U.S. patent application number 12/572106 was filed with the patent office on 2010-02-04 for hydromorphone therapy.
Invention is credited to Atul D. Ayer, Navjot Chadha, Anthony L. Kuczynski, Sonya Merrill.
Application Number | 20100028389 12/572106 |
Document ID | / |
Family ID | 46253688 |
Filed Date | 2010-02-04 |
United States Patent
Application |
20100028389 |
Kind Code |
A1 |
Merrill; Sonya ; et
al. |
February 4, 2010 |
HYDROMORPHONE THERAPY
Abstract
A hydromorphone composition, a hydromorphone dosage form and a
method for administering hydromorphone are disclosed, indicated for
the management of pain.
Inventors: |
Merrill; Sonya; (San Jose,
CA) ; Ayer; Atul D.; (Palo Alto, CA) ; Chadha;
Navjot; (Fremont, CA) ; Kuczynski; Anthony L.;
(Mountain View, CA) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Family ID: |
46253688 |
Appl. No.: |
12/572106 |
Filed: |
October 1, 2009 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10884744 |
Jul 2, 2004 |
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12572106 |
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08935223 |
Sep 22, 1997 |
5914131 |
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10884744 |
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08611294 |
Mar 5, 1996 |
5702725 |
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08935223 |
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08271593 |
Jul 7, 1994 |
5529787 |
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08611294 |
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Current U.S.
Class: |
424/400 ;
514/282 |
Current CPC
Class: |
A61P 25/00 20180101;
A61K 9/0004 20130101; A61K 31/485 20130101; A61K 9/2054 20130101;
A61K 9/2027 20130101; A61K 9/2031 20130101 |
Class at
Publication: |
424/400 ;
514/282 |
International
Class: |
A61K 9/00 20060101
A61K009/00; A61K 31/4355 20060101 A61K031/4355 |
Claims
1-31. (canceled)
32. A therapeutic composition for the relief of pain comprising:
(a) a hydromorphone formulation that on day four of once daily
administration to a population of subjects provides, for a 16 mg
dose of hydromorphone: (i) a plasma concentration maximum of about
2.6 ng/mL, (ii) a time to maximum plasma concentration of about
14.7 hours, (iii) a plasma concentration minimum of about 1.2
ng/mL, (iv) a time to minimum plasma concentration of about 13.1
hours following the maximum plasma concentration; and (v) an area
under the curve of 45 ng-hr/mL; and (b) an expandable push
composition, wherein the therapeutic composition is encased with a
semipermeable wall with a passageway through the semipermeable
wall.
33. A therapeutic composition according to claim 32, wherein the
hydromorphone formulation comprises hydromorphone, a hydrogel
polymer, a binder, and a lubricant.
34. A therapeutic composition according to claim 33, wherein the
formulation comprises from about 1 to about 65 mg of hydromorphone
or a pharmaceutically acceptable salt thereof.
35. A therapeutic composition according to claim 33, wherein the
hydrogel polymer comprises a maltodextrin polymer of 500 to
1,250,000 number average molecular weight; poly(alkylene oxide)
represented by a poly(ethylene oxide) of 50,000 to 750,000
weight-average molecular weight, poly(propylene oxide) of 50,000 to
750,000 weight-average molecular weight, alkali
carboxyalkylcellulose, wherein the alkali is sodium or potassium,
the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000
weight-average molecular weight; or a copolymer of ethylene-acrylic
acid, including methacrylic and ethacrylic acid of 10,000 to
500,000 number-average molecular weight.
36. A therapeutic composition according to claim 35, wherein the
hydrogel polymer comprises poly(ethylene oxide) of 50,000 to
750,000 molecular weight.
37. A therapeutic composition according to claim 36, wherein the
hydrogel polymer comprises poly(ethylene oxide) of about 200,000
molecular weight.
38. A therapeutic composition according to claim 33, wherein the
binder comprises poly-n-vinylamide, poly-nvinylacetamide,
poly(vinyl pyrrolidone), poly-n-vinylcaprolactone,
poly-nvinyl-5-methyl-2-pyrrolidone, or poly-n-vinyl-pyrrolidone
copolymers with a member selected from the group consisting of
vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl
butyrate, vinyl laureate, or vinyl stearate.
39. A therapeutic composition according to claim 38, wherein the
binder comprises poly(vinylpyrrolidone) of 38,000 to 42,000
molecular weight.
40. A therapeutic composition according to claim 39, wherein the
binder comprises poly(vinylpyrrolidone) of about 40,000 molecular
weight.
41. A therapeutic composition according to claim 33, wherein the
lubricant is selected from the group consisting of magnesium
stearate, sodium stearate, stearic acid, calcium stearate,
magnesium oleate, oleic acid, potassium oleate, caprylic acid,
sodium stearyl fumarate, and magnesium palmitate.
42. A therapeutic composition according to claim 41, wherein the
lubricant comprises magnesium stearate.
43. A therapeutic composition according to claim 33, wherein the
hydromorphone formulation is selected from the group consisting of:
(a) 8 mg of hydromorphone, 67.8 mg of poly(ethylene oxide), 4 mg of
poly(vinylpyrrolidone), and 0.2 mg of magnesium stearate; (b) 16 mg
of hydromorphone, 135.6 mg of poly(ethylene oxide), 8 mg of
poly(vinylpyrrolidone), and 0.4 mg of magnesium stearate; (c) 32 mg
of hydromorphone, 119.6 mg of poly(ethylene oxide), 8 mg of
poly(vinylpyrrolidone), and 0.4 mg of magnesium stearate; and (d)
64 mg of hydromorphone, 138.6 mg of poly(ethylene oxide), 10.7 mg
of poly(vinylpyrrolidone), and 0.53 mg of magnesium stearate.
44. A therapeutic composition according to claim 33, wherein the
hydromorphone formulation is selected from the group consisting of:
(a) 10.5% hydromorphone hydrochloride, 84.23% poly(ethylene oxide),
5% poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and
0.25% magnesium stearate for a 8 mg dose of hydromorphone; (b)
10.5% hydromorphone hydrochloride, 84.23% poly(ethylene oxide), 5%
poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25%
magnesium stearate for a 16 mg dose of hydromorphone; (c) 20%
hydromorphone hydrochloride, 74.68% poly(ethylene oxide), 5%
poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25%
magnesium stearate for a 32 mg dose of hydromorphone; and (d) 30%
hydromorphone hydrochloride, 64.73% poly(ethylene oxide), 5%
poly(vinylpyrrolidone), 0.02% butylated hydroxytoluene, and 0.25%
magnesium stearate for a 64 mg dose of hydromorphone.
45. A therapeutic composition according to claim 32, wherein the
push composition comprises an osmopolymer, an osmagent, a colorant,
a lubricant, and an antioxidant.
46. A therapeutic composition according to claim 45, wherein the
osmopolymer comprises polyalkylene oxide and a hydroxpropylalkyl
cellulose.
47. A therapeutic composition according to claim 46, wherein the
polyalkylene oxide comprises polyethylene oxide of 1,000,000 to
7,000,000 molecular weight.
48. A therapeutic composition according to claim 47, wherein the
polyalkylene oxide comprises polyethylene oxide of about 2,000,000
molecular weight.
49. A therapeutic composition according to claim 46, wherein the
hydroxpropylalkyl cellulose comprises hydroxypropylmethylcellulose
of 9,000 to 450,000 number average molecular weight.
50. A therapeutic composition according to claim 45, wherein the
osmagent is selected from the group consisting of sodium chloride,
potassium chloride, magnesium sulfate, lithium phosphate, lithium
chloride, sodium phosphate, potassium sulfate, sodium sulfate,
potassium phosphate, glucose, fructose and maltose.
51. A therapeutic composition according to claim 50, wherein the
osmagent comprises sodium chloride.
52. A therapeutic composition according to claim 45, wherein the
colorant is selected from the group consisting of FD&C No. 1
blue dye, FD&C No. 4 red dye, red ferric oxide, yellow ferric
oxide, titanium dioxide, carbon black, and indigo.
53. A therapeutic composition according to claim 45, wherein the
lubricant is selected from the group consisting of magnesium
stearate, sodium stearate, stearic acid, calcium stearate,
magnesium oleate, oleic acid, potassium oleate, caprylic acid,
sodium stearyl fumarate, and magnesium palmitate.
54. A therapeutic composition according to claim 53, wherein the
lubricant comprises magnesium stearate.
55. A therapeutic composition according to claim 45, wherein the
antioxidant is selected from the group consisting of ascorbic acid,
ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3
tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium
bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,
vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol,
and propylgallate.
56. A therapeutic composition according to claim 55, wherein the
antioxidant comprises butylated hydroxytoluene.
57. A therapeutic composition according to claim 45, wherein the
push composition is selected from the group consisting of: (a) 37.8
mg of poly(ethylene oxide), 18 mg of osmagent, 3 mg of
hydroxypropylmethylcellulose, 0.6 mg of a colorant, 0.15 mg of a
lubricant, and 0.06 mg of an antioxidant for a 8 mg dose of
hydromorphone; (b) 76.49 mg of poly(ethylene oxide), 36 mg of
osmagent, 6 mg of hydroxypropylmethylcellulose, 1.2 mg of a
colorant, 0.3 mg of a lubricant, and 0.12 mg of an antioxidant for
a 16 mg dose of hydromorphone; (c) 76.49 mg of poly(ethylene
oxide), 36 mg of sodium chloride, 6 mg of
hydroxypropylmethylcellulose, 1.2 mg of a colorant, 0.3 mg of a
lubricant, and 0.012 mg of an antioxidant for a 32 mg dose of
hydromorphone; and (d) 104.53 mg of poly(ethylene oxide), 49.2 mg
of sodium chloride, 8.2 mg of hydroxypropylmethylcellulose, 1.64 mg
of a colorant, 0.41 mg of a lubricant, and 0.123 mg of an
antioxidant for a 64 mg dose of hydromorphone.
58. A therapeutic composition according to claim 45, wherein the
push composition is selected from the group consisting of: (a)
64.3% of poly(ethylene oxide), 30% of osmagent, 5% of
hydroxypropylmethylcellulose, 0.4% of a colorant, 0.25% of a
lubricant, and 0.05% of an antioxidant for a 8 mg dose of
hydromorphone; (b) 64.3% of poly(ethylene oxide), 30% of osmagent,
5% of hydroxypropylmethylcellulose, 0.4% of a colorant, 0.25% of a
lubricant, and 0.05% of an antioxidant for a 16 mg dose of
hydromorphone; (c) 63.672% of poly(ethylene oxide), 30% of
osmagent, 5% of hydroxypropylmethylcellulose, 1% of a colorant,
0.25% of a lubricant, and 0.05% of an antioxidant for a 32 mg dose
of hydromorphone; and (d) 64.3% of poly(ethylene oxide), 30% of
osmagent, 5% of hydroxypropylmethylcellulose, 0.4% of a colorant,
0.25% of a lubricant, and 0.05% of an antioxidant for a 64 mg dose
of hydromorphone.
59. A therapeutic composition according to claim 32, wherein the
semipermeable wall comprises a member selected from the group
consisting of a cellulose ester polymer, a cellulose ether polymer
and a cellulose ester-ether polymer.
60. A therapeutic composition according to claim 59, wherein the
semipermeable wall comprises cellulose acetate having a DS of 2 to
3 and an acetyl content of 35 to 44.8%.
61. A therapeutic composition according to claim 60, wherein the
semipermeable wall comprises cellulose acetate having a DS of 2 to
3 and an acetyl content of 39.8%.
62. A therapeutic composition according to claim 59, wherein the
semipermeable wall comprises 99 weight % cellulose acetate having a
DS of 2 to 3 and an acetyl content of 39.8% and 1 weight %
poly(ethylene glycol).
63. A therapeutic composition according to claim 59, wherein the
semipermeable wall is selected from the group consisting of: (a)
27.2 mg of cellulose acetate and 0.275 mg of polyethylene glycol
for a 8 mg dose of hydromorphone; (b) 27.52 mg of cellulose acetate
and 0.27 mg of polyethylene glycol for a 16 mg dose of
hydromorphone; (c) 29.6 mg of cellulose acetate and 0.29 mg of
polyethylene glycol for a 32 mg dose of hydromorphone; and (d)
38.61 mg of cellulose acetate and 0.39 mg of polyethylene glycol
for a 64 mg dose of hydromorphone.
64. An osmotically controlled-release dosage form comprising: (a) a
hydromorphone formulation; (b) a push composition comprising an
osmagent, and (c) a semipermeable wall with a passageway through
the semipermeable wall, the semipermeable wall encasing the
hydromorphone formulation and the push composition, wherein the
osmotically controlled-release dosage form provides, for a 16 mg
dose of hydromorphone on day four of once daily administration to a
population of subjects: (i) a plasma concentration maximum of about
2.6 ng/mL, (ii) a time to maximum plasma concentration of about
14.7 hours, (iii) a plasma concentration minimum of about 1.2
ng/mL, (iv) a time to minimum plasma concentration of about 13.1
hours, and (v) an area under the curve of 44.8 ng-hr/ml.
65. A therapeutic composition for the relief of pain comprising
hydromorphone that on day four of once daily administration to a
population of subjects, provides, for a 16 mg dose of
hydromorphone: (a) a plasma concentration maximum of about 2.6
ng/mL, (b) a time to maximum plasma concentration of about 14.7
hours, (c) a plasma concentration minimum of about 1.2 ng/mL, (d) a
time to minimum plasma concentration of about 13.1 hours, and (e)
an area under the curve of 44.8 ng-hr/ml, in an osmotically
control-release dosage form comprising: (i) a hydromorphone
formulation; (ii) an expandable push composition, and (iii) a
semipermeable wall with a passageway through the semipermeable
wall, the semipermeable wall encasing the hydromorphone formulation
and the push composition.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is application is a division of U.S.
application Ser. No. 08/935,223 filed on Sep. 22, 1997, which
application Ser. No. 08/935,223 is a continuation-in-part of U.S.
application Ser. No. 08/611,294 filed on Mar. 5, 1996 now U.S. Pat.
No. 5,702,725 issued Dec. 30, 1997, which application Ser. No.
08/935,223 is a continuation of U.S. application Ser. No.
08/271,593 filed Jul. 7, 1994 and now U.S. Pat. No. 5,529,787
issued on Jun. 25, 1996.
FIELD OF THE INVENTION
[0002] This invention pertains to a novel dosage form comprising
hydromorphone for the management of pain. The invention concerns
also a novel therapeutic composition comprising hydromorphone
indicated for treating pain. The invention relates additionally to
a method for the management of pain by administering continuously
release-rate controlled doses of hydromorphone over an extended
time to produce analgesic therapy.
BACKGROUND OF THE INVENTION
[0003] Hydromorphone is an analgesic with its principal therapeutic
effect, the relief of pain. The precise mechanism of action of
hydromorphone is not medically understood, although it is thought
to relate to the existence of hydromorphone receptors in the
central nervous system. Generally, the analgesic action of
parenterally administered hydromorphone is apparent within fifteen
minutes and the onset of action of orally administered
hydromorphone is somewhat slower, with analgesia occurring within
thirty minutes. In human plasma, the half-life of hydromorphone is
about two and one-half hours. Hydromorphone is indicated for the
relief of moderate to severe pain, such as pain due to infection,
surgery, cancer, trauma, biliary colic, disease, renal colic,
myocardial infarction, and burns A pharmaceutically-acceptable
dosage form for oral administering hydromorphone to provide
analgesic therapy beyond its short half-life at a controlled-rate
over an extended period of time appears to be lacking in the
pharmaceutical and medical arts. The pharmacological and medical
properties of hydromorphone are known in Pharmaceutical Sciences,
Remington, 17th Ed., pp. 1099-1044, (1985); and in the
Pharmacological Basis of Therapeutics, Goodman and Rall, 8th Ed.,
pp. 485-518, (1990).
[0004] The present invention unexpectedly provides both a dosage
form comprising hydromorphone and a therapeutic composition
comprising hydromorphone for the management of pain. That is, the
prior art did not appreciate that hydromorphone, which is a complex
chemical 4,5-epoxy-3-hydroxy-17-methyl-morphinan-6-one, comprising
five rings substituted with different chemical groups, can be made
into a continuous release dosage form, or into a therapeutic
composition. The prior did not appreciate a dosage form and a
therapeutic composition can be made available comprising an osmogel
such as a polyalkylene oxide and other ingredients including an
osmagent. The prior art did not make obvious hydromorphone
formulated with a polyalkylene oxide, as the mechanism which
controlled the release of hydromorphone from polyalkylene oxide are
complex polymers. For example, the hydromorphone could become
immobile and trapped in the polyalkylene oxide, also, the
polyalkylene oxide could exhibit unacceptable swelling in the
presence of aqueous including biological fluid and thereby change
the rate of release of the hydromorphone from the polyalkylene
oxide. Further, the osmogel such as polyalkylene oxide, can possess
a glass-transition temperature below human body temperature, which
leads away from using hydromorphone in such an environment.
Additionally, the properties of hydromorphone and polyalkylene
oxide, exemplified by the crystallinity of hydromorphone in
polyalkylene oxide, the burst or lag effect of hydromorphone in
polyalkylene oxide, the hydromorphone solubility in a polyalkylene
oxide hydrogel all attest to the nonobviousness of the present
invention.
[0005] Prior to this invention, hydromorphone was administered in
conventional forms, such as a nonrate-controlling dose-dumping
tablet or by a dose-dumping capsule, and usually at multiple,
repetitive dosing intervals. This prior-art mode of therapy leads
to an initial high dose of hydromorphone in the blood, followed by
a decreased dose of hydromorphone in the blood. The concentration
differences in dosing patterns are related to the presence and
absence of administered drug, which is a major disadvantage
associated with conventional dosage forms. Conventional dosage
forms and their mode of operation, including dose peaks and
valleys, are discussed in Pharmaceutical Sciences, Remington, 18th
Ed., pp 1676-1686, (1990), Mark Publishing Co.; The Pharmaceutical
and Clinical Pharmacokinetics, 3rd Ed., pp 1-28, (1984), Lea and
Febiger, Philadelphia; and in U.S. Pat. Nos. 3,598,122 and
3,598,123, both issued to Zaffaroni.
[0006] The above presentation dictates of the critical need for a
dosage form and for a therapeutic composition that overcomes the
shortcomings of conventional dosage forms, including tablets,
capsules, elixirs and suspensions. These conventional dosage forms
and their accompanying peaks and valleys do not provide for
dose-regulated drug therapy over an extended period of time. The
hydromorphone as delivered by the prior art is often dosed two or
more times a day, which does not lend itself to controlled and
sustained therapy. This prior-art pattern of drug administration
speaks of the need for a dosage form and for a therapeutic
composition that can administer hydromorphone in a rate-controlled
dose over an extended time to provide constant therapy, and thereby
eliminate the peaks, valleys, and multiple uncontrolled dosing of
the prior art.
[0007] In view of the foregoing presentation, it is immediately
apparent that a serious need exists for an improvement in the
delivery of hydromorphone for its therapeutic analgesic effect. The
need exists to provide a novel therapeutic composition comprising
hydromorphone, and the need exists to provide a novel method of
administering hydromorphone to a patient in need of hydromorphone
therapy. The invention provides an oral, relatively-easy to
administer mode and manner of hydromorphone therapy.
OBJECTS OF THE INVENTION
[0008] Accordingly, in view of the above presentation it is an
immediate object of this invention to provide a dosage form and a
therapeutic composition for delivering hydromorphone for pain
relief, which dosage form and therapeutic composition overcome the
shortcomings known to the prior art.
[0009] Another object of the present invention is to make available
to the medical-pharmaceutical art a dosage form that delivers a
member selected from the group consisting of hydromorphone and its
pharmaceutically acceptable salts in a sustained-release dosage
program over time.
[0010] Another object of the invention is to provide a novel dosage
form for administering hydromorphone to a patient at a controlled
rate and in a continuous dose over time.
[0011] Another object of the invention is to provide a therapeutic
composition comprising an orally administrable solid hydromorphone
comprising an osmopolymer that can be administered as an oral,
solid therapeutic composition or administered from an osmotic
dosage form comprising the solid initially dry therapeutic
composition.
[0012] Another object of the invention is to provide a
pharmaceutically acceptable composition comprising a member
selected from the group consisting of hydromorphone and its
pharmaceutically acceptable salts for the relief of moderate to
severe pain due to surgery, cancer, trauma, tissue, bone, colic,
myocardial infarction, burns and rectal pain in a human
patient.
[0013] Another object of the invention is to provide a therapeutic
composition comprising hydromorphone and an osmotic attractant for
delivering a, known concentration per unit time for hydromorphone
therapy.
[0014] Another object of the invention is to provide a
hydromorphone formulation that delivers, in a controlled-continuous
releasing dose, hydromorphone to a patient in need of hydromorphone
therapy for maintaining a hydromorphone level in the blood as a
function of the hydromorphone releasing formulation.
[0015] Another object of the invention is to provide both a novel
dosage form and a novel dosage composition, which in both form,
delivers hydromorphone as an analgesic to relieve pain by altering
the psychological response to pain and suppress anxiety and
apprehension in a patient.
[0016] Another object of the invention is to provide a method for
administering hydromorphone to a patient for lessening a patient's
pain.
[0017] Another object of the invention is to make available a
composition comprising hydromorphone blended with a
pharmaceutically acceptable polymer and an osmotically active
agent.
[0018] Another object of the invention is to provide a dosage form
comprising an external coat comprising hydromorphone for immediate
hydromorphone therapy.
[0019] Another object of the invention is to provide a dosage form
that delivers hydromorphone that reduces and/or eliminates the
unwanted influences of a gastrointestinal environment on the
delivery of hydromorphone from the dosage form in the
gastrointestinal tract of a human.
[0020] Other objects, features and advantages of the invention will
be more apparent to those versed in the dispensing art, and from
the accompanying detailed specification, then in conjunction with
the accompanying claims.
BRIEF DESCRIPTION OF THE DRAWING
[0021] The drawing figures are not drawn to scale, and are set
forth to illustrate various embodiments of the invention. The
drawing figures are as follows:
[0022] Drawing FIG. 1 is a general view of a dosage form provided
by this invention, designed and shaped for the oral administration
of hydromorphone at a controlled rate over an extended time to a
patient in need of hydromorphone therapy;
[0023] Drawing FIG. 2 is a general view of the dosage form of
drawing FIG. 1, in opened section, depicting a dosage form of the
invention comprising an internally housed,
pharmaceutically-acceptable therapeutic hydromorphone
composition;
[0024] Drawing FIG. 3 is an opened view of drawing FIG. 1,
illustrating a dosage form internally comprising a hydromorphone
composition and a separate and contacting displacement composition
comprising means for pushing the pharmaceutical hydromorphone
composition form the dosage form;
[0025] Drawing FIG. 4 is a view of a dosage form provided by this
invention, which dosage form is illustrated comprising an
instant-release external overcoat on the dosage form, which
overcoat comprises an instant dose of hydromorphone for the
lessening of pain;
[0026] Drawing FIG. 5 depicts the mean plasma hydromorphone
concentration profile for hydromorphone;
[0027] Drawing FIG. 6 depicts the mean plasma hydromorphone
3-glucuronide concentration following hydromorphone treatment;
and
[0028] Drawing FIG. 7 depicts the mean plasma hydromorphone
concentration profile for hydromorphone treatment.
[0029] Drawing FIGS. 8 to 12 depict release rate patterns and
clinical data provided by the invention.
[0030] In the drawing figures and in the specification, like parts
in related figures are identified by like numbers. The terms
appearing earlier in the specification and in the description of
the drawing figures, as well as embodiments thereof, are further
described elsewhere in the disclosure.
DETAILED DESCRIPTION OF DRAWINGS
[0031] Turning now to the drawing figures in detail, which drawing
figures are examples of a dosage form and a therapeutic composition
provided by this 9 invention, and which examples are not to be
construed as limiting, one example of a dosage form is seen in
drawing FIG. 1. In drawing FIG. 1, a dosage form 10 is seen
comprising a body member 11 that comprises a wall 12. Wall 12 is an
exterior wall, and it surrounds and defines an internal area, or
compartment, not seen in drawing FIG. 1. Dosage form 10 comprises
at least one exit 13 that connects an exterior environment, such as
the gastrointestinal tract of a human, with the interior of dosage
form 10.
[0032] Dosage form 10 of drawing FIG. 2 illustrates a dosage form
comprising controlled-release delivery kinetics that delivers a
member selected from the group consisting of hydromorphone and its
pharmaceutically acceptable salts. The phrase "controlled-release"
denotes that dosage form 10 controls or governs the delivery of
hydromorphone 14, represented by dots, from internal space or
compartment 15. The controlled-release also denotes the delivery of
hydromorphone is at a known rate per unit time, over an extended
time or thirty-minutes up to twenty-four hours. Dosage form 10, as
provided by this invention, is useful for establishing therapeutic
hydromorphone therapeutic levels in the blood, including plasma, as
a analgesic or pain-lessening therapy. Dosage form 10 as seen in
FIG. 2, embraces the shape of a dosage tablet, and it could embrace
the shape of a caplet and other oral, buccal, or sublingual dosage
forms. The extended-continuous delivery time for the
sustain-release dosage form 10, provided by the invention, denotes
a sustained-release delivery time greater than conventional,
noncontrolled tablets, and noncontrolled, nonsustained-release
capsules that exhibit a dose-dumping of their drug.
[0033] In drawing FIG. 2, dosage form 10 is seen in opened-section
with a section of wall 12 removed for illustrating the internal
area 15 of dosage form 10. In drawing FIG. 2, dosage form 10
comprises body 11, wall 12, exit 13 and internal area or
compartment 15. Wall 12, which surrounds and defines internal
compartment 15, comprised totally or in at least a part, a
semipermeable composition. The phrase "semipermeable composition:
denotes that the semipermeable composition is permeable to the
passage of an exterior fluid, such as aqueous and biological fluid,
in the environment of use, including the gastrointestinal tract.
Wall 12 is impermeable to hydromorphone, represented by dots 14,
present in compartment 15. Wall 12 is nontoxic, inert, and it
maintains its physical and chemical integrity during the dispensing
life of hydromorphone. Wall 12 comprises a composition that does
not adversely effect an animal, a human, or components of the
dosage form. Wall 12, in one embodiment, comprises a member
selected from the group consisting of a cellulose ester polymer, a
cellulose ether polymer and a cellulose ester-ether polymer. These
cellulosic polymers have a degree of substitution (DS) on the
anhydroglucose unit, from greater than zero up to three inclusive.
By "degree of substitution" is meant that the average number of
hydroxyl groups originally present on the anhydroglucose unit
comprising the cellulose polymer that are replaced by a
substituting group. Representative wall 12 polymers comprise a
member selected from the group consisting of cellulose acylate,
cellulose diacylate, cellulose triacylate, cellulose acetate,
cellulose diacetate, cellulose triacetate, mono-, di- and
tricellulose alkenylates, and mono-, di- and tricellulose
alkinylates. Exemplary polymers include cellulose acetate having a
DS up to 1 and an acetyl content up to 21%; cellulose acetate
having a DS of 1 to 2 and an acetyl content of 21 to 35%; cellulose
acetate having a DS of 2 to 3 and an acetyl content of 35 to 44.8%.
More specific cellulosic polymers comprise cellulose propionate
having a DS of 1.8 and a propyl content of 39.2 to 45% and a
hydroxy content of 2.8 to 5.4; cellulose acetate butyrate having a
DS of 1.8, and acetyl content of 13 to 15% and a butyryl content of
34 to 39%; cellulose acetate butyrate having an acetyl content of 2
to 29%, a butyryl content of 17 to 53% and a hydroxyl content of
0.5 to 4.7; cellulose triacylates having a DS of 2.9 to 3, such as
cellulose trivalerate, cellulose trilaurate, cellulose
tripalmitate, cellulose trisuccinate, and cellulose trioctanoate;
celluloses diacylate having a DS of 2.2 to 2.6, such as cellulose
disuccinate, cellulose dipalmitate, cellulose dioctanoate,
cellulose dipentanoate, co-esters of cellulose, such as cellulose
acetate butyrate, and cellulose acetate propionate. The
poly(cellulose) used for the present invention comprises a
number-average molecular weight of 20,000 to 7,500,000.
[0034] Additional semipermeable polymers for the purpose of this
invention comprise acetaldehyde dimethycellulose acetate, cellulose
acetate ethylcarbamate, cellulose acetate methylcarbamate,
cellulose diacetate, propylcarbamate, cellulose acetate
diethylaminoacetate; semipermeable polyamide; semipermeable
polyurethane; semipermeable sulfonated polystyrene; semipermeable
cross-linked polymer formed by the coprecipitation of a polyanion
and a polycation as disclosed in U.S. Pat. Nos. 3,173,876;
3,276,586; 3,541,005; 3,541,006 and 3,546,876; semipermeable
polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No.
3,133,132; semipermeable crosslinked polystyrenes; semipermeable
cross-linked poly(sodium styrene sulfonate); semipermeable
crosslinked poly(vinylbenzyltrimethyl ammonium chloride); and
semipermeable polymers possessing a fluid permeability of
2.5.times.10.sup.-8 to 2.5.times.10.sup.-2 (cm.sup.2/hratm)
expressed per atmosphere of hydrostatic or osmotic pressure
difference across the semipermeable wall. The polymers are known to
the polymer art in U.S. Pat. Nos. 3,845,770; 3,916,899 and
4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W.
J. Roff, 1971, CRC Press, Cleveland, Ohio.
[0035] The drug hydromorphone 14, as seen in drawing FIG. 2, is
comprised of: 4,5-epoxy-3-hydroxy-17-methylmorphinan-6-one,
possessing analgesic therapy. Hydromorphone is known in The Merck
Index, 11th Ed., p. 762 (1990). Representative of hydromorphones 14
for this invention comprise a member selected from the group
consisting of hydromorphone and its pharmaceutically acceptable
salt. The hydromorphone salts are represented by a member selected
from the group consisting of the following: hydromorphone sulfate,
hydromorphone hydrochloride, hydromorphone trifluoracetate,
hydromorphone thiosemicarbazone hydrochloride, hydromorphone
pentafluoropropionate, hydromorphone p-nitrophenylhydrozone,
hydromorphone hydrazine, hydromorphone hydrobromide, hydromorphone
mucate, hydromorphone methylbromide, hydromorphone oleate,
hydromorphone n-oxide, hydromorphone acetate, hydromorphone
phosphate dibasic, hydromorphone phosphate monobasic, hydromorphone
inorganic salt, hydromorphone organic salt, hydromorphone acetate
trihydrate, hydromorphone bis(heptafluorobutyrate), hydromorphone
bis(methylcarbamate), hydromorphone (bis-pentafluoropropionate),
hydromorphone bis(pyridine-3-carboxylate), hydromorphone
bis(trifluoroacetate), hydromorphone bitartrate, hydromorphone
chlorohydrate, and hydromorphone sulfate pentahydrate. The dosage
form and the therapeutic composition in either manufacture
comprises 1 mg to 500 mg of hydromorphone 14 or hydromorphone 14
pharmaceutically acceptable salt.
[0036] The hydromorphone composition provided by the present
invention comprises hydromorphone 14 blended with a
pharmaceutically acceptable hydrogel polymer 16, represented by
dashes. Representative polymer hydrogels comprise a maltodextrin
polymer comprising the formula
(C.sub.6H.sub.12O.sub.5).sub..lamda.H.sub.2O, wherein .lamda. is 3
to 7,500, and the maltodextrin polymer comprises a 500 to 1,250,000
number-average molecular weight; a poly(alkylene oxide) represented
by a poly(ethylene oxide) and a poly(propylene oxide) having a
50,000 to 750,000 weight-average molecular weight, and more
specifically represented by a poly(ethylene oxide) of at least one
of 100,000, 200,000, 300,000 or 400,000 weight-average molecular
weights; an alkali carboxyalkylcellulose, wherein the alkali is
sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl
of 10,000 to 175,000 weight-average molecular weight; and a
copolymer of ethylene-acrylic acid, including methacrylic and
ethacrylic acid of 10,000 to 500,000 number-average molecular
weight. The therapeutic composition comprises 20 to 375 mg of a
polymer hydrogel. The therapeutic composition can be manufactured
into dosage form 10, and or can be used as the therapeutic
composition for its therapeutic effect.
[0037] Dosage form 10 comprises a therapeutically acceptable vinyl
polymer represented by vertical dashes 17. The vinyl-polymer
comprises a 5,000 to 350,000 viscosity-average molecular weight,
represented by a member selected from the group consisting of
poly-n-vinylamide, poly-n-vinylacetamide, poly(vinyl pyrrolidone),
also known as poly-n-vinylpyrrolidone, poly-n-vinylcaprolactone,
poly-n-vinyl-5-methyl-2-pyrrolidone, and poly-n-vinyl-pyrrolidone
copolymers with a member selected from the group consisting of
vinyl acetate, vinyl alcohol, vinyl chloride, vinyl fluoride, vinyl
butyrate, vinyl laureate, and vinyl stearate. The dosage form 10,
and the therapeutic composition comprises 0.01 to 25 mg of the
binder or vinyl polymer, that serves as a binder. Representative of
other binders include: acaia, starch, gelatin, and
hydroxypropylalkylcellulose of 9,200 to 250,000 molecular
weight.
[0038] The dosage form comprises a lubricant 18 represented by a
wavy line. The lubricant is used during manufacture to prevent
sticking to die walls or punch faces. Typical lubricants include:
magnesium stearate, sodium stearate, stearic acid, calcium
stearate, magnesium oleate, oleic acid, potassium oleate, caprylic
acid, sodium stearyl fumarate, and magnesium palmitate. The amount
of lubricant present in the therapeutic composition is 0.01 mg to
10 mg.
[0039] Drawing FIG. 3 depicts dosage form 10 in opened section,
illustrating internal compartment 15. Internal compartment 15
comprises therapeutic composition containing hydromorphone 14,
described in detail in drawing FIG. 2. The therapeutic composition
of drawing FIG. 2 is identified in drawing FIG. 3 as layer 20 or
therapeutic hydromorphone layer 20. Layer 20 comprises the
ingredients described in drawing FIG. 2 and the details previously
disclosed are included in this description of drawing FIG. 3. Layer
20 in drawing FIG. 3 initially is in contact with expandable layer
21.
[0040] Expandable layer 21 comprises 20 mg to 375 mg of an
expandable osmopolymer 22, represented by "V". The osmopolymer 22
in layer 21 possesses a higher molecular weight than osmopolymer 16
in the therapeutic hydromorphone composition. The osmopolymer 22
comprises a member selected from the group consisting of a
polyalkylene oxide and a carboxyalkylcellulose. The polyalkylene
oxide possesses a 1,000,000 to 10,000,000 weight-average molecular
weight. Representative of polyalkylene oxide include a member
selected from the group consisting of polymethylene oxide,
polyethylene oxide, polypropylene oxide, polyethylene oxide having
a 1,000,000 molecular weight, polyethylene oxide comprising a
5,000,000 molecular weight, polyethylene oxide comprising a
7,000,000 molecular weight, cross-linked polymethylene oxide
possessing a 1,000,000 molecular weight, and polypropylene oxide of
1,200,000 molecular weight. Typical osmopolymer 22
carboxyalkylcellulose comprises a member selected from the group
consisting of alkali carboxyalkylcellulose, sodium
carboxymethylcellulose, potassium carboxymethylcellulose, sodium
carboxyethylcellulose, lithium carboxymethylcellulose, sodium
carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose,
carboxymethylhydroxyethyl cellulose, carboxyethylhydroxyethylcellu
lose and carboxymethylhydroxypropylcellulose. The osmopolymers used
for the expandable layer exhibit an osmotic pressure gradient
across semipermeable wall 12. The osmopolymers imbibe fluid into
dosage form 10; thereby swelling and expanding as an osmotic
hydrogel (also known as osmogel) whereby, they push the
hydromorphone from the osmotic dosage form. The amount of
osmopolymer 22 in expandable layer 21 is 20 to 375 mg.
[0041] Expandable layer 21 comprises 0 to 75 mg and presently 5 to
75 mg of an osmotically effective compound 23, represented by
circles. The osmotically effective compounds are known also as
osmagents and as osmotically effective solutes. They imbibe an
environmental fluid, for example, from the gastrointestinal tract,
into dosage form 10, for contributing to the delivery kinetics of
expandable layer 21. Representative of osmotically active compounds
comprise a member selected from the group consisting of osmotic
salts, and osmotic carbohydrates. Representative of specific
osmagents include sodium chloride, potassium chloride, magnesium
sulfate, lithium phosphate, lithium chloride, sodium phosphate,
potassium sulfate, sodium sulfate, potassium phosphate, glucose,
fructose and maltose.
[0042] Expandable layer 21 comprises 1 to 75 mg of a
Hydropropylalkylcellulose, represented by triangles. The
hydroxypropylalkylcellulose possesses a 9,000 to 450,000
number-average molecular weight. The hydroxypropylalkylcellulose is
represented by a member selected from the group consisting of
hydroxypropylmethylcellulose, hydroxypropylethylcellulose,
hydroxypropylisopropylcellulose, hydroxypropylbutylcellulose, and
hydroxypropylpentylcellulose. Expandable layer 21 optionally
comprises a hydroxyalkylcellulose, also represented by triangles.
The hydroxyalkylcellulose comprises a member selected from the
group consisting of hydroxymethylcellulose, hydroxyethylcellulose,
hydroxypropylcellulose, and hydroxybutylcellulose comprising a
7,500 to 150,000 viscosity-average molecular weight. The amount of
hydroxyalkylcellulose in the layer is 0.00 mg to 40 mg.
[0043] Expandable layer 21 comprises 0 to 5 mg of a nontoxic
colorant or dye 25, identified by vertical wave lines. Colorant 25
includes Food and Drug Administration Colorant (FD&C), such as
FD&C No. 1 blue dye, FD&C No. 4 red dye, red ferric oxide,
yellow ferric oxide, titanium dioxide, carbon black, and indigo. A
lubricant 26, identified by half circles, is formulated into
expandable layer 21. Typical lubricants, comprise a member selected
from the group consisting of sodium stearate, potassium stearate,
magnesium stearate, stearic acid, calcium stearate, sodium oleate,
calcium palmitate, sodium laurate, sodium ricinoleate, and
potassium linoleate. The concentrate of lubricant is 0.01 to 10
mg.
[0044] An antioxidant 27, represented by slanted dashes, is present
in expandable formulation 21 to inhibit the oxidation of
ingredients comprising expandable formulation 21. Expandable
formulation 21 comprises 0.00 to 5 mg of an antioxidant.
Representative antioxidants comprise a member selected from the
group consisting of ascorbic acid, ascorbyl palmitate, butylated
hydroxyanisole, a mixture of 2 and 3
tertiary-butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium
isoascorbate, dihydroguaretic acid, potassium sorbate, sodium
bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate,
vitamin E, 4-chloro-2,6-ditertiary butylphenol, alphatocopherol,
and propylgallate.
[0045] Dosage form 10, as seen in drawing FIG. 4, depicts another
manufacture provided by the invention. Dosage form 10 comprises an
overcoat 28 on the outer surface of wall 12 of dosage form 10. The
overcoat 28 is a therapeutic composition comprising 0.5 to 75 mg of
hydromorphone 14 and 0.5 to 275 mg of a pharmaceutically acceptable
carrier selected from the group consisting of alkylcellulose,
hydroxyalkylcellulose and hydroxypropylalkylcellulose. The overcoat
is represented by methylcellulose, hydroxyethylcellulose,
hydroxybutylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxypropylethylcellulose and
hydroxypropylbutylcellulose. Overcoat 28 provides therapy
immediately as overcoat 28 dissolves or undergoes dissolution in
the presence of gastrointestinal fluid and concurrently therewith
delivers hydromorphone 14 into the gastrointestinal tract for
immediate hydromorphone therapy.
[0046] Dosage form 10, manufactured as an osmotically
controlled-release dosage form, comprises at least one passageway
13. The phrase "controlled-release" as used herein indicates that
control is exercised over both the duration and the profile of the
hydromorphone release pattern. The expression "passageway" as used
for the purpose of this invention, includes aperture, orifice,
bore, pore, porous element through which hydromorphone drug 14 can
be pumped, diffuse or migrate through a fiber, capillary tube,
porous overlay, porous insert, microporous member, and porous
composition. The passageway 13 includes also a compound that erodes
or is leached from wall 12 in the fluid environment of use to
produce at least one passageway. Representative compounds for
forming a passageway include erodible poly(glycolic) acid, or
poly(lactic) acid in the wall; a gelatinous filament; a
water-removable poly(vinyl alcohol); leachable compounds such as
fluid-removable pore-forming polysaccharides, acids, salts or
oxides. A passageway can be formed by leaching a compound from wall
12, such as sorbitol, sucrose, lactose, maltose, or fructose, to
form a controlled-release dimensional pore-passageway. The
passageway can have any shape, such as round, triangular, square
and elliptical, for assisting in the controlled-metered release of
hydromorphone 14 from the dosage form. The dosage form can be
manufactured with one or more passageways in spaced-apart relation
on one or more surfaces of the dosage form. A passageway and
equipment for forming a passageway are disclosed in U.S. Pat. Nos.
3,845,770 and 3,916,899 by Theeuwes and Higuchi; in U.S. Pat. No.
4,063,064 by Saunders et al.; and in U.S. Pat. No. 4,088,864 by
Theeuwes et al. Passageways comprising controlled-release
dimensions sized, shaped and adapted as a releasing-pore formed by
aqueous leaching to provide a releasing-pore of a
controlled-release rate are disclosed in U.S. Pat. Nos. 4,200,098
and 4,285,987 by Ayer and Theeuwes.
Process for Providing the Invention
[0047] Wall 12 of dosage form 10 is manufactured in one process
comprising an air suspension process. This process consists in
suspending and tumbling a compressed drug core comprising a
single-layered core or a bilayered core in a current of air and
wall-forming composition until a wall is applied to the
single-layered core or the bilayered core. The air suspension
procedure is well suited for independently forming the wall. The
air suspension procedure is described in U.S. Pat. No. 2,799,241; J
Amer Pharm Assoc, Vol. 48, pp. 451-454 (1959); and ibid.; Vol. 49,
pp. 82-84 (1960). Dosage form 10 can be coated also with a
wall-forming composition in an air suspension coater using a
solvent, such as a methylene dichloride-methanol cosolvent
comprising 80:20 wt:wt, or an ethanol-water cosolvent, or an
acetone-water cosolvent consisting of 95:5 wt:wt using 2.5 to 4%
solvents.
[0048] An air suspension coater using a methylene
dichloride-methanol cosolvent, for example, 80:20 wt:wt, can be
used for applying the wall. Other wall-forming techniques, such as
a pan-coating system wherein wall-forming compositions are
deposited by successive spraying of the drug-core composition to
provide a wall that defines and surrounds a compartment,
accompanied by tumbling in a rotating pan. Finally, the wall-coated
cores are dried in an oven, forced or nonforced air oven, at
30-50.degree. C. for up to a week to free the dosage form of
solvent. The walls formed by these techniques have a thickness of 1
to 30 mils (0.0254 to 0.762 mm).
[0049] Dosage form 10 of the invention is manufactured by other
manufacturing techniques. For example, in one manufacture the drug
and other core-forming ingredients comprising a single drug layer
or bilayer core with drug facing the exit means 13 are blended and
pressed into a solid layer or a solid bilayer. The drug and other
ingredients can be dry-blended or blended with a solvent and mixed
into a solid or semisolid formed by conventional methods such as
ball-milling, calendaring, stirring, roll-milling, or churning, and
can then be pressed into a preselected shape. The layer possesses
dimensions that correspond to the internal dimensions of the area
the single layer occupies in the dosage form, or in a bilayer where
it also possesses dimensions corresponding to the first and second
layer for forming a contacting arrangement therewith. In a
bilayered core, the push layer is placed in contact with the drug
layer. The push layer is manufactured using techniques for
providing the drug layer. The layering of the drug layer and the
push layer can be fabricated by conventional press-layering
techniques. Finally, a single layer or a two-layer compartment
forming members are surrounded and coated with an exterior wall. A
passageway is provided, such as by laser or mechanically drilled
through the wall to contact the drug layer. When the passageway is
formed by a laser, the dosage form is optically oriented
automatically by the laser equipment for forming the passageway on
the preselected surface for forming the passageway.
[0050] In another manufacture, dosage form 10 is manufactured by a
granulation technique. Granulation is a process of size enlargement
whereby small particles are gathered into larger aggregates in
which the original particles can still be identified. Granulation
can be divided into a dry method, wherein no liquid is used for the
aggregation, or into a wet method, wherein a liquid is used for
granule agglomeration of powder particles followed by a drying
process. Granulation is reported in Encyclopedia of Pharmaceutical
Technology, Vol. 7, pp. 121-160, (1993), published by Marcel
Dekker, Inc. In the wet granulation technique, for example, the
drug and other ingredients comprising the composition or
drug-forming layer, or the drug-forming expandable bilayer core are
blended using a solvent, such as ethyl alcohol-water 98:2 v:v
(volume:volume) as the granulation fluid. Other granulating fluid,
such as denatured alcohol 100%, can be used for this purpose. The
ingredients forming the drug core or bilayers are individually
passed through a mesh screen, such as a U.S. Sieve Series screen,
and then thoroughly blended in a mixer. Other ingredients
comprising the layer or layers are dissolved in a portion of the
granulation fluid, such as the cosolvent described above. Then, the
latter prepared wet blend is added slowly to the drug blend with
continual mixing in the blender. The granulating fluid is added
until a wet blend is produced, which wet mass is then forced
through a mesh screen onto oven trays. The blend is dried for 18 to
24 hours at 30-50.degree. C. The dry granules are then sized with a
mesh screen. Next, a lubricant is passed through a screen and added
to the dry screen granule blend. The granulation is placed in a
blender and blended for 1 to 15 minutes. A push layer is made by
the same wet granulation, which consists in suspending and tumbling
the 9 two contacting layers in a current of air until the
wall-forming composition surrounds the layers. The air suspension
procedure is described in U.S. Pat. No. 2,799,241; J Amer Pharm
Assoc, Vol. 48, pp. 451-454 (1979); and ibid., Vol. 49, pp. 82-84
(1960). Other standard manufacturing procedures are described in
Modern Plastics Encyclopedia, Vol. 46, pp. 62-70 (1969); and
Pharmaceutical Sciences, Remington, 14th Ed., pp. 1626-1678 (1970),
Mack Publishing Co., Easton, Pa. Granulation techniques are
described in ibid., pp. 1655-1660 (1970).
[0051] Exemplary solvents suitable for manufacturing the wall, a
single layer and a bilayer include inert inorganic and organic
solvents. The solvents include members selected from the group
consisting of aqueous solvents, alcohols, ketones, esters, ethers,
aliphatic hydrocarbons, halogenated solvents, cycloaliphatics,
aromatics, heterocyclic solvents, and mixtures thereof. Typical
solvents include acetone, diacetone, alcohol, methanol, ethanol,
isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate,
isopropyl acetate, n-butyl acetate, methyl isobutyl ketone, methyl
propyl ketone, n-hexane, n-heptane, ethylene glycol monoethyl
ether, ethylene glycol monoethyl acetate, methylene dichloride,
ethylene dichloride, propylene dichloride, carbon tetrachloride,
chloroform, nitroethane, nitropropane, tetrachloroethane, ethyl
ether, isopropyl ether, cyclohexane, cyclooctane, benzene, toluene,
naphtha, tetrahydrofuran, diglyme, aqueous and nonaqueous mixtures
thereof, such as acetone and water, acetone and methanol, acetone
and ethyl alcohol, methylene dichloride and methanol, and ethylene
dichloride and methanol.
DESCRIPTION OF EXAMPLES OF THE INVENTION
[0052] The following examples are illustrative of the present
invention and they should not be considered as limiting the scope
of the invention in any way, as these examples and other
equivalents thereof will become apparent to those versed in the art
in light of the present disclosure, drawings and accompanying
claims.
Example 1
[0053] A novel therapeutic composition comprising hydromorphone,
wherein the hydromorphone is a member selected from the group
consisting of hydromorphone pharmaceutically acceptable base and
hydromorphone pharmaceutically acceptable salt, is prepared as
follows: First, 175 g of hydromorphone hydrochloride, 647.5 g of
poly(ethylene oxide) possessing a 200,000 molecular weight, and
43.75 g of poly(vinyl pyrrolidone) having an average-molecular
weight of 40,000 are added to planetary mixing bowl and the
ingredients dry mixed for ten minutes. Then, 331 g of denatured
anhydrous alcohol is slowly added to the blended ingredients, with
continuous blending for approximately ten minutes. Next, the
freshly prepared wet granulation is passed through a 20-mesh
screen, allowed to dry at 25.degree. C. for about 20 hours, and
then passed through a 16-mesh screen. Next, the granulation is
transferred to the planetary mixer and lubricated with 8.75 g of
magnesium stearate to produce a therapeutic hydromorphone
composition. The composition is compressed into tablets comprising
35 mg of hydromorphone hydrochloride. The tablets are compressed
under 8.5 tons of pressure to provide extended-release
hydromorphone hydrochloride tablets.
Example 2
[0054] The therapeutic compositions manufactured by following the
above example provide compositions comprising 1 to 500 mg of a
member selected from the group consisting of hydromorphone,
hydromorphone base, hydromorphone salt and hydromorphone
derivative; at least one polymeric carrier for the hydromorphone
selected from 20 to 375 mg of poly(alkylene oxide) comprising a
50,000 to 750,000 molecular weight represented by poly(methylene
oxide), poly(ethylene oxide), poly(propylene oxide),
poly(isopropylene oxide) and poly(butylene oxide), or a polymeric
carrier for the hydromorphone consisting of 20 to 375 mg of
carboxymethylcellulose having a 10,000 to 175,000 molecular weight
represented by a member selected from the group consisting of
alkali carboxymethylcellulose, sodium carboxymethylcellulose and
potassium carboxymethylcellulose; 0.01 to 25 mg of poly(vinyl)
polymer possessing a 5,000 to 350,000 molecular weight represented
by poly(vinyl pyrrolidone), copolymer of poly(vinyl pyrrolidone and
vinyl acetate), copolymer of poly(vinyl pyrrolidone and vinyl
alcohol), copolymer of poly(vinyl pyrrolidone and vinyl chloride),
copolymer of poly(vinyl pyrrolidone and vinyl fluoride), copolymer
of poly(vinyl pyrrolidone and vinyl butyrate), copolymer of
poly(vinyl pyrrolidone and vinyl laureate), and copolymer of
poly(vinyl pyrrolidone with vinyl stearate); and 0 to 10 mg of a
lubricant represented by a member selected from the group
consisting of magnesium stearate, calcium stearate, potassium
oleate, sodium stearate, stearic acid and sodium palmitate. The
therapeutic composition may contain other ingredients, for example,
colorants, compression aids and binders. The composition can be
compressed at 1/4 to 10-ton force to yield an orally administrable
tablet comprising hydromorphone.
Example 3
[0055] The therapeutic composition provided by the invention can be
dry compressed into an orally administrable dosage form. For
example, a mixture of dry-powder ingredients comprising a
hydromorphone pharmaceutically acceptable base or a hydromorphone
pharmaceutically acceptable salt as represented by: hydrochloride,
hydrobromide, sulfate, bisulfate, acetate, valerate, oxalate,
oleate, laureate, borate, benzoate, lactate, phosphate, tosylate,
citrate, maleate, fumarate, succinate, tartrate and napsylate; a
tablet excipient represented by 0 to 200 mg of microcrystalline
cellulose; 20 to 375 mg of sodium carboxymethylcellulose of 10,000
to 175,000 molecular weight; 0.01 to 25 mg of a binder agent
represented by poly(vinyl pyrrolidone) of 5,000 to 350,000
molecular weight, a hydroxypropylmethylcellulose of 9,200 to 75,000
molecular weight, and gelatin; and 0 to 10 mg of a lubricant, such
as stearic acid, calcium stearate or magnesium stearate; are dried,
sieved and mixed with other optional ingredients, such as a
surfactant and a flavoring agent, then fed to a tablet press and
compressed to yield dry-compressed hydromorphone tablets for oral
administration to a patient in need of hydromorphone analgesic pain
relief. In a manufacture provided by the invention a therapeutic
composition made by wet-granulation or dry-granulation processes
can be surrounded with a semipermeable, polymeric wall. The
semipermeable wall is pervious to fluid, impervious to
hydromorphone, and an exit means, such as a passageway through the
semipermeable wall, provides for the delivery of hydromorphone at a
controlled-sustained rate through the exit means over time.
Example 4
[0056] A dosage form, adapted, designed and shaped as an osmotic
drug delivery device is manufactured as follows: First, 175 g of
hydromorphone hydrochloride, 647.5 g of poly(ethylene oxide)
possessing a 200,000 molecular weight, and 43.75 g of poly(vinyl
pyrrolidone) having a 40,000 molecular weight are added to a mixer
and mixed for ten minutes. Then, 331 g of denatured anhydrous
alcohol is added to the blended materials, with continuous mixing
for ten minutes. Then, the wet granulation is passed through a
20-mesh screen, allowed to dry at room temperature for 20 hours,
and then passed through a 16-mesh screen. Next, the granulation is
transferred to the mixer, mixed, and lubricated with 8.75 g of
magnesium stearate.
[0057] Then, a displacement or push composition for pushing the
therapeutic hydromorphone composition from the dosage form is
prepared as follows: First, 3910 g of hydroxypropylmethylcellulose
possessing a 11,200 molecular weight is dissolved in 45,339 g of
water. Then, 101 g of butylated hydroxytoluene is dissolved in 650
g of denatured anhydrous alcohol. Next, 2.5 kg of the
hydroxypropylmethylcellulose aqueous solution is added, with
continuous mixing, to the butylated hydroxytoluene alcohol
solution. Then, the binder solution preparation is completed by
adding, with continuous mixing, the remaining
hydroxypropylmethylcellulose aqueous solution to the butylated
hydroxytoluene alcohol solution.
[0058] Next, 36,000 g of sodium chloride is sized using a mill
equipped with a 21-mesh screen. Then, 1200 g of ferric oxide is
passed through a 40-mesh screen. Then, the screened materials,
76,400 g of pharmaceutically acceptable poly(ethylene oxide)
possessing a 7,500,000 molecular weight, and 2500 g of
hydroxypropylmethylcellulose having a 11,200 molecular weight are
added to the bowl of a fluid bed granulator. The bowl is attached
to the granulator and the granulation process is initiated for
effecting granulation. Next, the dry powders are air suspended and
mixed for ten minutes. Then, the binder solution is sprayed from
three nozzles onto the powder. The granulating is monitored during
the process as follows: total solution spray rate of 800 g/min;
inlet temperature of 43.degree. C.; and an air flow of 4300
m.sup.3/hr. At the end of the solution spraying process, 45,033 g
of the coated, granulated particles are dried for 35 minutes at
room temperature. The granules are sized using a mill with a 8-mesh
screen. The granulation is transferred to a tumbler, mixed, and
lubricated with 281.7 g of magnesium stearate.
[0059] Next, the drug composition comprising the hydromorphone
hydrochloride and the push composition is compressed into bilayer
tablets on a tablet press. First, 176 mg of the hydromorphone
hydrochloride composition is added to the die cavity and
precompressed. Then, 135 mg of the push composition is added, and
the layers are pressed under a pressure head of 3-metric tons into
a 11/32 in. (0.873 cm) diameter, contacting layer arrangement.
[0060] The bilayered arrangements are coated with a semipermeable
wall. The wall-forming composition comprises 100% cellulose acetate
having a 39.8% acetyl content. The wall-forming composition is
dissolved in acetone:water (95:5 wt:wt) cosolvent to make a
4%-solid solution. The wall-forming composition is sprayed onto and
around the bilayers in a 24-inch coater.
[0061] Next, one 20 mil (0.508 mm) exit passageway is drilled
through the semipermeable wall to connect the drug hydromorphone
layer with the exterior of the dosage form. The residual solvent is
removed by drying for 72 hours at 45.degree. C. and 45% humidity.
Next, the osmotic dosage systems are dried for four hours at
45.degree. C. to remove excess moisture. The dosage form produced
by this manufacture comprises 35.20 mg of hydromorphone
hydrochloride, 130.24 mg of poly(ethylene oxide) of 200,000
molecular weight, 8.80 mg of poly(vinyl pyrrolidone) of 40,000
molecular weight, and 1.76 mg of magnesium stearate. The push
composition comprises 85.96 mg of poly(ethylene oxide) of 7,500,000
molecular weight, 40.50 mg of sodium chloride, 6.75 mg of
hydroxypropylmethylcellulose, 1.35 mg of red ferric oxide, 0.34 mg
of magnesium stearate, and 0.10 mg of butylated hydroyxtoluene. The
semipermeable wall comprises 38.6 mg of cellulose acetate
comprising a 39.8% acetyl content. The dosage form comprises one 20
mil (0.508 mm) passageway, and the dosage form has a hydromorphone
hydrochloride mean release rate of 1.6 mg/hr over an extended
period of 28 hours.
Example 5
[0062] The procedure of Example 4 is followed, with all
manufacturing procedures as described, except in this example the
hydroxypropylmethylcellulose is replaced by a
hydroxypropylmethylcellulose having a 300,000 molecular weight.
Example 6
[0063] The procedure of Example 4 is followed, with all
manufacturing procedures as described, except in this example the
poly(ethylene oxide) in the hydromorphone drug composition is
replaced by a sodium carboxymethylcellulose possessing a 175,000
molecular weight, and the poly(ethylene oxide) in the push
composition is replaced by a sodium carboxymethylcellulose
possessing a 700,000 molecular weight. In an inventive embodiment,
the alkali carboxymethylcellulose present in the push composition
possesses a greater molecular weight than the alkali
carboxymethylcellulose of the hydromorphone drug composition.
Example 7
[0064] The dosage form prepared by the above examples can be
manufactured with a semipermeable wall composition comprising 65 to
100 wt % of a cellulose polymer comprising a member selected from
the group consisting of: cellulose ester, cellulose diester,
cellulose triester, cellulose ether, cellulose ester-ether,
cellulose acylate, cellulose diacylate, cellulose triacetate,
cellulose acetate butyrate, and the like. The wall can also
comprise from 0 to 40 wt % of a cellulose ether selected from the
group consisting of: hydroxypropylcellulose,
hydroxypropylmethylcellulose, hydroxypropylethylcellulose,
hydroxypropylbutylcellulose and hydroxypropylpentylcellulose. The
wall can further comprise 0 to 20 wt % of polyethylene glycol. The
total amount of all components comprising the wall is equal to 100
wt %. Semipermeable polymers are disclosed in U.S. Pat. Nos.
3,845,000, 3,916,899, 4,008,719, 4,036,228 and 4,111,201. These
patents are assigned to the ALZA Corporation of Palo Alto, Calif.,
the assignee of this patent application.
[0065] In another manufacture, the wall can be prepared according
to the above examples comprising the selectively permeable
cellulose ether: ethyl cellulose. The ethyl cellulose comprises an
ethoxy group with a degree of substitution (DS) of about 1.4 to 3,
equivalent to 40 to 50% ethoxy content, and a viscosity range of 7
to 100 centipoise or higher. A representative wall comprises 45 to
80 wt % ethylcellulose, from 5 to 30 wt % hydroxypropylcellulose,
and from 5 to 30 wt % polyethylene glycol, with the total amount of
all components comprising the wall equal to 100 wt %. In another
manufacture, the wall comprises 45 to 80 wt % ethylcellulose, 5 to
30 wt % hydroxypropylcellulose, and 2 to 20 wt % poly(vinyl
pyrrolidone). The total amount of all components comprising the
wall is equal to 100 wt %. The ethylcellulose polymer is known in
U.S. Pat. No. 4,519,801, assigned to the ALZA Corporation of Palo
Alto, Calif.
Example 8
[0066] The dosage form provided by the invention comprises a
hydromorphone drug composition consisting of 1 to 500 mg of
hydromorphone, hydromorphone base, hydromorphone salt or
hydromorphone derivative; at least one of 20 to 375 mg of
poly(alkylene oxide) of 50,000 to 750,000 molecular weight, or 25
to 375 mg of a carboxymethylcellulose of 10,000 to 175,000
molecular weight; at least one of 0.01 to 25 mg of a poly(vinyl
pyrrolidone) of 5,000 to 350,000 molecular weight, or 0 to 50 mg of
a hydroxypropylcellulose or hydroxypropylalkylcellulose of 7,500 to
75,000 molecular weight; and 0.01 to 10 mg of a lubricant, such as
magnesium stearate.
[0067] The dosage form provided by the invention comprises a push
composition consisting of at least one of 20 to 375 mg of a
poly(alkylene oxide) of 1,000,000 to 10,000,000 molecular weight,
or 20 to 425 mg of a carboxymethylcellulose, such as sodium
carboxymethylcellulose, and a potassium carboxymethylcellulose of
200,000 to 7,500,000, molecular weight; 0 to 75 mg of an osmagent,
also known as osmotically effective solute, represented by
magnesium sulfate, sodium chloride, lithium chloride, potassium
sulfate, sodium sulfate, lithium sulfate, potassium acid phosphate,
1 mannitol, urea, inositol, magnesium succinate, tartaric acid,
carbohydrates such as raffinose, sucrose, glucose, lactose,
fructose, sodium chloride and fructose, potassium chloride and
dextrose; 1 to 75 mg of a hydroxyalkylcellulose selected from the
group consisting of hydroethylcellulose, hydroxypropylcellulose,
hydroxyisopropylcellulose, hydroxybutylcellulose,
hydroxypropylmethylcellulose, hydroxypropylethylcellulose, and
hydroxypropylbutylcellulose, which hydroxyalkylcellulose comprises
a 9,000 to 450,000 molecular weight; 0 to 10 mg of an antioxidant
represented by d-alpha tocopherol acetate, di-alpha tocopherol,
ascorbyl palmitate, butylated hydroxyanisole, butylated
hydroxytoluene and propyl gallate; 0 to 10 mg of a lubricant
represented by magnesium stearate, calcium stearate, corn starch,
potato starch, bentonite, citrus pulp, and stearic acid; and 0 to
10 mg of a colorant.
Examples 9-12
[0068] Dosage forms are provided by following the above procedures
comprising the following: (A) A dosage form with a drug layer
comprising 8 mg of hydromorphone hydrochloride, 67.8 mg of
poly(ethylene oxide) possessing a 200,000 molecular weight, 4 mg of
poly(vinyl pyrrolidone) of 42,000 molecular weight, and 0.8 mg of
magnesium stearate; a hydrogel, expandable layer comprising 37.80
mg of poly(ethylene oxide) possessing a 2,000,000 molecular weight,
30 mg of osmagent sodium chloride, 3 mg of
hydroxypropylmethylcellulose of 9,200 molecular weight, 0.6 mg of
red ferric oxide, and 0.15 mg of lubricant magnesium stearate; a
semipermeable wall comprising 27.2 mg of cellulose acetate of 39.8%
acetyl content, and 0.275 mg of polyethylene glycol of 3,350
molecular weight; a mean release rate of 0.427 mg/hr for 17.3
hours; and a 25 mil (0.635 mm) passageway; (B) a dosage form with a
hydromorphone drug layer comprising 32 mg of hydromorphone
hydrochloride, 119.6 mg of poly(ethylene oxide) possessing a
200,000 molecular weight, 8 mg of poly(vinyl pyrrolidone) of 42,000
molecular weight, and 0.4 mg of magnesium stearate; an expandable
layer comprising 76.49 mg of hydrogel poly(ethylene oxide) of
2,000,000 molecular weight, 36 mg of osmagent sodium chloride, 6 mg
of hydroxypropylmethyl-cellulose of 9,200 molecular weight, 1.2 mg
of red ferric oxide, and 0.012 mg of butylated hydroxytoluene
antioxidant; a semipermeable wall comprising 29.6 mg of cellulose
acetate comprising an acetyl content of 39.8%, and 0.29 mg of
polyethylene glycol of 3,350 molecular weight; a hydromorphone
controlled-release rate of 1.811 mg/hr for 16.1 hours; and a 25 mil
(0.635 mm) passageway; (C) a dosage form comprising a hydromorphone
drug layer comprising 64.0 mg of hydromorphone hydrochloride, 138.6
mg of poly(ethylene oxide) of 200,000 molecular weight, and 0.53 mg
of lubricant magnesium stearate; a delivery layer comprising
104.533 mg of poly(ethylene oxide) of 2,000,000 molecular weight,
49.2 mg of osmagent sodium chloride, 8.2 mg of
hydroxypropylmethylcellulose of 9,200 molecular weight, 1.64 mg of
red ferric oxide colorant, 0.41 mg of magnesium stearate lubricant,
and 0.0164 mg of antioxidant butylated hydroxytoluene; a
semipermeable wall comprising 38.61 mg of cellulose acetate
comprising a 39.8% acetyl content and 0.39 mg of polyethylene
glycol of 3,350 molecular weight; a controlled rate of release of
3.77 mg/hr over an extended period of 15.3 hours; and a 25 mil
(0.635 mm) passageway for delivering the hydromorphone from the
dosage form; and (D) a dosage form comprising 16 mg of
hydromorphone hydrochloride, 135.6 mg of poly(ethylene oxide) of
200,000 molecular weight, 8 mg of poly(vinyl pyrrolidone) of 42,000
molecular weight, and 0.4 mg of lubricant magnesium stearate; a
hydrogel delivery layer comprising 76.49 mg of poly(ethylene oxide)
of 2,000,000 molecular weight, 36 mg of osmagent sodium chloride, 6
mg of hydroxypropylmethylcellulose, 1.2 mg of black ferric oxide
colorant, 0.3 mg of magnesium stearate lubricant, 0.12 mg of
antioxidant butylated hydroxytoluene; a semipermeable wall
comprising 27.52 mg of cellulose acetate of 39.8% acetyl content,
and 0.27 mg of polyethylene glycol of 3,350 molecular weight; a
controlled release rate of 0.957 mg/hr for 15.0 hours; and a 25 mil
(0.635 mm) passageway.
Example 13
[0069] A dosage form is provided by following the above teachings,
wherein the dosage form delivers 0.4 to 3.7 mg/hr at a controlled
rate, over an extended time up to 24 hours, to provide
hydromorphone to a patient in need of same.
Example 14
[0070] The dosage form prepared according to Example 13, wherein
the dosage form comprises 10 to 100 mg of hydromorphone.
Example 15
[0071] A dosage form is provided by following the above disclosure,
wherein the dosage form comprises 2 to 75 mg of hydromorphone that
is administered over 24 hours to produce from greater than zero ng
to 10 ng/ml of plasma, generally from 0.01 ng to 10 ng/ml, for
producing a plasma hydromorphone concentration.
Example 16
[0072] A dosage form adapted, designed and shaped as an osmotic
drug delivery device is manufactured as follows: first, sublots of
drug granulation were manufactured as follows: first, 2000 g of
hydromorphone hydrochloride, 16,950 g of a pharmaceutically
acceptable poly(ethylene oxide) comprising a 200,000 average
molecular weight, 900 g of poly(vinyl-pyrrolidone) of 40,000
average molecular weight, are added to the bowl of a granulator,
and the ingredients granulated to yield the granulation. Next, the
dry granulated powders were all suspended and mixed thoroughly for
three minutes. Then, a solution was prepared by dissolving 120 g of
poly(vinylpyrrolidone) of 40,000 average molecular weight in 5,800
g of anhydrous ethyl alcohol and the solution sprayed onto the
powder with mixing in a granulator bowl. The granulation is mixed
for twenty minutes with constant addition of the solution. Then,
the granulation is dried under vacuum to a moisture content of
below 1.5%. The granulating conditions were as follows: a solution
spray rate of 200 g/min; bowl temperature 25.degree. C.; vacuum
between 40 and 80 millibar. The granules were sized in a fluid air
mill with a 7 mesh screen (2.81 mm). The screen are U.S. Series, in
Perry's Chemical Engineers' Handbook, Sixth Edition, pp 21-15,
Table 21-6, (1984).
[0073] Next, the granulation was transferred to a tumbler and
lubricated with mixing with 142 of magnesium stearate.
[0074] Next, a push composition was prepared as follows: first, a
binder solution is prepared by dissolving 4000 g of
hydroxypropylmethylcellulose of 11,200 average molecular weight in
46,000 g of water. Then, 36,000 g of sodium chloride osmagent was
sized in a mill equipped with a 21 mesh screen. Then, 1200 g of
ferric oxide was passed through a 40 mesh screen. Then, all the
screened materials, and 76,400 g of pharmaceutically acceptable
poly(ethylene oxide) comprising a 2,000,000 molecular weight, 2516
g of hydroxypropylmethylcellulose comprising an 11,200 average
molecular weight were added to a fluid bed granulator bowl, and the
ingredients granulated to effect the process. The dry powders were
an suspended next, and mixed for 10 minutes. Then, the binder
solution was sprayed onto the powders at a rate of 700 g/min, at a
temperature of 25.degree. C., and at an air flow between 500 and
4000 m.sup.3/hr.
[0075] Next, at the end of the solution spraying, 43,550 g of the
granulated granules were dried for 20 minutes. Then, the granules
were sized in a mill equipped with a 7 mesh screen. Then, the
granulation was transferred to a tumbler and mixed with 88.2 g of
butylated hydroxytoluene and then mixed with 294 g of magnesium
stearate.
[0076] Next, the hydromorphone hydrochloride drug composition and
the push composition were compressed into bilayered tablets on a
tablet press. First, 80 mg of hydromorphone hydrochloride
composition was added to a die cavity and pre-compressed. Then, 60
g of the push composition was added and the layers pressed under a
pressure of 1200 pounds into a 9/32 inch (0.71 cm) round-contacting
layered arrangement.
[0077] Next, the bilayered arrangements were coated with a
semipermeable wall. The wall-forming composition comprises 99%
cellulose acetate having a 39.8% acetyl content, and 1%
polyethylene glycol having a 3350 molecular weight. The
wall-forming composition was dissolved in an acetone:water (96:4
wt:wt) cosolvent to make a 4% solids solution. The wall-forming
composition was sprayed onto and around the bilayers in a coater.
Next, one 25 mil (0.635 mm) exit passageway was drilled through the
semipermeable wall to connect the drug layer with the exterior of
the dosage form. The residual solvent was removed by drying for 96
hours at 45.degree. C. and 45% humidity. The dosage forms were
dried at 4 hours at 45.degree. C. to remove the moisture.
[0078] The dosage form produced by this manufacture provides 10%
hydromorphone hydrochloride, 84.75% poly(ethylene oxide) possessing
a 200,000 molecular weight, 5% poly(vinylpyrrolidone) possessing a
40,000 molecular weight and 0.25% magnesium stearate in the drug
composition. The push composition comprises 63.675% poly(ethylene
oxide) comprising a 2,000,000 molecular weight, 30% sodium
chloride, 5% hydroxypropylmethylcellulose comprising a 11,200
molecular weight, 1% ferric oxide, 0.075% butylated hydroxytoluene
and 0.25% magnesium stearate. The semipermeable wall comprises 99
wt % cellulose acetate comprising a 39.8% acetyl content, and 1%
polyethylene glycol comprising a 3350 molecular weight. The dosage
form comprises one passageway, 2.5 mils (0.635 mm), and the dosage
form had a hydromorphone hydrochloride mean release rate of 0.5
mg/hr.
Examples 17 to 20
[0079] The procedure set forth in Example 16 was repeated to
manufacture dosage forms as follows: (17) a dosage form comprising
a drug layer of 80 mg comprising 8 mg of drug expressed as 10.5%
hydromorphone hydrochloride, 84.23% polyethylene oxide of 200,000
molecular weight, 5% poly(vinylpyrrolidone of 40,000 molecular
weight and 0.25 mg of magnesium stearate; (18) a dosage form
comprising a drug layer of 160 mg comprising 16 mg of hydromorphone
hydrochloride, expressed in percent as 1.0% hydromorphone
hydrochloride, 84.75% poly(ethylene oxide) of 200,000 molecular
weight, and 5% poly(vinylpyrrolidone of 40,000 molecular weight,
and 0.25% magnesium stearate; (19) a dosage form comprising a 160
mg drug layer comprising 32 mg of hydromorphone hydrochloride
expressed as 20% hydromorphone hydrochloride, 74.75% poly(ethylene
oxide) of 200,000 molecular weight, 5% poly(vinylpyrrolidone) of
40,000 molecular weight, and 0.25 mg of magnesium stearate; and
(20) a dosage form comprising a drug composition of 214 mg
comprising 64 mg of hydromorphone with the total drug composition
comprising 30% hydromorphone, 64.75% poly(ethylene oxide) of
200,000 molecular weight, 5% poly(vinylpyrrolidone) of 40,000
molecular weight, and 0.25% magnesium stearate.
[0080] The push layer for the dosage forms of Examples 17, 18, 19,
and 20 weighted 60, 120, 120 and 164 mg respectively. The push
layers of Examples 17, 18, 19 and 20 comprise 64.3% poly(ethylene
oxide of 2,000,000 molecular weight, 30% sodium chloride, 5%
hydroxypropylmethylcellulose of 11,200 molecular weight, 0.075%
butylated hydroxytoluene, 1% ferric oxide, and 0.25% magnesium
stearate.
[0081] The semipermeable wall for the dosage forms of Examples 17,
18, 19 a and 20 comprises 99% cellulose acetate of 39.8% acetyl
content and 1% polyethylene glycol of 3350 molecular weight. The
dosage form comprise a 25 mil push composition as expressed in
weight %. The dosage form optionally comprise a color overcoat,
white, yellow, blue or red.
DISCLOSURE FOR USING THE INVENTION
[0082] The invention also concerns a method for administering 1 to
500 mg of hydromorphone to a patient in need of pain relief. The
method, in one administration, comprises admitting orally into the
patient 1 to 500 mg of a hydromorphone selected from the group
consisting of hydromorphone base or hydromorphone salt that is
administered from a therapeutic composition, or from a dosage form
in an extended-release profile for a 16 mg, a 32 mg or 64 mg total
dose of 0 to 20% in 0 to 4 hrs, 20 to 50% in 0 to 8 hrs, 55 to 85%
in 0 to 14 hrs, and 80 to 100% in 0 to 24 hrs and for an 8 mg
dosage form, no more than 20 to 50% in 0 to 8 hrs, no more than 55
to 85% in 0 to 14 hrs, and no less than 75 to 100% in 0 to 24
hrs.
[0083] The invention also concerns a method for administering 1 to
500 mg of hydromorphone to a patient. The method comprises
admitting orally 1 to 500 mg of hydromorphone to the patient, which
is administered from a dosage form comprising a semipermeable wall
permeable to aqueous-biological fluid and impervious to the passage
of hydromorphone. The semipermeable wall surrounds an internal
space or compartment comprising a hydromorphone drug composition
and a push composition. The hydromorphone drug composition
comprises 1 to 500 mg of hydromorphone, 20 to 375 mg of
poly(alkylene oxide) having a 50,000 to 750,000 molecular weight,
0.01 to 25 mg of poly(vinylpyrrolidone) having a 5,000 to 350,000
molecular weight, and 0 to 10 mg of a lubricant. The push
composition comprises 20 to 375 mg of a hydrogel polymer, such as a
poly(alkylene oxide) of 1,000,000 to 10,000,000 molecular weight, 0
to 75 mg of an osmagent, 0 to 75 mg of hydroxyalkylcellulose, 0.01
to 5.5 mg of a colorant, 0.01 to 10 mg of a lubricant, and 0 to 10
mg of an antioxidant; and exit means in the semipermeable wall for
delivering the hydromorphone from the dosage form by imbibing fluid
through the semipermeable wall into the dosage form, causing the
hydromorphone composition to become dispensable and causing the
push composition to expand and push the hydromorphone composition
through the exit, whereby, through the combined operations of the
dosage form, the hydromorphone is delivered at a therapeutically
effective dose at a controlled rate over a sustained period of
time.
[0084] A clinical pharmacokinetic study was performed on healthy
subjects to ascertain the therapeutic benefits obtained by
administering hydromorphone from a controlled, extended-release
dosage form provided by this invention, compared to the therapeutic
benefits obtained by administering hydromorphone from an
immediate-release dosage form. The study evaluated both the single-
and multiple-dose pharmacokinetics of hydromorphone and its
metabolite following oral administration of hydromorphone. The
dosing form of this invention was compared to an immediate-release
dosage form, dosing for four days.
[0085] The profile of the clinical study compared randomized,
cross-over doses using 18 healthy volunteers consisting of both
male and female patients. The controlled-extended release dosage
form provided by the invention was used to administer a 16-mg dose
of hydromorphone orally at 8:00 AM for four days. The
immediate-release dosage form was used to administer 4 mg of
hydromorphone orally every six hours at 8:00 AM, 2:00 PM, 8:00 PM,
and 2:00 AM daily for four days. There was a washout period of at
least three days between the two treatments.
[0086] The administration of hydromorphone by the osmotic dosage
form provided by the invention was followed by the collection of
venous blood samples for pharmacokinetic profile determinations on
day one and for 48 hours after the day-four dosing period. The
administration of hydromorphone by an immediate-release dosage form
was followed by the collection of venous blood samples for
pharmacokinetic profile determinations for 48 hours after the
day-four dosing period. The immediate-release dosing form used in
the clinical studies comprised a solid tablet consisting of 4 mg of
hydromorphone, yellow dye, lactose and magnesium stearate,
available by prescription as Dilaudid.RTM. hydromorphone. The
Physician's Desk Reference, 50.sup.th Ed., pp. 1335-1337
(1996).
[0087] The clinical samples were analyzed for hydromorphone
parameters, including area under the curve, maximum concentration,
minimum concentration and concentration average for the two
distinctly different hydromorphone treatments. The results of the
clinical studies are presented in the accompanying figures.
[0088] FIG. 5 depicts the mean plasma hydromorphone concentration
profiles for hydromorphone treatment on days four and five. The
osmotically controlled extended-release dosage form results are
illustrated by the solid line with black circles. This dosage form
was administered once-a-day, and it comprised 16 mg of
hydromorphone. The dashed line with clear squares in FIG. 5 depicts
plasma profile for the immediate-release dosage form administered
four-times-a-day, which comprised 4 mg per immediate-release dosage
form.
[0089] FIG. 6 depicts the mean plasma hydromorphone 3-glucuronide
concentration following hydromorphone treatment on days four and
five. In FIG. 6, the solid line with black circles denotes the
plasma profile for the invention's osmotic dosage form administered
once-a-day, which comprised 16 mg of hydromorphone. The dashed
lines with clear squares denote the plasma profile for the
immediate-release tablet orally administered four-times-a-day,
which comprised 4 mg for each administration.
[0090] FIG. 7 depicts the mean plasma hydromorphone concentration
profiles for hydromorphone treatment on day four, determined at
mealtime. The solid line with black circles in this figure
illustrates the clinical picture effected by oral administration
once-a-day of a 16 mg controlled-extended release dosage form. The
solid line with clear squares, in this figure, g illustrates the
clinical picture effected by oral administration four-times-a-day
of a 4 mg immediate-release dosage form. The mean steady state
hydromorphone data for 18 subjects is for the immediate-release
form administered four-times-a-day, with 4 mg each time, a plasma
concentration maximum of 3.4 ng/mil with 10.1 hours to reach the
maximum concentration, a plasma concentration minimum of 0.9 ng/ml
with 6.4 hours to reach the concentration minimum, and an area
under the curve of 41.2 ng-hr/ml. The mean steady state
hydromorphone data for 18 subjects is for the osmotic dosage form
administered once-a-day with a dose of 16 mg, a plasma
concentration maximum of 2.6 ng/ml with 14.7 hours to reach the
maximum concentration, a plasma concentration minimum of 1.2 ng/ml
with 13.1 hours to reach the minimum concentration, and an area
under the curve of 44.8 ng-hr/ml.
[0091] The invention provides methods for administering
hydromorphone to a patient, and methods for producing a plasma
concentration of hydromorphone. The method of the invention
provides for admitting orally to a patient a dosage form that
administers at a controlled rate, over a continuous time up to 24
hours, hydromorphone for its intended therapy. The method also
comprises administering orally to a patient a therapeutic dose of
hydromorphone from a single dosage form that administers the
hydromorphone over 24 hours. The method of the invention further
comprises administering hydromorphone for producing a first
hydromorphone concentration in the plasma, a second, elevated
hydromorphone concentration in the plasma, and a third, continuous
hydromorphone concentration in the plasma.
[0092] The method of the invention also comprises administering
hydromorphone for producing a first plasma hydromorphone
concentration in from 0 to 8 hours, a second, elevated plasma
hydromorphone concentration in 8 to 12 hours, and a third,
continuous plasma hydromorphone concentration over 12 to 24 hours.
The method provides pain relief in a patient in need of pain
relief. The method further provides a plasma concentration of
hydromorphone in a patient in need of hydromorphone comprising
orally administering to the patient a dosage form that provides a
controlled rate of extended administration of from 1 to 65 mg of
hydromorphone over a period of time up to 24 hours for producing
from greater than zero ng, including 0.01 ng, to 10 ng/ml of plasma
of hydromorphone for producing a plasma concentration of hemoglobin
in a human patient.
[0093] Further data that support the unexpected results provided by
the 18 invention are seen in the accompanying figures, wherein FIG.
8 depicts the area under a curve for a dosage form comprising 8 mg
of hydromorphone, FIG. 9 depicts the cumulative dose released from
8 mg dosage form over 25 hrs, FIG. 10 depicts the cumulative dose
release from a 16 mg dosage form over 25 hrs, FIG. 11 illustrates
the cumulative dose release from a 32 mg dosage form over 25 hrs,
and FIG. 12 illustrates the cumulative dose release from a 64 mg
dosage form over 25 hrs.
[0094] In as much as the foregoing specification comprises
disclosed embodiments, it is understood what variations and
modifications may be made herein, in accordance with the principles
disclosed, without departing from the invention.
* * * * *