U.S. patent application number 08/938898 was filed with the patent office on 2002-05-16 for treating pain by administering 24 hours opioid formulations exhibiting rapid rise of drug level.
Invention is credited to GOLDENHEIM, PAUL, KAIKO, ROBERT F., SACKLER, RICHARD S..
Application Number | 20020058050 08/938898 |
Document ID | / |
Family ID | 22559696 |
Filed Date | 2002-05-16 |
United States Patent
Application |
20020058050 |
Kind Code |
A1 |
SACKLER, RICHARD S. ; et
al. |
May 16, 2002 |
TREATING PAIN BY ADMINISTERING 24 HOURS OPIOID FORMULATIONS
EXHIBITING RAPID RISE OF DRUG LEVEL
Abstract
Patients are treated with 24-hour oral sustained release opioid
formulations which, upon administration, provide an initially rapid
opioid absorption such that the minimum effective analgesic
concentration of the opioid is more quickly achieved. These
sustained release opioid formulations include an effective amount
of at least one retardant material to cause said opioid analgesic
to be released at a such a rate as to provide an analgesic effect
after oral administration to a human patient for at least about 24
hours, and are characterized by providing an absorption half-life
from 1 to about 8 hours. A method of titrating a human patient
utilizing these sustained release opioid formulations is also
disclosed.
Inventors: |
SACKLER, RICHARD S.;
(GREENWICH, CT) ; GOLDENHEIM, PAUL; (WILTON,
CT) ; KAIKO, ROBERT F.; (WESTON, CT) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
22559696 |
Appl. No.: |
08/938898 |
Filed: |
September 26, 1997 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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08938898 |
Sep 26, 1997 |
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08578688 |
Jul 22, 1996 |
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5672360 |
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08578688 |
Jul 22, 1996 |
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PCT/US94/13606 |
Nov 22, 1994 |
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Current U.S.
Class: |
424/401 |
Current CPC
Class: |
A61K 9/5073 20130101;
A61K 9/5026 20130101; A61K 31/485 20130101; A61P 25/04 20180101;
A61K 9/5078 20130101; A61K 9/4808 20130101; A61K 9/2081 20130101;
A61P 29/00 20180101 |
Class at
Publication: |
424/401 |
International
Class: |
A61K 007/00 |
Foreign Application Data
Date |
Code |
Application Number |
Nov 22, 1994 |
US |
ZZZZZZZZZZZZZZ |
Claims
What is claimed is:
1. An oral sustained release opioid formulation comprising: an
opioid analgesic, an effective amount of at least one retardant
material to cause said opioid analgesic to be released at an
effective rate to provide an analgesic effect after oral
administration to a human patient for at least about 24 hours, said
formulation when administered in humans providing an initially
rapid rate of rise in the plasma concentration of said opioid
characterized by providing an absorption half-life from 1 to about
8 hours in the fasted state.
2. The sustained release formulation of claim 1, wherein said oral
sustained release provides an absorption half-life from 1 to about
6 hours.
3. The sustained release formulation of claim 1, wherein said oral
sustained release provides an absorption half-life from 1 to about
3 hours.
4. The sustained release formulation of claims 1-3, wherein said
opioid analgesic is selected from the group consisting of
hydromorphone, oxycodone, dihydrocodeine, codeine, dihydromorphine,
morphine, buprenorphine, salts of any of the foregoing, and
mixtures of any of the foregoing.
5. The sustained release formulation of claims 1-3, wherein said
opioid analgesic is selected from the group consisting of
alfentanil, allylprodine, alphaprodine, anileridine,
benzylmorphine, bezitramide, buprenorphine, butorphanol,
clonitazene, codeine, cyclazocine, desomorphine, dextromoramide,
dezocine, diampromide, dihydrocodeine, dihydromorphine,
dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl
butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levallorphan, levorphanol, levophenacyl morphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propiram,
propoxyphene, sufentanil, tramadol, tilidine, salts thereof and
mixtures thereof.
6. The sustained release formulation of claims 1-3, wherein said
opioid is morphine and the maximum plasma concentration of said
opioid is from about 2 ng/ml to about 14 ng/ml, based on a 30 mg
dose of morphine sulfate.
7. The sustained release formulation of claims 1-3, wherein said
opioid is morphine and the maximum plasma concentration of said
opioid is from about 3 ng/ml to about 8 ng/ml, based on a 30 mg
dose of morphine sulfate.
8. The sustained release formulation of claims 1-3, wherein said
opioid analgesic consists of from about 2 mg to about 64 mg
hydromorphone.
9. The sustained release formulation of claims 1-3, wherein said
opioid analgesic consists of from about 5 mg to about 800 mg
morphine.
10. The sustained release formulation of claims 1-3, wherein said
opioid analgesic consists of from about 5 mg to about 400 mg
oxycodone.
11. The sustained release formulation of claims 1-10, which
provides a peak plasma level of said opioid in-vivo from about 2 to
about 10 hours after administration.
12. The sustained release formulation of claims 1-11, wherein said
retardant material is selected from the group consisting of an
acrylic polymer, an alkylcellulose, shellac, zein, hydrogenated
vegetable oil, hydrogenated castor oil, and mixtures of any of the
foregoing.
13. The sustained release formulation claims 1-12, which comprise a
plurality of substrates including said opioid, each of said
substrates having a diameter from about 0.5 mm to about 2 mm.
14. The sustained release formulation of claim 13, wherein said
retardant material is coated on the surface of said substrates.
15. The sustained release formulation of claim 13, wherein said
substrates comprise inert beads coated with said opioid analgesic,
said subtrates further comprising an outer coating imparting
sustained release properties to said formulation and comprising
said retardant material.
16. The sustained release formulation of claim 13, wherein said
substrates comprise matrices of a substantially uniform mixture of
said opioid analgesic and said retardant material.
17. The sustained release formulations of claims 1-16, wherein a
portion of the dose of said opioid is included in said formulation
in immediate release form.
18. The sustained release formulations of claims 1-17, which
provide a peak plasma level of said opioid in-vivo from about 2 to
about 10 hours after administration.
19. A method for titrating human patients with a sustained release
oral opioid formulation, comprising: (1) administering to a human
patient on a once-a-day basis a unit dose of an oral sustained
release formulation comprising a dose of an opioid analgesic and an
effective amount of at least one retardant material to cause said
opioid to be released at an effective rate to provide an analgesic
effect after oral administration to a human patient for at least
about 24 hours, said formulation when administered in humans
providing an initially rapid rate of rise in the plasma
concentration of said opioid characterized by providing an
absorption half-life from 1 to about 8 hours in the fasted state;
(2) monitoring pharmacokinetic and pharmacodynamic parameters
elicited by said formulation in said human patient and determining
whether said pharmacokinetic and/or pharmacodynamic parameters are
appropriate to treat said patient on a repeated basis; (3)
titrating the patient by adjusting the dose of said opioid
analgesic administered to the patient by administering a unit dose
of said sustained release opioid analgesic formulation containing a
different amount of opioid analgesic if it is determined that said
pharmacokinetic and/or said pharmacodynamic parameters are not
satisfactory or maintaining the dose of said opioid analgesic in
said unit dose at a previously administered amount if said
pharmacokinetic and/or pharmacodynamic parameters are deemed
appropriate; (4) continuing the step (3) titration by adjusting the
dose of said opioid analgesic until appropriate steady-state
pharmacokinetic/pharmacod- ynamic parameters are achieved in said
patient; and (5) continuing the administration of the dose of said
opioid analgesic in said oral sustained release formulation on a
once-a-day basis until treatment is terminated.
20. A method for preparing a oral sustained release opioid
formulation for once-a-day administration which includes a dose of
an opioid analgesic and an effective amount of at least one
retardant material to cause said opioid to be released at an
effective rate to provide an analgesic effect after oral
administration to a human patient for at least about 24 hours,
characterized in that said formulation is prepared to provide an
initially rapid rate of rise in the plasma concentration of said
opioid characterized by providing an absorption half-life from 1 to
about 8 hours when administered to a patient in the fasted
state.
21. The method of claims 19-20, wherein said oral sustained release
formulation provides an absorption half-life from 1 to about 6
hours.
22. The method of claims 19-20, wherein said oral sustained release
formulation provides an absorption half-life from 1 to about 3
hours.
23. A method of treating a patient with a bioavailable
sustained-release opioid analgesic dosage form for once-a-day oral
administration, comprising preparing a plurality of substrates
comprising a unit dose of an opioid analgesic, each of said
substrates having a diameter from about 0.1 mm to about 3 mm, said
substrates being manufactured in a sustained release form to
provide therapeutically effective blood levels of said opioid
analgesic for about 24 hours or more, and administering said unit
dose to a patient to alleviate moderate to severe pain for about 24
hours or more.
24. The method of claim 23, further comprising preparing said
substrates in a form selected from the group consisting of
spheroids, beads, microspheres, seeds, pellets, ion-exchange resin
beads, granules, and mixtures thereof.
25. The method of claim 23, further comprising preparing said
substrates by coating inert beads with said opioid analgesic, and
thereafter overcoating with a hydrophobic material is selected from
the group consisting of an acrylic polymer, an alkylcellulose,
shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil,
and mixtures of any of the foregoing.
26. The method of claim 23, further comprising preparing said
substrates as matrices of a substantially uniform mixture of said
opioid analgesic and a hydrophobic material.
Description
BACKGROUND OF THE INVENTION
[0001] The present invention relates to bioavailable
sustained-released pharmaceutical formulations of analgesic drugs,
in particular opioid analgesics, which provide an extended duration
of effect when orally administered.
[0002] It is the intent of all sustained-release preparations to
provide a longer period of pharmacologic response after the
administration of the drug than is ordinarily experienced after the
administration of the rapid release dosage forms. Such longer
periods of response provide for many inherent therapeutic benefits
that are not achieved with corresponding short acting, immediate
release preparations. This is especially true in the treatment of
cancer patients or other patients in need of treatment for the
alleviation of moderate to severe pain, where blood levels of an
opioid analgesic medicament must be maintained at a therapeutically
effective level to provide pain relief. Unless conventional rapid
acting drug therapy in carefully administered at frequent intervals
to maintain effective steady state blood levels of the drug, peaks
and valleys in the blood level of the active drug occur because of
the rapid absorption, systemic excretion of the compound and
through metabolic inactivation, thereby producing special problems
in maintenance of analgesic efficacy.
[0003] The prior art teaching of the preparation and use of
compositions providing the sustained-release of an active compound
from a carrier is basically concerned with the release of the
active substance into the physiologic fluid of the alimentary
tract. However, it is generally recognized that the mere presence
of an active substance in the gastrointestinal fluids does not, by
itself, insure bioavailability.
[0004] In order to be absorbed, the active drug substance must be
in solution. The dissolution time required for a given proportion
of an active substance from a unit dosage form is determined as the
proportion of the amount of active drug substance released from a
unit dosage form over a specified time base by a test method
conducted under standardized conditions. The physiologic fluids of
the gastrointestinal tract are the media for determining
dissolution time. The present state of the art recognizes many
satisfactory test procedures to measure dissolution time for
pharmaceutical compositions, and these test procedures are
described in official compendia world wide.
[0005] The primary principle guiding the use of opioid analgesics
in the management of chronic pain is the individualization of
dosages to meet the different and changing opioid requirements
among and within each individual patient. Pain management
authorities stress the importance of titration. Titration to the
appropriate dose for a particular patient is necessitated by the
wide inter-individual differences in the response of different
patients to given doses of opioids. While a multitude of factors
are responsible for wide inter-individual differences in the
response to opioid analgesics, one important factor is rooted in
the wide inter-individual variation in metabolism and
pharmacokinetics.
[0006] Those opioids which are most efficiently titrated are those
with relatively short elimination half-lives in the range of 3 to 5
hours (e.g., morphine, hydromorphone, oxycodone) as compared to
long (12 to 72 hours) and more variable half-life analgesics(e.g.,
methadone, levorphanol). The shorter half life drugs approach
steady-state concentrations in approximately a day rather than in
several days to a week or more. Only at steady-state can one expect
that the balance between efficacy and side effects will persist at
a given dosing schedule. Having confidence that the patient is at
approximate steady-state a day or so following initiation of dosing
allows for much quicker assessment of whether the dosage is
appropriate for that individual.
[0007] Once-a-day orally administrable dosage forms have previously
been developed in the art and are commercially available.
Presently, however, there are no commercially available
sustained-release 24-hour opioid analgesic preparations; however,
experience with the 12-hour sustained release preparations have led
to a general understanding in the medical community that in order
to titrate a patient who is to receive opioid analgesic therapy it
is necessary to use an immediate release opioid analgesic dosage
form, such as a parenteral formulation, an immediate release
solution or tablet, or the like. Only after a suitable steady-state
level is achieved in the patient by using immediate release opioid
preparations may a patient be switched to a sustained release oral
opioid formulation.
[0008] It therefore follows that it would be very desirable for
practitioners to have available a sustained-release opioid
analgesic preparation which provides appropriate pharmacokinetic
parameters (e.g., absorption profile) and accompanying
pharmacodynamic response in the patient (e.g., relief from pain)
such that the same dosage form may be used to both titrate a
patient receiving opioid analgesic therapy and used in chronic
maintenance therapy after titration of the patient. This would
eliminate the need to first titrate a patient on an immediate
release opioid dosage form before switching the patient to a
sustained-release dosage form for chronic therapy as described
above. Preferably the sustained-release preparations will provide a
duration of effect lasting longer than about twelve hours such that
a drug that may be administered to a patient only once a day.
Preferably, the sustained release dosage form will not only provide
effective pain relief for a duration of greater than about 12
hours, but will additionally provide a pharmacokinetic and
pharmacodynamic profile which will allow a patient who is to
receive opioid analgesic therapy to be titrated and chronically
treated with the same sustained-release dosage form.
[0009] Many of the oral opioid analgesic formulations that are
currently available in the market must be administered every four
to six hours daily; a selected few are formulated for less frequent
12 hour dosing.
[0010] There is also a need to develop a drug formulation which
provides an absorption profile which is suitable for both titrating
a patient who is receiving opioid analgesic therapy and which also
provides sustained release of an opioid analgesic sufficient to
provide analgesia for at least about 12 hours duration. This would
eliminate the need to first titrate a patient with immediate
release dosage forms (e.g. parenteral, oral, rectal) of opioid
analgesic and then switch the patient to a sustained release form
of the opioid analgesic.
[0011] Morphine, which is considered to be the prototypic opioid
analgesic, has been formulated into twice-daily controlled-release
formulations (i.e., MS Contin.RTM. tablets, commercially available
from Purdue Frederick Company; and Kapanol.RTM., commercially
available from F. H. Faulding and Company; and Oramorph.RTM. SR,
previously referred to as Roxanol.RTM. SR, commercially available
from Roxane).
[0012] An orally administrable opioid formulation which would
provide an extended duration of analgesia without higher incidence
of adverse effects would be highly desirable. Such an oral
sustained-release formulation of an opioid analgesic would be
bioavailable and provide effective steady-state blood levels (e.g.,
plasma levels) of the drug when orally administered such that a
duration of analgesic efficacy about 24 hours or more is
obtained.
OBJECTS AND SUMMARY OF THE INVENTION
[0013] It is accordingly an object of the present invention to
provide a method for treating patients in moderate to severe pain
with an orally administered pharmaceutical dosage form of an opioid
analgesic that is suitable for once-a-day administration.
[0014] It is yet another object of the present invention to provide
a method for treating patients with a once-a-day opioid analgesic
formulation which provides greater analgesic efficacy than that
which is obtainable with the preferred Q12H (every 12 hour)
analgesic therapies.
[0015] It is further an object of the present invention to provide
an opioid analgesic dosage form which provides sustained-release of
the opioid and is also capable for use in titrating a patient
receiving opioid analgesic therapy.
[0016] In accordance with the above objects and others, the present
invention is related in part to the surprising discovery that in
order to provide a 24 hour dosage form of an opioid analgesic, it
is critical to formulate a sustained release formulation in pain
with an analgesic preparation which provides an initially rapid
opioid release so that the minimum effective analgesic
concentration can be quickly approached in many patients who have
measurable if not significant pain at the time of dosing. Due to
the unique release profile of the dosage form of the invention, it
is possible to use a single dosage form according to the present
invention to titrate a patient receiving opioid analgesic therapy
while providing sustained-release of an opioid analgesic to
once-a-day sustained release oral dosage opioid formulations which
comprise an opioid analgesic and an effective amount of at least
one retardant material to cause the opioid analgesic to be released
at an effective rate to provide an analgesic effect after oral
administration to a human patient for at least about 24 hours.
[0017] The inventive formulations, when administered in humans,
provide an initially rapid rate of rise in the plasma concentration
of the opioid characterized by providing an absorption half-life
from 1.5 to about 8 hours. In preferred embodiments, the inventive
once-daily oral sustained release formulations provides an
absorption half-life from 2 to about 4 hours.
[0018] The present invention is also directed to a method for
titrating human patients with a sustained release oral opioid
formulation. The first step of this method comprises administering
to a human patient on a once-a-day basis a unit dose of the
inventive once-a-day oral sustained release opioid formulations
described above and in the following paragraphs. Thereafter, the
method includes the further step of monitoring pharmacokinetic and
pharmacodynamic parameters elicited by said formulation in said
human patient and determining whether said pharmacokinetic and/or
pharmacodynamic parameters are appropriate to treat said patient on
a repeated basis. The patient is titrated by adjusting the dose of
said opioid analgesic administered to the patient by administering
a unit dose of said sustained release opioid analgesic formulation
containing a different amount of opioid analgesic if it is
determinied that said pharmacokinetic and/or said pharmacodynamic
parameters are not satisfactory or maintaining the dose of said
opioid analgesic in the unit dose at a previously administered
amount if said pharmacokinetic and/or pharmacodynamic parameters
are deemed appropriate. The titration is continued by further
adjusting the dose of the opioid analgesic until appropriate
steady-state pharmacokinetic/pharmacodynamic parameters are
acheived in the patient. Thereafter, the administration of the dose
of the opioid analgesic in the oral sustained release formulation
is continued on a once-a-day basis until treatment is
terminated.
[0019] The term "bioavailability" is defined for purposes of the
present invention as the extent to which the drug (e.g., opioid
analgesic) is absorbed from the unit dosage forms.
[0020] The term "sustained release" is defined for purposes of the
present invention as the release of the drug (e.g., opioid
analgesic) at such a rate that blood (e.g., plasma) levels are
maintained within the therapeutic range but below toxic levels over
a period of time of about 24 hours or longer.
[0021] The phrase "rapid rate of rise" with regard to opioid plasma
concentration is defined for purposes of the present invention as
signifying that the formulation provides a T.sub.1/2 (abs), or
half-life of absorption, from 1.5 about hours to about 8 hours.
[0022] The term T.sub.1/2 (abs) is defined for purposes of the
present invention as the amount of time necessary for one-half of
the absorbable dose of opioid to be transferred to plasma. This
value is calculated as a "true" value (which would take into
account the effect of elimination processes), rather than an
"apparent" absorption half-life.
[0023] The term "steady state" means that a plasma level for a
given drug has been achieved and which is maintained with
subsequent doses of the drug at a level which is at or above the
minimum effective therapeutic level and is below the minimum toxic
plasma level for a given drug. For opioid analgesics, the minimum
effective therapeutic level will be a partially determined by the
amount of pain relief achieved in a given patient. It will be well
understood by those skilled in the medical art that pain
measurement is highly subjective and great individual variations
may occur among patients.
[0024] The terms "maintenance therapy" and "chronic therapy" are
defined for purposes of the present invention as the drug therapy
administered to a patient after a patient is titrated with an
opioid analgesic to a steady state as defined above.
BRIEF DESCRIPTION OF THE DRAWINGS
[0025] The following drawings are illustrative of embodiments of
the invention and are not meant to limit the scope of the invention
as encompassed by the claims.
[0026] FIG. 1 is a graphical representation of the mean sedation
vs. time curve for Example 1 (fasted);
[0027] FIG. 2 is a graphical representation of the mean sedation
vs. time curve for Example 2 (fasted);
[0028] FIG. 3 is a graphical representation of the mean respiratory
rate vs. time curve for Example 1 (fasted);
[0029] FIG. 4 is a graphical representation of the mean respiratory
rate vs. time curve for Example 2 (fasted);
[0030] FIG. 5 is a graphical representation of the mean pupil size
v. time curve for Example 1 (fasted);
[0031] FIG. 6 is a graphical representation of the mean pupil size
vs. time curve for Example 2 (fasted);
[0032] FIG. 7 is a graphical representation of the means subject
questionnaire vs. time curve for Example 1 (fasted);
[0033] FIG. 8 is a graphical representation of the means subject
questionnaire vs. time curve for Example 2 (fasted);
[0034] FIG. 9 is a graphical representation of the mean plasma
morphine concentration-time profile obtained with the Comparative
Example (MS Contin 30 mg) (fasted) as compared to the capsules of
Example 1 (fed and fasted) and Example 2 (fasted);
[0035] FIG. 10 is a graphical representation of the mean plasma
morphine concentration-time profile obtained with the Comparative
Example (MS Contin 30 mg) (fasted) as compared to the capsules of
Example 3 (fed and fasted);
[0036] FIG. 11 is a graphical representation of the mean sedation
vs. time curve for Example 3 (fasted);
[0037] FIG. 12 is a graphical representation of the mean
respiratory rate vs. time curve for Example 3 (fasted);
[0038] FIG. 13 is a graphical representation of the mean pupil size
v. time curve for Example 3 (fasted); and
[0039] FIG. 14 is a graphical representation of the mean subject
modified specific drug effect questionnaire vs. time curve for
Example 2 (fasted).
DETAILED DESCRIPTION
[0040] Even at steady-state dosages of opioid analgesics, most
patients remain in measurable or significant pain. The
state-of-the-art approach to controlled release opioid therapy is
to provide formulations which exhibit zero order pharmacokinetics
and have minimal peak to trough fluctuation in opioid levels with
repeated dosing. This zero order release provides very slow opioid
absorption, and a generally flat serum concentration curve over
time. A flat serum concentration curve is generally considered to
be advantageous because it would in effect mimic a steady-state
level where efficacy is provided but side effects common to opioid
analgesics are minimized. However, by formulating sustained release
opioids in this manner, it has been discovered that the patients
often experience considerable discomfort at about the time the next
oral dose of the opioid is administered.
[0041] It has now been surprisingly discovered that quicker and
greater analgesic efficacy is achieved by 24 hour oral opioid
formulations which do not exhibit a substantially flat serum
Concentration curve, but which instead provide a more rapid initial
opioid release so that the minimum effective analgesic
concentration can be more quickly approached in many patients who
have measurable if not significant pain at the time of dosing. Even
at steady-state dosages of oral opioid analgesics, most patients
have been found to remain in measurable or significant pain and
would benefit greatly from treatment with the novel approach to
oral opioid treatment disclosed herein. Also surprising and
unexpected is the fact that while the methods of the present
invention achieve quicker and greater analgesic efficacy, there is
not a significantly greater incidence in side effects which would
normally be expected as higher peak plasma concentrations
occur.
[0042] Defining effective analgesic plasma opioid (e.g., morphine)
levels is very complex. However, there is generally a "minimally
effective analgesic concentration" (MEAC) in plasma for a
particular opioid below which no analgesia is provided. While there
is an indirect relationship between, e.g., plasma morphine levels
and analgesia, higher plasma levels are generally associated with
superior pain relief. There is a lag time or hysteresis, between
the time of peak plasma opioid levels and the time of peak drug
effects. This holds true for the treatment of pain with opioid
analgesics in general.
[0043] The inventive sustained release once-a-day formulations may
be characterized by the fact that they are designed to provide an
initially rapid rate of rise in the plasma concentration of said
opioid characterized by providing an absorption half-life from
about 1 to about 8 hours, when the oral sustained release
formulation is administered in the fasted state (i.e., without
food). In certain embodiments, the absorption half-life is
preferably from about 1 to about 6 hours, and more preferably from
about 1 to about 3 hours.
[0044] The inventive formulations may be further characterized by
having a surprisingly fast time to peak drug plasma concentration
(i.e., t.sub.max). The t.sub.max of the sustained release
formulations of the present invention may be from about 2 to about
10 hours. In certain preferred embodiments, the t.sub.max provided
by these formulations may be from about 4 to about 9 hours.
[0045] The administration of 24-hour opioid oral sustained release
formulations in accordance with the present invention reveals a
greater degree of intensity of certain pharmacodynamic endpoints
during the earlier portions of the plasma concentration curve
(e.g., 4-8 hours after oral administration), such as sedation
respiratory rate, pupil size, and/or combined scores from a
questionnaire of opioid effects reported by the subjects at serial
times following each treatment (i.e., administration of the oral
dosage form). Other measures of analgesic efficacy such as sum of
pain intensity difference (SPID) and total pain relief (TOTPAR)
have consistently higher numerical scores via the presently claimed
methods, while also generating in many cases fewer adverse events
(which in general are predominantly mild or moderate somnolence,
nausea and/or dizziness).
[0046] Opioid analgesic compounds which may be used in the present
invention include alfentanil, allylprodine, alphaprodine,
anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol, clonitazene, codeine, cyclazocine, desomorphine,
dextromoramide, dezocine, diampromide, dihydrocodeine,
dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine,
ethylmethylthiambutene, ethylmorphine, etonitazene fentanyl,
heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone,
ketobemidone, levallorphan, levorphanol, levophenacylmorphan,
lofentanil, meperidine, meptazinol, metazocine, methadone, metopon,
morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normorphine, norpipanone,
opium, oxycodone, oxymorphone, papaveretum, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide, propheptazine, promedol, properidine, propiram,
propoxyphene, sufentanil, tramadol, tilidine, salts thereof,
mixtures of any of the foregoing, mixed mu-agonists/antagonists,
mu-antagonist combinations, and the like. The opioid analgesic may
be in the form of the free base, a salt, a complex, etc. In certain
preferred embodiments, the opioid analgesic is selected from the
group consisting of hydromorphone, oxycodone, dihydrocodeine,
codeine, dihydromorphine, morphine, buprenorphine, salts of any of
the foregoing, and mixtures of any of the foregoing.
[0047] In one preferred embodiment the sustained-release opioid
oral dosage form of the present invention includes hydromorphone as
the therapeutically active ingredient in an amount from about 4 to
about 64 mg hydromorphone hydrochloride. In another preferred
embodiment, the opioid analgesic comprises morphine, and the
sustained release oral dosage forms of the present invention
include form about 5 mg to about 800 mg morphine, by weight.
Alternatively, the dosage form may contain molar equivalent amounts
of other hydromorphone or morphine salts or of the base. In certain
preferred embodiments wherein the opioid is morphine, the maximum
plasma concentration is from about 2 ng/ml to about 14 ng/ml, and
preferably is from about 3 ng/ml to about 8 ng/ml, based on a 30 mg
dose of morphine sulfate. In another preferred embodiment, the
opioid analgesic comprises oxycodone, the sustained release oral
dosage forms of the present invention include from about 5 mg to
about 400 mg oxycodone. In other preferred embodiments, the dosage
form contains an appropriate amount of another of the opioid
analgesics to provide a substantially equivalent therapeutic
effect.
[0048] The sustained release dosage forms of the present invention
generally achieve and maintain therapeutic levels substantially
without significant increases in the intensity and/or degree of
concurrent side effects, such as nausea, vomiting or drowsiness,
which are often associated with high blood levels of opioid
analgesics. There is also evidence to suggest that the use of the
present dosage forms leads to a reduced risk of drug addiction.
Furthermore, the sustained release dosage forms of the present
invention preferably releases the opioid analgesic at a rate that
is independent of pH, e.g., between pH 1.6 and 7.2. In other words,
the dosage forms of the present invention avoid "dose dumping" upon
oral administration.
[0049] In the present invention, the oral opioid analgesics have
been formulated to provide for an increased duration of analgesic
action allowing once-daily dosing. Surprisingly, these
formulations, at comparable daily dosages of conventional immediate
release drug, are associated with a lower incidence in severity of
adverse drug reactions and can also be administered at a lower
daily dose than conventional oral medication while maintaining pain
control.
[0050] The retardant material utilized in the sustained release
formulations of the invention may be one which is known in the art,
including but not limited to acrylic polymers, alkylcelluloses,
shellac, zein, hydrogenated vegetable oil, hydrogenated castor oil,
and mixtures of any of the foregoing.
[0051] In certain preferred embodiments of the present invention,
the sustained release opioid dosage forms comprise a plurality of
substrates comprising the active ingredient, which substrates are
coated with a sustained release coating comprising a retardant
material. The 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.
[0052] The sustained release preparations of the present invention
may be used in conjunction with any multiparticulate system, such
as beads, spheroids, microspheres, seeds, pellets, ion-exchange
resin beads, and other multi-particulate systems in order to obtain
a desired sustained release of the therapeutically active agent.
Beads, granules, spheroids, or pellets, etc., prepared in
accordance with the present invention can be presented in a capsule
or in any other suitable unit dosage form.
[0053] When the substrates of the present invention are inert
pharmaceutical beads, the inert pharmaceutical beads may be from
about 8 mesh to about 50 mesh. In certain preferred embodiments,
the beads are, e.g., nu pariel 18/20 beads.
[0054] In certain preferred embodiments of the present invention,
the sustained release opioid dosage forms comprise a plurality of
substrates comprising the active ingredient, which substrates are
coated with a sustained release coating. The 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.
[0055] In order to obtain a sustained release of the opioid
sufficient to provide an analgesic effect for the extended
durations set forth in the present invention, the substrate
comprising the therapeutically active agent may be coated with 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.
[0056] In order to obtain a sustained release of the opioid
sufficient to provide an analgesic effect for the extended
durations set forth in the present invention, the substrate
comprising the therapeutically active agent may be coated with a
sufficient amount of retardant 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.
[0057] The solvent which is used for the retardant material, which
is typically hydrophobic, may be any pharmaceutically acceptable
solvent, including water, methanol, ethanol, methylene chloride and
mixtures thereof. It is preferable however, that the coatings be
based upon aqueous dispersions of the hydrophobic material.
[0058] In certain preferred embodiments of the present invention,
the hydrophobic polymer comprising the sustained release coating is
a pharmaceutically acceptable acrylic polymer, including but not
limited to acrylic acid and methacrylic acid copolymers, methyl
methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl
methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic
acid), poly(methacrylic acid), methacrylic acid alkylamide
copolymer, poly(methyl methacrylate), poly(methacrylic acid
anhydride), methyl methacrylate, polymethacrylate, poly(methyl
methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate
copolymer and glycidyl methacrylate copolymers.
[0059] In certain preferred embodiments, the acrylic polymer is
comprised of one or more ammonio methacrylate copolymers. Ammonio
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.
[0060] In one preferred embodiment, the acrylic coating is an
acrylic resin lacquer used in the form of an aqueous dispersion,
such as that which is commercially available from Rohm Pharma under
the Tradename Eudragit.RTM.. In further preferred embodiments, the
acrylic coating comprises a mixture of two acrylic resin lacquers
commercially available from Rohm Pharma under the Tradenames
Eudragit.RTM. RL 30 D and Eudragit.RTM. RS 30 D, respectively.
Eudragit.RTM. RL 30 D and Eudragit.RTM. RS 30 D are copolymers of
acrylic and methacrylic esters with a low content of quaternary
ammonium groups, the molar ratio of ammonium groups to the
remaining neutral (meth)acrylic esters being 1:20 in Eudragit.RTM.
RL 30 D and 1:40 in Eudragit.RTM. RS 30 D. 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.
[0061] 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.
[0062] In other preferred embodiments, the hydrophobic polymer
which may be used for coating the substrates of the present
invention is a hydrophobic alkyl cellulosic material such as
ethylcellulose. Those skilled in the art will appreciate that other
cellulosic polymers, including other alkyl cellulosic polymers, may
be substituted for part or all of the ethylcellulose included in
the hydrophobic polymer coatings of the present invention.
[0063] 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.
[0064] 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.
[0065] In embodiments of the present invention where the coating
comprises an aqueous dispersion of a hydrophobic polymer, the
inclusion of an effective amount of a plasticizer in the aqueous
dispersion of hydrophobic polymer will further improve the physical
properties of the film. For example, because ethylcellulose has a
relatively high glass transition temperature and does not form
flexible films under normal coating conditions, it is necessary to
plasticize the ethylcellulose 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.
[0066] 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 especially preferred.
[0067] Examples of suitable plasticizers for the acrylic polymers
of the present invention include citric acid esters such as
triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and
possibly 1,2-propylene glycol, polyethylene glycols, propylene
glycol, diethyl phthalate, castor oil, 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 especially preferred.
[0068] The sustained release profile of the formulations of the
invention can be altered, for example, by varying the thickness of
the hydrophobic coating, changing the particular hydrophobic
material used, or altering the relative amounts of, e.g., different
acrylic resin lacquers, altering the manner in which the
plasticizer is added (e.g., when the sustained release coating is
derived from an aqueous dispersion of hydrophobic polymer), by
varying the amount of plasticizer relative to hydrophobic polymer,
by the inclusion of additional ingredients or excipients, by
altering the method of manufacture, etc.
[0069] Sustained release spheroids or beads, coated with an opioid
may be prepared, e.g. by dissolving the opioid analgesic in water
and then spraying the solution onto a substrate, for example, nu
pariel 18/20 beads, using a Wurster insert. Optionally, additional
ingredients are also added prior to coating the beads in order to
assist the opioid binding to the substrates, and/or to color the
solution, etc. For example, a product which includes hydroxypropyl
methylcellulose, etc. with or without colorant 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 sustained release coating. An example of a
suitable barrier agent is one which comprises hydroxypropyl
methylcellulose. 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.
[0070] The opioid, HPMC protected (optional) beads may then be
overcoated with hydrophobic polymer, preferably with an effective
amount of plasticizer.
[0071] 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 polymer.
[0072] The plasticized aqueous dispersion of hydrophobic polymer
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 aqueous
dispersion of hydrophobic polymer to obtain a predetermined
sustained-release of said therapeutically active agent when said
coated substrate is exposed to aqueous solutions, e.g. gastric
fluid, is preferably applied, taking into account the physically
characteristics of the therapeutically active agent, the manner of
incorporation of the plasticizer, etc. After coating with the
hydrophobic polymer, 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.
[0073] Next, the coated beads are cured in order to obtain a
stabilized release rate of the therapeutically active agent.
[0074] When the coating comprises an aqueous dispersion of
ethylcellulose, the coated substrate is preferably subjected to
curing at a temperature greater than the glass transition
temperature of the coating solution (i.e., ethylcellulose) and at a
relative humidity from about 60% to about 100%, until the curing
endpoint is reached, e.g., about 60.degree. C. and a relative
humidity from about 60% to about 100% for a time period from about
48 to about 72 hours, as described in U.S. Pat. No. 5,273,760,
hereby incorporated by reference.
[0075] In preferred embodiments of the present invention directed
to the acrylic coating, a stabilized product is obtained by
subjecting the coated substrate to oven curing at a temperature
above the Tg of the plasticized acrylic polymer for the required
time period, the optimum values for temperature and time for the
particular formulation being determined experimentally. In certain
embodiments of the present invention, the stabilized product is
obtained via an oven curing conducted at a temperature of about
45.degree. C. for a time period from about 24 to about 48 hours or
longer, as described in U.S. Pat. No. 5,286,493, hereby
incorporated by reference.
[0076] The release of the therapeutically active agent from the
sustained-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 polymer to water soluble material is determined by,
among other factors, the release rate required and the solubility
characteristics of the materials selected.
[0077] 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
polymers such as hydroxypropylmethylcellulose. The sustained
release coatings of the present invention can also include
erosion-promoting agents such as starch and gums. 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. 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 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.
[0078] In other embodiments of the present invention, the present
invention may utilize a multiparticulate sustained release matrix.
Suitable materials for inclusion in a sustained release matrix
are
[0079] (a) Hydrophilic polymers, such as gums, cellulose ethers,
acrylic resins and protein derived materials. Of these polymers,
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 polymer.
[0080] (b) Digestible, long chain (C.sub.8C.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. Hydrocarbons having a melting
point of between 25.degree. and 90.degree. C. are preferred. Of
these 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.
[0081] (c) Polyalkylene glycols. The oral dosage form may contain
up to 60% (by weight) of at least one polyalkylene glycol.
[0082] For example, a suitable matrix may be one which 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, hydroxyethyl
cellulose. The amount of the at least one hydroxyalkyl cellulose 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 certain preferred embodiments, 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.
[0083] In one embodiment, the ratio of, e.g., at least one
hydroxyalkyl cellulose or acrylic resin to 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 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.
[0084] At least one polyalkylene glycol may be, for example,
polypropylene glycol or, preferably, polyethylene glycol. The
number average molecular weight of the at least one polyalkylene
glycol is preferred between 1000 and 15000 especially between 1500
and 12000.
[0085] Another suitable sustained release matrix would comprise an
alkylcellulose (especially ethyl cellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0086] 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.
[0087] These sustained release matrices may be prepared, for
example, by
[0088] (a) forming granules comprising at least one water soluble
hydroxyalkyl cellulose and opioid or an opioid salt,
[0089] (b) mixing the hydroxyalkyl cellulose containing granules
with at least one C.sub.12-C.sub.36 aliphatic alcohol, and
[0090] (c) optionally, compressing and shaping the granules.
Preferably, the granules are formed by wet granulating the
hydroxyalkyl cellulose/opioid with water. The amount of water added
during the wet granulation step may be, e.g., between 1.5 and 5
times, especially between 1.75 and 3.5 times, the dry weight of the
opioid.
[0091] In yet other alternative embodiments, a spheronizing agent,
together with the active ingredient can be spheronized to form
spheroids. Microcrystalline cellulose is preferred, although
hydrous lactose impalpable is preferably utilized for morphine
sulfate sustained release formulations prepared by powder-layering
techniques. 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
hydroxy propyl cellulose, 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 ethyl cellulose. In
such embodiments, the sustained release coating will generally
include a water insoluble material such as (a) a wax, either alone
or in admixture with a fatty alcohol; or (b) shellac or zein.
[0092] The substrates of the present invention may also be prepared
via a melt pellitization technique. In such circumstance, the
opioid in finely divided form is combined with a binder (also in
particulate form) and other optional inert ingredients, and
thereafter the mixture is pelletized, e.g., by mechanically working
the mixture in a high shear mixer to form the pellets (granules,
spheres). Thereafter, the pellets (granules, spheres) may be sieved
in order to obtain pellets of the requisite size. The binder
material is preferably in particulate form and has a melting point
above about 40.degree. C. Suitable binder substances include, for
example, hydrogenated castor oil, hydrogenated vegetable oil, other
hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid
glycerides, and the like.
[0093] In certain preferred embodiments of the present invention,
an effective amount of opioid in immediate release form is included
in the 24 hour sustained release unit dose opioid formulation to be
administered. The immediate release form of the opioid is included
in an amount which is effective to shorten the time to maximum
concentration of the opioid in the blood (e.g., plasma). In such
embodiments, an effective amount of the opioid in immediate release
form may be coated onto the substrates of the present invention.
For example, where the extended release opioid from the formulation
is due to a controlled release coating, the immediate release layer
would be overcoated on top of the controlled release coating. On
the other hand, the immediate release layer may be coated onto the
surface of substrates wherein the opioid is incorporated in a
controlled release matrix. Where a plurality of the sustained
release substrates comprising an effective unit dose of the opioid
(e.g., multiparticulate systems including pellets, spheres, beads
and the like) are incorporated into a hard gelatin capsule, the
immediate release portion of the opioid dose may be incorporated
into the gelatin capsule via inclusion of the sufficient amount of
immediate release opioid as a powder or granulate within the
capsule. Alternatively, the gelatin capsule itself may be coated
with an immediate release layer of the opioid. One skilled in the
art would recognize still other alternative manners of
incorporating the immediate release opioid portion into the unit
dose. Such alternatives are deemed to be encompassed by the
appended claims. It has been discovered that by including such an
effective amount of immediate release opioid in the unit dose, the
experience of relatively higher levels of pain in patients is
significantly reduced.
[0094] The dosage form may be provided by preparing a dosage form
consistent with one of the above described methods or by other
means known to those skilled in the pharmaceutical art.
[0095] In addition to the above, the sustained release opioid
formulations may also be manufactured as tablets. In such
instances, the tablet may contain, in addition to the opioid and
the retardant material, 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. 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. Techniques and compositions for making solid oral dosage
forms are described in Pharmaceutical Dosage Forms: Tablets
(Lieberman, Lachman and Schwartz, editors) Second Edition,
published by Marcel Dekker, Inc., incorporated by reference herein.
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.
[0096] In order to titrate a human patient with the inventive
sustained release opioid formulations, a plurality of blood samples
are taken from the patient over the course of the dosing interval.
The samples thus obtained are then tested to determine the plasma
level of the opioid analgesic, and any active metabolites thereof.
The values thus obtained may then be utilized to determine
additional pharmacokinetic parameters. A determination as to
whether the patient has obtained an adequate pharmacodynamic
response with said dosage form will be made, e.g., reference to
predetermined blood levels, comparison of the results subjective
pain tests given to the patient, the adverse effect profile of the
drug in he patient, or the like. A determination may then be made
as to whether an upward or downward adjustment of the dose is
necessary.
[0097] The administration of the sustained release unit dosage form
is continued over the dosing interval of the unit dose to maintain
an adequate pharmacodynamic response with the sustained release
dosage form. Preferably the adequate pharmacodynamic response will
last between about 12 and about 24 hours, most preferably about 24
hours or greater.
[0098] The administration of the sustained release unit dosage form
is continued over the dosing interval of the unit dose to maintain
said adequate pharmacodynamic response with said sustained release
dosage form.
[0099] If necessary, the above steps are repeated until a
determination of adequate pharmacodynamic response is obtained with
the sustained release unit dosage form.
[0100] According to the above method, a patient may be titrated
with a sustained release opioid analgesic dosage form. Subsequent
maintenance therapy may be provided with the same sustained release
dosage form.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0101] The following examples illustrate various aspects of the
present invention. They are not to be construed to limit the claims
in any manner whatsoever.
EXAMPLES 1-2
[0102] In Example 1, morphine sulfate sustained-release beads with
a 5% w/w sustained release coating comprising Eudragit.RTM. RS were
prepared, including a 10% immediate release morphine sulfate
overcoat. In Example 2, morphine sulfate sustained-release beads
with an 8% w/w sustained-release coating comprising Eudragit.RTM.
RS were prepared, including a 10% immediate release morphine
sulfate overcoat.
[0103] Morphine sulfate beads were first manufactured using a rotor
processing technique. The formula of the morphine sulfate beads to
which the sustained-release coating was applied is set forth in
Table 1 below:
1 TABLE 1 Amt/Unit Ingredient (mg) Percent (%) Morphine Sulfate
Powder 30 mg 14.3% Lactose Hydrous Impalpable 42.5 mg 20.2% PVP 2.5
mg 1.2% Sugar Beads 18/20 125 mg 59.4% Purified Water qs mg --
Opadry Red YS-1-1841 10.5 mg 4.9% Total 210.5 mg 100.0%
[0104] A sustained-release coating was then applied to the morphine
sulfate beads. The formula for the sustained release coating of
Examples 1 and 2 is set forth in Table 2 below:
2TABLE 2 Example 1 Example 2 Ingredient (mg) % (mg) % Morphine Base
189.45 mg 86.7% 189.5 mg 83.0% Beads Retardant Coating Eudragit RS
30D 9.5 mg 4.3% 15.2 mg 6.7% Triethyl Citrate 1.9 mg 0.9% 3.0 mg
1.3% Talc 3.8 mg 1.7% 6.1 mg 2.7% Purified Water qs -- qs --
Overcoat Morphine Sulfate 3.0 mg 1.4% 3.0 mg 1.3% Powder Opadry Red
10.8 mg 5.0% 11.4 mg 5.0% YS-1-1841 Purified Water qs -- qs --
Total 218.45 mg 100.0% 228.2 mg 100.0%
[0105] The sustained-release coating was manufactured as follows.
The Eudragit RS30D was plasticized with triethyl citrate and talc
for approximately 30 minutes. A load of the morphine sulfate beads
was charged into a Wurster Insert of a Glatt equipped with a 1.2 mm
spray nozzle and the beads were coated to a weight gain of 5% and
8% for Examples 1 and 2, respectively. The final protective Opadry
dispersion overcoat was then applied in the Wurster Insert. Upon
completion the beads were cured for two days in a dry oven of
45.degree. C. The cured beads were then filled into gelatin
capsules at a 30 mg strength.
[0106] Dissolution testing was conducted on the gelatin capsules
via U.S.P. Apparatus II (Paddle Method). The capsules were placed
into 700 ml of simulated gastric fluid (without enzymes) for the
first hour at 100 rpm and 37.degree. C., and then placed into 900
ml of simulated gastric fluid (without enzymes) after the first
hour. The results of the percent of morphine sulfate dissolved in
relation to time for Examples 1 and 2 are set forth in Table 3
below:
3 TABLE 3 Percent Morphine Sulfate Dissolved Time Example 1 Example
2 1 hour 11.9% 10.2% 2 hours 15.4% 11.3% 4 hours 28.1% 12.8% 8
hours 58.3% 16.4% 12 hours 79.2% 29.6% 18 hours 92.0% 58.1% 24
hours 96.6% 73.2%
Clinical Evaluation of Examples 1-2
[0107] Ten normal, healthy male subjects were enrolled in a
four-way, randomized, single-dose, crossover
pharmacokinetic/pharmacodynamic study to characterize the effect of
food on the pharmacokinetic/pharmacodynamic profile of Example 1
compared with the same product and with morphine CR 30 mg tablet
(MS Contin.RTM.), each in the fasted state, using plasma morphine
concentration and pharmacodynamic parameters. A comparison of
Example 2 with morphine controlled release 30 mg tablet (MS
Contin.RTM.) was also made. Plasma morphine concentrations were
used for calculation of pharmacokinetic parameters including: (a)
absorption and elimination rates; (b) area under the curve (AUC);
(c) maximum plasma concentration (C.sub.max) ; (d) time to maximum
plasma concentration T.sub.max) ; (e) T.sub.1/2 (elimination).
Pharmacodynamic effect compared with plasma concentrations of
morphine was to be described from data obtained from the following
pharmacodynamic parameters: mood, sedation, respiratory rate,
pupillometry and an adjective questionnaire.
Clinical Laboratory Evaluations
[0108] Blood samples were collected for hematology (hemoglobin,
hematocrit, red blood cell count, white blood cell count with
differential, platelet count) and blood chemistry analyses
(calcium, inorganic phosphate, uric acid, total protein, albumin,
cholesterol, alkaline phosphatase, lactate dehydrogenase (LDH),
total bilirubin, serum glutamic oxaloacetic transaminase (SGOT),
serum glutamic pyruvate transaminase (SGPT), fasting blood glucose,
blood urea nitrogen (BUN), serum creatinine) pre- and post- (72
hours) study (i.e., 72 hours after Phase 4 dose). A urine sample
was collected for urinalysis (specific gravity, glucose, albumin,
bile, pH, acetone, microscopic examination) pre- and post- (72
hours) study (i.e., 72 hours after Phase 4 dose). A pre-study
urinalysis for illicit drugs was performed during the screening
process and immediately pre-dose for each administration of the
study drug (Day 1 of Phases 1 through 4).
[0109] Plasma morphine concentrations were determined from blood
samples which were drawn just prior to dosing (0 hour) and
thereafter at 0.5, 1, 2, 2.5, 3, 3.5, 4, 5, 6, 8, 10, 12, 18, 24,
36, 48 and 72 hours following each dose. Blood samples, each
approximately 10 ml, were drawn into tubes containing
ethylenediaminetetraacetic acid (EDTA) solution, an anticoagulant.
Following centrifugation, the plasma was pipetted into two 5-ml
polypropylene, labeled tubes and frozen at -20.degree. C. One set
of samples was shipped to the designated analytical laboratory in
sufficient dry ice to keep them frozen for 2 days, and the second
set was retained frozen at the study site as a back-up.
Pharmacodynamic Measurements
[0110] Measurements of the following pharmacodynamic parameters
were made just prior to blood sampling at baseline (within 30
minutes prior to dosing) and thereafter at 0.5, 1, 2, 2.5, 3, 3.5,
4, 5, 6, 8, 10, 12, 18, 24, 36, 48 and 72 hours following each
dose.
[0111] Mood (measured by a visual analog scale (VAS) on a subject
diary sheet)--10 minutes prior to blood sampling. The VAS was
anchored on one end as Worst Mood and the other end as Best
Mood.
[0112] Sedation (measured by VAS on a subject diary sheet)--10
minutes prior to blood sampling. The VAS was anchored on one end as
Asleep and the other end as Awake.
[0113] Respiratory rate (breaths per minute)--within 5 minutes of
blood sampling. (Data were recorded on a subject diary sheet.)
[0114] Pupil size--measured by pupillometry--within 5 minutes of
blood sampling. Only tie left eye was measured at all time periods.
(Data were recorded on a subject diary sheet.)
[0115] FIG. 1 is a graphical representation of the mean sedation
vs. time curve for Example 1 (fasted). FIG. 2 is a graphical
representation of the mean sedation vs. time curve for Example 2
(fasted). FIG. 3 is a graphical representation of the mean
respiratory rate vs. time curve for Example 1 (fasted). FIG. 4 is a
graphical representation of the mean respiratory rate vs. time
curve for Example 2 (fasted).
[0116] Plasma morphine concentrations were determined by a
high-performance liquid chromatographic procedure. Arithmetic mean
Cmax, Tmax, AUC, half-lives calculated from individual plasma
morphine concentration-versus-time, and oral bioavailability data
were as set forth in Tables 4 and 5 below:
4TABLE 4 Pharmaco- kinetic MS Contin .RTM. Ex. 2 Ex. 1 Parameter
(Fast) (Fast) (Fast) (Fed) C.sub.max (ng/ml) 13.05 3.95* 5.42*
5.87* T.sub.max (hours) 2.45 15.05* 5.85 6.90 AUC (0.72) (hr-ng/ml)
101.11 136.10* 109.37 111.33 AUG (0.00) (hr-ng/ml) 101.31 155.44*
117.77 114.45 T.sub.1/2 (elim; hrs) 2.81 89.68* 19.02 10.34
T.sub.1/2 (abs; hrs) 1.20 3.96 2.51 3.48
[0117]
5TABLE 5 (A = MS Contin; B = Example 2 fasted; C = Example 1 Fed;
and D = Example 1 fasted) Pharmaco- F.sub.0 (%) F.sub.0 (%) F.sub.0
(%) F.sub.0 (%) kinetic 90% C.I. 90% C.I. 90% C.I. 90% C.I.
Parameter (B vs. A) (C vs. A) (D vs. A) (D vs. C) C.sub.max 32.24
39.88 42.50 106.57 (ng/ml) (15.7- (23.3- (26.0- (65.2- 48.7) 56.5)
59.0) 148.0) T.sub.max 608.27 232.33 290.48 125.03 (hours) (435.6-
(58.8- (117.9- (50.7- 780.9) 405.8) 463.11) 199.3) AUG 134.53
105.02 106.04 100.97 (0.72) (111.1- (81.5- (82.6- (78.6- (hr-ng/ml)
158.0) 128.6) 129.5) 123.3) AUG 151.04 112.91 108.09 95.73 (0.00)
(112.6- (81.8- (77.1- (68.3- (hr-ng/ml) 189.4) 144.0) 139.0) 123.1)
T.sub.1/2 (elim; 3076.7 689.41 374.01 54.25 hrs) (2256.7- (24.9-
(-286.8- (-41.6- 3896.7) 1353.9) 1034.9) 150.1) T.sub.1/2 (abs;
281.21 167.18 239.86 143.48 hrs) (-123.1- (-11.7- (62.4- (37.2-
685.5) 346.0) 417.3) 249.8) *Statistically significant (p <
.0500) when compared to MS Contin .RTM. (based on untransformed
data) F.sub.0 (%) = Oral bioavailability (Test least squares
mean/Reference least squares mean)
[0118] Table 6 provides the mean (.+-.S.D.) plasma morphine
concentrations (ng/ml) following dosing with MS Contin.RTM. and
Examples 1 and 2.
6TABLE 6 Mean (.+-. S.D.) Plasma Morphine Concentrations (ng/ml)
Following Dosing With MS Contin .RTM. And Each Formulation Of
Morphine Beads Time MS Contin .RTM. Ex. 2 Ex. 1 Ex. 1 (hours) 30 mg
(Fast) (Fast) (Fast) (Fed) 0.00 0.00 .+-. 0.00 0.00 .+-. 0.00 0.00
.+-. 0.00 0.00 .+-. 0.00 0.50 3.04 .+-. 2.07 2.22 .+-. 1.09 1.82
.+-. 1.35 0.51 .+-. 0.79 1.00 6.78 .+-. 4.19 1.89 .+-. 0.54 2.09
.+-. 1.07 1.46 .+-. 0.95 2.00 11.43 .+-. 5.70 1.60 .+-. 0.69 2.33
.+-. 0.98 2.46 .+-. 0.91 2.50 10.30 .+-. 6.46 1.78 .+-. 1.16 2.22
.+-. 0.88 2.51 .+-. 0.88 3.00 9.40 .+-. 5.41 1.54 .+-. 0.97 2.61
.+-. 1.12 3.47 .+-. 1.77 3.50 8.09 .+-. 4.48 1.34 .+-. 0.98 2.82
.+-. 1.39 3.03 .+-. 1.26 4.00 7.11 .+-. 3.78 1.06 .+-. 0.49 3.60
.+-. 2.50 3.41 .+-. 1.82 5.00 7.25 .+-. 4.71 1.54 .+-. 1.21 4.09
.+-. 2.24 3.80 .+-. 1.29 6.00 5.27 .+-. 3.31 1.20 .+-. 0.77 4.11
.+-. 1.74 4.23 .+-. 1.68 8.00 3.19 .+-. 1.99 1.58 .+-. 1.00 3.80
.+-. 1.46 4.46 .+-. 1.51 10.0 1.87 .+-. 1.00 2.62 .+-. 1.05 3.57
.+-. 1.44 4.16 .+-. 1.37 12.0 1.70 .+-. 0.76 3.10 .+-. 1.64 2.83
.+-. 0.64 4.33 .+-. 2.20 18.0 1.23 .+-. 0.67 3.04 .+-. 1.11 2.40
.+-. 1.13 1.85 .+-. 1.12 24.0 1.38 .+-. 0.96 2.54 .+-. 0.55 1.82
.+-. 1.01 1.71 .+-. 0.73 36.0 0.85 .+-. 0.64 2.58 .+-. 1.04 1.35
.+-. 0.70 1.19 .+-. 0.40 48.0 0.22 .+-. 0.47 1.48 .+-. 0.48 0.69
.+-. 1.08 0.73 .+-. 0.56 72.0 0.05 .+-. 0.16 0.54 .+-. 0.66 0.16
.+-. 0.33 0.22 .+-. 0.46
[0119] Table 7 provides the mean (.+-.S.D.) pharmacokinetic
parameters following dosing with MS Contin.RTM. And Examples
1-2.
7TABLE 7 Mean (.+-. S.D.) Pharmacokinetic Parameters Following
Dosing With MS Contin .RTM. And Each Formulation Of Morphine Beads
MS Contin .RTM. Para- 30 mg Ex. 2 Ex. 1 Ex. 1 meter (Fast) (Fast)
(Fast) (Fed) C.sub.max 13.05 .+-. 3.95 .+-. 5.42 .+-. 5.87 .+-.
(ng/ml) 5.22 1.55 2.26 2.07 T.sub.max 2.45 .+-. 15.05 .+-. 5.85
.+-. 6.90 .+-. (hrs) 0.86 9.51 1.92 3.18 AUC(0.72) 101.11 .+-.
136.10 .+-. 109.37 .+-. 111.33 .+-. (hr-ng/ml) 41.91 34.58
.+-.43.06 36.2 3 1
[0120] In comparing Example 1 (fast) to MS Contin.RTM. (fast),
there was a statistically significant difference in C.sub.max.
There were no statistically significant differences between the two
treatments in T.sub.max, AUC (0,72), AUC (O, oo) and T.sub.1/2
(elim) or T.sub.1/2 (abs). The 90% confidence intervals for all
pharmacokinetic parameters were outside the 80-120% limits.
[0121] In comparing Example 1 (fed) to MS Contin.RTM. (fast), there
was a statistically significant difference in C.sub.max. There were
no statistically significant differences between the two treatments
in T.sub.max, AUC (0,72), AUC (O, oo) and T.sub.1/2 (elim) or
T.sub.1/2 (abs). The 90% confidence intervals for all
pharmacokinetic parameters were outside the 80-120% limits.
[0122] In comparing Example 1 under fed and fasting conditions,
there were no statistically significant differences in C.sub.max,
T.sub.max, AUC (0,72), AUC (O, oo) and T.sub.1/2 (elim) or
T.sub.1/2 (abs). The 90% confidence intervals for all
pharmacokinetic parameters were outside the 80-120% limits.
[0123] The effect of food on the absorption of Example 1 is
characterized by a greater C.sub.max and extended T.sub.max and
T.sub.1/2 (abs) values. The extent of absorption (based on AUCs),
however, is less than 3% different under fed and fasted
conditions.
[0124] In comparing Example 2 (fast) to MS Contin.RTM. (fast),
there were statistically significant differences in C.sub.max,
T.sub.max, AUC (0,72), AUC (O, oo) and T.sub.1/2 (elim). There was
no statistically significant difference between the two treatments
in T.sub.1/2 (abs). The 90% confidence intervals for all
pharmacokinetic parameters were outside the 80-120% limits.
[0125] Based on the 90% confidence interval analysis, neither
Example 1 under fasted or fed conditions nor Example 2 beads are
equivalent to MS Contin.RTM. tablets. However, while neither of the
experimental controlled-release morphine formulations are
bioequivalent to MS Contin.RTM. tablets, both provide a relatively
lower C.sub.max and extended T.sub.max and apparent T.sub.1/2
(elim) values.
[0126] Linear regression of each pharmacodynamic parameter on the
log-transformed concentrations for each subject and treatment
resulted in 48 of 240 regressions (48/240; 20%) having an R.sup.2
value of 20% or higher, of which 8 (8/240; 3%) had a value of 50%
or higher. When analyzed by treatment only, all R.sup.2 values were
lower than 10%. These values indicate no significant linear
relationship between the pharmacodynamic measurements and the log
concentrations.
[0127] Examination of the mean hysteresis curves revealed a
possible relationship between pupil size and morphine
concentration. For MS Contin.RTM. and Example 1, pupil size tended
to decrease with an increase in morphine concentration, then
increase as morphine concentration decreased. FIG. 5 is a graphical
representation of the mean pupil size v. time curve for Example 1
(fasted). FIG. 6 is a graphical representation of the mean pupil
size vs. time curve for Example 2 (fasted). No relationship was
observed between morphine concentrations and any of the other
parameters.
[0128] Two subjects (20%) reported six adverse experiences while
receiving MS Contin.RTM.. Three subjects (30%) reported six adverse
experiences while receiving controlled-release morphine beads
(Example 1; fasted). One subject in each of the following treatment
groups reported a single adverse experience: Example 1 (fed) and
Example 2 (fasted). No clinically significant changes in physical
examination or EKG results, clinical laboratory values or vital
sign measurements occurred during the study.
Modified Specific Drug Effect Questionnaire
[0129] The questionnaire was a modification of the 22-item
questionnaire used by Jasinski, D. R. (1977) Assessment of the
Abuse Potential of Morphine-Like Drugs (Methods Used in Man). In
Drug Addiction I (Martin, W. R., ed.) pp. 197-258. Springer-Verlag,
New York; and Preston, K. L., Jasinski, D. R., and Testa, M. (1991)
Abuse Potential and Pharmacological Comparison of Tramadol and
Morphine. Drug and Alcohol Dependence 27:7-17. The questionnaire
consisted of 10 items to be rated by the subject and observer. The
items were related to signs of opiate-agonist drugs and were as
follows:
[0130] Subject's Questions
[0131] 1. Do you feel any effects of the drugs?
[0132] 2. Is your skin itchy?
[0133] 3. Are you relaxed?
[0134] 4. Are you sleepy?
[0135] 5. Are you drunk?
[0136] 6. Are you nervous?
[0137] 7. Are you full of energy?
[0138] 8. Do you need to talk?
[0139] 9. Are you sick to your stomach?
[0140] 10. Are you dizzy?
[0141] The subject rated each of these questions by placing a
vertical mark along a 100-mm VAS anchored at one end by "not at
all" and at the other end by "an awful lot".
[0142] Observer's Questions
[0143] 1. Is the subject showing any drug effect?
[0144] 2. Is the subject scratching?
[0145] 3. Is the subject relaxed?
[0146] 4. Is the subject drunk?
[0147] 5. Is the subject nervous?
[0148] 6. Is the subject talking?
[0149] 7. Is the subject vomiting?
[0150] 8. Is the subject confused?
[0151] 9. Is the subject restless?
[0152] 10. Is the subject perspiring?
[0153] The observer rated each of these questions by placing a
vertical mark along a 100-mm VAS anchored at one end by "not at
all" and at the other end by "extremely". FIG. 7 is a graphical
representation of the means subject questionnaire vs. time curve
for Example 1 (fasted). FIG. 8 is a graphical representation of the
means subject questionnaire vs. time curve for Example 2
(fasted).
Adverse Experiences
[0154] Adverse experiences, whether spontaneously reported or
elicited upon direct questioning, were recorded and evaluated
promptly by the principal investigator to determine the severity,
duration and initiation of corrective measures, if warranted.
Subjects were to be followed until they returned to baseline
status.
Analytical
[0155] Plasma morphine analyses were conducted using high
performance liquid chromatography (HPLC). The limit of
quantification was 0.5 ng/mL. Appendix V contains the plasma
morphine analytical report.
Statistical and Pharmacometric Methods
Parameters
[0156] The serial plasma morphine values, collected from each
subject and treatment, were corrected for the zero-hour value by
subtraction of the zero-hour value from all subsequent values in
that series.
[0157] Any serial dataset in which the zero-hour value exceeded the
minimum assay sensitivity was, as noted above, deemed inadmissible
for data analysis. The following parameters were estimated for each
subject and treatment, using the baseline-corrected plasma
levels:
[0158] C.sub.max (ng/ml)--largest observed plasma morphine
value
[0159] T.sub.max (hours)--time of occurrence of C.sub.max, relative
to time of dosing
[0160] T.sub.1/2 (elim; hours)--apparent half-life of plasma
morphine elimination calculated according to:
[0161] T.sub.1/2 (elim)--0.693/K.sub.e
[0162] where K.sub.e is the terminal first-order apparent
elimination rate constant calculated by PROC NLIN in SAS Release
6.07 (SAS Institute, Cary, N.C.).
[0163] T.sub.1/2 (abs; hrs)--apparent half-life of absorption
calculated according to:
[0164] T.sub.1/2 (abs)--0.693/K.sub.a
[0165] FIG. 9 is a graphical representation of the mean plasma
morphine concentration-time profile obtained with the Comparative
Example (MS Contin 30 mg)(fasted) as compared to the capsules of
Example 1 (fed and fasted) and Example 2 (fasted).
[0166] From the results set forth above, it can be seen that the
formulation of Example 1 attains a higher and earlier Cmax but a
slightly lower extent of morphine absorption than the formulation
of Example 2. Visual examination of the time-action data in respect
to sedation, respiratory rate, pupil size, and combined scores from
a questionnaire of opioid effects reported by the subjects at
serial times following each treatment reveals greater degree of
intensity of each pharmacodynamic endpoint during the earlier
(e.g., 4-8 hours) portion of the time-action curves.
EXAMPLE 3
[0167] Beads with a higher loading of morphine sulfate were
produced with the use of the powder layering technique in the Glatt
Rotor Processor. The formulation of the high load beads is set
forth in Table 8 below:
8 TABLE 8 High Load Bead Percent Ingredient mg/unit (%) Morphine
Sulfate Powder 30.0 mg 63.3% Lactose 6.0 mg 12.7% Povidone C-30
1.25 mg 2.6% Sugar Beads 7.75 mg 16.4% Opadry 2.37 mg 5.0% Purified
Water qs -- Total 47.37 mg 100.0%
[0168] The sustained-release coating comprised an acrylic polymer
(i.e., Eudragit.RTM. RL). A HPMC protective coat was also included
between the Eudragit layer and the morphine immediate release layer
to further enhance stability. The formula of the sustained release
coating of Example 1 is set forth in Table 9 below:
9 TABLE 9 Amt/Unit Percent Ingredient (mg) (%) Morphine (high load)
base beads 42.63 mg 78.8% Retardant Coating Eudragit RS 30D 2.1 mg
3.9% Eudragit RL 30D 0.05 mg 0.1% Triethyl Citrate 0.45 mg 0.8%
Talc 0.85 mg 1.6% Overcoatings Opadry Blue YS-1-10542A 2.45 mg 4.5%
Purified Water qs Morphine Sulfate Powder 3.0 mg 5.5% Opadry Blue
YS-1-10542A 2.55 mg 4.8% Purified Water qs -- Total 54.08 mg
100.0%
[0169] The sustained release and the immediate release coatings
were applied as follows. The Eudragit RL 30D was plasticized with
triethyl citrate and talc for approximately 30 minutes. A load of
the morphine sulfate beads was charged into a Wurster Insert of a
Glatt equipped with a 1.2 mm spray nozzle and the beads are coated
to a weight gain of 5%. The final protective Opadry dispersion
overcoat was then applied in the Wurster Insert. Upon completion
the beads were cured for two days in a dry oven of 45.degree. C.
The cured beads were then filled into gelatin capsules at a 30 mg
strength. The cured beads were then filled into gelatin capsules at
a strength of 30 mg.
[0170] The capsules were then subjected to dissolution testing.
Dissolution testing was conducted on the finished products via USP
Apparatus II-(Paddle Method). The capsules were placed into 700 ml
of simulated gastric fluid (without enzymes) for the first hour at
100 rpm and 37.degree. C., and then placed into 900 ml of simulated
gastric fluid (without enzymes) after the first hour. The results
of dissolution testing is set forth in Table 10 below:
10 TABLE 10 Percent Morphine Time Sulfate Dissolved 1 hour 11.7% 2
hours 12.1% 4 hours 22.0% 8 hours 45.3% 12 hours 63.7% 18 hours
81.8% 24 hours 92.5%
Clinical Evaluation of Example 3
[0171] Thirteen normal, healthy male subjects were enrolled in this
five-way crossover, randomized, open-label study assessing the
effect of food on the pharmacokinetics and pharmacodynamics of
single 30-mg doses (capsules) of Example 3. The pharmacokinetic and
pharmacodynamic results of the extended-release formulations in
these fed and fasted subjects were also compared with those of MS
Contin.RTM. 30 mg tablets in fasted subjects. Plasma morphine level
was used to calculate pharmacokinetic parameters including: (a)
apparent absorption and elimination rates; (b) area-under-the-curve
(AUC); (c) maximum plasma concentration (C.sub.max); (d) time to
maximum plasma concentration (T.sub.max); (e) T.sub.1/2 (abs), and
(f) T.sub.1/2 (elim). Pharmacodynamic effects were assessed based
on evaluations of mood, sedation, respiratory rate, pupillometry,
and subject's adjective questionnaire.
[0172] Plasma morphine concentrations were determined by a
high-performance liquid chromatographic procedure. All subjects
completed the study and were included in the biopharmaceutical
analysis. Arithmetic mean C.sub.max, T.sub.max, AUC, half-lives
calculated from individual plasma morphine
concentration-versus-time, and oral bioavailability data are set
forth in Tables 11 and 12 below:
11 TABLE 11 Pharmaco- kinetic Ex. 3 Ex. 3 MS Contin .RTM. Parameter
(Fed) (Fast) (Fasted) C.sub.max (ng/ml) 5.45 4.03 11.65 T.sub.max
(hours) 8.04 12.92 2.77 AUC (0.72) (hr-ng/ml) 118.12 140.79 114.05
AUC (0.00) (hr-ng/ml) 137.67 166.19 114.05 T.sub.1/2 (elim; hrs)
21.19 54.51 1.26 T.sub.1/2 (abs; hrs) 3.12 2.44 3.34
[0173]
12 TABLET 12 Pharmaco- F.sub.0 (%) Ex. 3 vs. kinetic 90% C.I. MS
Contin .RTM. Parameter (Ex 3: Fed vs. Fast) (Both Fasted) C.sub.max
164.36 29.54 (ng/ml) (113.1-215.6) (14.3-44.7) T.sub.max 53.49
514.28 (hours) (13.3-93.7) (306.8-721.7) AUC (0.72) 89.93 119.35
(hr-ng/ml) (64.8-115.1) (89.2-149.5) AUG (0.00) 86.56 143.48
(hr-ng/ml) (62.5-110.6) (108.6-178.1) T.sub.1/2 (elim; hrs) 34.53
1609.0 (7.4-61.7) (1170-2048) T.sub.1/2 (abs; hrs) 135.27 191.45
(83.5-187.0) (92.0-290.9) F.sub.0 (%) = Oral bioavailability (Test
mean/Reference mean)
[0174] Table 13 provides the mean (.+-.S.D.) plasma morphine
concentrations (ng/ml) following dosing with MS Contin.RTM. and
Example 3.
13TABLE 13 Mean Plasma Morphine Concentrations .+-. Standard
Deviation Following Administration Time Ex. 3 Ex. 3 MS Contin .RTM.
(hours) 30 mg Fed 30 mg Fasted 30 mg Fasted 0.00 0.00 .+-. 0.00
0.00 .+-. 0.00 0.00 .+-. 0.00 0.50 0.201 .+-. 0.447 2.00 .+-. 1.48
3.42 .+-. 1.82 1.00 0.331 .+-. 0.479 2.27 .+-. 0.799 6.09 .+-. 2.03
2.00 1.65 .+-. 1.53 2.19 .+-. 0.936 8.82 .+-. 2.61 2.50 3.06 .+-.
1.04 2.20 .+-. 0.798 9.12 .+-. 2.97 3.00 3.53 .+-. 1.82 2.24 .+-.
1.05 9.91 .+-. 5.32 3.50 3.06 .+-. 1.16 2.87 .+-. 1.94 8.83 .+-.
3.58 4.00 3.23 .+-. 1.04 2.33 .+-. 1.13 8.12 .+-. 3.26 5.00 4.01
.+-. 1.50 2.91 .+-. 0.933 7.79 .+-. 3.47 6.00 4.00 .+-. 2.09 2.96
.+-. 1.24 6.07 .+-. 3.69 8.00 4.03 .+-. 1.90 2.58 .+-. 1.24 4.68
.+-. 3.88 10.0 3.95 .+-. 1.89 1.95 .+-. 0.965 2.61 .+-. 1.43 12.0
3.20 .+-. 1.47 2.18 .+-. 0.983 1.58 .+-. 0.815 18.0 2.06 .+-. 1.02
2.75 .+-. 1.53 1.46 .+-. 0.745 24.0 2.10 .+-. 0.963 2.72 .+-. 0.971
1.34 .+-. 0.890 36.0 1.66 .+-. 1.05 2.65 .+-. 1.18 1.08 .+-. 0.971
48.0 0.872 .+-. 0.681 1.53 .+-. 0.851 0.528 .+-. 0.831 72.0 0.300
.+-. 0.529 0.468 .+-. 0.650 0.00 .+-. 0.00
[0175] Table 14 provides the mean (.+-.S.D.) pharmacokinetic
parameters following dosing with MS Contin.RTM. And Example 3.
14TABLE 14 Mean Pharmacokinetic Parameters .+-. Standard Deviation
Following Administration of Each Formulation Ex. 3 Ex. 3 Ms Contin
.RTM. Parameter 30 mg Fed 30 mg Fasted 30 mg Fasted C.sub.max 5.45
.+-. 1.68 4.03 .+-. 1.55 11.65 .+-. 4.82 (ng/ml) T.sub.max 8.04
.+-. 8.31 12.92 .+-. 14.66 2.77 .+-. 0.927 (hrs) AUC(0.72) 118.12
.+-. 36.77 140.79 .+-. 51.23 114.05 .+-. 42.42 (hr-ng/ml)
[0176] The ratios of least-squares mean AUC for the 30 mg capsules
of Example 3 given under fed and fasted conditions indicate that
AUC values under fed conditions are within .+-.20% of those under
fasted conditions. The value of C.sub.max was 64% greater under fed
conditions. The value of T.sub.max under fed conditions was
approximately 50% of that when given under fasted conditions. The
apparent absorption rate was approximately 35% greater under fed
conditions, and the apparent elimination rate under fed conditions
was approximately 35% of that under fasted conditions, indicating
that absorption of morphine is slowed by the presence of food, and
elimination rate is increased.
[0177] The ratios of least-squares mean AUC for the 30 mg capsule
of Example 3 and the MS Contin.RTM. 30 mg tablet indicate that AUC
(0,72) values for Example 3 are within .+-.20% of those for MS
Contin.RTM., and AUC (0, 00) values are 44% greater for Example 3.
The value of C.sub.max for Example 3 was 29.5% of that for MS
Contin.RTM.. The value of T.sub.max under fed conditions was over
five times that for Example 3. The apparent absorption rate was
approximately 91% greater for Example 3, and the apparent
elimination rate for Example 3 was over 16 times that for MS
Contin.RTM., indicating that absorption and elimination of morphine
is slower for Example 3.
[0178] Linear regression of each pharmacodynamic parameter on the
log-transformed concentrations for each subject and treatment
resulted in 74 of 315 regressions (24%) having an R.sup.2 value of
20% or higher, and 12 of 315 (4%) having a value of 50% or higher.
When analyzed by treatment only, there were zero R.sup.2 values
higher than 10%. Of those individual R.sup.2 values above 20%, 21
occurred in the 63 regressions (33%) of Subject's Modified Specific
Drug Effect Questionnaire scores on log concentration, and 7 of the
63 (11%) were above 50%. These values indicate a possible linear
relationship between the log concentrations and Subject's MSDEQ
scores. Examination of the mean hysteresis curves also reveals a
possible relationship between morphine concentration and Subject's
MSDEQ scores. For each formulation, Subject Modified Specific Drug
Effect Questionnaire scores tended to increase with an increase in
morphine concentration, then decrease as morphine concentration
decreased. No relationships were observed between morphine
concentrations and any of the other pharmacodynamic parameters.
[0179] FIG. 10 is a graphical representation of the mean plasma
morphine concentration-time profile obtained with the Comparative
Example (MS Contin 30 mg) (fasted) as compared to the capsules of
Example 3 (fed and fasted). FIG. 11 is a graphical representation
of the mean sedation vs. time curve for Example 3 (fasted). FIG. 12
is a graphical representation of the mean respiratory rate vs. time
curve for Example 3 (fasted). FIG. 13 is a graphical representation
of the mean pupil size v. time curve for Example 3 (fasted). FIG.
14 is a graphical representation of the mean subject modified
specific drug effect questionnaire vs. time curve for Example 2
(fasted).
EXAMPLE 4
[0180] Beads with a higher loading of morphine sulfate were
produced with the use of the powder layering technique in the Glatt
Rotor Processor. The formulation of the high load beads is set
forth in Table 15 below.
15 TABLE 15 High Load Percent Ingredient Bead mg/unit (%) Morphine
Sulfate Powder 60.0 mg 56.4% Lactose 12.0 mg 11.3% Eudragit RS30D
4.16 mg 3.9% Povidone C-30 8.31 mg 7.8% Sugar Beads 16.80 mg 15.8%
Opadry 5.06 mg 4.8% Purified Water qs -- Total 106.33 mg 100%
[0181] These immediate release base beads were manufactured using
the powder layering technique in the Glatt Rotor Processor.
[0182] The sustained release coating comprised an ethylcellulose
acrylic polymer (i.e., Aquacoat ECD 30). A HPMC protective coat was
also included after the Aquacoat layer to further enhance
stability. The formula of the sustained-release coating of Example
1 is set forth in Table 16 below.
16 TABLE 16 Ingredient Amt/Unit (mg) Percent (%) Morphine (high
load) 106.33 mg 73.1% based beads Retardant Coating Aquacoat ECD 30
23.13 mg 15.9% Methocel E5 Premium 3.46 mg 2.4% Triethyl Citrate
5.32 mg 3.6% Purified Water qs -- Final Overcoat Opadry Blue
YS-1-10542A 7.28 mg 5.0% Purified Water qs -- Total 54.08 mg
100.0%
[0183] The sustained release coating and final overcoat were
applied as follows: The combination of Aquacoat ECD 30 and Methocel
E5 Premium was plasticized with triethyl citrate for approximately
30 minutes. A load of morphine sulfate beads was charged into a
Wurster Insert of a Glatt equipped with a 1.2 mm spray nozzle and
the beads are coated to a weight gain of 25%. Upon completion of
the Retardant the beads were cured for 3 days in a
Temperature/Humidity Chamber of 60.degree. C./80% RH. The cured
beads were then dried for 1 day in a dry oven of 60.degree. C. The
cured dried beads were charged into a Wurster Insert of a Glatt
equipped with a 1.2 mm spray nozzle and the final protective Opadry
dispersion overcoat was then applied. The finished sustained
release beads along with the Low Load Immediate Release Morphine
Sulfate beads were individually filled into the same gelatin
capsules at a combined strength of 60 mg. The sustained released
beads comprised 90% or 54 mg of strength and the Immediate Release
Beads comprised 10% or 6 mg of the capsule strength.
[0184] The capsules were then subjected to dissolution testing.
Dissolution testing was conducted on the finished products via USP
Apparatus II-(Paddle Method). The capsules were placed into 700 ml
of simulated gastric fluid (without enzymes) for the first hour at
100 rpm and 37.degree. C., and then placed into 900 ml of simulated
intestinal fluid (without enzymes) after the first hour. The
results of dissolution testing is set forth in Table 17 below.
17 TABLE 17 Time % Morphine Sulfate Dissolved 1 hour 10.4% 2 hours
11.4% 4 hours 17.5% 8 hours 31.8% 12 hours 54.0% 18 hours 88.6% 24
hours 102.3%
EXAMPLE 5
[0185] Beads with a higher loading of morphine sulfate were
produced with the use of the powder layering technique in the Glatt
Rotor Processor. The formulation of the high load beads is set
forth as per Table 18 in Example 5.
[0186] The sustained-release coating comprised an acrylic polymer
(i.e., Eudragit.RTM. RS/RL). A HPMC protective coating was also
included after the Eudragit layer to further enhance stability. The
formula of the sustained-release coating of Example 5 is set forth
in Table 18 below.
18 TABLE 18 Ingredient Amt/Unit (mg) Percent (%) Morphine (high
load) 106.33 mg 87.96% based beads Retardant Coating Eudragit RS 30
D 5.05 mg 4.18% Eudragit RL 30 D 0.27 mg 0.22% Triethyl Citrate
1.06 mg 0.88% Talc 2.13 mg 1.76% Final Overcoat Opadry Blue
YS-1-10542A 6.04 mg 5.0% Purified Water qs -- Total 120.88 mg
100.0%
[0187] The sustained-release and the final coatings were applied as
follows. The Eudragit RS/RL 30D was plasticized with triethyl
citrate and talc for approximately 30 minutes. A load of the
morphine sulfate beads was charged into a Wurster Insert of a Glatt
equipped with a 1.2 mm spray nozzle and the beads are coated to a
weight gain of 5%. The final protective Opadry dispersion overcoat
was then applied in the Wurster Insert. Upon completion the beads
were cured for two days in a dry oven of 45.degree. C. The cured
beads were then filled into gelatin capsules at a 60 mg
strength.
[0188] The capsules were then subjected to dissolution testing.
Dissolution testing was conducted on the finished products via USP
Apparatus II (Paddle Method). The capsules were placed into 700 ml
of simulated gastric fluid (without enzymes) for the first hour at
100 rpm and 37.degree. C., and then placed into 900 ml of simulated
intestinal fluid (without enzymes) after the first hour. The
results of dissolution testing is set forth in Table 19 below.
19 TABLE 19 Time % Morphine Sulfate Dissolved 1 hour 10.4% 2 hours
11.4% 4 hours 17.5% 8 hours 31.8% 12 hours 54.0% 18 hours 88.6% 24
hours 102.3%
EXAMPLE 6
Matrix Beads
[0189] Matrix Beads with a higher loading of morphine sulfate were
produced with the use of the powder layering technique in the Glatt
Rotor Processor. The formulation of the high load matrix beads is
set forth in Table 20 below.
20 TABLE 20 High Load Percent Ingredient Bead mg/unit (%) Morphine
Sulfate Powder 60.0 mg 46.0% Lactose 12.0 mg 9.2% Eudragit RS30D
29.10 mg 22.4% Povidone C-30 5.80 mg 4.5% Sugar Beads 16.80 mg
12.9% Opadry 6.50 mg 5.0% Purified Water qs -- Total 130.20 mg
100%
[0190] The matrix component is comprised of an ethylcellulose
polymer (i.e., Aquacoat ECD 30). A HPMC protective coat was also
included after the aquacoat layer to further enhance stability.
[0191] The matrix beads were made as follows. The Aquacoat ECD 30
was plasticized with tributyl citrate for approximately 30 minutes.
Morphine sulfate powder and lactose were blended for approximately
5 minutes in a hobart mixer. A load of sugar beads was charged into
the rotor insert of a Glatt equipped with a 1.2 mm spray
nozzle/powder feed assembly. An Accurate Powder Feeder was
positioned over the spray nozzle/powder feed assembly and charged
with the morphine sulfate/lactose blend. The morphine
sulfate/lactose blend is then layered onto the sugar beads using
the plasticized hydrophobic polymer dispersion (i.e., Aquacoat ECD
30 and tributyl citrate) as the binding agent. Upon completion of
the layering process the final protective Opadry dispersion
overcoat was then applied. The beads were then cured for one day in
a dry oven of 60.degree. C. The cured beads were then filled into
gelatin capsules at a 60 mg strength.
[0192] The capsules were then subjected to dissolution testing.
Dissolution testing was conducted on the finished products via USP
Apparatus II-(Paddle Method). The capsules were placed into 700 ml
of simulated gastric fluid (without enzymes) for the first hour at
100 rpm and 37.degree. C., and then placed into 900 ml of simulated
intestinal fluid (without enzymes) after the first hour. The
results of dissolution testing is set forth in Table 21 below.
21 TABLE 21 Time % Morphine Sulfate Dissolved 1 hour 32.4% 2 hours
44.8% 4 hours 59.6% 8 hours 76.6% 12 hours 88.0% 18 hours 97.6% 24
hours 102.2%
Clinical Evaluation of Examples 4, 5 and 6
[0193] Fourteen normal healthy human subjects were enrolled in a
six way crossover, randomized, open label study assessing the
effect of food on the pharmacokinetics and pharmacodynamics of a
single dose of either example 1, 2 or 3, with or without food.
Plasma samples were analyzed for morphine levels and the following
pharmacokinetic results were calculated, and the results are set
forth in Table 22 below.
22TABLE 22 Pharmacokinetic Parameter Per 60 mg Dose Example AUC
Cmax Tmax Number (ng/ml.hr) (ng/ml) (hours) 1 Fasted 120 6.1 5.5 1
Fed 131 8.3 8.8 2 Fasted 149 11.3 6.7 2 Fed 159 11.5 6.4 3 Fasted
154 14.3 1.8 3 Fed 154 12.7 2.8
EXAMPLE 7
Hydromorphone HCl 8 mg Once-a-Day Capsules
Drug Loading
[0194] Hydromorphone beads were prepared by dissolving
hydromorphone HCl in water, adding Opadry Y-5-1442 and mixing for
about 1 hour to obtain a 20% w/w suspension. This suspension was
then sprayed onto Nu-Pareil 18/20 mesh beads using a Wurster
insert.
First Overcoat
[0195] The loaded hydromorphone beads were then overcoated with a
5% w/w gain of Opadry Light Pink using a Wurster insert. This
overcoat was applied as a protective coating.
Retardant Coat
[0196] After the first overcoat, the hydromorphone beads were then
coated with a 5% weight gain of a retardant coating mixture of
Eudragit RS 30D and Eudragit RL 30D at a ratio of 90:10, RS to RL.
The addition of Triethyl Citrate (a plasticizer) and Talc
(anti-tacking agent) was also included in the Eudragit suspension.
The Wurster insert was used to apply the coating suspension.
Second Overcoat
[0197] Once the retardant coating was complete, the hydromorphone
beads were given a final overcoat of Opadry Light Pink to a 5%
weight gain using a Wurster insert. This overcoat was also applied
as a protective coating.
Curing
[0198] After the completion of the final overcoat, the
hydromorphone beads were cured in a 45.degree. C. oven for 2
days.
Encapsulation
[0199] Beads were hand filled in size #2 clear gelatin capsules at
an 8 mg strength of Hydromorphone HCl.
[0200] The formulation for Example 7 is set forth in Table 23
below:
23TABLE 23 HYDROMORPHONE HCl 8 mg ONCE A DAY CAPSULES Ingredient
mg/Capsule Loading Hydromorphone HCl 8.00 Opadry Light Pink
(Y-5-1442) 4.00 Purified Water.sup.1 q.s. 18/20 Mesh Sugar Spheres
148.00 Overcoating Opadry Light Pink (Y-5-1442) 8.40 Purified
Water.sup.1 q.s. Retardant Coating Eudragit RS 30D.sup.2 7.60
Eudragit RL 30D.sup.2 0.80 Triethyl Citrate 1.68 Talc 3.36 Purified
Water.sup.1 q.s. Second Overcoating Opadry Light Pink (Y-5-1442)
9.60 Purified Water.sup.1 q.s. Encapsulation Size #2 Clear Hard
Gelatin Capsules n/a Total Fill weight 191.44 mg .sup.1-Used in
processing and remains as residual moisture only. .sup.2-Dry
weight.
Dissolution Testing
[0201] The above capsules were tested using USP methodology and
were found to have the following results:
24 Time Initial 1 hour 17.2 2 hours 48.4 4 hours 77.4 8 hours 93.3
12 hours 97.2 18 hours 98.8 24 hours 98.8
[0202] A single-dose randomized, crossover bioavailability study
was conducted with the above 8 mg controlled release hydromorphone
HCl capsules and two immediate release 4 mg tablets (Dilaudid.RTM.)
as the reference in fed and fasted conditions. Blood samples were
assayed for hydromorphone levels and the following pharmacokinetic
parameters were calculated. The results are provided in Table 24
below:
25TABLE 24 AUC T.sub.max C.sub.max T.sub.1/2 Group (pg/ml/hr) % IR
(hr) (pg/ml) (abs) CR Fasted* 21059 101 4.9 1259 2.56 CR Fed* 25833
106 4.6 1721 3.92 IR Fasted** 20903 100 0.85 3816 0.18 IR Fed**
24460 100 1.15 3766 0.32 *CR = Example 7 **IR = Dilaudid
[0203] The examples provided above are not meant to be exclusive.
Many other variations of the present invention would be obvious to
those skilled in the art, and are contemplated to be within the
scope of the appended claims.
* * * * *