U.S. patent application number 10/190383 was filed with the patent office on 2003-07-10 for methods of making sustained release formulations of oxymorphone.
This patent application is currently assigned to Penwest Pharmaceuticals Company. Invention is credited to Baichwal, Anand R., Kao, Huai-Hung, McCall, Troy W..
Application Number | 20030129234 10/190383 |
Document ID | / |
Family ID | 27404938 |
Filed Date | 2003-07-10 |
United States Patent
Application |
20030129234 |
Kind Code |
A1 |
Baichwal, Anand R. ; et
al. |
July 10, 2003 |
Methods of making sustained release formulations of oxymorphone
Abstract
Sustained release formulations of oxymorphone or
pharmaceutically acceptable salts thereof; methods for making the
sustained release formulations of oxymorphone or pharmaceutically
acceptable salts thereof; and methods for using the sustained
release formulations of oxymorphone or pharmaceutically acceptable
salts thereof to treat patients suffering from pain are
provided.
Inventors: |
Baichwal, Anand R.;
(Wappingers Falls, NY) ; Kao, Huai-Hung; (Syosset,
NY) ; McCall, Troy W.; (Germantown, TN) |
Correspondence
Address: |
HALE AND DORR, LLP
60 STATE STREET
BOSTON
MA
02109
|
Assignee: |
Penwest Pharmaceuticals
Company
Patterson
NY
|
Family ID: |
27404938 |
Appl. No.: |
10/190383 |
Filed: |
July 3, 2002 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
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60329352 |
Oct 15, 2001 |
|
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60329426 |
Oct 15, 2001 |
|
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60303357 |
Jul 6, 2001 |
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Current U.S.
Class: |
424/470 ;
514/282 |
Current CPC
Class: |
A61K 9/2054 20130101;
A61K 9/2018 20130101; A61K 9/205 20130101; A61K 31/485 20130101;
A61P 25/04 20180101; A61P 29/00 20180101 |
Class at
Publication: |
424/470 ;
514/282 |
International
Class: |
A61K 031/485; A61K
009/26 |
Claims
What is claimed is:
1. A method for making a sustained release formulation that
comprises oxymorphone or a pharmaceutically acceptable salt thereof
and a sustained release delivery system, wherein the sustained
release delivery system comprises a hydrophilic compound, a
cross-linking agent and a pharmaceutical diluent; comprising the
steps of: mixing the hydrophilic compound, the cross-linking agent
and the pharmaceutical diluent to form granules; mixing the
granules with the oxymorphone or a pharmaceutically acceptable salt
thereof to form a granulated composition; and applying pressure to
the granulated composition to make the sustained release
formulation.
2. The method of claim 1, further comprising applying an outer
coating onto at least part of the sustained release
formulation.
3. The method of claim 1, wherein the oxymorphone or a
pharmaceutically acceptable salt thereof and the sustained release
delivery system are present in a ratio of from about 1:0.5 to about
1:25.
4. The method of claim 1, wherein the oxymorphone or
pharmaceutically acceptable salt thereof is present in an amount of
from about 1 mg to about 200 mg in the formulation.
5. The method of claim 4, wherein the oxymorphone or
pharmaceutically acceptable salt thereof is present in an amount of
from about 5 mg to about 80 mg in the formulation.
6. The method of claim 1, wherein the sustained release delivery
system is present in an amount of from about 80 mg to about 420 mg
in the formulation.
7. The method of claim 6, wherein the sustained release delivery
system is present in an amount of from about 80 mg to about 360 mg
in the formulation.
8. The method of claim 7, wherein the sustained release delivery
system is present in an amount of from about 80 mg to about 200 mg
in the formulation.
9. The method of claim 1, wherein the hydrophilic compound is
present in the sustained release delivery system in an amount of
from about 20% to about 80% by weight; the cross-linking agent is
present in the sustained release delivery system in an amount of
from about 0.5% to about 80% by weight; and the pharmaceutical
diluent is present in the sustained release delivery system in an
amount of from about 20% to about 80% by weight.
10. The method of claim 9, wherein the hydrophilic compound is
present in the sustained release delivery system in an amount of
from about 20% to about 60% by weight; the cross-linking agent is
present in the sustained release delivery system in an amount of
from about 2% to about 54% by weight; and the pharmaceutical
diluent is present in the sustained release delivery system in an
amount of from about 20% to about 80% by weight.
11. The method of claim 10, wherein the hydrophilic compound is
present in the sustained release delivery system in an amount of
from about 40% to about 60% by weight; the cross-linking agent is
present in the sustained release delivery system in an amount of
from about 20% to about 30% by weight; and the pharmaceutical
diluent is present in the sustained release delivery system in an
amount of from about 40% to about 80% by weight.
12. The method of claim 1, wherein the hydrophilic compound is a
heteropolysaccharide gum.
13. The method of claim 1, wherein the hydrophilic compound is
selected from xanthan gum, tragacanth gum, a pectin, acacia,
karaya, agar, carrageenan, and a gellan gum.
14. The method of claim 1, wherein the hydrophilic compound is a
xanthan gum or a derivative thereof.
15. The method of claim 1, wherein the cross-linking agent is a
homopolysaccharide gum.
16. The method of claim 15, wherein the homopolysaccharide gum is a
locust bean gum or a guar gum.
17. The method of claim 1, wherein the pharmaceutical diluent
selected from starch, lactose, dextrose, sucrose, microcrystalline
cellulose, sorbitol, xylitol, and fructose.
18. The method of claim 1, wherein the ratio of the hydrophilic
compound to the cross-linking agent is from about 1:9 to about
9:1.
19. The method of claim 1, wherein the ratio of the pharmaceutical
diluent to the hydrophilic compound is from about 1:8 to about
8:1.
20. The method of claim 1, wherein the sustained release delivery
system further comprises a hydrophobic polymer.
21. The method of claim 20, wherein the hydrophobic polymer is
present in the sustained release delivery system in an amount of
from about 0.5% to about 20% by weight.
22. The method of claim 21, wherein the hydrophobic polymer is
present in the sustained release delivery system in an amount of
from about 2% to about 10% by weight.
23. The method of claim 23, wherein the hydrophobic polymer is
selected from an alkylcellulose, a hydrophobic cellulosic material,
a polyvinyl acetate polymer, a polymer or copolymer of acrylic and
methacrylic acid esters, zein, a wax, a shellac and a hydrogenated
vegetable oil.
24. The method of claim 20, wherein the alkyl cellulose is ethyl
cellulose.
25. The method of claim 1, wherein the sustained release delivery
system further comprises a cationic cross-linking compound.
26. The method of claim 25, wherein the cationic cross-linking
compound is present in the sustained release delivery system in an
amount of from about 0.5% to about 30% by weight.
27. The method of claim 26, wherein the cationic cross-linking
compound is present in the sustained release delivery system in an
amount of about 5% to about 20% by weight.
28. The method of claim 25, wherein the cationic cross-linking
compound is selected from a monovalent metal cation, a multivalent
metal cation, and an inorganic salt.
29. The method of claim 28, wherein the cationic cross-linking
agent is an inorganic salt selected from an alkali metal sulfate,
an alkali metal chloride, an alkali metal borate, an alkali metal
bromide, an alkali metal citrate, an alkali metal acetate, an
alkali metal lactate, an alkaline earth metal sulfate, an alkaline
earth metal chloride, an alkaline earth metal borate, an alkaline
earth metal bromide, an alkaline earth metal citrate, an alkaline
earth metal acetate, an alkaline earth metal lactate, and a mixture
thereof.
30. The method of claim 25, wherein the cationic cross-linking
compound 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.
31. The method of claim 1, wherein the sustained release
formulation has an in vitro dissolution rate of from about 15% to
about 50% by weight oxymorphone after about 1 hour.
32. The method of claim 1, wherein the sustained release
formulation has as in vitro dissolution rate of from about 45% to
about 80% by weight oxymorphone after about 4 hours.
33. The method of claim 1, wherein the sustained release
formulation has as in vitro dissolution rate of at least about 80%
by weight oxymorphone after about 10 hours.
34. The method of claim 2, wherein the outer coating comprises a
hydrophobic polymer.
35. The method of claim 34, wherein the hydrophobic polymer is a
compound selected from an alkyl cellulose, a hydrophobic cellulosic
material, a polyvinyl acetate polymer, a polymer or copolymer of
acrylic and methacrylic acid esters, zein, a wax, a shellac and a
hydrogenated vegetable oil.
36. The method of claim 34, wherein the hydrophobic polymer is
present on the sustained release formulation to a weight gain from
about 1% to about 20% by weight of the uncoated tablet.
37. The method of claim 2, wherein the outer coating comprises a
plasticizer.
38. A method for making a sustained release formulation that
comprises oxymorphone or a pharmaceutically acceptable salt thereof
and a sustained release delivery system, wherein the sustained
release delivery system comprises a hydrophilic compound, a
cationic cross-linking compound, and a pharmaceutical diluent;
comprising the steps of: mixing the hydrophilic compound, the
cationic cross-linking compound and the pharmaceutical diluent to
form granules; mixing the granules with the oxymorphone or a
pharmaceutically acceptable salt thereof to form a granulated
composition; and applying pressure to the granulated composition to
make the sustained release formulation.
39. The method of claim 38, further comprising applying an outer
coating onto at least part of the sustained release
formulation.
40. The method of claim 38, wherein the ratio of oxymorphone or a
pharmaceutically acceptable salt thereof to the sustained release
delivery system is from about 1:0.5 to about 1:25.
41. The method of claim 38, wherein the oxymorphone or
pharmaceutically acceptable salt thereof is present in an amount of
from about 1 mg to about 200 mg in the formulation.
42. The method of claim 41, wherein the oxymorphone or
pharmaceutically acceptable salt thereof is present in an amount of
from about 5 mg to about 80 mg in the formulation.
43. The method of claim 38, wherein the sustained release delivery
system is present in an amount of from about 80 mg to about 420 mg
in the formulation.
44. The method of claim 43, wherein the sustained release delivery
system is present in an amount of from about 80 mg to about 360 mg
in the formulation.
45. The method of claim 44, wherein the sustained release delivery
system is present in an amount of from about 80 mg to about 200 mg
in the formulation.
46. The method of claim 38, wherein the hydrophilic compound is
present in the sustained release delivery system in an amount of
from about 20% to about 80% by weight; the cationic cross-linking
agent is present in the sustained release delivery system in an
amount of from about 0.5% to about 30% by weight; and the
pharmaceutical diluent is present in the sustained release delivery
system in an amount of from about 20% to about 80% by weight.
47. The method of claim 46, wherein the hydrophilic compound is
present in the sustained release delivery system in an amount of
from about 20% to about 60% by weight; the cationic cross-linking
agent is present in the sustained release delivery system in an
amount of from about 5% to about 20% by weight; and the
pharmaceutical diluent is present in the sustained release delivery
system in an amount of from about 20% to about 80% by weight.
48. The method of claim 47, wherein the hydrophilic compound is
present in the sustained release delivery system in an amount of
from about 40% to about 60% by weight; the cationic cross-linking
agent is present in the sustained release delivery system in an
amount of from about 5% to about 20% by weight; and the
pharmaceutical diluent is present in the sustained release delivery
system in an amount of from about 40% to about 80% by weight.
49. The method of claim 38, wherein the hydrophilic compound is a
heteropolysaccharide gum.
50. The method of claim 38, wherein the hydrophilic compound is
compound selected from xanthan gum, tragacanth gum, a pectin,
acacia, karaya, agar, carrageenan, and a gellan gum.
51. The method of claim 38, wherein the hydrophilic compound is a
xanthan gum or a derivative thereof.
52. The method of claim 38, wherein the cationic cross-linking
compound is selected from a monovalent metal cation, a multivalent
metal cation, and an inorganic salt.
53. The method of claim 52, wherein the cationic cross-linking
compound is an inorganic salt selected from an alkali metal
sulfate, an alkali metal chloride, an alkali metal borate, an
alkali metal bromide, an alkali metal citrate, an alkali metal
acetate, an alkali metal lactate, an alkaline earth metal sulfate,
an alkaline earth metal chloride, an alkaline earth metal borate,
an alkaline earth metal bromide, an alkaline earth metal citrate,
an alkaline earth metal acetate, an alkaline earth metal lactate,
or a mixture thereof.
54. The method of claim 38, wherein the cationic cross-linking
compound 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, sodium
fluoride, and mixtures thereof.
55. The method of claim 38, wherein the pharmaceutical diluent is
selected from starch, lactose, dextrose, sucrose, microcrystalline
cellulose, sorbitol, xylitol, and fructose.
56. The method of claim 38, wherein the sustained release delivery
system further comprises a hydrophobic polymer.
57. The method of claim 56, wherein the hydrophobic polymer is
present in the sustained release delivery system in an amount of
from about 0.5% to about 20% by weight.
58. The method of claim 57, wherein the hydrophobic polymer is
present in the sustained release delivery system in an amount of
from about 2% to about 10% by weight.
59. The method of claim 56, wherein the hydrophobic polymer is
selected from an alkyl cellulose, a polyvinyl acetate polymer, a
polymer or copolymer derived from acrylic and methacrylic acid
esters, zein, a wax, shellac and a hydrogenated vegetable oil.
60. The method of claim 59, wherein the hydrophobic polymer is an
alkyl cellulose and the alkyl cellulose is ethyl cellulose.
61. The method of claim 38, wherein the sustained release
formulation has an in vitro dissolution rate of from about 15% to
about 50% by weight oxymorphone after about 1 hour.
62. The method of claim 38, wherein the-sustained release
formulation has as in vitro dissolution rate of about 45% to about
80% by weight oxymorphone after about 4 hours.
63. The method of claim 38, wherein the sustained release
formulation has as in vitro dissolution rate of at least about 80%
by weight oxymorphone after about 10 hours.
64. The method of claim 39, wherein the outer coating comprises a
hydrophobic polymer.
65. The method of claim 64, wherein the hydrophobic polymer is
selected from an alkyl cellulose, a hydrophobic cellulosic
material, a polyvinyl acetate polymer, a polymer or copolymer of
acrylic and methacrylic acid esters, zein, a wax, a shellac and a
hydrogenated vegetable oil.
66. The method of claim 64, wherein the hydrophobic polymer is
present on the sustained release formulation to a weight gain from
about 1% to about 20% by weight of the uncoated table.
67. The method of claim 39, wherein the outer coating comprises a
plasticizer.
68. A method for making a sustained release formulation that
comprises from about 5 to about 80 mg oxymorphone hydrochloride and
about 80 mg to about 360 mg of a sustained release delivery system;
wherein the sustained release delivery system comprises about 8.3%
to about 41.7% by weight locust bean gum, about 8.3% to about 41.7%
by weight xanthan gum, about 20% to about 55% by weight dextrose,
about 5% to about 20% by weight calcium sulfate dihydrate, and
about 2% to about 10% ethyl cellulose; comprising the steps of:
mixing the locust bean gum, the xanthan gum, the dextrose, the
calcium sulfate, and the ethyl cellulose to form granules; mixing
the granules with the oxymorphone hydrochloride to form a
granulated composition; and applying pressure to the granulated
composition to make the sustained release formulation.
69. The method of claim 68, further comprising applying an outer
coating onto at least part of the sustained release
formulation.
70. The method of claim 68, comprising about 20 mg oxymorphone
hydrochloride.
71. The method of claim 68, comprising about 160 mg of a sustained
release delivery system.
72. The method of claim 68, wherein the sustained release delivery
system comprises about 25% locust bean gum, about 25% xanthan gum,
about 35% dextrose, about 10% calcium sulfate dihydrate, and about
5% ethyl cellulose.
73. A method for making a sustained release formulation that
comprises from about 5 to about 80 mg oxymorphone hydrochloride and
about 300 mg to about 420 mg of a sustained release delivery
system; wherein the sustained release delivery system comprises
about 8.3% to 41.7% by weight locust bean gum, about 8.3% to about
41.7% by weight xanthan gum, about 20% to about 55% by weight
dextrose, about 5% to about 20% by weight calcium sulfate
dihydrate, and about 2% to about 10% ethyl cellulose; comprising
the steps of: mixing the locust bean gum, the xanthan gum, the
dextrose, the calcium sulfate, and the ethyl cellulose to form
granules; mixing the granules with the oxymorphone hydrochloride to
form a granulated composition; and applying pressure to the
granulated composition to make the sustained release
formulation.
74. The method of claim 73, further comprising applying an outer
coating onto at least part of the sustained release
formulation.
75. The method of claim 73, comprising about 20 mg oxymorphone
hydrochloride.
76. The method of claim 73, comprising about 360 mg of a sustained
release delivery system.
77. The method of claim 73, wherein the sustained release delivery
system comprises about 25% locust bean gum, about 25% xanthan gum,
about 35% dextrose, about 10% calcium sulfate dihydrate, and about
5% ethyl cellulose.
Description
RELATED APPLICATIONS
[0001] This application claims priority to U.S. Provisional
Application No. 60/329,352 filed Oct. 15, 2001, U.S. Provisional
Application No. 60/329,426 filed Oct. 15, 2001, and to U.S.
Provisional Application No. 60/303,357 filed Jul. 6, 2001, the
disclosures of which are incorporated by reference herein in their
entirety.
FIELD OF THE INVENTION
[0002] The invention provides sustained release formulations of
oxymorphone and pharmaceutically acceptable salts thereof; methods
for making the sustained release formulations of oxymorphone and
pharmaceutically acceptable salts thereof; and methods for using
the sustained release formulations of oxymorphone and
pharmaceutically acceptable salts thereof to treat patients
suffering from pain.
BACKGROUND OF THE INVENTION
[0003] Pain is the most frequently reported symptom and it is a
common clinical problem which 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.
[0004] Oxymorphone HCl (14-hydroxydihydromorphinone 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; 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, a 10 mg oral immediate
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 beta hydroxy epimers.
[0005] 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 currently 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 immediate
release oxymorphone would necessitate 4-hourly administrations in
order to maintain optimal levels of analgesia in patients with
chronic pain. Moreover, immediate release oxymorphone exhibits low
oral bioavailability, because oxymorphone is extensively
metabolized in the liver.
[0006] There is a need in the art for new formulations of
oxymorphone require less frequent dosing. The invention is directed
to these, as well as other, important ends.
SUMMARY OF THE INVENTION
[0007] The invention provides compositions comprising oxymorphone
or a pharmaceutically acceptable salt thereof and a sustained
release delivery system, where the sustained release delivery
system comprises at least one hydrophilic compound, at least one
cross-linking agent (which may be cationic) and at least one
pharmaceutical diluent. The sustained release delivery system may
further comprise one or more additional hydrophobic polymers or
cross-linking compounds. The compositions may optionally comprise
an outer coating comprising at least one water insoluble compound,
and optionally one or more plasticizers and/or water soluble
compounds.
[0008] The invention provides compositions comprising an inner core
and an outer sustained release coating, where the inner core
comprises oxymorphone or a pharmaceutically acceptable salt thereof
and the outer sustained release coating comprises at least one
water insoluble compound. The outer sustained release coating may
optionally further comprise one or more plasticizers and/or water
soluble compounds.
[0009] The invention provides methods for treating pain in patients
by administering an effective amount of any of the compositions of
the invention. The pain may be moderate to severe, and may be acute
or chronic.
[0010] The invention also provides methods for making such
compositions.
[0011] These and other aspects of the invention are described in
detail herein.
BRIEF DESCRIPTION OF THE FIGURE
[0012] FIG. 1 is a linear scale graph, without standard deviations,
showing the mean oxymorphone plasma concentration versus time for
patients treated with the sustained release oxymorphone tablets of
the invention after fasting (A), for patients treated with
sustained release oxymorphone tablets of the invention after a high
fat meal (B), for patients treated with an oxymorphone solution
after fasting (C), and for patients treated with an oxymorphone
solution after a high fat meal (D).
DETAILED DESCRIPTION OF THE INVENTION
[0013] To overcome the difficulties associated with the very low
bioavailability of the oral immediate release formulation of
oxymorphone and with a 4 hourly dosing frequency of oxymorphone,
the invention provides an oral sustained release formulation of
oxymorphone comprising an analgesically effective amount of
oxymorphone or a pharmaceutically acceptable salt thereof. The
bioavailability of the oral sustained release formulations of the
invention is sufficiently high that the sustained release
formulations can be used to treat patients suffering from pain with
only once or twice daily dosing.
[0014] The invention provides compositions comprising oxymorphone
or a pharmaceutically acceptable salt thereof and a sustained
release delivery system, wherein the sustained release delivery
system comprises (i) at least one hydrophilic compound, at least
one cross-linking agent, and at least one pharmaceutical diluent;
(ii) at least one hydrophilic compound, at least one cross-linking
agent, at least one pharmaceutical diluent, and at least one
hydrophobic polymer; (iii) at least one hydrophilic compound, at
least one cross-linking agent, at least one pharmaceutical diluent,
and at least one cationic cross-linking agent different from the
first cross-linking agent; (iv) at least one hydrophilic compound,
at least one cross-linking agent, at least one pharmaceutical
diluent, at least one cationic cross-linking compound different
from the first cross-linking agent, and at least one hydrophobic
polymer; (v) at least one hydrophilic compound, at least one
cationic cross-linking compound, and at least one pharmaceutical
diluent; or (vi) at least one hydrophilic compound, at least one
cationic cross-linking compound, at least one pharmaceutical
diluent, and at least one hydrophobic compound.
[0015] The oxymorphone may be homogeneously dispersed in the
sustained release delivery system. Preferably, the oxymorphone or
pharmaceutically acceptable salt thereof may be present in the
composition in an amount of about 1 mg to about 200 mg, more
preferably in an amount of about 1 mg to about 100 mg, even more
preferably in an amount of about 5 mg to about 80 mg. Preferably,
the sustained release delivery system may be present in the
composition in an amount from about 80 mg to about 420 mg, more
preferably from about 80 mg to about 360 mg, even more preferably
from about 80 mg to about 200 mg. "Oxymorphone" includes
oxymorphone, metabolites thereof, derivatives thereof, and/or
pharmaceutically acceptable salts thereof. Metabolites of
oxymorphone include, for example, 6-hydroxy-oxymorphone (e.g.,
6-.alpha.-hydroxy-oxymorphone and/or
6-.beta.-hydroxy-oxymorphone).
[0016] Oxymorphone may be in the form of any pharmaceutically
acceptable salt known in the art. Exemplary pharmaceutically
acceptable salts include hydrochloric, sulfuric, nitric,
phosphoric, hydrobromic, maleric, malic, ascorbic, citric,
tartaric, pamoic, lauric, stearic, palmitic, oleic, myristic,
lauryl sulfuric, napthalinesulfonic, linoleic, linolenic acid, and
the like. The hydrochloride salt of oxymorphone is preferred.
[0017] The sustained release delivery system comprises at least one
hydrophilic compound. The hydrophilic compound preferably forms a
gel matrix that releases the oxymorphone or the pharmaceutically
acceptable salt thereof at a sustained rate upon exposure to
liquids. The rate of release of the oxymorphone or the
pharmaceutically acceptable salt thereof 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 compositions of the invention, the weight ratio of
oxymorphone to hydrophilic compound is generally in the range of
about 1:0.5 to about 1:25, preferably in the range of about 1:0.5
to about 1:20. The sustained release delivery system generally
comprises the hydrophilic compound in an amount of about 20% to
about 80% by weight, preferably in an amount of about 20% to about
60% by weight, more preferably in an amount of about 40% to about
60% by weight, still more preferably in an amount of about 50% by
weight.
[0018] The hydrophilic compound may be any known in the art.
Exemplary hydrophilic compounds include gums, cellulose ethers,
acrylic resins, polyvinyl pyrrolidone, protein-derived compounds,
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. Exemplary cellulose
ethers include hydroxyalkyl celluloses and carboxyalkyl celluloses.
Preferred cellulose ethers include hydroxyethyl celluloses,
hydroxypropyl celluloses, hydroxypropylmethyl-celluloses, carboxy
methylcelluloses, and mixtures thereof. Exemplary acrylic resins
include polymers and copolymers of acrylic acid, methacrylic acid,
methyl acrylate and methyl methacrylate. In some embodiments, the
hydrophilic compound is preferably a gum, more preferably a
heteropolysaccharide gum, most preferably a xanthan gum or
derivative thereof. Derivatives of xanthan gum include, for
example, deacylated xanthan gum, the carboxymethyl esters of
xanthan gum, and the propylene glycol esters of xanthan gum.
[0019] In another embodiment, the sustained release delivery system
may further comprise at least one cross-linking agent. The
cross-linking agent is preferably a compound that is capable of
cross-linking the hydrophilic compound to form a gel matrix in the
presence of liquids. As used herein, "liquids" includes, for
example, gastrointestinal fluids and aqueous solutions, such as
those used for in vitro dissolution testing. The sustained release
delivery system generally comprises the cross-linking agent in an
amount of about 0.5% to about 80% by weight, preferably in an
amount of about 2% to about 54% by weight, more preferably in an
amount of about 20% to about 30% by weight more, still more
preferably in an amount of about 25% by weight.
[0020] Exemplary cross-linking agents include homopolysaccharides.
Exemplary homopolysaccharides include galactomannan gums, such as
guar gum, hydroxypropyl guar gum, and locust bean gum. In some
embodiments, the cross-linking agent is preferably a locust bean
gum or a guar gum. In other embodiments, the cross-linking agents
may be alginic acid derivatives or hydrocolloids.
[0021] When the sustained release delivery system comprises at
least one hydrophilic compound and at least one cross-linking
agent, the ratio of hydrophilic compound to cross-linking agent may
be from about 1:9 to about 9:1, preferably from about 1:3 to about
3:1.
[0022] The sustained release delivery system of the invention may
comprise one or more cationic cross-linking compounds. Cationic
cross-linking compound may be used instead of or in addition to the
cross-linking agent. The cationic cross-linking compounds may 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,
preferably from about 5% to about 20% by weight.
[0023] 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-linking compound
may be one or more of 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, sodium
fluoride, or mixtures thereof.
[0024] When the sustained release delivery system comprises at
least one hydrophilic compound and at least one cationic
cross-linking compound, the ratio of hydrophilic compound to
cationic cross-linking compound may be from about 1:9 to about 9:1,
preferably from about 1:3 to about 3:1.
[0025] Two properties of desirable components of this system (e.g.,
the at least one hydrophilic compound and the at least one
cross-linking agent; or the at least one hydrophilic compound and
at least one cationic cross-linking compound) that form a gel
matrix upon exposure to liquids are fast hydration of the
compounds/agents and the ability to form a gel matrix having a high
gel strength. These two properties, which are needed to achieve a
slow release gel matrix, are maximized in the invention by the
particular combination 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-linking compound). For example, hydrophilic compounds (e.g.,
xanthan gum) have excellent water-wicking properties which provide
fast hydration. The combination of hydrophilic compounds with
materials that are capable of cross-linking the rigid helical
ordered structure of the hydrophilic compound (e.g., cross-linking
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.
[0026] The sustained release delivery system further comprises one
or more pharmaceutical diluents known in the art. Exemplary
pharmaceutical diluents include monosaccharides, disaccharides,
polyhydric alcohols and mixtures thereof. Preferred pharmaceutical
diluents include, for example, starch, lactose, dextrose, sucrose,
microcrystalline cellulose, sorbitol, xylitol, fructose, and
mixtures thereof. In other embodiments, the pharmaceutical diluent
is water-soluble, such as lactose, dextrose, sucrose, or mixtures
thereof. The ratio of pharmaceutical diluent to hydrophilic
compound is generally from about 1:8 to about 8:1, preferably 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, preferably 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.
[0027] The sustained release delivery system of the invention may
comprise one or more hydrophobic polymers. The hydrophobic polymers
may be used in an amount sufficient to slow the hydration of the
hydrophilic compound without disrupting it. For example, the
hydrophobic polymer may be present in the sustained release
delivery system in an amount of about 0.5% to about 20% by weight,
preferably in an amount of about 2% to about 10% by weight, more
preferably in an amount of about 3% to about 7% by weight, still
more preferably in an amount of about 5% by weight.
[0028] Exemplary hydrophobic polymers include alkyl celluloses
(e.g., C.sub.1-6 alkyl celluloses, carboxymethylcellulose), other
hydrophobic cellulosic materials or compounds (e.g., cellulose
acetate phthalate, hydroxypropylmethylcellulose phthalate),
polyvinyl acetate polymers (e.g., polyvinyl acetate phthalate),
polymers or copolymers derived from acrylic and/or methacrylic acid
esters, zein, waxes, shellac, hydrogenated vegetable oils, and
mixtures thereof. The hydrophobic polymer is preferably methyl
cellulose, ethyl cellulose or propyl cellulose, more preferably
ethyl cellulose.
[0029] The compositions of the invention 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.
[0030] In other embodiments, the invention provides oral sustained
release solid dosage formulations comprising from about 1 mg to 200
mg oxymorphone hydrochloride, preferably from about 5 mg to about
80 mg oxymorphone hydrochloride; and about 80 mg to about 200 mg of
a sustained release delivery system, preferably from about 120 mg
to about 200 mg of a sustained release delivery system, more
preferably 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, preferably about 25% locust bean gum;
about 8.3 to about 41.7% xanthan gum, preferably about 25% xanthan
gum; about 20 to about 55% dextrose, preferably about 35% dextrose;
about 5 to about 20% calcium sulfate dihydrate, preferably about
10% calcium sulfate dihydrate; and about 2 to 10% ethyl cellulose,
preferably about 5% ethyl cellulose.
[0031] In other embodiments, the invention provides oral sustained
release solid dosage formulations comprising from about 1 mg to 200
mg oxymorphone hydrochloride, preferably from about 5 mg to about
80 mg oxymorphone hydrochloride; and about 200 mg to about 420 mg
of a sustained release delivery system, preferably from about 300
mg to about 420 mg of a sustained release delivery system, more
preferably about 360 mg of a sustained release delivery system;
where the sustained release delivery system comprises about 8.3 to
about 41.7% locust bean gum, preferably about 25% locust bean gum;
about 8.3 to about 41.7% xanthan gum, preferably about 25% xanthan
gum; about 20 to about 55% dextrose, preferably about 35% dextrose;
about 5 to about 20% calcium sulfate dihydrate, preferably about
10% calcium sulfate dihydrate; and about 2 to 10% ethyl cellulose,
preferably about 5% ethyl cellulose.
[0032] The sustained release formulations of oxymorphone are
preferably orally administrable solid dosage formulations which may
be, for example, tablets, capsules comprising a plurality of
granules, sublingual tablets, powders, or granules; preferably
tablets. The tablets may be an enteric coating or a hydrophilic
coating.
[0033] The sustained release delivery system in the compositions of
the invention may be prepared by dry granulation or wet
granulation, before the oxymorphone or pharmaceutically acceptable
salt thereof is added, although the components may be held together
by an agglomeration technique to produce an acceptable product. In
the wet granulation technique, the components (e.g., hydrophilic
compounds, 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
which 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 amounts with the oxymorphone or the
pharmaceutically acceptable salt thereof 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 system and the oxymorphone may be blended with,
for example, a high shear mixer. The oxymorphone is preferably
finely and homogeneously dispersed in the sustained release
delivery system. The granulated composition, in an amount
sufficient to make a uniform batch of tablets, is subjected to
tableting in a conventional production scale tableting machine at
normal compression pressures, i.e., about 2,000-16,000 psi. The
mixture should not be compressed to a point where there is
subsequent difficulty with hydration upon exposure to liquids.
[0034] The average particle size of the granulated composition is
from about 50 .mu.m to about 400 .mu.m, preferably from about 185
.mu.m to about 265 .mu.m. The average density of the granulated
composition is from about 0.3 g/ml to about 0.8 .mu.g/ml,
preferably from about 0.5 g/ml to about 0.7 g/ml. The tablets
formed from the granulations are generally from about 6 to about 8
kg hardness. The average flow of the granulations are from about 25
to about 40 g/sec.
[0035] In other embodiments, the invention provides sustained
release coatings over an inner core comprising oxymorphone or a
pharmaceutically acceptable salt thereof. For example, the inner
core comprising oxymorphone or a pharmaceutically acceptable salt
thereof may be coated with a sustained release film which, upon
exposure to liquids, releases the oxymorphone or the
pharmaceutically acceptable salt thereof from the core at a
sustained rate.
[0036] In one embodiment, the sustained release coating comprises
at least one water insoluble compound. The water insoluble compound
is preferably a hydrophobic polymer. The hydrophobic polymer may be
the same as or different from the hydrophobic polymer used in the
sustained release delivery system. Exemplary hydrophobic polymers
include alkyl celluloses (e.g., C.sub.1-6 alkyl celluloses,
carboxymethylcellulose), other hydrophobic cellulosic materials or
compounds (e.g., cellulose acetate phthalate,
hydroxypropylmethylcellulose phthalate), polyvinyl acetate polymers
(e.g., polyvinyl acetate phthalate), polymers or copolymers 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 polymer is preferably,
methyl cellulose, ethyl cellulose or propyl cellulose, more
preferably ethyl cellulose. The sustained release formulations of
the invention may be coated with a water insoluble compound to a
weight gain from about 1 to about 20% by weight.
[0037] The sustained release coating may further comprise at least
one plasticizer such as triethyl citrate, dibutyl phthalate,
propylene glycol, polyethylene glycol, or mixtures thereof.
[0038] The sustained release coating may also contain at least one
water soluble compound, such as polyvinylpyrrolidones,
hydroxypropylmethylcellu- loses, or mixtures thereof. The sustained
release coating may comprise at least one water soluble compound in
an amount from about 1% to about 6% by weight, preferably in an
amount of about 3% by weight.
[0039] The sustained release coating may be applied to the
oxymorphone core by spraying an aqueous dispersion of the water
insoluble compound onto the oxymorphone core. The oxymorphone core
may be a granulated composition made, for example, by dry or wet
granulation of mixed powders of oxymorphone and at least one
binding agent; by coating an inert bead with oxymorphone and at
least one binding agent; or by spheronizing mixed powders of
oxymorphone and at least one spheronizing agent. Exemplary binding
agents include hydroxypropylmethylcelluloses. Exemplary
spheronizing agents include microcrystalline celluloses. The inner
core may be a tablet made by compressing the granules or by
compressing a powder comprising oxymorphone or the pharmaceutically
acceptable salt thereof.
[0040] In other embodiments, the compositions comprising
oxymorphone or a pharmaceutically acceptable salt thereof 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 oxymorphone or a
pharmaceutically acceptable salt thereof and a sustained release
delivery system, as described herein, are coated with a hydrophobic
polymer, as described herein. In still other embodiments, the
compositions comprising oxymorphone or a pharmaceutically
acceptable salt thereof and a sustained release delivery system, as
described herein, are coated with an enteric coating, such as
cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, polyvinylacetate phthalate, methacrylic acid copolymer,
shellac, hydroxypropylmethylcellul- ose succinate, cellulose
acetate trimelliate, or mixtures thereof. In still other
embodiments, the compositions comprising oxymorphone or a
pharmaceutically acceptable salt thereof and a sustained release
delivery system, as described herein, are coated with a hydrophobic
polymer, as described herein, and further coated with an enteric
coating, as described herein. In any of the embodiments described
herein, the compositions comprising oxymorphone or a
pharmaceutically acceptable salt thereof and a sustained release
delivery system, as described herein, may 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. Preferred hydrophilic
coatings comprise hydroxypropylmethylcellulose.
[0041] The invention provides methods for treating pain by
administering an effective amount of the sustained release
formulations of oxymorphone to a patient in need thereof. An
effective amount is an amount sufficient to eliminate all pain or
to alleviate the pain (i.e., reduce the pain compared to the pain
present prior to administration of the oxymorphone sustained
release formulation). "Sustained release" means that the
oxymorphone or pharmaceutically acceptable salt thereof is released
from the formulation at a controlled rate so that therapeutically
beneficial blood levels (but below toxic levels) of the oxymorphone
or pharmaceutically acceptable salt thereof are maintained over an
extended period of time. The sustained release formulations of
oxymorphone are administered in an amount sufficient to alleviate
pain for an extended period of time, preferably about 8 hours to
about 24 hours, more preferably for a period of about 12 hours to
about 24 hours. The oxymorphone sustained release oral solid dosage
formulations of the invention may be administered one to four times
a day, preferably once or twice daily, more preferably once daily.
The pain may be minor to moderate to severe, and is preferably
moderate to severe. The pain may be acute or chronic. The pain may
be associated with, for example, cancer, autoimmune diseases,
infections, surgical traumas, accidental traumas or osteoarthritis.
The patient may be an animal, preferably a mammal, more preferably
a human.
[0042] In certain embodiments, upon oral ingestion of the
oxymorphone sustained release formulation and contact of the
formulation with gastrointestinal fluids, the sustained release
formulation swells and gels to form 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 oxymorphone.
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. Since the oxymorphone
is dispersed throughout the formulation (and consequently
throughout the gel matrix), a constant amount of oxymorphone can be
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 bouyant in the stomach,
until substantially all of the oxymorphone is released.
[0043] In certain embodiments, the chemistry of certain of the
components of the formulation, such as the hydrophilic compound
(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 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 sustained release
formulation can loosely interact with the mucin in the
gastrointestinal tract and thereby provide another mode by which a
constant rate of delivery of the oxymorphone is achieved.
[0044] The two phenomenon discussed above (buoyancy and
muco-adhesive properties) are mechanisms by which the sustained
release formulations of the invention can interact with the mucin
and fluids of the gastrointestinal tract and provide a constant
rate of delivery of the oxymorphone.
[0045] When measured by USP Procedure Drug Release USP 23
(incorporated by reference herein in its entirety), the sustained
release formulations of the invention exhibit an in vitro
dissolution rate of about 15% to about 50% by weight oxymorphone
after 1 hour, about 45% to about 80% by weight oxymorphone after 4
hours, and at least about 80% by weight oxymorphone after 10 hours.
The in vitro and in vivo release characteristics of the sustained
release formulations of the invention may be modified using
mixtures of one or more different water insoluble and/or water
soluble compounds, using different plasticizers, varying the
thickness of the sustained release film, including providing
release-modifying compounds in the coating, and/or by providing
passageways through the coating.
[0046] When administered orally to patients the sustained release
formulations of the invention 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 oxymorphone analgesic effect is about 8 to about 24
hours; and (c) the relative oxymorphone bioavailability is about
0.5 to about 1.5 compared to an orally administered aqueous
solution of oxymorphone.
[0047] While the compositions of the invention may be administered
as the sole active pharmaceutical compound in the methods described
herein, they can also be used in combination with one or more
compounds which are known to be therapeutically effective against
pain.
[0048] The invention also provides pharmaceutical kits comprising
one or more containers filled with one or more of the compositions
of the invention. The kits may further comprise other
pharmaceutical compounds known in the art to be therapeutically
effective against pain, and instructions for use.
EXAMPLES
[0049] The following examples are for purposes of illustration only
and are not intended to limit the scope of the appended claims.
Examples 1 and 2
[0050] Two sustained release delivery systems were 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 was prepared by mixing ethyl cellulose with alcohol. While
running choppers/impellers, the slurry was added to the dry blended
mixture, and granulated for another 3 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 20 mesh screen. The
relative quantities of the ingredients are listed in Table 1.
1 TABLE 1 Sustained Release Delivery System Example 1 Example 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).sup.1
(10).sup.1 (20.0).sup.1 Total 100.0 100.0 .sup.1Volatile, removed
during processing
Examples 3 to 7
[0051] A series of tablets containing different amounts of
oxymorphone hydrochloride were prepared using the sustained release
delivery system of Example 1. The quantities of ingredients per
tablet are listed in Table 2.
2TABLE 2 Ex. 3 Ex. 4 Ex. 5 Ex. 6 Ex. 7 Component mg mg mg mg mg
Oxymorphone HCl, USP 5 10 20 40 80 Sustained release delivery
system 160 160 160 160 160 Silicified microcrystalline 20 20 20 20
20 cellulose, N.F. Sodium stearyl fumarate, NF 2 2 2 2 2 Total
weight 187 192 202 222 262 OPADRY .RTM. (colored) 7.48 7.68 8.08
8.88 10.48 OPADRY .RTM. (clear) 0.94 0.96 1.01 1.11 1.31
Examples 8 and 9
[0052] Two batches of tablets were prepared as described above for
Examples 1-7, using the sustained release delivery system of
Example 1. One batch was formulated to provide relatively fast
sustained release, the other batch was formulated to provide
relatively slow sustained release. Compositions of the tablets are
shown in Table 3.
3TABLE 3 Example 8 Example 9 slow release fast release Ingredients
mg/tablet mg/tablet Oxymorphone HCl, USP 20 20 Sustained Release
Delivery System 360 160 Silicified Microcrystalline 20 20
Cellulose, NF Sodium stearyl fumarate, NF 4 2 Coating (color) 12.12
12.12 Total weight 416.12 214.12
[0053] The tables of Examples 8 and 9 were tested for in vitro
release rate according to USP Procedure Drug Release USP 23. The
results are shown in Table 4.
4TABLE 4 Example 8 Example 9 Time (hr) slow release fast release
0.5 18.8% 21.3% 1 27.8% 32.3% 2 40.5% 47.4% 3 50.2% 58.5% 4 58.1%
66.9% 5 64.7% 73.5% 6 70.2% 78.6% 8 79.0% 86.0% 10 85.3% 90.6% 12
89.8% 93.4%
Example 10
[0054] Clinical Study
[0055] A clinical study was conducted to (1) assess the relative
bioavailability (rate and extent of absorption) of oxymorphone
sustained release (20 mg) (fast release formulation of Example 9)
compared to oral solution oxymorphone (10 mg) under fasted
conditions, (2) to assess the relative bioavailability of
oxymorphone sustained release (20 mg) compared to oral solution
oxymorphone (10 mg) under fed conditions, (3) to assess the
relative bioavailability of oxymorphone sustained release (20 mg)
fed compared to oxymorphone sustained release (20 mg) fasted, (4)
to assess the relative bioavailability of oral solution oxymorphone
fed compared to oral solution oxymorphone fasted, and (5) to assess
the relative safety and tolerability of sustained release
oxymorphone (20 mg) under fed and fasted conditions.
[0056] This study had a single-center, open-label, analytically
blinded, randomized, four-way crossover design. Subjects randomized
to Treatment A and Treatment C, as described below, were in a
fasted state following a 10-hour overnight fast. Subjects
randomized to Treatment B and Treatment D, 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 A
and Treatment B were discharged from the clinic on Day 3 following
the 48-hour procedures, and subjects assigned to receive Treatment
C and Treatment D 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:
[0057] Treatments A and B were of oxymorphone sustained release 20
mg tablets. Subjects randomized to Treatment A received a single
oral dose of one 20 mg oxymorphone sustained release tablet taken
with 240 ml of water after a 10-hour fasting period. Subjects
randomized to Treatment B received a single oral dose of one 20 mg
oxymorphone sustained release tablet taken with 240 ml of water 10
minutes after a standardized high fat meal.
[0058] Treatments C and D were of oxymorphone HCl solutions, USP,
1.5 mg/mil injection 10 ml vials. Subjects randomized to Treatment
C 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 D 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.
[0059] 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). 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.
[0060] The subjects were screened within 14 days prior to study
enrollment. The screening procedure included medical history,
physical examination (height, weight, frame size, vital signs, and
ECG), and clinical laboratory tests (hematology, serum chemistry,
urinalysis, HIV antibody screen, Hepatitis B surface antigen
screen, Hepatitis C antibody screen, and a screen for
cannabinoids).
[0061] During the study, the subjects were to remain in an upright
position (sitting or standing) for 4 hours after the study drug was
administered. Water was restricted 2 hours predose to 2 hours
postdose. During the study, the subjects were not allowed to engage
in any strenuous activity.
[0062] Subjects reported to the clinic on the evening prior to each
dosing. The subjects then observed a 10-hour overnight fast. On Day
1, subjects randomized to Treatment B and Treatment D received a
high-fat breakfast within 30 minutes prior to dosing. A
standardized meal schedule was then initiated with lunch 4 hours
postdose, dinner 10 hours postdose, and a snack 13 hours postdose.
On Day 2, a standardized meal was initiated with breakfast at 0815,
lunch at 1200, and dinner at 1800. Subjects randomized to Treatment
A and Treatment B received a snack at 2100 on Day 2.
[0063] Vital signs (sitting for 5 minutes and consisting of blood
pressure, pulse, respiration, and temperature), and 12-lead ECG
were assessed at the -13 hour point of each check-in period and at
the completion of each period. A clinical laboratory evaluation
(hematology, serum chemistry, urinalysis) and a brief physical
examination were performed at the -13 hour of each check-in period
and at the completion of the each period. Subjects were instructed
to inform the study physician and/or nurses of any adverse events
that occurred during the study.
[0064] 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 A and Treatment B. Blood samples
(7 mi) 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 C and Treatment D. A total of 80
blood samples (560 ml) per subject were drawn during the study for
drug analysis. Plasma samples were separated by centrifugation, and
then frozen at -70.degree. C., and kept frozen until assayed.
[0065] An LC/MS/MS method was developed and validated for the
determination of oxymorphone in human EDTA plasma. Samples were
spiked with internal standard, d.sub.3 oxymorphone, and placed on
the RapidTrace.RTM. (Zymark Corporation, Hopkinton, Mass.) for
automatic solid phase extraction. Extracts were dried under
nitrogen and reconstituted with acetonitrile before injection onto
an LC/MS/MS. The Perkin Elmer Sciex API III+, or equivalent, using
a turbo ion spray interface was employed in this study. Positive
ions were monitored in the MRM mode.
[0066] The pharmacokinetic parameters shown in Table 5 were
computed from the plasma oxymorphone concentration-time data.
5TABLE 5 AUC(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. AUC(0-inf) Area
under the drug concentration-time curve from time zero to infinity.
AUC(0-inf) = AUC(0-t) + Ct/Kel, where Kel is the terminal
elimination rate constant. AUC(0-24) Partial area under the drug
concentration-time curve from time zero to 24 hours. Cmax Maximum
observed drug concentration. Tmax Time of the observed maximum drug
concentration. Kel Elimination rate constant based on the linear
regression of the terminal linear portion of the LN(concentration)
time curve. T1/2el Half life, the time required for the
concentration to decline by 50%, calculated as LN(2)/Kel
[0067] Terminal elimination rate constants were computed using
linear regression of a minimum of three time points, at least two
of which were consecutive. Kel 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, T1/2el, AUC(0-inf), C1/F, MRT, and LN-transformed
T1/2el, AUC(0-inf), and C1/F were also not reported in these
cases.
[0068] A parametric (normal-theory) general linear model was
applied to each of the above parameters (excluding Tmax and Frel),
and the LN-transformed parameters Cmax, AUC(0-24), AUC(0-t),
AUC(0-inf), C1/F, and T1/2el. 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). The following treatment comparisons of
relative rate and extent of absorption were made: Treatment B
versus Treatment A, Treatment A versus Treatment C (dose normalized
to 20 mg). Treatment B versus Treatment D (dose normalized to 20
mg), and Treatment D versus Treatment C (dose normalized to 20 mg
for both treatments). The 90% confidence intervals of the ratios of
the treatment least squares parameter means were calculated. Tmax
was analyzed using the Wilcoxon Signed Ranks test. Summary
statistics were presented for Frel.
[0069] 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.
[0070] A total of 26 analytical runs were required to process the
clinical samples from this study. Of these 26 analytical runs, 26
were acceptable for oxymorphone. Standard curves for the 26
analytical runs in EDTA plasma used in this study covered a range
of 0.0500 to 20.000 mg/ml with a limit of quantitation of 0.0500
ng/ml for both compounds. Quality control samples analyzed with
each analytical run had coefficients of variation less than or
equal to 14.23% for oxymorphone.
[0071] 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.
[0072] The mean oxymorphone plasma concentration versus time curves
for Treatments A, B, C, and D are presented in FIG. 1 (linear
scale, without standard deviation).
[0073] Individual concentration versus time curves were
characterized by multiple peaks which occurred in the initial
12-hour period following the dose. In addition, a small "bump" in
plasma oxymorphone concentration was generally observed in the 24
to 48 hour post-dose period.
[0074] The arithmetic means of the plasma oxymorphone
pharmacokinetic parameters and the statistical comparisons for
Treatment B versus Treatment A are summarized in Table 6.
6TABLE 6 Summary of the Pharmacokinetic Parameters of Plasma
Oxymorphone for Treatments B and A Plasma Oxymorphone Treatment A
Treatment B Pharmacokinetic Arithmetic Arithmetic Mean Parameters
Mean SD Mean SD 90% CI Ratio Cmax(ng/ml) 1.7895 0.6531 1.1410
0.4537 125.4-191.0 158.2 Tmax(hr) 5.65 9.39 5.57 7.14 Auc(0-24)(ng
* hr/ml) 14.27 4.976 11.64 3.869 110.7-134.0 122.3 AUC(O-t)(ng *
hr/ml) 19.89 6.408 17.71 8.471 100.2-123.6 111.9 AUC(O-inf) 21.29
6.559 19.29 5.028 105.3-133.9 119.6 (ng * hr/ml) T 1/2el(hr) 12.0
3.64 12.3 3.99 57.4-155.2 106.3 Treatment B = 1 .times. 20 mg
oxymorphone sustained release Tablet, Fed: test Treatment A = 1
.times. 20 mg oxymorphone sustained release Tablet, Fasted:
reference
[0075] The arithmetic means of the plasma oxymorphone
pharmacokinetic parameters and the statistical comparisons for
Treatment A versus Treatment C are summarized in Table 7.
7TABLE 7 Summary of the Pharmacokinetic Parameters of Plasma
Oxymorphone for Treatments A and C Plasma Oxymorphone Treatment A
Treatment C Pharmacokinetic Arithmetic Arithmetic Mean Parameters
Mean SD Mean SD 90% CI Ratio Cmax(ng/ml) 1.1410 0.4537 2.2635
1.0008 33.4-66.0 49.7 Tmax(hr) 5.57 7.14 0.978 1.14 Auc(0-24)(ng *
hr/ml) 11.64 3.869 12.39 4.116 82.8-104.6 93.7 AUC(0-I)(ng * hr/ml
17.71 8.471 14.53 4.909 107.7-136.3 122.0 AUC(0-inf) 19.29 5.028
18.70 6.618 80.2-108.4 94.3 (ng * hr/ml) T 1/2el(hr) 12.3 3.99 16.2
11.4 32.9-102.1 67.5 Treatment A = 1 .times. 20 mg oxymorphone
sustained release Tablet, Fasted: test Treatment C = 10 mg/6.7 ml
oxymorphone HCI Oral Solution, Fasted: Dose Normalized to 20 ng:
reference.
[0076] The arithmetic means of the plasma oxymorphone
pharmacokinetic parameters and the statistical comparisons for
Treatment D versus Treatment C are summarized in Table 8.
8TABLE 8 Summary of the Pharmacokinetic Parameters of Plasma
Oxymorphone for Treatments A and C Plasma Oxymorphone Treatment B
Treatment D Pharmacokinetic Arithmetic Arithmetic Mean Parameters
Mean SD Mean SD 90% CI Ratio Cmax(ng/ml) 1.7895 0.6531 3.2733
1.3169 42.7-65.0 50.0 Tmax(hr) 5.65 9.39 1.11 0.768 Auc(0-24)(ng *
hr/ml) 14.27 4.976 17.30 5.259 74.4-90.1 82.2 AUC(0-t)(ng * hr/ml)
19.89 6.408 19.28 6.030 92.5-114.1 103.3 AUC(0-inf) 21.29 6.559
25.86 10.03 75.0-95.2 85.1 (ng * hr/ml) T 1/2el(hr) 12.0 3.64 20.6
19.3 31.9-86.1 59.0 Treatment B = 1 .times. 20 mg oxymorphone
sustained release Tablet, Fed: test Treatment D = 10 mg/6.7 ml
oxymorphone HCI Oral Solution, Fed: Dose Normalized to 20 mg:
reference.
[0077] The arithmetic means of the plasma oxymorphone
pharmacokinetic parameters and the statistical comparisons for
Treatment D versus Treatment C are summarized in Table 9.
9TABLE 9 Summary of the Pharmacokinetic Parameters of Plasma
Oxymorphone for Treatments A and C Plasma Oxymorphone Treatment D
Treatment C Pharmacokinetic Arithmetic Arithmetic Mean Parameters
Mean SD Mean SD 90% CI Ratio Cmax(ng/ml) 3.2733 1.3169 2.2635
1.0008 129.7-162.3 146.0 Tmax(hr) 1.11 0.768 0.978 1.14
Auc(0-24)(ng * hr/ml) 17.30 5.259 12.39 4.116 128.5-150.3 139.4
AUC(0-t)(ng * hr/ml) 19.20 6.030 14.53 4.909 117.9-146.5 132.2
AUC(0-inf) 25.86 10.03 18.70 6.618 118.6-146.6 132.6 (ng * hr/ml) T
1/2el(hr) 20.6 19.3 16.2 11.4 87.3-155.9 121.6 Treatment D = 10
mg/6.7 ml oxymorphone HCI Oral Solution, Fed: Dose Normalized to 20
mg: test. Treatment C = 10 mg/6.7 ml oxymorphone HCI Oral Solution,
Fasted: Dose Normalized to 20 mg: reference.
[0078] The relative bioavailability calculations are summarized in
Table 10.
10TABLE 10 Mean (S.D.) Relative Oxymorphone Bioavailability
Determined from AUC (0-inf) and AUC (0-24) Frel BA Frel AC Frel BD
Frel DC AUC(0-inf) 1.169 (0.2041) 1.040 (0.1874) 0.8863 (0.2569)
1.368 (0.4328) AUC(0-24) 1.299 (0.4638) (0.9598) (0.2151) 0.8344
(0.100) 1.470 (0.3922)
[0079] The objectives of this study were to assess the relative
bioavailability of oxymorphone from oxymorphone sustained 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 sustained release
formulation and from the oral solution.
[0080] The presence of a high fat meal had a substantial effect on
the oxymorphone Cmax, but less of an effect on oxymorphone AUC from
oxymorphone sustained release tablets. Least Squares (LS) mean Cmax
was 58% higher and LS mean AUC(0-t) and AUC(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
(0-inf) since mean Frel was 1.17. Individual Frel values based on
AUC (0-24) were similar (less than 20% different) to Frel values
based on AUC (0-inf) for all but 2 subjects. Comparison of mean
Frel from AUC (0-inf) to mean Frel from AUC (0-24) is misleading,
because not all subjects had a value for AUC (0-inf). Mean Tmax
values were similar (approximately 5.6 hours), and no significant
different in Tmax was shown using nonparametric analysis. Half
value durations were significantly different between the two
treatments.
[0081] The effect of food on oxymorphone bioavailability from the
oral solution was more pronounced, particularly in terms of AUC. LS
mean Cmax was 50% higher and LS mean AUC(0-t) and AUC(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(0-inf) since mean Frel was 1.37. Individual Frel values based
on AUC(0-24) were similar (less than 20% different) to Frel values
based on AUC(0-inf.) for all but 5 subjects. Comparison of mean
Frel from AUC(0-inf) to mean Frel from AUC(0-24) is misleading
because not all subjects had a value for AUC(0-inf). Mean Tmax
(approximately 1 hour) was similar for the two treatments and no
significant difference was shown.
[0082] Under fasted conditions, oxymorphone sustained 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(0-t) was 17% higher for oxymorphone sustained release,
whereas LS mean AUC(0-inf) values were nearly equal (mean
ratio=99%). However, AUC(0-t) is not the best parameter to evaluate
bioavailability since the plasma concentrations were measured for
48 hours for the sustained release formulation versus 36 hours for
the oral solution. Mean Frel values calculated from AUC(0-inf) and
AUC(0-24), (1.0 and 0.96, respectively) also showed similar extent
of oxymorphone availability between the two treatments.
[0083] There were differences in parameters reflecting rate of
absorption. LS mean Cmax was 49% lower for oxymorphone sustained
release tablets compared to the dose-normalized oral solution,
based on LN-transformed data. Half-value duration was significantly
longer for the sustained release formulation (means, 12 hours
versus 2.5 hours).
[0084] Under fed conditions, oxymorphone availability from
oxymorphone sustained 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(0-inf)
was 12% lower for oxymorphone sustained release. Mean Frel values
calculated from AUC(0-inf) and AUC(0-24), (0.89 and 0.83
respectively) also showed similar extent of oxymorphone
availability from the tablet. There were differences in parameters
reflecting rate of absorption. LS mean Cmax was 46% lower for
oxymorphone sustained release tablets compared to the
dose-normalized oral solution, based on LN-transformed data. Mean
Tmax was 5.7 hours for the tablet compared to 1.1 hours for the
oral solution. Half-value duration was significantly longer for the
sustained release formulation (means, 7.8 hours versus 3.1
hours).
[0085] The presence of a high fat meal did not appear to
substantially affect the availability following administration of
oxymorphone sustained release tablets. LS mean ratios were 97% for
AUC(0-t) and 91% for Cmax (Treatment B versus A), based on
LN-transformed data. This was consistent with the relative
bioavailability determination from AUC(0-24), since mean Frel was
0.97. AUC(0-inf) was not a reliable measure for bioavailability
since half-life could not be estimated accurately, and in many
cases at all. Half-life estimates were not accurate because in the
majority of subjects, the values for half-life were nearly as long
or longer (up to 2.8 times longer) as the sampling period. Mean
Tmax was later for the fed treatment compared to the fasted
treatment (5.2 and 3.6 hours, respectively), and difference was
significant.
[0086] Under fasted conditions, oxymorphone sustained 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 (0-t) was 104.5%. Mean Frel (0.83) calculated from AUC(0-24)
also showed similar extent of oxymorphone availability between the
two treatments. There were differences in parameters reflecting
rate of absorption. LS mean Cmax was 57% lower for oxymorphone
sustained release tablets compared to the dose-normalized oral
solution. Mean Tmax was 3.6 hours for the tablet compared to 0.88
for the oral solution. Half-value duration was significantly longer
for the sustained release formulation (means, 11 hours versus 2.2
hours).
[0087] Under fed conditions, availability from oxymorphone
sustained 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(0-t) was 14%
higher for oxymorphone sustained release. Mean Frel (0.87)
calculated from AUC (0-24) also indicated similar extent of
availability between the treatments. There were differences in
parameters reflecting rate of absorption. LS mean Cmax was 40%
lower for oxymorphone sustained release tablets compared to the
dose-normalized oral solution. Mean Tmax was 5.2 hours for the
tablet compared to 1.3 hour for the oral solution. Half-value
duration was significantly longer for the sustained release
formulation (means, 14 hours versus 3.9 hours).
[0088] The extent of oxymorphone availability from oxymorphone
sustained release 20 mg tablets was similar under fed and fasted
conditions since there was less than a 20% difference in LS mean
AUC(0-t) and AUC(0-inf) values for each treatment, based on
LN-transformed data. Tmax was unaffected by food; however, LS mean
Cmax 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 Cmax and AUC values
were increased approximately 50 and 30%, respectively. Tmax was
unaffected by food. Under both fed and fasted conditions,
oxymorphone sustained 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.
[0089] Bioavailability following oxymorphone sustained release 20
mg tablets was also similar under fed and fasted conditions since
there was less than a 20% difference in LS mean Cmax and AUC values
for each treatment. Tmax 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, Cmax was decreased 35% in the presence of
food. Tmax was unaffected by food. Under both fed and fasted
conditions, oxymorphone sustained 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.
[0090] Various modifications of the invention, in addition to those
described herein, will be apparent to one skilled in the art from
the foregoing description. Such modifications are intended to fall
within the scope of the appended claims.
* * * * *