ROBUST SUSTAINED RELEASE FORMULATIONS OF OXYMORPHONE AND METHODS OF USE THEREOF

FORMULATIONS A LIBERATION PROLONGEE ET STABLE D'OXYMORPHONE ET LEURS PROCEDES D'UTILISATION

English Abstract

Robust sustained release formulations, solid dosage forms comprising robust sustained release formulations, and methods for making and using these formulations and solid dosage forms are provided. Robustness of the sustained release formulation is related to the particle size of the hydrophilic gum. Sustained release formulations resist dose-dumping when ingested with alcohol. The formulations are useful for treating a patient suffering from a condition, e.g., pain. The formulations comprise at least one drug. In one embodiment, the drug is an opioid, e.g., oxymorphone.

French Abstract

La présente invention concerne des formulations à libération prolongée et stable, des formes de dosage solides contenant les formulations à libération prolongée et stable, et des procédés permettant de fabriquer et d'utiliser ces formulations et formes de dosage solides. La stabilité des formulations à libération prolongée est liée à la dimension des particules de la gomme hydrophile. Les formulations à libération prolongée résistent à une libération massive de la dose lorsqu'elles sont ingérées avec de l'alcool. Les formulations se révèlent utiles pour traiter un patient confronté à un état pathologique, par exemple, la douleur. Les formulations contiennent au moins un médicament. Dans un mode de réalisation, le médicament est un opioïde, comme par exemple, l'oxymorphone.

Claims

CLAIMS
What is claimed is:
1. A method of relieving pain comprising administering to a patient a
sustained
release oxymorphone formulation comprising a sustained release delivery system
and
from about 5 mg to about 80 mg of oxymorphone, wherein after oral
administration of a
single dose to the patient with about 200 mL to about 300 mL of about 4% to
about 40%
ethanol the formulation provides a secondary peak of blood oxymorphone
concentration
about 12 hours after administration, and the formulation provides analgesia to
the patient
for at least about 12 hours after administration.
2. The method of claim 1, wherein the sustained release oxymorphone
formulation
comprises from about 20 mg to about 60 mg of oxymorphone.
3. The method of claim 2, wherein the sustained release oxymorphone
formulation
comprises about 40 mg of oxymorphone.
4. The method of any one of claims 1, 2 or 3, wherein the sustained release
oxymorphone formulation is a solid dosage form.
5. The method of claim 4, wherein the solid dosage form is selected from the
group
consisting of a tablet, a capsule, a granule, and a powder.
6. The method of claim 5, wherein the solid dosage form is a tablet.
7. A method of relieving pain comprising administering to a patient a
sustained
release oxymorphone formulation comprising a sustained release delivery system
and
from about 5 mg to about 80 mg of oxymorphone, wherein after oral
administration of a
single dose to a patient the formulation provides a maximum blood
concentration of
oxymorphone less than about 5 times higher when ingested with about 200 mL to
about
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300 mL of up to about 40% ethanol compared to when ingested without ethanol,
and the
formulation provides analgesia to the patient for at least about 12 hours
after
administration.
8. The method of claim 7, wherein the maximum blood concentration of
oxymorphone is less than about 2.5 times higher when ingested with about 200
mL to
about 300 mL of up to about 40% ethanol compared to when ingested without
ethanol.
9. The method of claim 7, wherein the sustained release oxymorphone
formulation
comprises from about 20 mg to about 60 mg of oxymorphone.
10. The method of claim 9, wherein the sustained release oxymorphone
formulation
comprises about 40 mg of oxymorphone.
11. A method of relieving pain comprising administering to a patient a
sustained
release oxymorphone formulation comprising a sustained release delivery system
and
from about 5 mg to about 80 mg of oxymorphone, wherein after oral
administration of a
single dose to a patient the formulation provides a ratio of the maximum blood
concentration of oxymorphone when ingested with about 200 mL to about 300 mL
of
about 40% ethanol to the maximum blood concentration of oxymorphone when
ingested
after a high-fat meal without ethanol of about 0.5 to about 2, and the
formulation provides
analgesia to the patient for at least about 12 hours after administration.
12. The method of claim 11, wherein the ratio of the maximum blood
concentration of
oxymorphone when the formulation is ingested with about 200 mL to about 300mL
of
about 40% ethanol to the maximum blood concentration of oxymorphone when the
formulation is ingested after a high-fat meal without ethanol is from about
0.8 to about
1.5.
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13. The method of claim 11, wherein the sustained release oxymorphone
formulation
comprises from about 20 mg to about 60 mg of oxymorphone.
14. The method of claim 13, wherein the sustained release oxymorphone
formulation
comprises about 40 mg of oxymorphone.
15. A method of relieving pain comprising administering to a patient a
sustained
release oxymorphone formulation comprising a sustained release delivery system
and
from about 5 mg to about 80 mg of oxymorphone, wherein after oral
administration of a
single dose to a patient with about 200 mL to about 300 mL of about 4% to
about 40%
ethanol the formulation provides a maximum blood concentration of oxymorphone
from
about 0.1 ng/mL to about 15 ng/mL, and the formulation provides analgesia to
the patient
for at least about 12 hours after administration.
16. The method of claim 15, wherein the sustained release oxymorphone
formulation
provides a maximum blood concentration of oxymorphone from about 0.5 ng/mL to
about 7.5 ng/mL.
17. The method of claim 16, wherein the sustained release oxymorphone
formulation
provides a maximum blood concentration of oxymorphone from about 1 ng/mL to
about
4 ng/mL.
18. The method of claim 15, wherein the sustained release oxymorphone
formulation
comprises from about 10 mg to about 20 mg of oxymorphone and the formulation
provides a maximum blood concentration of oxymorphone from about 0.3 ng/mL to
about 3.2 ng/mL.
19. The method of claim 18, wherein the formulation provides a maximum blood
concentration of oxymorphone from about 0.4 ng/mL to about 2.8 ng/mL.
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20. The method of claim 18, wherein the formulation comprises about 10 mg of
oxymorphone and the formulation provides a maximum blood concentration of
oxymorphone from about 0.3 ng/mL to about 1.8 ng/mL.
21. The method of claim 20, wherein the formulation provides a maximum blood
concentration of oxymorphone from about 0.5 ng/mL to about 1.5 ng/mL.
22. The method of claim 15, wherein the formulation comprises from about 20 mg
to
about 40 mg of oxymorphone and the formulation provides a maximum blood
concentration of oxymorphone from about 0.5 ng/mL to about 7 ng/mL.
23. The method of claim 22, wherein the formulation provides a maximum blood
concentration of oxymorphone from about 0.9 ng/mL to about 6 ng/mL.
24. The method of claim 22, wherein the formulation comprises about 20 mg of
oxymorphone and the formulation provides a maximum blood concentration of
oxymorphone from about 0. 5 ng/mL to about 3.2 ng/mL.
25. The method of claim 24, wherein the formulation provides a maximum blood
concentration of oxymorphone from about 0.75 ng/mL to about 2.8 ng/mL.
26. The method of claim 15, wherein the formulation comprises from about 40 mg
to
about 80 mg of oxymorphone and the formulation provides a maxiinum blood
concentration of oxymorphone from about 1 ng/mL to about 15 ng/mL.
27. The method of claim 26, wherein the formulation provides a maxiinum blood
concentration of oxymorphone from about 1.9 ng/mL to about 12 ng/mL.
28. The method of claim 26, wherein the formulation comprises about 40 mg of
oxymorphone and the formulation provides a maximum blood concentration of
oxymorphone from about 1 ng/mL to about 7 ng/mL.
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29. The method of claim 28, wherein the formulation provides a maximum blood
concentration of oxymorphone from about 1.4 ng/mL to about 5 ng/mL.
30. The method of claim 26, wherein the formulation comprises about 80 mg of
oxymorphone and the formulation provides a maximum blood concentration of
oxymorphone from about 3.5 ng/mL to about 15 ng/mL.
31. The method of claim 30, wherein the formulation provides a maximum blood
concentration of oxymorphone from about 4 ng/mL to about 13 ng/mL.
32. A method of relieving pain comprising administering to a patient a
sustained
release oxymorphone formulation comprising a sustained release delivery system
and
from about 5 mg to about 80 mg of oxymorphone, wherein the formulation
provides a
minimum blood concentration of oxymorphone of at least about 0.013 ng/mL at
about 12
hours after oral administration of a single dose to a patient with about 200
mL to about
300 mL of about 4% to about 40% ethanol, and the formulation provides
analgesia to the
patient for at least about 12 hours after administration.
33. The method of claim 32, wherein the formulation comprises about 5 mg of
oxymorphone.
34. The method of claim 32, wherein the formulation comprises about 10 mg of
oxymorphone.
35. The method of claim 32, wherein the formulation comprises about 20 mg of
oxymorphone.
36. The method of claim 32, wherein the formulation comprises about 40 mg of
oxymorphone.

37. The method of claim 32, wherein the formulation comprises about 80 mg of
oxymorphone.
38. The method of claim 33, wherein the minimum blood concentration of
oxymorphone is at least about 0.07 ng/mL.
39. The method of claim 34, wherein the minimum blood concentration of
oxymorphone is at least about 0.15 ng/mL.
40. The method of claim 35, wherein the minimum blood concentration of
oxymorphone is at least about 0.3 ng/mL.
41. The method of claim 36, wherein the minimum blood concentration of
oxymorphone is at least about 0.6 ng/mL.
42. The method of claim 37, wherein the minimum blood concentration of
oxymorphone is at least about 1.2 ng/mL.
43. The method of any one of claims 7-42 wherein the sustained release
oxymorphone
formulation is a solid dosage form.
44. The method of claim 43, wherein the solid dosage form is selected from a
group
consisting of a tablet, a capsule, a granule, and a powder.
45. The method of claim 44, wherein the solid dosage form is a tablet.
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Description

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ROBUST SUSTAINED RELEASE FORMULATIONS OF OXYMORPHONE AND
METHODS OF USE THEREOF
1. FIELD OF THE INVENTION
The invention provides robust sustained release pharmaceutical fonnulations
and
methods for inaking and using same. The forinulations of the invention
coinprise at least
one drug and a sustained release delivery system.
2. BACKGROUND OF THE INVENTION
Sustained release drug fonnulations often contain higher amounts of drugs than
iimnediate release forinulations. Functionality and safety of a sustained
release
fonnulation are based on a known controlled rate of drug release from the
formulation
over an extended period of time after adininistration, such as 8-24 hours. The
drug
release profile of a formulation often depends on the chemical environment of
the
sustained release formulation, for example, on pH, ionic strength and presence
of solvents
such as ethanol.
The relatively high amount of drug that is present in a sustained release
fonnulation can, in soine instances, harm a patient if the forinulation
releases the drug at a
rate that is faster than the intended controlled release rate. If the
formulation releases the
drug at a rate that is slower than the intended controlled release rate, the
therapeutic
efficacy of the drug can be reduced.
In most cases, failure of a sustained release formulation results in a rapid
release
of the drug into the bloodstream. This rapid release is generally faster than
the intended
sustained release of the drug from the formulation, and is sometimes referred
to as "dose
dumping."
Dose dumping can create severe consequences for a patient, including permanent
hann and even death. Examples of drugs that can be fatal if the
therapeutically beneficial
dose is exceeded, e.g., by dose duinping, include pain medications such as
opioids.
Oral dosage forinulations are often taken with a commonly available beverage,
such as water, juice, a carbonated beverage or occasionally an ethanol-
containing
beverage. An ethanol-containing beverage is commonly referred to as an
alcoholic
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beverage, liquor, or siinply alcohol. As used herein, "alcohol" refers to
ethanol, or an
ethanol-containing ("alcoholic") beverage such as beer, wine, and hard liquors
such as
vodka, rum, or whiskey. Dose duinping in the presence of ethanol creates a
safety
concern because of the likelihood that a patient will ingest the fonnulation
with an
alcoholic beverage. This can be exacerbated where the drug may interact with
the
alcohol. An additional safety concern is that a patient will consuine
alcoholic beverages
while being treated with the drug in the formulation, even if the patient does
not ingest
the forinulation at the same time as an alcoholic beverage.
Patients who desire to abuse a drug, for exainple a diug that causes a
euphoric
effect, may want to intentionally induce dose duinping in order to magnify the
euphoric
effect of the drug. Furthermore, a person wanting to abuse a drug might
already be
abusing alcohol, which increases the likelihood of the sustained release
forinulation of the
drug to be ingested or taken concurrently with an alcoholic beverage.
In 2005, several diugs were either withdrawn from the market or had their
warning labels enhanced because of the effects of ethanol on the sustained
release
forinulations of the drug.
For instance, the United States Food and Diug Administration (FDA) asked
Purdue Phanna to withdraw Palladone (hydromorphone hydrochloride) extended
release capsules from the market because a study showed that when Palladone is
taken
with alcohol, its extended release formulation is damaged and can dose dump
(c.f. FDA
Press Release of July 13, 2005). FDA further warned that taking Palladone
with a
single alcoholic drink could have fatal consequences for the patient.
Alpharma issued a press release reporting that FDA had requested it to expand
warning inforination regarding alcohol in the labeling for KADIAN (c.f.
Alphanna
press release of
July 22, 2005). The enhanced warning was a result of in vitro studies showing
that the
extended release characteristics of KADIAN are coinpromised in the presence
of
alcohol.
AVINZA (morphine sulfate extended-release capsules) was found to have an
increased risk of dose dumping when taken with ethanol. In vitro studies
performed by
the FDA showed that when AVINZA 30 mg was mixed with 900 mL of buffer
solutions
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containing ethanol (20% and 40%), the dose of morphine that was released was
alcohol
concentration-dependent, leading to a more rapid release of moiphine, which in
vivo
could result in the absorption of a potentially fatal dose of morphine. As a
result, during
or around October, 2005, Ligand Pharmaceuticals Inc. revised several sections
of the
AVINZA prescribing infonnation to highlight and strengthen the warning that
patients
should not consume alcohol while taking AVINZA . Additionally, patients were
warned
not to use prescription or non-prescription medications containing alcohol
while on
AVINZA therapy.
FDA has also indicated that for future sustained release products, in vitro
testing
for alcohol-induced underinining of sustained release characteristics may be
advisable as
a routine characterization test. Furthermore, FDA's position is that for
certain drugs (e.g.,
drugs with a narrow therapeutic index or dire consequences of high C,,,aX or
low C,,,iõ),
alcohol sensitive sustained release formulations should not be approved. FDA
prefers
that formulations be made ethanol-resistant by design, rather than simply a
confiimation
that dose dumping does not occur through an in vivo study. (c.f. Summary of
FDA's
position on alcohol-induced dose dumping as presented at the Pharmaceutical
Sciences
Advisory Committee Meeting Oct. 26, 2005)
According to the FDA, an in vivo alcohol resistance test is not the preferred
approach due to potential hann the test could pose to a human subject. The
prefeiTed
approach, according to the FDA, is an in vitro dissolution test in the
presence of 40%
ethanol. This approach may be preferred because the strength of most coinmon
"hard"
liquors is about 80 proof, or about 40% ethanol. FDA is proposing classifying
forinulations into three groups: rugged, vulnerable and uncertain. At the
Pharmaceutical
Sciences Advisory Committee Meeting of Oct. 26, 2005, OPS (Office of
Pharmaceutical
Science) at the CDER (Center for Drug Evaluation and Research) personnel
presented
data showing that in a vulnerable formulation, a higher concentration of
ethanol (e.g.,
40%) is likely to trigger faster drug release than a lower concentration of
ethanol (e.g.,
20% or 4%). In FDA's exainple of a rugged forinulation, the drug release from
a
formulation dissolved in 40% ethanol is actually slightly slower (although
similar)
coinpared to a control formulation dissolved in a medium without ethanol.
(Presentations
at the Pharmaceutical Sciences Advisory Committee Meeting Oct. 26, 2005)
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Changes to product labeling (i.e., added warnings of the danger of taking the
drug
with alcohol) have only a limited effect and are not likely to deter a patient
who intends to
abuse the drug.
Pain is the most frequently reported syinptoin and it is a common clinical
problem
that confronts the clinician. Many millions of people in the United States
suffer from
severe pain that is chronically undertreated or inappropriately managed. The
clinical
usefulness of the analgesic properties of opioids has been recognized for
centuries, and
morphine and its derivatives have been widely used for analgesia for decades
in a variety
of clinical pain states.
Oxymorphone HCl (14-hydroxydihydroinorphinone hydrochloride) is a semi-
synthetic phenanthrene-derivative opioid agonist, used in the treatment of
acute and
chronic pain, with analgesic efficacy comparable to other opioid analgesics.
Oxymorphone is currently marketed as an injection (1 mg/ml in 1 ml ampules)
for
intrainuscular, subcutaneous, and intravenous administration. At one time, a
10 mg oral
iininediate release tablet formation of oxymorphone HCl was marketed.
Oxymorphone
HCl is metabolized principally in the liver and undergoes conjugation with
glucuronic
acid and reduction to 6-alpha and 6-beta hydroxy epimers.
An important goal of analgesic therapy is to achieve continuous relief of
chronic
pain. Regular administration of an analgesic is generally required to ensure
that the next
dose is given before the effects of the previous dose have worn off.
Compliance with
opioids increases as the required dosing frequency decreases. Non-compliance
results in
suboptimal pain control and poor quality of life outcomes. Scheduled rather
than "as
needed" administration of opioids is cuirently recommended in guidelines for
their use in
treating chronic non-malignant pain. Unfortunately, evidence from prior
clinical trials
and clinical experience suggests that the short duration of action of
iininediate release
oxyinorphone would necessitate administration every four hours in order to
maintain
optimal levels of analgesia in patients with chronic pain: Moreover,
iinniediate release
oxyinorphone exhibits low oral bioavailability, because oxymorphone is
extensively
metabolized in the liver.
Because many drugs, e.g., opioids such as oxyinorphone, can cause serious
adverse effects or even death to a patient if the sustained release
formulation fails, there is
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a need in the art for pharmaceutical foi7nulations that are more robust or
rugged, and
therefore safer, when coinpared to currently available sustained release
forinulations.
Several sustained release formulations have been described in U.S. Pat. No.
5,399,358, the disclosure of which is incoiporated by reference herein in its
entirety. It
has now been unexpectedly discovered that the particle size of hydrophilic
gums, e.g.,
xanthan guin, affects the robustness and dissolution properties of sustained
release
fonnulations.
Citation of a reference in Section 2 of the application is not an admission
that the
reference is prior art.
3. SUMMARY OF THE INVENTION
The invention provides sustained release pharmaceutical formulations and solid
dosage forms coinprising the sustained release forinulations. The invention
also provides
methods for treating a patient using the sustained release formulations and
methods for
preventing dose dumping, for example, by providing to patients a
therapeutically
effective amount of a sustained release drug forinulation. The pharmaceutical
foimulations described herein are less likely to dose dump compared to
conventional
sustained release formulations, which makes them more rugged, safer, and
applicable to a
wide variety of drugs.
The invention further provides ethanol-resistant pharmaceutical formulations
and
methods for increasing drug safety and reducing the potential for drug abuse.
This can be
achieved by providing, prescribing and/or administering to patients an
effective amount
of an ethanol-resistant drug formulation. The ethanol-resistant drug
formulations are
safer and have less potential for abuse when compared to commercially
available
formulations because their sustained release dissolution profile in an aqueous
solution or
in an ethanol-containing solution is essentially the same. In one einbodiment,
the drug in
the ethanol-resistant forinulation comprises an opioid compound or a
derivative thereof.
The invention also provides ethanol-resistant pharmaceutical formulations and
methods for preventing dose dumping. This can be achieved by providing,
prescribing
and/or administering to patients an effective amount of an ethanol-resistant
drug
fonnulation. The ethanol-resistant pharmaceutical formulations described
herein do not

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dose duinp in the presence of beverage-strength ethanol. In one einbodiment,
the di-ug in
the etlianol-resistant formulation coinprises an opioid compound, a
pharmaceutically
acceptable salt of an opioid coinpound, or a derivative thereof.
In one aspect, the invention provides a sustained release forinulation
coinprising: a
drug; and a sustained release delivery system comprising a hydrophilic gum, a
hoinopolysaccharide gum, and a pharmaceutical diluent, wherein at least about
30% of
the hydrophilic gum used to make the sustained release foi7nulation can pass
through a
#270 mesh sieve and the sustained release forinulation releases less than
about 70% of the
drug within 2 hours after ingestion with either an ethanol-free or an ethanol-
containing
beverage.
In another aspect, the invention provides a sustained release formulation
coinprising: a drug; and a sustained release delivery system comprising a
hydrophilic
gum, a cationic cross-linlcing compound selected from monovalent cations,
multivalent
cations and salts, and a pharmaceutical diluent, wherein at least about 30% of
the
hydrophilic gum used to make the sustained release formulation can pass
through a #270
mesh sieve and the sustained release forinulation releases less than about 70%
of the drug
within 2 hours after ingestion with either an ethanol-free or an ethanol-
containing
beverage.
In some embodiments, the hydrophilic gum is a heteropolysaccharide gum. In
some embodiments, the hydrophilic gum is xanthan gum.
In one embodiment, the sustained release delivery system further coinprises a
cationic cross-linking compound selected from monovalent cations, multivalent
cations,
and salts. In one embodiment, the cationic cross-linlcing agent is a sodium
salt.
In yet another aspect, the invention provides a sustained release formulation
comprising: a drug; and a sustained release delivery system comprising a
hydrophilic
gum, a homopolysaccharide gum, and a pharmaceutical diluent, wherein at least
about
30% of the hydrophilic gum particles used to make the sustained release
forinulation are
smaller than about 53 microns in diameter and the sustained release
formulation releases
less than 70% of the drug within 2 hours after ingestion with either an
ethanol-free or an
ethanol-containing beverage.
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In still another aspect, the invention provides a sustained release
forinulation
coinprising: a drug; and a sustained release delivery system coinprising a
hydrophilic
gum, a cationic cross-linking coinpound selected from monovalent cations,
multivalent
cations and salts, and a phannaceutical diluent, wherein at least about 30% of
the
hydrophilic gum particles used to make the sustained release fonnulation are
smaller than
about 53 microns in diameter and the sustained release formulation releases
less than 70%
of the drug within 2 hours after ingestion with either an ethanol-free or an
ethanol-
containing beverage. In some embodiments, the sustained delivery system fiu-
ther
comprises a hydrophobic polymer.
In some embodiments, the sustained release forinulation further comprises an
outer coating. In some einbodiinents, the outer coating comprises a
hydrophobic polymer
and/or a plasticizer.
In some embodiments, the drug is a water-soluble drug. In some embodiments,
the drug is an anti-depressant, a drug used to treat bipolar disorder, panic
disorder,
epilepsy, migraine, and/or attention deficit hyperactivity disorder. In some
embodiments,
the di-ug is selected from the group consisting of alprazolam, lithium
carbonate,
divalproex sodium, neutral sulfate salts of dextroamphetamine and amphetamine
with the
dextro isomer of amphetainine saccharate and d,l-amphetamine aspartate
monohydrate,
tramadol hydrochloride, and other pharmaceutically acceptable salts of the
active
pharmaceutical ingredient thereof.
In some embodiments, the drug is an opioid, e.g., alfentanil, allylprodine,
alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine,
butorphanol,
clonitazene, codeine, cyclazocine, desomorphine, dextromorainide, dezocine,
diainproinide, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine,
ethylmethylthiambutene, ethylmoiphine, etonitazine, fentanyl, heroin,
hydrocodone,
hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan,
levorphanol, levophenacyhnoiphan, lofentanil, meperidine, meptazinol,
metazocine,
methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, norinophine, norpipanone, opium,
oxycodone, oxymorphone, 6-hydroxyoxyinorphone, papaveretum, pentazocine,
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phenadoxone, phenoinoiphan, phenazocine, phenoperidine, piininodine,
piritramide,
propheptazine, proinedol, properidine, propirain, propoxyphene, sufentanil,
tramadol,
tilidine, a stereoisoiner thereof, a metabolite thereof, an ether thereof, an
ester thereof, and
a derivative thereof and a pharinaceutically acceptable salt thereof.
Additionally, the invention provides methods for making sustained release
phannaceutical fonnulations and solid dosage fonns comprising the sustained
release
fonnulations.
In one aspect, the invention provides a method for making a sustained release
forinulation coinprising: a drug; and a sustained release delivery system,
wherein the
sustained release delivery system coinprises a hydrophilic gum, a
homopolysaccharide
gum, and a pharmaceutical diluent, the method comprising: providing the
hydrophilic
gum with at least a fraction of particles less than about 53 microns in
diameter;
granulating the hydrophilic gum, the hoinopolysaccharide gum and the
phannaceutical diluent to form granules; mixing the granules with the di-ug to
form a
granulated coinposition; and applying pressure to the granulated composition
to make
the fonnulation.
In another aspect, the invention provides a method for making a sustained
release
forinulation coinprising: a drug; and a sustained release delivery system,
wherein the
sustained release delivery system comprises a hydrophilic gum, a cationic
cross-linking
compound selected from monovalent cations, multivalent cations and salts, and
a
pharmaceutical diluent, the method comprising: providing the hydrophilic gum
with at
least a fraction of particles less than about 53 microns in diameter;
granulating the
hydrophilic gum, the hoinopolysaccharide gum and the pharmaceutical diluent to
form
granules; mixing the granules with the drug to forin a granulated composition;
and
applying pressure to the granulated coinposition to make the formulation.
In some einbodiments, providing comprises receiving, inanufacturing, and/or
processing the hydrophilic gum. In some einbodiments, processing coinprises
measuring
the size of at least a fraction of the hydrophilic gum particles and/or
passing at least a
fraction of the hydrophilic gum through a sieve. In some einbodiments, the
sieve is a
#270 mesh sieve.
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In some einbodiments, the method for malcing the sustained release foi-
inulation
and a solid dosage forin further coinprises applying an outer coating onto at
least part of
the sustained release foimulation.
In some einbodiinents, granulating coinprises mixing ingredients with a
solution
coinprising water. In other embodiinents, granulating coinprises mixing
ingredients with
an alcohol solution, for exainple a solution comprising ethanol.
In one aspect, the invention provides a method for malcing a sustained release
forinulation comprising: a diug; and a sustained release delivery system,
wherein the
sustained release deliveiy system comprises a hydrophilic gum, a
homopolysaccharide
gum, and a pharmaceutical diluent, the method coinprising: mixing the
hydrophilic gum
of average and/or mean particle size larger than about 53 microns in diameter,
the
homopolysaccharide gum and the pharmaceutical diluent with a solution
comprising
water to form granules; mixing the granules with drug to fonn a granulated
composition;
and applying pressure to the granulated composition to make the formulation.
In another aspect, the invention provides a method for making a sustained
release
formulation coinprising: a drug; and a sustained release delivery system,
wherein the
sustained release delivery system comprises a hydrophilic gum, a cationic
cross-linking
coinpound selected from monovalent cations, multivalent cations and salts, and
pharinaceutical diluent, the method comprising: mixing the hydrophilic gum of
average
and/or mean particle size larger than about 53 microns in diaineter, the
cationic cross-
linking compound and the pharmaceutical diluent with a solution coinprising
water to
form granules; mixing the granules with the drug to form a granulated
composition; and
applying pressure to the granulated composition to make the formulation.
In one embodiment, a method for making a sustained release formulation further
coinprises recording a dissolution profile of the sustained release
formulation or a solid
dosage form coinprising the sustained release formulation in an ethanol-
containing
solution.
In one einbodiinent, the invention provides a method for relieving pain
comprising
adiniiustering to a patient a therapeutically effective amount of a sustained
release
fonnulation or a solid dosage form comprising a sustained release formulation
described
herein.
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In another einbodiinent, the invention provides a method for treating a
patient
having a condition comprising administering to the patient a therapeutically
effective
amount of a sustained release formulation or a solid dosage form coinprising a
sustained
release forinulation described herein.
In another aspect, the invention provides a method for reducing dose duinping
of a
sustained release di-ug fonnulation comprising providing a patient a sustained
release
fonnulation described herein.
In yet another aspect, the invention provides a solid dosage fonn comprising a
sustained release forinulation described herein. In some embodiments, the
solid dosage
fonn is a powder, a granule, a tablet, or a capsule.
In one aspect, the sustained release formulation comprises from about 5 to
about
80 ing of oxymorphone hydrochloride and about 80 mg to about 360 ing of a
sustained
release delivery system; wherein the sustained release delivery system
comprises from
about 8.3% to about 41.7% by weight locust bean gum from about 8.3% to about
41.7%
by weight xanthan gum wherein at least about 30% of the xanthan gum particles
can pass
through a #270 mesh sieve; from about 20% to about 55% by weight dextrose,
from about
5% to about 20% by weight calciun-i sulfate dihydrate, and from about 2% to
about 10%
ethyl cellulose, and the sustained release forinulation releases less than 70%
of the drug
within 2 hours after ingestion with either an ethanol-free or an ethanol-
containing
beverage.
In another aspect, the sustained release fonnulation comprises from about 5 to
about 80 mg of oxymorphone hydrochloride and from about 300 mg to about 420 mg
of a
sustained release delivery system; wherein the sustained release delivery
system
comprises from about 8.3% to about 41.7% by weight locust bean gum, from about
8.3%
to about 41.7% by weight xanthan gum having at least about 30% of particles
smaller
than about 53 microns in diameter; from about 20% to about 55% by weight
dextrose,
from about 5% to about 20% by weight calcium sulfate dihydrate, and from about
2% to
about 10% ethyl cellulose, and the sustained release foi-mulation releases
less than 70% of
the drug within 2 hours after ingestion with either an ethanol-free or an
ethanol-
containing beverage.

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In one einbodiment, the sustained release fonnulation comprises about 20 ilig
of
oxyinorphone hydrochloride. In another einbodiinent, the sustained release
formulation
coinprises about 160 mg of a sustained release delivery system. In yet another
einbodiinent, the sustained release formulation comprises about 360 mg of a
sustained
release delivery system. In still another embodiment, the sustained release
delivery
system coinprises about 25% locust bean gum, about 25% xanthan gum, about 35%
dextrose, about 10% calcium sulfate dihydrate, and about 5% ethyl cellulose.
In another aspect, the invention provides a method of preventing dose-dumping
of
a drug in the presence of ethanol comprising: providing a patient who could
consuine
ethanol while being treated with the drug an effective amount of the drug in
the form of
an ethanol-resistant sustained release forinulation comprising: the drug; and
a sustained
release delivery system, the delivery system comprising at least one
hydrophilic gum, at
least one hoinopolysaccharide gum and at least one pharmaceutical diluent,
wherein at
least about 30% of the hydrophilic gum used to make the sustained release
formulation
can pass through a #270 mesh sieve and the sustained release formulation
releases less
than about 70% of the drug within 2 hours after ingestion with either an
ethanol-free or an
ethanol-containing beverage.
In one aspect, the invention provides a method of preventing dose-dumping of a
drug in the presence of ethanol comprising: providing a patient who could
consume
ethanol while being treated with the drug an effective amount of the drug in
the form of
an ethanol-resistant sustained release fonnulation comprising: the drug; and a
sustained
release delivery system, the delivery system comprising at least one
hydrophilic gum, at
least one cationic cross-linking compound selected from monovalent metal
cations,
multivalent metal cations and salts, and at least one pharmaceutical diluent,
wherein at
least about 30% of the hydrophilic gum used to make the sustained release
formulation
can pass through a #270 mesh sieve and the sustained release forinulation
releases less
than about 70% of the drug within 2 hours after ingestion with either an
ethanol-free or an
ethanol-containing beverage.
In another aspect, the invention provides a method of improving safety of a
drug
formulation comprising: providing a patient who could consuine ethanol while
being
treated with the drug an effective amount of the drug in the forin of an
ethanol-resistant
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sustained release formulation coinprising: the drug; and a sustained release
delivery
system, the sustained release delivery system comprising at least one
hydrophilic gum, at
least one homopolysaccharide gum and at least one pharmaceutical diluent,
wherein the
iinprovement in safety is a result of controlled hydrophilic gum particle size
and ethanol-
resistant sustained release properties of the formulation.
In yet another aspect, the invention provides a method of iinproving safety of
a
drug forinulation coinprising: providing a patient who could consume ethanol
while being
treated with the drug an effective amount of the drug in the forin of an
ethanol-resistant
sustained release forinulation comprising: the drug; and a sustained release
delivery
system, the delivery system coinprising at least one hydrophilic gum, at least
one cationic
cross-linking coinpound selected from monovalent metal cations, multivalent
metal
cations and salts, and at least one pharmaceutical diluent, wherein the
improvement in
safety is a result of controlled hydrophilic gum particle size and ethanol-
resistant
sustained release properties of the formulation.
In one aspect, the invention provides a sustained release oxymorphone
forinulation comprising a sustained release deliveiy system and from about 5
mg to about
80 mg of oxymorphone, wherein after oral administration of a single dose to a
patient
with about 200 mL to about 300 mL of about 4% to about 40% ethanol the
formulation
provides a secondary pealc of blood oxylnorphone concentration about 12 hours
after
administration, and the formulation provides analgesia to the patient for at
least about 12
hours after administration.
In some einbodiments, the formulation coinprises from about 20 mg to about 60
mg of oxymorphone or about 40 mg of oxymorphone. In one embodiment, the
formulation is a solid dosage, for exainple, a tablet, a granule, a capsule or
a powder.
In another aspect, the invention provides a sustained release oxymorphone
formulation comprising a sustained release deliveiy system and from about 5 mg
to about
80 mg of oxyinoi-phone, wherein after oral administration of a single dose to
a patient the
forinulation provides a maximum blood concentration of oxymorphone less than
about 5
tiines higher when ingested with about 200 mL to about 300 mL of up to about
40%
ethanol compared to when ingested without ethanol, and the formulation
provides
analgesia to the patient for at least about 12 hours after administration.
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In one embodiment, the maxiinuin blood concentration of oxyinorphone is less
than about 2.5 times higher when ingested with about 200 mL to about 300 inL
of up to
about 40% ethanol compared to when ingested without ethanol.
In some embodiments, the forinulation coinprises from about 20 ing to about 60
mg of oxymorphone or about 40 mg of oxymorphone. In one embodiment, the
forinulation is a solid dosage, for example, a tablet, a granule, a capsule or
a powder.
In yet another aspect, the invention provides a sustained release oxymorphone
fonnulation coinprising a sustained release delivery system and from about 5
mg to about
80 mg of oxyinorphone, wherein after oral adininistration of a single dose to
a patient the
formulation provides a ratio of the maxiinum blood concentration of
oxyinoiphone when
ingested with about 200 mL to about 300 inL of about 40% ethanol to the
inaxiinum
blood concentration of oxymorphone when ingested after a high-fat meal without
ethanol
froin about 0.5 to about 2, and the formulation provides analgesia to the
patient for at
least about 12 hours after administration.
In one embodiment, the ratio of the maxiinum blood concentration of
oxyinorphone when the formulation is ingested with about 200 mL to about 300
mL of
about 40% ethanol to the maximum blood concentration of oxymorphone when the
forinulation is ingested after a high-fat meal without ethanol is from about
0.8 to about
1.5.
In some embodiments, the formulation comprises from about 20 mg to about 60
ing of oxyinorphone or about 40 mg of oxymorphone. In one embodiment, the
formulation is a solid dosage, for example, a tablet, a granule, a capsule or
a powder.
In one aspect, the invention provides a sustained release oxymorphone
formulation comprising a sustained release delivery system and from about 5 mg
to about
80 mg of oxymorphone, wherein after oral administration of a single dose to a
patient
with about 200 mL to about 300 inL of about 4% to about 40% ethanol the
fonnulation
provides a maximum blood concentration of oxymorphone from about 0.1 ng/mL to
about 15 ng/mL, and the formulation provides analgesia to the patient for at
least about 12
hours after administration.
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In some embodiments, the formulation provides a maxiinum blood concentration
of oxymorphone from about 0.5 ng/rnL to about 7.5 ng/mL or from about 1 ng/hnL
to
about 4 ng/mL.
In one einbodiinent, the formulation comprises from about 101ng to about 20 mg
of oxyinorphone and the formulation provides a maximum blood concentration of
oxymorphone from about 0.3 ng/mL to about 3.2 ng/mL or from about 0.4 ng/mL to
about 2.8 ng/mL.
In some embodiments, the fonnulation coinprises about 10 mg of oxyinoiphone
and the formulation provides a maximum blood concentration of oxylnorphone
from
about 0.3 ng/mL to about 1.8 ng/mL or from about 0.5 ng/mL to about 1.5 ng/mL.
In another embodiment, the fonnulation comprises from about 20 mg to about 40
mg of oxymorphone and the forinulation provides a maximum blood concentration
of
oxymorphone from about 0.5 ng/mL to about 7 ng/mL or from about 0.9 ng/mL to
about
6 ng/mL.
In yet another embodiment, the formulation comprises about 20 mg of
oxyinorphone and the formulation provides a maximum blood concentration of
oxymoiphone from about 0.5 ng/mL to about 3.2 ng/mL or from about 0.75 ng/mL
to
about 2.8 ng/mL.
In one embodiment, the formulation coinprises from about 40 mg to about 80 mg
of oxymoiphone and the formulation provides a maximum blood concentration of
oxyinorphone from about 1 ng/mL to about 15 ng/mL or from about 1.9 ng/mL to
about
12 ng/mL.
In another embodiment, the formulation comprises about 40 mg of oxymorphone
and the formulation provides a maximum blood concentration of oxymorphone from
about 1 ng/mL to about 7 ng/mL or from about 1.4 ng/mL to about 5 ng/mL.
In yet another embodiment, the fonnulation comprises about 80 mg of
oxyrnorphone and the formulation provides a maximum blood concentration of
oxyinorphone from about 3.5 ng/mL to about 15 ng/mL or from about 4 ng/mL to
about
13 ng/mL.
In one aspect, the invention provides a sustained release oxymorphone
fonnulation comprising a sustained release delivery system and from about 5 mg
to about
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80 mg of oxyinorphone, wherein the foi-inulation provides a miniinum blood
concentration of oxyinorphone of at least about 0.013 ng/mL at about 12 hours
after oral
administration of a single dose to a patient with about 200 mL to about 300 mL
of about
4% to about 40% ethanol, and the forinulation provides analgesia to the
patient for at least
about 12 hours after administration.
In one einbodiment, the formulation comprises about 5 mg of oxyinorphone and
provides a ininiinuin blood concentration of oxyinorphone of at least about
0.07 ng/mL.
In another einbodiinent, the formulation comprises about 10 mg of oxyinorphone
and provides a miniinum blood concentration of oxyinorphone of at least about
0.15
ng/mL.
In yet another einbodiinent, the forinulation comprises about 20 mg of
oxymorphone and provides a minimum blood concentration of oxymorphone of at
least
about 0.3 ng/mL.
In one einbodiment, the formulation coinprises about 40 mg of oxymorphone and
provides a minimum blood concentration of oxyinorphone of at least about 0.6
ng/mL.
In yet another einbodiment, the formulation coinprises about 80 mg of
oxymorphone and provides a minimum blood concentration of oxymorphone of at
least
about 1.2 ng/mL.
In some embodiments, the formulation is a solid dosage form, for example, a
tablet, a capsule, a granule, or a powder.
In one aspect, the invention provides a method of relieving pain comprising
administering to a patient a sustained release oxymorphone formulation
comprising a
sustained release delivery system and from about 5 mg to about 80 mg of
oxymorphone,
wherein after oral administration of a single dose to the patient with about
200 mL to
about 300 mL of about 4% to about 40% ethanol the forinulation provides a
secondary
peak of blood oxymorphone concentration about 12 hours after administration,
and the
formulation provides analgesia to the patient for at least about 12 hours
after
administration.
In some embodiments, the forinulation comprises from about 20 mg to about 60
mg of oxyinorphone or about 40 mg of oxymorphone. In one embodiment, the
fonnulation is a solid dosage, for example, a tablet, a granule, a capsule or
a powder.

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In another aspect, the invention provides a method of relieving pain
coinprising
administering to a patient a sustained release oxyinorphone fonnulation
comprising a
sustained release delivery system and from about 5 mg to about 80 mg of
oxymoiphone,
wherein after oral administration of a single dose to a patient the
forinulation provides a
inaxiinuin blood concentration of oxyinoiphone less than about 5 times higher
when
ingested with about 200 mL to about 300 mL of up to about 40% ethanol compared
to
when ingested without ethanol, and the formulation provides analgesia to the
patient for
at least about 12 hours after adininistration.
In one embodiment, the inaxiinum blood concentration of oxymorphone is less
than about 2.5 times higher when ingested with about 200 mL to about 300 mL of
up to
about 40 / ethanol coinpared to when ingested without ethanol.
In some embodiments, the formulation comprises from about 20 mg to about 60
mg of oxymorphone or about 40 ing of oxymorphone. In one embodiment, the
fonnulation is a solid dosage, for exainple a tablet, a granule, a capsule or
a powder.
In yet another aspect, the invention provides a method of relieving pain
comprising administering to a patient a sustained release oxyinorphone
forinulation
coinprising a sustained release delivery system and from about 5 mg to about
80 mg of
oxymorphone, wherein after oral adininistration of a single dose to a patient
the
forinulation provides a ratio of the maximum blood concentration of
oxymorphone when
ingested with about 200 mL to about 300 mL of about 40% ethanol to the maximum
blood concentration of oxymorphone when ingested after a high-fat meal without
ethanol
of about 0.5 to about 2, and the forinulation provides analgesia to the
patient for at least
about 12 hours after administration.
In one einbodiinent, the ratio of the inaxiinuin blood concentration of
oxymorphone when the forinulation is ingested with about 200 mL to about 300
mL of
about 40% ethanol to the maxiinum blood concentration of oxymorphone when the
forinulation is ingested after a high-fat meal without ethanol is from about
0.8 to about
1.5.
In some einbodiments, the formulation comprises from about 20 mg to about 60
mg of oxymorphone or about 40 mg of oxymorphone. In one einbodiment, the
formulation is a solid dosage, for example, a tablet, a granule, a capsule or
a powder.
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In one aspect, the invention provides a method of relieving pain comprising
administering to a patient a sustained release oxymorphone fonnulation
comprising a
sustained release delivery system and from about 5 rng to about 80 mg of
oxymorphone,
wherein after oral administration of a single dose to a patient with about 200
mL to about
300 inL of about 4% to about 40% ethanol the formulation provides a maxiinum
blood
concentration of oxyinorphone from about 0.1 ng/mL to about 15 ng/mL, and the
formulation provides analgesia to the patient for at least about 12 hours
after
adininistration.
In some embodiments, the formulation provides a maxiinuin blood concentration
of oxyrnoiphone from about 0.5 nghnL to about 7.5 ng/mL or from about 1 ng/hnL
to
about 4 ng/mL.
In one einbodiment, the fonnulation comprises from about 10 mg to about 20 mg
of oxymoiphone and the formulation provides a maximum blood concentration of
oxyinoiphone froin about 0.3 ng/mL to about 3.2 ng/mL or from about 0.4 ng/mL
to
about 2.8 ng/mL.
In some enlbodiments, the formulation comprises about 10 mg of oxyinoiphone
and the formulation provides a maximum blood concentration of oxymorphone from
about 0.3 ng/mL to about 1.8 ng/inL or from about 0.5 ng/mL to about 1.5
ng/mL.
In another embodiment, the formulation comprises from about 20 mg to about 40
mg of oxymorphone and the formulation provides a maximum blood concentration
of
oxymorphone from about 0.5 ng/inL to about 7 ng/mL or from about 0.9 ng/mL to
about
6 ng/mL.
In yet another embodiment, the formulation comprises about 20 mg of
oxyinorphone and the formulation provides a maximum blood concentration of
oxyinorphone from about 0.5 ng/mL to about 3.2 ng/mL or from about 0.75 ng/mL
to
about 2.8 ng/mL.
In one embodiment, the formulation comprises from about 40 mg to about 80 ing
of ox}nnorphone and the forinulation provides a maximum blood concentration of
ox}nnorphone from about I ng/inL to about 15 ng/mL or from about 1.9 ng/inL to
about
12 ng/mL.
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In another einbodiinent, the formulation comprises about 40 mg of oxymoiphone
and the fonnulation provides a maxiinum blood concentration of oxymorphone
from
about 1 ng/mL to about 7 ng/mL or from about 1.4 ng/inL to about 5 ng/hnL.
In yet another embodiment, the foilnulation comprises about 80 mg of
oxymorphone and the forinulation provides a inaxiinum blood concentration of
oxymorphone from about 3.5 ng/mL to about 15 ng/mL or from about 4 ng/mL to
about
13 ng/mL.
In another aspect, the invention provides a method of relieving pain
comprising
adininisteiing to a patient a sustained release oxymorphone forinulation
coinprising a
sustained release delivery system and from about 5 mg to about 80 mg of
oxyinorphone,
wherein the formulation provides a minimum blood concentration of oxyinorphone
of at
least about 0.013 ng/mL at about 12 hours after oral administration of a
single dose to a
patient with about 200 inL to about 300 mL of about 4% to about 40% ethanol,
and the
forinulation provides analgesia to the patient for at least about 12 hours
after
administration.
In one embodiment, the formulation comprises about 5 mg of oxymorphone and
provides a minimum blood concentration of oxymorphone of at least about 0.07
ng/mL.
In another embodiment, the formulation comprises about 10 mg of oxymorphone
and provides a minimum blood concentration of oxyinoiphone of at least about
0.15
ng/mL.
In yet another embodiment, the fonnulation comprises about 20 mg of
oxyinoiphone and provides a minimum blood concentration of oxymorphone of at
least
about 0.3 ng/mL.
In one einbodiinent, the forinulation comprises about 40 mg of oxyinorphone
and
provides a minimum blood concentration of oxymorphone of at least about 0.6
ng/mL.
In yet another embodiment, the fonnulation coinprises about 80 mg of
oxymorphone and provides a minimum blood concentration of oxymorphone of at
least
about 1.2 ng/mL. Sustained release fonnulations described herein can be used
in tlierapy.
Furthermore, sustained release formulations described herein can be used in
the
manufacture of a medicament for treatinent of a condition. In one embodiment,
the
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sustained release forinulations described herein can be used for the
manufacture of a
medicament for relieving pain.
In some embodiments, the foi7nulation is a solid dosage forin, for exainple, a
tablet, a capsule, a granule, or a powder.
These and otlier aspects and einbodiinents of the invention are described in
detail
herein.
4. DETAILED DESCRIPTION OF THE INVENTION
4.1. Definitions
As used herein, unless specifically indicated otherwise, the conjunction "or"
is
used in the inclusive sense of "and/or" and not the exclusive sense of
"either/or."
As used herein, the terin "robust" refers to a property of a sustained release
formulation that makes it less likely to have its dissolution profile
substantially modified,
injured, or otherwise fail. An example of a failure of a sustained release
formulation is
dose dumping. "Robust" and "rugged" are meant to be synonyms.
As used herein, the term "fine" refers to a particle size of a polymer having
a
diaineter smaller than 53 microns, or alternatively, having particles capable
of passing
through a #270 mesh sieve.
As used herein, the term "dose dumping" refers to a rapid release of a drug or
an
active ingredient from a sustained release formulation into the bloodstream.
This rapid
release is generally faster than the sustained release of a drug from the
forinulation. Dose
dumping also refers to a release having a peak concentration of the drug in
the blood
plasma higher than the peak concentration of the intended sustained release of
the drug.
Dose duinping can, in some instances, allow dangerous overdosing to occur,
which can
lead to fatal consequences.
As used herein, the terin "sustained release" means that the drug is released
from
the fonnulation at a controlled rate so that therapeutically beneficial blood
levels (but
below toxic levels) of the drug are maintained over an extended period of
time.
As used herein, tenns "sustained release", "extended release" and "controlled
release" are meant to be synonyms, i.e., have identical meaning.
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As used herein, the terin "inunediate release" means that the drug is released
from
the foilnulation in a short period of time, e.g., within about 4 hours after
adininistration of
the foilnulation.
As used herein, the term "AUC" refers to the area under the concentration-time
curve.
As used herein, the tenn "C,,,aX" refers to the maxiinum observed
concentration.
As used herein, the terrn "RSD" refers to the relative standard deviation.
As used herein, the term "CI" refers to the confidence interval.
As used herein, the term "high-fat meal" refers to a meal wherein
approximately
50 percent of total caloric content of the meal is derived from fat. An
example of a high-
fat meal is two eggs fried in butter, two strips of bacon, two slices of toast
with butter,
four ounces of hash brown potatoes and eight ounces of whole milk.
As used herein, the terin "liquids" includes, for example, gastrointestinal
fluids,
aqueous solutions (such as those used for in vitro dissolution testing), and
mucosas (e.g.,
of the mouth, nose, lungs, esophagus, and the like).
As used herein, the term "ethanol-resistant" refers to releasing less than 50%
of an
active ingredient (e.g., a drug) within one hour in a dissolution profile
measurement by
USP Procedure Di-ug Release USP 23 in 0.1N HCl and 40% ethanol solution.
As used herein, the terin "di-ug" includes any pharmaceutically active
chemical or
biological compound, and any phaimaceutically acceptable salt thereof, used
for
alleviating symptoms, treating or preventing a condition.
Drugs suited for the robust sustained release formulations described herein
include, but are not limited to, alprazolam (XANAX XR ), lithium carbonate
(LITHOBID ), divalproex sodiuin (DEPAKOTE ), neutral sulfate salts of
dextroamphetamine and amphetamine, with the dextro isomer of amphetamine
saccharate
and d,l-amphetamine aspartate monohydrate (ADDERALL XR ), tramadol
hydrochloride (TRAMADOL ER ) and opioids such as morphine (AVINZA and
KADIAN ) and oxycodone (OXYCONTIN ).
As used herein, the terin "opioid" includes stereoisomers thereof, metabolites
thereof, salts thereof, ethers thereof, esters thereof and/or derivatives
thereof (e.g.,
pharinaceutically acceptable salts thereof). The opioids may be inu-
antagonists and/or

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mixed mu-agonists/antagonists. Exeinplaxy opioids include alfentanil,
allylprodine,
alphaprodine, anileridine, benzyhnoiphine, bezitramide, buprenoiphine,
butorphanol,
clonitazene, codeine, cyclazocine, desomorphine, dextromorainide, dezocine,
diampromide, dihydrocodeine, dihydroinorphine, dimenoxadol, diinepheptanol,
dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine,
ethoheptazine,
ethyhnethylthiambutene, ethylmorphine, etonitazine, fentanyl, heroin,
hydrocodone,
hydroinorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan,
levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol,
metazocine,
methadone, metopon, inorphine, myrophine, nalbuphine, narceine, nicomorphine,
norlevorphanol, normethadone, nalorphine, normophine, norpipanone, opium,
oxycodone, oxymorphone, 6-hydroxyoxymorphone, papaveretuin, pentazocine,
phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine,
piritramide,
propheptazine, promedol, properidine, propiram, propoxyphene, sufentanil,
tramadol,
tilidine, stereoisomers thereof, inetabolites thereof, salts thereof, ethers
thereof, esters
thereof, and/or derivatives thereof. In some embodiments, the opioid is
morphine,
codeine, hydromorphone, hydrocodone, oxycodone, dihydrocodeine,
dihydromorphine,
oxymorphone, 6-hydroxyoxymorphone (including 6-a-hydroxyoxymorphone and/or 6-
(3-
hydroxyoxymorphone), or tramadol.
As used herein, the term "oxymorphone" includes oxymorphone, metabolites
thereof, and derivatives thereof. Metabolites of oxymorphone include, for
exainple, 6-
hydroxyoxymorphone (e.g., 6-a-hydroxyoxyrnorphone and/or 6-(3-
hydroxyoxymorphone).
As used herein, the term "condition" includes any disease or a collection of
symptoms that requires treathnent with a drug. Exemplary conditions include
panic
disorder (with or without agoraphobia), bipolar disorder (inanic depressive
illness), acute
manic or mixed episodes associated with bipolar disorder, epilepsy, migraine,
attention
deficit hyperactivity disorder (ADHD), depression and pain.
The pain can be minor to moderate, or moderate to severe. The pain can be
acute
or chronic. The pain can also be persistent and require continuous around-the-
clock relief
for an extended period of time. The pain can be associated with, for example,
cancer,
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autoimmune diseases, infections, surgical traumas, or accidental traumas. The
patient can
be an animal, a mammal, or a human.
The drug may be in the fonn of any pharmaceutically acceptable salt known in
the
art. Exemplaiy phannaceutically acceptable salts include hydrochloric,
sulfuric, nitric,
phosphoric, hydrobromic, maleric, malic, ascorbic, citric, tartaric, painoic,
lauric, stearic,
palrnitic, oleic, myristic, lauryl sulfuric, napthalinesulfonic, linoleic,
linolenic acid, and
the like.
The robust sustained release formulations of diugs are administered in an
amount
sufficient to alleviate symptoms, treat or prevent a condition for an extended
period of
time, for exainple about 8 hours to about 24 hours, or for a period of about
12 hours to
about 24 hours. The robust sustained release oral solid dosage formulations
described
herein may be administered four times a day, three tiines a day, twice daily,
or only once
daily.
The sustained release forinulations of opioids are administered in an amount
sufficient to alleviate pain for an extended period of time, for example about
8 hours to
about 24 hours, or for a period of about 12 hours to about 24 hours. The
opioid sustained
release oral solid dosage formulations described herein may be administered
four times a
day, three times a day, twice daily, or only once daily.
A therapeutically effective amount of a drug is an amount sufficient to
eliminate
or to alleviate symptoms of a condition (e.g., reduce the pain compared to the
pain present
prior to administration of the opioid sustained release formulation).
The drug can be present in the coinposition in an amount of about 0.5
milligrams
to about 1000 milligrains, in an amount of about 1 milligram to about 800
milligrains, in
an ainount of about 1 milligram to about 200 milligrams, or in an amount of
about 1
milligram to about 100 milligrams.
4.2. Particle size effects on robustness of sustained release formulations
It has been unexpectedly discovered that the particle size of hydrophilic
gums,
e.g., xanthan gum, affects dissolution properties of the sustained release
forinulations and
solid dosage forins comprising the sustained release formulations, thereby
affecting their
robustness. Discovering such a quality-by-design principle and understanding
how it
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applies to the dissolution profile of an extended release forrnulation of a
drug (e.g., an
opioid) had heretofore been unlcnown.
In particular, particle size of hydrophilic gums has been found to affect
robustness
of ethanol/ethylcellulose granulated formulation. For exainple,
ethanol/ethylcellulose
granulated fonnulations comprising xanthan gum as the hydrophilic gum are
robust when
the fraction of particles smaller than 53 microns in diameter is about 30% or
more. For a
different hydrophilic gum, this fraction might be smaller or larger, for
example between
about 20-80%, about 40-60%, or about 50%. Furthermore, if hydrophilic gum
particles
are screened through a different mesh filter, the size distribution of the
hydrophilic gum
required to produce a robust sustained release formulation can be different.
Robustness
of the sustained release fonnulations described herein is likely to be a
combination of the
choice of hydrophilic gum and particle size distribution. In general, the
coarser the
hydrophilic gum is, the larger the fraction of small particles is required for
a robust
formulation. Similarly, the finer the hydrophilic gum is, the smaller the
fraction of small
par-ticles is required for a robust formulation. In some instances, it may be
desirable for
the fonnulation to have a percentage of the hydrophilic gum larger than the
amount that
makes the formulation robust. If the hydrophilic gum is xanthan gum, the
fonnulation
may comprise more than 30% of xanthan gum particles smaller than 53 microns,
for
exainple, about 40%, about 50%, or about 60%.
Without intending to be bound by any theory, the hydrophilic properties of
certain
hydrophilic gums (e.g., xanthan gum) contribute to the initial hydration of
the sustained
release formulations and the solid dosage forms, which in one embodiment
comprise a
drug, one or more heteropolysaccharide gums and one or more homopolysaccharide
gums, and in another einbodiment comprise a drug, one or more
heteropolysaccharide
gums and one or more cross-linlcing compound selected from inonovalent
cations,
inultivalent cations, and salts.
Integrity of sustained release forinulations and solid dosage forms
coinprising
hydrophilic gums, e.g., xanthan guin, has also been found to be sensitive to
the method
used for granulation of formulations coinprising xanthan gum particles.
When the granulation method of choice is wet-granulation with non-aqueous
solvents such as alcohols, glycerol, propylene glycol, or other non-aqueous
solvents, the
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particle size of xanthan gum will have a substantial effect on hydration and
integrity of
the granulated sustained release formulation and the solid dosage foi7n.
Rapid hydration of xanthan gum in cold water contributes to the integrity of
non-
water granulated sustained release formulations and finished solid dosage
forins described
herein. The rate of hydration of xanthan gum was found to depend on the
xanthan gum
particle size. Xanthan gum particles of small diameter will, for exainple,
hydrate faster
than xanthan gum pai-ticles of large diaineter. Therefore, non-water
granulated sustained
release foilnulations and solid dosage forms coinprising xanthan gum particles
of smaller
average and/or mean diameter will hydrate faster and be more robust than
granulated
sustained release formulations and solid dosage for-ms coinprising xanthan gum
particles
of larger average and/or mean diameter.
In some embodiments, wet-granulation with non-aqueous solvents includes a
dispersion of one or more hydrophobic materials (e.g., an alkylcellulose, a
copolyiner of
acrylic and methacrylic acid esters, waxes, shellac, zein, hydrogenated
vegetable oils, and
mixtures of any of the foregoing) in an amount effective to slow the hydration
of the
formulation when exposed to an environmental fluid.
For example, when the granulation method of choice is wet granulation with
ethanol and ethylcellulose, the size of xanthan gum particles affects the
hydration
properties and integrity of the granulated sustained release formulation and
the solid
dosage form.
When the granulation method of choice is wet granulation with water or any
other
aqueous solution, the hydration will be effected using the water from the
aqueous
solution, and the particle size of xanthan gum will have a lesser, negligible,
or even non-
existent effect on the hydration of the solid dosage foi-lnulation. Based on
their poor cold-
water solubility, certain homopolysaccharide gums, such as locust bean guin,
are not
expected to contribute to the initial hydration of the sustained release
forinulation and
solid dosage form. Therefore, the average and/or mean particle size of these
homopolysaccharides gums does not affect the hydration properties and
integrity of the
sustained release forinulation and the solid dosage form.
Particle size can be measured using any suitable method used in the art.
Perhaps
the most common method of measuring particle size comprises screening
particles
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through a sieve. Other exeinplary methods include optical methods, e.g., laser
diffraction
measurements, light microscopy, surface area measurements (e.g., mercury
porosimetry,
nitrogen gas adsorption, krypton gas adsorption). Other physical measurements
can also
be used to calculate particle size.
Robustness and integrity of solid dosage forms, such as tablets, capsules,
granules
and powders, can be measured using several techniques, such as dissolution
profile
ineasureinents. Exeinplary dissolution profile measurements include drug
release
measurements using a USP Type I, Type II, Type III, or Type IV dissolution
apparatus.
4.3. Ethanol effects on robustness of sustained release formulations
It has been discovered that the sustained release formulations described
herein
retain their sustained release dissolution properties in the presence of
ethanol.
Without intending to be bound by any theory, the physicochemical properties of
the hydrophilic compound (e.g., xanthan gum) cross-linked by a cross-linking
agent (e.g.,
locust bean guin), are such that they together form a gum or gum-like matrix,
which is
insoluble or substantially insoluble in ethanol. These solubility properties
of the
foimulation may be attributed to the hydrophilic nature of the sustained
release delivery
system, which in one embodiment comprises one or more hydrophilic gums and one
or
more hoinopolysaccharide gums, and in another embodiment comprises or one or
more
hydrophilic gums, and one or more monovalent cations, inultivalent cations,
and/or salts.
Small amounts of hydrophobic agents (e.g., hydrophobic polymers such as
ethylcellulose), do not substantially modify the dissolution properties of the
forinulation
in ethanol, presumably because the sustained release delivery system retains
its
hydrophilic character. Properties of the drug are not likely to affect the gum
or gum-like
properties of the matrix, making the formulations described herein suitable
and/or
adaptable to a wide range of drugs.
Several factors are believed to affect the release of a drug from the
forinulation in
the presence of ethanol: solubility of the drug in ethanol, materials
comprising the
forniulation (e.g., hydrophilic compounds are more resistant to ethanol than
hydrophobic
compounds), and dosage forin of the foi-inulation (e.g., tablets are more
resistant to
ethanol than capsules).

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Additional factors believed to affect the release of a dlug from the
fonnulation in
the presence of ethanol are: degree of coinpression of the dosage (e.g.,
harder tablets are
more resistant to ethanol than softer tablets), tablet coinposition (e.g.,
monolithic tablet
compositions are less resistant to ethanol than inultiparticulate particle
unit dosage forms
enclosed in a gelatin capsule), and presence of a gel-like coating which is
resistant to
dissolution in ethanol (e.g., certain celluloses).
The sustained release forinulations described herein can, therefore, be used
to
prevent or substantially reduce any undesired effects of ethanol on the
release of the drug
from a fol-mulation. Exemplary undesired effects include dose duinping and
altered
sustained release dissolution profiles.
Alteration of a sustained release profile can be exhibited, for example, in
the
bioavailability profile of the drug, such as altered blood plasma
concentration time curve
after administration of the drug with or without a beverage containing
ethanol. Typical
parameters measured are the high peak drug concentration (Cmax), an increase
of which
can increase the safety risk of a drug, drug concentration at the end of the
therapeutic
period (C,,,in), a decrease of which can reduce the efficacy of the drug. The
sustained
release formulations described herein exhibit mean increases in C,,,a, of
about 1.7 fold
when taken with 40% alcohol coinpared to 0% alcohol. This is considered
acceptable
because CmaX ratios in an individual when a drug is administered to a fed
(with a standard
high-fat meal) vs. a fasted individual can vary from about 0.7 to about 3.5,
with a mean
C,,,aX ratio of about 1.5. Therefore, taking a drug with 40% ethanol has a
coinparable
effect to taking the drug after a high-fat meal. Talcing the drug with 20% or
4% ethanol
has a smaller effect on Cmax than a high-fat meal, as exhibited by the mean
Cmax ratios of
about 1.2 and about 1.1, respectively.
In an exemplary scenario, a formulation with an altered sustained release
profile
by ethanol may, for exainple, release a larger amount of the drug shortly
after
administration (e.g., within 0-6 hours), resulting in a higher-than-intended
C,,,aX. If the
drug is toxic, a higher-than-intended C,naX can lead to harmful side effects
for the patient,
including death. As a consequence of this rapid release, less drug is
available for
subsequent release, resulting in a lower-than-intended C,,,;,, at the end of
the therapeutic
period (i.e., just prior to adininistration of a subsequent dose). A lower-
than-intended
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C,,,in can result in reduced efficacy or even inefficacy of the drug, which
can result in
recurrence of a condition in a patient.
A higher-tlian-intended peak drug concentration Cinax can be, for example, a
concentration more than four times higher than intended C,,,aX. A lower-than-
intended
C,,,;n concentration can be, for exainple, a concentration less than one third
of the intended
Cmin.
At the Phannaceutical Sciences Advisory Coinmittee Meeting of Oct. 26, 2005,
FDA personnel presented results of a post-approval in vivo study of a known
drug. The
study showed that taking the drug with a beverage containing 40% alcohol led
to a five-
fold increase in C,nax and taking the same drug with a beverage containing 20%
alcohol
led to a doubling of C,,,ax. Taking the drug with a beverage containing 5%
alcohol led to a
small mean effect, but at least one subject doubled their C,,,a,.
The sustained release formulations described herein can, therefore, be used to
increase safety of drugs with potentially harmful effects at high
concentrations and to
reduce abuse of drugs producing a euphoric effect, such as opioids. The
fonnulations
described herein can also be used to reduce or prevent harm to a patient in
situations
where a reduced level of a drug (e.g., lower than the therapeutically
beneficial level) can
adversely affect the health of the patient. The formulations described herein
can be useful
for forinulation of narrow therapeutic range drugs, sometimes referred to as
narrow
therapeutic index drugs.
If a forinulation described herein is ingested with an alcoholic beverage, or
ingested by a patient prior to or after consumption of an alcoholic beverage,
the
formulation will essentially retain its sustained release properties and will
slowly release
the drug from the resulting hydrophilic gel matrix.
Because the formulations described herein do not dose dump in the presence of
ethanol, they can be used for formulation of drugs that are at risk to be
taken with ethanol,
such as abuse-potential drugs and drugs prescribed to alcohol and/or drug
abusers, or
drugs that produce harmful or lethal side effects if over-dosed. Exainples of
such drugs
include opioids.
In addition, patients being treated for conditions such as panic disorder
(with or
without agoraphobia), bipolar disorder (manic depressive illness), acute manic
or mixed
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episodes associated with bipolar disorder, epilepsy, migraine, attention
deficit
hyperactivity disorder (ADHD), depression and/or pain may be inore likely to
consume
alcohol coinpared to the general population. This could be a result of the
patients' desire
to experience the euphoric effects from inebriation and/or to eliminate or
alleviate the
symptoms of their condition, such as pain.
Due to the slow release of the drug from the fonnulations described herein,
the
patient (e.g., a drug addict) would not experience the euphoria that would be
immediately
available by abusing conventional formulations (e.g., opioid formulations) by
oral
inhalation/ingestion or oral ingestion with an alcoholic beverage.
Accordingly, the drug
forinulations described herein would not be abused by patients or their
potential for abuse
would be significantly reduced (e.g., when coinpared to conventional opioid
formulations).
For example, the sustained release fonnulations described herein resist
extraction
of the drug from the fonnulation by grounding up the solid dosage forms into
powder,
pouring over 95% ethanol, diluting the resulting solution with water to
beverage-strength
ethanol, and removing the undissolved material by filtration through a coffee
or other
paper filter. Ethanol content of hard liquors is typically in the range of 40-
45%. This
method of extraction is envisioned to be einployed by drug addicts, wanting to
abuse a
drug from the sustained release forinulation, such as an opioid, by injecting
themselves
with the diug extracted from the formulation.
Additionally, because the drug is released slowly from a sustained release
fonnulation over an extended period of time, many sustained release
formulations contain
relatively high amounts of the drug. Sustained release formulations containing
high
ainounts of drugs can be more harmfitl to a patient when they fail compared to
immediate
release formulations, which generally contain smaller amounts of the drug.
Therefore,
the drug formulations described herein can increase safety of drugs that can
be hannful
and/or lethal at higher than therapeutically beneficial levels.
4.4. Sustained release delivery system
The sustained release delivery system comprises at least one hydrophilic
compound. In soine embodiments, the hydrophilic compound is a gum, for example
a
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heteropolysaccharide gum, forms a gel matrix that releases the drug at a
sustained rate
upon exposure to liquids.
The rate of release of the drug from the gel matrix depends on the drug's
partition
coefficient between the components of the gel matrix and the aqueous phase
within the
gastrointestinal tract. In the coinpositions described herein, the weight
ratio of drug to
hydrophilic coinpound is generally in the range of about 1:0.5 to about 1:25,
or in the
range of about 1:0.5 to about 1:20. The sustained release delivery system
generally
coinprises the hydrophilic compound in an amount of about 20% to about 80% by
weight,
in an amount of about 20% to about 60% by weight, in an amount of about 40% to
about
60% by weight, or in an amount of about 50% by weight.
The hydrophilic compound can be any known in the art. Exemplary hydrophilic
coinpounds include gums, cellulose ethers, acrylic resins, polyvinyl
pyrrolidone, protein-
derived coinpounds, and mixtures thereof. Exemplary gums include
heteropolysaccharide gums and homopolysaccharide gums, such as xanthan,
tragacanth,
pectins, acacia, karaya, alginates, agar, guar, hydroxypropyl guar,
carrageenan, locust
bean gums, and gellan gums. Exeinplary cellulose ethers include hydroxyalkyl
celluloses
and carboxyalkyl celluloses, such as hydroxyethyl celluloses, hydroxypropyl
celluloses,
hydroxypropylmethyl-celluloses, carboxy methylcelluloses, and mixtures
thereof.
Exemplary aciylic resins include polymers and copolyiners of acrylic acid,
methacrylic
acid, methyl acrylate and methyl methacrylate. In some embodiments, the
hydrophilic
compound is a gum, for example a heteropolysaccharide gum, such as a xanthan
gum or
derivative thereof. Derivatives of xanthan gum include, for example,
deacylated xanthan
gum, the carboxyinethyl esters of xanthan gum, and the propylene glycol esters
of
xanthan gum.
In another embodiment, the sustained release delivery system further comprises
at
least one cross-linking agent. The cross-linlcing agent can be a coinpound
that is capable
of cross-linking the hydrophilic compound to form a gel matrix in the presence
of liquids.
The sustained release delivery system generally comprises the cross-linking
agent in an
amount of about 0.5% to about 80% by weight, in an amount of about 2% to about
54%
by weight, in an amount of about 20% to about 30% by weight, or in an ainount
of about
25% by weight.
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Exeinplary cross-linking agents include homopolysaccharides. Exeinplary
hoinopolysaccharides include galactomannan gums, such as guar gum,
hydroxypropyl
guar gum, and locust bean gum. In some einbodiments, the cross-linlcing agent
is a locust
bean gum, a guar gum, or a derivative thereof. In other einbodiinents, the
cross-linking
agent is an alginic acid derivative or a hydrocolloid.
When the sustained release delivery system coinprises at least one hydrophilic
coinpound and at least one cross-linlcing agent, the ratio of hydrophilic
coinpound to
cross-linlcing agent is generally from about 1:9 to about 9:1, or from about
1:3 to about
3:1.
In some einbodiments, the sustained release delivery system coinprises one or
more cationic cross-linlcing coinpounds. In some embodiments, the cationic
cross-linking
coinpound can be used instead of or in addition to the cross-linking agent.
The cationic
cross-linking compound can be used in an amount sufficient to cross-link the
hydrophilic
compound to form a gel matrix in the presence of liquids. The cationic cross-
linking
compound is present in the sustained release delivery system in an amount of
about 0.5%
to about 30% by weight, or from about 5% to about 20% by weight.
Exemplary cationic cross-linking compounds include monovalent metal cations,
multivalent metal cations, and inorganic salts, including alkali metal and/or
alkaline earth
metal sulfates, chlorides, borates, bromides, citrates, 'acetates, lactates,
and mixtures
thereof. For example, the cationic cross-linlcing coinpound can be one or more
of calcium
sulfate, sodium chloride, potassiuin sulfate, sodium carbonate, lithium
chloride,
tripotassium phosphate, sodium borate, potassium bromide, potassium fluoride,
sodium
bicarbonate, calcium chloride, magnesium chloride, sodium citrate, sodium
acetate,
calcium lactate, inagnesiuin sulfate, sodium fluoride, or mixtures thereof.
When the sustained release delivery system comprises at least one hydrophilic
coinpound and at least one cationic cross-linking coinpound, the ratio of the
hydrophilic
coinpound to the cationic cross-linking compound is generally from about 1:9
to about
9:1, or from about 1:3 to about 3:1.
Two properties of compounds (e.g., the at least one hydrophilic compound and
the
at least one cross-linking agent; or the at least one hydrophilic compound and
the at least
one cationic cross-linlcing coinpound) that forin a gel matrix upon exposure
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fast hydration of the coinpounds/agents and a gel matrix having a high gel
strength.
These two properties, which are needed to achieve a slow release gel matrix,
are
maximized by the particular combination of coinpounds (e.g., the at least one
hydrophilic
coinpound and the at least one cross-linking agent; or the at least one
hydrophilic
coinpound and the at least one cationic cross-linlting compound). For example,
hydrophilic compounds (e.g., xanthan gum) have excellent water-wicking
properties that
provide fast hydration. The coinbination of hydrophilic coinpounds with
materials that
are capable of cross-linking the rigid helical ordered structure of the
hydrophilic
coinpound (e.g., cross-linlcing agents and/or cationic cross-linking
compounds) thereby
act synergistically to provide a higher than expected viscosity (i.e., high
gel strength) of
the gel matrix.
In some embodiments, the sustained release delivery system further coinprises
one
or more pharmaceutical diluents known in the art. Exemplary pharmaceutical
diluents
include monosaccharides, disaccharides, polyhydric alcohols and inixtures
thereof, such
as starch, lactose, dextrose, sucrose, inicrociystalline cellulose, sorbitol,
xylitol, fi-uctose,
and mixtures thereof In other einbodiments, the phannaceutical diluent is
water-soluble,
such as lactose, dextrose, sucrose, or mixtures thereof. The ratio of
pharinaceutical
diluent to hydrophilic compound is generally from about 1:8 to about 8:1, or
from about
1:3 to about 3:1. The sustained release delivery system generally comprises
one or more
pharmaceutical diluents in an amount of about 20% to about 80% by weight, for
example
about 35% by weight. In other embodiments, the sustained release delivery
system
comprises one or more pharmaceutical diluents in an amount of about 40% to
about 80%
by weight.
In some einbodiments, the sustained release delivery system further comprises
one
or more hydrophobic polymers. The hydrophobic polymers can be used in an
amount
sufficient to slow the hydration of the hydrophilic coinpound without disr-
upting it. For
exainple, the hydrophobic polyiner may be present in the sustained release
delivery
system in an amount of about 0.5% to about 20% by weight, in an amount of
about 2% to
about 10% by weight, in an ainount of about 3% to about 7% by weight, or in an
ainount
of about 5% by weight.
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Exeinplary hydrophobic polymers include alkyl celluloses (e.g., C1_6 alkyl
celluloses, carboxyinethylcellulose), other hydrophobic cellulosic materials
or
coinpounds (e.g., cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate),
polyvinyl acetate polyiners (e.g., polyvinyl acetate phthalate), polyiners or
copolymers
derived from acrylic and/or methacrylic acid esters, zein, waxes, shellac,
hydrogenated
vegetable oils, and mixtures thereof. The hydrophobic polylner can be, for
exainple,
methyl cellulose, ethyl cellulose, or propyl cellulose.
The compositions described herein may be further admixed with one or more
wetting agents (such as polyethoxylated castor oil, polyethoxylated
hydrogenated castor
oil, polyethoxylated fatty acid from castor oil, polyethoxylated fatty acid
from
hydrogenated castor oil), one or more lubricants (such as magnesium stearate),
one or
more buffering agents, one or more colorants, and/or other conventional
ingredients.
In some embodiments, the robust sustained release formulations comprising a
drug are solid dosage formulations, such as orally administrable solid dosage
formulations, for exainple, tablets, capsules comprising a plurality of
granules, sublingual
tablets, powders, or granules. In some embodiments, the orally administrable
solid
dosage formulations are tablets. The tablets optionally comprise an enteric
coating or a
hydrophobic coating.
4.5. Robust sustained release formulations comprising oxymorphone
In one einbodiment, the robust sustained release forinulations described
herein
comprise an analgesically effective amount of oxymorphone or a
pharmaceutically
acceptable salt thereof.
Administration of oxymorphone is frequently hindered by the very low
bioavailability of the oral iminediate release formulations of oxymoiphone,
which require
a 4 hourly dosing frequency. The bioavailability of the robust sustained
release
formulations described herein is sufficiently high that the robust sustained
release
forinulations can be used to treat patients suffering from pain with only once
or twice
daily dosing.
The robust sustained release forinulations of oxyinorphone are administered in
an
amount sufficient to alleviate pain for an extended period of time, for
example, for a
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period of about 8 hours to about 24 hours, or for a period of about 12 hours
to about 24
hours.
The oxyinorphone sustained release oral solid dosage formulations described
herein can be administered four times a day, three times a day, twice daily,
or once daily.
In certain einbodiinents, upon oral ingestion of the robust sustained release
formulation comprising oxyinorphone and contact of this forinulation with
gastrointestinal fluids, the robust sustained release formulation swells and
gels to forin a
hydrophilic gel matrix from which the oxymorphone is released. The swelling of
the gel
matrix causes a reduction in the bulk density of the formulation and provides
the
buoyancy necessary to allow the gel matrix to float on the stomach contents to
provide a
slow delivery of the oxyinorphone. The hydrophilic matrix, the size of which
is
dependent upon the size of the original formulation, can swell considerably
and become
obstructed near the opening of the pylorus. Because the oxyinorphone is
dispersed
throughout the fonnulation (and consequently throughout the gel matrix), a
constant
amount of oxymorphone is released per unit time in vivo by dispersion or
erosion of the
outer portions of the hydrophilic gel matrix. The process continues, with the
gel matrix
remaining buoyant in the stomach, until substantially all of the oxyinorphone
is released.
In certain embodiments, the chemistry of certain of the components of the
formulation, such as the hydrophilic compound (e.g., xanthan gunl), is such
that the
components are considered to be self-buffering agents which are substantially
insensitive
to the solubility of the oxymorphone and the pH changes along the length of
the
gastrointestinal tract. Moreover, the chemistry of the components is believed
to be
similar to certain known muco-adhesive substances, such as polycarbophil. Muco-
adhesive properties are desirable for buccal delivery systems. Thus, the
robust sustained
release forinulation can loosely interact with the mucin in the
gastrointestinal tract and
thereby provide another mode by which a constant rate of delivery of the
oxymoiphone is
achieved.
In one embodiment, when measured by USP Procedure Drug Release USP 23
(incorporated by reference herein in its entirety), the robust sustained
release formulations
described herein exhibit an in vitf o dissolution rate of about 15% to about
50% by weight
oxyinoiphone after 1 hour, about 45% to about 80% by weight oxyinorphone after
4
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hours, and at least about 80% by weight oxyinorphone after 10 hours. The in
vitro and in
vivo release characteristics of the robust sustained release forinulations
described herein
can be modified using mixtures of one or more different water insoluble and/or
water
soluble compounds, using different plasticizers, varying the thiclrness of the
sustained
release film, including providing release-modifying coinpounds in the coating,
and/or by
providing passageways through the coating.
Soine einbodiinents provide robust sustained release solid dosage fonnulations
coinprising from about 1 ing to about 200 mg of oxymorphone hydrochloride, or
from
about 5 mg to about 80 ing of oxymorphone hydrochloride; and from about 80 mg
to
about 200 ing of a sustained release delivery system, or from about 120 mg to
about 200
mg of a sustained release delivery system, or about 160 mg of a sustained
release delivery
system; where the sustained release delivery system comprises about 8.3 to
about 41.7%
locust bean gum, or about 25% locust bean gum; from about 8.3 to about 41.7%
xanthan
gum having at least about 30% of particles smaller than about 53 microns in
diameter, or
about 25% xanthan gum with at least about 30% of particles smaller than about
53
microns in diameter; from about 20 to about 55% dextrose, or about 35%
dextrose; from
about 5 to about 20% calcium sulfate dihydrate, or about 10% calcium sulfate
dihydrate;
and from about 2 to 10% ethyl cellulose, or about 5% ethyl cellulose.
Other einbodiments provide robust sustained release solid dosage formulations
comprising from about 1 mg to about 200 mg of oxymorphone hydrochloride, or
from
about 5 mg to about 80 mg of oxymorphone hydrochloride; and from about 80 mg
to
about 200 ing of a sustained release deliveiy system, or from about 120 mg to
about 200
mg of a sustained release delivery system, or about 160 mg of a sustained
release delivery
system; where the sustained release delivery system comprises from about 8.3
to about
41.7% locust bean gum, or about 25% locust bean gum; from about 8.3 to about
41.7%
xanthan gum wherein at least about 30% of the xanthan gum particles can pass
through a
#270 mesh sieve, or about 25% xanthan gum of which at least about 30% of the
particles
can pass through a #270 mesh sieve; from about 20 to about 55% dextrose, or
about 35%
dextrose; from about 5 to about 20% calcium sulfate dihydrate, or about 10%
calcium
sulfate dihydrate; and from about 2 to about 10% ethyl cellulose, or about 5%
ethyl
cellulose.
34

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Some embodiments provide robust sustained release solid dosage foi-mulations
coinprising from about 1 mg to about 200 mg of oxyinoiphone hydrochloride, or
from
about 5 mg to about 80 mg of oxymorphone hydrochloride; and from about 200 mg
to
about 420 mg of a sustained release delivery system, or from about 300 mg to
about 420
ing of a sustained release delivery system, or about 360 mg of a sustained
release delivery
system; where the sustained release delivery system coinprises from about 8.3
to about
41.7% locust bean gum, or about 25% locust bean gum; from about 8.3 to about
41.7%
xanthan gum having at least about 30% of pai-ticles smaller than about 53
microns in
diameter, or about 25% xanthan gum with at least about 30% of particles
smaller than
about 53 microns in diameter; from about 20 to about 55% dextrose, or about
35%
dextrose; from about 5 to about 20% calcium sulfate dihydrate, or about 10%
calcium
sulfate dihydrate; and from about 2 to 10% ethyl cellulose, or about 5% ethyl
cellulose.
Other einbodiinents provide robust sustained release solid dosage fonnulations
coinprising from about 1 mg to about 200 mg of oxymorphone hydrochloride, or
from
about 5 ing to about 80 mg of oxymorphone hydrochloride; and from about 200 mg
to
about 420 ing of a sustained release delivery system, or from about 300 mg to
about 420
mg of a sustained release delivery system, or about 360 mg of a sustained
release delivery
system; where the sustained release delivery system comprises from about 8.3
to about
41.7% locust bean gum, or about 25% locust bean gum; from about 8.3 to about
41.7%
xanthan gum wherein at least about 30% of the xanthan gum particles can pass
through a
#270 mesh sieve, or about 25% xanthan gum of which at least about 30% of the
particles
can pass through a #270 mesh sieve; from about 20 to about 55% dextrose, or
about 35%
dextrose; from about 5 to about 20% calcium sulfate dihydrate, or about 10%
calcium
sulfate dihydrate; and from about 2 to 10% ethyl cellulose, or about 5% ethyl
cellulose.
When administered orally to patients the robust sustained release fonnulations
described herein exhibit the following in vivo characteristics: (a) a peak
plasma level of
oxymorphone occurs within about 2 to about 6 hours after administration; (b)
the duration
of the oxyinorphone analgesic effect is about 8 to about 24 hours; and (c) the
relative
oxymoiphone bioavailability is about 0.5 to about 1.5 compared to an orally
administered
aqueous solution of oxymorphone.

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While the oxyinoiphone coinpositions described herein can be administered as
the
sole active pharinaceutical coinpound in the methods described herein, they
can also be
used in combination with one or more coinpounds which are known to be
therapeutically
effective against pain.
In one embodiment, pharmaceutical kits comprising one or more containers
filled
with one or more of robust sustained release oxyinorphone forinulations
described herein
are provided. The kits can further comprise other pharmaceutical coinpounds
known in
the art to be therapeutically effective against pain, and instructions for
use.
4.6. Preparation of the robust sustained release formulations
The robust sustained release formulations described herein can be prepared by
wet
granulation methods. The solid dosage forins described herein can be prepared
by direct
compression or by wet granulation of the formulations.
In some einbodiments, the sustained release forinulations are manufactured by
a
wet granulation technique. In the wet granulation technique, the coinponents
(e.g.,
hydrophilic compounds such a xanthan gum, cross-linking agents, pharmaceutical
diluents, cationic cross-linking compounds, hydrophobic polymers, etc.) are
mixed
together and then moistened with one or more liquids (e.g., water, propylene
glycol,
glycerol, alcohol) to produce a moistened mass that is subsequently dried. The
dried
mass is then milled with conventional equipment into granules of the sustained
release
delivery system. Thereafter, the sustained release delivery system is mixed in
the desired
ainounts with the drug and, optionally, one or more wetting agents, one or
more
lubricants, one or more buffering agents, one or more coloring agents, or
other
conventional ingredients, to produce a granulated composition. The sustained
release
delivery systein and the drug can be blended with, for example, a high shear
mixer. The
drug can be finely and homogeneously dispersed in the sustained release
delivery system.
The granulated coinposition, in an amount sufficient to make a uniforin batch
of tablets, is
subjected to tableting in a conventional production scale tableting machine at
norinal
coinpression pressures, i.e., about 2,000-16,000 psi. The mixture should not
be
coinpressed to a point where there is subsequent difficulty with hydration
upon exposure
to liquids. Exeinplary methods for preparing sustained release delivery
systems are
36

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WO 2008/045047 PCT/US2006/039781
described in U.S. Patent Nos. 4,994,276, 5,128,143, 5,135,757, 5,455,046,
5,512,297 and
5,554,387, the disclosures of which are incolporated by reference herein in
their entirety.
It has been unexpectedly discovered that the particle size of the hydrophilic
coinpound (e.g., xanthan gum) affects the robustness and integrity of the
formulation and
solid dosage forins when the sustained release delivery system is wet-
granulated with a
non-aqueous solution, such as an ethanol/ethylcellose suspension.
In particular, the fraction of small particles (e.g., smaller than 53 microns
in
diameter) of the hydrophilic compound (e.g., xanthan gum) affects the
robustness and
integrity of the sustained release formulations and solid dosage forins
prepared by wet-
granulation with a non-aqueous solvent. For example, if the xanthan gum used
to make
the formulation contains less than a certain fraction (e.g., about 30%) of
small xanthan
gum particles, the sustained release formulation is prone to failure. When the
fraction
of small xanthan gum particles used to make the formulation meets or exceeds
certain
threshold value, the formulations are robust and not prone to failure. For
example, once a
threshold fraction of about 30% of xanthan gum particles smaller than 53
microns in
diameter is met or exceeded, no change in robustness and integrity of the
formulation and
solid dosage form is observed (see Table 4).
It will be apparent to one skilled in the art that other combinations of
xanthan gum
particle sizes and threshold fractions may also be used to manufacture robust
sustained
release formulations described herein. For example, a formulation comprising
xanthan
gum particles smaller than 45, 38, 32, 25, or 20 microns in diameter may be
robust when
the threshold fraction is less than about 30%, for exainple between about 5-
25%, or
between about 10-20%. A fonnulation coinprising xanthan guin particles smaller
than
63, 75, 90, 106, 125, or 150 microns in diaineter may be robust when the
threshold
fraction is more than about 30%, for exainple between about 30-100%, or
between about
50-90%. Robustness and integrity of sustained release formulations and solid
dosage
forms granulated with a non-aqueous solution can be iinproved by controlling
the particle
size distribution of the hydrophilic compound (e.g., xanthan gum). Control of
the particle
size distribution of the hydrophilic coinpound can be achieved, for example,
by screening
the hydrophilic coinpound (e.g., xanthan gum) particles through a sieve,
(e.g., a #270
mesh sieve) which allows particles smaller than a certain size (e.g., 53
microns in
37

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WO 2008/045047 PCT/US2006/039781
diameter) to pass through. Batches, lots, and combinations thereof having a
desired
fraction of particles of a desired size can then be used for combination with
other
coinponents to make a robust sustained release forinulation.
Alternatively, the hydrophilic coinpound (e.g., xanthan gum) can be
manufactured
to have a desired particle distribution, in which case no screening or other
processing is
required. Furthermore, the hydrophilic compound having a desired particle size
distribution (such as average particle size, mean particle size, ininiinum
particle size,
maximum particle size, or a combination thereof) can be received from an
external
source, for example, a commercial manufacturer or a distributor.
When the sustained release delivery system is wet-granulated with water or any
other aqueous solution, the particle size of the hydrophilic coinpound (e.g.,
xanthan gum)
does not appear to affect the robustness and integrity of the sustained
release formulation
and the solid dosage form (see Table 5).
The average particle size of the pharmaceutical forinulations before tableting
is
from about 50 microns to about 400 microns, or from about 185 microns to about
265
microns. The average density of the pharmaceutical formulations is from about
0.3 g/ml
to about 0.8 g/ml, or from about 0.5 g/ml to about 0.7 g/inl. The tablets
formed from the
pharmaceutical foimulations are generally from about 6 to about 8 kg hardness.
When the tableting step in making the solid dosage forinulation is performed
using wet granulation instead of direct coinpression, the particle size of the
hydrophilic
coinpound (e.g., xanthan gum) does not affect the robustness and dissolution
properties of
the solid dosage fonn.
In some embodiments, the sustained release coatings over an inner core
comprise
at least one drug. For example, the inner core comprising the drug can be
coated with a
sustained release film, which, upon exposure to liquids, releases the drug
from the core at
a sustained rate.
In one embodiment, the sustained release coating comprises at least one water
insoluble coinpound. The water insoluble compound can be a hydrophobic
polyrner. The
hydrophobic polymer can be the same as or different from the hydrophobic
polymer used
in the sustained release delivery system. Exemplary hydrophobic polyiners
include alkyl
celluloses (e.g., C1_6 alkyl celluloses, carboxyinethylcellulose), other
hydrophobic
38

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WO 2008/045047 PCT/US2006/039781
cellulosic materials or coinpounds (e.g., cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate), polyvinyl acetate polylners (e.g.,
polyvinyl
acetate phthalate), polymers or copolyiners derived from acrylic and/or
methacrylic acid
esters, zein, waxes (alone or in admixture with fatty alcohols), shellac,
hydrogenated
vegetable oils, and mixtures thereof. The hydrophobic polyiner can be, for
example,
methyl cellulose, ethyl cellulose, or propyl cellulose. The robust sustained
release
forinulations can be coated with a water insoluble coinpound to a weight gain
from about
I to about 20% by weight.
The sustained release coating can further comprise at least one plasticizer
such as
triethyl citrate, dibutyl phthalate, propylene glycol, polyethylene glycol, or
mixtures
thereof.
The sustained release coating can also contain at least one water soluble
compound, such as polyvinylpyrrolidones, hydroxypropylmethylcelluloses, or
mixtures
thereof. The sustained release coating can comprise at least one water soluble
compound
in an amount froin about 1% to about 6% by weight, for example, in an amount
of about
3% by weight.
The sustained release coating can be applied to the drug core by spraying an
aqueous dispersion of the water insoluble compound onto the drug core. The di-
a.g core
can be a granulated composition made, for example, by dry or wet granulation
of mixed
powders of drug and at least one binding agent; by coating an inert bead with
an drug and
at least one binding agent; or by spheronizing mixed powders of an drug and at
least one
spheronizing agent. Exeinplary binding agents include
hydroxypropylmethylcelluloses.
Exemplary spheronizing agents include microcrystalline celluloses. The inner
core can
be a tablet made by compressing the granules or by compressing a powder
coniprising a
diug.
In other embodiments, the compositions comprising at least one drug and a
sustained release delivery system, as described herein, are coated with a
sustained release
coating, as described herein. In still other embodiments, the compositions
comprising at
least one drug and a sustained release delivery system, as described herein,
are coated
with a hydrophobic polymer, as described herein. In still other einbodiments,
the
compositions comprising at least one drug and a sustained release delivery
system, as
39

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WO 2008/045047 PCT/US2006/039781
described herein, are coated with an enteric coating, such as cellulose
acetate phthalate,
hydroxypropyhnethylcellulose phtlialate, polyvinylacetate phthalate,
methacrylic acid
copolynler, shellac, hydroxypropyhnethylcellulose succinate, cellulose acetate
triinelliate,
or mixtures thereof. In still otller embodiments, the compositions comprising
at least one
drug and a sustained release delivery system, as described herein, are coated
with a
hydrophobic polyiner, as described herein, and further coated with an enteric
coating, as
described herein. In any of the embodiments described herein, the
colnpositions
coinprising the drug and a sustained release delivery system, as described
herein, can
optionally be coated with a hydrophilic coating which may be applied above or
beneath
the sustained release film, above or beneath the hydrophobic coating, and/or
above or
beneath the enteric coating. Exemplary hydrophilic coatings coinprise
hydroxypropyhnethylcellulose.
Without intending to be bound by any theory of the invention, upon oral
ingestion
of the drug sustained release formulation and contact of the forinulation with
gastrointestinal fluids, the sustained release formulation swells and gels to
form a
hydrophilic gel matrix from which the drug is released. The swelling of the
gel matrix
causes a reduction in the bulk density of the forinulation and provides the
buoyancy
necessary to allow the gel matrix to float on the stomach contents to provide
a slow
delivery of the drug. The hydrophilic matrix, the size of which is dependent
upon the size
of the original forinulation, can swell considerably and become obstructed
near the
opening of the pylorus. Because the drug is dispersed throughout the
formulation (and
consequently tluoughout the gel matrix), a constant amount of drug can be
released per
unit time in vivo by dispersion or erosion of the outer portions of the
hydrophilic gel
matrix. This phenomenon is referred to as a zero order release profile or zero
order
kinetics. The process continues, with the gel matrix remaining buoyant in the
stomach,
until substantially all of the drug is released.
Without intending to be bound by any theory of the invention, the chemistry of
certain of the components of the formulation, such as the hydrophilic
coinpound (e.g.,
xanthan gum), is such that the components are considered to be self-buffering
agents
which are substantially insensitive to the solubility of the drugs and the pH
changes along
the length of the gastrointestinal tract. Moreover, the chemistry of the
components is

CA 02653017 2009-02-26
WO 2008/045047 PCT/US2006/039781
believed to be similar to certain known inuco-adhesive substances, such as
polycarbophil.
Muco-adhesive properties are desirable for buccal delivery systems. Thus, it
may be
possible that the sustained release fonnulation could potentially loosely
interact with the
inucin in the gastrointestinal tract and thereby provide another mode by which
a constant
rate of delivery of the drug is achieved.
The two phenomena discussed above (hydrophilic gel matrix and inuco-adhesive
properties) are possible mechanisms by which the robust sustained release
forinulations
described herein could interact with the mucin and fluids of the
gastrointestinal tract and
provide a constant rate of delivery of the drugs.
4.7. Usefulness of robust sustained release formulations
The robust sustained release foimulations and solid dosage forms described
herein
are useful for formulation of drugs that pose a risk to the patient in case of
a formulation
failure. The formulations and solid dosage forms coinprising the forinulations
described
herein are useful for providing (e.g., prescribing, administering) drugs that
pose a risk to
the patient in case of a forinulation failure. Exainples of such drugs
include, for.example,
opioids such as oxymorphone.
The robust sustained release formulations and solid dosage forms described
herein
are useful for treating a condition (e.g., pain), by prescribing and/or
administering a
therapeutically effective amount of the robust sustained release formulations
of the drug
(e.g., an opioid such as oxymorphone) to a patient who could consume ethanol
while
being treated with the drug. A therapeutically effective amount is an amount
sufficient to
eliminate the condition or to alleviate the condition (i.e., reduce the
symptoms compared
to the syinptoins present prior to administration of the robust sustained
release
forinulation).
While the forinulations and solid dosage forms described herein can be
administered as the sole active pharmaceutical coinposition in the methods
described
herein, they can also be used in coinbination with one or more compounds
and/or
compositions that are known to be therapeutically effective against the
condition.
Pharinaceutical kits comprising one or more of the diug forinulations
described
herein are provided. Pharinaceutical kits can, for example, comprise one or
more
containers filled with one or more of the robust sustained release
formulations and/or
41

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WO 2008/045047 PCT/US2006/039781
solid dosage forins described herein. The kits can further coinpr-ise other
pharinaceutical
compounds lcnown in the art to be therapeutically effective against a
condition, and
instructions for use.
5. EXAMPLES
The following examples are for purposes of illustration only and are not
intended
to limit the scope of the appended claims.
Some experiments were perfomled with albuterol sulfate, which has dosage,
solubility and other physicocheinical properties similar to opioids, such as
oxymorphone
and oxycodone.
Example 1
Preparation of TIMERx-NO sustained release
delivery system using ethanol/ethylcellulose granulation
Lots of TIMERx-NO sustained release delivery system were prepared according
to the procedures related to those identified in U.S. Patent Nos. 4,994,276,
5,128,143 and
5,554,387, incorporated herein by reference in their entirety.
Lots of xanthan gum (Jungbunzlauer, Perhoven, Austria or CP Kelco, Chicago,
IL) were particle-size tested using a series of mesh sieves. These sieves
included a #270
mesh sieve, which allowed particles smaller than 53 microns in diameter to
pass through
(fine particles). The weight fraction of xanthan gum particles passing through
the sieves
(i.e., fraction of fine xanthan guin) was determined. Batches with known
fractions of fine
xanthan gum particles were then prepared. TIMERx-N was prepared by dry
blending
the requisite amounts of xanthan gum, locust bean gum, calcium sulfate, and
dextrose in a
high speed mixer/granulator for 3 minutes. A slurry of hydrophobic polymer
(ethylcellulose) was prepared by dissolving ethyl cellulose in ethyl alcohol.
The slurry
was added to the dry blended mixture and the material was subsequently
granulated for 4
minutes while running the choppers/impeller. The granulation was then dried in
a fluid
bed dryer to a LOD (loss on drying) of less than 9% by weight (e.g., typical
LOD was -3-
5%). The granulation was then milled using a 1.0 mm (0.040") screen. The
ingredients of
the sustained release excipient are set forth in Table 1:
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Table 1
TIMERx-NOO Composition
Component %
1. Xanthan Gum 25
2. Locust Bean Gum 25
3. Calcium Sulfate 10
4. Dextrose 35
5. Ethyl Cellulose 5
6. Ethyl Alcohol -20*
*reinoved during processing
Example 2
Preparation of TIMERx-M50A sustained release
delivery system using water granulation
Lots of TIMERx-M50A@ sustained release delivery system were prepared
according to the procedures related to those identified in U.S. Patent No.
5,399,358,
incorporated herein by reference in its entirety.
Xanthan gum batches with Icnown fractions of fine particles were prepared
according to Exainple 1. TIMERx-M50A was prepared by dry blending the
requisite
amounts of xanthan gum, locust bean gum, calcium sulfate, and mannitol in a
high speed
mixer/granulator for 3 minutes. While rumling choppers/impellers, water was
added to
the dry blended mixture, and the mixture was granulated for another 3 minutes.
The
granulation was then dried in a fluid bed dryer to a loss on drying (LOD) of
less than
about 6% by weight. Typical LOD was between -3-5%. The granulation was then
milled using a 0.065" screen. The ingredients of the sustained release
delivery system are
set forth in Table 2.
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Table 2
TIMERx-M50A0 Composition
Component %
Xanthan Gum 20
Locust Bean Gum 30
Mannitol 40
Calcium Sulfate 10
Water -30-40*
*reinoved during processing
Example 3
Preparation of sustained release formulations and solid
dosage forms with variable amounts of fine xanthan gum
A sustained release fonnulation was prepared by screening albuterol sulfate,
ProSolv SMCCO 90 (Silicified Microcrystalline Cellulose, JRS Pharma LP,
Patterson,
New York) and TIMERx-NO or TIMERx-M50A0 separately through a #20 mesh sieve.
The albuterol sulfate, ProSolv SMCCO 90 and either TIMERx-NO or TIMERx-M50A0,
prepared according to Examples 1 and 2, respectively, were blended for 11
minutes in a
Patterson-Kelley P/K Blendmaster V-Blender. PruvTM (Sodium Stearyl Fumarate,
NF,
JRS Pharma LP, Patterson, New York) was added to this mixture and the mixture
was
blended for five minutes. The blended granulation was compressed to 224.0 mg
and -11
Kp hardness on a tablet press using 5/16" round standard concave beveled edge
tooling.
The final tablet composition is listed in the Table 3.
Table 3
Tablet Com osition
Component % mg/tablet
Albuterol sulfate 17.9 40.0
TIMERx-NO or TIMERx-M50A0 71.4 160.0
ProSolv SMCCO 90 8.9 20.0
PruvTM 1.8 4.0
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Example 4
Dissolution profile measurements of solid dosage forms
with variable amounts of fine xanthan gum
Albuterol sulfate tablets with TIMERx-NO and TIMERx-M50A0 sustained
release delivery systems were prepared as described in Exainple 3. Dissolution
profiles
of tablets were evaluated using a USP Apparatus 2 dissolution tester in 900 mL
of 50 mM
potassium phosphate buffer (pH 4.5). The solution was stirred at 50 r.p.in. A
series of
samples of about 1.5 mL were withdrawn at predeterinined intervals for a
period of up to
14 hours.
Drug release for all tablets was monitored by RP-HPLC using a Waters
Syininetry0 C18 coluinn (4.6 x 250 mm) (or equivalent) preceded by a
Phenomenex0
SecurityGuardTM C18 (4 x 3.0 mm) guard column. Monitoring wavelength was set
to 226
nin. The mobile phase consisted of buffer: acetonitrile:methanol in 85:10:5
v/v ratios.
The buffer consisted of 1 mL triethylamine and 1 mL trifluoroacetic acid in 1
L of H20.
The coluinn temperature was 30 C and the flow rate was set to 1.5 mL/min. To
deterinine the percentage of drug released at each timepoint, the
concentration of the
sainple taken at that timepoint was coinpared to the concentration of a
standard solution.
The standard solution was prepared by dissolving 45 mg of albuterol sulfate in
100 mL of
50 mM potassium phosphate buffer (pH 4.5) and then taking 5 inL of this
solution and
diluting it to 50 mL with more of 50 mM potassium phosphate buffer (pH 4.5).
Results of dissolution experiments with tablets made with
alcohol/ethylcellulose-
granulated TIMERx-NOO comprising xanthan gum with different particle size
distributions
are shown in Table 4.

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Table 4
Sustained % albuterol sulfate released
release
delivery TIMERx-NOO (ethanol/ethylcellulose-granulated)
system
Fraction
of fine
xanthan 13.7% 27.9% 31.6% 42.0%0 0 0 48.5% 85.2% 88.8%
gum
Time
0.5 hr 102.3 94.2 17.2 17.7 16.8 19.0 18.9
1 hr 102.7 96.9 28.7 27.9 27.6 29.3 29.0
2 hrs 45.2 43.4 44.3 44.9 44.5
3 hrs 57.8 55.5 57.1 56.8 56.7
4 hrs 68.0 65.9 67.0 66.3 66.7
6 hrs 82.6 79.9 80.8 79.5 80.8
8 hrs 91.7 88.6 89.2 88.1 89.8
hrs 97.2 93.7 94.0 93.1 94.5
121irs 100.5 96.6 96.9 96.3 97.2
14 hrs 102.7 97.9 98.4 98.2 98.7
Tablets coinprising 13.7% and 27.9% of fine xanthan gum in the
ethanol/ethylcelluose-granulated TIMERx-NO released nearly the entire quantity
of drug
almost immediately. This is an example of undesired dose dumping. Tablets with
31.6%
or more of fine xanthan gum dissolved in the expected sustained release
manner. The
data in Table 4 indicate that there appears to be no substantial difference in
dissolution
profiles of formulations containing between about 31.6% and about 88.8% of
fine
xanthan gum particles.
Results of dissolution experiments with tablets made with water-granulated
TIMERx-M50A coinprising xanthan gum with different particle size
distributions are
shown in Table 5.
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Table 5
Sustained release % albuterol sulfate released
delivery system
TIMERx-M50A0 (water- granulated)
Xanthan gum
particle size < #80 mesh < #200 mesh
(<180 microns) (<75 microns)
Time
0.5 hr 17.5 19.8
1 hr 29.5 29.9
2 hrs 47.6 45.4
3 hrs 62.6 58.1
4 hrs 74.2 68.6
6 hrs 88.4 83.0
8 hrs 96.8 91.6
hrs 101.0 96.5
121u=s 103.4 99.0
14 hrs 104.8 99.9
Tablets made by direct coinpression of water-granulated TIMERx-M50A
formulations comprising xanthan gum are not sensitive to xanthan gum particle
size. The
data in Table 5 indicate that there appears to be no substantial difference
between the
dissolution profiles of tablets made with xanthan gum having particle size of
less than 180
microns and less than 75 microns when xanthan gunz is granulated with water in
the
process of making the formulation.
Table 6 shows dissolution profiles of tablets made by direct compression and
granulation of ethanol/ethylcellulose-granulated sustained release
formulations with
different fractions of #270 (fine) mesh xanthan gum particles.
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Table 6
Sustained % albuterol sulfate released
release
delivery TIMERx-NOO (ethanol/ethylcellulose-granulated)
system
Fraction
of fine 27.9% 27.9% 34.8% 42.0%
xanthan (tablet made (tablet (tablet made (tablet made
gum by direct made by by direct by direct
compression) wet compression) compression)
Time 14ranulation)
0.5 hr 80.1 17.3 17.2 17.9
1 hr 92.8 25.6 28.7 29.0
2 hrs 39.2 45.2 46.3
3 hrs 50.7 57.8 59.7
4 hrs 59.6 68.0 70.5
6 hrs 72.5 82.6 83.9
8 hrs 81.2 91.7 92.1
hrs 88.1 97.2 97.2
12 hrs 91.9 100.5 99.2
14 hrs 102.7 99.7
Coinparison of dissolution profiles of tablets comprising TIMERx-N that were
manufactured either using direct compression or wet granulation in the
tableting step,
shows that robustness of tablets appears to be sensitive to xanthan gun
particle size when
the tablets are manufactured by direct compression, but not when they are
manufactured
by wet granulation. Tablets with ethanol/ethylcellulose-granulated TIMERx-NOO
with
27.9% of fine particles had desired dissolution profiles when tableted using
wet
granulation, but not when tableted using direct compression. Direct
compression of
ethanol/ethylcellulose-granulated formulations produced tablets with desired
dissolution
profiles when the fraction of fine xanthan gum was more than about 30%.
Example 5
Ethanol resistance of solid dosage forms with variable amounts of fine xanthan
gum
Tablets of TIMERx-N formulations of albuterol sulfate were prepared as
described in Example 3. Dissolution profiles of each formulation were measured
as
described in Example 4. A medium of 40% ethanol and 60% 0.1 M HC1 was used as
a
48

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model of dissolution in the presence of alcohol. 0.1M HC1 was chosen to mimic
the
biological environment of upper GI tract/stomach area, where the sustained
release
formulation first begins to release the drug.
Dissolution experiments were performed using a USP II Type dissolution
apparatus according to inethods described above. Results of dissolution
experiments with
tablets made with alcohol/ethylcellulose-granulated TIMERx-NOO coinprising
xanthan
gum with different particle size distributions are shown in Table 7.
Table 7
Sustained % albuterol sulfate released
release
delivery TIMERx-NO (ethanol/ethylcellulose-granulated)
system
Fraction of
fine
xantlian 28% in 35% 86% in
gum in 28% in 40% 35% in 42% in 42% in 86% in o
dissolution buffer E 1 anol buffer Ethanol buffer Ethanol buffer Ethan~ol
medium
Time
0.5 hr 98.5 100.0 15.7 28.8 18.7 16.1 17.8 15.8
1 hr 99.9 101.2 26,8 38.1 29.6 25.5 27.5 24.1
2 hrs 99.8 99.5 45.2 51.5 46.9 40.3 45.1 34.9
3 hrs 99.8 99.5 58.7 63.6 60.2 53.0 57.9 44.6
4 hrs 99.8 99.5 69.6 76.9 70.9 63.7 67.7 52.5
6 hrs 99.8 99.5 86.5 92.8 85.4 78.0 81.5 66.0
ghrS 99.8 99.5 96.8 99.0 94.2 87.6 89.4 74.2
hrs 99.8 99.5 103.3 101.7 98,9 96.6 94.3 80.9
12 hrs 99.8 99.5 105.9 103.5 101.7 103.1 96.9 85.5
14 hrs 99.8 99.5 108.0 105.0 103.7 106.5 98.1 88.9
Tablets comprising 28% of fine xanthan gum in the ethanol/ethylcelluose-
granulated TIMERx-N released nearly the entire quantity of drug almost
immediately.
This is an example of undesired dose dumping. Tablets with 35% or more of fine
xanthan guin dissolve in the expected sustained release manner. The data in
Table 7
indicate that there appears to be no substantial difference in dissolution
profiles of
formulations containing between about 35% and about 86% of fine xanthan gum
49

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particles, although the formulation containing about 86% of fine xanthan gum
particles
dissolved sliglltly slower in 40% ethanol solution than in a standard buffer.
Therefore, foi7nulations coinprising about 30% or more of fine xanthan gum,
exhibit robust dissolution propei-ties, and dissolve in a sustained release
manner in the
presence and absence of beverage-strength ethanol.
Example 6
Preparation of robust sustained release oxymorphone formulations
and solid dosage forms
A controlled release delivery system was prepared by dry blending xanthan gum,
locust bean gum, calcium sulfate dihydrate, and dextrose in a high speed
mixed/granulator for a few minutes. A sluny was prepared by mixing ethyl
cellulose
with alcohol. While running choppers/impellers, the slurry was added to the
dry blended
mixture, and granulated for a few minutes. The granulation was then dried to a
LOD
(loss on drying) of less than about 10% by weight. The granulation was then
milled using
a screen. The relative quantities of the ingredients used to prepare the
sustained release
delivery system are listed in Table 8A.
Table 8A
Excipient % of Formulation
Locust Bean Gum, FCC 25.0
Xanthan Gum, NF 25.0
Dextrose, USP 35.0
Calcium Sulfate Dihydrate, NF 10.0
Ethylcellulose, NF 5.0
Alcohol, SD3A (Anyhdrous) (10)
Total 100.0
Tablets coinprising 40 mg of oxymorphone hydrochloride were prepared using the
controlled release delivery system shown in Table 8A. The quantities of
ingredients per
tablet are listed in Table 8B.

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Table 8B
Component Amount per tablet
[mg]
Oxymoiphone HCI, USP (mg) 40
TIMERx-N sustained release delivery system 160
Silicified microcrystalline cellulose, N.F. 20
Sodium stearyl fumarate, N.F. ' 2
Total theoretical weight of uncoated drug product 222
Methylparaben 0.08140
Opadry (colored) 8.88
Opadry (clear) 1.11
Total theoretical weight of final drug product 232.07
(coated)
Example 7
Extraction-resistance of powdered sustained release oxymorphone tablets
Tablets of TIMERx-N sustained release formulations with 40 mg of
oxymorphone were tested for abuse potential in an intravenous route of
administration. A
person, such as a drug addict, trying to abuse the formulation, may attempt to
extract the
opioid from the tablets and inject themselves with the resulting solution.
Tablets of TIMERx-N sustained release forinulations with 40 mg of
oxyinorphone were prepared according to procedures in Example 6 and ground
into
powder. In the water extraction test, the resulting powder was dispersed into
30 mL of
water and stirred for 5 seconds. In the 95% ethanol/water extraction test, the
resulting
powder was dispersed into 15 mL of 95% ethanol, stirred for 5 seconds, and
then diluted
with an additional 15 mL of water. In the 95% ethanol extraction test, the
resulting
powder was dispersed into 30 mL of 95% ethanol and stirred for 5 seconds. In
each test,
the resulting solution was allowed to set for 15 minutes before being filtered
through a
paper filter. Oxymorphone recovery from the filtered solutions was measured
using
HPLC at 40 C, using a Zorbax XDB-C18 coluinn and a UV detector set at 230
rnm.
Recovery of oxymorphone from each test is shown in Table 9.
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Table 9
Tablet % Dose recovered after extraction in
water 95% etlianol / water 95 % ethanol
1 3.3 14.8 87.3
2 3.8 13.3 85.3
3 3.3 11.3 82,5
Mean 3.5 13.0 85.0
When sustained release tablets comprising 40 mg of oxyinorphone, forinulated
with TIMERx-N made with xanthan gum in which at least 30% of particles can
pass
through a #270 mesh sieve, were powdered and extracted with water,
approximately 3-
4% of oxymorphone was released into water after 15 ininutes. To mimic abuse by
dropping a tablet into 95% ethanol and then diluting it to an ingestible
concentration,
powdered tablets were first suspended in 95% ethanol for 5 seconds, followed
by dilution
with water to provide a 47.5% ethanol solution. In this experiment,
approximately 11-
15% of oxyinorphone was released into the water/ethanol solution after 15
minutes. The
powdered sustained release 40 mg oxymoiphone tablets formulated with TIMERx-N
with xanthan gum of which at least 30% of the particles can pass through a
#270 mesh
sieve, therefore, resist extraction in more than one potential abuse scenario.
Example 8
Dissolution profiles of sustained release oxymorphone
tablets in the presence of beverage-strength ethanol
Sustained release 40 mg oxymorphone tablets were prepared as described in
Example 6. Dissolution tests were perforined on sets of 12 tablets in 500 mL
of 0.1N
HCl and ethanol/0.1N HCl solutions at 4%, 20%, and 40% ethanol concentrations.
Oxyinorphone release was determined by HPLC as described above.
Tablets remained intact throughout the dissolution tests in all media. Mean
concentrations of oxymorphone released are shown in Table 10A. Similarity
factors (f2)
for the ethanol dissolution media against the 0.1N HCl medium were calculated
using
standard methods and the results indicate that the drug release rate is
inversely correlated
with the amount of ethanol in the dissolution medium (Table 10B). An increase
in
ethanol content of the dissolution medium moderately decreased the drug
release rate.
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Results of dissolution experiments are summarized in Table 10A.
Table 10A
Medium Mean % oxymorphone released (n=12)
0 hrs 0.5 hrs 1 hr 2 hrs 4 hrs 8 hrs 12 hrs
0.1NHC1 0 22 33 49 70 97 102
RSD /a * 0 3.2 2.7 1.8 1.0 0.6 0.6
Range 0 21-23 32-35 48-50 69-71 96-97 101-102
4% Etl:anol 0 22 33 49 69 96 102
RSD %* 0 3.3 3.0 2.5 2.0 1.6 1.8
Range 0 21-23 31-34 46-50 66-70 93-99 99-106
20% 0 18 28 42 61 89 100
Etlzanol 0 2.1 2.4 2.5 2.9 2.0 1.9
% RSD* 0 17-18 27-29 40-45 59-66 86-93 97-103
40% 0 15 24 37 54 78 94
Ethafzol 0 6.0 2.2 1.8 1.9 2.3 3.2
RSD %* 0 14-18 23-25 35-38 52-56 74-81 90-101
* RSD = Relative Standard Deviation
The presence of up to 40% ethanol did not significantly affect the dissolution
profile of sustained release 40 mg oxymorphone tablets. The presence of 4%
ethanol had
an insignificant effect on the dissolution profile of 40 mg sustained release
oxymorphone
tablets compared to their dissolution profile in the absence of ethanol.
Oxymorphone
release was inversely correlated with the amount of ethanol in the dissolution
medium.
Presence of 20% and 40% ethanol in the dissolution medium slowed down the
release of
oxymorphone, which was still released in a controlled manner. No dose dumping
was
obseived at concentrations of ethanol between 0% and 40%. Therefore, tablets
with
sustained release formulations described herein release oxymorphone in a
controlled
manner in the presence of up to at least 40% ethanol.
Table lOB
Similarity factor (f2) for dissolution profiles of 40 mg
oxymorphone sustained release tablets in 0.1N HCl and ethanol
solutions
Medium 4% ethanol 20% ethanol 40% ethanol
Relative to 0.1N 97 60 45
HCl
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Similarity factors for ethanol-containing media relative to 0.1N HCl medium
(0%
ethanol) were 97, 60 and 45 for the 4%, 20% and 40% ethanol solutions,
respectively.
Thus, oxyinorphone tablets resist beverage strength concentrations of ethanol
and do not
dose dmnp in the presence of at least up to 40% ethanol.
Example 9
Effect of ethanol on bioavailability of oxymorphone from
sustained release oxyinorphone tablets
Healthy volunteers were used in a study to assess the pharinacokinetics of
oxyinorphone 40 mg sustained release tablets when co-administered with 240 mL
of
40%, 20%, 4%, and 0% (water) ethanol.
The study design was a randomized, open-label, single-dose, four-period
crossover in 28 subjects. To block the opioid effects of oxymorphone,
naltrexone HCl
(50 mg) was administered approximately 12 and 2 hours prior to each
oxymoiphone
administration, and again at 12 hours after administration. Subjects were
fasted overnight
for at least 8 hours prior to dosing. Water was allowed ad lib except fi=om 1
hour before
dosing until 1 hour after dosing. A standardized meal was served 4 hours and
10 hours
after dosing.
Oxylnorphone 40 mg sustained release tablets were administered on four
separate
occasions with 240 mL of: A) 40% ethanol, B) 20% ethanol, C) 4% ethanol, or D)
0 /
ethanol. Serial blood samples were obtained from 0 to 48 hours after dosing.
Plasma
samples were assayed for oxymorphone. Pharmacokinetic parameters for
oxymorphone
were deterinined using non-compartmental methods for data evaluation. Point
estimates
and 90% confidence intervals (CIs) for natural logarithmic transformed Cmax,
AUCo_t, and
AUCo_iõf were calculated using Least Squares Means (LSMeans). Any treatment in
which a subject vomited during the dosing interval (0-12 hours) was excluded
from the
primary pharmacokinetic analysis.
Thirty subjects were enrolled in the study. Twenty-five subjects completed the
study, meaning these subjects received all four treatinents. Subjects who
vomited within
the dosing interval (0-12 hours) were to have that treatment excluded from the
pharmacokinetic analysis. There were 10 subjects who vomited between 0-12
hours on
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treatment A (40% ethanol) and 5 subjects who vomited between 0-12 hours on
treatment
B (20%) ethanol. There were no subjects who vomited on treatments C (4%
ethanol) or
D (0% ethanol). Mean plasma concentration-time data for each treatment,
excluding
subject data from a treatinent if the subject vomited, are shown in Table 11.
Table 11
Mean oxymorphone plasma concentrations (excluding subjects with emesis)
[pg/ml]
Time 0% ethanol 4% ethanol 20% ethanol 40% ethanol
(hr) (N=25) (N=25) (N=2% (N=15)
0 hr 0.000 4.200 1.115 0.000
0.25 hr 316,248 269.400 255.910 686.880
0.5 hr 1218.988 1067.048 1307.611 1968.407
0.75 hr 1572.360 1469.992 2067.158 2520.593
1 hr 1716.480 1556.372 2135.500 2630.867
1.5 hrs 1726.720 1785.560 2352.500 2746.200
2 hrs 1930.840 1944.920 2442.000 2466.000
31irs 1694.800 1854.040 2179.750 2556.667
41irs 1450.800 1754.880 1838.400 2416.000
hrs 1800.600 2002.400 1768.700 2402.533
6 hrs 1681.080 1877.440 1591.350 1944.933
8 hrs 1262.880 1517.480 1359.550 1061.200
hrs 1002.800 1187.000 1162.000 889.200
12 hrs 1429.316 1489.280 1420.050 1223.667
16 hrs 876.800 872.760 958.400 854.067
24 hrs 443.872 451.920 403.305 407.933
36 hrs 254.988 238.020 241.980 261.647
48 hrs 95.180 99.976 85.675 116.207

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Statistical analyses of the pharinacokinetic paraineters are presented in
Table 12.
Table 12
Pharmacokinetic Oxymorphone treatment (excluding subjects that vomited)
parameter (SD) 40% ethanol 20% ethanol 4% ethanol 0% ethanol
C,i,ax, pg/mL 3917 3089 2564 2373
(1672) (1150) (1037) (870)
T,nax, h 1,50 1.50 3.0 2.0
(0.75-6.0) (0.75-8.0) (1.0-12.0) (0.5-12.0)
AUCo_t, pg=h/mL 36385 35389 35146 33350
(12441) (11495) (12534) (11864)
AUC0_1õf, pg=h/mL 39973" 36889 37551b 36034b
(13595) (12356) (13452) (11388)
tvz, h 11.3a 9.9 10.46 10.7b
(3.5) (3.2) (4.1) (4.7)
N 15 20 25 25
Median and range reported for T,,,aX
`n=13
bn=24
Geometric mean ratios (GMR) and 90% CI for those treatments in which subjects
completed the study without vomiting between 0-12 hours are shown in Table 13.
Table 13
Oxymorphone treatment
Pharmacolcinetic 40% ethanol/0% ethanol 20% ethanol/0% ethanol 4% ethanol/0%
ethanol
Parameter Ratio 90% CI Ratio 90% CI Ratio 90% CI
C,nax 1.703 1.476,1.966 1.309 1.151, 1.488 1.073 0.952,1.209
AUCo_11.129 1.03, 1.24 1,040 0.95, 1.13 1.055 0.97, 1.14
AUCp_1õf 1.127 1.03, 1.24 1.010 0.93, 1.09 1.022 0.95, 1.10
The mean plasma concentration-time data in Table 11 show that the 40% and 20%
ethanol treatments produce higher plasma concentrations during the first 4 to
6 hours
coinpared to the 0% ethanol treatment. The 4% ethanol treatment mean plasma
concentrations were similar to those for the 0% ethanol treatment. All data
were
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comparable from 16 to 48 hours after dosing. Secondary peaks were obseived at
5 hours
for the 4% and 0% ethanol treatinents and 12 hours for all four treatments.
Although the
40% ethanol treatment mean plasma concentration was higher than 0%, 4%, or 20%
from
0.5 to 6 hours, the concentration then declined and was lower than the other
three
treatments at 8 to 12 hours. C,,,ax was the only pharinacolcinetic parameter
that appeared
to be directly related to the ethanol treatment (Table 12). From the ratios
shown in Table
13, it can be seen that the increases in C,,,ax were 70%, 31 %, and 7% for the
40% ethanol,
20% ethanol and 4% ethanol treatments, respectively, coinpared to the 0%
ethanol
treatment. Changes in AUCo_t and AUCo_iõf ranged from 1% to 13% for the
ethanol
treatments coinpared to 0% ethanol (Table 13). Other than Cmaxo no significant
differences for the phannacokinetic parameters were observed among various
treatments.
Analysis of all subjects regardless of whether they vomited is presented in
Tables
14 and 15. Mean plasma concentration-time data for each treatment, without any
exclusions for vomiting, are shown in Table 14.
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Table 14
Mean oxymorphone plasma concentrations (including subjects who vomited)
[pg/ml]
Time 0% ethanol 4% ethanol 20% ethanol 40% ethanol
(hr) (N=25) (N=25) (N=25) (N=25)
0 hr 0.000 4.200 0.892 0.000
0.251u 316.248 269.400 205.892 544.828
0.5 hr 1218.988 1067.048 1090.458 1775.428
0,75 hr 1572.360 1469.992 1718,917 2641.636
1 hr 1716.480 1556.372 1860.552 2640.640
1.5 hrs 1726.720 1785.560 2045.680 2481.396
21us 1930.840 1944.920 2138.240 2208.060
3 hrs 1694.800 1854.040 1981.320 2166.160
4 hrs 1450.800 1754.880 1720.920 2152.960
51us 1800.600 2002.400 1695.680 2635.628
61us 1681.080 1877.440 1481.040 2311.740
8 lu s 1262.8 80 1517.480 1226.040 1259.644
hrs 1002.800 1187.000 1024.568 866.844
12 hrs 1429.316 1489.280 1250.080 981,016
16 hrs 876.800 872.760 844.264 692.216
24 hrs 443.872 451.920 359.224 338.700
254.988 238.020 227.056 233.728
95.180 99.976 80.784 97.752
Mean plasma concentration-time profiles without excluding treatments (n=25) in
which subjects vomited (Table 14), showed the 40% ethanol treatment with a
secondary
peak at 5 hours, which was not clearly evident in Table 11, where only 15
subjects were
represented. The 20% ethanol treatment (n=25) appeared to be similar to that
of Table
11, where there were 20 subjects. The 4% and 0% ethanol treatments represented
the
same sainple of subjects as those in Table 11. As previously indicated in
Table 12, Cmax
was the only phannacolcinetic parameter that appeared to be directly related
to the ethanol
treatment (Table 15).
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Table 15
Mean Oxymorphone treatment (including subjects who vomited, N=25)
Pharmacokinetic 40% ethanol 20% ethanol 4% ethanol 0% ethanol
Parameter (SD)
Cmax, pg/mL 4124 2815 2564 2373
(2251) (1227) (1037) (870)
T,nnx, h 1.50 2.0 3.0 2.0
(0.75-6.0) (0.75-8.0) (1.0-12.0) (0.5-12.0)
AUCo_t, pg li/m1 33677 31815 35146 33350
(13772) (13456) (12533) (11864)
AUCo_iõf, pg h/ml 37128a 34677b 37551 36034
(14803) (13432) (13452) (11388)
h 11.7a 9.9b 10.4 10.7
(4.5) (3.1) (4.1) (4.7)
N 25 25 25 25
an =22
bn=23
GMR data shown in Table 16 indicate that increases in Cmax were 62%, 15%, and
8% for the 40% ethanol, 20% ethanol and 4% ethanol treatinents, respectively,
as
compared to the 0% ethanol treatment. Changes in AUCo_t and AUCo_;,,f ranged
from -
10% to 7% for the ethanol treatments as compared to 0% ethanol (Table 16). The
40%
and 20% Cmax, AUCo_t and AUCo_iõf increases were lower when subjects who
vomited
were included.
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Table 16
Oxymorphone treatment (including subjects who vomited, N=25)
40% ethanol 20 % ethanol 4% ethanol
Parameter /0% ethanol /0% ethanol /0% ethanol
Ratio 90% CI Ratio 90% CI Ratio 90% CI
Cmax 1.623 1.365, 1.931 1.145 0.963, 1.362 1.077 0.905, 1.281
AUCo-t 0.961 0.79, 1.18 0.897 0.73, 1.10 1.070 0.87, 1.31
AUCo-int 0.953 0.78, 1.16 0.920 0.75, 1.12 1.034 0.85, 1.26
Example 10
Effect of food on bioavailability of 40 mg sustained release oxymorphone
tablets and 4 x 10 mg oxymorphone immediate release tablets
A study was perforined in healthy volunteers to assess the effect of food on
the
bioavailability of sustained release 40 ing oxyinorphone tablets and
oxymorphone
iininediate release tablets (4x 10 mg). The study design was a randomized,
open-label,
single-dose, four-period crossover in 28 subjects. The 40 mg oxymorphone
sustained
release tablet and 4x 10 mg oxymorphone immediate release tablets were
evaluated under
fed and fasted conditions. To block the opioid effects of oxymorphone,
naltrexone HCl
(50 ing) was administered approximately 12 hours prior to each oxymorphone
administration. Subjects were fasted overnight for at least 8 hours prior to
dosing. For
the fed treatment subjects were served a high-fat breakfast and were dosed 10
minutes
after completion of the breakfast. Each dose was administered with 240 mL of
water.
Subjects were not pennitted any other food until 4 hours after dosing. Serial
blood
sainples were obtained from 0 to 72 hours after dosing. Plasma samples were
assayed for
oxyinoiphone. Pharinacolcinetic parameters for oxylnorphone were deterinined
using
non-coinpartinental inethods. Point estimates and 90% CIs for natural
logaritlunic
transformed Cmax, AUCo-t, and AUCo-iõf were calculated using LSMeans.

CA 02653017 2009-02-26
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Twenty-five subjects coinpleted the study. The mean plasma concentration-time
data for the fasted and fed treatinents for the sustained release tablet are
shown in Table
17.
Table 17
Mean oxymorphone plasma concentrations
40 mg sustained release oxymorphone tablets [ng/ml]
Time Fasted Fed
(hr)
0 0.00 0.00
0.25 hr 0.47 0.22
0.50 hr 1.68 0.97
0.75 hr 1.92 1.90
1 hr 2.09 2.61
1.5 hrs 2.18 3.48
2 hrs 2.18 3.65
3 hrs 2.00 2.86
4 hrs 1.78 2.45
hrs 1.86 2.37
6 hrs 1.67 2.02
8 hrs 1.25 1.46
hrs 1.11 1.17
12 hrs 1.34 1.21
24 hrs 0.55 0.47
36 hrs 0.21 0.20
48 hrs 0.06 0.05
60 hrs 0.03 0.01
72 hrs 0.00 0.00
As shown in Table 17 the fed treatment produced higher plasma oxymorphone
concentrations during the first 8 hours compared to the fasted treatment. The
mean
plasma concentrations for both treatments were similar from 10 to 48 hours
after dosing.
Secondary peaks were observed at 5 hours for the fasted treatment and at 12
hours both
treatments. The mean plasma oxymorphone concentration-time data or the fasted
and fed
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treatments for the immediate release tablets are shown in Table 18. The fed
treatment
produced higher plasma concentrations during the first 10 hours coinpared to
the fasted
treatment. The mean plasma concentrations for both treatments were similar
from 12 to
48 hours after dosing. Secondary peaks were seen at 12 hours for the fasted
and fed
treatinents.
Mean plasma oxyiuorphone concentration time profiles for the fed and fasted
treatments for the immediate release oxymorphone tablets (4 x 10 mg) are shown
in Table
18.
Table 18
Mean oxymorphone plasma concentration
4 x 10 mg IR oxymorphone tablets [ng/ml]
Time (hr) Fasted Fed
0 0.00 0,00
0.25 hr 3.34 1.79
0.50 hr 7.28 6.59
0.75 hr 6.60 9.49
1 hr 6.03 9.91
1.5 hrs 4.67 8.76
2 hrs 3.68 7.29
3 hrs 2.34 4.93
4 hrs 1.65 3.11
hrs 1.48 2.19
6 hrs 1.28 1.71
8 hrs 0.92 1.28
hrs 0.78 1.09
12 hrs 1.04 1.24
24 hrs 0.40 0.44
36 hrs 0.16 0.18
48 hrs 0.04 0.05
60 hrs 0.01 0.01
72 hrs 0.00 0.00
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The fed treatment with 4 x 10 mg immediate release oxyinoiphone tablets
produced higher plasma oxyinoiphone concentrations during the first 10 hours
coinpared
to the fasted treatment. The mean plasma oxyinorphone concentrations for both
treatments were similar from 12 to 48 hours after dosing. Secondary peaks were
obseived at 12 hours for the fasted treatment and fed treatments. C,,,a, was
increased in
the presence of food for both the sustained release and the immediate release
tablets and
AUC was increased by food for the immediate release tablets (Table 19). From
the GMR
data (Table 20) it can be seen that food increased Ca, by 51% and 38% for the
sustained
release and iininediate release tablets, respectively, when coinpared to
administration
under fasted conditions. Food increased AUCo_t and AUCo_iõf by 43% and 38%,
respectively for the iininediate release tablets. For the sustained release
tablet
adininistered with food, the AUCo_t and AUCo_inf increases were less than 10%
and the
90% CIs were within 80-125%.
Table 19
Oxymorphone treatment (N=25)
Mean 40 mg sustained release tablet 4x10 mg immediate release
Pharmacokinetic tablets
Parameter (SD) Fed Fasted Fed Fasted
Cmax, pg/1nL 4250 2790 12090 9070
(1210) (840) (5420) (4090)
Tinax, h 2.00 1.00 1.00 0.50
(0.5-5.0) (0.5-12.0) (0.25-3.0) (0.25-2.0)
AUCo_, pg=h/mL 38200 35700 51350 36000
(11040) (10580) (20200) (12520)
AUCo-ine, hg'h/mL 41170 40620 54100 39040
(10460) (11380) (20260) (12440)
ti, h 10.5 12.2 9.6 11.7
(5.5) (7.6) (3.6) (6.2)
Median and range reported for Tmax
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Table 20
Oxymorphone treatment
Pharmacolcinetic 40 mg sustained release tablet 4 x 10 mg immediate release
parameter tablet
Ratio (fed/fasted) 90% CI Ratio (fed/fasted) 90% CI
C,,,ax 1.507 1.3777, 1.376 1.156, 1.637
AUCo-t 1.07 1.6970 1.43 1.32, 1.55
AUCo-inf 1.02 0.94, 1.22 1.38 1.28, 1.41
0.91, 1.15
From the GMR data (Table 20) it can be seen that food increased Cmax by 51%
and 38% for the sustained release and iimnediate release tablets,
respectively, when
compared to administration under fasted conditions. Food increased AUCo_t and
AUCo_iõf
by 43% and 38%, respectively for the immediate release tablets. For the
sustained release
tablet, the AUCo_t and AUCo_;,,f increases with food were small and the 90%
CIs were
within 80-125%.
The in vitro study (Exainple 8) showed that 40% ethanol did not increase the
dissolution rate of the oxymoiphone sustained release 40 mg tablet. These data
indicate
that the forinulation drug release matrix is not compromised by beverage-
strength ethanol
concentrations and the premature release of oxymorphone in vivo when exposed
to
ethanol at concentrations up to 40% does not occur. However, the data from the
human
ethanol study demonstrated that co-administration of 240 mL of 40% ethanol,
and to a
lesser extent 20% ethanol, increased the C,,,ax of oxymorphone from the 40 mg
sustained
release tablet while having no demonstrable effect on the AUC (Tables 12 and
13). The
in vitro and in vivo results suggest that beverage-strength ethanol does not
directly effect
the integrity of formulation, but may cause other effect(s), that can lead to
an apparent
increased rate of absorption of oxymorphone.
Interestingly, an increased rate of absorption of oxymorphone is also obseived
when oxyinoiphone 40 mg sustained release tablets are administered after a
high-fat meal
(Tables 19 and 20). The magnitude of the increase and the plasma concentration-
time
course are similar when oxymorphone tablets formulated with TIMERx-NO are
administered after a high-fat meal or with ethanol (see Tables 11 and 16).
This
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obsei-vation suggests that there may be a common mechanism between food and
ethanol
leading to the increase in C,,,ax. The phai-macolcinetic parameters measured
following
dosing of oxymoiphone immediate release tablets and oral solutions were also
affected
when taken after a high-fat meal (Tables 19 and 20). In addition to an
increase in C,,,ax,
the AUC for the iminediate release tablets also increased, unlike the results
for the
sustained release tablets, where AUC did not change appreciably after ethanol
or food.
These differences suggest that the sustained release tablets are not releasing
oxyinorphone
at an accelerated rate in the presence of ethanol, but that it is only the
level of
oxyinorphone dissolved in the gastrointestinal tract that is affected by the
food or ethanol.
The in vitro results indicate no oxyinorphone sustained release forinulation-
ethanol interaction. The results from the bioavailability study demonstrated
that there is a
pharmacokinetic interaction when 40 mg oxymorphone sustained release tablet is
consumed with 240 mL of 40% ethanol, which represents an excessive intake of
ethanol,
with resultant increases in peak plasma concentrations similar to those
observed when
oxyinorphone sustained release tablets are taken after a standardized high-fat
meal. The
underlying mechanism of this phenomenon is not clear at present.
Based on evaluation of the in vitro and earlier in vivo data, the increases in
Cmax
observed are not believed to be caused by early release of oxymorphone owing
to
disintegration of the sustained release delivery system (i.e., dose dumping),
but instead by
an apparent increased rate of absorption, which is independent of the
formulation.
Similar results are expected to be obtained with other drugs, because the
properties of the sustained release system affect the dissolution properties
of the
fonnulation to a significantly larger extent than the nature of the drug in
the formulation.
Ethanol dissolution testing is contemplated to become a standard procedure in
the
development of new sustained release products.
The patents, patent applications, and publications cited herein are
incorporated by
reference herein in their entirety.
Various modifications of the invention, in addition to those described herein,
will
be apparent to one slcilled in the art from the foregoing description. Such
modifications
are intended to fall within the scope of the appended claims.