U.S. patent application number 11/426170 was filed with the patent office on 2007-05-03 for oxymorphone controlled release formulations.
Invention is credited to Anand R. Baichwal, Haui-Hung Kao, David Lee, Troy McCall.
Application Number | 20070098793 11/426170 |
Document ID | / |
Family ID | 27501826 |
Filed Date | 2007-05-03 |
United States Patent
Application |
20070098793 |
Kind Code |
A1 |
Kao; Haui-Hung ; et
al. |
May 3, 2007 |
OXYMORPHONE CONTROLLED RELEASE FORMULATIONS
Abstract
The invention pertains to a method of relieving pain by
administering a controlled release pharmaceutical tablet containing
oxymorphone which produces a mean minimum blood plasma level 12 to
24 hours after dosing, as well as the tablet producing the
sustained pain relief.
Inventors: |
Kao; Haui-Hung; (Syosset,
NY) ; Baichwal; Anand R.; (Wappingers Falls, NY)
; McCall; Troy; (Smyrna, GA) ; Lee; David;
(Chadds, PA) |
Correspondence
Address: |
MAYER, BROWN, ROWE & MAW LLP
P.O. BOX 2828
CHICAGO
IL
60690-2828
US
|
Family ID: |
27501826 |
Appl. No.: |
11/426170 |
Filed: |
June 23, 2006 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10190192 |
Jul 3, 2002 |
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11426170 |
Jun 23, 2006 |
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60329445 |
Oct 15, 2001 |
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60329432 |
Oct 15, 2001 |
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60303357 |
Jul 6, 2001 |
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60329444 |
Oct 15, 2001 |
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Current U.S.
Class: |
424/468 ;
514/282 |
Current CPC
Class: |
A61K 9/0053 20130101;
A61P 29/00 20180101; A61K 47/26 20130101; A61K 31/485 20130101;
A61K 47/02 20130101; A61K 47/36 20130101; A61K 9/2054 20130101;
A61K 9/2018 20130101; A61K 47/38 20130101; A61P 25/04 20180101;
A61K 9/205 20130101; A61K 9/209 20130101; A61K 9/2009 20130101;
A61K 47/10 20130101 |
Class at
Publication: |
424/468 ;
514/282 |
International
Class: |
A61K 31/485 20060101
A61K031/485; A61K 9/22 20060101 A61K009/22 |
Claims
1. A method for treating pain in a human subject in need of acute
or chronic pain relief, comprising the steps of: (a) Providing a
solid oral dosage form of a controlled release oxymorphone
formulation, comprising about 20 mg to about 40 mg oxymorphone or a
pharmaceutically acceptable salt thereof; and (b) administering a
single dose of the dosage form to the subject, wherein there is no
substantial difference between the oxymorphone area under the curve
(AUC.sub.(0-inf)) when the dosage form is administered to the
subject under fed versus fasted conditions, and wherein the
oxymorphone C.sub.max is at least about 50% higher when the dosage
form is administered to the subject under fed as compared to fasted
conditions.
2. The method of claim 1 wherein the dosage form comprises about 40
mg oxymorphone or a pharmaceutically acceptable salt thereof, and
wherein the oxymorphone C.sub.max is about 58% higher when the
dosage form is administered to the subject under fed as compared to
fasted conditions.
3. The method of claim 1 wherein the dosage form comprises about 20
mg oxymorphone or a pharmaceutically acceptable salt thereof.
4. The method of claim 1 wherein the dosage form comprises about 20
mg to about 40 mg oxymorphone hydrochloride.
5. The method of claim 1 wherein the difference in AUC.sub.(0-inf)
between fed and fasted conditions is less than about 20%.
6. The method of claim 1 wherein the difference in AUC.sub.(0-inf)
between fed and fasted conditions is about 18%.
7. The method of claim 1 wherein the duration of the analgesic
effect is through at least about 12 hours after administration.
8. The method of claim 1 wherein upon oral administration of the
dosage form to the subject under fed or fasting conditions: (i) the
dosage form provides detectable blood plasma levels of 6-OH
oxymorphone and oxymorphone; (ii) the blood plasma levels of 6-OH
oxymorphone and oxymorphone peak within about 1 hour to about 8
hours after administration; (iii) the blood plasma levels of 6-OH
oxymorphone and oxymorphone exhibit a ratio of AUC.sub.(0-inf) of
blood plasma level versus time for 6-OH oxymorphone compared to
oxymorphone in a range of about 0.5 to about 1.5; and (iv) the
duration of the analgesic effect is through at least about 12 hours
after administration.
9. A method for treating pain in a human subject in need of acute
or chronic pain relief, comprising the steps of: (a) Providing a
solid oral dosage form comprising about 5 mg to about 80 mg
oxymorphone or a pharmaceutically acceptable salt thereof in a
controlled release delivery system, the system comprising a filler
and a hydrophilic material; and (b) administering a single dose of
the dosage form to the subject, wherein there is no substantial
difference between the oxymorphone AUC.sub.(0-inf) when the dosage
form is administered to the subject under fed versus fasted
conditions.
10. The method of claim 9 wherein the oxymorphone C.sub.max is at
least about 50% higher when the dosage form is administered to the
subject under fed as compared to fasted conditions.
11. The method of claim 9 wherein wherein the difference in
AUC.sub.(0-inf) between fed and fasted conditions is less than
about 20%.
12. The method of claim 9 wherein the difference in AUC.sub.(0-inf)
between fed and fasted conditions is about 18%.
13. The method of claim 9 wherein upon oral administration of the
dosage form to the subject under fed or fasting conditions: (i) the
dosage form provides detectable blood plasma levels of 6-OH
oxymorphone and oxymorphone; (ii) the blood plasma levels of 6-OH
oxymorphone and oxymorphone peak within about 1 hour to about 8
hours after administration; (iii) the blood plasma levels of 6-OH
oxymorphone and oxymorphone exhibit a ratio of AUC.sub.(0-inf) of
blood plasma level versus time for 6-OH oxymorphone compared to
oxymorphone in a range of about 0.5 to about 1.5; and (iv) the
duration of the analgesic effect is through at least about 12 hours
after administration.
14. The method of claim 9 wherein the hydrophilic material is
selected from the group consisting of a gum, a cellulose ether, an
acrylic resin, a protein-derived material, and mixtures
thereof.
15. The method of claim 9 wherein the hydrophilic material is a gum
selected from the group consisting of a heteropolysaccharide gum, a
homopolysaccharide gum, and mixtures thereof.
16. The method of claim 15 wherein the gum is selected from the
group consisting of xanthan, tragacanth, acacia, karaya, alginates,
agar, guar, hydroxypropyl guar, carrageenan, locust bean, and
mixtures thereof.
17. The method of claim 9 wherein the hydrophilic material is a
cellulose ether selected from the group consisting of a
hydroxyalkyl cellulose, a carboxyalkyl cellulose, and mixtures
thereof.
18. The method of claim 9 wherein the hydrophilic material is
selected from the group consisting of hydroxyethyl cellulose,
hydroxypropyl cellulose, hydroxypropyl methylcellulose,
carboxymethylcellulose, and mixtures thereof.
19. The method of claim 9 wherein the hydrophilic material
comprises at least one of: a. a heteropolysaccharide; or b. a
heteropolysaccharide and a cross-linking agent capable of
cross-linking the heteropolysaccharide; or c. a mixture of (a), (b)
and a polysaccharide gum.
20. The method of claim 19 wherein the heteropolysaccharide is a
water soluble polysaccharide containing two or more kinds of sugar
units and having a branched or helical configuration.
21. The method of claim 19 wherein the heteropolysaccharide is
selected from the group consisting of xanthan gum, deacylated
xanthan gum, carboxymethyl ether xanthan gum, propylene glycol
ester xanthan gum and mixtures thereof.
22. The method of claim 19 wherein the cross-linking agent is a
homopolysaccharide gum.
23. The method of claim 19 wherein the homopolysaccharide gum is
locust bean gum.
24. The method of claim 19 wherein the filler is selected from the
group consisting of sucrose, dextrose, lactose, microcrystalline
cellulose, fructose, xylitol, sorbitol, and mixtures thereof.
25. A controlled release oxymorphone oral tablet dosage form,
comprising: a. a controlled release delivery system; and b. about 5
mg to about 80 mg of a pharmaceutically acceptable salt of
oxymorphone, wherein upon oral administration of a single dose of
the tablet to a human subject, there is no substantial difference
in the AUC.sub.(0-inf) between the administration of the tablet in
fed and fasting conditions.
26. The dosage form of claim 25 wherein upon oral administration
thereof the oxymorphone C.sub.max is at least about 50% higher when
the dosage form is administered to the subject under fed as
compared to fasted conditions.
27. The dosage form of claim 25 wherein the dosage form comprises
about 40 mg oxymorphone, and wherein the oxymorphone C.sub.max is
about 58% higher when the dosage form is administered to the
subject under fed as compared to fasted conditions.
28. The dosage form of claim 25 wherein the controlled release
delivery system comprises a heteropolysaccharide and an agent
capable of cross-linking the heteropolysaccharide in presence of
gastrointestinal fluid.
29. The dosage form of claim 28 wherein the heteropolysaccharide
and the agent capable of cross-linking the heteropolysaccharide are
present in a weight ratio of about 1:3 to about 3:1.
30. The dosage form of claim 28 wherein the heteropolysaccharide
and the agent capable of cross-linking the heteropolysaccharide are
present in a weight ratio of about 1:1.
31. The dosage form of claim 28 wherein the heteropolysaccharide
comprises xanthan gum or deacylated xanthan gum.
32. The dosage form of claim 28 wherein the agent capable of
cross-linking the heteropolysaccharide comprises a
homopolysaccharide gum.
33. The dosage form of claim 32 wherein the homopolysaccharide gum
comprises locust bean gum.
34. The dosage form of claim 25 wherein the controlled release
delivery system further comprises a hydrophobic polymer.
35. The dosage form of claim 34 wherein the hydrophobic polymer is
selected from hydrophobic cellulosic materials, polymers or
copolymers derived from acrylic or methacrylic acid esters,
copolymers of acrylic and methacrylic acid esters, zein, waxes,
shellac, and hydrogenated vegetable oils.
36. The dosage form of claim 34 wherein the hydrophobic polymer
comprises an alkylcellulose.
37. The dosage form of claim 25 wherein the system comprises a
filler selected from sucrose, dextrose, lactose, microcrystalline
cellulose, fructose, xylitol and sorbitol.
38. The dosage form of claim 25 further comprising a cationic
cross-linking agent.
39. The dosage form of claim 38 wherein the cationic cross-linking
agent is an alkali metal sulfate, chloride, borate, bromide,
citrate, acetate or lactate or an alkaline earth metal sulfate,
chloride, borate, bromide, citrate, acetate or lactate.
40. The dosage form of claim 38 wherein the cationic cross-linking
agent is selected from calcium sulfate, sodium chloride, potassium
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, magnesium sulfate and
sodium fluoride.
41. The dosage form of claim 38 wherein the cationic cross-linking
agent is present in an amount of about 0.5% to about 16%, by weight
of the composition.
42. The dosage form of claim 28 wherein the weight ratio of
heteropolysaccharide to oxymorphone is about 10:1 to about
1:10.
43. The dosage form claim 25 wherein oxymorphone is present in an
amount of about 20 mg.
44. The dosage form of claim 25 wherein the controlled release
delivery system comprises about 10% to about 99% of a gelling agent
comprising a heteropolysaccharide gum and a homopolysaccharide gum,
about 1% to about 20% of a cationic crosslinking agent, and about
0% to about 89% of an inert pharmaceutical diluent, by total weight
of the controlled release delivery system.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 10/190,192 filed Jul. 3, 2002 and claims
priority to U.S. Provisional Patent Applications Ser. Nos.
60/329,445 filed Oct. 15, 2001, 60/329,432 filed Oct. 15, 2001,
60/303,357 filed Jul. 6, 2001, and 60/329,444 filed Oct. 15, 2001,
which are incorporated herein by reference to the extent permitted
by law.
BACKGROUND OF THE INVENTION
[0002] Pain is the most frequently reported symptom and it is a
common clinical problem which confronts the clinician. Many
millions of people in the USA suffer from severe pain that,
according to numerous recent reports, 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 employed for
analgesia for decades in a variety of clinical pain states.
[0003] Oxymorphone HCl (14-hydroxydihydromorphinone hydrochloride)
is a semi-synthetic phenanthrene-derivative opioid agonist, widely
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; 1.5
mg/ml in 1 ml ampules; 1.5 mg/ml in 10 ml multiple dose vials) for
intramuscular, subcutaneous, and intravenous administration, and as
5 mg rectal suppositories. At one time, 2 mg, 5 mg and 10 mg oral
immediate release (IR) tablet formulations of oxymorphone HCl were
marketed. Oxymorphone HCl is metabolized principally in the liver
and undergoes conjugation with glucuronic acid and reduction to
6-alpha- and beta-hydroxy epimers.
[0004] 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. (Ferrell B et al. Effects of
controlled-release morphine on quality of life for cancer pain.
Oncol. Nur. Forum 1989;4:521-26). Scheduled, rather than "as
needed" administration of opioids is currently recommended in
guidelines for their use in chronic non-malignant pain.
Unfortunately, evidence from prior clinical trials and clinical
experience suggests that the short duration of action of immediate
release oxymorphone would necessitate administration every 4-6
hours in order to maintain optimal levels of analgesia in chronic
pain. A controlled release formulation which would allow less
frequent dosing of oxymorphone would be useful in pain
management.
[0005] For instance, a controlled release formulation of morphine
has been demonstrated to provide patients fewer interruptions in
sleep, reduced dependence on caregivers, improved compliance,
enhanced quality of life outcomes, and increased control over the
management of pain. In addition, the controlled release formulation
of morphine was reported to provide more constant plasma
concentration and clinical effects, less frequent peak to trough
fluctuations, reduced dosing frequency, and possibly fewer side
effects. (Thirlwell M P et al., Pharmacokinetics and clinical
efficacy of oral morphine solution and controlled-release morphine
tablets in cancer patients. Cancer 1989; 63:2275-83; Goughnour B R
et al., Analgesic response to single and multiple doses of
controlled-release morphine tablets and morphine oral solution in
cancer patients. Cancer 1989; 63:2294-97; Ferrell B. et al.,
Effects of controlled-release morphine on quality of life for
cancer pain. Oncol. Nur. Forum 1989; 4:521-26.
[0006] There are two factors associated with the metabolism of some
drugs that may present problems for their use in controlled release
systems. One is the ability of the drug to induce or inhibit enzyme
synthesis, which may result in a fluctuating drug blood plasma
level with chronic dosing. The other is a fluctuating drug blood
level due to intestinal (or other tissue) metabolism or through a
hepatic first-pass effect.
[0007] Oxymorphone is metabolized principally in the liver,
resulting in an oral bioavailability of about 10%. Evidence from
clinical experience suggests that the short duration of action of
immediate release oxymorphone necessitates a four hour dosing
schedule to maintain optimal levels of analgesia. It would be
useful to clinicians and patients alike to have controlled release
dosage forms of oxymorphone to use to treat pain and a method of
treating pain using the dosage forms.
SUMMARY OF THE INVENTION
[0008] The present invention provides methods for relieving pain by
administering a controlled release pharmaceutical tablet containing
oxymorphone which produces at least a predetermined minimum blood
plasma level for at least 12 hours after dosing, as well as tablets
that produce the sustained pain relief over this time period.
BRIEF DESCRIPTION OF THE FIGURES
[0009] FIG. 1 is a pharmacokinetic profile for 6-hydroxy
oxymorphone with PID scores.
[0010] FIG. 2 is a pharmacokinetic profile for oxymorphone with PID
scores.
[0011] FIG. 3 is a pharmacokinetic profile for 6-hydroxy
oxymorphone with categorical pain scores.
[0012] FIG. 4 is a pharmacokinetic profile for oxymorphone with
categorical pain scores.
[0013] FIG. 5 is a graph of the mean blood plasma concentration of
oxymorphone versus time for clinical study 1.
[0014] FIG. 6 is a graph of the mean blood plasma concentration of
oxymorphone versus time for clinical study 2.
[0015] FIG. 7 is a graph of the mean blood plasma concentration of
oxymorphone versus time for clinical study 3.
[0016] FIG. 8 is a graph of the mean blood plasma concentration of
6-hydroxy oxymorphone versus time for clinical study 3.
[0017] FIG. 9 is a graph of the mean blood plasma concentration of
oxymorphone for immediate and controlled release tablets from a
single dose study.
[0018] FIG. 10 is a graph of the mean blood plasma concentration of
oxymorphone for immediate and controlled release tablets from a
steady state study.
DETAILED DESCRIPTION OF THE INVENTION
[0019] The present invention provides methods for alleviating pain
for 12 to 24 hours using a single dose of a pharmaceutical
composition by producing a blood plasma level of oxymorphone and/or
6-OH oxymorphone of at least a minimum value for at least 12 hours
or more. As used herein, the terms "6-OH oxymorphone" and
"6-hydroxy oxymorphone" are interchangeable and refer to the analog
of oxymorphone having an alcohol (hydroxy) moiety that replaces the
carboxy moiety found on oxymorphone at the 6-position.
[0020] To overcome the difficulties associated with a 4-6 hourly
dosing frequency of oxymorphone, this invention provides an
oxymorphone controlled release oral solid,dosage form, comprising a
therapeutically effective amount of oxymorphone or a
pharmaceutically acceptable salt of oxymorphone. It has been found
that the decreased rate of release of oxymorphone from the oral
controlled release formulation of this invention does not
substantially decrease the bioavailability of the drug as compared
to the same dose of a solution of oxymorphone administered orally.
The bioavailability is sufficiently high and the release rate is
such that a sufficient plasma level of oxymorphone and/or 6-OH
oxymorphone is maintained to allow the controlled release dosage to
be used to treat patients suffering moderate to severe pain with
once or twice daily dosing. The dosing form of the present
invention can also be used with thrice daily dosing.
[0021] It is critical when considering the present invention that
the difference between a controlled release tablet and an immediate
release formulation be fully understood. In classical terms, an
immediate release formulation releases at least 80% of its active
pharmaceutical ingredient within 30 minutes. With reference to the
present invention, the definition of an immediate release
formulation will be broadened further to include a formulation
which releases more than about 80% of its active pharmaceutical
ingredient within 60 minutes in a standard USP Paddle Method
dissolution test at 50 rpm in 500 ml media having a pH of between
1.2 and 6.8 at 37.degree. C. "Controlled release" formulations, as
referred to herein, will then encompass any formulations which
release no more than about 80% of their active pharmaceutical
ingredients within 60 minutes under the same conditions.
[0022] The controlled release dosage form of this invention
exhibits a dissolution rate in vitro, when measured by USP Paddle
Method at 50 rpm in 500 ml media having a pH between 1.2 and 6.8 at
37.degree. C., of about 15% to about 50% by weight oxymorphone
released after 1 hour, about 45% to about 80%, by weight
oxymorphone released after 4 hours, and at least about 80% by
weight oxymorphone released after 10 hours.
[0023] When administered orally to humans, an effective controlled
release dosage form of oxymorphone should exhibit the following in
vivo characteristics: (a) peak plasma level of oxymorphone occurs
within about 1 to about 8 hours after administration; (b) peak
plasma level of 6-OH oxymorphone occurs within about 1 to about 8
hours after administration; (c) duration of analgesic effect is
through about 8 to about 24 hours after administration; (d)
relative oxymorphone bioavailability is in the range of about 0.5
to about 1.5 compared to an orally-administered aqueous solution of
oxymorphone; and (e) the ratio of the area under the curve of blood
plasma level vs. time for 6-OH oxymorphone compared to oxymorphone
is in the range of about 0.5 to about 1.5. Of course, there is
variation of these parameters among subjects, depending on the size
and weight of the individual subject, the subject's age, individual
metabolism differences, and other factors. Indeed, the parameters
may vary in an individual from day to day. Accordingly, the
parameters set forth above are intended to be mean values from a
sufficiently large study so as to minimize the effect of individual
variation in arriving at the values. A convenient method for
arriving at such values is by conducting a study in accordance with
standard FDA procedures such as those employed in producing results
for use in a new drug application (or abbreviated new drug
application) before the FDA. Any reference to mean values herein,
in conjunction with desired results, refer to results from such a
study, or some comparable study. Reference to mean values reported
herein for studies actually conducted are arrived at using standard
statistical methods as would be employed by one skilled in the art
of pharmaceutical formulation and testing for regulatory
approval.
[0024] In one specific embodiment of the controlled release matrix
form of the invention, the oxymorphone or salt of oxymorphone is
dispersed in a controlled release delivery system that comprises a
hydrophilic material which, upon exposure to gastrointestinal
fluid, forms a gel matrix that releases oxymorphone at a controlled
rate. The rate of release of oxymorphone from the matrix depends on
the drug's partition coefficient between components of the matrix
and the aqueous phase within the gastrointestinal tract. In a
preferred form of this embodiment, the hydrophilic material of the
controlled release delivery system comprises a mixture of a
heteropolysaccharide gum and an agent capable of cross-linking the
heteropolysaccharide in presence of gastrointestinal fluid. The
controlled release delivery system may also comprise a
water-soluble pharmaceutical diluent mixed with the hydrophilic
material. Preferably, the cross-linking agent is a
homopolysaccharide gum and the inert pharmaceutical diluent is a
monosaccharide, a disaccharide, or a polyhydric alcohol, or a
mixture thereof.
[0025] In a specific preferred embodiment, the appropriate blood
plasma levels of oxymorphone and 6-hydroxy oxymorphone are achieved
using oxymorphone in the form of oxymorphone hydrochloride, wherein
the weight ratio of heteropolysaccharide to homopolysaccharide is
in the range of about 1:3 to about 3:1, the weight ratio of
heteropolysaccharide to diluent is in the range of about 1:8 to
about 8:1, and the weight ratio of heteropolysaccharide to
oxymorphone hydrochloride is in the range of about 10:1 to about
1:10. A preferred heteropolysaccharide is xanthan gum and a
preferred homopolysaccharide is locust bean gum. The dosage form
also comprises a cationic cross-linking agent and a hydrophobic
polymer. In the preferred embodiment, the dosage form is a tablet
containing about 5 mg to about 80 mg of oxymorphone hydrochloride.
In a most preferred embodiment, the tablet contains about 20 mg
oxymorphone hydrochloride.
[0026] The invention includes a method which comprises achieving
appropriate blood plasma levels of drug while providing extended
pain relief by administering one to three times per day to a
patient suffering moderate to severe, acute or chronic pain, an
oxymorphone controlled release oral solid dosage form of the
invention in an amount sufficient to alleviate the pain for a
period of about 8 hours to about 24 hours. This type and intensity
of pain is often associated with cancer, autoimmune diseases,
infections, surgical and accidental traumas and osteoarthritis.
[0027] The invention also includes a method of making an
oxymorphone controlled release oral solid dosage form of the
invention which comprises mixing particles of oxymorphone or a
pharmaceutically acceptable salt of oxymorphone with granules
comprising the controlled release delivery system, preferably
followed by directly compressing the mixture to form tablets.
[0028] Pharmaceutically acceptable salts of oxymorphone which can
be used in this invention include salts with the inorganic and
organic acids which are commonly used to produce nontoxic salts of
medicinal agents. Illustrative examples would be those salts formed
by mixing oxymorphone with hydrochloric, sulfuric, nitric,
phosphoric, phosphorous, hydrobromic, maleric, malic, ascorbic,
citric or tartaric, pamoic, lauric, stearic, palmitic, oleic,
myristic, lauryl sulfuric, naphthylenesulfonic, linoleic or
linolenic acid, and the like. The hydrochloride salt is
preferred.
[0029] It has now been found that 6-OH oxymorphone, which is one of
the metabolites of oxymorphone, may play a role in alleviating
pain. When oxymorphone is ingested, part of the dosage gets into
the bloodstream to provide pain relief, while another part is
metabolized to 6-OH oxymorphone. This metabolite then enters the
bloodstream to provide further pain relief. Thus it is believed
that both the oxymorphone and 6-hydroxyoxymorphone levels are
important to pain relief.
[0030] The effectiveness of oxymorphone and 6-hydroxyoxymorphone at
relieving pain and the pharmacokinetics of a single dose of
oxymorphone were studied. The blood plasma levels of both
oxymorphone and 6-hydroxyoxymorphone were measured in patients
after a single dose of oxymorphone was administered. Similarly, the
pain levels in patients were measured after a single administration
of oxymorphone to determine the effective duration of pain relief
from a single dose. FIGS. 1-2 show the results of these tests,
comparing pain levels to oxymorphone and 6-hydroxy oxymorphone
levels.
[0031] For these tests, pain was measured using a Visual Analog
Scale (VAS) or a Categorical Scale. The VAS scales consisted of a
horizontal line, 100 mm in length. The left-hand end of the scale
(0 mm) was marked with the descriptor "No Pain" and the right-hand
end of the scale (100 mm) was marked with the descriptor "Extreme
Pain". Patients indicated their level of pain by making a vertical
mark on the line. The VAS score was equal to the distance (in mm)
from the left-hand end of the scale to the patient's mark. For the
categorical scale, patients completed the following statement, "My
pain at this time is" using the scale None=0, Mild=1, Moderate=2,
or Severe=3.
[0032] As can be seen from these figures, there is a correlation
between pain relief and both oxymorphone and 6-hydroxyoxymorphone
levels. As the blood plasma levels of oxymorphone and
6-hydroxyoxymorphone increase, pain decreases (and pain intensity
difference and pain relief increases). Thus, to the patient, it is
the level of oxymorphone and 6-hydroxyoxymorphone in the blood
plasma which is most important. Further it is these levels which
dictate the efficacy of the dosage form. A dosage form which
maintains a sufficiently high level of oxymorphone or
6-hydroxyoxymorphone for a longer period need not be administered
frequently. Such a result, is accomplished by embodiments of the
present invention.
[0033] The oxymorphone controlled release oral solid dosage form of
this invention can be made using any of several different
techniques for producing controlled release oral solid dosage forms
of opioid analgesics.
[0034] In one embodiment, a core comprising oxymorphone or
oxymorphone salt is coated with a controlled release film which
comprises a water insoluble material and which upon exposure to
gastrointestinal fluid releases oxymorphone from the core at a
controlled rate. In a second embodiment, the oxymorphone or
oxymorphone salt is dispersed in a controlled release delivery
system that comprises a hydrophilic material which upon exposure to
gastrointestinal fluid forms a gel matrix that releases oxymorphone
at a controlled rate. A third embodiment is a combination of the
first two: a controlled release matrix coated with a controlled
release film. In a fourth embodiment the oxymorphone is
incorporated into an osmotic pump. In any of these embodiments, the
dosage form can be a tablet, a plurality of granules in a capsule,
or other suitable form, and can contain lubricants, colorants,
diluents, and other conventional ingredients.
[0035] Osmotic Pump
[0036] An osmotic pump comprises a shell defining an interior
compartment and having an outlet passing through the shell. The
interior compartment contains the active pharmaceutical ingredient.
Generally the active pharmaceutical ingredient is mixed with
excipients or other compositions such as a polyalkylene. The shell
is generally made, at least in part, from a material (such as
cellulose acetate) permeable to the liquid of the environment where
the pump will be used, usually stomach acid. Once ingested, the
pump operates when liquid diffuses through the shell of the pump.
The liquid dissolves the composition to produce a saturated
situation. As more liquid diffuses into the pump, the saturated
solution containing the pharmaceutical is expelled from the pump
through the outlet. This produces a nearly constant release of
active ingredient, in the present case, oxymorphone.
[0037] Controlled Release Coating
[0038] In this embodiment, a core comprising oxymorphone or
oxymorphone salt is coated with a controlled release film which
comprises a water insoluble material. The film can be applied by
spraying an aqueous dispersion of the water insoluble material onto
the core. Suitable water insoluble materials include alkyl
celluloses, acrylic polymers, waxes (alone or in admixture with
fatty alcohols), shellac and zein. The aqueous dispersions of alkyl
celluloses and acrylic polymers preferably contain a plasticizer
such as triethyl citrate, dibutyl phthalate, propylene glycol, and
polyethylene glycol. The film coat can contain a water-soluble
material such as polyvinylpyrrolidone (PVP) or
hydroxypropylmethylcellulose (HPMC).
[0039] The core can be a granule made, for example, by wet
granulation of mixed powders of oxymorphone or oxymorphone salt and
a binding agent such as HPMC, or by coating an inert bead with
oxymorphone or oxymorphone salt and a binding agent such as HPMC,
or by spheronising mixed powders of oxymorphone or oxymorphone salt
and a spheronising agent such as microcrystalline cellulose. The
core can be a tablet made by compressing such granules or by
compressing a powder comprising oxymorphone or oxymorphone
salt.
[0040] The in vitro and in vivo release characteristics of this
controlled release dosage form can be modified by using mixtures of
different water insoluble and water soluble materials, using
different plasticizers, varying the thickness of the controlled
release film, including release-modifying agents in the coating, or
by providing passageways through the coating.
[0041] Controlled Release Matrix
[0042] It is important in the present invention that appropriate
blood plasma levels of oxymorphone and 6-hydroxy oxymorphone be
achieved and maintained for sufficient time to provide pain relief
to a patient for a period of 12 to 24 hours. The preferred
composition for achieving and maintaining the proper blood plasma
levels is a controlled-release matrix. In this embodiment, the
oxymorphone or oxymorphone salt is dispersed in a controlled
release delivery system that comprises a hydrophilic material
(gelling agent) which upon exposure to gastrointestinal fluid forms
a gel matrix that releases oxymorphone at a controlled rate. Such
hydrophilic materials include gums, cellulose ethers, acrylic
resins, and protein-derived materials. Suitable cellulose ethers
include hydroxyalkyl celluloses and carboxyalkyl celluloses,
especially hydroxyethyl cellulose (HEC), hydroxypropyl cellulose
(HPC), HPMC, and carboxy methylcellulose (CMC). Suitable acrylic
resins include polymers and copolymers of acrylic acid, methacrylic
acid, methyl acrylate and methyl methacrylate. Suitable gums
include heteropolysaccharide and homopolysaccharide gums, e.g.,
xanthan, tragacanth, acacia, karaya, alginates, agar, guar,
hydroxypropyl guar, carrageenan, and locust bean gums.
[0043] Preferably, the controlled release tablet of the present
invention is formed from (I) a hydrophilic material comprising (a)
a heteropolysaccharide; or (b) a heteropolysaccharide and a
cross-linking agent capable of cross-linking said
heteropolysaccharide; or (c) a mixture of (a), (b) and a
polysaccharide gum; and (II) an inert pharmaceutical filler
comprising up to about 80% by weight of the tablet; and (III)
oxymorphone.
[0044] The term "heteropolysaccharide" as used herein is defined as
a water-soluble polysaccharide containing two or more kinds of
sugar units, the heteropolysaccharide having a branched or helical
configuration, and having excellent water-wicking properties and
immense thickening properties.
[0045] A preferred heteropolysaccharide is xanthan gum, which is a
high molecular weight (>10.sup.6) heteropolysaccharide. Other
preferred heteropolysaccharides include derivatives of xanthan gum,
such as deacylated xanthan gum, the carboxymethyl ether, and the
propylene glycol ester.
[0046] The cross linking agents used in the controlled release
embodiment of the present invention which are capable of
cross-linking with the heteropolysaccharide include
homopolysaccharide gums such as the galactomannans, i.e.,
polysaccharides which are composed solely of mannose and galactose.
Galactomannans which have higher proportions of unsubstituted
mannose regions have been found to achieve more interaction with
the heteropolysaccharide. Locust bean gum, which has a higher ratio
of mannose to the galactose, is especially preferred as compared to
other galactomannans such as guar and hydroxypropyl guar.
[0047] Preferably, the ratio of heteropolysaccharide to
homopolysaccharide is in the range of about 1:9 to about 9:1,
preferably about 1:3 to about 3:1. Most preferably, the ratio of
xanthan gum to polysaccharide material (i.e., locust bean gum,
etc.) is preferably about 1:1.
[0048] In addition to the hydrophilic material, the controlled
release delivery system can also contain an inert pharmaceutical
diluent such as a monosaccharide, a disaccharide, a polyhydric
alcohol and mixtures thereof. The ratio of diluent to hydrophilic
matrix-forming material is generally in the range of about 1:3 to
about 3:1.
[0049] The controlled release properties of the controlled release
embodiment of the present invention may be optimized when the ratio
of heteropolysaccharide gum to homopolysaccharide material is about
1:1, although heteropolysaccharide gum in an amount of from about
20 to about 80% or more by weight of the heterodisperse
polysaccharide material provides an acceptable slow release
product. The combination of any homopolysaccharide gums known to
produce a synergistic effect when exposed to aqueous solutions may
be used in accordance with the present invention. It is also
possible that the type of synergism which is present with regard to
the gum combination of the present invention could also occur
between two homogeneous or two heteropolysaccharides. Other
acceptable gelling agents which may be used in the present
invention include those gelling agents well-known in the art.
Examples include vegetable gums such as alginates, carrageenan,
pectin, guar gum, xanthan gum, modified starch,
hydroxypropylmethylcellulose, methylcellulose, and other cellulosic
materials such as sodium carboxymethylcellulose and hydroxypropyl
cellulose. This list is not meant to be exclusive.
[0050] The combination of xanthan gum with locust bean gum with or
without the other homopolysaccharide gums is an especially
preferred gelling agent. The chemistry of certain of the
ingredients comprising the excipients of the present invention such
as xanthan gum is such that the excipients are considered to be
self-buffering agents which are substantially insensitive to the
solubility of the medicament and likewise insensitive to the pH
changes along the length of the gastrointestinal tract.
[0051] The inert filler of the sustained release excipient
preferably comprises a pharmaceutically acceptable saccharide,
including a monosaccharide, a disaccharide, or a polyhydric
alcohol, and/or mixtures of any of the foregoing. Examples of
suitable inert pharmaceutical fillers include sucrose, dextrose,
lactose, microcrystalline cellulose, fructose, xylitol, sorbitol,
mixtures thereof and the like. However, it is preferred that a
soluble pharmaceutical filler such as lactose, dextrose, sucrose,
or mixtures thereof be used.
[0052] The cationic cross-linking agent which is optionally used in
conjunction with the controlled release embodiment of the present
invention may be monovalent or multivalent metal cations. The
preferred salts are the inorganic salts, including various alkali
metal and/or alkaline earth metal sulfates, chlorides, borates,
bromides, citrates, acetates, lactates, etc. Specific examples of
suitable cationic cross-linking agents include calcium sulfate,
sodium chloride, potassium 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,
magnesium sulfate and sodium fluoride. Multivalent metal cations
may also be utilized. However, the preferred cationic cross-linking
agents are bivalent. Particularly preferred salts are calcium
sulfate and sodium chloride. The cationic cross-linking agents of
the present invention are added in an amount effective to obtain a
desirable increased gel strength due to the, cross-linking of the
gelling agent (e.g., the heteropolysaccharide and
homopolysaccharide gums). In preferred embodiments, the cationic
cross-linking agent is included in the sustained release excipient
of the present invention in an amount from about 1 to about 20% by
weight of the sustained release excipient, and in an amount about
0.5% to about 16% by weight of the final dosage form.
[0053] In the controlled release embodiments of the present
invention, the sustained release excipient comprises from about 10
to about 99% by weight of a gelling agent comprising a
heteropolysaccharide gum and a homopolysaccharide gum, from about 1
to about 20% by weight of a cationic crosslinking agent, and from
about 0 to about 89% by weight of an inert pharmaceutical diluent.
In other embodiments, the sustained release excipient comprises
from about 10 to about 75% gelling agent, from about 2 to about 15%
cationic crosslinking agent, and from about 30 to about 75% inert
diluent. In yet other embodiments, the sustained release excipient
comprises from about 30 to about 75% gelling agent, from about 5 to
about 10% cationic cross-linking agent, and from about 15 to about
65% inert diluent.
[0054] The sustained release excipient used in this embodiment of
the present invention (with or without the optional cationic
cross-linking agent) may be further modified by incorporation of a
hydrophobic material which slows the hydration of the gums without
disrupting the hydrophilic matrix. This is accomplished in
preferred embodiments of the present invention by granulating the
sustained release excipient with the solution or dispersion of a
hydrophobic material prior to the incorporation of the medicament.
The hydrophobic polymer may be selected from an alkylcellulose such
as ethylcellulose, other hydrophobic cellulosic materials, polymers
or copolymers derived from acrylic or methacrylic acid esters,
copolymers of acrylic and methacrylic acid esters, zein, waxes,
shellac, hydrogenated vegetable oils, and any other
pharmaceutically acceptable hydrophobic material known to those
skilled in the art. The amount of hydrophobic material incorporated
into the sustained release excipient is that which is effective to
slow the hydration of the gums without disrupting the hydrophilic
matrix formed upon exposure to an environmental fluid. In certain
preferred embodiments of the present invention, the hydrophobic
material is included in the sustained release excipient in an
amount from about 1 to about 20% by weight. The solvent for the
hydrophobic material may be an aqueous or organic solvent, or
mixtures thereof.
[0055] Examples of commercially available alkylcelluloses are
Aquacoat coating (aqueous dispersion of ethylcellulose available
from FMC of Philadelphia, Pa.) and Surelease coating (aqueous
dispersion of ethylcellulose available from Colorcon of West Point,
Pa.). Examples of commercially available acrylic polymers suitable
for use as the hydrophobic material include Eudragit RS and RL
polymers (copolymers of acrylic and methacrylic acid esters having
a low content (e.g., 1:20 or 1:40) of quaternary ammonium compounds
available from Rohm America of Piscataway, N.J.).
[0056] The controlled release matrix useful in the present
invention may also contain a cationic cross-linking agent such as
calcium sulfate in an amount sufficient to cross-link the gelling
agent and increase the gel strength, and an inert hydrophobic
material such as ethyl cellulose in an amount sufficient to slow
the hydration of the hydrophilic material without disrupting it.
Preferably, the controlled release delivery system is prepared as a
pre-manufactured granulation.
EXAMPLES
Example 1
[0057] Two controlled release delivery systems are prepared by dry
blending xanthan gum, locust bean gum, calcium sulfate dehydrate,
and dextrose in a high speed mixed/granulator for 3 minutes. A
slurry is prepared by mixing ethyl cellulose with alcohol. While
running choppers/impellers, the slurry is added to the dry blended
mixture, and granulated for another 3 minutes. The granulation is
then dried to a LOD (loss on drying) of less than about 10% by
weight. The granulation is then milled using 20 mesh screen. The
relative quantities of the ingredients are listed in the table
below. TABLE-US-00001 TABLE 1 Controlled Release Delivery System
Formulation 1 Formulation 2 Excipient (%) (%) Locust Bean Gum, FCC
25.0 30.0 Xanthan Gum, NF 25.0 30.0 Dextrose, USP 35.0 40.0 Calcium
Sulfate Dihydrate, NF 10.0 0.0 Ethylcellulose, NF 5.0 0.0 Alcohol,
SD3A (Anhydrous) (10).sup.1 (20.0).sup.1 Total 100.0 100.0
[0058] A series of tablets containing different amounts of
oxymorphone hydrochloride were prepared using the controlled
release delivery Formulation 1 shown in Table 1. The quantities of
ingredients per tablet are as listed in the following table.
TABLE-US-00002 TABLE 2 Sample Tablets of Differing Strengths
Component Amounts in Tablet (mg) Oxymorphone HCl, 5 10 20 40 80 USP
(mg) Controlled release 160 160 160 160 160 delivery system
Silicified 20 20 20 20 20 microcrystalline cellulose, N.F. Sodium
stearyl 2 2 2 2 2 fumarate, NF Total weight 187 192 202 222 262
Opadry (colored) 7.48 7.68 8.08 8.88 10.48 Opadry (clear) 0.94 0.96
1.01 1.11 1.31
Examples 2 and 3
[0059] Two batches of 20 mg tablets were prepared as described
above, using the controlled release delivery system of Formulation
1. One batch was formulated to provide relatively fast controlled
release, the other batch was formulated to provide relatively slow
controlled release. Compositions of the tablets are shown in the
following table. TABLE-US-00003 TABLE 3 Slow and Fast Release
Compositions Example 2 Example 3 Example 4 Ingredients Slow (mg)
Fast (mg) Fast (mg) Oxymorphone HCl, USP 20 20 20 Controlled
Release Delivery System 360 160 160 Silicified Microcrystalline
Cellulose, 20 20 20 NF Sodium stearyl fumarate, NF 4 2 2 Total
weight 404 202 202 Coating (color or clear) 12 12 9
[0060] The tablets of Examples 2, 3, and 4 were tested for in vitro
release rate according to USP Procedure Drug Release U.S. Pat. No.
23. Release rate is a critical variable in attempting to control
the blood plasma levels of oxymorphone and 6-hydroxyoxymorphone in
a patient. Results are shown in the following Table 4.
TABLE-US-00004 TABLE 4 Release Rates of Slow and Fast Release
Tablets Time Example 2 Example 3 Example 4 (hr) (Slow Release)
(Fast Release) (Fast Release) 0.5 18.8 21.3 20.1 1 27.8 32.3 31.7 2
40.5 47.4 46.9 3 50.2 58.5 57.9 4 58.1 66.9 66.3 5 64.7 73.5 74.0 6
70.2 78.6 83.1 8 79.0 86.0 92.0 10 85.3 90.6 95.8 12 89.8 93.4
97.3
Clinical Studies
[0061] Three clinical studies were conducted to assess the
bioavailability (rate and extent of absorption) of oxymorphone.
Study 1 addressed the relative rates of absorption of controlled
release (CR) oxymorphone tablets (of Examples 2 and 3) and oral
oxymorphone solution in fasted patients. Study 2 addressed the
relative rates of absorption of CR oxymorphone tablets (of Examples
2 and 3) and oral oxymorphone solution in fed patients. Study 3
addressed the relative rates of absorption of CR oxymorphone
tablets (of Example 4) and oral oxymorphone solution in fed and
fasted patients.
[0062] The blood plasma levels set forth herein as appropriate to
achieve the objects of the present invention are mean blood plasma
levels. As an example, if the blood plasma level of oxymorphone in
a patient 12 hours after administration of a tablet is said to be
at least 0.5 ng/ml, any particular individual may have lower blood
plasma levels after 12 hours. However, the mean minimum
concentration should meet the limitation set forth. To determine
mean parameters, a study should be performed with a minimum of 8
adult subjects, in a manner acceptable for filing an application
for drug approval with the US Food and Drug Administration. In
cases where large fluctuations are found among patients, further
testing may be necessary to accurately determine mean values.
[0063] For all studies, the following procedures were followed,
unless otherwise specified for a particular study.
[0064] The subjects were not to consume any alcohol-, caffeine-, or
xanthine-containing foods or beverages for 24 hours prior to
receiving study medication for each study period. Subjects were to
be nicotine and tobacco free for at least 6 months prior to
enrolling in the study. In addition, over-the-counter medications
were prohibited 7 days prior to dosing and during the study.
Prescription medications were not allowed 14 days prior to dosing
and during the study.
[0065] Pharmacokinetic and Statistical Methods
[0066] The following pharmacokinetic parameters were computed from
the plasma oxymorphone concentration-time data:
[0067] AUC.sub.(0-t) Area under the drug concentration-time curve
from time zero to the time of the last quantifiable concentration
(Ct), calculated using linear trapezoidal summation.
[0068] AUC.sub.(0-inf) Area under the drug concentration-time curve
from time zero to infinity.
AUC.sub.(0-inf)=AUC.sub.(0-t)+Ct/K.sub.el, where K.sub.el is the
terminal elimination rate constant.
[0069] AUC.sub.(0-24) Partial area under the drug
concentration-time curve from time zero to 24 hours.
[0070] C.sub.max Maximum observed drug concentration.
[0071] T.sub.max Time of the observed maximum drug
concentration.
[0072] K.sub.el Elimination rate constant based on the linear
regression of the terminal linear portion of the LN (concentration)
time curve.
[0073] Terminal elimination rate constants for use in the above
calculations were in turn computed using linear regression of a
minimum of three time points, at least two of which were
consecutive. K.sub.el values for which correlation coefficients
were less than or equal to 0.8 were not reported in the
pharmacokinetic parameter tables or included in the statistical
analysis. Thus AUC.sub.(0-inf) was also not reported in these
cases.
[0074] A parametric (normal-theory) general linear model was
applied to each of the above parameters (excluding T.sub.max), and
the LN-transformed parameters C.sub.max, AUC.sub.(0-24),
AUC.sub.(0-t), and AUC.sub.(0-inf). Initially, the analysis of
variance (ANOVA) model included the following factors: treatment,
sequence, subject within sequence, period, and carryover effect. If
carryover effect was not significant, it was dropped from the
model. The sequence effect was tested using the subject within
sequence mean square, and all other main effects were tested using
the residual error (error mean square).
[0075] Plasma oxymorphone concentrations were listed by subject at
each collection time and summarized using descriptive statistics.
Pharmacokinetic parameters were also listed by subject and
summarized using descriptive statistics.
[0076] Study 1--Two Controlled Release Formulations; Fasted
Patients
[0077] Healthy volunteers received a single oral dose of 20 mg CR
oxymorphone taken with 240 ml water after a 10-hour fast. Subjects
received the tablets of Example 2 (Treatment 1A) or Example 3
(Treatment 1B). Further subjects were given a single oral dose of
10 mg/10 ml oxymorphone solution in 180 ml apple juice followed
with 60 ml water (Treatment 1C). The orally dosed solution was
used, to simulate an immediate release (IR) dose.
[0078] This study had a single-center, open-label, randomized,
three-way crossover design using fifteen subjects. Subjects were in
a fasted state following a 10-hour overnight fast. There was a
14-day washout interval between the three dose administrations. The
subjects were confined to the clinic during each study period.
Subjects receiving Treatment 1C were confined for 18 hours and
subjects receiving Treatments 1A or 1B were confined for 48 hours
after dosing. Ten-milliliter blood samples were collected during
each study period at the 0 hour (predose), and at 0.5, 1, 1.5, 2,
3, 4, 5, 6, 7, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, and 48
hours postdose for subjects receiving Treatment 1A or 1B and 0,
0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 10,
12, 14, 16, and 18 hours post-dose. The mean plasma concentration
of oxymorphone versus time for each treatment across all subjects
is shown in table 5. TABLE-US-00005 TABLE 5 Mean Plasma
Concentration vs. Time (ng/ml) Time (hr) Treatment 1A Treatment 1B
Treatment 1C 0 0.000 0.000 0.0000 0.25 0.9489 0.5 0.2941 0.4104
1.3016 0.75 1.3264 1 0.5016 0.7334 1.3046 1.25 1.2041 1.5 0.5951
0.8192 1.0813 1.75 0.9502 2 0.6328 0.7689 0.9055 2.5 0.7161 3
0.5743 0.7341 0.6689 4 0.5709 0.6647 0.4879 5 0.7656 0.9089 0.4184
6 0.7149 0.7782 0.3658 7 0.6334 0.6748 0.3464 8 0.5716 0.5890
0.2610 10 0.4834 0.5144 0.2028 12 0.7333 0.6801 0.2936 14 0.6271
0.6089 0.2083 16 0.4986 0.4567 0.1661 18 0.4008 0.3674 0.1368 20
0.3405 0.2970 24 0.2736 0.2270 28 0.3209 0.2805 32 0.2846 0.2272 36
0.2583 0.1903 48 0.0975 0.0792
[0079] The results are shown graphically in FIG. 5. In both Table 5
and FIG. 5, the results are normalized to a 20 mg dosage. The
immediate release liquid of Treatment 1C shows a classical curve,
with a high and relatively narrow peak, followed by an exponential
drop in plasma concentration. However, the controlled release
oxymorphone tablets exhibit triple peaks in blood plasma
concentration. The first peak occurs (on average) at around 3
hours. The second peak of the mean blood plasma concentration is
higher than the first, occurring around 6-7 hours, on average).
[0080] Occasionally, in an individual, the first peak is higher
than the second, although generally this is not the case. This
makes it difficult to determine the time to maximum blood plasma
concentration (T.sub.max) because if the first peak is higher than
the second, maximum blood plasma concentration (C.sub.max) occurs
much earlier (at around 3 hours) than in the usual case where the
second peak is highest. Therefore, when we refer to the time to
peak plasma concentration (T.sub.max) unless otherwise specified,
we refer to the time to the second peak. Further, when reference is
made to,the second peak, we refer to the time or blood plasma
concentration at the point where the blood plasma concentration
begins to drop the second time. Generally, where the first peak is
higher than the second, the difference in the maximum blood plasma
concentration at the two peaks is small. Therefore, this difference
(if any) was ignored and the reported C.sub.max was the true
maximum blood plasma concentration and not the concentration at the
second peak. TABLE-US-00006 TABLE 6 Pharmacokinetic Parameters of
Plasma Oxymorphone for Study 1 Treatment 1A Treatment 1B Treatment
1C Mean SD Mean SD Mean SD C.sub.max 0.8956 0.2983 1.0362 0.3080
2.9622 1.0999 T.sub.max 7.03 4.10 4.89 3.44 0.928 0.398
AUC.sub.(0-t) 17.87 6.140 17.16 6.395 14.24 5.003 AUC.sub.(0-inf)
19.87 6.382 18.96 6.908 16.99 5.830 T.sub.1/2el 10.9 2.68 11.4 2.88
6.96 4.61 Units: C.sub.max in ng/ml, T.sub.max in hours, AUC in ng
* hr/ml, T.sub.1/2el in hours.
[0081] Relative bioavailability determinations are set forth in
Tables 7 and 8. For these calculations, AUC was normalized for all
treatments to a 20 mg dose. TABLE-US-00007 TABLE 7 Relative
Bioavailability (F.sub.rel) Determination Based on AUC.sub.(0-inf)
F.sub.rel (1A vs. 1C) F.sub.rel (1B vs. 1C) F.sub.rel (1A vs. 1B)
1.193 ..+-.. 0.203 1.121 ..+-.. 0.211 1.108 ..+-.. 0.152
[0082] TABLE-US-00008 TABLE 8 Relative Bioavailability
Determination Based on AUC.sub.(0-18) F.sub.rel (1A vs. 1C)
F.sub.rel (1B vs. 1C) F.sub.rel (1A vs. 1B) 0.733 ..+-.. 0.098
0.783 ..+-.. 0.117 0.944 ..+-.. 0.110
[0083] Study 2--Two CR Formulations; Fed Patients
[0084] Healthy volunteers received a single oral dose of 20 mg CR
oxymorphone taken with 240 ml water in a fed state. Subjects
received the tablets of Example 2 (Treatment 2A) or Example 3
(Treatment 2B). Further subjects were given a single oral dose of
10 mg/10 ml oxymorphone solution in 180 ml apple juice followed
with 60 ml water (Treatment 2C). The orally dosed solution was used
to simulate an immediate release (IR) dose.
[0085] This study had a single-center, open-label, randomized,
three-way crossover design using fifteen subjects. The subjects
were in a fed state, after a 10-hour overnight fast followed by a
standardized FDA high-fat breakfast. There was a 14-day washout
interval between the three dose administrations. The subjects were
confined to the clinic during each study period. Subjects receiving
Treatment 2C were confined for 18 hours and subjects receiving
Treatments 2A or 2B were confined for 48 hours after dosing.
Ten-milliliter blood samples were collected during each study
period at the 0 hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6,
7, 8, 10, 12, 14, 16, 18, 20, 24, 28, 32, 36, and 48 hours postdose
for subjects receiving Treatment 2A or 2B and 0, 0.25, 0.5, 0.75,
1, 1.25, 1.5, 1.75, 2, 2.5, 3, 4, 5, 6, 7, 8, 10, 12, 14, 16, and
18 hours postdose. The mean plasma concentration of oxymorphone
versus time for each treatment across all subjects is shown in
table 9. TABLE-US-00009 TABLE 9 Mean Plasma Concentration vs. Time
(ng/ml) Time (hr) Treatment 2A Treatment 2B Treatment 2C 0 0.000
0.000 0.0000 0.25 1.263 0.5 0.396 .0553 1.556 0.75 1.972 1 0.800
1.063 1.796 1.25 1.795 1.5 1.038 1.319 1.637 1.75 1.467 2 1.269
1.414 1.454 2.5 1.331 3 1.328 1.540 1.320 4 1.132 1.378 1.011 5
1.291 1.609 0.731 6 1.033 1.242 0.518 7 0.941 0.955 0.442 8 0.936
0.817 0.372 10 0.669 0.555 0.323 12 0.766 0.592 0.398 14 0.641
0.519 0.284 16 0.547 0.407 0.223 18 0.453 0.320 0.173 20 0.382
0.280 24 0.315 0.254 28 0.352 0.319 32 0.304 0.237 36 0.252 0.207
48 0.104 0.077
[0086] The results are shown graphically in FIG. 6. Again, the
results have been normalized to a 20 mg dosage. As with Study 1,
the immediate release liquid of Treatment 2C shows a classical
curve, with a high and relatively narrow peak, followed by an
exponential drop in plasma concentration, while the controlled
release oxymorphone tablets exhibit triple peaks in blood plasma
concentration. Thus, again when we refer to the time to peak plasma
concentration (T.sub.max) unless otherwise specified, we refer to
the time to the second peak. TABLE-US-00010 TABLE 10
Pharmacokinetic Parameters of Plasma Oxymorphone for Study 2
Treatment 2A Treatment 2B Treatment 2C Mean SD Mean SD Mean SD
C.sub.max 1.644 0.365 1.944 0.465 4.134 0.897 T.sub.max 3.07 1.58
2.93 1.64 0.947 0.313 AUC.sub.(0-t) 22.89 5.486 21.34 5.528 21.93
5.044 AUC.sub.(0-inf) 25.28 5.736 23.62 5.202 24.73 6.616
T.sub.1/2el 12.8 3.87 11.0 3.51 5.01 2.02 Units: C.sub.max in
ng/ml, T.sub.max in hours, AUC in ng * hr/ml, T.sub.1/2el in
hours.
[0087] In Table 10, the T.sub.max has a large standard deviation
due to the two comparable peaks in blood plasma concentration.
Relative bioavailability determinations are set forth in Tables 11
and 12. TABLE-US-00011 TABLE 11 Relative Bioavailability
Determination Based on AUC.sub.(0-inf) F.sub.rel (2A vs. 2C)
F.sub.rel (2B vs. 2C) F.sub.rel (2A vs. 2B) 1.052 ..+-.. 0.187
0.949 ..+-.. 0.154 1.148 ..+-.. 0.250
[0088] TABLE-US-00012 TABLE 12 Relative bioavailability
Determination Based on AUC.sub.(0-18) F.sub.rel (2A vs. 2C)
F.sub.rel (2B vs. 2C) F.sub.rel (2A vs. 2B) 0.690 ..+-.. 0.105
0.694 ..+-.. 0.124 1.012 ..+-.. 0.175
[0089] As may be seen from tables 5 and 10 and FIGS. 1 and 2, the
C.sub.max for the CR tablets (treatments 1A, 1B, 2A and 2B) is
considerably lower, and the T.sub.max much higher than for the
immediate release oxymorphone. The blood plasma level of
oxymorphone remains high well past the 8 (or even the 12) hour
dosing interval desired for an effective controlled release
tablet.
[0090] Study 3--One Controlled Release Formulation; Fed and Fasted
Patients
[0091] This study had a single-center, open-label, analytically
blinded, randomized, four-way crossover design. Subjects randomized
to Treatment 3A and Treatment 3C, as described below, were in a
fasted state following a 10-hour overnight fast. Subjects
randomized to Treatment 3B and Treatment 3D, as described below,
were in the fed state, having had a high fat meal, completed ten
minutes prior to dosing. There was a 14-day washout interval
between the four dose administrations. The subjects were confined
to the clinic during each study period. Subjects assigned to
receive Treatment 3A and Treatment 3B were discharged from the
clinic on Day 3 following the 48-hour procedures, and subjects
assigned to receive Treatment 3C and Treatment 3D were discharged
from the clinic on Day 2 following the 36-hour procedures. On Day 1
of each study period the subjects received one of four
treatments:
[0092] Treatments 3A and 3B: Oxymorphone controlled release 20 mg
tablets from Example 3. Subjects randomized to Treatment 3A
received a single oral dose of one 20 mg oxymorphone controlled
release tablet taken with 240 ml of water after a 10-hour fasting
period. Subjects randomized to Treatment 3B received a single oral
dose of one 20 mg oxymorphone controlled release tablet taken with
240 ml of water 10 minutes after a standardized high fat meal.
[0093] Treatments 3C and 3D: oxymorphone HCl solution, USP, 1.5
mg/ml 10 ml vials. Subjects randomized to Treatment 3C received a
single oral dose of 10 mg (6.7 ml) oxymorphone solution taken with
240 ml of water after a 10-hour fasting period. Subjects randomized
to Treatment 3D received a single oral dose of 10 mg (6.7 ml)
oxymorphone solution taken with 240 ml of water 10 minutes after a
standardized high-fat meal.
[0094] A total of 28 male subjects were enrolled in the study, and
24 subjects completed the study. The mean age of the subjects was
27 years (range of 19 through 38 years), the mean height of the
subjects was 69.6 inches (range of 64.0 through 75.0 inches), and
the mean weight of the subjects was 169.0 pounds (range 117.0
through 202.0 pounds).
[0095] A total of 28 subjects received at least one treatment. Only
subjects who completed all 4 treatments were included in the
summary statistics and statistical analysis.
[0096] Blood samples (7 ml) were collected during each study period
at the 0 hour (predose), and at 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10,
12, 14, 16, 20, 24, 30, 36, and 48 hours post-dose (19 samples) for
subjects randomized to Treatment 3A and Treatment 3B. Blood samples
(7 ml) were collected during each study period at the 0 hour
(predose), and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 3, 4, 5,
6, 8, 10, 12, 14, 16, 20, and 36 hours post-dose (21 samples) for
subjects randomized to Treatment 3C and Treatment 3D.
[0097] The mean oxymorphone plasma concentration versus time curves
for Treatments 3A, 3B, 3C, and 3D are presented in FIG. 7. The
results have been normalized to a 20 mg dosage. The data is
contained in Table 13. The arithmetic means of the plasma
oxymorphone pharmacokinetic parameters and the statistics for all
Treatments are summarized in Table 1. TABLE-US-00013 TABLE 13 Mean
Plasma Concentration vs. Time (ng/ml) Time Treatment Treatment
Treatment Treatment (hr) 3A 3B 3C 3D 0 0.0084 0.0309 0.0558 0.0000
0.25 0.5074 0.9905 0.5 0.3853 0.3380 0.9634 1.0392 0.75 0.9753
1.3089 1 0.7710 0.7428 0.8777 1.3150 1.25 0.8171 1.2274 1.5 0.7931
1.0558 0.7109 1.1638 1.75 0.6357 1.0428 2 0.7370 1.0591 0.5851
0.9424 3 0.6879 0.9858 0.4991 0.7924 4 0.6491 0.9171 0.3830 0.7277
5 0.9312 1.4633 0.3111 0.6512 6 0.7613 1.0441 0.2650 0.4625 8
0.5259 0.7228 0.2038 0.2895 10 0.4161 0.5934 0.1768 0.2470 12
0.5212 0.5320 0.2275 0.2660 14 0.4527 0.4562 0.2081 0.2093 16
0.3924 0.3712 0.1747 0.1623 20 0.2736 0.3021 0.1246 0.1144 24
0.2966 0.2636 0.1022 0.1065 30 0.3460 0.3231 36 0.2728 0.2456
0.0841 0.0743 48 0.1263 0.1241
[0098] TABLE-US-00014 TABLE 14 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 3 Treatment 3A Treatment 3B Treatment 3C
Treatment 3D Mean SD Mean SD Mean SD Mean SD C.sub.max 1.7895
0.6531 1.1410 0.4537 2.2635 1.0008 2.2635 1.0008 T.sub.max 5.65
9.39 5.57 7.14 0.978 1.14 0.978 1.14 AUC.sub.(0-t) 14.27 4.976
11.64 3.869 12.39 4.116 12.39 4.116 AUC.sub.(0-inf) 19.89 6.408
17.71 8.471 14.53 4.909 14.53 4.909 T.sub.1/2el 21.29 6.559 19.29
5.028 18.70 6.618 18.70 6.618 12.0 3.64 12.3 3.99 16.2 11.4 16.2
11.4
[0099] The relative bioavailability calculations are summarized in
tables 15 and 16. TABLE-US-00015 TABLE 15 Relative Bioavailability
Determination Based on AUC.sub.(0-inf) F.sub.rel (3A vs. 3C)
F.sub.rel (3B vs. 3D) F.sub.rel (3D vs. 3C) F.sub.rel (3A vs. 3B)
1.040 ..+-.. 0.8863 ..+-.. 0.2569 1.368 ..+-.. 0.4328 1.169 ..+-..
0.2041 0.1874
[0100] TABLE-US-00016 TABLE 16 Relative bioavailability
Determination Based on AUC.sub.(0-24) F.sub.rel (3A vs. 2C)
F.sub.rel (3B vs. 3D) F.sub.rel (3D vs. 3C) F.sub.rel (3A vs. 3B)
0.9598 ..+-.. 0.8344 ..+-.. 0.100 1.470 ..+-.. 0.3922 1.299 ..+-..
0.4638 0.2151
[0101] The objectives of this study were to assess the relative
bioavailability of oxymorphone from oxymorphone controlled release
(20 mg) compared to oxymorphone oral solution (10 mg) under both
fasted and fed conditions, and to determine the effect of food on
the bioavailability of oxymorphone from the controlled release
formulation, oxymorphone CR, and from the oral solution.
[0102] The presence of a high fat meal had a substantial effect on
the oxymorphone C.sub.max, but less of an effect on oxymorphone AUC
from oxymorphone controlled release tablets. Least Squares (LS)
mean C.sub.max was 58% higher and LS mean AUC.sub.(0-t) and
AUC.sub.(0-inf) were 18% higher for the fed condition (Treatment B)
compared to the fasted condition (Treatment A) based on
LN-transformed data. This was consistent with the relative
bioavailability determination from AUC.sub.(0-inf) since mean
F.sub.rel was 1.17. Mean T.sub.max values were similar
(approximately 5.6 hours), and no significant difference in
T.sub.max was shown using nonparametric analysis. Half value
durations were significantly different between the two
treatments.
[0103] The effect of food on oxymorphone bioavailability from the
oral solution was more pronounced, particularly in terms of AUC. LS
mean C.sub.max was 50% higher and LS mean AUC.sub.(0-t) and
AUC.sub.(0-inf) were 32-34% higher for the fed condition (Treatment
D) compared to the fasted condition (Treatment C) based on
LN-transformed data. This was consistent with the relative
bioavailability determination from AUC.sub.(0-inf) since mean
F.sub.rel was 1.37. Mean T.sub.max (approximately 1 hour) was
similar for the two treatments and no significant difference was
shown.
[0104] Under fasted conditions, oxymorphone controlled release 20
mg tablets exhibited similar extent of oxymorphone availability
compared to 10 mg oxymorphone oral solution normalized to a 20 mg
dose (Treatment A versus Treatment C). From LN-transformed data, LS
mean AUC.sub.(0-t) was 17% higher for oxymorphone CR, whereas LS
mean AUC.sub.(0-inf) values were nearly equal (mean ratio=99%).
Mean F.sub.rel values calculated from AUC.sub.(0-inf) and
AUC.sub.(0-24), (1.0 and 0.96, respectively) also showed similar
extent of oxymorphone availability between the two treatments.
[0105] As expected, there were differences in parameters reflecting
rate of absorption. LS mean C.sub.max was 49% lower for oxymorphone
controlled release tablets compared to the dose-normalized oral
solution, based on LN-transformed data. Half-value duration was
significantly longer for the controlled release formulation (means,
12 hours versus 2.5 hours).
[0106] Under fed conditions, oxymorphone availability from
oxymorphone controlled release 20 mg was similar compared to 10 mg
oxymorphone oral solution normalized to a 20 mg dose (Treatment B
versus Treatment D). From LN-transformed data, LS mean
AUC.sub.(0-inf) was 12% lower for oxymorphone CR. Mean F.sub.rel
values calculated from AUC.sub.(0-inf) and AUC.sub.(0-24), (0.89
and 0.83 respectively) also showed similar extent of oxymorphone
availability from the tablet. As expected, there were differences
in parameters reflecting rate of absorption. LS mean C.sub.max was
46% lower for oxymorphone controlled release tablets compared to
the dose-normalized oral solution, based on LN-transformed data.
Mean T.sub.max was 5.7 hours for the tablet compared to 1.1 hours
for the oral solution. Half-value duration was significantly longer
for the controlled release formulation (means, 7.8 hours versus 3.1
hours).
[0107] The presence of a high fat meal did not appear to
substantially affect the availability following administration of
oxymorphone controlled release tablets. LS mean ratios were 97% for
AUC.sub.(0-t) and 91% for C.sub.max (Treatment B versus A), based
on LN-transformed data. This was consistent with the relative
bioavailability determination from AUC.sub.(0-24), since mean
F.sub.rel was 0.97. Mean T.sub.max was later for the fed treatment
compared to the fasted treatment (5.2 and 3.6 hours, respectively),
and difference was significant.
[0108] Under fasted conditions, oxymorphone controlled release 20
mg tablets exhibited similar availability compared to 10 mg
oxymorphone oral solution normalized to a 20 mg dose (Treatment A
versus Treatment C). From LN-transformed data, LS mean ratio for
AUC.sub.(0-t) was 104.5%. Mean F.sub.rel (0.83) calculated from
AUC.sub.(0-24) also showed similar extent of oxymorphone
availability between the two treatments. Mean T.sub.max was 3.6
hours for the tablet compared to 0.88 for the oral solution.
Half-value duration was significantly longer for the controlled
release formulation (means, 11 hours versus 2.2 hours).
[0109] Under fed conditions, availability from oxymorphone
controlled release 20 mg was similar compared to 10 mg oxymorphone
oral solution normalized to a 20 mg dose (Treatment B versus
Treatment D). From LN-transformed data, LS mean AUC.sub.(0-t) was
14% higher for oxymorphone CR. Mean F.sub.rel (0.87) calculated
from AUC.sub.(0-24) also indicated similar extent of availability
between the treatments. Mean T.sub.max was 5.2 hours for the tablet
compared to 1.3 hour for the oral solution. Half-value duration was
significantly longer for the controlled release formulation (means,
14 hours versus 3.9 hours).
[0110] The extent of oxymorphone availability from oxymorphone
controlled release 20 mg tablets was similar under fed and fasted
conditions since there was less than a 20% difference in LS mean
AUC.sub.(0-t) and AUC.sub.(0-inf) values for each treatment, based
on LN-transformed data. T.sub.max was unaffected by food; however,
LS mean C.sub.max was increased 58% in the presence of the high fat
meal. Both rate and extent of oxymorphone absorption from the
oxymorphone oral solution were affected by food since LS mean
C.sub.max and AUC values were increased approximately 50 and 30%,
respectively. Tinax was unaffected by food. Under both fed and
fasted conditions, oxymorphone controlled release tablets exhibited
similar extent of oxymorphone availability compared to oxymorphone
oral solution since there was less than a 20% difference in LS mean
AUC(0-t) and AUC(0-inf) values for each treatment.
[0111] Bioavailability following oxymorphone controlled release 20
mg tablets was also similar under fed and fasted conditions since
there was less than a 20% difference in LS mean C.sub.max and AUC
values for each treatment. T.sub.max was later for the fed
condition. The presence of food did not affect the extent of
availability from oxymorphone oral solution since LS mean AUC
values were less than 20% different. However, C.sub.max was
decreased 35% in the presence of food. T.sub.max was unaffected by
food. Under both fed and fasted conditions, oxymorphone controlled
release tablets exhibited similar extent of availability compared
to oxymorphone oral solution since there was less than a 20%
difference in LS mean AUC values for each treatment.
[0112] The mean 6-OH oxymorphone plasma concentration versus time
curves for Treatments 3A, 3B, 3C, and 3D are presented in FIG. 8.
The data is contained in Table 17. TABLE-US-00017 TABLE 17 Mean
Plasma Concentration vs. Time (ng/ml) 6-Hydroxyoxymorphone
Treatment Treatment Treatment Treatment Time (hr) 3A 3B 3C 3D 0
0.0069 0.0125 0.0741 0.0000 0.25 0.7258 0.4918 0.5 0.5080 0.1879
1.2933 0.5972 0.75 1.3217 0.7877 1 1.0233 0.4830 1.1072 0.8080 1.25
1.0069 0.7266 1.5 1.1062 0.7456 0.8494 0.7001 1.75 0.7511 0.6472 2
1.0351 0.7898 0.6554 0.5758 3 0.9143 0.7619 0.6196 0.5319 4 0.8522
0.7607 0.4822 0.5013 5 0.8848 0.8548 0.3875 0.4448 6 0.7101 0.7006
0.3160 0.3451 8 0.5421 0.5681 0.2525 0.2616 10 0.4770 0.5262 0.2361
0.2600 12 0.4509 0.4454 0.2329 0.2431 14 0.4190 0.4399 0.2411
0.2113 16 0.4321 0.4230 0.2385 0.2086 20 0.3956 0.4240 0.2234
0.1984 24 0.4526 0.4482 0.2210 0.2135 30 0.4499 0.4708 36 0.3587
0.3697 0.1834 0.1672 48 0.3023 0.3279
[0113] TABLE-US-00018 TABLE 18 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 3 Treatment 3A Treatment 3B Treatment 3C
Treatment 3D Mean SD Mean SD Mean SD Mean SD C.sub.max 1.2687
0.5792 1.1559 0.4848 1.5139 0.7616 0.9748 0.5160 T.sub.max 3.61
7.17 5.20 9.52 0.880 0.738 1.30 1.04 AUC.sub.(o-t) 22.47 10.16
22.01 10.77 10.52 4.117 9.550 4.281 AUC.sub.(o-inf) 38.39 23.02
42.37 31.57 20.50 7.988 23.84 11.37 T.sub.1/2el 39.1 36.9 39.8 32.6
29.3 12.0 44.0 35.00
[0114] Study 4--Controlled Release 20 mg vs Immediate Release 10
mg
[0115] A study was conducted to compare the bioavailability and
pharmacokinetics of controlled release and immediate release
oxymorphone tablets under single-dose and multiple-dose (steady
state) conditions. For the controlled release study, healthy
volunteers received a single dose of a 20 mg controlled release
oxymorphone table on the morning of Day 1. Beginning on the morning
of Day 3, the volunteers were administered a 20 mg controlled
release oxymorphone tablet every 12 hours through the morning dose
of Day 9. For the immediate release study, healthy volunteers
received a single 10 mg dose of an immediate release oxymorphone
tablet on the morning of Day 1. On the morning of Day. 3,
additional 10 mg immediate release tablets were administered every
six hours through the first two doses on Day 9.
[0116] FIG. 9 shows the average plasma concentrations of
oxymorphone and 6-6-hydroxy oxymorphone for all subjects after a
single dose either controlled release (CR) 20 mg or immediate
release (IR) 10 mg oxymorphone. The data in the figure (as with the
other relative experimental data herein) is normalized to a 20 mg
dose. The immediate release tablet shows a classical curve, with a
high, relatively narrow peak followed by an exponential drop in
plasma concentration. The controlled release oxymorphone tablets
show a lower peak with extended moderate levels of oxymorphone and
6-hydroxy oxymorphone. Table 19 shows the levels of oxymorphone and
6-hydroxy oxymorphone from FIG. 9 in tabular form. TABLE-US-00019
TABLE 19 Mean Plasma Concentration (ng/ml) Oxymorphone
6-Hydroxyoxymorphone Controlled Immediate Controlled Immediate
Release Release Release Release Hour 20 mg 10 mg 20 mg 10 mg 0.00
0.00 0.00 0.00 0.00 0.25 0.22 1.08 0.14 0.73 0.50 0.59 1.69 0.45
1.22 1.00 0.77 1.19 0.53 0.79 1.50 0.84 0.91 0.53 0.57 2.00 0.87
0.75 0.60 0.47 3.00 0.83 0.52 0.55 0.34 4.00 0.73 0.37 0.53 0.27
5.00 0.94 0.36 0.46 0.23 6.00 0.81 0.28 0.41 0.18 8.00 0.73 0.20
0.37 0.14 10.0 0.60 0.19 0.35 0.15 12.0 0.67 0.25 0.32 0.13 16.0
0.39 0.16 0.29 0.13 24.0 0.23 0.07 0.29 0.13 30.0 0.12 0.01 0.17
0.04 36.0 0.05 0.00 0.11 0.00 48.0 0.00 0.00 0.07 0.01
[0117] FIG. 10 shows the average plasma concentrations of
oxymorphone and 6-hydroxyoxymorphone for all subjects in the steady
state test, for doses of controlled release 20 mg tablets and
immediate release 10 mg tablets of oxymorphone. The figure shows
the plasma concentrations after the final controlled release tablet
is given on Day 9, and the final immediate release tablet is given
12 hours thereafter. The steady state administration of the
controlled release tablets clearly shows a steady moderate level of
oxymorphone ranging from just over 1 ng/ml to almost 1.75 ng/ml
over the course of a twelve hour period, where the immediate
release tablet shows wide variations in blood plasma concentration.
Table 20 shows the levels of oxymorphone and 6-hydroxyoxymorphone
from FIG. 10 in tabular form. TABLE-US-00020 TABLE 20 Summary of
Mean Plasma Concentration (ng/ml) Oxymorphone 6-Hydroxyoxymorphone
Controlled Immediate Controlled Immediate Release Release Release
Release Day Hour 20 mg 10 mg 20 mg 10 mg 4 0.00 1.10 0.75 0.89 0.72
5 0.00 1.12 0.84 1.15 0.88 6 0.00 1.20 0.92 1.15 0.87 7 0.00 1.19
0.91 1.27 1.00 8 0.00 1.19 0.86 1.29 0.98 9 0.00 1.03 1.07 1.09
1.05 0.25 2.64 1.70 0.50 3.12 1.50 2.09 1.00 2.47 1.70 1.68 1.50
2.05 1.63 1.55 2.00 1.78 1.64 1.30 3.00 1.27 1.47 1.11 4.00 0.98
1.39 0.98 5.00 1.01 1.21 0.89 6.00 0.90 1.06 0.84 6.25 1.17 0.88
6.50 1.88 1.06 7.00 2.12 1.20 7.50 2.24 1.15 8.00 1.32 2.01 0.97
1.03 9.00 1.52 0.90 10.0 1.32 1.24 0.85 0.84 11.0 1.11 0.74 12.0
1.18 0.96 0.79 0.70
[0118] TABLE-US-00021 TABLE 21 Mean Single-Dose Pharmacokinetic
Results Controlled Immediate Release 20 mg Release 10 mg oxymor-
6-OH- oxymor- 6-OH- phone oxymorphone phone oxymorphone
AUC.sub.(o-t) 14.74 11.54 7.10 5.66 AUC.sub.(o-inf) 15.33 16.40
7.73 8.45 C.sub.max(ng/ml) 1.12 0.68 1.98 1.40 T.sub.max(hr) 5.00
2.00 0.50 0.50 T1/2(hr) 9.25 26.09 10.29 29.48
[0119] Parent 6-OH oxymorphone AUC.sub.(0-t) values were lower than
the parent compound after administration of either dosage form, but
the AUC.sub.(0-inf) values are slightly higher due to the longer
half-life for the metabolite. This relationship was similar for
both the immediate-release (IR) and controlled release (CR) dosage
forms. As represented by the average plasma concentration graph,
the CR dosage form has a significantly longer time to peak
oxymorphone concentration and a lower peak oxymorphone
concentration. The 6-OH oxymorphone peak occurred sooner than the
parent peak following the CR dosage form, and simultaneously with
the parent peak following the IR dosage form.
[0120] It is important to note that while the present invention is
described and exemplified using 20 mg tablets, the invention may
also be used with other strengths of tablets. In each strength, it
is important to note how a 20 mg tablet of the same composition
(except for the change in strength) would act. The blood plasma
levels and pain intensity information are provided for 20 mg
tablets, however the present invention is also intended to
encompass 5 to 80 mg controlled release tablets. For this reason,
the blood plasma level of oxymorphone or 6-hydroxyoxymorphone in
nanograms per milliliter of blood, per mg oxymorphone (ng/mgml)
administered is measured. Thus at 0.02 ng/mgml, a 5 mg tablet
should produce a minimum blood plasma concentration of 0.1 ng/ml. A
stronger tablet will produce a higher blood plasma concentration of
active molecule, generally proportionally. Upon administration of a
higher dose tablet, for example 80 mg, the blood plasma level of
oxymorphone and 6-OH oxymorphone may more than quadruple compared
to a 20 mg dose, although conventional treatment of low
bioavailability substances would lead away from this conclusion. If
this is the case, it may be because the body can only process a
limited amount oxymorphone at one time. Once the bolus is
processed, the blood level of oxymorphone returns to a proportional
level.
[0121] It is the knowledge that controlled release oxymorphone
tablets are possible to produce and effective to use, which is most
important, made possible with the high bioavailability of
oxymorphone in a controlled release tablet. This also holds true
for continuous periodic administration of controlled release
formulations. The intent of a controlled release opioid formulation
is the long-term management of pain. Therefore, the performance of
a composition when administered periodically (one to three times
per day) over several days is important. In such a regime, the
patient reaches a "steady state" where continued administration
will produce the same results, when measured by duration of pain
relief and blood plasma levels of pharmaceutical. Such a test is
referred to as a "steady state" test and may require periodic
administration over an extended time period ranging from several
days to a week or more. Of course, since a patient reaches steady
state in such a test, continuing the test for a longer time period
should not affect the results. Further, when testing blood plasma
levels in such a test, if the time period for testing exceeds the
interval between doses, it is important the regimen be stopped
after the test is begun so that observations of change in blood
level and pain relief may be made without a further dose affecting
these parameters.
[0122] Study 5--Controlled Release 40 mg vs Immediate Release
4.times.10 mg under Fed and Fasting Conditions
[0123] The objectives of this study were to assess the relative
bioavailability of oxymorphone from oxymorphone controlled release
(40 mg) compared to oxymorphone immediate release (4.times.10 mg)
under both fasted and fed conditions, and to determine the effect
of food on the bioavailability of oxymorphone from the controlled
release formulation, oxymorphone CR, and from the immediate release
formulation, oxymorphone IR.
[0124] This study had a single-center, open-label, analytically
blinded, randomized, four-way crossover design. Subjects randomized
to Treatment 5A and Treatment 5C, as described below, were in a
fasted state following a 10-hour overnight fast. Subjects
randomized to Treatment SB and Treatment 5D, as described below,
were in the fed state, having had a high fat meal, completed ten
minutes prior to dosing. There was a 14-day washout interval
between the four dose administrations. The subjects were confined
to the clinic during each study period. Subject assigned to receive
Treatment 5A and Treatment 5B were discharged from the clinic on
Day 3 following the 48-hour procedures, and subjects assigned to
receive Treatment 5C and Treatment 5D were discharged from the
clinic on Day 2 following the 36-hour procedures. On Day 1 of each
study period the subjects received one of four treatments:
[0125] Treatments 5A and 5B: Oxymorphone controlled release 40 mg
tablets from Table 2. Subjects randomized to Treatment 5A received
a single oral dose of one 40 mg oxymorphone controlled release
tablet taken with 240 ml of water after a 10-hour fasting period.
Subjects randomized to Treatment 5B received a single oral dose of
one 40 mg oxymorphone controlled release tablet taken with 240 ml
of water 10 minutes after a standardized high fat meal.
[0126] Treatments 5C and 5D: Immediate release tablet (IR)
4.times.10 mg Oxymorphone. Subjects randomized to Treatment 5C
received a single oral dose of 4.times.10 mg oxymorphone IR tablet
taken with 240 ml of water after a 10-hour fasting period. Subjects
randomized to Treatment 5D received a single oral dose of
4.times.10 mg oxymorphone IR tablet taken with 240 ml of water 10
minutes after a standardized high-fat meal.
[0127] A total of 28 male subjects were enrolled in the study, and
25 subjects completed the study. A total of 28 subjects received at
least one treatment. Only subjects who completed all 4 treatments
were included in the summary statistics and statistical
analysis.
[0128] Blood samples (7 ml) were collected during each study period
at the 0 hour (predose), and at 0.25, 0.5, 0.75, 1.0, 1.5, 2, 3, 4,
5, 6, 8, 10, 12, 24, 36, 48, 60, and 72 hours post-dose (19
samples) for subjects randomized to all Treatments.
[0129] The mean oxymorphone plasma concentration versus time curves
for Treatments 5A, 5B, 5C, and 5D are presented in FIG. 11. The
data is contained in Table 22. The arithmetic means of the plasma
oxymorphone pharmacokinetic parameters and the statistics for all
Treatments are summarized in Table 23. TABLE-US-00022 TABLE 22 Mean
Plasma Concentration vs. Time (ng/ml) Treatment Treatment Treatment
Treatment Time (hr) 5A 5B 5C 5D 0 0.00 0.00 0.00 0.00 0.25 0.47
0.22 3.34 1.79 0.50 1.68 0.97 7.28 6.59 0.75 1.92 1.90 6.60 9.49 1
2.09 2.61 6.03 9.91 1.5 2.18 3.48 4.67 8.76 2 2.18 3.65 3.68 7.29 3
2.00 2.86 2.34 4.93 4 1.78 2.45 1.65 3.11 5 1.86 2.37 1.48 2.19 6
1.67 2.02 1.28 1.71 8 1.25 1.46 0.92 1.28 10 1.11 1.17 0.78 1.09 12
1.34 1.21 1.04 1.24 24 0.55 0.47 0.40 0.44 36 0.21 0.20 0.16 0.18
48 0.06 0.05 0.04 0.05 60 0.03 0.01 0.01 0.01 72 0.00 0.00 0.00
0.00
[0130] TABLE-US-00023 TABLE 23 Pharmacokinetic Parameters of Plasma
Oxymorphone for Study 5 Treatment Treatment Treatment Treatment 5A
5B 5C 5D Mean SD Mean SD Mean SD Mean SD C.sub.max 2.79 0.84 4.25
1.21 9.07 4.09 12.09 5.42 T.sub.max 2.26 2.52 1.96 1.06 0.69 0.43
1.19 0.62 AUC.sub.(o-t) 35.70 10.58 38.20 11.04 36.00 12.52 51.35
20.20 AUC.sub.(o-inf) 40.62 11.38 41.17 10.46 39.04 12.44 54.10
20.26 T.sub.1/2el 12.17 7.57 10.46 5.45 11.65 6.18 9.58 3.63
[0131] The relative bioavailability calculations are summarized in
Tables 24 and 25. TABLE-US-00024 TABLE 24 Relative Bioavailability
Determination Based on AUC.sub.(o-inf) F.sub.rel (5D vs. 5C)
F.sub.rel (5B vs. 5A) 1.3775 1.0220
[0132] TABLE-US-00025 TABLE 25 Relative bioavailability
Determination Based on AUC.sub.(o-24) F.sub.rel (5D vs. 5C)
F.sub.rel (5B vs. 5A) 1.4681 1.0989
[0133] The mean 6-OH oxymorphone plasma concentration versus time
curves for Treatments 5A, 5B, 5C, and 5D are presented in FIG. 12.
The data is contained in Table 26. TABLE-US-00026 TABLE 26 Mean
Plasma Concentration vs. Time (ng/ml) 6-Hydroxyoxymorphone
Treatment Treatment Treatment Treatment Time (hr) 5A 5B 5C 5D 0
0.00 0.00 0.00 0.00 0.25 0.27 0.05 2.36 0.50 0.50 1.32 0.31 5.35
1.98 0.75 1.37 0.59 4.53 2.97 1 1.44 0.82 3.81 2.87 1.5 1.46 1.09
2.93 2.58 2 1.46 1.28 2.37 2.29 3 1.39 1.14 1.69 1.72 4 1.25 1.14
1.33 1.26 5 1.02 1.00 1.14 1.01 6 0.93 0.86 0.94 0.86 8 0.69 0.72
0.73 0.77 10 0.68 0.67 0.66 0.75 12 0.74 0.66 0.70 0.77 24 0.55
0.52 0.54 0.61 36 0.23 0.30 0.28 0.27 48 0.18 0.20 0.20 0.19 60
0.09 0.10 0.09 0.09 72 0.06 0.06 0.04 0.05
[0134] TABLE-US-00027 TABLE 27 Pharmacokinetic Parameters of Plasma
6-Hydroxyoxymorphone for Study 5 Treatment Treatment Treatment
Treatment 5A 5B 5C 5D Mean SD Mean SD Mean SD Mean SD C.sub.max
1.88 0.69 1.59 0.63 6.41 3.61 3.79 1.49 T.sub.max 1.48 1.18 2.73
1.27 0.73 0.47 1.18 0.74 AUC.sub.(o-t) 28.22 10.81 26.95 11.39
33.75 10.29 32.63 13.32 AUC.sub.(o-inf) 33.15 11.25 32.98 10.68
37.63 17.01 36.54 13.79 T.sub.1/2el 17.08 7.45 21.92 8.41 16.01
6.68 16.21 7.42
[0135] The above description incorporates preferred embodiments and
examples as a means of describing and enabling the invention to be
practiced by one of skill in the art. It is imagined that changes
can be made without departing from the spirit and scope of the
invention described herein and defined in the appended claims.
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