U.S. patent application number 15/014995 was filed with the patent office on 2016-06-02 for abuse-resistant controlled-release opioid dosage form.
The applicant listed for this patent is Purdue Pharma L.P.. Invention is credited to Frank S. CARUSO, Huai-Hung KAO.
Application Number | 20160151353 15/014995 |
Document ID | / |
Family ID | 23116001 |
Filed Date | 2016-06-02 |
United States Patent
Application |
20160151353 |
Kind Code |
A1 |
CARUSO; Frank S. ; et
al. |
June 2, 2016 |
ABUSE-RESISTANT CONTROLLED-RELEASE OPIOID DOSAGE FORM
Abstract
Abuse-resistant, controlled release opioid tablets are a
combination containing an opioid antagonist such as naloxone at a
level above that needed to suppress the euphoric effect of the
opioid, if the combination were crushed to break the controlled
release properties causing the opioid and opioid antagonist to be
released as a immediate release product as a single dose. The
controlled release nature of the table prevents the accumulation of
orally effective amounts of opioid antagonist when taken normally.
The opioid antagonist is contained in a controlled-release matrix
and released, over time, with the opioid.
Inventors: |
CARUSO; Frank S.; (Colts
Neck, NJ) ; KAO; Huai-Hung; (Syosset, NY) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Purdue Pharma L.P. |
Stamford |
CT |
US |
|
|
Family ID: |
23116001 |
Appl. No.: |
15/014995 |
Filed: |
February 3, 2016 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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14859195 |
Sep 18, 2015 |
9283216 |
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15014995 |
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14725369 |
May 29, 2015 |
9161937 |
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14859195 |
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14067821 |
Oct 30, 2013 |
9084729 |
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14725369 |
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13777537 |
Feb 26, 2013 |
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14067821 |
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13494431 |
Jun 12, 2012 |
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13777537 |
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11901232 |
Sep 14, 2007 |
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13494431 |
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10143111 |
May 10, 2002 |
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11901232 |
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60290439 |
May 11, 2001 |
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Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 9/4858 20130101;
A61P 25/04 20180101; A61K 9/2018 20130101; A61K 31/485 20130101;
A61K 2300/00 20130101; A61K 9/4866 20130101; A61K 9/0053 20130101;
A61K 9/2054 20130101; A61P 25/36 20180101; A61K 9/0002 20130101;
A61K 31/46 20130101; A61K 31/485 20130101; A61K 9/48 20130101; A61K
9/2013 20130101; A61K 9/2027 20130101; A61K 9/20 20130101; A61P
43/00 20180101 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/20 20060101 A61K009/20 |
Claims
1-4. (canceled)
5. A method of preparing an oral controlled release pharmaceutical
composition comprising: combining oxycodone and naloxone, wherein
the oxycodone and the naloxone are present in the prepared
pharmaceutical composition in a ratio of 5:1 to 1:1; and wherein
the prepared pharmaceutical composition releases the naloxone and
the oxycodone such that at least 87.5% of the naloxone is released
from the composition over 8-12 hours.
6. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 10-160 mg.
7. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 10-80 mg.
8. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 10-40 mg.
9. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 10 mg and the
naloxone is present in an amount of 2-10 mg.
10. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 20 mg and the
naloxone is present in an amount of 5-20 mg.
11. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 40 mg and the
naloxone is present in an amount of 8-40 mg.
12. The method of claim 5, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 80 mg and the
naloxone is present in an amount of 16-80 mg.
13. The method of claim 5, wherein the naloxone is present in the
prepared pharmaceutical composition in an amount of 2-160 mg.
14. The method of claim 5, wherein the naloxone is present in the
prepared pharmaceutical composition in an amount of 2-40 mg.
15. The method of claim 5, wherein the naloxone is present in the
prepared pharmaceutical composition in an amount of 5-20 mg.
16. The method of claim 5, wherein the oxycodone and the naloxone
are present in the prepared pharmaceutical composition in a ratio
of 4:1 to 1:1.
17. The method of claim 5, wherein the oxycodone is in the form of
oxycodone hydrochloride.
18. The method of claim 5, wherein the naloxone is in the form of a
pharmaceutically acceptable salt thereof.
19. The method of claim 5, wherein the release rate of the naloxone
from the prepared pharmaceutical composition is approximately 100
percent to approximately 25 percent of the release rate of the
oxycodone.
20. The method of claim 5, wherein the release rate of the naloxone
from the prepared pharmaceutical composition is approximately 100
percent of the release rate of the oxycodone.
21. The method of claim 5, wherein >90% of the oxycodone is
released from the prepared pharmaceutical composition over 10
hours.
22. The method of claim 5, wherein >90% of the naloxone is
released from the prepared pharmaceutical composition over 10
hours.
23. The method of claim 5, wherein the oxycodone and the naloxone
are released from the prepared pharmaceutical composition over a
period greater than 4 hours.
24. The method of claim 5, wherein the prepared pharmaceutical
composition further comprises a controlled release matrix that
contains the oxycodone and the naloxone.
25. The method of claim 5, wherein the prepared pharmaceutical
composition is in the form of a tablet.
26. The method of claim 5, wherein the naloxone is not readily
separable from the oxycodone in the prepared pharmaceutical
composition.
27. The method of claim 5, wherein sufficient naloxone is released
to block the opioid euphoric effect when the prepared
pharmaceutical composition is crushed.
28. The method of claim 5, wherein the naloxone is released as
immediate release capable of inducing withdrawal in dependent
individuals if the prepared pharmaceutical composition is crushed
and the controlled release properties broken.
29. The method of claim 5, wherein the naloxone is released at a
rate ineffective for inducing withdrawal when the prepared
pharmaceutical composition is taken orally in intact form.
30. The method of claim 5, wherein the release of the naloxone does
not block the action of the oxycodone when the controlled release
properties of the prepared pharmaceutical composition are
intact.
31. A method of preparing an oral controlled release pharmaceutical
composition comprising: combining oxycodone hydrochloride and a
pharmaceutically acceptable salt of naloxone; wherein 2-40 mg of
the pharmaceutically acceptable salt of naloxone is present in the
prepared pharmaceutical composition; wherein the oxycodone
hydrochloride and the pharmaceutically acceptable salt of naloxone
are present in the prepared pharmaceutical composition in a ratio
of 4:1 to 1:1; wherein the prepared pharmaceutical composition
releases the pharmaceutically acceptable salt of naloxone and the
oxycodone hydrochloride such that at least 87.5% of the
pharmaceutically acceptable salt of naloxone is released from the
composition over 8-12 hours.
32. The method of claim 31, wherein the oxycodone is present in the
prepared pharmaceutical composition in an amount of 10, 20, 40, or
80 mg.
33. The method of claim 31, wherein the release rate of the
naloxone from the prepared pharmaceutical composition is
approximately 100 percent of the release rate of the oxycodone.
34. A method of preparing an oral controlled release pharmaceutical
composition comprising: combining oxycodone and naloxone; wherein
2-40 mg of the naloxone is present in the prepared pharmaceutical
composition; wherein the oxycodone and the naloxone are present in
the prepared pharmaceutical composition in a ratio of 5:1 to 1:1;
wherein the prepared pharmaceutical composition releases the
naloxone and the oxycodone such that 20-30% of the oxycodone and
20-30% of the naloxone are released from the composition over 1
hour; 60-70% of the oxycodone and 60-70% of the naloxone are
released from the composition over 4 hours; and >90% of the
oxycodone and >90% of the naloxone are released from the
composition over 10 hours.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 14/859,195, filed Sep. 18, 2015, which is a
continuation of U.S. patent application Ser. No. 14/725,369, filed
May 29, 2015 (now issued as U.S. Pat. No. 9,161,937), which is a
continuation of U.S. patent application Ser. No. 14/067,821, filed
Oct. 30, 2013 (now issued as U.S. Pat. No. 9,084,729), which is a
continuation of U.S. patent application Ser. No. 13/777,537, filed
Feb. 26, 2013 (now abandoned), which is a continuation of U.S.
patent application Ser. No. 13/494,431, filed Jun. 12, 2012 (now
abandoned), which is a continuation of U.S. patent application Ser.
No. 11/901,232, filed Sep. 14, 2007 (now abandoned), which is a
divisional of U.S. patent application Ser. No. 10/143,111, filed
May 10, 2002 (now abandoned), which claims benefit of priority to
U.S. Provisional Application No. 60/290,439, filed May 11,
2001.
FIELD OF THE INVENTION
[0002] The present invention relates to controlled-release
analgesic pharmaceutical formulations. More specifically, the
invention relates to abuse-deterring controlled-release analgesic
tablets.
[0003] Opioid compounds have long been known both for their
powerful analgesic properties, and for their strong potential for
abuse. While highly effective at controlling pain, opioids can also
be addictive. Abuse of opioids, particularly heroin, but also
including morphine, codeine, oxycodone, hydromorphone, oxymorphone,
and others, is a problem in modern society. Opioid addicts can
obtain drugs from a variety of illicit sources. These street drugs
are of questionable quality. Therefore, to potential abusers,
prescription pharmaceutical opioids can be particularly attractive
as a drug source because of their high purity and dependable
dosage.
[0004] Abusers extract the pharmaceutical opioid, and other
constituents, from the tablets. To do so, the tablets are crushed
and often dissolved. The result may be further treated before it is
ultimately injected or snorted to achieve a "high". This type of
intravenous or intranasal abuse is well documented.
[0005] The potential for abuse of pharmaceutical opioids is not a
new problem. To combat the effects of opioid abuse, opioid
antagonists have been used to block the euphoria associated with
opioid abuse, and to induce withdrawal symptoms in addicts. One
opioid antagonist used previously, and even now, is naloxone.
Naloxone is a powerful antagonist of the opioid receptor. Naloxone
is highly effective when taken parenterally, but poorly effective
when taken orally because of its metabolism in the liver and, thus,
has a high oral:parenteral potency ratio. When injected in humans,
amounts as small as 0.2-0.4 mg can block the opioid receptors and
prevent the user from experiencing the drug's effects, whether
analgesia or mood alteration, euphoria. Because of the high
oral:parenteral potency ratio (.about.100) the antagonist action of
oral doses of naloxone is much lower than the action of injections
of naloxone. Because antagonists such as naloxone are less
effective when taken orally, they have not been used to deter oral
abuse and have been limited to deterring parenteral or intranasal
abuse.
[0006] Recently however, a new form of abuse of opioid agonists has
emerged involving oral abuse instead of abuse by injection or
snorting. This practice has emerged largely because of the
availability of high-opioid content controlled release (CR)
formulations. "Chewing" involves crushing the opioid formulation
and taking the entire contents, meant for 2 or more doses, at once.
This practice releases all the opioid at once to generate a "high."
The crushing may take place in the mouth as suggested by the name,
but also may occur by other means to make the opioid readily
available including, crushing or dissolving the tablet prior to
injection or administered intranasally.
[0007] Recently, high potency prescription opioid tablets
containing large milligram doses of opioids have been introduced.
These tablets are controlled release tablets and are designed to
provide pain relief for 12 hours or more. Because the tablets have
action over a long time period (12 hours instead of 4 hours for
immediate release tablets), the tablets contain much higher
quantities of opioid compounds. For potential abusers, these
tablets are very attractive. Their high dosages make them a compact
way to access large amounts of opioid. The fact that they are
pharmaceuticals guarantees both the quality and quantity of drug in
the tablet. Thus, the potential abuser knows he or she is obtaining
a high purity drug in a known dosage. Prior oral opioid dosage
formulations contained relatively low doses of opioid and were not
generally targets for oral abuse. Their immediate release
formulations release the opioid all at once, but with low amounts
of opioid that would not be sufficient for oral abuse without
putting several low dosage units together. In contrast, abusers
have found that the new CR tablets contain large doses of opioid,
which can be abused orally by chewing the tablets or crushing them
to release all of the opioid at one time (immediate release). The
present invention deters such oral abuse.
[0008] Oxycontin.RTM., a controlled release oxycodone tablet from
Purdue Pharma, is available in strengths as high as 160 mg
oxycodone per tablet. The high opioid content makes these tablets
especially attractive to abusers. Illegal trade in controlled
release opioid tablets is becoming more prevalent. In order to
obtain a euphoric effect (high) from such tablets, an abuser may
crush the tablet and extract the opioid compound by dissolution for
injection, or intranasal administration. Also, the abuser can
achieve a euphoric effect from the drug by simply taking the drug
orally, after chewing the tablet or grinding it to break the
controlled release matrix and converting it to an immediate release
product. Therefore, it would be desirable to have a formulation
which would prevent the oral abuse of controlled release tablets if
crushed to convert it to an immediate release product, without
significantly affecting the analgesic action of opioid compounds in
the intact controlled release tablet.
[0009] WO 01/58447 discloses pharmaceutical combinations of opioid
agonists and antagonists in a controlled release matrix. The
antagonist is present and released in amounts, over time, that
attenuate or reduce the side effects of the opioid agonist, yet in
amounts insufficient to block the opioid effect. The preferred
antagonist is Naltrexone, which is highly effective when
administered orally or parenterally. The antagonist is released
only in very small amounts, 100-1000 times less than the opioid. WO
'447 is silent with respect to including an anti-abusive amount of
antagonist in the dose to prevent abuse. The intravenous use of
small amounts of naloxone, 0.25 or 1 .mu.g kg.sup.-1hr.sup.-1, is
also disclosed as having attenuating effects.
[0010] WO '447 does not present release rates for the antagonist in
its CR formulation, but directs those skilled in the art to the
Crain patents (U.S. Pat. Nos. 5,767,125; 5,580,876; 5,512,578; and
5,472,943). The Crain patents collectively disclose instant release
formulations with "ultra-low" doses of certain antagonists to
selectively block only the excitatory opioid receptors to attenuate
opioid side effects, without blocking inhibitory receptors, which
would lead to opioid blocking. These doses are on the order of
pico-molar amounts. Crain '578 suggests that only naltrexone is
useful in oral administration and that 1 .mu.g doses are sufficient
for attenuating opioid side effects by selectively blocking the
excitatory opioid receptors and leaving the inhibitory opioid
receptors free for receiving the opioid agonist (which may be
administered in lower than normal doses with similar analgesic
effect). The normal oral dose of naltrexone is about 50 mg versus
"ultra low" does of 1 .mu.g of naltrexone described in Crain '578
patent.
[0011] The prior art does not discuss controlled release
formulation containing agonist and antagonist to deter abuse.
Accordingly, there is a need for a composition that deters abuse in
the high opioid-content controlled release formulation prevalent
today.
SUMMARY OF THE INVENTION
[0012] Abuse-resistant, controlled release opioid tablets are a
combination containing an opioid antagonist having a high
oral:parenteral potency ratio (i.e. oral:parenteral >1), such as
naloxone, at a level insufficient to block the opioid effects or to
attenuate the opioid side-effects in the controlled release
formulation administered over an extended period, but above that
needed to suppress the euphoric effect of the opioid if
administered all at once. If the combination tablet is crushed to
break the controlled release properties, the opioid and opioid
antagonist is released as an immediate release product in a single
dose, and the antagonist blocks the euphoric effects of the
agonist. The opioid antagonist is contained in a controlled-release
matrix and released over time, with the opioid agonist.
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention employs the principle that certain
opioid antagonists are ineffective in low oral doses. Therefore,
one can administer a low oral dose over a long period of time
(controlled release) from a tablet containing a large, orally
effective amount of antagonist, without adversely affecting the
action of the opioid. However, if the antagonist is administered
all at once, it will block the opioid effect and may induce
withdrawal in dependent individuals.
[0014] The present invention is intended for use in controlled
release compositions. The term, "controlled release" or "CR" when
used herein, is intended to refer to tablets intended to release an
active pharmaceutical ingredient over an extended period of time,
usually over 4 hours, generally 8-12 or up to 24 hours. One method
of determining this is to check the intended dosing schedule. Any
tablet intended to be taken less frequently than once every four
hours should be considered controlled release regardless of
labeling as controlled release, sustained release, extended
release, etc. Often, these tablets contain polymeric matrices which
may be cross-linked. Examples of such controlled release
formulations are the Contin.RTM. system, produced by Purdue
Fredrick Pharmaceuticals, or the TimerX.RTM. system by Pennwest
Pharmaceuticals. Other controlled release polymers can also be
used, such as methacrylate (Eudragit.RTM.), hydroxylpropyl
methylcellulose (HPMC), or Carbopol.RTM.. The present invention may
be used with these or other controlled release formulations.
[0015] The tablet of the present invention contains an opioid
agonist in a controlled release matrix, along with an opioid
antagonist. The antagonist is present at such a level, and
dispensed at such a rate, that it will not block the action of the
opioid agonist when an intact controlled release tablet is taken
orally. Crushing the tablet will release sufficient antagonist all
at once as an immediate release formulation to block the opioid
response and also, induce abstinence. Antagonists need to reach an
effective dose to work, so their slow release coupled with fast
metabolism means they are maintained at ineffective, low levels in
normal, recommended, therapeutic, non-abusive use. This low level
of antagonist can be released over a long time period without
affecting the therapeutic action of the opioid agonist. Even with
sustained release over such long periods, the antagonist does not
accumulate to blocking levels, since it is metabolized before it
can accumulate to such levels. Because of the nature of the opioid
antagonist action, the level of antagonist should be varied with
the opioid dosage of the tablet. Also, depending on the antagonist,
the oral:parenteral potency ratio, and the release rates, the
levels of antagonists employed will vary. Regardless, there should
be sufficient antagonist to block the opioid effect (high) and
induce withdrawal in dependent individuals, if the tablet is
crushed, converting the formulation to immediate release. Under
normal conditions, the release rate is not sufficient for blocking
the opioid effect nor suitable for selectively blocking the
excitatory opioid receptors to attenuate opioid side effects. For
Naloxone, the presently preferred antagonist, it is believed that
15 mg (immediate release) should begin to block the opioid
receptors and initiate withdrawal.
[0016] The specific opioid agonists, antagonists, CR matrices, and
the combinations disclosed herein are merely exemplary. Other
agonists, antagonists, matrices, and combinations may be used in
conjunction with the teachings herein.
[0017] The opioid agonist can be any agonist in general use as an
analgesic, including, but not limited to, morphine, oxycodone,
levorphanol, meperdine, hydrocodone, codeine, dihydrocodeine,
hydromorphone, propoxyphene, methadone, and oxymorphone.
Specifically, any addictive opioid in a controlled release dosage
form is the target of the present invention. Most particularly,
controlled release oxycodone has recently been the target of abuse,
and would therefore make a good candidate for use in the present
invention. Of course, the release rate of the opioid agonist is
established to achieve the desired analgesic effect.
[0018] Potency of the antagonist is measured as the oral:parenteral
potency ratio, which indicates the amount of antagonist required
orally to achieve an equivalent effect to an effective parenteral
dose. For example, an antagonist having an oral:parenteral potency
ratio of 10:1 requires 10 times the parenteral dose to be effective
orally. The opioid antagonists used herein will have greater
antagonistic effect when administered parenterally than when
administered orally (oral:parenteral potency ratio >1).
Accordingly, the desired antagonists block the opioid effect and
induce withdrawal when administered at relatively low levels
parenterally or intranasally. At the same time, these antagonists
require relatively large levels to be effective when administered
orally for recommended, therapeutic use. Thus, effective
parenteral/intranasal doses are ineffective when administered
orally. Preferably, the oral:parenteral potency ratio is at least
approximately 10:1, more preferably at least approximately 25:1,
and most preferably at least approximately 100:1 as is the case
with Naloxone. Appropriate opioid antagonists having substantially
greater effectiveness when administered by injection than when
administered orally, include, but are not limited to: naloxone;
naltrexone; N-cyclopropylmethyl-7,8-dihydro-14-hydroxynormorphinone
or 21-cyclopropyl z,
-(1-hydroxy-1-methylethyl)-6,14-endo-ethano-tetrahydrooripavine (or
diphenorphine); and the pharmaceutically-acceptable salts
thereof.
[0019] It has previously been known that opioid antagonists, such
as naloxone, can block opioid receptors and reduce or eliminate the
effect of opioids. Such antagonists are useful in treating opioid
overdoses and to help treat addiction, in some cases. By blocking
opioid receptors, the antagonists reverse and block the response to
opioids. The high oral:parenteral potency ratio antagonists, such
as naloxone, while very effective when injected, are significantly
less effective when taken orally. Therefore, a dosage form designed
for oral administration can have a significant amount of opioid
antagonist, without adversely affecting the therapeutic efficacy of
the opioid. Similarly, these levels of antagonists do not attenuate
the side effects of the opioid. Such an antagonist would be
effective in deterring intravenous or intranasal abuse when present
in low levels, but would be ineffective in deterring oral abuse.
Were the tablets to include sufficient antagonist to deter oral
abuse, the antagonist would also reduce or inhibit the therapeutic
efficacy of the drug. A tablet containing an orally effective
amount of antagonists in a CR formulation releasing ineffective
amounts of antagonist under normal use would be effective against
both oral and parenteral abuse, without minimizing the
effectiveness of the opioid under normal use.
[0020] The amount of antagonist in the composition will depend on
the relative strength of the antagonist, the amount and strength of
the opioid, the release rate of the antagonist, and the
oral:parenteral potency ratio. In any event, the combination of
antagonist type, oral:parenteral potency ratio, quantity, and
release rate do not result in blockage of the opioid effect or
attenuation of its side effects, when administered orally in its
intended, intact dosage form.
[0021] Strengths of controlled release opioid tablets vary with the
particular opioid used. In the case of oxycodone, strengths of 10,
20, 40, 80, and 160 mg may be used in a controlled release formula.
The amount of opioid antagonist (such as naloxone) in such a tablet
may also vary from about 2 mg to 40 mg or more. There should be at
least 5 to 20 mg (preferably 10 to 20 mg) of naloxone in a tablet
to prevent oral abuse by chewing a number of small, low dose
tablets or a higher strength tablet. That is, the accumulation of
an abusive dose by combining 2 or more low-dose tablets should also
accumulate an effective amount of antagonist. Higher dose opioid
tablets should contain an effective amount of antagonist without
accumulation. Prevention of abuse by parenteral or intranasal
administration will also be accomplished, since in the case of
injection or snorting, only about 0.2 to 0.4 mg naloxone is needed
to antagonize the opioid effect, to induce abstinence in dependent
individuals, and to prevent abuse. Therefore the larger amount
needed to prevent oral abuse will necessarily prevent abuse by
injection or intranasal administration as well.
[0022] For oxycodone tablets of 10 or 20 mg tablet strength, the
amount of naloxone, opioid antagonist used can range from 5 to 40
mg. As the tablet strength rises, the ratio of opioid to opioid
antagonist varies from 1:3 to 4:1, since a 160 mg opioid tablet may
contain 80 mg opioid antagonist. Although the ratio can vary, it is
preferable to select one ratio for all tablet strengths. Physicians
prefer to titrate patients using several low dose tablets which add
up to the desired dosage. This is easiest if a constant ratio is
maintained. Thus, a constant ratio across tablet strengths is
useful even though that ratio can be any appropriate ratio in the
range set forth above.
[0023] Drug abusers are creative when finding ways to defeat
anti-abusive measures. Currently, several methods of oral abuse are
contemplated. As discussed above, it should be remembered that the
compositions of the invention contain sufficient antagonist to be
effective orally and, therefore, necessarily contain a parenterally
or intranasally effective blocking amount. Accordingly, parenteral
and intranasal abuse are not discussed here.
[0024] Abusers may "chew" a single large dose tablet to achieve
instant release of an abusive dose of opioid. Compositions
containing these abusive amounts of opioid should contain enough
antagonist to block oral abuse by "chewing."
[0025] Two or more lower dose tablets may be "chewed" together to
achieve an abusive dose. To the extent that each tablet itself does
not contain an orally, effective amount of antagonist, when
combined to an abusive dose, the combined antagonist should be
orally effective. That is if, for example, a 10 mg tablet is not
sufficient to achieve a high, it need not contain the full orally
effective amount of antagonist. If two 10 mg tablets are sufficient
for a high, they then should contain a combined amount of
antagonist which is effective orally for blocking the opioid
effect.
[0026] Additionally, two or more high-dose tablets could be taken
orally, without crushing, to achieve a "high." Such a combination
would take advantage of the CR properties to sustain a high for the
entire dosage period up to 12 hours. This type of abuse is uncommon
since most abusers want the instant high or rush afforded by the
immediate release of the crushed tablets. Such a combination,
according to one embodiment of the invention, should also release a
blocking amount of antagonist when taken orally without chewing.
This arrangement would also prevent the dire effects of accidental
overdose. Although this type of arrangement would be beneficial in
many situations, it could limit a prescribing doctor's options, and
therefore, may not be appropriate in all situations. Tablets
according to this embodiment are not preferred, but are certainly
within the scope of the invention.
[0027] Tablets according to the invention may take into
consideration any of the above abusive regimes individually or any
combination thereof.
[0028] The basic underlying premise of the invention is that the
tablet contains 1) an amount of antagonist which is orally
effective for blocking the opioid effect and 2) that the antagonist
is available, normally, only at levels that are ineffective to
block the opioid effect or to attenuate the opioid side-effects.
One of the ways to achieve this is to control the release rate of
the antagonist. The release rate of the antagonist is best thought
of in terms of a percent of the release rate of the opioid agonist.
The rate is controlled between approximately 100%-0% of the release
rate of the opioid, preferably 100%-25%. Table 1 shows release
rates of opioid and antagonist as % released. In the case of 0%,
the antagonist is never released unless the tablet is crushed. But,
that is the subject of another application.
[0029] In the case of Naloxone, the short half-life (about one
hour) ensures that the Naloxone does not accumulate to blocking
levels, even when released at the same rate as the opioid. In
slower release formulations (50% and 75%), the unreleased portion
remaining after 10-12 hours passes to the large intestine where the
absorption rate is much slower than in the stomach and small
intestine. Accordingly, the amount of antagonist released beyond
10-12 hours does not contribute to any blocking or attenuating
effect.
[0030] These release rates ensure that under normal usage the
antagonist has no blocking or attenuating effect. Simultaneously,
however, an orally effective blocking dose of the antagonist is
present in the event that the CR properties are defeated.
[0031] The type and application of CR matrix used will determine
release rates. Manipulation of release rates, even of two compounds
with two different rates is known in the art. Any known or later
developed CR techniques may be used. It is important to remember
though, that the antagonist should not be readily distinguishable
or separable from the agonist, since would be abusers could
possibly use mechanical separation techniques prior to defeating
the CR formulation.
TABLE-US-00001 TABLE 1 Release Rates from CR formulation ANTAGONIST
(as % of AGONIST release rate) AGONIST 100% 50% 25% 1 HR 20-30%
20-30% 10-15% 5-7.5% 4 HRS 60-70% 60-70% 30-35% 15-17.5% 10 HRS
>90% >90% 45-50% 22.5-25%
[0032] Release rates are a percentage of agonist or antagonist with
respect to its total content in the composition.
[0033] The tablets may be made by any traditional method of
manufacture of controlled release tablets. Two principal processes
are wet process (including wet granulation) and dry process
(including direct mixing and roller compaction process.) Exemplary
compositions for those processes are reproduced below.
TABLE-US-00002 TABLE 2 Preferred Naloxone Ranges for Differing
Strengths of Oxycodone Tablets Oxycodone (mg) 10 20 40 80 160
Naloxone (mg) 2-10 4-20 8-40 16-80 20-160
[0034] For oxymorphone, the doses for controlled release tablets
may be 10, 20, or 40 mg and the naloxone dose ranges may be the
same as set forth for oxycodone.
[0035] The preferred oxycodone:naloxone ratio is 5:1 to 1:1.
TABLE-US-00003 TABLE 3 Formula 1 of Oxycodone HCl 10-mg Tablets
with Naloxone Component mg/Tablet percent (by wt) Oxycodone
Hydrochloride 10.00 2.22% Naloxone 10.00 2.22% Lactose
(spray-dried) 281.50 62.56% Hydroxypropyl Methylcellulose, 135.00
30.00% K100M Silicone Dioxide 9.00 2.00% Magnesium Stearate 4.50
1.00% Total: 450.00 100.00%
TABLE-US-00004 TABLE 4 Formula 2 of Oxycodone HCl 10-mg Tablets
with Naloxone Component mg/Tablet percent (by wt) Oxycodone
Hydrochloride 10.00 3.77% Naloxone 10.00 3.77% Lactose
(spray-dried) 157.55 59.45% Hydroxypropyl Methylcellulose, 79.50
30.00% K100M Silicone Dioxide 5.30 2.00% Magnesium Stearate 2.65
1.00% Total: 265.00 100.00%
TABLE-US-00005 TABLE 5 Formula 3 of Oxycodone HCl 10-mg Tablets
with Naloxone Component mg/Tablet percent (by wt) Oxycodone
Hydrochloride 10.00 8.33% Naloxone 10.00 8.33% Lactose
(spray-dried) 60.40 50.33% Hydroxypropyl Methylcellulose, 36.00
30.00% K100M Silicone Dioxide 2.40 2.00% Magnesium Stearate 1.20
1.00% Total: 120.00 100.00%
[0036] Alternate compositions may also be used. Preferably, tablets
according to the present invention will have the following
compositions:
TABLE-US-00006 Material Quantity (%) Oxycodone Hydrochloride, USP
2.000-35.000 Naloxone 2.000-20.000 Microcrystalline Cellulose, NF
(Avicel PH102) 10.000-50.000 Ammonia Methacrylate Copolymer, NF
30.000-70.000 (Eudragit RSPO) Colloidal Silicon Dioxide, NF
(Cab-O-Sil) 0-5.000 Sodium Lauryl Sulfate, NF 0-5.000 Magnesium
Hydroxide, USP 0-2.000 Povidone, USP 0-15.000 Stearic Acid, NF
0-5.000 Magnesium Stearate, NF 0-5.000
[0037] Dissolution was conducted according to USP XXIV Apparatus 3
(Reciprocating Cylinder) for Formulation 1-3. The apparatus 3 is to
simulate the gastrointestinal conditions of human. The 1st hour is
at pH 1.2 of 0.1N HCl. The 2nd and 3rd hours are at pH 4.5 of 10 mM
of potassium phosphate monobasic. The conditions after the 3rd
hours are at pH 6.8 of 10 mM of potassium phosphate monobasic. All
dissolution vessels contain 250 mL of dissolution solution. The dip
rate is set at 10 dips per minute. The bath temperature is set at
37.5.degree. C. The HPLC parameters are set as follows:
Column--Inertsil ODS 3, 50 mm.times.4.6 mm, 3 .mu.m particle size.
Mobile phase: 80% 30 mM sodium hexanesulfonate pH 3.0+/-1, 20%
acetonitrile. Injection volume is 75 .mu.L. Column temperature is
35.degree. C., Flow rate is set at 1.0 mL/min. Wavelength is set at
225 nm. Run time is 5.5 minutes.
[0038] Dissolution results for Formulation 1-3 were as follows:
TABLE-US-00007 Formulation 1 Tablet not Crushed Tablet Crushed % %
% % Oxycodone Naloxone Oxycodone Naloxone Time Dissolved Dissolved
Dissolved Dissolved 0 0.0 0.0 0.0 0.0 1 29.8 27.8 88.2 94.6 2 47.8
45.4 3 59.8 57.4 4 68.5 65.9 8 91.1 87.5 12 100.7 97.9
TABLE-US-00008 Formulation 2 Tablet not Crushed Tablet Crushed % %
% % Oxycodone Naloxone Oxycodone Naloxone Time Dissolved Dissolved
Dissolved Dissolved 0 0.0 0.0 0.0 0.0 1 40.1 37.0 104.9 102.8 2
63.2 60.3 3 77.3 75.3 4 86.5 85.2 8 105.6 106.1 12 110.5 112.6
TABLE-US-00009 Formulation 3 Tablet not Crushed Tablet Crushed % %
% % Oxycodone Naloxone Oxycodone Naloxone Time Dissolved Dissolved
Dissolved Dissolved 0 0.0 0.0 0.0 0.0 1 59.0 52.5 100.5 90.9 2 85.4
78.0 3 97.4 90.3 4 102.5 95.9 8 105.4 99.7 12 105.4 99.8
[0039] From these tests, it is evident that under normal,
non-crushing use, the amount of antagonist, here naloxone, released
over time is insufficient to block the opioid effect. Even Example
3, which has the highest initial release rate of antagonist, only
makes about 5 mg naloxone available in the first hour. Due to the
short half-life of naloxone, and the slow release rate, the
antagonist does not accumulate in the body to a level that blocks
the opioid effect. On the other hand, in the crushed tablet,
substantially all of the antagonist is available in the first hour.
Thus, an opioid blocking amount of antagonist is readily available
to deter oral and other forms of abuse. Regardless of the
antagonist used, the combination of the antagonist content, the
release rate, and the antagonist half-life achieves the goals of
the invention to block the opioid effect when administered as for
instant release, yet not blocking the opioid effect when
administered as intended and recommended as a controlled release
formulation.
[0040] It is well known that the various opioids have differing
relative strengths. Often, these are compared and related to a
standard for determining relative doses of each. Although this
application discusses opioid content in terms of oxycodone, those
skilled in the art will readily appreciate that other opioids,
stronger and weaker, can be used in equivalent dosage amounts.
Likewise, the antagonist is similarly selected and dosed.
[0041] The scope of the invention is not limited to the above
examples, which are provided only for purposes of illustration. The
above description is written in the context of a tablet. Other oral
dosage forms, capable of being made in CR formulations may be used.
Among the oral dosage forms available are capsules, caplets,
microspheres, gel caps and even liquid formulations.
* * * * *