U.S. patent application number 11/814020 was filed with the patent office on 2008-08-21 for use of oxycodone for treating visceral pain.
This patent application is currently assigned to EURO-CELTIQUE S.A.. Invention is credited to Asbjorn Mohr Drewes, Lars Arendt Nielsen.
Application Number | 20080200493 11/814020 |
Document ID | / |
Family ID | 35871217 |
Filed Date | 2008-08-21 |
United States Patent
Application |
20080200493 |
Kind Code |
A1 |
Drewes; Asbjorn Mohr ; et
al. |
August 21, 2008 |
Use of Oxycodone for Treating Visceral Pain
Abstract
It is possible to effectively treat moderate to severe visceral
pain by administering analgesic medications comprising the opioid
oxycodone or pharmaceutically acceptable salts thereof. Visceral
pain and especially acute (i.e. non-chronic) visceral pain can be
effectively treated by administering oxycodone at a dosage which is
lower than the corresponding dosage of other opioids like
morphine.
Inventors: |
Drewes; Asbjorn Mohr;
(Silkenborg, DK) ; Nielsen; Lars Arendt; (Aalborg,
DK) |
Correspondence
Address: |
DARBY & DARBY P.C.
P.O. BOX 770, Church Street Station
New York
NY
10008-0770
US
|
Assignee: |
EURO-CELTIQUE S.A.
De La Petrusse
LU
|
Family ID: |
35871217 |
Appl. No.: |
11/814020 |
Filed: |
January 17, 2006 |
PCT Filed: |
January 17, 2006 |
PCT NO: |
PCT/EP2006/050252 |
371 Date: |
May 2, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60645490 |
Jan 18, 2005 |
|
|
|
Current U.S.
Class: |
514/282 |
Current CPC
Class: |
A61K 9/0095 20130101;
A61P 29/00 20180101; A61P 25/00 20180101; A61K 31/485 20130101;
A61P 25/04 20180101 |
Class at
Publication: |
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61P 25/00 20060101 A61P025/00 |
Claims
1-20. (canceled)
21. A method of treating visceral pain in a patient, which method
comprises the administration of an effective amount of oxycodone or
a pharmaceutically acceptable salt thereof.
22. Method according to claim 21, for the treatment of acute
visceral pain.
23. Method according to claim 21, for the selective treatment of
visceral pain.
24. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in an oral
dosage form.
25. Method according to claim 21, for the treatment of pancreatitis
pain, labor pain, pain from abdominal surgery associated with
ileus, pain in irritable bowel syndrome, abdominal pain in nonulcer
dyspepsia or in dysmenorrhea, liver pain, kidney pain, epigastric
pain pleural pain, painful biliary colic or appendicitis pain.
26. Method according to claim 21, wherein the visceral pain results
from diseases of the stomach, dudenum or colon, from Crohn's
disease, from pain of the gall bladder, severe menstruational pain,
or corresponding post operative pain conditions.
27. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in a
once-a-day, twice-a-day, three-times-a-day, or four-times-a-day
dosage form.
28. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in a
twice-a-day dosage form at an amount of about 5 mg.
29. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in a
once-a-day dosage form at an amount of about 10 mg.
30. Method according to claim 21, wherein the medicament is a
three-times-a-day dosage form containing oxycodone or a
pharmaceutically acceptable salt thereof at an amount of about 5
mg.
31. Method according, to claim 21, wherein the medicament is a
four-times-a-day dosage form containing oxycodone or a
pharmaceutically acceptable salt thereof at an amount of about 5
mg.
32. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in a
sustained release dosage form containing not more than 40 mg
oxycodone or a pharmaceutically acceptable salt thereof, preferably
not more than 30 mg oxycodone or a pharmaceutically acceptable salt
thereof and even more preferably not more than 10 mg oxycodone or
pharmaceutically acceptable salt thereof.
33. Method according to claim 21, wherein the medicament is a
single-entity formulation.
34. Method according claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in an oral
dosage form containing oxycodone or a pharmaceutically acceptable
salt thereof at a dosage which is lower than the corresponding
dosage of morphine required for providing the same therapeutic
effect.
35. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is orally administered at
a dosage which provides a significantly better effect than the
orally equipotent dosage of morphine wherein the equipotency refers
to the treatment of cutaneous and muscular pain.
36. Method according to claim 21, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is orally administered at
a dosage which is lower than the equipotent dosage of oral
morphine, wherein the equipotency refers to the treatment of
cutaneous and muscular pain.
37. Method according to claim 36 wherein the ratio of the dosage of
oxycodone to the dosage of morphine is less than 1:2, preferably
less than 1:2.5, more preferably less than 1:3 and most preferably
less than 1:4.
38. Method according to claim 2, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is contained in an oral
controlled release dosage form to control visceral pain in human
patients, the dosage form comprising: a) from 5 mg to 80 mg
oxycodone or a salt thereof; b) an effective amount of a controlled
release acrylic resin matrix, said acrylic resin matrix being
selected so that the formulation provides substantially
pH-independent in-vitro dissolution characteristics; c) a
pharmaceutical diluent.
39. A method of treating moderate to severe visceral pain in a
patient already being treated with morphine or a salt thereof, the
method comprising: (a) discontinuing treatment with morphine; and
(b) administering oxycodone or a salt thereof in an amount of less
than 50% by weight of the morphine or salt thereof.
40. Method according to claim 39, wherein the oxycodone or a
pharmaceutically acceptable salt thereof is orally administered in
amount of less than 45% by weight of the morphine or salt thereof,
preferably less than 40% by weight, more preferably less than 35%
by weight, even more preferably less than 30% by weight and most
preferred 25% by weight of the morphine or salt thereof.
41. A method of treating moderate to severe visceral pain in a
patient already being treated with hydromorphone, oxymorphone,
codeine, hydrocodone or salts thereof, the method comprising: (a)
discontinuing treatment with hydromorphone, oxymorphone, codeine,
hydrocodone or salts thereof; and (b) administering oxycodone or a
salt thereof in an amount of less than the equipment weight of the
hydromorphone, oxymorphone, codeine, hydrocodone or salts
thereof.
42. A method of treating moderate to severe visceral pain in a
patient, the method comprising: (a) administering to a human
patient a unit dose containing oxycodone or a salt thereof in an
amount of 5 mg; (b) monitoring pharmacodynamic parameters elicited
by said unit dose in said human patient and determine whether said
pharmacodynamic parameters are appropriate for treatment of said
patient on a repeated basis; (c) titrating the patient adjusting
the dose of oxycodone or a salt thereof administered to the patient
by administering a unit dose of oxycodone or a salt thereof with a
different amount of oxycodone or a salt thereof if it is determined
that said pharmacodynamic parameters are not satisfactory or
maintaining the dose of oxycodone or a salt thereof in said unit
dose at a previously adminstered amount if said pharmacodynamic
parameters are deemed appropriate; (d) continuing the step (c)
titration by adjusting the dose of oxycodone or a salt thereof
until appropriate steady-state pharmacodynamic parameters are
achieved in said patient, and (e) continuing the administration of
the dose of oxycodone or a salt thereof until treatment is
terminated.
43. Method according to claim 42, wherein the patient is titrated
with a unit dose containing oxycodone or a salt thereof in an
amount of 5 mg to 10 mg.
Description
[0001] The present invention refers to the treatment of visceral
pain.
[0002] There is a continuing need for analgesic medications which
are suitable for effectively treating visceral pain and especially
acute visceral pain. Deep pain from the internal organs is a common
cause of visits to doctors and long-term sick leave in the western
world. The causes for visceral pain can be sought in both organic
and functional conditions, but what is common to these is that
there is complex activation of the nervous system. In many cases,
the visceral pain persists despite the original cause having been
wholly or partially eliminated. In many cases morphine is currently
used for the treatment of moderate to severe visceral pain.
[0003] There is also a continuing need for analgesic medications
able to provide high efficacy pain relief while reducing the
possibility of undesirable effects. Accordingly, it is most
desirable to have analgesic medications which provide high efficacy
pain relief at low dosages in order to avoid or at least reduce
undesirable effects and especially side-effects observed at higher
dosages or for certain specific analgesics.
[0004] Although opioids are prescribed with increasing frequency,
knowledge of their effect on visceral pain is limited. However, it
is known that, in addition to analgesic effects, morphine may also
cause a number of undesirable effects, including, for example,
respiratory depression, nausea, vomiting, dizziness, mental
clouding, dysphoria, pruritus, constipation, increased biliary
tract pressure, urinary retention and hypotension.
[0005] The effect of certain active agents on patients is highly
variable. Visceral pain differs from pain in the skin in many ways
and is often more difficult to treat. In the literature different
types of pain associated with disease of the viscera are suggested.
These types comprise true or localized visceral pain, referred
visceral pain, localized parietal pain, and referred parietal pain.
The present invention especially refers to the treatment of true or
localized visceral pain.
[0006] True visceral pain often occurs early in the disease and is
characterized by a vague, diffuse, dull, aching pain, which is
localized but can have a tendency to radiate. It can be accompanied
by a feeling of malaise, and, when severe, it induces strong
autonomic phenomena such as sweating, vasomotor responses,
bradycardia, nausea and vomiting, and sometimes an alarm reaction.
It is usually felt in the midline and deep in the body.
[0007] There are a variety of conditions in which visceral pain may
exist. For example, pancreatitis pain, labor pain, pain from
abdominal surgery associated with ileus, pain in irritable bowel
syndrome, abdominal pain in nonulcer dyspepsia, or in dysmenorrhea.
Likewise, liver pain, kidney pain, epigastric pain, pleural pain,
and painful biliary colic, appendicitis pain may all be considered
to be visceral pain. Substernal pain or pressure from early
myocardial infarction is also visceral. Diseases of the stomach,
dudenum or colon can cause visceral pain. And there are more.
[0008] According to an embodiment of the present invention it has
been found that it is possible to effectively treat moderate to
severe visceral pain by administering analgesic medications
comprising the opioid oxycodone or pharmaceutically acceptable
salts thereof. Moreover, it has been found that visceral pain and
especially acute (i.e. non-chronic) visceral pain can be
effectively treated by administering oxycodone at a dosage which is
lower than the corresponding dosage of other opioids like morphine.
Accordingly, the present invention inter alia refers to a method of
effectively treating moderate to severe visceral pain by
administering oxycodone at relatively low dosages.
[0009] According to an embodiment of the present invention it has
been found that treating visceral pain with a specific dosage of
oxycodone is more effective than treating the same visceral pain
with a higher corresponding dosage of morphine, whereas almost the
same effect is observed if cutaneous or muscular pain is treated by
administering corresponding dosages of oxycodone or morphine. In
other words, according to the present invention it has been found
that visceral pain and especially acute moderate to severe visceral
pain can be effectively treated by administering oxycodone at
relatively low dosages, whereas the "corresponding dosage" of
morphine would be less effective in treating the same visceral
pain. According to the present invention the "corresponding dosage"
of morphine does not mean the same quantitative amount of morphine,
but refers to the usual equipotent amount of morphine, i.e. to the
amount of morphine which usually provides a similar pain relief to
the patient. The usual equipotent weight ratio of morphine to
oxycodone for oral administration is about 2:1 (the corresponding
molar ratio is about 1.8:1).
[0010] According to another embodiment of the invention a method of
selectively treating moderate to severe visceral pain in a patient
is provided, the method comprising administering oxycodone in an
effective amount to provide analgesia in the patient in need
thereof. The present invention for the first time allows for the
selective treatment of moderate to severe visceral pain, since it
was not known prior to the present invention that this specific
pain can be effectively treated by administering oxycodone at low
dosages, whereas other opioids (like morphine) at dosages, which
would have been considered equipotent by the skilled person, are
less effective. Patients suffering exclusively from acute visceral
pain, according to the present invention would not or no longer be
treated with the opioids commonly used for this purpose (like
morphine, hydromorphone, oxymorphone, codeine, and hydrocodone) but
with oxycodone. Accordingly, the present invention opens a new
therapeutic window for the opioid oxycodone.
[0011] According to another embodiment of the invention a method of
treating moderate to severe visceral pain in a patient already
being treated with morphine or a salt thereof is provided, the
method comprising:
(a) discontinuing treatment with morphine; and (b) administering
oxycodone or a salt thereof in an amount of less than 50% by weight
of the morphine or salt thereof.
[0012] According to another embodiment of the invention a method of
treating moderate to severe visceral pain in a patient already
being treated with hydromorphone, oxymorphone, codeine, hydrocodone
or salts thereof is provided, the method comprising:
(a) discontinuing treatment with hydromorphone, oxymorphone,
codeine, hydrocodone or salts thereof; and (b) administering
oxycodone or a salt thereof in an amount of less than the
equipotent weight of the hydromorphone, oxymorphone, codeine,
hydrocodone or salts thereof.
[0013] An embodiment of the present invention also allows the
treatment of acute visceral pain by administering oxycodone at a
dosage which is sufficiently low in order to reduce or avoid
undesired side effects. This means, that therapeutic levels can be
achieved without or with fewer concurrent side effects, such as
nausea, vomiting, constipation and drowsiness, which may be
associated with high blood levels of oxycodone.
[0014] The finding that visceral pain can be effectively treated by
administering low dosages of oxycodone allows for the use of
immediate release formulations and sustained release formulations.
It may be preferred according to the present invention to treat
visceral pain and especially acute visceral pain by administering
oxycodone-containing once-a-day, twice-a-day, three-times-a-day, or
four-times-a-day dosage forms. According to the present invention
it may be especially preferred to use oxycodone-containing
sustained release formulations, wherein the dosage does not exceed
40 mg oxycodone, preferably does not exceed 30 mg oxycodone and
even more preferably does not exceed 10 mg oxycodone. According to
the present invention it may be most preferred to use
oxycodone-containing sustained release formulations and preferably
once-a-day, twice-a-day, three-times-a-day, or four-times-a-day
dosage forms comprising about 10 mg, about 9 mg, about 8 mg, about
7 mg, about 6 mg or about 5 mg oxycodone. It is also preferred in
certain embodiments to use single-entity oxycodone or salts
thereof, e.g., oxycodone or salts thereof without APAPs or other
active agents.
[0015] The present invention relates to the treatment of visceral
pain including pancreatitis pain, labor pain, pain from abdominal
surgery associated with ileus, pain in irritable bowel syndrome,
abdominal pain in nonulcer dyspepsia, or in dysmenorrhea, liver
pain, kidney pain, epigastric pain, pleural pain, and painful
biliary colic and appendicitis pain by administering analgesic
medications comprising the oxycodone alone or in combination with
other active agents and especially other analgesics. Furthermore,
the present invention refers to the treatment of visceral pain
resulting from diseases of the stomach, dudenum or colon, from
Crohn's disease, pain of the gall bladder, severe menstruational
pain, and certain post operative pain conditions. The present
invention also relates to the treatment of moderate, moderately
severe, and/or severe visceral pain.
[0016] The dosage form to be used for treating visceral pain
according to the present invention preferably is an oral dosage
form like a tablet or capsule, but could also be a suppository or
any other solid or liquid dosage form which can be administered
orally, via implant, parenterally, sublingually or rectally.
Preferably, the formulation in accordance with the present
invention is an oral tablet, capsule, or in any other suitable oral
unit dosage form.
[0017] According to the present invention, visceral pain can be
treated by administering oxycodone or a pharmaceutically acceptable
salt thereof. The phrase "pharmaceutically acceptable salt"
includes, but is not limited to, metal salts such as sodium salt,
potassium salt, cesium salt and the like; alkaline earth metals
such as calcium salt, magnesium salt and the like; organic amine
salts such as triethylamine salt, pyridine salt, picoline salt,
ethanolamine salt, triethanolamine salt, dicyclohexylamine salt,
N,N'-dibenzylethylenediamine salt and the like; inorganic acid
salts such as hydrochloride, hydrobromide, sulfate, phosphate and
the like; organic acid salts such as formate, acetate,
trifluoroacetate, maleate, fumarate, tartrate and the like;
sulfonates such as methanesulfonate, benzenesulfonate,
p-toluenesulfonate, and the like; amino acid salts such as
arginate, asparginate, glutamate and the like.
[0018] The Oxycodone-containing formulations which are suitable for
treating visceral pain according to the present invention can be
immediate release formulations or sustained release formulations.
It may be preferred to use sustained release formulations for
treating visceral pain and it may be especially advantageous to
administer once-a-day, twice-a-day, three-times-a-day, or
four-times-a-day dosage forms comprising oxycodone.
[0019] In certain embodiments such oral dosage form includes a
sustained-release material which is incorporated into a matrix
along with the oxycodone or pharmaceutically acceptable salt
thereof to provide for the sustained release of the oxycodone. The
sustained-release material may be hydrophobic or hydrophilic as
desired. The oral dosage form may be prepared as granules,
spheroids, matrix multiparticulates, etc. which comprise oxycodone
or a pharmaceutically acceptable salt thereof in a sustained
release matrix, which may be compressed into a tablet or
encapsulated. The oral dosage form may optionally include other
pharmaceutically acceptable ingredients (e.g., diluents, binders,
colorants, lubricants, etc.).
[0020] A non-limiting list of suitable sustained-release materials
which may be included in a sustained-release matrix of a dosage
form which may be used for treating visceral pain according to the
present invention include hydrophilic and/or hydrophobic materials,
such as gums, cellulose ethers, acrylic resins, protein derived
materials, waxes, shellac, and oils such as hydrogenated castor oil
and hydrogenated vegetable oil. However, any pharmaceutically
acceptable hydrophobic or hydrophilic sustained-release material
which is capable of imparting sustained-release of the oxycodone or
pharmaceutically acceptable salt thereof may be used in accordance
with the present invention. Preferred sustained-release polymers
include alkylcelluloses such as ethylcellulose, acrylic and
methacrylic acid polymers and copolymers; and cellulose ethers,
especially hydroxyalkylcelluloses (especially
hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred
acrylic and methacrylic acid polymers and copolymers include methyl
methacrylate, methyl methacrylate copolymers, ethoxyethyl
methacrylates, ethyl acrylate, trimethyl ammonioethyl methacrylate,
cyanoethyl methacrylate, aminoalkyl methacrylate copolymer, poly
(acrylic acid), poly (methacrylic acid), methacrylic acid
alkylamine copolymer, poly (methyl methacrylate), poly (methacrylic
acid) (anhydride), polymethacrylate, polyacrylamide, poly
(methacrylic acid anhydride), and glycidyl methacrylate
copolymers.
[0021] Oxycodone-containing formulations which may be used for
treating visceral pain according to the present invention, for
example, are described in WO 02/087512 and EP 0 576 643, both
incorporated herein by reference.
[0022] EP 0 576 643 refers to a solid, controlled release, oral
dosage form, the dosage form comprising a therapeutically effective
amount of oxycodone or a salt thereof in a matrix.
[0023] The oral dosage forms described in EP 0 576 643 may be
especially suitable for the present invention. The dosage forms
according to EP 0 576 643 include "twice-a-day" formulations. The
oral dosage form may be presented as, for example, granules,
spheroids or pellets in a capsule or in any other suitable solid
form.
[0024] According to the present invention it may preferred that the
oral dosage form contains between 1 and 50 mg, preferably between 1
and 15 mg, more preferably between 5 and 10 mg and especially about
5 mg of oxycodone hydrochloride. Alternatively the dosage form may
contain the same or molar equivalent amounts of other oxycodone
salts or of the oxycodone base.
[0025] The matrix of the dosage form to be used for treating
visceral pain according to the present invention may preferably be
a controlled release matrix, although also 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
comprise
(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 dosage form may contain
between 1% and 80% (by weight) of at least one hydrophilic or
hydrophobic polymer. (b) Digestible, long chain (C8-C50, especially
C12-C40), 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. C. and 90.degree. C. are preferred. Of these
long chain hydrocarbon materials, fatty (aliphatic) alcohols are
preferred. The dosage form may contain up to 60% (by weight) of at
least one digestible, long chain hydrocarbon. (c) Polyalkylene
glycols. The dosage form may contain up to 60% (by weight) of at
least one polyalkylene glycol.
[0026] One particular suitable matrix comprises at least one water
soluble hydroxyalkyl cellulose, at least one C12-C36, preferably
C14-C22, aliphatic alcohol and, optionally, at least one
polyalkylene glycol.
[0027] The at least one hydroxyalkyl cellulose may preferably be a
hydroxy (C1 to C6) alkyl cellulose, such as hydroxypropylcellulose,
hydroxypropylmethylcellulose and, especially, hydroxyethyl
cellulose. The amount of the at least one hydroxyalkyl cellulose in
the 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.
[0028] The at least one aliphatic alcohol may be, for example,
lauryl alcohol, myristyl alcohol or stearyl alcohol. In
particularly preferred embodiments, however, the at least one
aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The
amount of the at least one aliphatic alcohol in an oral dosage form
will be determined by the precise rate of oxycodone release
required.
[0029] According to another preferred embodiment, the controlled
release composition may comprise 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. RS 30D commercially available from
Rohm Pharma.
[0030] 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.
[0031] As an alternative to a controlled release matrix, the dosage
form to be used for treating visceral pain may comprise 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 dosage form may comprise 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. Details with respect to
film coated spheroids and the manufacture of the above-mentioned
dosage forms are also described in EP 0 576 643, incorporated
herein by reference.
[0032] Controlled release oxycodone-containing formulations which
may be especially suitable for treating visceral pain according to
the present invention may comprise oxycodone hydrochloride, lactose
(spray dried), Povidone, Eudragit.RTM. RS 30 D (solids),
Triaceting, stearyl alcohol, talc and magnesium stearate.
[0033] Further sustained release formulations containing oxycodone
and being suitable for treating visceral pain according to the
present invention are described in WO 02/087512, incorporated
herein by reference.
[0034] According to the present invention, it may be preferred to
use a dosage form providing an analgesic effect for at least about
24 hours after oral administration at steady; and the dosage form
providing a mean C24/Cmax oxycodone ratio of 0.6 to 1.0 after oral
administration at steady state to the patients. In certain
embodiments of the invention, the dosage form after administration
to patients may provide a mean T.sub.max of oxycodone in-vivo which
occurs at about 2 to about 17 hours (e.g., about 2 to about 8
hours) after administration at steady state of the dosage form. The
term "mean" for purposes of the present invention, when used to
define a pharmacokinetic value (e.g., T.sub.max) represents the
arithmetic mean value measured across a patient population. In
certain embodiments of the invention, the mean T.sub.max of
oxycodone in-vivo may occur at about 6.5 hours to about 17 hours,
at about 8 to about 16 hours, at about 10 to about 16 hours, or at
about 12 to about 16 hours after administration at steady state of
the dosage form. The term "steady state" means that the amount of
the drug reaching the system is approximately the same as the
amount of the drug leaving the system. Thus, at "steady state", the
patient's body eliminates the drug at approximately the same rate
that the drug becomes available to the patient's system through
absorption into the blood stream.
[0035] In certain embodiments the sustained release oral dosage
form which may be used for treating visceral pain according to the
present invention comprises a matrix which includes a sustained
release material and oxycodone or a pharmaceutically acceptable
salt thereof. In certain embodiments, the matrix is compressed into
a tablet and may be optionally overcoated with a coating that in
addition to the sustained release material of the matrix may
control the release of the oxycodone or pharmaceutically acceptable
salt thereof from the formulation, such that blood levels of active
ingredient are maintained within the therapeutic range over an
extended period of time. In certain alternate embodiments, the
matrix may be encapsulated.
[0036] In certain embodiments the sustained release oral dosage
form to be used according to the present invention can be an
osmotic dosage form which comprises a single layer or bilayer core
comprising oxycodone or a pharmaceutically acceptable salt thereof;
an expandable polymer; a semipermeable membrane surrounding the
core; and a passageway disposed in the semipermeable membrane for
sustained release of the oxycodone or pharmaceutically acceptable
salt thereof, such that blood levels of active ingredient are
maintained within the therapeutic range over an extended period of
time when administered to patients.
[0037] In certain embodiments the sustained release oral dosage
form to be used according to the present invention comprises a
substantially homogenous core comprising oxycodone or a
pharmaceutically acceptable salt thereof and an expandable polymer;
a semipermeable membrane surrounding the core; and a passageway
disposed in the semipermeable membrane for sustained release of the
oxycodone or pharmaceutically acceptable salt thereof, such that
blood levels of active ingredient are maintained within the
therapeutic range over an extended period of time when administered
to a patients.
[0038] Another sustained release oral analgesic dosage form which
may be suitable for the use according to the present invention is
described in EP 1 449 531, incorporated herein by reference. Said
dosage form comprises a combination of a pharmaceutical extrudate
in the form of multiparticulates including 5 mg to 400 mg oxycodone
or a salt thereof dispersed in a matrix. EP 1 449 531 is also
related in part to a new melt-extruded oral sustained-release
dosage forms which comprise a pharmaceutically acceptable
hydrophobic material, a retardant selected from waxes, fatty
alcohols, and fatty acids, and a drug. The extrudate can be divided
into unit doses of the opioid analgesic. The unit doses of
multiparticulates may then be incorporated into a solid
pharmaceutical dosage formulation, e.g. via compression or shaping
into tablets, by placing a requisite amount inside a gelatin
capsule, or by forming the extruded product into the form of a
suppository.
[0039] Further controlled release matrices or controlled release
dosage forms which may be suitable according to the present
invention are described in the following documents:
[0040] EP 0 548 448, incorporated herein by reference, refers to a
stabilized solid controlled release dosage form having a coating
derived from an aqueous dispersion of ethylcellulose is obtained by
overcoating a substrate including a therapeutically active with an
aqueous dispersion of ethylcellulose and then curing the coated
substrate at a temperature and relative humidity elevated to a
suitable level above ambient conditions until the coated dosage
form attains a stabilized dissolution profile substantially
unaffected by exposure to storage conditions of elevated
temperature and/or elevated relative humidity.
[0041] EP 0 531 611 incorporated herein by reference, refers to a
controlled release dosage form having a matrix of sodium alginate
and a calcium salt. When the composition is to be administered
rectally, the matrix is combined with a therapeutically active
agent and a suitable suppository base. When the composition is to
be administered orally, the matrix further includes a higher
aliphatic alcohol. EP 0 553 392, EP 0 630 646 and EP 0 636 366
refer to controlled release dosage forms having certain coatings.
EP 0 647 448 and EP 0 698 389 also refer to orally administrable
opioid formulations providing controlled or sustained release of
the active agent. Each of the foregoing documents is incorporated
herein by reference.
[0042] Once-a-day sustained release opioid formulations are
disclosed in U.S. Pat. Nos. 5,478,577; 5,672,360; 5,958,459;
6,103,261; 6,143,322; 5,965,161; 5,958,452 and 5,968,551, all
incorporated by reference herein.
[0043] Moreover, there are also commercially available
oxycodone-containing oral preparations which may be used for
treating visceral pain according to the present invention. These
commercially available oxycodone-containing preparations include
Oxynorm.RTM. (immediate release preparation) and OxyContin.RTM..
OxyContin is a controlled release analgesic, which is commercially
available from Purdue Pharma L.P. OxyContin.RTM. is available in 10
mg, 20 mg, 40 mg, and 80 mg dosage strengths. OxyContin is also
commercially available in the U.K by Napp Pharmaceuticals in a 5 mg
dosage strength. According to the present invention low dosage
preparations may be preferred. Dosage forms having an
OxyContin.RTM.-like matrix and comprising about 5 mg of oxycodone
hydrochloride may be especially preferred
[0044] It may be preferred according to the present patent
application to provide a dosage form which comprises a combination
of opioid agonist and opioid antagonist in order to reduce or
prevent the abuse potential. Suitable dosage forms comprising
combinations of opioid agonist and opioid antagonist are described,
for example, in WO 99/32119, WO 99/32120, WO 01/58447, WO 03/013479
and WO 03/013476.
[0045] Subsequently, it is referred to different aspects of the
present invention. However, it is to be understood that the present
invention is not limited to these aspects.
[0046] It should be understood that for purposes of the present
invention, the following terms have the following meanings:
[0047] The term "visceral pain" is defined for purposes of the
present invention as referring to pain within the viscera of the
human body and especially to pain from the internal organs.
[0048] The term "acute visceral pain" is defined for purposes of
the present invention as referring to visceral pain which is not
chronic.
[0049] The term "effective" in connection with the analgesic effect
is defined for purposes of the present invention as a satisfactory
reduction in or elimination of pain, along with the process of a
tolerable level of side effects, as determined by the human
patient.
[0050] The term "selectively treating" is defined for purposes of
the present invention as referring to the selective use of
oxycodone for effectively treating a specific pain, namely acute
visceral pain. The treatment of visceral pain with e.g. morphine
would also lead to some analgesic effect, but would not be
considered "selective" since such analgesic effect would be
significantly lower in comparison to oxycodone and would also be
observed for other pain. In other words, no selective effect would
be observed for the treatment of visceral pain with morphine.
[0051] The present invention includes the following aspects:
[0052] According to one aspect of the present invention, a method
of effectively treating visceral pain is provided which comprises
administering oxycodone at a dosage which is sufficiently low in
order to reduce or avoid undesired side effects.
[0053] According to another aspect of the present invention, a
method of effectively treating visceral pain is provided which
comprises administering a oxycodone-containing dosage form, wherein
the dosage form provides immediate release or sustained release of
the oxycodone.
[0054] According to another aspect of the present invention, a
method of effectively treating visceral pain is provided which
comprises administering oxycodone at a dosage which provides a
significantly better effect than the orally equipotent dosage of
morphine or other opioid, wherein the equipotency refers to the
treatment of cutaneous and muscular pain.
[0055] According to a further aspect of the present invention, a
method of selectively treating acute visceral pain in a patient is
provided, the method comprising orally administering oxycodone in
an effective amount to provide analgesia in a patient in need
thereof.
[0056] According to another embodiment of the invention a method of
treating moderate to severe visceral pain in a patient already
being treated orally with morphine or a salt thereof is provided,
the method comprising:
(a) discontinuing oral treatment with morphine; and (b) orally
administering oxycodone or a salt thereof in an amount of less than
50% by weight of the morphine or salt thereof. It may be preferred
to orally administer oxycodone or a salt thereof in an amount of
less than less than 45% by weight, preferably less than 40% by
weight, more preferably less than 35% by weight, even more
preferably less than 30% by weight and most preferred 25% by weight
of the morphine or salt thereof.
[0057] Furthermore, the present invention includes the following
aspects:
[0058] A method of treating acute visceral pain by administering
oxycodone at a dosage which is lower than the corresponding dosage
of morphine required for providing the same therapeutic effect.
[0059] A method of treating visceral pain by administering
oxycodone at a dosage which is lower than the corresponding dosage
of morphine required for treating the same visceral pain as
efficiently.
[0060] A method for effectively treating visceral pain by orally
administering oxycodone at a dosage which is lower than the
equipotent dosage of oral morphine, wherein the equipotency refers
to the treatment of cutaneous and muscular pain. The weight ratio
of the aforementioned dosage of oxycodone to the aforementioned
dosage of morphine is preferably less than 1:2, more preferably
less than 1:2.5, even more preferably less than 1:3 and most
preferably less than 1:4.
[0061] Use of oxycodone or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for treating visceral
pain.
[0062] Use of oxycodone or a pharmaceutically acceptable salt
thereof, wherein oxycodone or a pharmaceutically acceptable salt
thereof is used for the manufacture of a medicament for treating
acute visceral pain.
[0063] Use of oxycodone or a pharmaceutically acceptable salt
thereof, wherein oxycodone or a pharmaceutically acceptable salt
thereof is used for the manufacture of a medicament for selectively
treating visceral pain.
[0064] Use of oxycodone or a pharmaceutically acceptable salt
thereof, wherein the medicament is an oral dosage form containing
oxycodone or a pharmaceutically acceptable salt thereof.
[0065] Use of an oral controlled dosage form for the manufacture of
a medicament to control visceral pain in human patients, the oral
controlled release dosage form comprising:
a) from 5 mg to 80 mg oxycodone or a salt thereof; b) an effective
amount of a controlled release acrylic resin matrix, said acrylic
resin matrix being selected so that the formulation provides
substantially pH-independent in-vitro dissolution characteristics;
c) a pharmaceutical diluent.
[0066] According to the present invention, the term "substantially
pH-independent" means that the difference, at any given time,
between the amount of oxycodone released at pH 1.2 and the amount
released at pH 7.5 (when measured in-vitro using USP Basket Method
at 100 rpm in 900 ml aqueous buffer), is 15%, preferably 10% (by
weight based on the total amount of oxycodone or salt thereof in
the dosage form) or less. Use of an oral controlled dosage
formulation for the manufacture of a medicament to control visceral
pain in human patients, the oral controlled release dosage
formulation comprising:
a) about 5 mg oxycodone or a salt thereof; b) an effective amount
of a controlled release acrylic resin matrix, said acrylic resin
matrix being selected so that the formulation provides
substantially pH-independent in-vitro dissolution characteristics;
and c) a pharmaceutical diluent.
[0067] Further aspects are described in the claims.
[0068] According to another aspect of the invention a method of
treating moderate to severe visceral pain in a patient is provided,
the method comprising repeatedly administering 5 mg
sustained-release oxycodone twice a day, three-times-a-day, or
four-times-a-day.
[0069] According to another aspect of the invention a method of
treating moderate to severe visceral pain in a patient is provided,
the method comprising repeatedly administering 10 mg sustained
release oxycodone once a day. It should be understood that the
following aspects of the present inventions may be specific or
preferred embodiments of the foregoing aspects of the present
invention:
[0070] According to the present invention it may be preferred that
the oxycodone-containing medicament is in the form of a solid oral
dosage form like a tablet or capsule.
[0071] According to the present invention it may be preferred that
the oxycodone-containing oral dosage form provides immediate
release of the oxycodone.
[0072] According to the present invention it may be preferred that
the oxycodone-containing oral dosage form provides sustained
release of the oxycodone.
[0073] According to the present invention it may be preferred that
the oxycodone-containing sustained release dosage form is orally
administered on a once daily or twice daily basis.
[0074] According to the present invention it may be preferred that
the oxycodone-containing medicament comprises oxycodone in an
amount of from about 1 mg to about 50 mg, preferably between 1 and
15 mg, more preferably between 5 and 10 mg and especially of about
5 mg or an equivalent amount of pharmaceutically acceptable salt
thereof. If the oxycodone-containing medicament is in the form of a
sustained release dosage form to be administered on a once daily or
twice daily basis, the amount of oxycodone in some cases may be
higher and may be in the range from about 5 mg to about 160 mg, but
preferably is not exceeding 40 mg, more preferably is not exceeding
20 mg and most preferably is not exceeding 10 mg.
[0075] According to another aspect of the invention a method of
treating moderate to severe visceral pain in a patient is provided,
the method comprising:
(a) administering to a human patient a unit dose containing
oxycodone or a salt thereof in an amount of 5 mg; (b) monitoring
pharmacodynamic parameters elicited by said unit dose in said human
patient and determining whether said pharmacodynamic parameters are
appropriate for continued treatment of said patient on a repeated
basis; (c) titrating the patient by adjusting the dose of oxycodone
or a salt thereof administered to the patient by administering a
unit dose of oxycodone or a salt thereof with a different amount of
oxycodone or a salt thereof if it is determined that said
pharmacodynamic parameters are not satisfactory or maintaining the
dose of oxycodone or a salt thereof in said unit dose at a
previously administered amount if said pharmacodynamic parameters
are deemed appropriate; (d) continuing the step (c) titration by
adjusting the dose of oxycodone or a salt thereof until appropriate
steady-state pharmacodynamic parameters are achieved in said
patient; and (e) continuing the administration of the dose of
oxycodone or a salt thereof until treatment is terminated. I may be
preferred that the patient is titrated with a unit dose containing
oxycodone or a salt thereof in an amount of 5 mg to 10 mg.
[0076] According to other embodiments of the present invention, the
oxycodone-containing medicament may comprise another active agent,
preferably another opioid or nonopioid analgesic agent. Preferred
combinations of oxycodone and other active agents are described
herein above.
Experimental Evidence
[0077] The foregoing is also supported by the experimental evidence
referred to below.
[0078] The experimental studies referred to below, are based on a
comparison of different drugs at healthy volunteers by applying
experimental pain, since clinical studies provide insufficient
information, partly due to the great difference that exists between
patients and partly due to the fact that most diseases produce many
symptoms other than pain, which affects the assessment of
pain-killing efficacy. Experimental pain can be administered under
controlled conditions in healthy volunteers so that this bias can
be avoided. However, several experimental stimuli are necessary to
simulate the complex clinical situation. It is also necessary to
use different opioids to obtain sufficient differentiated knowledge
about deep pain on different pain mechanisms, and an assessment of
the clinical action spectrum of opioids. For testing the efficacy
of different opioids for treating visceral pain a standardized test
battery of cutaneous, muscular and visceral stimuli was applied.
Blood samples were taken for determination of the opioid
concentration in plasma.
[0079] In recent years methods by which deep and visceral stimuli
can be administered reproducibly have been developed. These methods
allow activation of the pain system with different stimuli, with
the possibility of activating various types of nerve pathways in
the same experiment. In the trial described herein the efficacy of
different opioids on different types of stimuli of skin, muscles
and bowel in healthy volunteers have been compared. Cutaneous and
muscular pain was administered by pressure, current and temperature
(skin only). The stimulation of the internal organs was also
produced by pressure via a balloon located at the bottom of the
oesophagus. The balloon can be distended and produce mechanical
stimuli, which feel like mild pain/discomfort. In addition, cold
and heat stimuli can be administered by passing water of differing
temperature through the balloon.
Aim
[0080] The purpose of the present study was to compare the efficacy
of two different opioids on different experimental pain models,
where the pain induced is very similar to clinical pain. The
experimental pain induced must therefore activate different
peripheral deep/visceral pain pathways in several organs during
controlled conditions. During the trial the intensity of pain was
measured as a result of a well-defined pain stimulus consecutively,
but the analgesic effect of orally administered opioid is built up
according to the flowchart below:
[0081] Each of the experiments was carried out on healthy
volunteers and includes 24 individuals aged between 18 and 65,
male/female ratio 1:1, without any previous chronic or recurrent
diseases causing pain. The subjects have also undergone a physical
examination and have been screened for any diseases with testing of
urine (dipsticks for protein and sugar) and blood tests
(haemoglobin, C-reactive protein, platelelets, leukocytes,
creatinine, aspartate aminotransferase, alkaline phosphatase,
prothrombin time) before they were included in the study. The
duration of each of the sub-trials will be maximum 2 hours. The
subjects were included three times, with a minimum of one week
between each trial.
Trial Design and Methods
[0082] In the series of trials morphine was compared with
oxycodone. In addition, both drugs have been compared with a
placebo. The drug substances were tested by using experimental pain
models including cutaneous, intramuscular and visceral pain
stimulation in healthy subjects.
[0083] The trials were conducted according to a block-randomised
(three blocks), balanced (opioid sequence) double-blind,
placebo-controlled cross-over design with three arms (opioids and
placebo) and open therapeutic control. Blinding for patients and
those giving treatment was undertaken by pouring the medicine
together with grape juice (ensuring blinding of placebo) according
to the following pattern.
TABLE-US-00001 Opioid Placebo mg morphine 30 mg oxycodon 15 mg 100
ml 15 ml morphine DAK 15 ml Oxynorm oral grape juice oral solution
2 mg/ml + solution 1 mg/ml + 85 ml grape juice 85 ml grape
juice
[0084] At least 7 days pass between each dose, which ensures
sufficient wash-out.
Experimental Pain Models/Pain Stimuli
[0085] Several separate trials have been performed, where the
placebo and the 2 opioids were tested on the experimental pain
models. Beforehand a test has been performed in which the subjects
have tested the various pain stimuli and have learnt to score them
on the scales used (intensity and referred spread of pain). Pain
stimuli are given before and during treatment (at the expected
maximum effect of the drug). The model was first tested on skin,
muscle and oesophageal stimuli. Stimuli with cutaneous, muscular
and visceral tests were applied at the various intensities tested
for the trial and after 30, 60 and 90 minutes.
[0086] The effect of opioids on mechanical stimuli was studied by
stimulating skin and muscle with a pressure algometer (Somedia
algometer) and by stimulating the oesophagus with a balloon, where
the cross-sectional area can be calculated (impedance planimetry).
Sensation for electrical stimulations was studied on the skin and
in the muscles of the lower arm ("single and repeated stimuli"). It
was ensured in this way that both pure peripheral pain and central
mechanisms ("repeated stimuli") are studied. The effect of thermal
stimuli was measured on the skin of the lower arm (Somedic
thermotest) and in the osophagus by warm and cold water perfusing
the balloon. A stimulus-response curve was produced for all types
of stimuli. The pain intensity was scored on a visual analogue
scale (VAS) from 0 (no pain) to 10 (intolerable), which combines
non-painful (0-4.9 on the scale) and painful (5-10 on the scale)
stimuli. Stimuli with an intensity of 1, 3, 5=pain detection
threshold and 7=moderate pain are given.
Kinetics
[0087] Blood samples of 10 ml for assessment of the variation in
plasma concentration for the opioids were taken from a peripheral
venflon for opioid dosage (blank test) and 30, 45, 60, 90 and 120
minutes after dosage. A total of 240 ml blood is therefore taken
over the whole trial (4 weeks).
Preparations and Dose
[0088] Morphine DAK oral solution 2 mg/ml; Dose 30 mg
[0089] Oxynorm oral solution 1 mg/ml; Dose: 15 mg
[0090] It was assumed that the equipotent ratio of morphine to
oxycodone is about 2:1 by weight.
Statistical Treatment of Data
[0091] The pain threshold was determined for the various stimuli
before the trial and after 30 min (expected initial effect), 60 and
90 minutes (expected maximum effect). Stimuli were produced at
different intensities for stimulation in skin, muscles and
oesophagus. Data were stored electronically and entered on CRFs.
The analgesic effect before and during the trial was determined by
2-sided variance analysis with the factors 1) either placebo versus
morphine or morphine versus oxycodone and 2) intensity or pain
stimulus and the dependent variable "pain score". The effect on
pain quality was studied by the Danish version of the "McGill Pain
Questionnaire" being filled in at maximum pain.
[0092] The effect on pain threshold after 90 minutes was counted as
the primary endpoint. The other data (effect on other pain
intensities, change in the qualitative descriptive words, change in
reported area of pain) were regarded as secondary, descriptive
variables. The plasma measurements were thus to be regarded as
secondary endpoints used in the descriptive phase to support the
effect on pain data.
Results
[0093] In the skin both opioids, morphine and oxycodone, were
significantly more analgesic than placebo and there was no
significant difference between morphine and oxycodone for all
modalities tested (see FIG. 1). Note also that the potency ratio of
2:1 (oxycodone:morphine) was confirmed in this study as being
"equipotent" for cutaneous pain.
[0094] In muscle opioids again were significantly more analgesic
than placebo and there was no significant difference between
morphine and oxycodone for all modalities tested (see FIG. 1). Note
also that the potency ratio of 2:1 (oxycodone:morphine) was
confirmed in this study as being "equipotent" for muscular
pain.
[0095] In viscera (oesophagus here), a in comparison to than
morphine and placebo significantly better analgesic effect was
observed for oxycodone against mechanical stimulation (via balloon
distension) (see FIG. 2). Morphine, however, also provided a
certain analgesic effect (in comparison to placebo).
[0096] There was also significantly greater analgesia by oxycodone
against heat pain stimulation (via hot water into the balloon) in
comparison to morphine and placebo (see FIG. 2). Morphine, however,
also provided a certain analgesic effect (in comparison to
placebo).
[0097] The foregoing results clearly confirm that visceral pain and
especially acute visceral pain can be effectively and selectively
treated by administering oxycodone at a dosage which is lower than
the corresponding, i.e. equipotent dosage of other opioids like
morphine.
[0098] Having thus described in detail preferred embodiments of the
present invention, it is to be understood that the invention
defined by the above paragraphs is not to be limited to particular
details set forth in the above description as many apparent
variations thereof are possible without departing from the spirit
or scope of the present invention.
[0099] All documents cited or referenced herein ("herein cited
documents") including any manufacturer's instructions,
descriptions, product specifications, and product sheets for any
products mentioned herein or in any document referenced herein, are
hereby incorporated herein by reference, and may be employed in the
practice of the invention. Citation or identification of any
document in this application is not an admission that such document
is available as prior art to the present invention. It is noted
that in this disclosure, terms such as "comprises", "comprised",
"comprising" and the like can have the meaning attributed to it in
U.S. Patent law; e.g., they can mean "includes", "included",
"including", and the like.
* * * * *