid compositions are coated with layers by applying one or
more coating mixtures. Coating mixtures are prepared by any
conventional means, for example, by dissolving the above-mentioned
polymers and optionally plasticizers in a suitable solvent or
mixture of solvents, for example water, methanol, ethanol,
isopropanol, acetone, ethylacetate, ethylene chloride, or mixtures
thereof. Examples of plasticizers include, but are not limited to,
citric acid esters, such as triethyl citrate and tributyl citrate;
dibutyl phthalate; 1,2-propylene glycol; polyethylene glycols;
castor oil; and triacetin. If the coating mixture is an aqueous
dispersion, a small amount of talc, glyceral monostearate, or
colloidal silicon dixide may be added to reduce the tendency of the
aqueous dispersion to stick during processing. The coating mixture
can also contain additives such as coloring agents and/or magnesium
stearate, which are well known in the coating art.
The coating solution can be applied to the solid composition by any
means available to those of ordinary skill in the art such as, for
example, spraying or dipping. Conventional coating apparatuses,
well known to those of ordinary skill in the art, can be used to
coat the solid composition (See, e.g., Remingtons Pharmaceutical
Sciences, 18.sup.th ed. Mack Publishing Co., Easton, Pa., 1990).
Conventional coating apparatuses include, but are not limited to,
coating-granulating apparatuses of the centrifugal fluidized type,
pan-coating apparatuses, and fluidized-bed granulating coating
apparatuses. For example, a Wuster fluidized-bed system can be used
in which an air jet, injected from underneath, fluidizes the coated
material and effects drying while the polymer coating is sprayed
on. When the solid composition is coated with more than one
coating, the first coating solution is applied and then allowed to
dry before the second coating solution is applied. In one
embodiment, the coating solutions are applied to provide a dosage
form that has a dissolution profile substantially unaffected by
exposure to accelerated-storage conditions.
The phrase "accelerated-storage conditions," as used herein, means
storage conditions of elevated temperature and/or elevated relative
humidity to which the oral dosage form is subjected for the purpose
of obtaining regulatory approval, e.g., the FDA for approval in the
U.S., and an expiration date. For example, a generally accepted
test employed in FDA guidelines relates to the storage of a drug
product (i.e., in its container and package) at 40.degree. C. and
75% Relative Humidity (RH). The length of time that the drug
product can be stored under these conditions without chemically
degrading and with its dissolution and physical characteristics
remaining unchanged, is used to determine the expiration date of
the drug product. For example, storage for three months without
chemical degradation and without change in dissolution or
appearance can result in the drug product being accorded a two year
expiration date. Other generally accepted accelerated tests include
those where the drug product is subjected to storage at 37.degree.
C. and 80% relative humidity for one month or longer, in one
embodiment three months.
5.5 Oral Dosage Form
5.5.1 Amount Per Dosage Unit
In the oral dosage form of the present invention, the amount of the
therapeutic agent per dosage unit is that which is an effective
amount for its particular indication and is independent of the
amount of the adverse-effect agent. For example, if the therapeutic
agent is an opioid agonist, the amount of the opioid agonist in the
oral dosage form of the present invention is generally from about
75 ng to about 1000 mg, in one embodiment from about 75 ng to about
750 mg. One of ordinary skill in the art can readily determine,
without undue experimentation, the amount of therapeutic agent
needed for a particular indication.
The amount of the adverse-effect agent in the oral dosage form of
the present invention is such that the adverse-effect agent can
give the intended adverse effect. When the adverse-effect agent is
intended to reduce or eliminate the pharmacological effects of the
therapeutic agent, the amount of the adverse-effect agent in the
oral dosage form is at least sufficient to reduce or eliminate the
effects of the therapeutic agent when both agents are released.
In the present invention, the phrase "to reduce or eliminate the
effects of the therapeutic agent," as used herein, means that the
effects of the therapeutic agent that attract potential abusers are
eliminated or become lessened. For example, an adverse-effect agent
can reduce the euphoric effect of a therapeutic agent.
When the adverse-effect agent is an opioid antgonist, the amount of
the opioid antagonist, present in a oral dosage form of the present
invention, can be from about 10 ng to 275 mg. The opioid
antagonists cyclazocine and naltrexone, when administered orally,
retain much of their efficacy with a long duration of action,
approaching 24 hours, Accordingly, amounts of less than 100 mg of
these opioid antagonists are typically used in the oral
formulations of the invention.
When the adverse-effect agent is intended to cause an undesired
physiological reaction, such as a emesis, the amount of the
adverse-effect agent in the oral dosage form is at least sufficient
to cause such effect upon release.
For safety reasons, the amount of the adverse-effect agent present
in the oral dosage form should not be harmful to humans even if
fully released. One of ordinary skill in the art can readily
determine, without undue experimentation, the amount of
adverse-effect agent needed to elicit the intended adverse-effect
without being harmful.
In certain embodiments of the present invention, the ratio of the
therapeutic agent to the adverse-effect agent in the oral dosage
form is about 1:1 to about 50:1 by weight, in one embodiment about
1:1 to about 20:1 by weight. In certain other embodiments, the
ratio is about 1:1 to about 10:1 by weight. In another embodiment
of the invention, the therapeutic agent includes oxycodone or
hydrocodone and is present in the amount of about 15-45 mg, and the
adverse-effect agent includes naltrexone and is present in about
0.5-5 mg.
In another embodiment the first composition has a sustained-release
coating, the therapeutic agent is an opioid agonist and the
adverse-effect agent is an opioid antagonist. In embodiments in
which the opioid agonist is hydrocodone, the sustained-release oral
dosage forms can include analgesic doses from about 5 mg to about
80 mg of hydrocodone per dosage unit. In oral dosage forms where
the opioid agonist is hydromorphone, it may be included in an
amount from about 2 mg to about 64 mg hydromorphone hydrochloride
per dosage unit. In another embodiment, the opioid agonist is
morphine, and the oral dosage forms of the present invention
include from about 2.5 mg to about 800 mg morphine per dosage unit.
In yet another embodiment, the opioid agonist is oxycodone and the
oral dosage forms include from about 2.5 mg to about 800 mg
oxycodone, in another embodiment from about 20 mg to about 30 mg
oxycodone per dosage unit. Controlled-release oxycodone
formulations are known in the art. The opioid agonist can be
tramadol in an amount from about 25 mg to 800 mg tramadol per
dosage unit. The dosage form can contain more than one opioid
agonist.
5.5.2 Embodiments of the Oral Dosage Form
In one embodiment, the first composition and the second composition
are coated as explained in section 5.4, supra to provide the first
coated composition and the second coated composition. As discussed
above, the first composition, comprising a therapeutic agent, is
coated with an outer acid-soluble layer, an inner base-soluble
layer and, optionally, an innermost sustained release coating; and
the second composition, comprising an adverse-effect agent, is
coated with an inner acid-soluble layer, an outer base-soluble
layer, and, optionally, a layer substantially insoluble in the
gastrointestinal tract. The first composition and the second
composition are then combined to provide a unit dosage of the oral
composition of the invention. In one embodiment, the first
composition and the second composition are similar in their size,
shape and color so that they cannot be readily distinguished from
each other. For example, the first composition and the second
composition can each be powders, granules, or beads that are
combined and incorporated into a capsule or tablet using methods
well known to those of ordinary skill in the art. The capsule may
be hard or soft, for example, gelatin. The capsule can also contain
pharmaceutically acceptable excipients.
FIG. 3 shows a cross-sectional view of a capsule 30, which has a
first part 33 and a second part 34 and contains powders, granules,
or beads of a first composition 31 and powders or granules of a
second composition 32.
FIG. 5 shows a cross-sectional view of a dosage form according to
the invention in the form of a tablet 50. The first composition is
in the form of powders or granules 51 and the coated second
composition is in the form of powders, granules, or beads 52. The
first composition and the coated second composition are mixed with
a pharmaceutically acceptable matrix 53 and compressed into a
tablet.
In another embodiment the capsule or tablet contains the first
composition without the outer acid-soluble layer and without the
inner base-soluble layer and the second composition coated with an
outer base-soluble layer and an inner acid-soluble layer.
FIG. 6. Depicts another embodiment of the oral dosage form of the
invention in the form of a tablet comprising a core that is a
mixture of an uncoated first composition 64 and a second
composition coated with a base-soluble outer layer and an acid
soluble inner layer 65. The core is then coated with an inner
base-soluble layer 62, and an outer acid-soluble layer 61, and an
optional innermost sustained release coating 63. Alternatively, the
second composition can be coated with a layer that is substantially
insoluble in the gastrointestinal tract.
Another embodiment of the oral dosage form of the invention is a
two-layer tablet 40 as shown in FIG. 4. A solid nucleus of the
first composition 45 is covered with an innermost sustained-release
coating 43 (optional), an inner base-soluble layer 42, and an outer
acid-soluble layer 41. A solid nucleus of the second composition 44
is covered with an inner acid-soluble layer 46, an outer
base-soluble layer 47, and an outermost layer that is substantially
insoluble in the gastrointestinal tract 48 (optional). The two
coated nuclei are then compressed into a two-layer tablet 40 using
conventional tableting equipment and standard techniques to provide
a two-layered tablet. The compressed two-layer tablet can then
optionally be coated with an additional coating to provide a tablet
of uniform appearance. In one embodiment, the additional coating is
a coating that dissolves in the stomach after the tablet is
swallowed.
In another embodiment of the two-layer tablet, the first
composition is uncoated, i.e., is not covered with the outer
acid-soluble layer or the inner base-soluble layer, but the second
composition is coated with an outer base-soluble layer and an inner
acid-soluble layer.
Yet another embodiment of the oral dosage 70 is shown in FIG. 7. A
solid nucleus of the second composition 77 is coated with an
innermost acid-soluble layer 76 and an outer base-soluble layer 75.
Then, the second composition is further coated with a layer of the
first composition 74, an optional innermost pH-independent layer
73, an inner base-soluble layer 72, and an outer acid-soluble layer
71. The oral dosage 70 may be a tablet or a granule.
6. EXAMPLES
The following prophetic examples are set forth to assist in
understanding the invention and should not, of course, be construed
as specifically limiting the invention described and claimed
herein. Such variations of the invention, including the
substitution of all equivalents now known or later developed, which
would be within the purview of those skilled in the art, and
changes in formulation or minor changes in experimental design, are
to be considered to fall within the scope of the invention
incorporated herein.
Example 1
Capsule
(1) Preparation of Oxycodone Granules and Naltrexone HCl
Granules
TABLE-US-00001 Ingredient Amount/unit (mg) Oxycodone HCl or 20.00
Naltrexone HCl 5.00 Spray Dried Lactose 59.25 Providone 5.00
Eudragit RS 30D (dry wt.) 10.00 Triacetin 2.00 Total 131.00
EUDRAGIT RS 30 D is plasticized by mixing with triacetin. The
dispersion is then combined with the oxycodone HCl or naltrexene
HCl, spray dried lactose, and providone using a fluid-bed
granulator. The resulting mixture is granulated. If necessary the
granules are dried. The granules are then screened with a sieve to
provide granules of an appropriate size.
(2) Coating
An acid-soluble coating solution is prepared by dispersing 15.0 g
EUDRAGIT E100 in 200 ml of ethanol to provide a clear solution, and
4 g of the plasticizer triethyl citrate is added to the
solution.
A base-soluble coating solution is prepared by dispersing 15.0 g
EUDRAGIT L in 200 ml of ethanol to provide a clear solution.
The oxycodone HCl granules are spray coated with the base-soluble
coating solution and dried. After drying, the resulting oxycodone
HCl granules coated with the base-soluble coating are then spray
coated with the acid-soluble coating solution and the resulting
granules dried.
The naltrexone HCl granules are spray coated with the acid-soluble
coating solution and dried. After drying, the resulting naltrexone
HCl granules coated with the acid-soluble coating are then spray
coated with the base-soluble coating solution and the resulting
granules dried.
(3) Encapsulating
The coated oxycodone HCl granules and the coated naltrexone HCl
granules are mixed together to provide a mixture, and a gelatin
capsule is filled with the mixture.
Example 2
Tablet
Stearyl alcohol is melted, and the melted stearyl alcohol (25.00 mg
per unit) is mixed with the coated granules obtained in Example 1
to wax them. The waxed granules are cooled in a fluid bed dryer and
then blended with talc (2.50 mg per unit) and magnesium stearate
(1.25 mg per unit) to provide a blend. The resulting blend is
compressed into a tablet using a tablet press.
The present invention is not to be limited in scope by the specific
embodiments disclosed in the examples which are intended as
illustrations of a few aspects of the invention and any embodiments
that are functionally equivalent are within the scope of this
invention. Indeed, various modifications of the invention in
addition to those shown and described herein will become apparent
to those skilled in the art and are intended to fall within the
scope of the appended claims.
A number of references have been cited, the entire disclosures of
which are incorporated herein by reference.
* * * * *