U.S. patent application number 10/747865 was filed with the patent office on 2004-09-09 for controlled-release compositions containing opioid agonist and antagonist.
Invention is credited to Oshlack, Benjamin, Wright, Curtis.
Application Number | 20040176402 10/747865 |
Document ID | / |
Family ID | 26877115 |
Filed Date | 2004-09-09 |
United States Patent
Application |
20040176402 |
Kind Code |
A1 |
Oshlack, Benjamin ; et
al. |
September 9, 2004 |
Controlled-release compositions containing opioid agonist and
antagonist
Abstract
Controlled-release dosage forms containing an opioid agonist; an
opioid antagonist; and a controlled release material release during
a dosing interval an analgesic or sub-analgesic amount of the
opioid agonist along with an amount of said opioid antagonist
effective to attenuate a side effect of said opioid agonist. The
dosage form provides analgesia for at least about 8 hours when
administered to human patients. In other embodiments, the dose of
antagonist released during the dosing interval enhances the
analgesic potency of the opioid agonist.
Inventors: |
Oshlack, Benjamin; (New
York, NY) ; Wright, Curtis; (Norwalk, CT) |
Correspondence
Address: |
Davidson, Davidson & Kappel, LLC
14th Floor
485 Seventh Avenue
New York
NY
10018
US
|
Family ID: |
26877115 |
Appl. No.: |
10/747865 |
Filed: |
December 29, 2003 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10747865 |
Dec 29, 2003 |
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09781076 |
Feb 8, 2001 |
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6716449 |
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60181358 |
Feb 8, 2000 |
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Current U.S.
Class: |
514/282 ;
424/449 |
Current CPC
Class: |
A61K 9/1623 20130101;
A61K 9/1635 20130101; A61K 31/485 20130101; A61K 9/2013 20130101;
A61K 38/33 20130101; A61K 9/1652 20130101; A61K 9/0031 20130101;
A61K 9/5047 20130101; A61K 9/5084 20130101; A61K 9/2027 20130101;
A61K 9/1617 20130101; A61K 9/5026 20130101; A61K 9/2018 20130101;
A61K 9/0043 20130101; A61K 9/5078 20130101; A61K 9/2054
20130101 |
Class at
Publication: |
514/282 ;
424/449 |
International
Class: |
A61K 031/485; A61K
009/70 |
Claims
What is claimed is:
1. A controlled-release dosage form comprising an opioid agonist;
an opioid antagonist; and a controlled release material; said
dosage form releasing during a dosing interval an analgesic or
sub-analgesic amount of the opioid agonist along with an amount of
said opioid antagonist effective to attenuate a side effect of said
opioid agonist selected from the group consisting of
anti-analgesia, hyperalgesia, hyperexcitability, physical
dependence, tolerance, and a combination of any of the foregoing,
said dosage form providing analgesia for at least about 8 hours
when administered to human patients.
2. The controlled release dosage form of claim 1, wherein the dose
of antagonist released during the dosing interval enhances the
analgesic potency of the opioid agonist.
3. The controlled-release dosage form of claim 1, wherein the
opioid agonist and the opioid antagonist are released at
substantially proportionate rates.
4. The controlled-release dosage form of claim 1, wherein the
dosage form is administered via a route selected from the group
consisting of orally for gastrointestinal absorption,
transdermally, via oral mucosa, intranasally, via injection, and
rectally.
5. The controlled-release dosage form of claim 1, wherein the
dosage form comprises a solid, oral dosage form.
6. The controlled-release dosage form of claim 1, wherein the
dosage form comprises a transdermal delivery system.
7. The controlled-release dosage form of claim 1, wherein the
dosage form comprises an injectable formulation
8. The controlled-release dosage form of claim 1, wherein the
dosage form comprises an intranasal formulation.
9. The controlled-release dosage form of claim 5, wherein the
opioid agonist and the antagonist are contained in a plurality of
substrates coated with a coating comprising said controlled-release
material, said substrates being selected from the group consisting
of granules, pellets, beads and spheroids.
10. The controlled-release oral dosage form of claim 1, wherein the
opioid antagonist is treated to modify its release rate before it
is combined with the opioid agonist, such that when the opioid
agonist and the treated antagonist are combined into the
controlled-release dosage form, the opioid agonist and antagonist
are released from the dosage form at substantially proportionate
rates.
11. The controlled-release dosage form of claim 1, wherein the
dosage form is orally administered and said opioid antagonist is
treated to modify its release rate before it is combined with the
opioid agonist, such that when the opioid agonist and the treated
antagonist are combined into the controlled-release dosage form,
the dosage form releases the agonist and the antagonist at such
rate that the opioid agonist and the opioid antagonist are
therapeutically effective over the dosing interval.
12. The controlled-release dosage form of claim 1, wherein the
opioid antagonist is present as granulates comprising the opioid
antagonist dispersed in a first controlled release matrix, and
wherein the opioid agonist is present as granulates comprising the
opioid agonist dispersed in a second controlled-release matrix, the
first controlled-release matrix providing controlled-release of the
opioid antagonist and the second matrix providing
controlled-release of the opioid agonist.
13. The controlled-release oral dosage form of claim 12, wherein
the oral dosage form releases the opioid agonist and the antagonist
at substantially proportionate rates.
14. The controlled-release oral dosage form of claim 5, wherein the
opioid antagonist is prepared as granulates comprising the
antagonist dispersed in a controlled-release matrix, said
granulates being combined with the opioid agonist and a further
controlled release material, such that the opioid antagonist and
opioid agonist are preferably released at substantially the same
proportionate rate.
15. The controlled-release dosage form of claim 1, wherein the
opioid antagonist is selected from the group consisting of
naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine,
pharmaceutically acceptable salts thereof and mixtures thereof.
16. The controlled-release dosage form of claim 1, wherein the
opioid agonist is selected from the group consisting of oxycodone,
morphine, hydromorphone, hydrocodone and pharmaceutically
acceptable salts thereof.
17. The controlled release dosage form of claim 15, wherein said
opioid agonist is a bimodally-acting opioid agonist selected from
the group consisting of-morphine, codeine, fentanyl analogs,
pentazocine, methadone, buprenorphine, enkephalins, dynorphins,
endorphins and similarly acting opioid alkaloids and opioid
peptides.
18. The controlled-release dosage form of claim 1, wherein the
amount of the opioid receptor antagonist administered is about 100
to about 1000 fold less than the amount of the opioid agonist
administered.
19. The controlled-release dosage form of claim 1, wherein the
dosage form provides controlled-release of the opioid agonist and
opioid antagonist over about a 12 hour period.
20. The controlled-release dosage form of claim 1, wherein the
dosage form provides controlled-release of the opioid agonist and
opioid antagonist over about a 24 hour period.
21. A controlled-release dosage form comprising an opioid agonist;
an opioid antagonist; and a controlled release material; said
dosage form releasing during a dosing interval an analgesic or
sub-analgesic amount of the opioid agonist along with an amount of
said opioid antagonist effective to enhance the potency of said
amount of opioid agonist released from the dosage form, said dosage
form providing analgesia for at least about 8 hours when
administered to human patients.
22. The controlled-release dosage form of claim 21, wherein the
amount of the opioid receptor antagonist administered is about 100
to about 1000 fold less than the amount of the opioid agonist
administered.
23. The controlled release dosage form of claim 21, wherein said
amount of opioid antagonist is simultaneously effective to
attenuate a side effect of said opioid agonist selected from the
group consisting of anti-analgesia, hyperalgesia,
hyperexcitability, physical dependence, tolerance, and a
combination of any of the foregoing.
24. The controlled-release dosage form of claim 21, wherein the
opioid antagonist is selected from the group consisting of
naloxone, naltrexone, diprenorphine, etorphine, dihydroetorphine,
pharmaceutically acceptable salts thereof and mixtures thereof.
25. The controlled release dosage form of claim 24, wherein said
opioid agonist is a bimodally-acting opioid agonist selected from
the group consisting of morphine, codeine, fentanyl analogs,
pentazocine, methadone, buprenorphine, enkephalins, dynorphins,
endorphins and similarly acting opioid alkaloids and opioid
peptides.
26. A method for enhancing the analgesic potency of an opioid
analgesic contained in a controlled release dosage form, comprising
preparing a controlled release dosage form containing an opioid
agonist; an opioid antagonist; and a-controlled release material in
a manner such that said dosage form delivers to human patients
during an intended dosing interval an analgesic or sub-analgesic
amount of the opioid agonist along with an amount of said opioid
antagonist effective to enhance the potency of said amount of
opioid agonist released from the dosage form, said dosage form
providing analgesia for at least about 8 hours when administered to
human patients.
27. The method of claim 26, wherein the amount of the opioid
receptor antagonist administered is about 100 to about 1000 fold
less than the amount of the opioid agonist administered.
28. The method of claim 27, wherein said amount of opioid
antagonist is simultaneously effective to attenuate a side effect
of said opioid agonist selected from the group consisting of
anti-analgesia, hyperalgesia, hyperexcitability, physical
dependence, tolerance, and a combination of any of the
foregoing.
29. The method of claim 28, wherein the opioid antagonist is
selected from the group consisting of naloxone, naltrexone,
diprenorphine, etorphine, dihydroetorphine, pharmaceutically
acceptable salts thereof and mixtures thereof.
30. The method of claim 29, wherein said opioid agonist is a
bimodally-acting opioid agonist selected from the group consisting
of morphine, codeine, fentanyl analogs, pentazocine, methadone,
buprenorphine, enkephalins, dynorphins, endorphins and similarly
acting opioid alkaloids and opioid peptides.
31. The method of claim 30, wherein the opioid agonist and the
opioid antagonist are delivered from the dosage form at
substantially the same proportionate rate.
32. The method of claim 26, further comprising: (i) pretreating
either the opioid agonist or the opioid antagonist to modify its
release rate; and (ii) combining the pretreated drug with the other
drug to produce the dosage form in which the opioid agonist and the
opioid antagonist are delivered from the dosage form at
substantially the same proportionate rate.
33. A method for attenuating a side effect of of an opioid
analgesic contained in a controlled release dosage form, said side
effect selected from the group consisting of anti-analgesia,
hyperalgesia, hyperexcitability, physical dependence, tolerance,
and a combination of any of the foregoing, comprising preparing a
controlled release dosage form containing an opioid agonist; an
opioid antagonist; and a controlled release material in a manner
such that said dosage form delivers to human patients during the
intended dosing interval an analgesic or sub-analgesic amount of
the opioid agonist along with an amount of said opioid antagonist
effective to enhance the potency of said amount of opioid agonist
released from the dosage form, said dosage form providing analgesia
for at least about 8 hours when administered to human patients.
34. The method of claim 33, wherein the amount of the opioid
receptor antagonist administered is about 100 to about 1000 fold
less than the amount of the opioid agonist administered.
35. The method of claim 34, wherein the opioid antagonist is
selected from the group consisting of naloxone, naltrexone,
diprenorphine, etorphine, dihydroetorphine, pharmaceutically
acceptable salts thereof and mixtures thereof.
36. The method of claim 35, wherein said opioid agonist is a
bimodally-acting opioid agonist selected from the group consisting
of morphine, codeine, fentanyl analogs, pentazocine, methadone,
buprenorphine, enkephalins, dynorphins, endorphins and similarly
acting opioid alkaloids and opioid peptides.
37. A transdermal delivery system for an opioid analgesic,
comprising an opioid agonist and an opioid antagonist contained in
a reservoir or matrix and capable of delivery from the device in a
controlled manner, such that when the device is applied to the skin
of a human patient, the opioid agonist is delivered at an mean
relative release rate effective to provide analgesia to said
patient for at least 3 days, and the opioid antagonist is delivered
at a mean relative release rate sufficient to reduce side effects
associated with the opioid agonist but not sufficient to negate the
analgesic effectiveness of the opioid.
38. The transdermal delivery system of claim 37, wherein the amount
of antagonist delivered from the transdermal delivery system is
effective to enhance the analgesic potency of the opioid agonist
delivered from the device.
39. The transdermal delivery system of claim 37, wherein the amount
of the opioid receptor antagonist delivered from the device is
about 100 to about 1000 fold less than the amount of the opioid
agonist delivered.
Description
[0001] This application claims benefit of U.S. Provisional No.
60/181,358 filed Feb. 8, 2000 the disclosure of which is hereby
incorporated by reference in its entirety.
BACKGROUND OF THE INVENTION
[0002] Opioids, also known as opioid agonists, are a group of drugs
that exhibit opium or morphine-like properties. Opioid agonists are
known in the literature and to those-skilled in the art. (Merck
Manual, 16th Ed. (1992)). Because of their analgesic efficacy,
opioid agonists have been used to provide pain relief to patients.
Side effects are also associated with the use of opioid analgesics.
For example, it has been reported that administration of opioid
agonists such as morphine are associated with side effects,
including nausea, vomiting, pruritis, urinary retention, and
respiratory depression. Gan, et al. Anesthesiology, vol. 87, No. 5,
1075-1081 (1997). Chronic use of morphine has also been reported to
increase physical dependence and increase tolerance of the drug,
Shen et al., Brain Res., Vol. 597, 74-83 (1992), and to induce
constipation.
[0003] Attempts to reduce the side effects of opioid agonists,
without affecting its analgesic efficacy, have also been reported.
For example, Gan, et al. Anesthesiology, vol. 87, No. 5, 1075-1081
(1997) report that the administration of 0.25
.mu.g.kg-.sup.1.h-.sup.1 or 1 .mu.g.kg-.sup.1.h-.sup.1 naloxone
(opioid antagonist) by infusion concomitantly with intravenous
morphine, was effective in reducing certain potential side effects
of morphine (e.g., the incidence of nausea, vomiting and
prurities).
OBJECTS AND SUMMARY OF THE INVENTION
[0004] It is an object of the invention to promote patient
compliance and thereby increase the efficacy of opioid agonist
treatment in patients who are being treated with opioid
agonist.
[0005] It is a further object of the invention to reduce the side
effects associated with opioid agonist treatment.
[0006] It is also an object of the invention to provide agonist
therapy in which the analgesically effective blood levels of the
opioid agonist are maintained during an extended period of time,
while also maintaining the pharmacologically effective blood levels
of the antagonist for reducing the side effects associated with the
opioid treatment.
[0007] It is also an object of the invention to enhance the
analgesic potency of an opioid agonist in controlled release form
and simultaneously attenuate development of physical dependence,
tolerance and other undesirable side effects caused by the chronic
administration of the opioid agonist.
[0008] It is also an object of the invention to provide agonist
therapy in which analgesically effective blood levels of the opioid
agonist are maintained over an extended period of time, while also
selectively enhancing the analgesic potency of the opioid agonist.
Preferably, the selective enhancement of analgesic potency of the
opioid agonist occurs while simultaneously attenuating development
of physical dependence, tolerance and other undesirable side
effects caused by the chronic administration of the opioid
agonist.
[0009] In view of the above-mentioned objects and others, the
invention is directed to a controlled release oral dosage form
comprising opioid agonist and opioid antagonist, wherein the dosage
form releases the opioid agonist and the antagonist in a
controlled-release manner.
[0010] The invention is further directed to a controlled-release
dosage form comprising an opioid agonist and the opioid antagonist,
wherein the opioid agonist or the opioid antagonist, before it is
combined with the other, is treated to modify its release rate,
such that when combined into the controlled-release dosage form,
the opioid agonist and the antagonist are released from the dosage
form at appropriately similar times.
[0011] The invention is further directed to a controlled-release
dosage form comprising opioid agonist and opioid antagonist,
wherein the opioid agonist is present in an amount that is
analgesically effective when administered to a human, and wherein
the opioid antagonist is present in an amount which does not cause
a reduction in the level of analgesia provided by the dosage form
to a non-therapeutic level. In certain embodiments, the opioid
antagonist is also present in an amount that is effective in
reducing opioid-related side effects.
[0012] In certain embodiments of the present invention, the
controlled release dosage form comprises a transdermal delivery
system, an oral mucosal delivery system, a composition for
intranasal administration, an injectable composition, and a solid
oral composition.
[0013] In certain preferred embodiments, the present invention
comprises a controlled release dosage form that delivers an opioid
agonist and an opioid antagonist over an extended period of time.
In these oral embodiments, the dosage form includes an amount of an
opioid agonist, preferably a biomodally-acting opioid agonist, and
an amount of an opioid antagonist, and upon administration the
dosage form delivers an analgesic or sub-analgesic amount of the
opioid agonist over the-dosing interval, along with an amount of
the opioid antagonist effective to enhance the analgesic potency of
the opioid agonist and attenuate the anti-analgesia, hyperalgesia,
hyperexcitability, physical dependence and/or tolerance effects of
the opioid agonist.
[0014] Certain embodiments of the invention are directed to
controlled-release dosage forms comprising an opioid agonist and
the opioid antagonist, wherein the opioid agonist or the opioid
antagonist, before it is combined with the other, is treated to
modify its release rate, such that when combined into the
controlled-release dosage form, the opioid agonist and the
antagonist are released from the dosage form at appropriately
similar times.
[0015] The present invention is also directed to the use of the
above-mentioned controlled release formulations for maintenance
treatement of previously detoxified opiate addicts.
[0016] In certain preferred embodiments, the opioid agonist is
selected from the group consisting of hydromorphone, oxycodone,
hydrocodone, morphine, pharmaceutically acceptable salts thereof
and mixtures thereof.
[0017] In certain preferred embodiments, the opioid agonist is a
bimodally-acting opioid agonist selected from, e.g., morphine,
codeine, fentanyl analogs, pentazocine, buprenorphine, methadone,
enkephalins, dynorphins, endorphins, and similarly acting opioid
alkaloids and opioid peptides.
[0018] In certain preferred embodiments, the opioid antagonist is
selected from the group consisting of naltrexone, naloxone,
nalmefene, pharmaceutically acceptable salt thereof and mixtures
thereof.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention is directed to controlled-release
dosage forms comprising an opioid agonist and an opioid antagonist,
the dosage form providing controlled-release of the opioid agonist
and controlled-release of the opioid antagonist. In preferred
embodiments, the release rate of the agonist and the antagonist
from the dosage form are controlled to maintain an analgesically
effective amount of the agonist in the blood throughout the dosing
period and to maintain the concentration of the opioid antagonist
throughout the dosing period sufficient for decreasing the side
effects associated with the opioid agonist but not sufficient to
negate the analgesic efficacy of the agonist. In preferred
embodiments, the invention is directed to controlled release solid
dosage forms that release an opioid agonist and an opioid
antagonist over an extended period of time. In these oral
embodiments, the dosage form includes an amount of an opioid
agonist, preferably a biomodally-acting opioid agonist, and an
amount of an opioid antagonist, and upon oral administration the
dosage form releases an analgesic or sub-analgesic amount of the
opioid agonist over the dosing interval, along with an amount of
the opioid antagonist effective to enhance the analgesic potency of
the opioid agonist and attenuate the anti-analgesia, hyperalgesia,
hyperexcitability, physical dependence and/or tolerance effects of
the opioid agonist.
[0020] The present invention is further directed toga
controlled-release solid oral dosage form comprising an opioid
agonist and an opioid antagonist, the dosage form providing
controlled-release of the opioid agonist and controlled-release of
the opioid antagonist, the dosage form, when administered to
patients, providing analgesia together with reduction of side
effects associated with the opioid agonist. It is preferred that
such dosage form releases the opioid agonist and the antagonist at
substantially proportionate rates. Preferably, the release rates of
the opioid agonist and antagonist are approximately proportionate
over time, more preferably over a dosing period.
[0021] In certain embodiments, the controlled-release composition
of the present invention provides reduction of opioid associated
side effects, e.g., nausea, vomiting, pruritis, urinary retention,
respiratory depression, constipation, physical dependence,
tolerance, hyperexcitability, and hyperalgeia.
[0022] U.S Pat. Nos. 5,512,578; 5,472,943; 5,580,876; and
5,767,125, (Crain et al.), each of which are hereby incorporated by
reference in their entireties, describe combinations of opioid
antagonists with morphine or other bimodally acting opioid
agonists. The combinations described therein are said to enhance
the analgesic effects of the bimodal opioid agonist, while at the
same time attenuating the physical dependence, tolerance,
hyperexcitability, hyperalgeia, and other undesirable (excitatory)
side effects associated with chronic use of bi-modally acting
opioid agonists. However, these patents do not contemplate
providing a mechanism or manner of preparation of the combination
dosage form in which the agonist and the antagonist are each
released from the dosage form in a controlled-release manner,
allowing the agonist and antagonist to be absorbed by (or delivered
to) the patient, such that the requisite analgesia together with
reduction of opioid agonist related side effects and/or increased
opioid potency may be provided throughout a prolonged dosing
period. The above-cited documents also do not provide
controlled-release formulations for maintaining the analgesically
effective blood levels of agonist during an extended period of
time, while at the same time maintaining the pharmacologically
effective blood levels of the antagonist for reducing the side
effects associated with the opioid treatment. Such
controlled-release compositions would be desirable, e.g., because
they would allow for the limitation of peak concentrations and
increase patient compliance because the drug is taken less
frequently.
[0023] The term "controlled-release dosage form," refers to a
dosage form which provides a longer period of pharmacological
response after the administration of the agonist and the antagonist
than is ordinarily provided after the administration of the rapid
release dosage form. In certain preferred embodiments of the
invention, the controlled-release dosage form releases the opioid
agonist and the opioid agonist from the dosage form at such a rate
that blood (e.g., plasma) concentration (levels) are maintained
within the analgesically effective range (above the minimum
effective analgesic concentration or "MEAC") over a dosing period.
In certain embodiments of the invention, the opioid antagonist is
released from the controlled-release dosage form at such a rate
that blood (e.g., plasma) concentration of the antagonist are
maintained within the pharmacologically effective range for
reducing the opioid agonist associated side effects over a dosing
period. In other preferred embodiments, the opioid antagonist is
delivered from the controlled-release dosage form at such a rate
that the controlled release formulations provide the benefits set
forth in the above-mentioned Crain, et al. patents, namely,
enhancement of the analgesic potency of the opioid agonist while
simultaneously attenuating anti-analgesia, hyperalgesia,
hyperexcitability, physical dependence and/or tolerance effects of
the opioid agonist. One skilled in the art will understand that due
to the enhancement of analgesia caused by the particular
combinations of opioid agonist/opioid antagonist encompassed by the
present invention, the analgesic efficacy may be greater than that
reflected by blood plasma levels of the opioid agonist. For
purposes of the present invention, the controlled release obtained
via in-vitro dissolution testing of the formulation (i.e.,
measuring the release of the opioid agonist and the opioid
antagonist) may serve as a surrogate measure of the dosing interval
for the controlled release dosage form in-vivo, particularly in the
case of oral formulations. Such in-vitro testing may be undertaken
utilizing the USP Paddle Method of U.S. Pharmacopeia XXII (1990) at
100 rpm at 900 ml aqueous buffer (pH between 1.6 and 7.2) at
37.degree. C. The analytical method may be, e.g., high performance
liquid chromatography.
[0024] In preferred embodiments, the controlled-release dosage form
of the present invention is administrable (i.e., provides the
requisite effects stated above) at least every 8 hours. In certain
preferred embodiments, the controlled release dosage form is
administrable twice daily (every 12 hours), or once-a-day (every 24
hours). In embodiments where the controlled release dosage form is
a, transdermal delivery system, the transdermal delivery system
preferably provides the requisite effect for at least about 3 days.
In certain preferred embodiments, the transdermal delivery system
may be worn on the skin of a human patient for at least about 5
days, and preferably about 7 days, while provided attenuation of
the anti-analgesia, hyperalgesia, hyperexcitability, physical
dependence and/or tolerance effects of the opioid agonist.
Preferably, the opioid antagonist simultaneously provides
enhancement of the analgesic potency of the opioid agonist.
[0025] In the present invention, a very low dose of an opioid
antagonist is combined with a dose of an opioid agonist (analgesic)
so as to enhance the degree of analgesia an attenuate undesired
side effects. The dosage form is prepared in a manner which causes
the opioid agonist and the opioid antagonist to be delivered when
the dosage form is administered, e.g., to a human patient.
[0026] The rate of delivery of the opioid agonist will be such that
substantially the entire dose of opioid agonist contained in the
dosage form is delivered from the dosage form after administration,
in those embodiments in which the controlled release dosage form is
an oral mucosal delivery system, a composition for intranasal
administration, an injectable composition, and a solid oral
composition. The rate of delivery of the opioid antagonist will be
such that an effective amount of the opioid antagonist is delivered
to attenuate the anti-analgesia, hyperalgesia, hyperexcitability,
physical dependence and/or tolerance effects of the opioid agonist
during the intended dosing interval. Preferably, rate of delivery
of the opioid antagonist will be such that an effective amount of
the opioid antagonist is delivered to enhance the analgesic potency
of the opioid analgesic during the dosing interval of the
controlled release dosage form. It is not necessary that
substantially all of the opioid antagonist be delivered from the
controlled release dosage form to meet these goals.
[0027] When the controlled release dosage form comprises a
transdermal delivery system, The rate of delivery of the opioid
agonist will be such that a sufficient mean relative release rate
(or flux rate) of the opioid agonist contained in the dosage form
is delivered from the transdermal dosage form upon administration.
The rate of delivery of the opioid antagonist will be such that an
effective amount of the opioid antagonist is delivered to attenuate
the anti-analgesia, hyperalgesia, hyperexcitability, physical
dependence and/or tolerance effects of the opioid agonist during
the intended dosing interval. Preferably, rate of delivery of the
opioid antagonist will be such that an effective amount of the
opioid antagonist is delivered to enhance the analgesic potency of
the opioid analgesic during the dosing interval of the controlled
release dosage form. It is not necessary that substantially all of
the opioid antagonist be delivered from the controlled release
dosage form to meet these goals.
[0028] In accordance with the present invention, the dose of opioid
antagonist which is delivered from the dosage form during the
dosing interval is preferably from about 100 to about 1000 times
less than the dose of the opioid agonist (preferably,
bimodally-acting opioid agonist) delivered from the dosage form. As
described in the Crain, et al. patents mentioned above, excitatory
opioid receptor antagonists bind to and inactivate excitatory
opioid receptors on neurons in the nociceptive pathways. The
excitatory opioid receptor antagonists of the invention are
preferably seleted from the group consisting of naloxone,
naltrexone, diprenorphine, etorphine and dihydroetorphine.
Naltrexone and naloxone are especially preferred in certain
embodiments of the invention.
[0029] The controlled release dosage forms of the present invention
preferably deliver the opioid antagonist (e.g., excitatory opioid
receptor antagonists) at such a level that the opioid antagonist
has selective antagonist action at excitatory, but not inhibitory,
opioid receptors. In addition, since the antagonists preferably
enhance the analgesic potency of the agonists, the agonists become
effective when administered at reduced doses which would otherwise
be subanalgesic. It may be possible to achieve an analgesic effect
with 10-100 times lower doses of the (bimodally acting) opioid
agonists with the excitatory opioid receptor antagonists of the
invention than when the opioid agonist is administered alone. This
is because the excitatory opioid receptor antagonists may enhance
the analgesic effects of the opoid agonists by attenuating the
anti-analgesic excitatory side effects of the opioid agonists.
Therefore, in certain preferred embodiments of the invention, the
opioid agonist is included in the dosage form and is delivered in
an amount which is less than that which has been typically
administered for analgesia. In certain embodiments of the
invention, the opioid antagonist is delivered such that the amount
of opioid agonist included in the dosage form is, e.g., about 10 to
about 100 times less than the amount of that opioid agonist
typically dosed over the dosing interval.
[0030] Certain embodiments of the invention are directed to
controlled-release dosage forms comprising an opioid agonist and
the opioid antagonist wherein the opioid agonist or the opioid
antagonist, before it is combined with the other, is treated to
modify its release rate, such that when combined into the
controlled-release dosage form, the opioid agonist and the
antagonist are released from the dosage form at appropriately
similar times. For example, one of the drugs may be pretreated,
e.g., with a controlled release material, to modify its release
rate such that when combined into a unitary dosage form with the
other drug, the release rates of the two drugs will be
substantially similar.
[0031] It may also be possible to obtain a similar release rate for
both the opioid agonist and opioid antagonist, in situations where
the drugs chosen would provide different release rates from the
controlled release dosage form because, e.g., they have differing
solubilities, by choosing a salt of one of the drugs which provides
a closer match in solubilities. Additionally (or alternatively),
the particular choice of opioid antagonist can be matched as
closely as possible with respect to the solubility of the opioid
analgesic.
[0032] Alternatively, in certain embodiments of the present
invention it is not necessary to adjust release rates, etc. as set
forth above due to the choice of agonist and/or antagonist which
has, for example, a long half-life.
[0033] In addition, the excitatory opioid receptor antagonists can
be administered in the controlled release formulations of the
invention along with sub-analgesic doses of opioid receptor
agonists for long-term maintenance treatment of previously
detoxified opiate, cocaine and alcohol addicts to prevent
protracted physical dependence.
[0034] Opioid agonists useful in the present invention include, but
are not limited to, alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, desomorphine, dextromoramide,
dezocine, diampromide, diamorphone, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptariol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, etholheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levorphanol, levophenacylmorphan, lofentanil,
meperidine, meptazinol, metazocine, methadone, metopon, morphine,
myrophine, narceine, nicomorphine, norlevorphanol, nonnethadone,
nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone,
oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan,
phenazocine, phenoperidine, piminodine, piritramide, propheptazine,
promedol, properidine, propoxyphene, sufentanil, tilidine,
tramadol, mixtures of any of the foregoing, salts of any of the
foregoing, and the like.
[0035] In certain preferred embodiments, the bimodally-acting
opioid agonist is selected from the group consisting of morphine,
codeine, fentanyl analogs, pentazocine, methadone, buprenorphine,
enkephalins, dynorphins, endorphins and similarly acting opioid
alkaloids and opioid peptides.
[0036] In certain preferred embodiments, the opioid agonist is
selected from the group consisting of hydrocodone, morphine,
hydromorphone, oxycodone, codeine, levorphanol, meperidine,
methadone, or salts thereof or mixtures thereof. In certain
preferred embodiments, the opioid agonist is oxycodone or
hydrocodone. Equianalgesic doses of these opioids, in comparison to
a 15 mg dose of hydrocodone, are set forth in Table 1 below:
1TABLE 1 Equianalgesic Doses of Opioids Opioid Calculated Dose (mg)
Oxycodone 13.5 Codeine 90.0 Hydrocodone 15.0 Hydromorphone 3.375
Levorphanol 1.8 Meperidine 135.0 Methadone 9.0 Morphine 27.0
[0037] In certain embodiments of the invention, the opioid agonist
is a bimodally acting opioid agonist. "Bimodally acting opioid
agonists" are opioid agonist that bind to and activate both
inhibitory and excitatory opioid receptors on nociceptive neurons
which mediate pain. Activation of the inhibitory receptors results
in opioid analgesia, whereas the activation of the excitatory
receptors results in undesirable side effects, including the
development of physical dependence and tolerance to the opioid
agonist, anti-analgesic actions, hyperexcitability and hyperalgeia.
Examples of bimodally acting opioid agonists include morphine,
codeine, fenfenyl analogs, pentazocine, methadone, buprenorphine,
einkephialins, dynorphias, endorphins and similarly acting opioid
alkaloids and opioid peptides.
[0038] The excitatory opioid receptor antagonists of the invention
are preferably seleted from the group consisting of naloxone,
naltrexone, diprenorphine, etorphine, dihydroetorphine,
pharmaceutically acceptable salts thereof and mixtures thereof.
Other opioid antagonists include nalmefene, cyclazacine,
levallorphan, pharmaceutically acceptable salts thereof and
mixtures thereof. In certain preferred embodiments, the opioid
antagonist is naloxone or naltrexone.
[0039] For purposes of the present invention, the term "opioid
agonist" is interchangeable with the term "opioid" or "opioid
analgesic" and shall include the base of the opioid, mixed
agonist-antagonists, partial agonists, pharmaceutically acceptable
salts thereof, stereoisomers thereof, ethers and esters thereof,
and mixtures thereof.
[0040] For purposes of the present invention, the term "opioid
antagonist" shall include the base, pharmaceutically acceptable
salts thereof, stereoisomers thereof, ethers and esters thereof,
and mixtures thereof.
[0041] The invention disclosed herein is meant to encompass all
pharmaceutically acceptable salts thereof of the disclosed opioid
agonists and antagonists. The pharmaceutically acceptable salts
include, but are not limited to, metal salts such as sodium salt,
potassium salt, secium salt and the like; alkaline earth metals
such as calcium salt, magnesium salt and the like; organic amine
salts such as triethylamine salt, pyridine salt, picoline salt,
ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt and the like; inorganic acid
salts such as hydrochloride, hydrobromide, sulfate, phosphate and
the like; organic acid salts such as formate, acetate,
trifluoroacetate, maleate, tartrate and the like; sulfonates such
as methanesulfonate, benzenesulfonate, p-toluenesulfonate, and the
like; amino acid salts such as arginate, asparginate, glutamate and
the like.
[0042] Some of the opioid agonists and antagonists disclosed herein
may contain one or more asymmetric centers and may thus give rise
to enantiomers, diastereomers, and other stereoisomeric forms. The
present invention is also meant to encompass all such possible
forms as well as their racemic and resolved forms and mixtures
thereof. When the compounds described herein contain olefinic
double bonds or other centers of geometric asymmetry, and unless
specified otherwise, it is intended to include both E and Z
geometric isomers. All tautomers are intended to be encompassed by
the present invention as well
[0043] As used herein, the term "stereoisomers" is a general term
for all isomers of individual molecules that differ only in the
orientation of their atoms is space. It includes enantiomers and
isomers of compounds with more than one chiral center that are not
mirror images of one another (diastereomers).
[0044] The term "chiral center" refers to a carbon atom to which
four different groups are attached.
[0045] The term "enantiomer" or "enantiomeric" refers to a molecule
that is nonsuperimposeable on its mirror image and hence optically
active wherein the enantiomer rotates the plane of polarized light
in one direction and its mirror image rotates the plane of
polarized light in the opposite direction.
[0046] The term "racemic" refers to a mixture of equal parts of
enantiomers and which is optically inactive.
[0047] The term "resolution" refers to the separation or
concentration or depletion of one of the two enantiomeric forms of
a molecule.
[0048] The present invention is further directed to a method of
decreasing the potential for abuse of an opioid agonist in an oral
dosage form. The method comprises providing the opioid agonist in
an oral dosage form as described herein.
[0049] The controlled-release compositions of the present invention
includes, but is not limited to, a transdermal delivery system, an
oral mucosal delivery system, a composition for intranasal
administration, an injectable composition, and a solid oral
composition.
Transdermal Delivery System
[0050] The controlled release formulations of the present invention
may be formulated as a transdermal delivery system, such as
transdermal patches. In certain embodiments of the present
invention, a transdermal patch comprises an opioid agonist and an
opioid antagonist contained in a reservoir or a matrix, and an
adhesive which allows the transdermal device to adhere to the skin,
allowing the passage of the active agent from the transdermal
device through the skin of the patient. Once the agonist/antagonist
has penetrated the skin layer, the drugs are absorbed into the
blood stream where they exert desired pharmaceutical effects. The
transdermal patch releases both the opioid agonist and the opioid
antagonist in a controlled-release manner, such that the blood
levels of the opioid agonist is maintained at an analgesically
effective level through out the dosing period, and the blood levels
of the antagonist is maintained at a concentration that is
sufficient to reduce side effects associated with the opioid
agonist but not sufficient to negate the analgesic effectiveness of
the opioid. Preferably, the amount of antagonist delivered from the
transdermal delivery system is effective to enhance the analgesic
potency of the opioid agonist delivered from the dosage form.
[0051] Transdermal delivery system providing a controlled-release
of an opioid agonist is known. For example, Duragesic.RTM. patch
(commercially available from Janssen Pharmaceutical) contains an
opioid agonist (fentanyl) and is said to provide adequate analgesia
for up to 48, to 72 hours (2 to 3 days).
[0052] Transdermal delivery systems containing buprenorphine (an
opioid agonist), for providing prolonged analgesia, are also
described. Although other types of opioid analgesic transdermal
formulations have been reported in the literature (such as
fentanyl, discussed above), buprenorphine transdermal delivery
systems are of particular interest because buprenorphine is a
potent, partial agonist opioid analgesic with desirable therapeutic
properties. For example, buprenorphine is 50 to 100 times more
potent than morphine, but has a much safer therapeutic index than
morphine (see Wallenstein S L, et al., Crossover Trials in Clinical
Analgesic Assays: Studies of Buprenorphine and Morphine,
Pharmacotherapy, G(5): 225-235, 1986 hereby incorporated by
reference).
[0053] There are several types of transdermal formulations of
buprenorphine reported in the literature. See, for example, U.S.
Pat. No. 5,240,711 (Hille et al.), U.S. Pat. No. 5,225,199 (Hidaka
et al.), U.S. Pat. No. 5,069,909 (Sharma et al.), U.S. Pat. No.
4,806,341 (Chien et al.), and U.S. Pat. No. 5,026,556 (Drust et
al.), all of which are hereby incorporated by reference.
[0054] The transdermal delivery system used in the present
invention may also be prepared in accordance with U.S. Pat. No.
5,069,909 (Sharma et al.), hereby incorporated by reference. This
patent describes a laminated composite for administering
buprenorphine transdermally to treat pain. The transdermal delivery
system used in the present invention may also be prepared in
accordance with U.S. Pat. No. 4,806,341 (Chien et al.), hereby
incorporated by reference. This patent describes a transdermal
morphinan narcotic analgesic or antagonist (including
buprenorphine) pharmaceutical polymer matrix dosage unit having a
backing layer which is substantially impervious to the
buprenorphine, and a polymer matrix disc layer which is adhered to
the backing layer and which has microdispersed therein effective
dosage amounts of the buprenorphine.
[0055] The transdermal delivery system used in the present
invention may also be that described in U.S. Pat. No. 5,026,556
(Drust et al.), hereby incorporated by reference. Therein,
compositions for the transdermal delivery of buprenorphine comprise
buprenorphine in a carrier of a polar solvent material selected
from the group consisting of C.sub.3-C.sub.4 diols, C.sub.3-C.sub.6
triols, and mixtures thereof, and a polar lipid material selected
from the group consisting of fatty alcohol esters, fatty acid
esters, and mixtures thereof; wherein the polar solvent material
and the lipid material are present in a-weight ratio of solvent
material:lipid material of from 60:40 to about 99:1. The
transdermal delivery system used in the present invention may also
be that described in U.S. Pat. No. 4,588,580 (Gale, et. al.),
hereby incorporated by reference. That system comprises a reservoir
for the drug having a skin proximal, material releasing surface
area in the range of about 5-160 cm.sup.2 and containing between
0.1 and 50% by weight of a skin permeable form of the
buprenorphine. The reservoir contains an aqueous gel comprising up
to about 47-95% ethanol, 1-10% gelling agent, 0.1-10%
buprenorphine, and release rate controlling means disposed in the
flow path of the drug to the skin which limits the flux of the
buprenorphine from the system through the skin.
[0056] The present invention is contemplated to encompass all
transdermal formulations, e.g., the technologies described above,
with the inclusion of an opioid antagonist, such that the opioid
antagonist is released in a controlled-release maimer along with
the opioid agonist.
[0057] The transdermal delivery systems of the invention preferably
deliver an analgesic or sub-analgesic amount of the opioid agonist
together with an amount of the opioid antagonist effective to
attenuate the anti-analgesia, hyperalgesia, hyperexcitability,
physical dependence and/or tolerance effects of the opioid agonist.
Preferably, the amount of opioid antagonist delivered
simultaneously enhances the analgesic potency of the opioid agonist
delivered from the transdermal delivery system.
[0058] The transdermal delivery systems may deliver the opioid
agonist and/or the opioid antagonist in accordance with first order
pharmacokinetics, zero order pharmacokinetics, or both first and
zero order pharmacokinetics during the dosing interval. The term
"first order" pharmacokinetics is defined as plasma concentrations
which increase over a specified time period. The term "zero order"
pharmacokinetics contemplates an amount of drug released from a
buprenorphine formulation which substantially maintains plasma
concentrations at a relatively constant level. For purposes of the
present invention, a relatively constant plasma concentration is
defined as a concentration which does not decrease more than about
30% over a 48 hour time period.
[0059] The term "delivers" when used with respect to transdermal
delivery devices means that the transdermal delivery device
provides a mean relative release rate or flux of the drug out of
the device and through the skin of the patient. The term "mean
relative release rate" is determined from the amount of drug
released per unit time from the transdermal delivery device through
the skin and into the bloodstream of a human patient. Mean relative
release rate may be expressed, e.g., as g drug/cm.sup.2/hr. For
example; a transdermal delivery device that releases 1.2 mg of
buprenorphine over a time period of 72 hours is considered to have
a relative release rate of 16.67 g/hr. For purposes of the
invention, it is understood that relative release rates may change
between any particular time points within a particular dosing
interval, and the term therefore only reflects the overall release
rate during the particular dosing interval. For purposes of the
present invention, relative release rate should be considered
synonomous with the term "flux rate".
[0060] For example, delivery of buprenorphine transdermally to
human patients has previously been reported, e.g., in U.S. Pat. No.
5,968,547, hereby incorporated by reference, such that mean
relative release rates are achieved as follows: a mean relative
release rate of from about 3 g/hr to about 86 g/hr from initiation
of the dosing interval until about 72 hours thereafter; and a mean
relative release rate of about 0.3 g/hr to about 9 g/hr from about
72 hours after the initiation of the dosing interval until at least
about 120 hours after the initiation of the dosing interval.
[0061] In certain embodiments of transdermal dosage form is a
transdermal patch comprising a backing layer which is impermeable
to the active substance, a pressure-sensitive adhesive reservoir
layer, and optionally a removable protective layer, the reservoir
layer by weight comprising 20 to 90% of a polymeric matrix, 0.1 to
30% of a softening agent, 0.1 to 20% of said opioid agonist and
opioid antagonist and 0.1 to 30% of a solvent for the opioid
agonist and opioid antagonist.
[0062] The controlled release dosage form can also comprise a
transdermal plaster comprising:
[0063] (1) a film layer which comprises a polyester film of 0.5 to
4.9 .mu.m thickness, 8 to 85 g/mm strength, respectively in the two
directions intersecting substantially at right angles, 30 to 150%
elongation, in the two directions intersecting substantially at
right angles and an elongation ratio of A to B of 1.0 to 5.0,
wherein A and B represent data in two directions intersecting at
right angles, and A is greater than B, and wherein said polyester
film comprises 0.01 to 1.0% by weight, based on the total weight of
said polyester film, of solid fine particles in which
[0064] (a) the average particle size is 0.001 to 3.0 .mu.m, and (b)
the average particle size is substantially not more than 1.5 times
the thickness of said polyester film; and (2) an adhesive layer (a)
which is composed of an adhesive containing said opioid agonist and
opioid antagonist and further wherein said adhesive layer (a) is
laminated on said film layer over the surface in a 2 to 60 .mu.m
thickness.
[0065] The controlled release dosage can be a transdermal patch
comprising a laminated composite for administering said opioid
agonist and opioid antagonist to an individual transdermally
comprising: (a) a polymer backing layer that is substantially
impermeable to said opioid agonist and opioid antagonist; and (b) a
reservoir layer comprising a water-base acrylate pressure-sensitive
adhesive, 1 to 12% by weight opioid agonist and opioid antagonist
and 2 to 25% by weight of a permeation enhancer comprising
propylene glycol monolaurate in combination with capric acid or
oleic acid, wherein the skin contact area of the composite is 10 to
100 cm.sup.2 and the rate of administration from the composite is
about 1 to about 100 .mu.g/hr.
[0066] The controlled release dosage form can be a transdermal
comprising:
[0067] (a) a backing layer which is substantially impervious to
said opioid agonist and opioid antagonist; and (b) a polymer matrix
layer which is adhered to said backing layer and which has
dispersed therein said opioid agonist and opioid, said polymer
being bioacceptable and permitting said opioid agonist and opioid
antagonist to be transmitted for transdermal absorption, said
opioid agonist and opioid antagonist being stable in said polymer
matrix.
[0068] The controlled release dosage form can be a transdermal
patch comprising (a) a polar solvent material selected from the
group consisting of C.sub.3 -C.sub.4 diols, C.sub.3 -C.sub.6
triols, and mixtures thereof; and (b) a polar lipid material
selected from the group consisting of fatty alcohol esters, fatty
acid esters, and mixtures thereof; wherein said polar solvent
material and said polar lipid material are present in a weight
ratio of solvent maternal:lipid material of from about 60:40 to
about 99:1.
Oral Mucosal Delivery System
[0069] In certain embodiments of-the present invention, the
controlled release opioid agonist/antagonist formulation may be
prepared as a controlled-release oral mucosal delivery system. Such
a system is described by McQuinn, R. L. et al., "Sustained Oral
Mucosal Delivery in Human Volunteers J. Controlled Release; (34)
1995 (243-250). Therein, oral mucosal patches were prepared by
homogeneously mixing buprenorphine free base (8%), Carbopol 934
(52%), polyisobutylene (35%) and polyisoprene (5%, w/w) via a
two-roll mill and then compressing the mixture to the appropriate
thickness. A membrane backing (ethylcellulose) was applied to one
side of the compressed material and then circular disks (0.5
cm.sup.2) were punched from the material. The backing was included
in order to retard drug release from one side of the disk and to
prohibit adhesion to opposing side tissues. Each soft, flexible
disk was approximately 0.6 mm thick and contained 2.9 mg
buprenorphine. These patches were worn by the subjects for 12
hours. Gum and lip application was tested, although adhesion at the
gum site was considered superior. After the initial appearance of
serum buprenorphine (.gtoreq.25 pg/ml), levels generally increased
relatively rapidly and persisted until the patch was removed. After
the patch was removed, buprenorphine levels fell promptly and were
at a relatively low (but measureable) level by 24 hours post-dose.
It was estimated that 0.42.+-.0.18 mg were delivered via the gum
treatment. From this discussion, it is apparent that an oral
mucosal patch can be prepared which will provide plasma
concentrations considered desirable according to the present
invention.
[0070] The present invention is contemplated to encompass all oral
mucosal delivery systems, e.g., the technologies described above,
with the inclusion of an opioid antagonist, such that the opioid
antagonist is released in a controlled-release manner along with
the opioid agonist.
[0071] For example, the oral mucosal delivery device can comprise a
compressed mixture comprising a polymer with a cellulose backing.
The polymer can be selected from the group consisting of Carbopol
934, polyisobutylene, polyisoprene and mixtures thereof and said
cellulose can be an alkylcellulose, e.g., ethylcellulose.
Suppositories
[0072] The controlled release formulations of the present invention
may be formulated as a pharmaceutical suppository for rectal
administration comprising an opioid agonist and an opioid
antagonist in a controlled release matrix, and a suppository
vehicle (base). Preparation of controlled release suppository
formulations is described in, e.g., U.S. Pat. No. 5,215,758, hereby
incorporated by reference in its entirety.
[0073] Prior to absorption, the drug must be in solution. In the
case of suppositories, solution must be preceded by dissolution of
the base, or the melting of the base and subsequent partition of
the drug from the base into the rectal fluid. The absorption of the
drug into the body may be altered by the suppository-base. Thus,
the particular base to be used in conjunction with a particular
drug must be chosen giving consideration to the physical properties
of the drug. For example, lipid-soluble drugs will not partition
readily into the rectal fluid, but drugs that are only slightly
soluble in the lipid base will partition readily into the rectal
fluid.
[0074] Among the different factors affecting the dissolution time
(or release rate) of the drugs are the surface area of the drug
substance presented to the dissolution solvent medium, the pH of
the solution, the solubility of the substance in the specific
solvent medium, and the driving forces of the saturation
concentration of dissolved materials in the solvent medium.
Generally, factor affecting the absorption of drugs from
suppositories administered rectally include suppository vehicle,
absorption site pH, drug pKa, degree of ionization, and lipid
solubility.
[0075] The suppository base chosen should be compatible with the
opioid agonist/antagonist to be incorporated into the composition.
Further, the suppository base is preferably non-toxic and
nonirritating to mucous membranes, melts or dissolves in rectal
fluids, and is stable during storage.
[0076] In certain preferred embodiments of the present invention
for both water-soluble and water-insoluble drugs, the suppository
base comprises a fatty acid wax selected from the group consisting
of mono-, di- and triglycerides of saturated, natural fatty acids
of the chain length C.sub.12 to C.sub.18.
[0077] In preparing the suppositories of the present invention
other excipients may be used. For example, a wax may be used to
form the proper shape for administration via the rectal route. This
system can also be used without wax, but with the addition of
diluent filled in a gelatin capsule for both rectal and oral
administration.
[0078] Examples of suitable commercially available mono-, di- and
triglycerides include saturated natural fatty acids of the 12-18
carbon atom chain sold under the trade name Novata TM (types AB,
AB, B,BC, BD, BBC, E, BCF, C, D and 299), manufactured by Henkel,
and Witepsol TM (types H5, H12, Hi5, H175, Hi85, H19, H32, H35,
H39, H42, W25, W35, W45, S55, S58, E75, E76 and E85), manufactured
by Dynamit Nobel.
[0079] Other pharmaceutically acceptable suppository bases may be
substituted in whole or in part for the above-mentioned mono-, di-
and triglycerides. The amount of base in the suppository is
determined by the size (i.e. actual weight) of the dosage form, the
amount of alginate and drug used. Generally, the amount of
suppository base is from about 20 percent to about 90 percent by
weight of the total weight of the suppository. Preferably, the
amount of base in the suppository is from about 65 percent to about
80 percent, by weight of the total weight of the suppository.
[0080] In certain embodiments, the controlled-release matrix
comprises a pharmaceutically acceptable sodium alginate and a
pharmaceutically acceptable calcium salt, the calcium salt being in
an amount sufficient to cross-link with the sodium alginate and
thereby provide controlled-release of the opioid agonist and the
antagonist from the matrix when the suppository base melts
subsequent to administration.
[0081] The present invention is contemplated to encompass all
suppository systems, e.g., the technologies described above, with
the inclusion of an opioid antagonist, such that the opioid
antagonist is released in a controlled-release manner along with
the opioid agonist.
[0082] For example, the suppository can comprise a controlled
release matrix comprising a pharmaceutically acceptable sodium
alginate and a pharmaceutically acceptable calcium, and a suitable
vehicle which melts or dissolves in rectal fluids, said calcium
salt being in an amount sufficient to cross-link with the sodium
alginate and thereby provide a controlled release of said
therapeutically active agent from said matrix when said vehicle
melts or dissolves. The calcium salt can be selected from the group
consisting of calcium phosphate, dicalcium phosphate, calcium
chloride, calcium carbonate, calcium acetate, calcium gluconate,
and mixtures thereof.
Compositions for Intranasal Administration
[0083] The controlled release formulation of the present invention
includes compositions for nasal administration. Controlled release
dosage forms containing an opioid agonist is described in European
Patent No. EP 205282 and PCT Application No. WO 8203768 (both
providing controlled release of morphine), and also in U.S. Pat.
No. 5,629,011 (morphine-6-glucuronide and morphine-6-sulfate, both
being metabolites of morphine). Each of these documents are
incorporated herein by reference in their entireties. The present
invention is contemplated to encompass all such nasal formulations
as described above, with the inclusion of an opioid antagonist,
such that the opioid antagonist is released in a controlled-release
manner.
[0084] In certain embodiments, the nasal composition comprises an
opioid agonist and the opioid antagonist in bioadhesive
microspheres. Preferably the microspheres are prepared from a
bio-compatible material that will gel in contact with the mucosal
surface. Substantially uniform solid microspheres are preferred.
Starch microspheres (crosslinked if necessary) are a preferred
material. Other materials that can be used to form microspheres
include starch derivatives, modified starches such as amylodextrin,
gelatin, albumin, collagen, dextran and dextran derivatives,
polyvinyl alcohol, polylactide-co-glycolide, hyaluronic acid and
derivatives thereof such as benzyl and ethyl esters, gellan gum and
derivatives thereof such as benzyl and ethyl esters and pectin and
derivatives thereof such as benzyl and ethyl esters. By the term
"derivatives" we particularly mean esters and ethers of the parent
compound that can be unfunctionalised or functionalised to contain,
for example, ionic groupings.
[0085] Suitable starch derivatives include hydroxyethyl starch,
hydroxypropyl starch, carboxymethyl starch, cationic starch,
acetylated starch, phosphorylated starch, succinate derivatives of
starch and grafted starches. Such starch derivatives are well known
and described in the art (for example Modified Starches: Properties
and Uses, O. B. Wurzburg, CRC Press Boca Raton (1986)).
[0086] Suitable dextran derivatives include,
diethylaminoethyl-dextran (DEAE-dextran), dextran sulphate, dextran
methyl-benzylamide sulphonates, dextran methyl-benzylamide
carboxylates, carboxymethyl dextran, diphosphonate dextran, dextran
hydrazide, palmitoyldextran and dextran phosphate.
[0087] Preparation of these microspheres is well described in the
pharmaceutical literature (see for example Davis et-al., (Eds),
"Microspheres and Drug Therapy", Elsevier Biomedical Press, 1984,
which is incorporated herein by reference). Emulsion and phase
separation methods are both suitable. For example, albumin
microspheres may be made using the water-in-oil emulsification
method where a dispersion of albumin is produced in a suitable oil
by homogenization techniques or stirring techniques, with the
addition if necessary of small amounts of an appropriate surface
active agent. The size of the microspheres is largely dictated by
the speed of stirring or homogenization conditions. The agitation
can be provided by a simple laboratory stirrer or by more
sophisticated devices such as a microfluidizer or homogenizer.
Emulsification techniques are also used to produce starch
microspheres as described in GB 1 518 121 and EP 223 303 as well as
for the preparation of microspheres of gelatin. Proteinaceous
microspheres may also be prepared by coacervation methods such as
simple or complex coacervation or by phase separation techniques
using an appropriate solvent or electrolyte solution. Full details
of the methods of preparing these systems can be obtained from
standard text books (see for example Florence and Attwood,
Physicochemical Principles of Pharmacy 2nd Ed., MacMillan Press,
1988, Chapter 8).
[0088] The controlled-release nasal composition according to the
invention can be administered by any appropriate method according
to their form. A composition comprising microspheres or a powder
can be administered using a nasal insufflator device. Examples of
these are already employed for commercial powder systems intended
for nasal application (e.g. Fisons Lomudal System).
[0089] The insufflator produces a finely divided cloud of the dry
powder or microspheres. The insufflator is preferably provided with
means to ensure administration of a substantially fixed amount of
the composition. The powder or microspheres may-be used directly
with an insufflator which is provided with a bottle or container
for the powder or microspheres. Alternatively the powder or
microspheres may be filled into a capsule such as a gelatin
capsule, or other single dose device adapted for nasal
administration. The insufflator preferably has means to break open
the capsule or other device.
[0090] A composition comprising a solution or dispersion in an
aqueous medium can be administered as a spray using an appropriate
device such as a metered dose aerosol valve or a metered dose pump.
A gas or liquid propellant can be used. Details of other devices
can be found in the pharmaceutical literature (see for example
Bell, A. Intranasal Delivery Devices, in Drug Delivery Devices
Fundamentals and Applications, Tyle P. (ed), Dekker, New York,
1988), Remington's Pharmaceutical Sciences, Mack Publishing Co.,
1975.
[0091] The present invention is contemplated to encompass all nasal
formulations, e.g., the technologies described above, with the
inclusion of an opioid antagonist, such that the opioid antagonist
is released in a controlled-release manner along with the opioid
agonist.
[0092] For example, the intranasal formulation can comprise an
effective amount of an absorption promoting agent to allow nasal
absorption of the agents after nasal administration of the
composition. The absorption promoting agent can be selected from
the group consisting of a cationic polymer, a surface active agent,
a chelating agent, a mucolytic agent, a cyclodextrin, and
combinations thereof.
Injectable Formulations
[0093] The controlled-release injectable compositions containing an
opioid antagonist is described in, e.g., U.S. Pat. No. 5,942,241 to
Chasin et al, which is incorporated herein by reference in its
entirety. The present invention is contemplated to encompass all
such injectable formulations, with the inclusion of an opioid
antagonist, such that the opioid antagonist is also released in a
controlled-release manner along with the opioid agonist.
[0094] In certain embodiments, the controlled-release injectable
composition comprise an opioid agonist and antagonist in
controlled-release microparticles, e.g., microspheres or
microcapsules. The slow release of the drugs is brought about
through controlled diffusion out of the matrix and/or selective
breakdown of the coating of the preparation or selective breakdown
of a polymer matrix.
[0095] In certain embodiments, the slow release formulation is
prepared as microspheres in a size distribution range suitable for
local infiltration or injection. The diameter and shape of the
microspheres or other particles can be manipulated to modify the
release characteristics. For example, larger diameter microspheres
will typically provide slower rates of release and reduced tissue
penetration and smaller diameters of microspheres will produce the
opposite effects, relative to microspheres of different mean
diameter but of the same composition. In addition, other particle
shapes, such as, for example, cylindrical shapes, can also modify
release rates by virtue of the increased ratio of surface area to
mass inherent to such alternative geometrical shapes, relative to a
spherical shape. The diameter of injectable microspheres are in a
size range from, for example, from about 5 microns to about 200
microns in diameter. In a more preferred embodiment, the
microspheres range in diameter from about 20 to about 120
microns.
[0096] A wide variety of biodegradable materials may be utilized to
provide the controlled release injectable dosage forms. Any
pharmaceutically acceptable biodegradable polymers known to those
skilled in the art may be utilized. It is preferred that the
biodegradable controlled release material degrade in vivo over a
period of less than about two years, with at least 50% of the
controlled release material degrading within about one year, and
more preferably six months or less. More preferably, the controlled
release material will degrade significantly within one to three
months, with at least 50% of the material degrading into non-toxic
residues which are removed by the body, and 100% of the drug being
released within a time period from about two weeks to about two
months. The controlled release material should preferably degrade
by hydrolysis, and most preferably by surface erosion, rather than
by bulk erosion, so that release is not only sustained but also
provides desirable release rates. However, the pharmacokinetic
release profile of these formulations may be first order, zero
order, bi- or multi-phasic, to provide the desired reversible local
anesthetic effect over the desired time period.
[0097] The controlled release material should be biocompatible. In
the case of polymeric materials, biocompatibility is enhanced by
recrystallization of either the monomers forming the polymer and/or
the polymer Using standard techniques.
[0098] Suitable biodegradable polymers can be utilized as the
controlled-release material. The polymeric material may comprise a
polylactide, a polyglycolide, a poly(lactide-co-glycolide), a
polyanhydride, a polyorthoester, polycaprolactones,
polyphosphazenes, polysaccharides, proteinaceous polymers, soluble
derivatives of polysaccharides, soluble derivatives of
proteinaceous polymers, polypeptides, polyesters, and
polyorthoesters or mixtures or blends of any of these. The
polysaccharides may be poly-1,4-glucans, e.g., starch glycogen,
amylose, amylopectin, and mixtures thereof. The biodegradable
hydrophilic or hydrophobic polymer may be a water-soluble
derivative of a poly-1,4-glucan, including hydrolyzed amylopectin,
hydroxyalkyl derivatives of hydrolyzed amylopectin such as
hydroxyethyl starch (HES), hydroxyethyl amylose, dialdehyde starch,
and the like. Preferred controlled release materials which are
useful in the formulations of the invention include the
polyanhydrides, co-polymers of lactic acid and glycolic acid
wherein the weight ratio of lactic acid to glycolic acid is no more
than 4:1 (i.e., 80% or less lactic acid to 20% or more glycolic
acid by weight), and polyorthoesters containing a catalyst or
degradation enhancing compound, for example, containing at least 1%
by weight anhydride catalyst such as maleic anhydride. Other useful
polymers include protein polymers such as gelatin and fibrin and
polysaccharides such as hyaluronic acid. Since polylactic acid
takes at least one year to degrade in vivo, this polymer should be
utilized by itself only in circumstances where such a degradation
rate is desirable or acceptable.
[0099] The polymeric material may be prepared by any method known
to those skilled in the art. For example, where the polymeric
material is comprised of a copolymer of lactic and glycolic acid,
this copolymer may be prepared by the procedure set forth in U.S.
Pat. No. 4,293,539 (Ludwig, et al.), the disclosure of which is
hereby incorporated by-reference in its entirety. In brief, Ludwig
prepares such copolymers by condensation of lactic acid and
glycolic acid in the presence of a readily removable polymerization
catalyst (e.g., a strong acid ion-exchange resin such as Dowex
HCR-W2-H). The amount of catalyst is not critical to the
polymerization, but typically is from about 0.01 to about 20 parts
by weight relative to the total weight of combined lactic acid and
glycolic acid. The polymerization reaction may be conducted without
solvents at a temperature from about 100 C. to about 250 C. for
about 48 to about 96 hours, preferably under a reduced pressure to
facilitate removal of water and by-products. The copolymer is then
recovered by filtering the molten reaction mixture to remove
substantially all of the catalyst, or by cooling and then
dissolving the reaction mixture in an organic solvent such as
dichloromethane or acetone and then filtering to remove the
catalyst.
[0100] The substrates of the presently described formulations in
certain preferred embodiments are manufactured using a method that
evenly disperses the local anesthetic throughout the formulation,
such as emulsion preparation, solvent casting, spray drying or hot
melt, rather than a method such as compression molding. A desired
release profile may be achieved by using a mixture of polymers
having different release rates.
[0101] Methods for manufacture of microspheres are well known and
are typified in the following examples. Examples of suitable
methods of making microspheres include solvent evaporation, phase
separation and fluidized bed coating.
[0102] In solvent evaporation procedures, the local anesthetic
agent, if soluble in organic solvents, may be entrapped in the
biodegradable polymer by dissolving the polymer in a volatile
organic solvent, adding the drug to the organic phase, emulsifying
the organic phase in water which contains less than 2% polyvinyl
alcohol, and finally removing the solvent under vacuum to form
discrete, hardened monolithic microspheres.
[0103] Phase separation microencapsulation-procedures are suitable
for entrapping water-soluble agents in the polymer to prepare
microcapsules and microspheres. Phase separation involves
coacervation of the polymer from an organic solvent by addition of
a nonsolvent such as silicone oil. In a preferred embodiment, the
microspheres may be prepared by the process of Ramstack et al.,
1995, in published international patent application WO 95/13799,
the disclosure of which is incorporated herein in its entirety. The
Ramstack et al. process essentially provides for a first phase,
including an active agent and a polymer, and a second phase, that
are pumped through a static mixer into a quench liquid to form
microparticles containing the active agent. The first and second
phases can optionally be substantially immiscible and the second
phase is preferably free from solvents for the polymer and the
active agent and includes an aqueous solution of an emulsifier.
[0104] In fluidized bed coating, the drug is dissolved in an
organic solvent along with the polymer. The solution is then
processed, e.g., through a Wurster air suspension coating apparatus
to form the final microcapsule product.
[0105] The present invention is contemplated to encompass all
injectable formulations, e.g., the technologies described above,
with the inclusion of an opioid antagonist, such that the opioid
antagonist is released in a controlled-release manner along with
the opioid agonist.
[0106] For example, injectable composition can comprise a plurality
of substrates in a pharmaceutically acceptable medium for
injection, said substrates comprising an effective amount of a
biocompatible, biodegradable controlled release material comprising
a polymer selected from the group consisting of polyanhydrides,
copolymers of lactic acid and glycolic acid, poly(lactic) acid,
poly(glycolic) acid, polyesters, polyorthoesters, proteins,
polysaccharides and combinations thereof.
Controlled Release Oral Dosage Forms
[0107] The opioid agonist and antagonist combination may be
formulated as a controlled-release oral dosage form, including
tablets and capsules. In preferred embodiments, the
controlled-release oral dosage form provides a controlled release
of an opioid agonist and a controlled-release of an opioid
antagonist, such that when the dosage form is administered to a
human, the blood levels of the agonist is maintained throughout the
dosing period at an analgesically effective level, and the
antagonist at a level sufficient to decrease the side effects
associated with the opioid agonist but not sufficient to negate-the
analgesic effect of the opioid agonist.
[0108] The term "release rate," as used in the application, refers
to a rate at which a drug is released from the dosage form. The
release pattern of a drug is a function of its properties, such as
its physicochemical properties. Solubility is one such property.
Since drug must be in solution before they can be absorbed into the
body. The release rate of the drug from an oral dosage form may be
measured, for example, by measuring the dissolution rate of the
drug from the dosage form using an in vitro test method conducted
under standardized conditions, e.g., U.S.P. paddle, 100 rpm in
simulated gastric fluid for the first hour and thereafter in
simulated intestinal fluid. For purposes of the present invention,
release rate may be used as a surrogate measure of drug delivery
in-vivo.
[0109] In certain embodiments of the present invention, the ratio
of the opioid agonist to the antagonist in the controlled-release
oral dosage form is about 1:1 to about 100:1 by weight. In
preferred embodiments, the ratio of the opioid agonist with the
antagonist is about 40:1 to about 50:1 by weight, more preferably
about 20:1. In other preferred embodiments of the invention the
amount of the opioid receptor antagonist administered is about 100
to about 1000 fold less than the amount of the opioid agonist
administered
[0110] Controlled-release oral dosage forms according the invention
may be prepared using the methods available to one skilled in the
art. In certain embodiments of the present invention,
controlled-release tablets comprise the opioid agonist and
antagonist in a controlled release matrix. The controlled-release
matrix may include hydrophilic and/or hydrophobic materials, such
as gums, cellulose ethers, acrylic resins, protein derived
materials; the list is not meant to be exclusive, and any
pharmaceutically acceptable hydrophobic material or hydrophilic
material which is capable of imparting controlled release of the
opioid may be used in accordance with the present invention. The
opioid agonist particles may, alternatively or additionally, be
film coated with a material that permits release of the opioid
agonist at a sustained rate in an aqueous medium. The film coat is
chosen so as to achieve, in combination with the other stated
properties, a desired in-vitro release rate. The sustained release
coating formulations of 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.
[0111] The dosage forms comprising an opioid agonist and opioid
antagonist may optionally be coated with one or more materials
suitable for the regulation of the opioid agonist release or for
the protection of the formulation. In one embodiment, coatings are
provided to permit either pH-dependent or pH-independent release,
e.g., when exposed to gastrointestinal fluid. A pH-dependent
coating serves to release the opioid in desired areas of the
gastro-intestinal (GI) tract, e.g., the stomach or small intestine,
such that an absorption profile is provided which is capable of
providing at least about eight hours and preferably about twelve
hours to up to about twenty-four hours of analgesia to a patient.
When a pH-independent coating is desired, the coating is designed
to achieve optimal release of the opioid regardless of pH-changes
in the environmental fluid, e.g., the GI tract. It is also possible
to formulate compositions which release a portion of the dose in
one desired area of the GI tract, e.g., the stomach, and release
the remainder of the dose in another area of the GI tract, e.g.,
the small intestine.
[0112] Formulations according to the invention that utilize
pH-dependent coatings to obtain formulations may also impart a
repeat-action effect whereby unprotected drug is coated over the
enteric coat and is released in the stomach, while the remainder,
being protected by the enteric coating, is released further down
the gastrointestinal tract. Coatings which are pH-dependent may be
used in accordance with the present invention include shellac,
cellulose acetate phthalate (CAP), polyvinyl acetate phthalate
(PVAP), hydroxypropylmethylcellulose phthalate, and methacrylic
acid ester copolymers, zein, and the like.
[0113] In certain preferred embodiments, the substrate (e.g.,
tablet core bead, matrix particle) containing the opioid
agonist/opioid antagonist combination is coated with a hydrophobic
material selected from (i) an alkylcellulose; (ii) an aciylic
polymer; or (iii) mixtures thereof. The coating may be applied in
the form of an organic or aqueous solution or dispersion. The
coating may be applied to obtain a weight gain from about 2 to
about 25% of the substrate in order to obtain a desired sustained
release profile. Coatings derived from aqueous dispersions are
described, e.g., in detail in U.S. Pat. Nos. 5,273,760 and
5,286,493, assigned to the Assignee of the present invention and
hereby incorporated by reference.
[0114] Other examples of sustained release formulations and
coatings which may be used in accordance with the present invention
include Assignee's U.S. Pat. Nos. 5,324,351; 5,356,467, and
5,472,712, hereby incorporated by reference in their entirety.
[0115] Alkylcellulose Polymers
[0116] Cellulosic materials and polymers, including
alkylcelluloses, provide hydrophobic materials well suited for
coating the beads according to the invention. Simply by way of
example, one preferred alkylcellulosic polymer is ethylcellulose,
although the artisan will appreciate that other cellulose and/or
alkylcellulose polymers may be readily employed, singly or in any
combination, as all or part of a hydrophobic coating according to
the invention.
[0117] One commercially-available aqueous dispersion of
ethylcellulose is Aquacoat.RTM. (FMC Corp., Philadelphia, Pa.,
U.S.A.). Aquacoat.RTM. is prepared by dissolving the ethylcellulose
in a water-immiscible organic solvent and then emulsifying the same
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. The plasticizer
is not incorporated in the pseudolatex during the manufacturing
phase. Thus, prior to using the same as a coating, it is necessary
to intimately. mix the Aquacoat.RTM. with a suitable plasticizer
prior to use.
[0118] Another aqueous dispersion of ethylcellulose is commercially
available as Surelease.RTM. (Colorcon, Inc., West Point, Pa.,
U.S.A.). This product is prepared by incorporating plasticizer into
the dispersion during the manufacturing process. A hot melt of a
polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic
acid) is prepared as a homogeneous mixture, which is then diluted
with an alkaline solution to obtain an aqueous dispersion which can
be applied directly onto substrates.
[0119] Acrylic Polymers
[0120] In other preferred embodiments of the present invention, the
hydrophobic material comprising the controlled release coating is a
pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cyanoethyl
methacrylate, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamide copolymer, poly(methyl methacrylate),
polymethacrylate, poly(methyl methacrylate) copolymer,
polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic
acid anhydride), and glycidyl methacrylate copolymers.
[0121] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Anmonio
methacrylate copolymers are well known in the art, and are
described in NF XVII as fully polymerized copolymers of acrylic and
methacrylic acid esters with a low content of quaternary ammonium
groups.
[0122] In order to obtain a desirable dissolution profile, it may
be necessary to incorporate two or more ammonio methacrylate
copolymers having differing physical properties, such as different
molar ratios of the quaternary ammonium groups to the neutral
(meth)acrylic esters.
[0123] Certain methacrylic acid ester-type polymers are useful for
preparing pH-dependent coatings which may be used in accordance
with the present invention. For example, there are a family of
copolymers synthesized from diethylaminoethyl methacrylate and
other neutral methacrylic esters, also known as methacrylic acid
copolymer or polymeric methacrylates, commercially available as
Eudragit.RTM. from Rohm Tech, Inc. There are several different
types of Eudragit.RTM.. For example, Eudragit.RTM. E is an example
of a methacrylic acid copolymer which swells and dissolves in
acidic media. Eudragit.RTM. L is a methacrylic acid copolymer which
does not swell at about pH <5.7 and is soluble at about pH
>6. Eudragit.RTM. S does not swell at about pH <6.5 and is
soluble at about pH >7. Eudragit.RTM. RL and Eudragit.RTM. RS
are water swellable, and the amount of water absorbed by these
polymers is pH-dependent, however, dosage forms coated with
Eudragit.RTM. RL and RS are pH-independent.
[0124] In certain preferred embodiments, the acrylic coating
comprises a mixture of two acrylic resin lacquers commercially
available from Rohm Pharma under the Tradenames Eudragit.RTM. RL30D
and Eudragit.RTM. RS30D, respectively. Eudragit.RTM. RL30D and
Eudragit.RTM. RS30D are copolymers of acrylic and methacrylic
esters with a low content of quatemary ammonium groups, the molar
ratio of ammonium groups to the remaining neutral (meth)acrylic
esters being 1:20 in Eudragit.RTM. RL30D and 1:40 in Eudragit.RTM.
RS30D. The mean molecular weight is about 150,000. The code
designations RL (high permeability) and RS (low permeability) refer
to the permeability properties of these agents. Eudragit.RTM. RL/RS
mixtures are insoluble in water and in digestive fluids. However,
coatings formed from the same are swellable and permeable in
aqueous solutions and digestive fluids.
[0125] The Eudragit.RTM. RL/RS dispersions of the present invention
may be mixed together in any desired ratio in order to ultimately
obtain a sustained release formulation having a desirable
dissolution profile. Desirable sustained release formulations may
be obtained, for instance, from a retardant coating derived from
100% Eudragit.RTM. RL, 50% Eudragit.RTM. RL and 50% Eudragit.RTM.
RS, and 10% Eudragit.RTM. RL:Eudragit.RTM. 90% RS. Of course, one
skilled in the art will recognize that other acrylic polymers may
also be used, such as, for example, Eudragit.RTM. L.
[0126] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic material, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic material will further improve the
physical properties of the sustained release coating. For example,
because ethylcellulose has a-relatively high glass transition
temperature and does not form flexible films under normal coating
conditions, it is preferable to incorporate a plasticizer into an
ethylcellulose coating containing sustained release coating before
using the same as a coating material. Generally, the amount of
plasticizer included in a coating solution is based on the
concentration of the film-former, e.g., most often from about 1 to
about 50 percent by weight of the film-former. Concentration of the
plasticizer, however, can only be properly determined after careful
experimentation with the particular coating solution and method of
application.
[0127] Examples of suitable plasticizers for ethylcellulose include
water insoluble plasticizers such as dibutyl sebacate, diethyl
phthalate, triethyl citrate, tributyl citrate, and triacetin,
although it is possible that other water-insoluble plasticizers
(such as acetylated monoglycerides, phthalate esters, castor oil,
etc.) may be used. Triethyl citrate is an especially preferred
plasticizer for the aqueous dispersions of ethyl cellulose of the
present invention.
[0128] Examples of suitable plasticizers for the acrylic polymers
of the present invention include, but are not limited to citric
acid esters such as triethyl citrate NF XVI, tributyl citrate,
dibutyl phthalate, and possibly 1,2-propylene glycol. Other
plasticizers which have proved to be suitable for enhancing the
elasticity of the films formed from acrylic films such as
Eudragit.RTM. RL/RS lacquer solutions include polyethylene glycols,
propylene glycol, diethyl phthalate, castor oil, and triacetin.
Triethyl citrate is an especially preferred plasticizer for the
aqueous dispersions of ethyl cellulose of the present
invention.
[0129] It has further been found that the addition of a small
amount of talc reduces the tendency of the aqueous dispersion to
stick during processing, and acts as a polishing agent.
[0130] When a hydrophobic controlled release coating material is
used to coat inert pharmaceutical beads such as nu pariel 18/20
beads, which are already coated with an opioid agonist, a plurality
of the resultant solid controlled release beads may thereafter be
placed in a gelatin capsule, with the opioid antagonist in a
substantially non-releasable form. The-dosage form provides an
effective controlled release dose of the opioid agonist when
ingested and contacted by an environmental fluid, e.g., gastro
fluid or dissolution media.
[0131] The controlled release bead formulations of the present
invention slowly release the opioid agonist, e.g., when ingested
and exposed to gastric fluids, and then to intestinal fluids. The
controlled release profile of the formulations of the invention can
be altered, for example, by varying the amount of overcoating with
the hydrophobic material, altering the manner in which the
plasticizer is added to the hydrophobic material, by varying the
amount of plasticizer relative to hydrophobic material, by the
inclusion of additional ingredients or excipients, by altering the
method of manufacture, etc. The dissolution profile of the ultimate
product may also be modified, for example, by increasing or
decreasing the thickness of the retardant coating.
[0132] Spheroids or beads coated with an opioid agonist may be
prepared, e.g., by dissolving the drug in water and then spraying
the solution onto a substrate, for example, nu pariel 18/20 beads,
using a Wuster insert. Optionally, additional ingredients are also
added prior to coating the beads in order to assist the binding of
the opioid to the beads, and/or to color the solution, etc. For
example, a product which includes hydroxypropylmethylcellulose,
etc. with or without colorant (e.g., Opadry.RTM., commercially
available from Colorcon, Inc.) may be added to the solution and the
solution mixed (e.g., for about 1 hour) prior to application of the
same onto the beads. The resultant coated substrate, in this
example beads, may then be optionally overcoated with a barrier
agent, to separate the therapeutically active agent from the
hydrophobic controlled release coating. An example of a suitable
barrier agent is one which comprises hydroxypropylmethylcellulose.
However, any film-former known in the art may be used. It is
preferred that the barrier agent does not affect the dissolution
rate of the final product.
[0133] The beads may then be overcoated with an aqueous dispersion
of the hydrophobic material. The aqueous dispersion of hydrophobic
material -preferably further includes an effective amount of
plasticizer, e.g. triethyl citrate. Pre-formulated aqueous
dispersions of ethylcellulose, such as Aquacoat.RTM. or
Sureleas.RTM., may be used. If Sureleas.RTM. is used, it is not
necessary to separately add a plasticizer. Alternatively,
pre-formulated aqueous dispersions of acrylic polymers such as
Eudragit.RTM. can be used.
[0134] The coating solutions of the present invention preferably
contain, in addition to the film-former, plasticizer, and solvent
system (i.e., water), a colorant to provide elegance and product
distinction. Color may be added to the solution of the
therapeutically active agent instead, or in addition to the aqueous
dispersion of hydrophobic material. For example, color may be added
to Aquacoat.RTM. via the use of alcohol or propylene glycol based
color dispersions, milled aluminum lakes and opacifiers such as
titanium dioxide by adding color with shear to water soluble
polymer solution and then using low shear to the plasticized
Aquacoat.RTM.. Alternatively, any suitable method of providing
color to the formulations of the present invention may be used.
Suitable ingredients for providing color to the formulation when an
aqueous dispersion of an acrylic polymer is used include titanium
dioxide and color pigments, such as iron oxide pigments. The
incorporation of pigments, may, however, increase the retard effect
of the coating.
[0135] Plasticized hydrophobic material may be applied onto the
substrate comprising the therapeutically active agent by spraying
using any suitable spray equipment known in the art. In a preferred
method, a Wurster fluidized-bed system is used in which an air jet,
injected from underneath, fluidizes the core material and effects
drying while the acrylic polymer coating is sprayed on. A
sufficient amount of the hydrophobic material to obtain a
predetermined controlled release of the opioid agonist and opioid
antagonist when the coated substrate is exposed to aqueous,
solutions, e.g. gastric fluid, is preferably applied, taking into
account the physical characteristics of the therapeutically active
agent, the manner of incorporation of the plasticizer, etc. After
coating with the hydrophobic material, a further overcoat of a
film-former, such as Opadry.RTM., is optionally applied to the
beads. This overcoat is provided, if at all, in order to
substantially reduce agglomeration of the beads.
[0136] The release of the therapeutically active agent from the
controlled release formulation of the present invention can be
further influenced, i.e., adjusted to a desired rate, by the
addition of one or more release-modifying agents, or by providing
one or more passageways through the coating. The ratio of
hydrophobic material to water soluble material is determined by,
among other factors, the release rate required and the solubility
characteristics of the materials selected.
[0137] The release-modifying agents which function as pore-formers
may be organic or inorganic, and include materials that can be
dissolved, extracted or leached from the coating in the environment
of use. The pore-formers may comprise one or more hydrophilic
materials such as hydroxypropylmethylcellulose. The
release-modifying agent may also comprise a semi-permeable polymer.
In certain preferred embodiments, the release-modifying agent is
selected from hydroxypropylmethylcellulose, lactose, metal
stearates, and mixtures of any of the foregoing. The sustained
release coatings of the present invention can also include
erosion-promoting agents such as starch and gums.
[0138] The sustained release coatings of the present invention can
also include materials useful for making microporous lamina in the
environment of use, such as polycarbonates comprised of linear
polyesters of carbonic acid in which carbonate groups reoccur in
the polymer chain.
[0139] The sustained release coatings of the present invention may
also include an exit means comprising at least one passageway,
orifice, or the like. The passageway may be formed by such methods
as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889;
4,063,064; and 4,088,864 (all of which are hereby incorporated by
reference). The passageway can have any shape such as round,
triangular, square, elliptical, irregular, etc.
[0140] In other embodiments of the present invention, the
controlled release formulation is achieved via a matrix having a
controlled release coating as set forth above. The present
invention also comprises sustained-release tablets comprising an
opioid agonist and opioid antagonist particles, wherein the agonist
and the antagonist are dispersed in a controlled release matrix
that affords in-vitro dissolution rates of the opioid agonist
within the preferred ranges and that releases the opioid agonist in
a pH-dependent or pH-independent manner. The materials suitable for
inclusion in a controlled release matrix will depend on the method
used to form the matrix.
[0141] For example, a matrix in addition to the opioid agonist and
the opioid antagonist, may include hydrophilic and/or hydrophobic
materials, such as gums, cellulose ethers, acrylic resins, protein
derived materials. Such matrices may also include digestible, long
chain (C.sub.8-C.sub.50, especially C.sub.12-C.sub.40), substituted
or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,
glyceryl esters of fatty acids, mineral and vegetable oils and
waxes, and stearyl alcohol; and polyalkylene glycols. Of these
polymers, acrylic polymers, especially Eudragit.RTM.0 RSPO--the
cellulose ethers, especially hydroxyalkylcelluloses and
carboxyalkylcelluloses, are preferred. The oral dosage form may
contain between 1% and 80% (by weight) of at least one hydrophilic
or hydrophobic material. When the hydrophobic material is a
hydrocarbon, the hydrocarbon preferably has a melting point of
between 25.degree. and 90.degree. C. Of the long chain hydrocarbon
materials, fatty (aliphatic) alcohols are preferred. The oral
dosage form may contain up to 60% (by weight) of at least one
digestible, long chain hydrocarbon. In certain embodiments, the
oral dosage form contains up to 60% (by weight) of at least one
polyalkylene glycol as part of the controlled release matrix.
[0142] The hydrophobic material is preferably selected from the
group consisting of alkylcelluloses, acrylic and methacrylic acid
polymers and copolymers, shellac, zein, hydrogenated castor oil,
hydrogenated vegetable oil, or mixtures thereof. In certain
preferred embodiments of the present invention, the hydrophobic
material is a pharmaceutically acceptable acrylic polymer,
including but not limited to acrylic acid and methacrylic acid
copolymers, methyl methacrylate, methyl methacrylate copolymers,
ethoxyethyl methacrylates, cyanoethyl methacrylate, aminoalkyl
methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid),
methacrylic acid alkylamine copolymer, poly(methyl methacrylate),
poly(methacrylic acid)(anhydride), polymethacrylate,
polyacrylamide, poly(methacrylic acid anhydride), and glycidyl
methacrylate copolymers. In other embodiments, the hydrophobic
material is selected from materials such as hydroxyalkylcelluloses
such as hydroxypropylmethylcellulose and mixtures of the foregoing.
Preferred hydrophobic materials are water-insoluble with more or
less pronounced hydrophilic and/or hydrophobic trends. Preferably,
the hydrophobic materials useful in the invention have a melting
point from about 300 to about 200.degree. C., preferably from about
45.degree. to about 90.degree. C. The list is not meant to be
exclusive, and any pharmaceutically acceptable hydrophobic material
or hydrophilic material which is capable of imparting controlled
release of the opioid agonist and opioid antagonist may be used in
accordance with the present invention.
[0143] The hydrophobic material may comprise natural or synthetic
waxes , fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or
preferably cetostearyl alcohol), fatty acids, including but not
limited to fatty acid esters, fatty acid glycerides (mono-, di-,
and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes,
stearic aid, stearyl alcohol and hydrophobic and hydrophilic
materials having hydrocarbon backbones. Suitable waxes include, for
example, beeswax, glycowax, castor wax and carnauba wax. For
purposes of the present invention, a wax-like substance is defined
as any material which is normally solid at room temperature and has
a melting point of from about 30.degree. to about 100.degree.
C.
[0144] Suitable hydrophobic materials which may be used in
accordance with the present invention include digestible, long
chain (C.sub.8-C.sub.50, especially C.sub.12-C.sub.40), substituted
or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols,
glyceryl esters of fatty acids, mineral and vegetable oils and
natural and synthetic waxes. Hydrocarbons having a melting point of
between 25.degree. and 90.degree. C. are preferred. Of the long
chain hydrocarbon materials, fatty (aliphatic) alcohols are
preferred in certain embodiments. The oral dosage form may contain
up to 60% (by weight) of at least one digestible, long chain
hydrocarbon.
[0145] A combination of two or more hydrophobic materials may be
included in the matrix formulations. If an additional hydrophobic
material is included, it is preferably selected from natural and
synthetic waxes, fatty acids, fatty alcohols, and mixtures of the
same. Examples include beeswax, carnauba wax, stearic acid and
stearyl alcohol. This list is not meant to be exclusive.
[0146] An example of a suitable matrix comprises at least one water
soluble hydroxyalkyl cellulose, at least one C.sub.12-C.sub.36,
preferably C.sub.14-C.sub.22, aliphatic alcohol and, optionally, at
least one polyalkylene glycol. The at least one hydroxyalkyl
cellulose is preferably a hydroxy (C.sub.1 to C.sub.6) alkyl
cellulose, such as hydroxypropylcellulose,
hydroxypropylmethylcellulose and, especially,
hydroxyethylcellulose. The amount of the at least one
hydroxyalkylcellulose in the present oral dosage form will be
determined, inter alia, by the precise rate of opioid release
required. The at least one aliphatic alcohol may be, for example,
lauryl alcohol, myristyl alcohol or stearyl alcohol. In
particularly preferred embodiments of the present oral dosage form,
however, the at least one aliphatic alcohol is cetyl alcohol or
cetostearyl alcohol. The amount of the at least one aliphatic
alcohol in the present oral dosage form will be determined, as
above, by the precise rate of opioid release required. It will also
depend on whether at least one polyalkylene glycol is present in or
absent from the oral dosage form. In the absence of at least one
polyalkylene glycol, the oral dosage form preferably contains
between 20% and 50% (by wt) of the at least one aliphatic alcohol.
When at least one polyalkylene glycol is present in the oral dosage
form, then the combined weight of the at least one aliphatic
alcohol and the at least one polyalkylene glycol preferably
constitutes between 20% and 50% (by wt) of the total dosage.
[0147] In one embodiment, the ratio of, e.g., the at least one
hydroxyalkyl cellulose or acrylic resin to the at least one
aliphatic alcohol/polyalkylene glycol determines, to a considerable
extent, the release rate of the opioid from the formulation. A
ratio of the at least one hydroxyalkyl cellulose to the at least
one aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is
preferred, with a ratio of between 1:3 and 1:4 being particularly
preferred.
[0148] The at least one polyalkylene glycol may be, for example,
polypropylene glycol or, which is preferred, polyethylene glycol.
The number average molecular weight of the at least one
polyalkylene glycol is preferred between 1,000 and 15,000
especially between 1,500 and 12,000.
[0149] Another suitable controlled release matrix would comprise an
alkylcellulose (especially ethyl cellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0150] In another preferred embodiment, the matrix includes a
pharmaceutically acceptable combination of at least two hydrophobic
materials.
[0151] In addition to the above ingredients, a controlled release
matrix may also contain suitable quantities of other materials,
e.g. diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
[0152] In order to facilitate the preparation of a solid,
controlled release, oral dosage form according to this invention,
any method of preparing a matrix formulation known to those skilled
in the art may be used. For example incorporation in the matrix may
be effected, for example, by (a) forming granules comprising at
least one water soluble hydroxyalkyl cellulose and opioid
agonist/opioid antagonist; (b) mixing the hydroxyalkyl cellulose
containing granules with at least one C.sub.12-C.sub.36 aliphatic
alcohol; and (c) optionally, compressing and shaping the granules.
Preferably, the granules are formed by wet granulating the
hydroxyalkylcellulose/opioid agonist/opioid antagonist with water.
In a particularly preferred embodiment of this process, the amount
of water added during the wet granulation step is preferably
between 1.5 and 5 times, especially between 1.75 and 3.5 times, the
dry weight of the opioid.
[0153] In yet other alternative embodiments, a spheronizing agent,
together with the active ingredient can be spheronized to form
spheroids. Microcrystalline cellulose is preferred. A suitable
microcrystalline cellulose is, for example, the material sold as
Avicel PH 101 (Trade Mark, FMC Corporation). In such embodiments,
in addition to the active ingredient and spheronizing agent, the
spheroids may also contain a binder. Suitable binders, such as low
viscosity, water soluble polymers, will be well known to those
skilled in the pharmaceutical art. However, water soluble hydroxy
lower alkyl cellulose, such as hydroxypropylcellulose, are
preferred. Additionally (or alternatively) the spheroids may
contain a water insoluble polymer, especially an acrylic polymer,
an acrylic copolymer, such as a methacrylic acid-ethyl acrylate
copolymer, or ethylcellulose. In such embodiments, the sustained
release coating will generally include a hydrophobic material such
as (a) a wax, either alone or in admixture with a fatty alcohol; or
(b) shellac or zein.
[0154] Sustained release matrices can also be prepared via
melt-granulation or melt-extrusion techniques. Generally,
melt-granulation techniques involve melting a normally solid
hydrophobic material, e.g. a wax, and incorporating a powdered drug
therein. To obtain a sustained release dosage form, it may be
necessary to incorporate an additional hydrophobic substance, e.g.
ethylcellulose or a water-insoluble acrylic polymer, into the
molten wax hydrophobic material. Examples of sustained release
formulations prepared via melt-granulation techniques are found in
U.S. Pat. No. 4,861,598, assigned to the Assignee of the present
invention and hereby incorporated by reference in its entirety.
[0155] The additional hydrophobic material may comprise one or more
water-insoluble wax-like thermoplastic substances possibly mixed
with one or more wax-like thermoplastic substances being less
hydrophobic than said one or more water-insoluble wax-like
substances. In order to achieve constant release, the individual
wax-like substances in the formulation should be substantially
non-degradable and insoluble in gastrointestinal fluids during the
initial release phases. Useful water-insoluble wax-like substances
may be those with a water-solubility that is lower than about
1:5,000 (w/w).
[0156] In addition to the above ingredients, a sustained release
matrix may also contain suitable quantities of other materials,
e.g., diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art. The quantities of these additional materials will be
sufficient to provide the desired effect to the desired
formulation. In addition to the above ingredients, a sustained
release matrix incorporating melt-extruded multiparticulates may
also contain suitable quantities of other materials, e.g. diluents,
lubricants, binders, granulating aids, colorants, flavorants and
glidants that are conventional in the pharmaceutical art in amounts
up to about 50% by weight of the particulate if desired.
[0157] Specific examples of pharmaceutically acceptable carriers
and excipients that may be used to formulate oral dosage forms are
described in the Handbook of Pharmaceutical Excipients, American
Pharmaceutical Association (1986), incorporated by reference
herein.
[0158] The preparation of a suitable melt-extruded matrix according
to the present invention may, for example, include the steps of
blending the opioid agonist, opioid antagonist, together with at
least one hydrophobic material and preferably the additional
hydrophobic material to obtain a homogeneous mixture. The
homogeneous mixture is then heated to a temperature sufficient to
at least soften the mixture sufficiently to extrude the same. The
resulting homogeneous mixture is then extruded to form strands. The
extrudate is preferably cooled and cut into multiparticulates by
any means known in the art. The strands are cooled and cut into
multiparticulates. The extrudate preferably-has a diameter of from
about 0.1 to about 5 mm and provides sustained release of the
opioid agonist and antagonist for a time period of from about 8 to
about 24 hours.
[0159] An optional process for preparing the melt extrusions of the
present invention includes directly metering into an extruder a
hydrophobic material, the opioid agonist and antagonist, and an
optional binder; heating the homogenous mixture; extruding the
homogenous mixture to thereby form strands; cooling the strands
containing the homogeneous mixture; cutting the strands into
particles having a size from about 0.1 mm to about 12 mm. In this
aspect of the invention, a relatively continuous manufacturing
procedure is realized.
[0160] The diameter of the extruder aperture or exit port can also
be adjusted to vary the thickness of the extruded strands.
Furthermore, the exit part of the extruder need not be round; it
can be oblong, rectangular, etc. The exiting strands can be reduced
to particles using a hot wire cutter, guillotine, etc.
[0161] The melt extruded multiparticulate system can be, for
example, in the form of granules, spheroids or pellets depending
upon the extruder exit orifice. For purposes of the present
invention, the terms "melt-extruded multiparticulate(s)" and
"melt-extruded multiparticulate system(s)" and "melt-extruded
particles" shall refer to a plurality of units, preferably within a
range of similar size and/or shape and containing one or more
active agents and one or more excipients, preferably including a
hydrophobic material as described herein. In this regard, the
melt-extruded multiparticulates will be of a range of from about
0.1 to about 12 mm in length and have a diameter of from about 0.1
to about 5 mm. In addition, it is to be understood that the
melt-extruded multiparticulates can be any geometrical shape within
this size range. Alternatively, the extrudate may simply be cut
into desired lengths and divided into unit doses of the
therapeutically active agent without the need of a spheronization
step.
[0162] In one preferred embodiment, oral dosage forms are prepared
to include an effective amount of melt-extruded multiparticulates
within a capsule. For example, a plurality of the melt-extided
multiparticulates may be placed in a gelatin capsule in an amount
sufficient to provide an effective sustained release dose when
ingested and contacted by gastric fluid.
[0163] In another preferred embodiment, a suitable amount of the
multiparticulate extrudate is combined with the coated opioid
antagonist particles and compressed into an oral tablet using
conventional tableting equipment using standard techniques.
Techniques and compositions for making tablets (compressed and
molded), capsules (hard and soft gelatin) and pills are also
described in Remington's Pharmaceutical Sciences, (Arthur Osol,
editor), 1553-1593 (1980), incorporated by reference herein.
[0164] In yet another preferred embodiment, the extrudate can be
shaped into tablets as set forth in U.S. Pat. No. 4,957,681
(Klimesch, et al.), described in additional detail above and hereby
incorporated by reference.
[0165] Optionally, the sustained release melt-extruded
multiparticulate systems or tablets can be coated, or the gelatin
capsule can be further coated, with a sustained release coating
such as the sustained release coatings described above. Such
coatings preferably include a sufficient amount of hydrophobic
material to obtain a weight gain level from about 2 to about 30
percent, although the overcoat may be greater depending upon the
physical properties of the particular opioid analgesic compound
utilized and the desired release rate, among other things.
[0166] The melt-extruded unit dosage forms of the present invention
may further include combinations of melt-extruded multiparticulates
containing one or more of the therapeutically active agents
disclosed above before being encapsulated. Furthermore, the unit
dosage forms can also include an amount of an immediate release
opioid agonist for prompt therapeutic effect. The immediate release
opioid agonist may be incorporated, e.g., as separate pellets
within a gelatin capsule, or may be coated on the surface of the
multiparticulates after preparation of the dosage forms (e.g.,
controlled release coating or matrix-based). The unit dosage forms
of the present invention may also contain a combination of
controlled release beads and matrix multiparticulates to achieve a
desired effect.
[0167] The sustained release formulations of the present invention
preferably slowly release the opioid agonist, e.g., when ingested
and exposed to gastric fluids, and then to intestinal fluids. The
sustained release profile of the melt-extruded formulations of the
invention can be altered, for example, by varying the amount of
retardant, i.e., hydrophobic material, by varying the amount of
plasticizer relative to hydrophobic material, by the inclusion of
additional ingredients or excipients, by altering the method of
manufacture, etc.
[0168] In other embodiments of the invention, the melt extruded
material is prepared without the inclusion of the opioid agonist
and/or coated opioid antagonist particles, which are added
thereafter to the extrudate. Such formulations typically will have
the drugs blended together with the extruded matrix material, and
then the mixture would be tableted in order to provide a slow
release of the opioid agonist. Such formulations may be
advantageous, for example, when the therapeutically active agent
included in the formulation is sensitive to temperatures needed for
softening the hydrophobic material and/or the retardant
material.
[0169] In certain embodiments, the opioid antagonist is present as
granulates comprising the opioid antagonist dispersed in a first
controlled release matrix, and the opioid agonist is present as
granulates comprising the opioid agonist dispersed in a second
controlled-release matrix, the first controlled-release matrix
providing controlled-release of the opioid antagonist and the
second matrix providing controlled-release of the opioid agonist.
In certain preferred embodiments, the first and second matrices
cause the opioid agonist and the opioid antagonist to be released
at substantially the same rate. In other embodiments, the opioid
antagonist is prepared as granulates comprising the antagonist
dispersed in a controlled-release matrix, said granulates being
combined with the opioid agonist and a further controlled release
material, such that the opioid antagonist and opioid agonist are
preferably released at substantially the same rate.
Additional Drugs
[0170] The oral dosage font of the present invention may further
include, in addition to an opioid agonist and antagonist, one or
more drugs that may or may not act synergistically therewith. Thus,
in certain embodiments, a combination of two opioid agonists may be
included in the dosage form, in addition to the opioid antagonist.
For example, the dosage, form may include two opioid agonist having
different properties, such as half-life, solubility, potency, and a
combination of any of the foregoing. In yet further embodiments,
one or more opioid agonist is included and a further non-opioid
drug is also included, in addition to the opioid antagonist. Such
non-opioid drugs would preferably provide additional analgesia, and
include, for example, aspirin, acetaminophen; non-steroidal
anti-inflammatory drugs ("NSAIDS"), e.g., ibuprofen, ketoprofen,
etc.; N-methyl-D-aspartate (NMDA) receptor antagonists, e.g., a
morphinan such as dextromethorphan or dextrorphan, or ketamine;
cycooxygenase-II inhibitors ("COX-II inhibitors"); and/or glycine
receptor antagonists.
[0171] In certain preferred embodiments of the present invention,
the invention allows for the use of lower doses of the opioid
analgesic by virtue of the inclusion of an additional non-opioid
agonist, such as an NSAID or a COX-2 inhibitor. By using lower
amounts of either or both drugs, the side effects associated with
effective pain management in humans are reduced.
[0172] Suitable non-steroidal anti-inflammatory agents, including
ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,
fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen,
carprofen, oxaprozin, pramoprofen, muroprofen, trioxaprofen,
suprofen, aminoprofen, tiaprofenic acid, fluprofen, bucloxic acid,
indomeihacin, sulindac, tolmetin, zomepirac, tiopinac, zidometacin,
acemetacin, fentiazac, clidanac, oxpinac, mefenamic acid,
meclofenamic acid, flufenamic acid, niflumic acid, tolfenamic acid,
diflurisal, flufenisal, piroxicam, sudoxicam or isoxicam, and the
like. Useful dosages, of these drugs are well known to those
skilled in the art.
[0173] N-methyl-D-aspartate (NMDA) receptor antagonists are well
known in the art, and encompass, for example, morphinans such as
dextromethorphan or dextrorphan, ketamine, d-methadone or
pharmaceutically acceptable salts thereof. For purposes of the
present invention, the term "NMDA antagonist" is also deemed to
encompass drugs that block a major intracellular consequence of
NMDA-receptor activation, e.g. a ganglioside such as GM.sub.1 or
GT.sub.1b a phenothiazine such as trifluoperazine or a
naphthalenesulfonamide such as
N-(6-aminothexyl)-5-chloro-1-naphthalene- sulfonamide. These drugs
are stated to inhibit the development of tolerance to and/or
dependence on addictive drugs, e.g., narcotic analgesics such as
morphine, codeine, etc. in U.S. Pat. Nos. 5,321,012 and 5,556,838
(both to Mayer, et al.), and to treat chronic pain in U.S. Pat. No.
5,502,058 (Mayer, et al.), all of which are hereby incorporated by
reference. The NMDA antagonist may be included alone, or in
combination with a local anesthetic such as lidocaine, as described
in these Mayer, et.al. patents.
[0174] The treatment of chronic pain via the use of glycine
receptor antagonists and the identification of such drugs is
described in U.S. Pat. No. 5,514,680 (Weber, et al.), hereby
incorporated by reference.
[0175] COX-2 inhibitors have been reported in the art and many
chemical structures are known to produce inhibition of
cyclooxygenase-2. COX-2 inhibitors are described, for example, in
U.S. Pat. Nos. 5,616,601; 5,604,260; 5,593,994; 5,550,142;
5,536,752; 5,521,213; 5,475,995; 5,639,780; 5,604,253; 5,552,422;
5,510,368; 5,436,265; 5,409,944; and 5,130,311, all of which are
hereby incorporated by reference. Certain preferred COX-2
inhibitors include celecoxib (SC-58635), DUP-697, flosulide
(CGP-28238), meloxicam, 6-methoxy-2 naphthylacetic acid (6-MNA),
MK-966 (also known as Vioxx), nabumetone (prodrug for.6-MNA),
nimesulide, NS-398, SC-5766, SC-58215, T-614; or combinations
thereof. Dosage levels of COX-2 inhibitor on the order of from
about 0.005 mg to about 140 mg per kilogram of body weight per day
are therapeutically effective in combination with an opioid
analgesic. Alternatively, about 0.25 mg to about 7 g per patient
per day of a COX-2 inhibitor is administered in combination with
an- opioid analgesic.
[0176] In yet further embodiments, a non-opioid drug can be
included which provides a desired effect other than analgesia,
e.g., antitussive, expectorant, decongestant, antihistamine drugs,
local anesthetics, and the like.
[0177] In certain preferred embodiments of the invention, the
controlled release oral dosage form comprises an opioid agonist and
an opioid antagonist in combination with acetominophen.
[0178] Acetaminophen is an analgesic/antipyretic drug which has
been utilized for treating mild to moderate pain such as headache,
neuralgia, and musculoskeletal pain. The recommended daily adult
dose is about 325 to about 650 mg every 4 hours, not to exceed a
total dose of 4 g in 24 hours. The maximum dose of immediate
release acetaminophen is generally considered to be about 1000
mg.
[0179] It is contemplated that the combination formulations and
methods of the present invention may include such acetaminophen
doses as those set forth above, or lower doses per 4 hour dosing
interval. Thus, it is possible that controlled release formulations
prepared in accordance with the-present invention include a greater
total acetominophen dose than the 325 - 650 mg dose, but that dose
will be released in a controlled-release manner over a longer
dosing interval (e.g., over 8 hours or more).
[0180] It is contemplated that the dosage of acetaminophen and
opioid agonist in the formulations and method of the present
invention may be similar or the same as dosages which are already
commercially available and accepted by clinicians. Acetaminophen is
commercially available in the United States in fixed combination
with opioid-agonists, namely, codeine, oxycodone and hydrocodone.
Typical oral capsule dosages of acetaminophen/codeine combinations
include 325 mg acetaminophen and 15 mg codeine phosphate, 325 mg
acetaminophen and 30 mg codeine phosphate and 325 mg acetaminophen
and 60 mg codeine phosphate. Tablets typically include 300 mg
acetaminophen and 7.5 mg codeine phosphate, 300 mg acetaminophen
and 15 mg codeine phosphate, 300 mg acetaminophen and 30 mg codeine
phosphate, and 300 mg acetaminophen and 60 mg codeine
phosphate.
[0181] Hydrocodone/acetaminophen capsules are typically available
in fixed combinations of 5 mg hydrocodone (as the bitartrate salt)
and 500 mg acetaminophen. Hydrocodone/acetaminophen tablets are
typically available in fixed combinations of 500 mg acetaminophen
and 2.5 mg hydrocodone bitartrate, 500 mg acetaminophen and 5 mg
hydrocodone bitartrate, 500 mg acetaminophen and 7.5 mg
hydrocodone, 7.5 mg hydrocodone bitartrate and 650 or 750 mg
acetaminophen, and 10 mg hydrocodone bitartrate and 500, 650, 660
mg acetaminophen. Oxycodone/acetaminophen capsules and caplets are
available in fixed combination of 5 mg oxycodone (as the
hydrochloride salt) and 500 mg acetaminophen, and in tablets as 5
mg oxycodone hydrochloride and 325 mg acetaminophen.
[0182] The fixed combinations described above are for information
purposes only and are not meant to limit the possible relative
amounts of opioid and acetaminophen contained in the formulations
encompassed within the present invention. As disclosed herein and
in accordance with the present invention, it is contemplated that
in certain embodiments, the opioid agonist/opioid
antagonist/acetaminophen combinations encompassed herein will have
greater or lesser dosages of either the opioid agonist or
acetaminophen, and that the ratio of opioid agonist to
acetaminophen will vary based on the particular opioid agonist and
opioid antagonist chosen for a formulation and the amount of opioid
antagonist included therein, among other things.
[0183] In certain preferred embodiments, the oral dosage form
comprises an opioid agonist (hydrocodone or oxycodone) and opioid
antagonist (naltrexone, naloxone and nalmefene) and
acetaminophen.
[0184] In yet further embodiments, a non- opioid drug can be
included which provides a desired effect other than analgesia,
e.g., antitussive, expectorant, decongestant, antihistamine drugs,
local anesthetics, and the like.
[0185] All of the documents cited in this application are
incorporated herein by reference in their entireties.
DETAILED DESCRIPTION OF CERTAIN PREFERRED EMBODIMENTS
[0186] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLE 1
Controlled Release Morphine/Naltrexone Beads
[0187] The objective of this Example is to prepare a controlled
release naltrexone bead (antagonist) to be incorporated into
controlled release opioid products (agonist).
[0188] Morphine/Naltrexone CR Capsule
[0189] A Naltrexone controlled release bead (NXCR) is developed
which can be incorporated into hard gelatin capsules containing
other opioid controlled release beads. Morphine sulfate controlled
release beads (MSCR) is formulated as an example to be mixed with
NXCR beads and the mixture is encapsulated.
2 Formula 1A. NXCR beads Amt/unit* Amt/batch Ingredients (mg) (g)
Step 1. Drug Naltrexone HCl 2.0 14.0 layering Non-pareil beads 96.0
672.0 (30/35 mesh) Plasdone C30 1.0 7.0 Talc 1.0 7.0 Water 280 Step
2. Seal coat Opadry Clear 5.0 35.0 (Hydroypropylmethyl) cellulose)
Water 315.0 Step 3. Sustained Eudragit 13.23 92.61 release coat
RS30D (dry) Tributyl citrate 3.51 24.57 Tween 80 0.03 0.21 Talc
13.23 92.61 Water 624.0 Step 4. Seal coat Opadry Clear 5.0 35.0
(Hydroxypropylmethyl cellulose) Water 315.0 Total 140 980
[0190] Bead Manufacturing Procedure (NXCR Beads)
[0191] 1. Dissolve naltrexone HCl and plasdone in water. Spray the
drug solution onto non-pareil beads in a fluid bed coater with
Wurster insert. Spray Opadry clear solution as seal coat.
[0192] 2. Spray Opadry Clear onto the drug loaded beads as seal
coat in the fluid bed coater.
[0193] 3. Disperse Eudragit RS30D, tributyl citrate, Tween 80 and
talc in water. Spray the dispersion onto the beads in the fluid bed
coater.
[0194] 4. Dissolve Opadry Clear in water. Spray the solution onto
the beads in the fluid bed coater.
[0195] 5. Cure the beads at 60.degree. C. for 24 hours.
[0196] Dissolution Method
[0197] 1. Apparatus--USP Type II (paddle), 50 rpm at 37.degree.
C.
[0198] 2. Sampling time--1, 2, 4, 12, 24, and 36 hours.
[0199] 3. Media--900 ml pH 6.5 phosphate buffer.
[0200] 4. Analytical method--High performance liquid
chromatography.
[0201] Results and Discussion:
[0202] The NXCR beads were found to have the following dissolution
results:
3 Time (hr) 1 4 8 12 18 Mean % 10 13 24 40 75 dissolved nd = none
detected
[0203] The dissolution results show that the drug release rate of
naltrexone could be suitable for dosing every 24 hours.
4 Formula 1B (Formulation for the Morphine beads-MSCR beads)
Amt/unit* Amt/batch Ingredients (mg) (kg) Step 1. Drug loading
Morphine sulfate 60.0 45.0 Lactose impalpable 12.0 9.0 Eudragit
RS30D (dry) 2.0 1.5 Povidone 3.5 2.63 Nupareil PG 30/35 16.8 12.6
Opadry blue 4.9 3.68 Water 31.5 Step 2. Controlled MSIR beads (step
1) 99.2 74.41 Release Coat Eudragit RS 30D (dry) 4.712 3.53
Eudragit RL 30D (dry) 0.248 0.19 Triethyl citrate 0.992 0.74 Talc
1.884 1.49 Opadry blue 5.639 4.23 Water q. s. Total 112.675 159
[0204] Manufacturing Procedure (MSCR Beads)
[0205] 1. Disperse povidone and Eudragit RS30D in water. Blend
morphine sulfate and lactose.
[0206] 2. Load beads in Rotor processor. Spray the drug powder
blend and the binder solution onto beads.
[0207] 3. Film-coat the above beads in the Rotor processor.
[0208] 4. Disperse Eudragit RS30D, RL 30D, Triethyl citrate, talc
and triehtyl citrate in water. Coat the above beads in a fluid bed
coated with Wurster insert.
[0209] 5. Cure the beads.
[0210] Dissolution Method
[0211] 1. Apparatus--USP Type II (paddle), 100 rpm at 37.degree.
C.
[0212] 2. Sampling time--1, 2, 4, 12, 24, and 36 hours.
[0213] 3. Media--700 ml SGF for first 55 min then converted to 900
ml SIF
[0214] 4. Analytical method--High performance liquid
chromatography.
[0215] Results and Discussion:
[0216] The MSCR beads were found to have the following dissolution
results:
5 Time (hr) 1 2 4 8 12 18 24 Mean % 4 8 23 49 70 83 85 dissolved nd
= none detected
[0217] The dissolution results show that the drug release rate of
morphine sulfate could be suitable for dosing every 24 hours.
[0218] Example 1C. Morphine CR/Naltrexone CR Capsule
6 Amt/unit* Amt/batch Ingredients (mg) (kg) Step 1. Morphine
sulfate CR beads 112.675 159 Encapsulation Naltrexone HCl CR beads
140.0 105 Total 232.675 264
[0219] Manufacturing Procedure (MSCR/NXCR Capsule)
[0220] Fill 112.675mg of the MSCR beads (Example 1B) and 140 mg of
the naltrexone CR beads (Example 1A) into a suitable sized
capsule.
EXAMPLE 2
Hydromorphone/Naltrexone CR Capsule
[0221] Naltrexone controlled release pellets are developed which
can be incorporated into hard gelatin capsules containing other
opioid controlled release pellets. Hydromorphone HCl controlled
release pellets (HHCR) are formulated as an example to be mixed
with Naltrexone CR pellets and the mixture is encapsulated.
7 Formula 2A Naltrexone HCl CR Pellets Amt/unit Amt/batch
Ingredient (mg) (gm) Naltrexone HCl 2.0 33.3 Eudragit RSPO 70.0
1166.7 Eudragit RLPO 8.0 133.3 Stearic Acid 40.0 666.7 Total 120.0
2000.0
[0222] PROCESS:
[0223] 1. Blend Naltrexone HCl, Eudragit RSPO, Eudragit RLPO, and
Stearic Acid in a twin shell blender.
[0224] 2. Continuously feed the blended material into a twin screw
extruder and collect the resultant strands on a conveyor.
[0225] 3. Allow the strands to cool a Conveyor.
[0226] 4. Cut the cooled strands into pellets-using a
Pelletizer.
[0227] 5. Screen the pellets and collect desired sieve portion.
[0228] Dissolution Method
[0229] 1. Apparatus--USP Type I (Basket), 75 rpm at 37.degree.
C.
[0230] 2. Sampling Time: 1, 2, 4, 8, 12
[0231] 3. Media: 700 mL of SGF for one hour/900 mL SIF
thereafter
[0232] 4. Analytical Method: High Performance Liquid
Chromatography
[0233] Results
8 Time (hour) 1 2 4 8 12 Mean % 13.9 20.3 27.3 37.6 45.3
Dissolved
[0234]
9 Formula B (Hydromorphone HCl CR Pellets) Amt/unit Amt/batch
Ingredient (mg) (Kg) Hydromorphone HCl 12.0 3.2 Eudragit RSPO 76.5
20.4 Ethylcellulose 4.5 1.2 Stearyl Alcohol 27.0 7.2 Total 120.0
32.0
[0235] Process:
[0236] 1. Pass Stearyl Alcohol flakes through an impact mill.
[0237] 2. Blend the Hydromorphone HCl, Eudragit, Ethycellulose and
milled Stearyl Alcohol in a twin shell blender.
[0238] 3. Continuously feed the blended material into a twin screw
extruder and collect the resultant strands on a conveyor.
[0239] 4. Allow the strands to cool a Conveyor.
[0240] 5. Cut the cooled strands into pellets using a
Pelletizer.
[0241] 6. Screen the pellets and collect desired sieve portion.
[0242] Dissolution Method
[0243] 1. Apparatus--USP Type I (Basket), 100 rpm at 37.degree.
C.
[0244] 2. Sampling Time: 1, 2, 4, 8, 12, 18, 24
[0245] 3. Media: 900mL (USP) SIF +3 g NaCl/L
[0246] 4. Analytical Method: High Performance Liquid
Chromatography
[0247] Results
10 Time (hour) 1 2 4 8 12 18 24 Mean % Dissolved 12.6 23.8 43.2
69.5 84.7 96.5 100.8
[0248]
11 Formula 2C. Hydromorphone HCl CR/Naltrexone CR Capsule Amt/unit
Amt/batch Ingredients (mg) (kg) Hydromorphone HCl CR Pellets 120.0
12.0 Naltrexone HCl CR Pellets 120.0 12.0 Total 240.0 24.0
[0249] Process
[0250] 1. Fill 120.0 mg of Hydromorphone HCl CR Pellets (Example
3B) and 120 mg of the Naltrexone HCl CR Pellets (Example 3A) into
a-suitable sized capsule.
EXAMPLE 3
CR Opioid Agonist/Antagonist Granulate (Tableted)
[0251] Controlled release tablets containing an opioid agonist
(oxycodone HCl) and opioid antagonist (naltrexone HCl) are prepared
in which both drugs are present as granulates, the granulates
comprising the opioid agonist and the antagonist dispersed in a
controlled release matrix. The granulates are combined with melted
wax (stearyl alcohol) to produce waxed granulates, which are then
milled and mixed with other excipients and compressed into
tablets.
12 Amt/unit Amt/batch Ingredient (mg) (kg) Oxycodone HCl 10.00
11.00 Naltrexone HCl 0.50 0.55 Spray Dried Lactose 68.75 75.62
Povidone 5.00 5.50 Eudragit RS 30D (dry wt.) 10.00 11.00 Triacetin
2.00 2.20 Stearyl Alcohol 25.00 27.50 Talc 2.50 2.75 Magnesium
Stearate 1.25 1.38 Opadry White 5.00 5.50 Purified Water 31.16*
Total 130.00 143.00 *Remains in product as residual moisture
only.
[0252] Process:
[0253] 1. Solution Preparation Plasticize the Eudragit with
Triacetin by mixing. Dissolve Naltrexone HCl into the plasticized
solution.
[0254] 2. Granulation Place Oxycodone HCl, Spray Dried Lactose, and
Povidone into a fluid bed granulator and apply the above
solution.
[0255] 3. Milling Pass the granulation through a rotating impeller
mill.
[0256] 4. Drying . Dry granulation if moisture content is too
high.
[0257] 5. Waxing Melt Stearyl Alcohol and wax the above granulation
by adding melted Stearyl Alcohol onto granulation while mixing.
[0258] 6. Cooling Cool the waxed granulation in a fluid bed
dryer.
[0259] 7. Milling Pass the cooled waxed granulation through a
rotating impeller mill.
[0260] 8. Blending Blend the milled waxed granulation, Talc and
Magnesium Stearate.
[0261] 9. Compression Compress the resultant granulation using a
tablet press.
[0262] 10. Coating Prepare a film coating solution by dispersing
the Opadry in Purified Water and applying it to the tablet
cores.
EXAMPLE 4
CR Opioid Agonist/Antagonist Granulate (Tableted)
[0263] Controlled release tablets containing an opioid agonist
(morphine sulfate) and opioid antagonist (naltrexone HCl) are
prepared. The controlled release tablets comprise granulates
comprising the opioid agonist and the antagonist dispersed in a
controlled-release matrix. The granulates are combined with melted
wax (cetostearyl alcohol) to produce waxed granulates, which are
then milled and mixed with other excipients and compressed into
tablets.
13 Amt/unit Amt/batch Ingredient (mg) (kg) Morphine Sulfate 30.00
108.0 (pentahydrate) Naltrexone HCl 0.50 1.8 Spray Dried Lactose
69.5 250.2 Hydroxyethyl Cellulose 10.0 36.0 Purified Water 75.9*
Cetostearyl Alcohol 35.0 126.0 Talc 3.0 10.8 Magnesium Stearate 2.0
7.2 Opadry Purple 3.0 10.8 Purified Water 61.2* Total 153.00 550.8
*Remains in product as residual moisture only.
[0264] Process:
[0265] 1. Solution Preparation Dissolve Naltrexone HCl in Purified
Water by mixing.
[0266] 2. Granulation Place Morphine Sulfate, Spray Dried Lactose,
and Hydroxyethyl Cellulose in a mixer and granulate with Naltrexone
HCl solution above.
[0267] 3. Drying Dry the above granulation in a fluid bed
dryer.
[0268] 4. Milling Pass the granulation through a mill.
[0269] 5. Drying Dry granulation if moisture content is too
high.
[0270] 6. Waxing Melt Cetostearyl Alcohol and wax the above
granulation by adding melted Cetostearyl Alcohol onto granulation
while mixing.
[0271] 7. Cooling Cool the waxed granulation in a fluid bed
dryer.
[0272] 8. Milling Pass the cooled waxed granulation through a
mill.
[0273] 9. Blending Blend the milled waxed granulation, Talc and
Magnesium Stearate.
[0274] 10. Compression Compress the resultant granulation using a
tablet press.
[0275] 11. Coating Prepare a film coating solution by dispersing
the Opadry in Purified Water and applying it to the tablet
cores.
EXAMPLE 5
Tableted CR Opioid Agonist/Antagonist Extrudate
[0276] Controlled-release capsules containing an opioid agonist
(hydromorphone HCl) and opioid antagonist (naltrexone) are
prepared. Extruded drug-containing pellets are prepared by
combining a wax with ethylcellulose and Eudragit and feeding the
mixture into a twin screw extruder. The pellets are then filled
into hard gelatin capsules.
[0277] Formula:
14 Amt/unit Amt/batch Ingredient (mg) (gm) Hydromorphone HCl 12.0
120.0 Eudragit RSPO 76.0 760.0 Ethylcellulose 4.5 45.0 Stearyl
Alcohol 27.0 270.0 Naltrexone HCl 0.5 5.0 Hard Gelatin Capsules
Total 120.0 1200.0
[0278] Process:
[0279] 1. Milling Pass stearyl alcohol flakes through an impact
mill.
[0280] 2. Blending Mix Hydromorphone HCl, Eudragit, Ethycellulose,
milled Stearyl Alcohol, and Naltrexone HCl in a twin shell
blender.
[0281] 3. Extrusion Continuously feed the blended material into a
twin screw extruder and collect the resultant strands on a
conveyor.
[0282] 4. Cooling Allow the strands to cool a Conveyor.
[0283] 5. Pelletizing Cut the cooled strands into pellets using a
Pelletizer.
[0284] 6. Screening Screen the pellets and collect desired sieve
portion.
[0285] 7. Encapsulation Fill the extruded pellets into hard gelatin
capsules at 120 mg.
EXAMPLE 6
Tableted CR Opioid Agonist/Antagonist Extrudate
[0286] Controlled-release tablets containing an opioid agonist
(hydrocodone bitartrate) and opioid antagonist (naltrexone HCl) are
prepared. The tablets contain the drugs in the form of extruded
pellets.
[0287] Formula
15 Amt/unit Amt/batch Ingredient (mg) (kg) Hydrocodone Bitartrate
30.0 15.0 Naltrexone HCl 0.5 0.25 Stearyl Alcohol 44.0 22.0
Anhydrous Dicalcium 62.0 31.0 Phosphate (Powdered) Microcrystalline
Cellulose 62.0 31.0 Glyceryl Behenate 20.0 10.0 Magnesium Stearate
2.0 1.0 Opadry Red 10.0 5.0 Purified Water 28.4* Total 230.5 115.25
*Remains in product as residual moisture only.
[0288] Process:
[0289] 1. Milling Pass the Stearyl Alcohol flakes through an
occillating mill.
[0290] 2. Blending Mix the Hydrocodone Bitartrate, Naloxone HCl,
milled Stearyl Alcohol, Anhydrous Dicalcium Phosphate,
Microcrystalline Cellulose, and Glyceryl Behenate in a twin shell
blender.
[0291] 3. Extrusion Continuously feed the blended material into a
twin screw extruder and collect the resultant heated material on a
conveyor.
[0292] 4. Cooling Allow the extrudate to cool on the conveyor.
[0293] 5. Milling Mill the cooled extrudate using an occillating
mill.
[0294] 6. Blending Blend the milled extrudate and Magnesium
Stearate.
[0295] 7. Compression Compress the resultant granulation using a
tablet press.
[0296] 8. Coating Prepare a film coating solution by dispersing the
Opadry in Purified Water and applying it to the tablet cores.
EXAMPLE 7
Tableted CR Opioid Agonist/Antagonist (Modified Release)
[0297] Controlled release tablets containing an opioid agonist
(morphine sulfate) and opioid antagonist (naltrexone HCl) are
prepared. In this Example, opioid antagonist is treated with a
controlled-release carrier (Eudragit RS 30D) to modify its release
rate before it is combined with the opioid agonist and formulated
into a controlled-release tablet.
[0298] Formula:
16 Amt/unit Amt/batch Ingredient (mg) (kg) Naltrexone HCl 0.50 1.80
Eudragit RS 30D (dry wt.) 0.03 0.10 Triacetin 0.01 0.04 Morphine
Sulfate 30.00 108.00 (pentahydrate) Spray Dried Lactose 69.46
250.06 Hydroxyethyl Cellulose 10.00 36.00 Purified Water 75.90*
Cetostearyl Alcohol 35.00 126.00 Talc 3.00 10.80 Magnesium Stearate
2.00 7.20 Opadry Purple 3.00 10.80 Purified Water 61.20* Total
153.0 550.8 *Remains in product as residual moisture only.
[0299] Process:
[0300] 1. Solution Preparation Plasticize the Eudragit by mixing
with Triacetin.
[0301] 2. Pre-Granulation Pre-granulate the Naltrexone HCl in a
fluid bed granulator by applying the above solution.
[0302] 3. Granulation Place Naltrexone HCl granulation (from
above), Morphine Sulfate, Spray Dried Lactose, and Hydroxyethyl
Cellulose in a mixer and granulate with Purified Water.
[0303] 4. Drying Dry the above granulation in a fluid bed
dryer.
[0304] 5. Milling Pass the granulation through a mill.
[0305] 6. Drying Dry granulation if moisture content is too
high.
[0306] 7. Waxing Melt Cetostearyl Alcohol and wax the above
granulation by adding melted Cetostearyl Alcohol onto granulation
while mixing.
[0307] 8. Cooling Cool the waxed granulation in a fluid bed
dryer.
[0308] 9. Milling Pass the cooled waxed granulation through a
mill.
[0309] 10; Blending Blend the milled waxed granulation, Talc and
Magnesium Stearate.
[0310] 11. Compression Compress the resultant granulation using a
tablet press.
[0311] 12. Coating Prepare a film coating solution by dispersing
the Opadry in Purified Water and applying it to the tablet
cores.
EXAMPLE 8
Transdermal Delivery System
[0312] A transdermal patch is prepared in accordance with the
disclosure of WO 96/19975 for Example 1 therein as follows, with
the modification that a requisite amount of naltrexone is included:
1.139 g of a 47.83 w/% polyacrylate solution with a selfnetting
acrylate copolymers containing 2-ethylhexylacrylates, vinyl
acetates, acrylic acid (dissolving
agent:ethylacetate:heptan:isopropanol:toluol:acetylacetonate in the
ratio of 37:26:26:4:1), 100 g laevulinic acid, 150 g oleyloleate,
100 g polyvinylpyrollidone, 150 g ethanol, 200 g ethyl acetate and
100 g buprenorphine base and 1 g naltrexone are homogenized. The
mixture is stirred for about.2 hours and then examined visually to
determine if all solid substances have been dissolved. One has to
control the evaporation loss by method of weighing back and makes
up for the solvent with the help of ethylacetate, if necessary.
Thereafter, the mixture is put onto a 420 mm wide, transparent
polyester foil, since the surface weight of the dried layer of
paste is 80 g per m.sup.2. The polyester foil which can be
dissolved again with treatment of silicone serves as a protective
layer. The solvent is removed by drying with heated air which is
led over a moist lane. With this treatment of warmth not only do
solvents evaporate but the the laevulinic acid melts as well.
Thereafter, the sealing film is covered with a polyester foil 15
mu.ab. A surface of about 16 cm.sup.2 is cut with the help of the
appropriate cutting tool, and the rims that have been left between
the individual systems are removed.
EXAMPLE 9
[0313] The formulation utilized for Example 8 is substantially the
same as that described in Example 3 of WO 96/19975, which is
prepared in accordance with Example 8 and is stated therein to
include 10% buprenorphine (with a proportional amount of naltrexone
as set forth in Example above), 10% levulinic acid, 10%
polyvinylpyrollidone, 10% oleyloeate, the remainder comprising
polyacrylate. In order to achieve the nominal delivery rate of 25
ug/hr expected for the formulation of Example 1, the total of
buprenoiphine included in the transdermal patch is about 10 mg, the
active surface area is about 12.5 cm.sup.2 and the patch size may
be, e.g., about 30.6 cm.sup.2.
[0314] The dosing regimen was one (1) patch containing 10 mg
buprenorphine base and 0.1 mg naltrexone /patch reservoir applied
to the subject's skin and maintained in contact with the skin for a
time period of seven (7) days.
EXAMPLE 10
Transdermal Device
[0315] The following ingredients are used in making the
pharmaceutical-containing polymer matrix discs: active agent, 10
parts (consisting of hydromorphone and naltrexone in a 10:1 ratio);
DC-360 polysiloxane medical fluid (20 cps), 10 parts; silicone
(medical-grade) 382 elastomer, 80 parts; catalyst M, 20 drops per
100 g. of the mixture.
[0316] The active agent is thoroughly dispersed in the 80 parts of
Silastic medical-grade 382 elastomer by using a high torque mixer
(sold by Cole-Parmer Company) at about 1000 RPM.
[0317] With continued agitation, 20 parts of DC-360 (silicone
medical fluid) and 20 drops (for every 100 g of the mixture) of a
cross-linking agent, designated as catalyst M, which is stannous
octanoate, are added to the active agent-elastomer microdispersed
mixture. After each addition of the mixture, material is thoroughly
mixed, and the dispersed mixture is placed under vacuum to remove
entrapped air.
[0318] The active agent-polydimethylsiloxane dispersion is placed
into a device maker and is cross-linked at an elevated temperature
(25 degrees-100 degrees C.) to form a cross-linked, medicated
polymer sheet, which has a thickness of 0.2-3 mm.
[0319] The medicated polymer sheet is removed from the device maker
and is cut into circular discs of about 3-20 sq. cm. The discs are
attached to a backing layer of heat sealable polyester film which
is laminated to aluminum foil. This laminate is sold by 3M Company
as Scotchpak 1006. The medicated discs are attached using an
adhesive polymer solution, which is a silicone adhesive polymer
sold by Dow Coming as DC-355. Alternately, the discs can be formed
directly on the backing layer.
[0320] The skin permeation enhancer-adhesive film is made using the
following ingredients: skin permeation enhancer, 6.5 parts; acetone
30 parts; and adhesive polymer solution, 100 parts. The skin
permeation enhancer-adhesive layer is made by dissolving the 6.5
parts by weight of a skin permeation enhancer in 30 parts of
acetone. The acetone solution then is added to 100 parts of a
silicone adhesive solution sold by Dow-Corning under the
designation DC-355.
[0321] The mixture is thoroughly mixed to form a homogeneous
mixture of skin permeation enhancer and adhesive polymer, which is
applied to a strip of a release liner which is a siliconized, or a
Teflon-coated polyester film to permit easy removal of the release
liner just prior to application of the final polymer matrix disc
dosage unit to the subject to be transdermally treated. The
adhesive mixture is applied at a controlled thickness. The formed
layer has a thickness of about 50-200 microns. The layer is dried
completely in vacuum to remove volatile matter.
[0322] The skin permeation enhancer-adhesive polymer layer with
release liner is applied onto the active agent-containing polymer
matrix disc with the attached backing layer under a constant
pressure to provide a firmly adhered strip of a four-layered
structure as follows:
[0323] 1. Backing layer
[0324] 2. Active agent-containing polymer matrix layer
[0325] 3. Skin permeation enhancer-adhesive layer
[0326] 4. Release film layer which can be readily removed to permit
application to the skin of the subject to receive transdermally the
active agent.
[0327] By use of an appropriate cutter, the strip is cut to provide
the transdermal polymer matrix dosage units which are circular in
shape and have an area of about 10 sq. cm.
[0328] The above polymer matrix disc dosage units are made using
the following skin permeation enhancers:
1-dodecylazacycloheptan-2-one (sold Linder the trademark Azone),
propyl myristate and propyl oleate.
[0329] The transdermal absorption of the active agent from the
polymer matrix dosage units of this invention is evaluated by using
a skin specimen from a "hairless" mouse or human cadaver by
following the procedure described by P. R. Keshary and Y. W. Chien,
in Drug. Develop. & Ind. Pharm., 10 (6) 883-913 (1984).
EXAMPLE 11
Oral Mucosal Delivery System
[0330] Oral mucosal patches are prepared by homogeneously mixing
buprenorphine free base and naltrexone (8%, in a 20:1 ratio),
Carbopol 934 (52%), polyisobutylene (35%) and polyisoprene (5%,
w/w) via a two-roll mill and then compressing the mixture to the
appropriate thickness. A membrane backing (ethylcellulose) is
applied to one side of the compressed material and then circular
disks (0.5 cm.sup.2) are punched from the material. The backing is
included in order to retard drug release from one side of the disk
and to prohibit adhesion to opposing side tissues. Each soft,
flexible disk is approximately 0.6 mm thick and contains
approximately 3 mg buprenorphine and an appropriate amount of
naltrexone. The patches are suitable for gum and lip
application.
EXAMPLES 12-14
Suppositories
[0331] Morphine and naltrexone were tested in the controlled
release system of the invention.
[0332] The following three suppository formulations set forth in
Table 1 demonstrate the principle of the invention with regard to a
controlled release suppository:
17TABLE 1 Morphine Suppository Formulations EXAMPLE INGREDIENT 1 2
3 Morphine Sulphate 30.0 mg 30.0 mg 30.0 mg Naltrexone HCL .5 mg .5
mg .5 mg Sodium Alginate 327 mg 409 mg 450 mg (low viscosity LF
grade) DiCalcium phosphate 32.5 mg 40.5 mg 45.0 mg Novata-B 1410.0
mg 1320.0 mg 1275.0 mg Total 1800.0 mg 1800.0 mg 1800.0 mg
[0333] Novata-B is a mixture of mono-, di- and triglycerides based
on saturated natural fatty acids of the chain lengths C.sub.12 to
C.sub.18, with a specific melting range (33.4 degrees C-25.5
degrees C.).
[0334] The suppositories were prepared according to the following
method: morphine sulphate powder, naltrexone HCL powder, sodium
alginate and calcium phosphate were all passed through a #200
sieve, individually. All three powders were intimately mixed in a
suitable mixing apparatus. Novata B was melted in a stainless steel
pot, keeping the temperature below 60 degrees C.
[0335] The mixed powder was then added to the completely melted wax
(around 50 degrees C.) with constant stirring. The temperature was
then cooled slowly to 40 degrees C. and kept constant at that
temperature. The uniform suspension was then transferred to a
automated suppository filing kettle, and continuously stirred at 38
degrees C.
[0336] After the fill weight was determined, the suppository shells
were filled to the suggested fill weight at a temperature of about
37 degrees C. (e.g., between 36 degrees-38 degrees C.). The
suppositories were allowed to cool, then sealed.
EXAMPLES 15- 19
Compositions for Nasal Administration
[0337] In Examples 15-19, formulations exemplified in U.S. Pat. No.
5,629,011 are modified in order to include an opioid antagonist, in
accordance with the present invention.
[0338] In Example 15, a bioadhesive powder formulation of
morphine-6-glucuronide and naltrexone is prepared using
microspheres of cross-linked starch. The microspheres are prepared
by the method described in EP 223 302. A preferred size of
microspheres is 1-100 .mu.m. The formulation may be prepared by
dissolving 75 mg of the agonist and a sufficient amount of
naltrexone in 30 ml water and mixed with 1 g of starch
microspheres. The product is freeze-dried to produce a free flowing
powder. The powder can be administered to the nasal cavity using an
insufflator device.
[0339] In Example 16, the bioadhesive microsphere system disclosed
in Example 15 are prepared but in addition an absorption enhancing
agent is employed. A preferred material is lysophosphatidyl
glycerol (LPG). 100 mg LPG is added to the suspension of the
morphine metabolite and microspheres.
[0340] In Example 17, a liquid formulation is prepared with added
absorption enhancing agent as follows: 150 mg of
morphine-6-glucuronide and a sufficient amount of naltrexone are
dissolved in 10 ml of a 0.5% solution of medium viscosity grade of
Chitosan (80% degree of deacetylation, Protan Limited). The
substituted cyclodextrin material dimethyl-beta-cyclodextrin (Sigma
Chemical Comp) is added to provide a concentration of 5%. The
liquid formulation can be administered using a conventional pump
spray device.
[0341] In Example 18, the formulation disclosed in Example 17 is
prepared but in the place of the dimethyl-beta-cyclodextrin,
alpha-cyclodextrin (Sigma Chemical Co.) at the same concentration
of 50 mg/ml is added.
[0342] In Example 19, the microsphere formulation described in
Example 16 is prepared but instead of the enhancing agent, a
chelating agent in the form of EDTA is employed 50 mg of EDTA is
added to the suspension of morphine metabolite and microspheres.
The product is freeze dried as detailed in Example 15.
EXAMPLE 20
Microspheres for Injection
[0343] In Examples 20, buprenorphine/naltrexone microspheres are
prepared by dissolving the agents and the polymer in ethyl acetate.
The polymer is 50:50 poly (D,L) lactic co-glycolic acid which has a
mole percent composition of 50% lactide and 50% glycolide. This
dispersed phase is then added to a solution of polyvinyl alcohol
(PVA) in water (the continuous phase) with stirring. The resulting
emulsion is monitored for droplet size, which is in turn controlled
by the rate of stirring. The emulsion is then added to water to
extract the solvent and to harden the microspheres. The mixture is
then filtered and the microspheres are dried under vacuum at room
temperature. The desired particle size fraction is then collected
by sieving. The microspheres are then suspended in a suitable media
for injection such as water.
Conclusion
[0344] Although the invention has been described above with respect
to certain examples, the embodiments depicted in these examples are
merely illustrative of various aspects of the invention. In
particular, the above examples are meant to provide a guide to
those skilled in the art as to the manufacture of controlled
release dosage forms that perform in accordance with the present
invention. One skilled in the art will appreciate that these dosage
forms have not been tested in-vivo to assure that the requisite
effects of the invention are achieved, namely, that the amount of
the opioid antagonist included and delivered from the controlled
release dosage form during the intended dosing interval is indeed
effective to enhance the analgesic potency of the opioid agonist
and attenuate the anti-analgesia, hyperalgesia, hyperexcitability,
physical dependence and/or tolerance effects of the opioid agonist,
or to enhance the analgesic potency of the opioid agonist to the
extent that a sub-analgesic amount of the opioid agonist can be
delivered from the controlled release dosage form over the dosing
interval. However, based on the data contained in U.S Pat. Nos.
5,512,578; 5,472,943; 5,580,876; and 5,767,125, all to Crain et al.
("the Crain patents"), each of which are hereby incorporated by
reference in their entireties, one skilled in the art utilizing the
information contained herein would be able to adjust the dosage of
the opioid antagonist contained in the dosage form and its release
rate without undue experimentation to achieve the requirements of
the appended claims. Furthermore, one skilled in the art utilizing
the information contained herein will recognize that the dose of
opioid agonist included in the examples set forth herein are
generally regarded as "analgesic doses" and that the dose of opioid
agonist may be adjusted downward to compensate for the enhancement
of analgesic potency afforded by the concurrent delivery of the
opioid antagonist
[0345] Many obvious modifications may be made to the illustrated
examples, and such modifications are considered to be within the
scope of the present invention.
* * * * *