U.S. patent application number 09/933411 was filed with the patent office on 2002-02-14 for controlled release oxycodone compositions.
Invention is credited to Chasin, Mark, Kaiko, Robert Francis, Minogue, John Joseph, Oshlack, Benjamin.
Application Number | 20020018810 09/933411 |
Document ID | / |
Family ID | 25178688 |
Filed Date | 2002-02-14 |
United States Patent
Application |
20020018810 |
Kind Code |
A1 |
Oshlack, Benjamin ; et
al. |
February 14, 2002 |
Controlled release oxycodone compositions
Abstract
A method for substantially reducing the range in daily dosages
required to control pain in approximately 90% of patients is
disclosed whereby an oral solid controlled release dosage
formulation having from about 10 to about 40 mg of oxycodone or a
salt thereof is administered to a patient. The formulation provides
a mean maximum plasma concentration of oxycodone from about 6 to
about 60 ng/ml from a mean of about 2 to about 4.5 hours after
administration, and a mean minimum plasma concentration from about
3 to about 30 ng/ml from about 10 to about 14 hours after repeated
"q12h" (i.e., every 12 hour) administration through steady-state
conditions. Another embodiment is directed to a method for
substantially reducing the range in daily dosages required to
control pain in substantially all patients by administering an oral
solid controlled release dosage formulation comprising up to about
160 mg of oxycodone or a salt thereof, such that a mean maximum
plasma concentration of oxycodone up to about 240 ng/ml from a mean
of up to about 2 to about 4.5 hours after administration, and a
mean minimum plasma concentration up to about 120 ng/ml from about
10 to about 14 hours after repeated "q12h" (i.e., every 12 hour)
administration through steady-state conditions are achieved.
Controlled release oxycodone formulations for achieving the above
are also disclosed.
Inventors: |
Oshlack, Benjamin; (New
York, NY) ; Chasin, Mark; (Manalpan, NJ) ;
Minogue, John Joseph; (Mount Vernon, NY) ; Kaiko,
Robert Francis; (Weston, CT) |
Correspondence
Address: |
DAVIDSON, DAVIDSON & KAPPEL, LLC
485 SEVENTH AVENUE, 14TH FLOOR
NEW YORK
NY
10018
US
|
Family ID: |
25178688 |
Appl. No.: |
09/933411 |
Filed: |
August 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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09933411 |
Aug 20, 2001 |
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09784888 |
Feb 16, 2001 |
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09784888 |
Feb 16, 2001 |
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09481909 |
Jan 12, 2000 |
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09481909 |
Jan 12, 2000 |
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08909328 |
Aug 11, 1997 |
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08909328 |
Aug 11, 1997 |
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08613344 |
Mar 11, 1996 |
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5630870 |
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08613344 |
Mar 11, 1996 |
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08081302 |
Jun 18, 1993 |
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5549912 |
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08081302 |
Jun 18, 1993 |
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07800549 |
Nov 27, 1991 |
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5266331 |
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Current U.S.
Class: |
424/468 ;
514/282 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 31/485 20130101; A61P 25/04 20180101; A61K 9/2013 20130101;
A61K 9/5015 20130101; A61K 9/2081 20130101; A61K 9/2027
20130101 |
Class at
Publication: |
424/468 ;
514/282 |
International
Class: |
A61K 009/22 |
Claims
1. A controlled release oxycodone formulation for oral
administration to human patients, comprising from about 10 mg to
about 160 mg oxycodone, based on the hydrochloride salt, said
formulation providing a mean maximum plasma concentration of
oxycodone from about 6 to about 240 ng/ml from a mean of about 2 to
about 4.5 hours after administration, said formulation providing a
desired analgesic effect for at least about 12 hours.
2. The controlled release oxycodone formulation of claim 1,
comprising from about 10 to about 40 mg oxycodone based on the
hydrochloride salt, said formulation providing a mean maximum
plasma concentration of oxycodone from about 6 to about 60 ng/ml
from a mean of about 2 to about 4.5 hours after administration.
3. The controlled release oxycodone formulation of claim 1,
comprising from about 40 mg to about 160 mg oxycodone based on the
hydrochloride salt, said formulation providing a mean maximum
plasma concentration of oxycodone from about 60 to about 240 ng/ml
from a mean of about 2 to about 4.5 hours after administration.
4. The solid controlled release oxycodone formulation of claim 1,
comprising oxycodone hydrochloride dispersed in an effective amount
of a controlled release matrix selected from the group consisting
of hydrophilic polymers, hydrophobic polymers, digestible
substituted or unsubstituted hydrocarbons having from about 8 to
about 50 carbon atoms, polyalkylene glycols, and mixtures of any of
the foregoing, and a suitable amount of a suitable pharmaceutical
diluent.
5. The solid controlled release oxycodone formulation of claim 1,
comprising: (a) an analgesically effective amount of spheroids
comprising oxycodone or a salt thereof and either a spheronising
agent or an acrylic polymer or copolymer, such that the total
dosage of oxycodone in said dosage form is from about 10 to about
160 mg based on the hydrochloride salt; and (b) a film coating on
said spheroids which controls the release of the oxycodone or
oxycodone salt at a controlled rate in an aqueous medium, wherein
said composition provides an in vitro dissolution rate of the
dosage form.
6. The controlled release oxycodone formulation of claim 1,
comprising a tablet wherein said oxycodone is dispersed in a
controlled release matrix.
7. The controlled release oxycodone formulation of claim 1, wherein
said oxycodone is in the form of the hydrochloride salt.
8. A method for substantially reducing the range in daily dosages
required to control pain human patients, comprising administering
an oral controlled release dosage formulation comprising from about
10 to about 160 mg oxycodone or a salt thereof based on the
hydrochloride salt which provides a mean maximum plasma
concentration of oxycodone from about 6 to about 240 ng/ml from a
mean of about 2 to about 4.5 hours after administration.
9. A method for substantially reducing the range in daily dosages
required to control pain in substantially all human patients,
comprising administering an oral solid controlled release dosage
formulation comprising from about 10 mg to about 40 mg oxycodone or
a salt thereof based on the hydrochloride salt which provides a
mean maximum plasma concentration of oxycodone from about 6 to
about 60 ng/ml from a mean of up to about 2 to about 4.5 hours
after administration.
10. A method for substantially reducing the range in daily dosages
required to control pain in substantially all human patients,
comprising administering an oral solid controlled release dosage
formulation comprising from about 40 mg to about 160 mg oxycodone
or a salt thereof based on the hydrochloride salt which provides a
mean maximum plasma concentration of oxycodone from about 60 to
about 240 ng/ml from a mean of up to about 2 to about 4.5 hours
after administration.
Description
[0001] This application is a continuation of 08/081,302, filed Jun.
18, 1993, which is a continuation-in-part of Ser. No. 07/800,549,
filed Nov. 27, 1991, now U.S. Pat. No. 5,266,331, hereby
incorporated by reference.
BACKGROUND OF THE INVENTION
[0002] Surveys of daily dosages of opioid analgesics required to
control pain suggest that an approximately eight-fold range in
daily dosages is required to control pain in approximately 90% of
patients. This extraordinary wide range in the appropriate dosage
makes the titration process particularly time consuming and
resource consuming, as well as leaving the patient without
acceptable pain control for an unacceptably long duration.
[0003] In the management of pain with opioid analgesics, it has
been commonly observed and reported that there is considerable
inter-individual variation in the response to a given dose of a
given drug, and, therefore, considerable variability among patients
in the dosage of opioid analgesic required to control pain without
unacceptable side effects. This necessitates considerable effort on
the part of clinicians in establishing the appropriate dose in an
individual patient through the time consuming process of titration,
which requires careful assessment of both therapeutic and side
effects and dosage adjustments over a period of days and sometimes
longer before the appropriate dosage is determined. The American
Pain Society's 3rd Edition of Principles of Analgesic Use in the
Treatment of Acute Pain and Cancer Pain explains that one should
"be aware that the optimal analgesic dose varies widely among
patients. Studies have shown that in all age groups, there is
enormous variability in doses of opioids required to provide
relief, even among opioid naive patients with identical surgical
lesions . . . This great variability underscores the need to write
analgesic orders that include provision for supplementary doses,
and to use intravenous boluses and infusions to provide rapid
relief of severe pain . . . Give each analgesic an adequate trial
by dose titration . . . before switching to another drug."
[0004] An opioid analgesic treatment which acceptably controls pain
over a substantially narrower daily dosage range would, therefore,
substantially improve the efficiency and quality of pain
management.
[0005] It has previously been known in the art that controlled
release compositions of opioid analgesics such as morphine,
hydromorphone or salts thereof could be prepared in a suitable
matrix. For example, U.S. Pat. No. 4,990,341 (Goldie), also
assigned to the assignee of the present invention, describes
hydromorphone compositions wherein the dissolution rate in vitro of
the dosage form, when measured by the USP Paddle Method at 100 rpm
in 900 ml aqueous buffer (pH between 1.6 and 7.2) at 37.degree. C.,
is between 12.5 and 42.5% (by wt) hydromorphone released after 1
hour, between 25 and 55% (by wt) released after 2 hours, between 45
and 75% (by wt) released after 4 hours and between 55 and 85% (by
wt) released after 6 hours.
SUMMARY OF THE INVENTION
[0006] It is an object of the present invention to provide a method
for substantially improving the efficiency and quality of pain
management.
[0007] It is another object of the present invention to provide an
opioid analgesic formulation which substantially improves the
efficiency and quality of pain management.
[0008] It is another object of the present invention to provide a
method and formulation(s) which substantially reduce the
approximately eight-fold range in daily dosages required to control
pain in approximately 90% of patients.
[0009] It is another object of the present invention to provide a
method and formulation(s) which substantially reduce the
variability in daily dosages and formulation requirements necessary
to control pain in substantially all patients.
[0010] It is yet another object of the present invention to provide
a method for substantially reducing the time and resources need to
titrate patients requiring pain, relief on opioid analgesics.
[0011] It is yet another object of the present invention to provide
controlled release opioid formulations which have substantially
less inter-individual variation with regard to the dose of opioid
analgesic required to control pain without unacceptable side
effects.
[0012] The above objects and others are attained by virtue of the
present invention, which is related to a solid controlled release
oral dosage form, the dosage form comprising from about 10 to about
40 mg of oxycodone or a salt thereof in a matrix wherein the
dissolution rate in vitro of the dosage form, when measured by the
USP Paddle Method at 100 rpm in 900 ml aqueous buffer (pH between
1.6 and 7.2) at 37.degree. C. is between 12.5 and 42.5% (by wt)
oxycodone released after 1 hour, between 25 and 56% (by wt)
oxycodone released after 2 hours, between 45 and 75% (by wt)
oxycodone released after 4 hours and between 55 and 85% (by wt)
oxycodone released after 6 hours, the in vitro release rate being
substantially independent of pH, such that the peak plasma level of
oxycodone obtained in vivo occurs between 2 and 4.5 hours after
administration of the dosage form.
[0013] USP Paddle Method is the Paddle Method described, e.g., in
U.S. Pharmacopoeia XXII (1990).
[0014] In the present specification, "substantially independent of
pH" means that the difference, at any given time, between the
amount of oxycodone released at, e.g., pH 1.6, and the amount
released at any other pH, e.g., pH 7.2 (when measured in vitro
using the USP Paddle Method at 100 rpm in 900 ml aqueous buffer),
is 10% (by weight) or less. The amounts released being, in all
cases, a mean of at least three experiments.
[0015] The present invention is further related to a method for
substantially reducing the range in daily dosages required to
control pain in approximately 90% of patients, comprising
administering an oral solid controlled release dosage formulation
comprising from about 10 to about 40 mg of oxycodone or a salt
thereof, said formulation providing a mean maximum plasma
concentration of oxycodone from about 6 to about 60 ng/ml from a
mean of about 2 to about 4.5 hours after administration, and a mean
minimum plasma concentration from about 3 to about 30 ng/ml from a
mean of about 10 to about 14 hours after repeated "q12h" (i.e.,
every 12 hour) administration through steady-state conditions.
[0016] The present invention is further related to a method for
substantially reducing the range in daily dosages required to
control pain in substantially all patients, comprising
administering an oral solid controlled release dosage formulation
comprising up to about 160 mg of oxycodone or a salt thereof, said
formulation providing a mean maximum plasma concentration of
oxycodone up to about 240 ng/ml from a mean of up to about 2 to
about 4.5 hours after administration, and a mean minimum plasma
concentration up to about 120 ng/ml from a mean of about 10 to
about 14 hours after repeated "12h" (i.e., every 12 hour)
administration through steady-state conditions.
[0017] The present invention is further related to controlled
release oxycodone formulations comprising from about 10 to about 40
mg oxycodone or a salt thereof, said formulations providing a mean
maximum plasma concentration of oxycodone from about 6 to about 60
ng/ml from a mean of about 2 to about 4.5 hours after
administration, and a mean minimum plasma concentration from about
3 to about 30 ng/ml from about 10 to about 14 hours after repeated
q12h administration through steady-state conditions.
[0018] The present invention is further related to controlled
release oxycodone formulations comprising up to about 160 mg
oxycodone or a salt thereof, said formulations providing a mean
maximum plasma concentration of oxycodone up to about 240 ng/ml
from a mean of about 2 to about 4.5 hours after administration, and
a mean minimum plasma concentration up to about 120 ng/ml from
about 10 to about 14 hours after repeated q12h administration
through steady-state conditions.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] 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.
[0020] FIGS. 1-4 are graphs showing the time-effect curves for pain
intensity differences and pain relief for Example 17;
[0021] FIG. 5 is a graph- showing the mean plasma oxycodone
concentration for a 10 mg controlled release oxycodone formulation
prepared in accordance with the present invention and a study
reference standard.
DETAILED DESCRIPTION
[0022] It has now been surprisingly discovered that the presently
claimed controlled release oxycodone formulations acceptably
control pain over a substantially narrower, approximately four-fold
(10 to 40 mg every 12 hours--around-the-clock dosing) in
approximately 90% of patients. This is in sharp contrast to the
approximately eight-fold range required for approximately 90% of
patients for opioid analgesics in general.
[0023] The use of from about 10 mg to about 40 mg of 12-hourly
doses of controlled-release oxycodone to control pain in
approximately 90% of patients relative to a wider dosage range of
other m.mu.-agonist analgesics, indicated for moderate to severe
pain, is an example of the unique characteristics of the present
invention. It should also be appreciated that the remaining 10% of
patients would also be successfully managed with 12-hourly
controlled-release oxycodone over a relatively narrower dosage
range than with the use of other similar analgesics. Substantially
all of those remaining 10% of patients not managed with controlled
release oxycodone, 10 mg to 40 mg every 12 hours, would be managed
using dosages of greater than 40 mg every 12 hours through 160 mg
every 12 hours utilizing any one of a number or multiples of
formulation strengths such as 10, 20, 40, 80 and 160 mg unit
dosages or combinations thereof. In contrast, the use of other
similar analgesics such as morphine would require a wider range of
dosages to manage the remaining 10% of patients. For example, daily
dosages of oral morphine equivalents in the range of 1 gram to more
than 20 grams have been observed. Similarly, wide dosage ranges of
oral hydromorphone would also be required.
[0024] Morphine, which is considered to be the prototypic opioid
analgesic, has been formulated into a 12 hour controlled-release
formulations (i.e., MS Contin.RTM. tablets, commercially available
from Purdue Pharma, L. P.). Despite the fact that both
controlled-release oxycodone and controlled release morphine
administered every 12 hours around-the-clock possess qualitatively
comparable clinical pharmacokinetic characteristics, the oxycodone
formulations of the presently claimed invention can be used over
approximately 1/2 the dosage range as compared to commercially
available controlled release morphine formulations (such as MS
Contin.RTM.) to control 90% of patients with significant pain.
[0025] Repeated dose studies with the controlled release oxycodone
formulations administered every 12 hours in comparison with
immediate release oral oxycodone administered every 6 hours at the
same total daily dose result in comparable extent of absorption, as
well as comparable maximum and minimum concentrations. The time of
maximum concentration occurs at approximately 2-4.5 hours after
oral administration with the controlled-release product as compared
to approximately 1 hour with the immediate release product. Similar
repeated dose studies with MS Contin.RTM. tablets as compared to
immediate release morphine provide for comparable relative results
as with the controlled release oxycodone formulations of the
present invention.
[0026] There exists no substantial deviation from parallelism of
the dose-response curves for oxycodone either in the forms of the
controlled release oxycodone formulations of the present invention,
immediate release oral oxycodone or parenteral oxycodone in
comparison with oral and parenteral opioids with which oxycodone
has been compared in terms of dose-response studies and relative
analgesic potency assays. Beaver, et al., "Analgesic Studies of
Codeine and Oxycodone in Patients with Cancer. II. Comparisons of
Intramuscular Oxycodone with Intramuscular Morphine and Codeine",
J. Pharmacol. and Exp. Ther., Vol. 207, No. 1, pp. 101-108,
reported comparable dose-response slopes for parenteral oxycodone
as compared to parenteral morphine and comparable dose-response
slopes for oral as compared to parenteral oxycodone.
[0027] A review of dose-response studies and relative analgesic
assays of mu-agonist opioid analgesics, which include oxycodone,
morphine, hydromorphone, levorphanol, methadone, meperidine,
heroin, all indicate no significant deviation from parallelism in
their dose response relationships. This is so well established that
it has become an underlining principal providing for establishing
relative analgesic potency factors and dose ratios which are
commonly utilized when converting patients from one m.mu.-agonist
analgesic to another regardless of the dosage of the former. Unless
the dose-response curves are parallel, conversion factors would not
be valid across the wide range of dosages involved when
substituting one drug for another.
[0028] The clinical significance provided by the controlled release
oxycodone formulations of the present invention at a dosage range
from about 10 to about 40 mg every 12 hours for acceptable pain
management in approximately 90% of patients with moderate to severe
pain, as compared to other opioid analgesics requiring
approximately twice the dosage range provides for the most
efficient and humane method of managing pain requiring repeated
dosing. The expertise and time of physicians and nurses, as well as
the duration of unacceptable pain patients must endure during the
opioid analgesic titration process is substantially reduced through
the efficiency of the controlled release oxycodone formulations of
the present invention.
[0029] It is further clinically significant that a dose of about 80
mg controlled release oxycodone administered every 12 hours will
provide acceptable pain relief management in, e.g., approximately
95% of patients with moderate to severe pain, and that about 160 mg
controlled release oxycodone administered every 12 hours will
provide acceptable pain relief management in, e.g., approximately
all patients with moderate to severe pain.
[0030] In order to obtain a controlled release drug dosage form
having at least a 12 hour therapeutic effect, it is usual in the
pharmaceutical art to produce a formulation that gives a peak
plasma level of the drug between about 4-8 hours after
administration (in a single dose study). The present inventors have
surprisingly found that, in the case of oxycodone, a peak plasma
level at between 2-4.5 hours after administration gives at least 12
hours pain relief and, most surprisingly, that the pain relief
obtained with such a formulation is greater than that achieved with
formulations giving peak plasma levels (of oxycodone) in the normal
period of up to 2 hours after administration.
[0031] A further advantage of the present composition, which
releases oxycodone at a rate that is substantially independent of
pH, is that it avoids dose dumping upon oral administration. In
other words, the oxycodone is released evenly throughout the
gastrointestinal tract.
[0032] The present oral dosage form may be presented as, for
example, granules, spheroids or pellets in a capsule or in any
other suitable solid form. Preferably, however, the oral dosage
form is a tablet.
[0033] The present oral dosage form preferably contains between 1
and 500 mg, most especially between 10 and 160 mg, of oxycodone
hydrochloride. Alternatively, the dosage form may contain molar
equivalent amounts of other oxycodone salts or of the oxycodone
base.
[0034] The present matrix may be any matrix that affords in vitro
dissolution rates of oxycodone within the narrow ranges required
and that releases the oxycodone in a pH independent manner.
Preferably the matrix is a controlled release matrix, although
normal release matrices having a coating that controls the release
of the drug may be used. Suitable materials for inclusion in a
controlled release matrix are
[0035] (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.
[0036] (b) Digestible, long chain (C.sub.8-C.sub.50, especially
C.sub.12-C.sub.40), substituted or unsubstituted hydrocarbons, such
as fatty acids, fatty alcohols, glyceryl esters of fatty acids,
mineral and vegetable oils and waxes. 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.
[0037] (c) Polyalkylene glycols. The oral dosage form may contain
up to 60% (by weight) of at least one polyalkylene glycol.
[0038] One particular suitable matrix comprises at least one water
soluble hydroxyalkyl cellulose, at least one C.sub.12-C.sub.36,
preferably C.sub.14-C.sub.22, aliphatic alcohol and, optionally, at
least one polyalkylene glycol.
[0039] 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 oxycodone release
required. Preferably however, the oral dosage form contains between
5% and 25%, especially between 6.25% and 15% (by wt) of the at
least one hydroxyalkyl cellulose.
[0040] The at least one aliphatic alcohol may be, for example,
lauryl alcohol, myristyl alcohol or stearyl alcohol. In
particularly preferred embodiments of the present oral dosage form,
however, the at least one aliphatic alcohol is cetyl alcohol or
cetostearyl alcohol. The amount of the at least one aliphatic
alcohol in the present oral dosage form will be determined, as
above, by the precise rate of oxycodone 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.
[0041] In one preferred embodiment, the controlled release
composition comprises from about 5 to about 25% acrylic resin and
from about 8 to about 40% by weight aliphatic alcohol by weight of
the total dosage form. A particularly preferred acrylic resin
comprises Eudragit.RTM.0 RS PM, commercially available from Rohm
Pharma.
[0042] In the present preferred dosage form, the ratio of, e.g.,
the at least one hydroxyalkyl cellulose or acrylic resin to the at
least one aliphatic alcohol/polyalkylene glycol determines, to a
considerable extent, the release rate of the oxycodone from the
formulation. A ratio of the at least one hydroxyalkyl cellulose to
the at least one aliphatic alcohol/polyalkylene glycol of between
1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being
particularly preferred.
[0043] The at least one polyalkylene glycol may be, for example,
polypropylene glycol or, which is preferred, polyethylene glycol.
The number average molecular weight of the at least one
polyalkylene glycol is preferred between 1000 and 15000 especially
between 1500 and 12000.
[0044] Another suitable controlled release matrix would comprise an
alkylcellulose (especially ethyl cellulose), a C.sub.12 to C.sub.36
aliphatic alcohol and, optionally, a polyalkylene glycol.
[0045] In addition to the above ingredients, a controlled release
matrix may also contain suitable quantities of other materials,
e.g. diluents, lubricants, binders, granulating aids, colorants,
flavorants and glidants that are conventional in the pharmaceutical
art.
[0046] As an alternative to a controlled release matrix, the
present matrix may be a normal release matrix having a coat that
controls the release of the drug. In particularly preferred
embodiments of this aspect of the invention, the present dosage
form comprises film coated spheroids containing active ingredient
and a non-water soluble spheronising agent. The term spheroid is
known in the pharmaceutical art and means a spherical granule
having a diameter of between 0.5 mm and 2.5 mm especially between
0.5 mm and 2 mm.
[0047] The spheronising agent may be any pharmaceutically
acceptable material that, together with the active ingredient, can
be spheronised to form spheroids. Microcrystalline cellulose is
preferred.
[0048] A suitable microcrystalline cellulose is, for example, the
material sold as Avicel PH 101 (Trade Mark, FMC Corporation).
According to a preferred aspect of the present invention, the film
coated spheroids contain between 70% and 99% (by wt), especially
between 80% and 95% (by wt), of the spheronising agent, especially
microcrystalline cellulose.
[0049] In addition to the active ingredient and spheronising 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.
[0050] The spheroids are preferably film coated with a material
that permits release of the oxycodone (or salt) at a controlled
rate in an aqueous medium. The film coat is chosen so as to
achieve, in combination with the other ingredients, the in-vitro
release rate outlined above (between 12.5% and 42.5% (by wt)
release after 1 hour, etc.).
[0051] The film coat will generally include a water insoluble
material such as
[0052] (a) a wax, either alone or in admixture with a fatty
alcohol,
[0053] (b) shellac or zein,
[0054] (c) a water insoluble cellulose, especially ethyl
cellulose,
[0055] (d) a polymethacrylate, especially Eudragit.RTM..
[0056] Preferably, the film coat comprises a mixture of the water
insoluble material and a water soluble material. The ratio of water
insoluble to water soluble material is determined by, amongst other
factors, the release rate required and the solubility
characteristics of the materials selected.
[0057] The water soluble material may be, for example,
polyvinylpyrrolidone or, which is preferred, a water soluble
cellulose, especially hydroxypropylmethyl cellulose.
[0058] Suitable combinations of water insoluble and water soluble
materials for the film coat include shellac and
polyvinylpyrrolidone or, which is preferred, ethyl cellulose and
hydroxypropylmethyl cellulose.
[0059] In order to facilitate the preparation of a solid,
controlled release, oral dosage form according to this invention
there is provided, in a further aspect of the present invention, a
process for the preparation of a solid, controlled release, oral
dosage form according to the present invention comprising
incorporating hydromorphone or a salt thereof in a controlled
release matrix. Incorporation in the matrix may be effected, for
example, by
[0060] (a) forming granules comprising at least one water soluble
hydroxyalkyl cellulose and oxycodone or a oxycodone salt,
[0061] (b) mixing the hydroxyalkyl cellulose containing granules
with at least one C.sub.12-C.sub.36 aliphatic alcohol, and
[0062] (c) optionally, compressing and shaping the granules.
Preferably, the granules are formed by wet granulating the
hydroxyalkyl cellulose/oxycodone with water. In a particularly
preferred embodiment of,this process, the amount of water added
during the wet granulation step is preferably between 1.5 and 5
times, especially between 1.75 and 3.5 times, the dry weight of the
oxycodone.
[0063] The present solid, controlled release, oral dosage form may
also be prepared, in the form of film coated spheroids, by
[0064] (a) blending a mixture comprising oxycodone or a oxycodone
salt and a non-water soluble spheronising agent,
[0065] (b) extruding the blended mixture to give an extrudate,
[0066] (c) spheronising the e-xtrudate until spheroids are formed,
and
[0067] (d) coating the spheroids with a film coat.
[0068] The present solid, controlled release, oral dosage form and
processes for its preparation will now be described by way of
example only.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0069] The following examples illustrate various aspects of the
present invention. They are not meant to be construed to limit the
claims in any manner whatsoever.
EXAMPLE 1
Controlled Release Oxycodone HCl 30 mg Tablets--Aqueous
Manufacture
[0070] The required quantities of oxycodone hydrochloride,
spray-dried lactose, and Eudragit.RTM. RS PM are transferred into
an appropriate-size mixer, and mixed for approximately 5 minutes.
While the powders are mixing, the mixture is granulated with enough
water to produce a moist granular mass. The granules are then dried
in a fluid bed dryer at 60.degree. C., and then passed through an
8-mesh screen. Thereafter, the granules are redried and pushed
through a 12-mesh screen. The required quantity of stearyl alcohol
is melted at approximately 60-70.degree. C., and while the granules
are mixing, the melted stearyl alcohol is added. The warm granules
are returned to the mixer.
[0071] The coated granules are removed from the mixer and allowed
to cool. The granules are then passed through a 12-mesh screen. The
granulate is then lubricated by mixing the required quantity of
talc and magnesium stearate in a suitable blender. Tablets are
compressed to 375 mg in weight on a suitable tableting machine. The
formula for the tablets of Example 1 is set forth in Table 1
below:
1TABLE 1 Formula of Oxycodone HCl 30 mg Tablets Component mg/Tablet
% (by wt) Oxycodone Hydrochloride 30.0 8 Lactose (spray-dried)
213.75 57 Eudragit .RTM. RS PM 45.0 12 Purified Water q.s* --
Stearyl Alcohol 75.0 20 Talc 7.5 2 Magnesium Stearate 3.75 1 Total
375.0 100 *Used in manufacture and remains in final product as
residual quantity only.
[0072] The tablets of Example 1 are then tested for dissolution via
the USP Basket Method, 37.degree. C., 100 RPM, first hour 700 ml
gastric fluid at pH 1.2, then changed to 900 ml at 7.5. The results
are set forth in Table 2 below:
2TABLE 2 Dissolution of Oxycodone 30 mg Controlled Release Tablets
Time % Oxycodone Dissolved 1 33.1 2 43.5 4 58.2 8 73.2 12 81.8 18
85.8 24 89.2
EXAMPLE 2
Controlled Oxycodone HCl 10 mg Release Tablets--Organic
Manufacture
[0073] The required quantities of oxycodone hydrochloride and spray
dried lactose are transferred into an appropriate sized mixer and
mix for approximately 6 minutes. Approximately 40 percent of the
required Eudragit.RTM. RS PM powder is dispersed in Ethanol. While
the powders are mixing, the powders are granulated with the
dispersion and the mixing continued until a moist granular mass is
formed. Additional ethanol is added if needed to reach granulation
end point. The granulation is transferred to a fluid bed dryer and
dried at 30.degree. C.; and then passed through a 12-mesh screen.
The remaining Eudragit.RTM. RS PM is dispersed in a solvent of 90
parts ethanol and 10 parts purified water; and sprayed onto the
granules in the fluid bed granulator/dryer at 30.degree. C. Next,
the granulate is passed through a 12-mesh screen. The required
quantity of stearyl alcohol is melted at approximately
60-70.degree. C. The warm granules are returned to the mixer. While
mixing, the melted stearyl alcohol is added. The coated granules
are removed from the mixer and allowed to cool. Thereafter, they
are passed through a 12-mesh screen.
[0074] Next, the granulate is lubricated by mixing the required
quantities of talc and magnesium stearate in a suitable blender.
The granulate is then compressed to 125 mg tablets on a suitable
tableting machine.
[0075] The formula for the tablets of Example 2 (10 mg controlled
release oxycodone) is set forth in Table 3 below:
3TABLE 3 Formula of Oxycodone HCl 10 mg Controlled Release Tablets
Percent Component Mg/Tablet (by wt) Oxycodone hydrochloride 10.00 8
Lactose (spray-dried) 71.25 57 Eudragit .RTM. RS PM 15.00 12
Ethanol q.s.* -- Purified Water q.s.* -- Stearyl Alcohol 25.00 20
Talc 2.50 2 Magnesium Stearate 1.25 1 Total 125.00 mg 100 *Used
only in the manufacture and remains in final product as residual
quantity only.
[0076] The tablets of Example 2 are then tested for dissolution via
USP Basket Method at 37.degree. C., 100 RPM, first hour 700 ml
simulated gastric (pH 1.2) then changed to 900 ml at pH 7.5.
[0077] The results are set forth in Table 4 below:
4TABLE 4 Dissolution of Oxycodone 10 mg Controlled Release Tablets
Hour % Dissolved 1 35.9 2 47.7 4 58.5 8 67.7 12 74.5 18 76.9 24
81.2
EXAMPLES 3-4
Controlled Release Oxycodone 10 and 20 mg Tablets (Aqueous
Manufacture)
[0078] Eudragit.RTM. RS 30D and Triacetin.RTM. are combined while
passing though a 60 mesh screen, and mixed under low shear for
approximately 5 minutes or until a uniform dispersion is
observed.
[0079] Next, suitable quantities of Oxycodone HCl, lactose, and
povidone are placed into a fluid bed granulator/dryer (FBD) bowl,
and the suspension sprayed onto the powder in the fluid bed. After
spraying, the granulation is passed through a #12 screen if
necessary to reduce lumps. The dry granulation is placed in a
mixer.
[0080] In the meantime, the required amount of stearyl alcohol is
melted at a temperature of approximately 70.degree. C. The melted
stearyl alcohol is incorporated into the granulation while mixing.
The waxed granulation is transferred to a fluid bed
granulator/dryer or trays and allowed to cool to room temperature
or below. The cooled granulation is then passed through a #12
screen. Thereafter, the waxed granulation is placed in a
mixer/blender and lubricated with the required amounts of talc and
magnesium stearate for approximately 3 minutes, and then the
granulate is compressed into 125 mg tablets on a suitable tableting
machine.
[0081] The formula for the tablets of Example 3 is set forth in
Table 5 below:
5TABLE 5 Formula of Controlled Release Oxycodone 10 mg Tablets
Component Mg/Tablet % (by wt) Oxycodone Hydrochloride 10.0 8.0
Lactose (spray dried) 69.25 55.4 Povidone 5.0 4.0 Eudragit .RTM. RS
30D (solids) 10.0* 8.0 Triacetin .RTM. 2.0 1.6 Stearyl Alcohol 25.0
20.0 Talc 2.5 2.0 Magnesium Stearate 1.25 1.0 Total 125.0 100.0
*Approximately 33.33 mg Eudragit .RTM. RS 30D Aqueous dispersion is
equivalent to 10 mg of Eudragit .RTM. RS 30D dry substance.
[0082] The tablets of Example 3 are then tested for dissolution via
the USP Basket Method at 37.degree. C., 100 RPM, first hour 700 ml
simulated gastric fluid at pH 1.2, then changed to 900 ml at pH
7.5. The results are set forth in Table 6 below:
6TABLE 6 Dissolution of Oxycodone 10 mg Controlled Release Tablets
Hour % Oxycodone Dissolved 1 38.0 2 47.5 4 62.0 8 79.8 12 91.1 18
94.9 24 98.7
[0083] The formula for the tablets of Example 4 is set forth in
Table 7 below:
7TABLE 7 Formula of Controlled Release Oxycodone 20 mg Tablets
Component Mg/Tablet Oxycodone Hydrochloride 20.0 Lactose (spray
dried) 59.25 Povidone 5.0 Eudragit .RTM. RS 30D (solids) 10.0*
Triacetin .RTM. 2.0 Stearyl Alcohol 25.0 Talc 2.5 Magnesium
Stearate 1.25 Total 125.0
[0084] The tablets of Example 4 are then tested for dissolution via
the USP Basket Method at 37.degree. C., 100 RPM, first hour 700 ml
simulated gastric fluid at pH 1.2, then changed to 900 ml at pH
7.5. The results are set forth in Table 8 below:
8TABLE 8 Dissolution of Oxycodone 20 mg Controlled Release Tablets
Hour % Oxycodone Dissolved 1 31 2 44 4 57 8 71 12 79 18 86 24
89
EXAMPLES 5-6
[0085] In Example 5, 30 mg controlled release oxycodone
hydrochloride tablets are prepared according to the process set
forth in Example 1.
[0086] In Example 6, 10 mg controlled release oxycodone
hydrochloride tablets are prepared according to the process set
forth in Example 2.
[0087] Thereafter, dissolution studies of the tablets of Examples 5
and 6 are conducted at different pH levels, namely, pH 1.3, 4.56,
6.88 and 7.5.
[0088] The results are provided in Tables 9 and 10 below:
9TABLE 9 Example 5 Percentage Oxycodone HCl 30 mg Tablets Dissolved
Over Time pH 1 2 4 8 12 18 24 1.3 29.5 43.7 61.8 78.9 91.0 97.0
97.1 4.56 34.4 49.1 66.4 82.0 95.6 99.4 101.1 6.88 33.8 47.1 64.4
81.9 92.8 100.5 105.0 7.5 27.0 38.6 53.5 70.0 81.8 89.7 96.6
[0089]
10TABLE 10 Example 6 Percentage Oxycodone HCl - 10 mg Tablets
Dissolved Over Time pH 1 2 4 8 12 18 24 1.3 25.9 41.5 58.5 73.5
85.3 90.7 94.2 4.56 37.8 44.2 59.4 78.6 88.2 91.2 93.7 6.88 34.7
45.2 60.0 75.5 81.4 90.3 93.9 7.5 33.2 40.1 51.5 66.3 75.2 81.7
86.8
EXAMPLES 7-12
[0090] In Examples 7-12, 4 mg and 10 mg oxycodone HCl tablets were
prepared according to the formulations and methods set forth in the
assignee's U.S. Pat. No. 4,990,341.
[0091] In Example 7, oxycodone hydrochloride (10.00 gm) was wet
granulated with lactose monohydrate (417.5 gm) and hydroxyethyl
cellulose (100.00 gm), and the granules were sieved through a 12
mesh screen. The granules were then dried in a fluid bed dryer at
50.degree. C. and sieved through a 16 mesh screen.
[0092] Molten cetostearyl alcohol (300.0 gm) was added to the
warmed oxycodone containing granules, and the whole was mixed
thoroughly. The mixture was allowed to cool in the air,
regranulated and sieved through a 16 mesh screen.
[0093] Purified Talc (15.0 gm) and magnesium stearate (7.5 gm) were
then added and mixed with the granules. The granules were then
compressed into tablets.
[0094] Example 8 is prepared in the same manner as Example 7;
however, the formulation includes 10 mg oxycodone HCl/tablet. The
formulas for Examples 7 and 8 are set forth in Tables 11 and 12,
respectively.
Table 11
Formulation of Example 7
[0095]
11TABLE 11 Formulation of Example 7 Ingredient mg/tablet g/batch
Oxycodone hydrochloride 4.0 10.0 Lactose monohydrate 167.0 417.5
Hydroxyethylcellulose 40.0 100.0 Cetostearyl alcohol 120.0 300.0
Purified talc 6.0 15.0 Magnesium stearate 3.0 7.5
Table 12
Formulation of Example 8
[0096]
12TABLE 12 Formulation of Example 8 Ingredient mg/tablet g/batch
Oxycodone hydrochloride 10.0 25.0 Lactose monohydrate 167.0 417.5
Hydroxyethylcellulose 40.0 100.0 Cetostearyl alcohol 120.0 300.0
Purified talc 6.0 15.0 Magnesium stearate 3.0 7.5
[0097] In Example 9, 4 mg oxycodone HCl controlled release tablets
are prepared according to the excipient formula cited in Example 2
of U.S. Pat. No. 4,990,341. The method of manufacture is the same
as set forth in Examples 7 and 8 above. Example 10 is prepared
according to Example 9, except that 10 mg oxycodone HCl is included
per tablet. The formulas for Examples 9 and 10 are set forth in
Tables 13 and 14, respectively.
13TABLE 13 Formulation of Example 9 Ingredient mg/tablet g/batch
Oxycodone hydrochloride 4.0 10.0 Anhydrous Lactose 167.0 417.5
Hydroxyethylcellulose 30.0 75.0 Cetostearyl alcohol 90.0 225.0 Talc
6.0 15.0 Magnesium stearate 3.0 7.5
[0098]
14TABLE 14 Formulation of Example 14 Ingredient mg/tablet g/batch
Oxycodone hydrochloride 10.0 25.0 Anhydrous lactose 167.0 417.5
Hydroxyethylcellulose 30.0 75.0 Cetostearyl alcohol 90.0 225.0 Talc
6.0 15.0 Magnesium stearate 3.0 7.5
[0099] In Example 11, oxycodone 4 mg controlled release tablets are
prepared with the same excipient formula cited in Example 3 of U.S.
Pat. No. 4,990,341.
[0100] Oxycodone hydrochloride (32.0 gm) was wet granulated with
lactose monohydrate (240.0 gm) hydroxyethyl cellulose (80.0 gm) and
methacrylic acid copolymer (240.0 gm, Eudragit.RTM. L-100-55), and
the granules were sieved through a 12 mesh screen. The granules
were then dried in a Fluid Bed Dryer at 50.degree. C. and passed
through a 16 mesh screen.
[0101] The warmed oxycodone containing granules was added molten
cetostearyl alcohol (240.0 gm), and the whole was mixed thoroughly.
The mixture was allowed to cool in the air, regranulated and sieved
through a 16 mesh screen. The granules were then compressed into
tablets.
[0102] Example 12 is prepared in identical fashion to Example 11,
except that 10 mg oxycodone HCl is included per tablet. The
formulations for Examples 11 and 12 are set forth in Tables 15 and
16, respectively.
15TABLE 15 Formulation of Example 11 Ingredient mg/tablet g/batch
Oxycodone hydrochloride 4.0 32.0 Lactose monohydrate 30.0 240.5
Hydroxyethylcellulose 10.0 80.0 Methacrylic acid copolymer 30.0
240.0 Cetostearyl alcohol 30.0 240.0
[0103]
16TABLE 16 Formulation of Example 12 Ingredient mg/tablet g/batch
Oxycodone hydrochloride 10.0 80.0 Lactose monohydrate 30.0 240.5
Hydroxyethylcellulose 10.0 80.0 Methacrylic acid copolymer 30.0
240.0 Cetostearyl alcohol 30.0 240.0
[0104] Next, dissolution studies were conducted on the tablets of
Examples 7-12 using the USP basket method as described in the U.S.
Pharmacopoeia XXII (1990). The speed was 100 rpm, the medium was
simulated gastric fluid for the first hour followed by simulated
intestinal fluid thereafter, at a temperature of 37.degree. C.
Results are given in Table 17.
17TABLE 17 DISSOLUTION STUDIES OF EXAMPLES 7-12 Time % Oxycodone
Dissolved (hrs) Ex. 7 Ex. 8 Ex. 9 Ex. 10 Ex. 11 Ex. 12 1 23.3 25.5
28.1 29.3 31.3 40.9 2 35.6 37.5 41.5 43.2 44.9 55.6 4 52.9 56.4
61.2 63.6 62.1 74.2 8 75.3 79.2 83.7 88.0 82.0 93.9 12 90.7 94.5
95.2 100.0 91.4 100.0
EXAMPLES 13-16
Clinical Studies
[0105] In Examples 13-16, randomized crossover bioavailability
studies were conducted employing the formulation of Examples 2
(organic manufacture) and 3 (aqueous manufacture).
[0106] In Example 13, a single dose fast/fed study was conducted on
24 subjects with oxycodone tablets prepared according to Example
3.
[0107] In Example 14, a steady-state study was conducted on 23
subjects after 12 hours with oxycodone tablets prepared according
to Example 2, and compared to a 5 mg oxycodone immediate-release
solution.
[0108] In Example 15, a single dose study was conducted on 22
subjects using oxycodone tablets prepared according to Example 3,
and compared to a 20 mg oxycodone immediate release solution.
[0109] In Example 16, a 12 subject single-dose study was conducted
using 3.times.10 mg oxycodone tablets prepared according to Example
3, and compared to a 30 mg oxycodone immediate release
solution.
[0110] The results of Examples 13-16 are set forth in Table 18.
18TABLE 18 AUC Cmax Tmax Example Dosage ng/ml/hr ng/ml hr 13 10 mg
CR Fast 63 6.1 3.8 10 mg CR Fed 68 7.1 3.6 14 5 mg IR q6h 121 17
1.2 10 mg CR q12h 130 17 3.2 15 20 mg IR 188 40 1.4 2 .times. 10 mg
CR 197 18 2.6 16 30 mg IR 306 53 1.2 3 .times. 10 mg CR 350 35 2.6
30 mg CR 352 36 2.9 IR denotes immediate-release oxycodone
solution. CR denotes controlled-release tablets
EXAMPLE 17
Clinical Studies
[0111] In Example 17, a single dose, double blind, randomized study
determined the relative analgesic efficacy, the acceptability, and
relative duration of action of an oral administration of controlled
release oxycodone 10, 20 and 30 mg prepared according to the
present invention (CR OXY) compared to immediate release oxycodone
15 mg (IR OXY), immediate release oxycodone 10 mg in combination
with acetaminophen 650 mg (IR OXY/APAP) and placebo in 180 patients
with moderate or severe pain following abdominal or gynecological
surgery. Patients rated their pain intensity and pain relief hourly
for up to 12 hours postdosing. Treatments were compared using
standard scales for pain intensity and relief, and onset and
duration of pain relief.
[0112] All active treatments were significantly superior to placebo
for many of the hourly measures, and for sum pain intensity
differences (SPID) and total pain relief (TOTPAR). A dose response
was seen among the 3 dose levels of CR OXY for pain relief and peak
pain intensity difference (PID), with CR OXY 20 mg and 30 mg being
significantly better than the 10 mg dose. IR OXY was significantly
superior to CR OXY 10 mg at hr 1 and 2. IR OXY/APAP was
significantly superior to the 3 doses of CR OXY at hr 1, and to CR
OXY 10 mg at hrs 2 through 5. Onset time was significantly shorter
for the IR OXY and IR OXY/APAP treatment groups in comparison to
the 3 CR OXY treatments. The distribution functions for duration of
relief revealed significantly longer duration of relief for the
three CR OXY doses than for IR OXY and IR OXY/APAP. No serious
adverse experiences were reported. The results are more
particularly reported in Table.19 below.
19TABLE 19 PATIENT DISPOSITION TREATMENT GROUP IR OXY CR OXY 15 mg
PLACEBO 10 mg 20 mg 30 mg 2 PERC* TOTAL Enrolled and 31 31 30 30 30
30 182 Randomized to Study Treatment Entered the 31 31 30 30 30 30
182 Study Treat- ment Phase Completed 31 30 30 30 30 30 181 the
Study Discontinued 0 1 0 0 0 0 1 from the Study Excluded from 0 1 0
0 0 0 1 Efficacy Analysis Vomited prior to 1 hr post dose
Inadvertently 1 0 0 0 0 0 1 received rescue during study Analysis
30 30 30 30 30 30 180 Population: Evaluable for Safety and Efficacy
Evaluable for 31 31 30 30 30 30 182 Safety *2 tablets of Percocet
.RTM.
[0113] The time-effect curves for pain intensity, pain intensity
differences and pain relief are shown in FIGS. 1-4. CR OXY 10 mg
had significantly (p<0.05) lower pain intensity scores than the
placebo-treated patients at hours 3-11 and lower pain scores than
IR OXY 15 mg and Percocet.RTM. at hour 10. CR OXY 20 mg has
significantly (p<0.05) lower pain intensity scores compared to
placebo at hours 2-11 and significantly (p<0.05) lower pain
scores than CR OXY 10 mg, IR OXY 15 mg and Percocet at hours 9-11.
CR OXY 30 mg had significantly (p<0.05) lower pain scores than
placebo at hours 2-11 and lower pain scores than CR OXY 10 mg at
hours 2, 3, and 5 and lower scores than Percocet.RTM. at hour
10.
[0114] For hourly pain relief scores categorical and visual analog
scales (CAT and VAS), CR OXY 10 mg had significantly (p<0.05)
higher pain relief scores than placebo at hours 3-11 and higher
relief scores than IR OXY and Percocet.RTM. at hour 10 (and
Percocet.RTM. at hour 11). CR OXY 20 mg had significantly
(p<0.05) higher relief scores than placebo at hours 2-12 and
higher relief scores than Percocet.RTM. at hours 9-12. In addition,
CR OXY had significantly (p<0.05) higher pain relief than IR OXY
at hours 10-12. CR OXY 30 mg had significantly (p<0.05) higher
pain relief scores than placebo at hours 2-12 and higher scores
than Percocet.RTM. at hours 9-12 and IR OXY 15 mg at hour 10.
[0115] Each treatment group was significantly (p<0.05) better
than placebo with respect to the sum of the pain intensity
differences (SPID) and total pain relief (TOTPAR).
[0116] Duration of pain relief as measured by the patient stopwatch
method showed that CR OXY 10 mg, 20 mg and 30 mg had significantly
(p<0.05) longer duration of action compared to IR OXY 15 mg and
2 tablets Percocet.RTM.. In addition, the three controlled-release
formulations had significantly (p<0.05) longer times to
remedication, compared to Percocet.RTM..
[0117] Before remedication, a total of 104 (57%) of patients
reported 120 adverse experiences. The most common were somnolence,
fever, dizziness and headache.
[0118] Based upon the results of this study it is concluded that
the controlled release oxycodone formulations of the present
invention relieve moderate to severe post-operative pain, e.g., due
to abdominal or gynecological surgery in women. There is a dose
response noted in which placebo < 10 mg < 20 mg < 30 mg CR
OXY following a single dose. Onset of action occurred in one hour
with peak effects noted from 2 to 5 hours and a duration of effect
from 10 to 12 hours. In the chronic pain situation steady state
dosing may prolong this effect., Side effects are expected and
easily managed. Headache may be related to dose. Dizziness and
somnolence were reported.
[0119] IR OXY 15 mg has an intermediate peak effect compared to
controlled release oxycodone. Its duration of action is shorter
(6-8 hours). Percocet.RTM. is quite effective in terms of onset,
peak effect and safety. The duration of action is 6-8 hours.
[0120] In summary, CR OXY was clearly an effective oral analgesic,
with a slower onset but a longer duration of effect than either IR
OXY or IR OXY/APAP.
EXAMPLE 18
Clinical Studies
[0121] In Example 18, a steady state crossover trial was conducted
in 21 normal male subjects comparing
[0122] a. CR OXY 10 mg administered every 12 hours (q12h); and
[0123] b. Roxicodone.RTM. oral solution 5 mg (ROX) administered
every 6 hours (q6h),
[0124] Treatment (b) was the study reference standard. The average
age was 34 years, height 176 cm and weight 75 kg. No unusual
features were noted about the group.
[0125] FIG. 5 shows the mean plasma oxycodone concentrations for
the two formulations over the 12 hour dosing interval. The results
are summarized in Table 18 in terms of mean values, ratios of mean
values and 90% confidence intervals.
[0126] As inspection of Table 18 reveals, with one exception, no
significant differences were detected between the two formulations.
The single exception is the mean t.sub.max for CR OXY of 3.18 hours
which, as expected for a controlled release formulation,
significantly exceeded the ROX mean of 1.38 hours. Mean AUC-based
bioavailability, (ROX=100%)-was 104.4% with 90% confidence limits
of 90.9 to 117.9%. Thus, the FDA specification of .+-.20% is met so
that the study results support an assertion of equal oxycodone
availability.
20TABLE 20 SUMMARY OF PHARMACOKINETIC PARAMETERS FOR OXYCODONE
FOLLOWING A SINGLE DOSE OF CR OXY (10 mg q12H) AND ROXICODONE .RTM.
ORAL SOLUTION (5 mg g6h) ROXI- OXY/ CODONE ROXI 90% PARAMETERS CR
OXY SOLUTION (%) CI* C.sub.max (ng/mL) 15.11 (4.69) 15.57 (4.41)
97.08 85.59- ARITH. MEAN 108.50 (SD) GEOMETRIC 14.43 15.01 95.14
MEAN C.sub.min (ng/mL) 6.24 (2.64) 6.47 (3.07) 96.41 80.15- ARITH.
MEAN 112.74 (SD) GEOMETRIC 5.62 5.83 96.48 MEAN t.sub.max (hrs)
3.18 (2.21) 1.38 (0.71)* 230.17 160.71- ARITH. MEAN 298.71 (SD) AUC
(0-12 hrs) 103.50 (40.03) 99.10 (35.04) 104.44 90.92- ARITH. MEAN
117.94 (SD) GEOMETRIC 97.06 93.97 103.29 MEAN % Swing 176.36
(139.0) 179.0 (124.25) 98.53 62.06- ARITH. MEAN 134.92 (SD) %
Fluctuation 108.69 (38.77) 117.75 (52.47) 92.22 76.81- ARITH. MEAN
107.57 End Point -1.86 (2.78) -1.86 (2.19) 99.97 117.77- ARITH.
MEAN 22.23 (SD) *90% Confidence Interval -Significant Difference p
< 0.05
EXAMPLE 19
Clinical Studies
[0127] In Example 19, twenty-four normal, healthy male subjects
were enrolled in a randomized single-dose two-way crossover study
to compare the plasma oxycodone concentrations obtained after
dosing with two controlled-release oxycodone 10 mg tablets versus
20 mg (20 ml of 5 mg/5 ml) of immediate release (IR) oxycodone
hydrochloride solution. Twenty-three subjects completed the study
and were eligible for analysis.
[0128] Plasma oxycodone concentrations were determined by a high
performance liquid chromatographic procedure. Arithmetic Mean
C.sub.max, t.sub.max, AUC, and half-lives calculated from
individual plasma oxycodone concentration-versus-time data are set
forth in Table 21:
21TABLE 21 Reference Test Pharmaco- Product Product 90% kinetic IR
Oxycodone CR Oxycodone Confidence Parameter 20 mg 2 .times. 10 mg
F. (%) Interval C.sub.max 41.60 18.62 44.75 32.5- (ng/ml) 57.0
t.sub.max 1.30 2.62 200.83 169.8- (hours) 232.6 AUC 194.35 199.62
102.71 89.5- (0-36) 115.9 (mg .times. hr/ml) AUC 194.38 208.93
107.49 92.9- (0-.infin.) 121.9 t.sub.1/2(elim) 3.21 7.98* 249.15
219.0- (hrs) 278.8 t.sub.1/4(abs) 0.35 0.92* 264.17 216.0- (hrs)
310.7 F. % = Oral bioavailability (CR oxycodone 2 .times. 10 mg/IR
oxycodone 20 mg) *Statistically significant (p = 0.0001)
[0129] For C.sub.max, t.sub.max, t.sub.1/2(elim) and t.sub.1/2(abs)
there were statistically significant differences between the CR OXY
and IR OXY. There were no statistically significant differences
between the two treatments in the extent of absorption [AUC (0,36),
AUC (0,.infin.). The 90% confidence interval for CR OXY relative to
IR OXY relative was 89.5%-115.9% for AUC (0,36) and 92.9% - 121.9%
for AUC (0,.infin.). Based on the 90% confidence interval analysis,
the controlled-release oxycodone tablets were equivalent in extent
of absorption (AUC 0,36) to the immediate-release oxycodone
solution. The controlled-release oxycodone absorption was slower by
approximately 1.3 hours. No statistically significant differences
were noted between the two treatments with reference to adverse
experiences, none of which were considered clinically unusual for
opiates for this type of study.
[0130] The above studies demonstrate a significant dose-response
relationship utilizing the controlled release oxycodone
formulations of the present invention at dosages of 10, 20 and 30
mg which does not deviate from parallelism with dose-response
slopes for MS Contin in similarly designed well-controlled
analgesic efficacy studies of MS Contin reported by Kaiko R. S.,
Van Wagoner D., Brown J., et al., "Controlled-Release Oral Morphine
(MS Contin.RTM. Tablets, MSC) in Postoperative Pain.", Pain Suppl.,
5:S149 1990, who compared 30, 60, 90, and 120 mg of MS Contin as
compared with 10 mg of intramuscular morphine and placebo and
Bloomfield, et al., "Analgesic Efficacy and Potency of Two Oral
Controlled-Release Morphine Preparations", Clinical Pharmacology
& Therapeutics, (in press), who compared 30 and 90 mg of MS
Contin as compared to 30 and 90 mg of another controlled-release
oral morphine preparation, Oramorph SR 30 mg tablets.
[0131] 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.
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