U.S. patent application number 13/941076 was filed with the patent office on 2014-05-22 for nanoparticulate meloxicam formulations.
The applicant listed for this patent is Alkermes Pharma Ireland Limited. Invention is credited to Eugene R. Cooper, Laura Kline, John Pruitt, Tuula Ryde.
Application Number | 20140141083 13/941076 |
Document ID | / |
Family ID | 43124706 |
Filed Date | 2014-05-22 |
United States Patent
Application |
20140141083 |
Kind Code |
A1 |
Cooper; Eugene R. ; et
al. |
May 22, 2014 |
NANOPARTICULATE MELOXICAM FORMULATIONS
Abstract
The present invention is directed to nanoparticulate
compositions comprising meloxicam particles having an effective
average particle size of less than about 2000 nm.
Inventors: |
Cooper; Eugene R.; (Berwyn,
PA) ; Ryde; Tuula; (Malvern, PA) ; Pruitt;
John; (Suwansee, GA) ; Kline; Laura;
(Harleysville, PA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alkermes Pharma Ireland Limited |
Dublin |
|
IE |
|
|
Family ID: |
43124706 |
Appl. No.: |
13/941076 |
Filed: |
July 12, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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12788203 |
May 26, 2010 |
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13941076 |
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10784900 |
Feb 24, 2004 |
8512727 |
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12788203 |
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60450705 |
Mar 3, 2003 |
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Current U.S.
Class: |
424/489 ;
514/226.5 |
Current CPC
Class: |
A61K 9/14 20130101; A61K
9/145 20130101; A61K 9/5138 20130101; A61K 9/146 20130101; A61K
9/10 20130101; A61K 9/5192 20130101; A61K 9/5169 20130101; A61K
9/0019 20130101; A61K 9/0053 20130101; A61P 29/00 20180101; A61K
31/5415 20130101; A61K 9/5123 20130101 |
Class at
Publication: |
424/489 ;
514/226.5 |
International
Class: |
A61K 9/51 20060101
A61K009/51; A61K 9/00 20060101 A61K009/00; A61K 31/5415 20060101
A61K031/5415 |
Claims
1.-23. (canceled)
24. An oral dosage form comprising: (a) particles of meloxicam or a
salt thereof having an effective average particle size of less than
or about 2000 nm; and (b) at least one surface stabilizer adsorbed
on the surface of the particles of meloxicam or a salt thereof.
25. The oral dosage form of claim 24, wherein the meloxicam or a
salt thereof is selected from the group consisting of a crystalline
phase, an amorphous phase, and a semi-crystalline phase.
26. The oral dosage form of claim 24, wherein the effective average
particle size of the meloxicam particles or a salt thereof is
selected from the group consisting of about 1500 nm, less than
about 1500 nm, about 1000 nm, less than about 1000 nm, about 900
nm, less than about 900 nm, about 800 nm, less than about 800 nm,
about 700 nm, less than about 700 nm, about 600 nm, less than about
600 nm, about 500 nm, less than about 500 nm, about 400 nm, less
than about 400 nm, about 300 nm, less than about 300 nm, about 250
nm, less than about 250 nm, about 200 nm, less than about 200 nm,
about 150 nm, less than about 150 nm, about 100 nm, less than about
100 nm, about 75 nm, less than about 75 nm, about 50 nm, and less
than about 50 nm.
27. The oral dosage form of claim 24, wherein the dosage form
further comprises one or more pharmaceutically acceptable
excipients, one or more pharmaceutically acceptable carriers, or a
combination thereof.
28. The oral dosage form of claim 24, wherein the meloxicam or a
salt thereof is present in an amount of from about 99.5% to about
0.001%, by weight, based on the total combined weight of the
meloxicam or a salt thereof and the at least one surface
stabilizer.
29. The oral dosage form of claim 24, wherein the at least one
surface stabilizer is present in an amount of from about 0.01% to
about 99.5%, by weight, based on the total combined weight of the
meloxicam or a salt thereof and the at least one surface
stabilizer.
30. The oral dosage form of claim 24, wherein the dosage form
further comprises one or more non-nanoparticulate active
agents.
31. The oral dosage form of claim 30, wherein the
non-nanoparticulate active agent is not meloxicam.
32. The oral dosage form of claim 24, wherein the dosage form
comprises from about 2.5 mg to about 120 mg of meloxicam or a salt
thereof.
33. The oral dosage form of claim 24, wherein the dosage form
comprises about 2.5 mg, about 5 mg, about 7.5 mg, about 15 mg,
about 30 mg, about 60 mg, about 75 mg, about 90 mg, about 105 mg,
or about 120 mg of meloxicam or a salt thereof.
34. The oral dosage form of claim 24, wherein the T.sub.max of a
7.5 mg orally administered dose, when assayed in the plasma of a
mammalian subject following administration of an initial dose, is
less than about 5 hours, less than about 4 hours, less than about 3
hours, less than about 2 hours, less than about 1 hour, less than
about 50 minutes, less than about 45 minutes, less than about 40
minutes, less than about 35 minutes, less than about 30 minutes,
less than about 20 minutes, less than about 15 minutes, less than
about 10 minutes, or less than about 5 minutes.
35. The oral dosage form of claim 24, wherein the C.sub.max of a
7.5 mg orally administered dose, when assayed in the plasma of a
mammalian subject following administration of an initial dose, is
greater than about 1 .mu.g/mL, greater than about 3 .mu.g/mL,
greater than about 5 .mu.g/mL, greater than about 10 .mu.g/mL, or
greater than about 15 .mu.g/mL.
36. The oral dosage form of claim 24, wherein the C.sub.max, upon
administration to a mammalian subject, is greater than about 20%,
greater than about 40%, greater than about 60%, greater than about
80%, greater than about 100%, greater than about 140%, greater than
about 180%, greater than about 200%, greater than about 240%,
greater than about 280%, greater than about 300%, greater than
about 340%, greater than about 380%, or greater than about 400% of
the C.sub.max exhibited by a non-nanoparticulate meloxicam
formulation, where meloxicam is present at the same dosage
amount.
37. A method of making an oral dosage form comprising contacting
meloxicam or a salt thereof with at least one surface stabilizer
for a time and under conditions sufficient to provide an oral
dosage form comprising particles of meloxicam or a salt thereof
having an effective average particle size of less than or about
2000 nm and at least one surface stabilizer adsorbed on the surface
of the particles of meloxicam or a salt thereof.
38. The method of claim 37, wherein contacting comprising grinding
or homogenizing.
39. A method for treating a subject in need thereof comprising
orally administering to a subject an effective amount of an oral
dosage form comprising: (a) particles of meloxicam or a salt
thereof having an effective average particle size of less than or
about 2000 nm; and (b) at least one surface stabilizer adsorbed on
the surface of the particles of meloxicam or a salt thereof.
40. The method of claim 39, wherein the subject is a human.
41. The method of claim 39, wherein the dosage form comprises from
about 2.5 mg to about 120 mg of meloxicam or a salt thereof.
42. The method of claim 39, wherein the dosage form comprises about
2.5 mg, about 5 mg, about 7.5 mg, about 15 mg, about 30 mg, about
60 mg, about 75 mg, about 90 mg, about 105 mg, or about 120 mg of
meloxicam or a salt thereof.
43. The method of claim 39, wherein upon oral administration of a
7.5 mg dose to the subject, the T.sub.max, when assayed in the
plasma of the subject following administration of an initial dose,
is less than about 5 hours, less than about 4 hours, less than
about 3 hours, less than about 2 hours, less than about 1 hour,
less than less than about 50 minutes, less than about 45 minutes,
less than about 40 minutes, less than about 35 minutes, less than
about 30 minutes, less than about 20 minutes, less than about 15
minutes, less than about 10 minutes, or less than about 5
minutes.
44. The method of claim 39, wherein upon oral administration of a
7.5 mg dose to the subject, the C.sub.max, when assayed in the
plasma of the subject following administration of an initial dose,
is greater than about 1 .mu.g/mL, greater than about 3 .mu.g/mL,
greater than about 5 .mu.g/mL, greater than about 10 .mu.g/mL, or
greater than about 15 .mu.g/mL.
45. The method of claim 39, wherein the C.sub.max, upon
administration to the subject, is greater than about 20%, greater
than about 40%, greater than about 60%, greater than about 80%,
greater than about 100%, greater than about 140%, greater than
about 180%, greater than about 200%, greater than about 240%,
greater than about 280%, greater than about 300%, greater than
about 340%, greater than about 380%, or greater than about 400% of
the C.sub.max exhibited by a non-nanoparticulate meloxicam
formulation, where meloxicam is present at the same dosage amount.
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 12/788,203, filed May 26, 2010, which is a
continuation-in-part of U.S. patent application Ser. No.
10/784,900, filed Feb. 24, 2004, which claims priority to U.S.
Provisional Patent Application No. 60/450,705, filed Mar. 3, 2003.
The contents of these applications are incorporated herein by
reference in their entirety.
BACKGROUND OF THE INVENTION
[0002] Nanoparticulate active agent compositions are described in
U.S. Pat. No. 5,145,684 ("the '684 patent") as particles comprising
a poorly soluble therapeutic or diagnostic agent having adsorbed
onto or associated with the surface thereof a non-crosslinked
surface stabilizer.
[0003] Methods of making nanoparticulate active agent compositions
are described in, for example, U.S. Pat. Nos. 5,518,187 and
5,862,999, both for "Method of Grinding Pharmaceutical Substances;"
U.S. Pat. No. 5,718,388, for "Continuous Method of Grinding
Pharmaceutical Substances;" and U.S. Pat. No. 5,510,118 for
"Process of Preparing Therapeutic Compositions Containing
Nanoparticles."
[0004] Nanoparticulate active agent compositions are also
described, for example, in U.S. Pat. No. 5,298,262 for "Use of
Ionic Cloud Point Modifiers to Prevent Particle Aggregation During
Sterilization;" U.S. Pat. No. 5,302,401 for "Method to Reduce
Particle Size Growth During Lyophilization;" U.S. Pat. No.
5,318,767 for "X-Ray Contrast Compositions Useful in Medical
Imaging;" U.S. Pat. No. 5,326,552 for "Novel Formulation For
Nanoparticulate X-Ray Blood Pool Contrast Agents Using High
Molecular Weight Non-ionic Surfactants;" U.S. Pat. No. 5,328,404
for "Method of X-Ray Imaging Using Iodinated Aromatic
Propanedioates;" U.S. Pat. No. 5,336,507 for "Use of Charged
Phospholipids to Reduce Nanoparticle Aggregation;" U.S. Pat. No.
5,340,564 for "Formulations Comprising Olin 10-G to Prevent
Particle Aggregation and Increase Stability;" U.S. Pat. No.
5,346,702 for "Use of Non-Ionic Cloud Point Modifiers to Minimize
Nanoparticulate Aggregation During Sterilization;"U.S. Pat. No.
5,349,957 for "Preparation and Magnetic Properties of Very Small
Magnetic-Dextran Particles;" U.S. Pat. No. 5,352,459 for "Use of
Purified Surface Modifiers to Prevent Particle Aggregation During
Sterilization;" U.S. Pat. No. 5,399,363 and U.S. Pat. No.
5,494,683, both for "Surface Modified Anticancer Nanoparticles;"
U.S. Pat. No. 5,401,492 for "Water Insoluble Non-Magnetic Manganese
Particles as Magnetic Resonance Enhancement Agents;" U.S. Pat. No.
5,429,824 for "Use of Tyloxapol as a Nanoparticulate Stabilizer;"
U.S. Pat. No. 5,447,710 for "Method for Making Nanoparticulate
X-Ray Blood Pool Contrast Agents Using High Molecular Weight
Non-ionic Surfactants;" U.S. Pat. No. 5,451,393 for "X-Ray Contrast
Compositions Useful in Medical Imaging;" U.S. Pat. No. 5,466,440
for "Formulations of Oral Gastrointestinal Diagnostic X-Ray
Contrast Agents in Combination with Pharmaceutically Acceptable
Clays;" U.S. Pat. No. 5,470,583 for "Method of Preparing
Nanoparticle Compositions Containing Charged Phospholipids to
Reduce Aggregation;" U.S. Pat. No. 5,472,683 for "Nanoparticulate
Diagnostic Mixed Carbamic Anhydrides as X-Ray Contrast Agents for
Blood Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,500,204
for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for
Blood Pool and Lymphatic System Imaging;" U.S. Pat. No. 5,518,738
for "Nanoparticulate NSAID Formulations;" U.S. Pat. No. 5,521,218
for "Nanoparticulate Iododipamide Derivatives for Use as X-Ray
Contrast Agents;" U.S. Pat. No. 5,525,328 for "Nanoparticulate
Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood Pool
and Lymphatic System Imaging;" U.S. Pat. No. 5,543,133 for "Process
of Preparing X-Ray Contrast Compositions Containing Nanoparticles;"
U.S. Pat. No. 5,552,160 for "Surface Modified NSAID Nanoparticles;"
U.S. Pat. No. 5,560,931 for "Formulations of Compounds as
Nanoparticulate Dispersions in Digestible Oils or Fatty Acids;"
U.S. Pat. No. 5,565,188 for "Polyalkylene Block Copolymers as
Surface Modifiers for Nanoparticles;" U.S. Pat. No. 5,569,448 for
"Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer
Coatings for Nanoparticle Compositions;" U.S. Pat. No. 5,571,536
for "Formulations of Compounds as Nanoparticulate Dispersions in
Digestible Oils or Fatty Acids;" U.S. Pat. No. 5,573,749 for
"Nanoparticulate Diagnostic Mixed Carboxylic Anydrides as X-Ray
Contrast Agents for Blood Pool and Lymphatic System Imaging;" U.S.
Pat. No. 5,573,750 for "Diagnostic Imaging X-Ray Contrast Agents;"
U.S. Pat. No. 5,573,783 for "Redispersible Nanoparticulate Film
Matrices With Protective Overcoats;" U.S. Pat. No. 5,580,579 for
"Site-specific Adhesion Within the GI Tract Using Nanoparticles
Stabilized by High Molecular Weight, Linear Poly(ethylene Oxide)
Polymers;" U.S. Pat. No. 5,585,108 for "Formulations of Oral
Gastrointestinal Therapeutic Agents in Combination with
Pharmaceutically Acceptable Clays;" U.S. Pat. No. 5,587,143 for
"Butylene Oxide-Ethylene Oxide Block Copolymers Surfactants as
Stabilizer Coatings for Nanoparticulate Compositions;" U.S. Pat.
No. 5,591,456 for "Milled Naproxen with Hydroxypropyl Cellulose as
Dispersion Stabilizer;" U.S. Pat. No. 5,593,657 for "Novel Barium
Salt Formulations Stabilized by Non-ionic and Anionic Stabilizers;"
U.S. Pat. No. 5,622,938 for "Sugar Based Surfactant for
Nanocrystals;" U.S. Pat. No. 5,628,981 for "Improved Formulations
of Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral
Gastrointestinal Therapeutic Agents;" U.S. Pat. No. 5,643,552 for
"Nanoparticulate Diagnostic Mixed Carbonic Anhydrides as X-Ray
Contrast Agents for Blood Pool and Lymphatic System Imaging;" U.S.
Pat. No. 5,718,388 for "Continuous Method of Grinding
Pharmaceutical Substances;" U.S. Pat. No. 5,718,919 for
"Nanoparticles Containing the R(-) Enantiomer of Ibuprofen;" U.S.
Pat. No. 5,747,001 for "Aerosols Containing Beclomethasone
Nanoparticle Dispersions;" U.S. Pat. No. 5,834,025 for "Reduction
of Intravenously Administered Nanoparticulate Formulation Induced
Adverse Physiological Reactions;" U.S. Pat. No. 6,045,829
"Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV)
Protease Inhibitors Using Cellulosic Surface Stabilizers;" U.S.
Pat. No. 6,068,858 for "Methods of Making Nanocrystalline
Formulations of Human Immunodeficiency Virus (HIV) Protease
Inhibitors Using Cellulosic Surface Stabilizers;" U.S. Pat. No.
6,153,225 for "Injectable Formulations of Nanoparticulate
Naproxen;" U.S. Pat. No. 6,165,506 for "New Solid Dose Form of
Nanoparticulate Naproxen;" U.S. Pat. No. 6,221,400 for "Methods of
Treating Mammals Using Nanocrystalline Formulations of Human
Immunodeficiency Virus (HIV) Protease Inhibitors;" U.S. Pat. No.
6,264,922 for "Nebulized Aerosols Containing Nanoparticle
Dispersions;" U.S. Pat. No. 6,267,989 for "Methods for Preventing
Crystal Growth and Particle Aggregation in Nanoparticle
Compositions;" U.S. Pat. No. 6,270,806 for "Use of PEG-Derivatized
Lipids as Surface Stabilizers for Nanoparticulate Compositions;"
U.S. Pat. No. 6,316,029 for "Rapidly Disintegrating Solid Oral
Dosage Form," U.S. Pat. No. 6,375,986 for "Solid Dose
Nanoparticulate Compositions Comprising a Synergistic Combination
of a Polymeric Surface Stabilizer and Dioctyl Sodium
Sulfosuccinate;" U.S. Pat. No. 6,428,814 for "Bioadhesive
Nanoparticulate Compositions Having Cationic Surface Stabilizers;"
U.S. Pat. No. 6,431,478 for "Small Scale Mill;" U.S. Pat. No.
6,432,381 for "Methods for Targeting Drug Delivery to the Upper
and/or Lower Gastrointestinal Tract," U.S. Pat. No. 6,592,903 for
"Nanoparticulate Dispersions Comprising a Synergistic Combination
of a Polymeric Surface Stabilizer and Dioctyl Sodium
Sulfosuccinate," U.S. Pat. No. 6,582,285 for "Apparatus for
sanitary wet milling;" U.S. Pat. No. 6,656,504 for "Nanoparticulate
Compositions Comprising Amorphous Cyclosporine;" U.S. Pat. No.
6,742,734 for "System and Method for Milling Materials;" U.S. Pat.
No. 6,745,962 for "Small Scale Mill and Method Thereof;" U.S. Pat.
No. 6,811,767 for "Liquid droplet aerosols of nanoparticulate
drugs;" U.S. Pat. No. 6,908,626 for "Compositions having a
combination of immediate release and controlled release
characteristics;" U.S. Pat. No. 6,969,529 for "Nanoparticulate
compositions comprising copolymers of vinyl pyrrolidone and vinyl
acetate as surface stabilizers;" and U.S. Pat. No. 6,976,647 for
"System and Method for Milling Materials," U.S. Pat. No. 6,991,191
for "Method of Using a Small Scale Mill;" U.S. Pat. No. 7,101,576
for "Nanoparticulate Megestrol Formulation," U.S. Pat. No.
7,198,795 for "In vitro methods for evaluating the in vivo
effectiveness of dosage forms of microparticulate of
nanoparticulate active agent compositions;" U.S. Pat. No. 7,244,451
for "Methods of making nanoparticulate drug compositions comprising
copolymers of vinyl pyrrolidone and vinyl acetate as surface
stabilizers"; U.S. Pat. No. 7,276,249 for "Nanoparticulate Fibrate
Formulations"; U.S. Pat. No. 7,288,267 for "Bioadhesive
nanoparticulate compositions having cationic surface stabilizers";
U.S. Pat. No. 7,320,802 for "Methods of treatment using
nanoparticulate fenofibrate compositions"; and U.S. Pat. No.
7,390,505 for "Nanoparticulate topiramate formulations", all of
which are specifically incorporated by reference.
[0005] Meloxicam, also known as
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2-H-1,2-benzothiazine-3-carbo-
xamide 1,1-dioxide, is a member of the enolic acid group of
nonsteroidal anti-inflammatory drugs (NSAIDs). Meloxicam is an
oxicam derivative with the following chemical structure:
##STR00001##
[0006] Meloxicam has an empirical formula of
C.sub.14H.sub.13N.sub.3O.sub.4S.sub.2 and a molecular weight of
351.41. See The Physicians' Desk Reference, 56th Ed., pp. 1054
(2002); and The Merck Index, 13th Ed., pp. 1040-1041 (Merck &
Co. 2001). Meloxicam is practically insoluble in water with higher
solubility observed in strong acids and bases. It is very slightly
soluble in methanol. The Physicians' Desk Reference, 56th Ed., pp.
1054.
[0007] 4-hydroxy-2H-1,2-benzothiazine-3-carboxamide-1,1-dioxides
and salts thereof, as well as methods of preparing these compounds,
pharmaceutical compositions containing them as active ingredients,
and methods of using them as antiphlogistics, are discussed in U.S.
Pat. No. 4,233,299, herein incorporated by reference. The
pharmacology of meloxicam in horses is discussed in Lees et al.,
Brit. Vet. J., 147: 97 (1991); veterinary trials in dogs are
discussed in Henderson et al., Prakt. Tierarzt., 75:179 (1994); the
physiochemical properties of meloxicam are discussed in Tsai et
al., Helv. Chim. Acta, 76:842 (1993); the pharmacology, mechanism
of action, and clinical efficacy are discussed in Brit. J.
Rheumatol., 35(Suppl. 1):1-77 (1996); and clinical trials of
gastrointestinal tolerability in arthritis is discussed in Hawkey
et al., Brit. J. Rheumatol., 37:937 (1998), and Dequeker et al.,
Brit. J. Rheumatol., 37:946 (1998).
[0008] Meloxicam exhibits anti-inflammatory, analgesic, and
antifebrile activities. Like other NSAIDs, the primary mechanism of
action of meloxicam is via inhibition of the cyclooxygenase (COX-2)
enzyme system resulting in decreased prostaglandin synthesis. See
The Physicians' Desk Reference, 56th Ed., pp. 1054 (2002). In
contrast, COX-2 is not present in healthy tissue and its expression
is induced in certain inflammatory states. See Vane et al., Proc.
Natl. Acad. Sci. USA, 91:2046-2050 (1994); Oulette et al., Proc.
Natl. Acad. Sci., 98:14583-14588 (2001); and Seibert et al., Proc.
Natl. Acad. Sci., 91:12013-12017 (1994).
[0009] The pathological production of prostaglandins by COX-2 is
implicated in a number of human disease states, including
rheumatoid arthritis, osteoarthritis, pyrexia, asthma, bone
resorption, cardiovascular diseases, nephrotoxicity,
atherosclerosis, and hypotension. Id. Elevated levels of
prostaglandins enhance or prolong pro-inflammatory signals which
cause the pain, stiffness, and inflammation associated with these
conditions. See Smith et al., Proc. Natl. Acad. Sci.,
95:13313-13318 (1998).
[0010] Meloxicam is superior to traditional non-selective NSAIDs
because it selectively inhibits COX-2, thus causing fewer
gastrointestinal problems such as bleeding, heartburn, reflux,
diarrhea, nausea, and abdominal pain. Meloxicam preferentially
inhibits COX-2 with a COX-2/COX-1 inhibition ratio of 0.09. It is
desirable to selectively inhibit COX-2 and the pathological
production of prostaglandins for which that enzyme is responsible
because the therapeutic analgesic/anti-inflammatory properties of
NSAIDs occur by inhibition of inducible COX-2 at the site of
inflammation. Conversely, the majority of adverse drug reactions to
NSAIDs, including gastrointestinal ulcers and renal failure, result
from inhibition of the constitutive COX-1 enzymes. This is because
as a result of such COX-1 inhibition, prostaglandins necessary for
gastric mucosal production and renal blood circulation are not
produced. See Vane et al., Proc. Natl. Acad. Sci. USA, 91:2046
(1994); Oulette et al., Proc. Natl. Acad. Sci., 98:14583 (2001);
and Seibert et al., Proc. Natl. Acad. Sci., 91:12013 (1994).
Compounds that selectively inhibit the biosynthesis of
prostaglandins by inhibiting the activity of the inducible enzyme,
COX-2, exert anti-inflammatory effects without the adverse side
effects associated with COX-1 inhibition.
[0011] Some of the trade names under which a commercially available
meloxicam product has been or is marketed include MOBIC.RTM.,
MOBEC.RTM., MOBICOX.RTM., MOVALIS.RTM., and MOVATEC.RTM.. Meloxicam
has been shown to be useful in the symptomatic treatment of painful
osteoarthritis (arthrosis, degenerative joint disease), symptomatic
treatment of rheumatoid arthritis, symptomatic treatment of
ankylosing spondylitis, and symptomatic treatment of the signs and
symptoms of osteoarthritis, including pain, stiffness, and
inflammation.
[0012] The form of meloxicam currently marketed in the United
States is MOBIC.RTM. (Boehringer Ingelheim Pharmaceuticals, Inc.,
Ridgefield, Conn.), provided in 7.5 and 15 mg tablets. The
bioavailability of a single 30 mg oral dose is 89% as compared to a
30 mg intravenous bolus injection. The pharmacokinetics of a single
intravenous dose of meloxicam is dose-proportional in the range of
5 to 60 mg. See The Physicians' Desk Reference, 56th Ed., pp. 1054
(2002). After administration of multiple oral doses of meloxicam,
the pharmacokinetics is dose-proportional in the range of 7.5 to 15
mg. The rate or extent of absorption is not affected by multiple
dose administration. Under fasted steady state conditions, the mean
Cmax is achieved within four to five hours, with a second meloxicam
concentration peak occurring at approximately twelve to fourteen
hours post-dose, which suggests gastrointestinal recirculation.
Under steady state fed conditions in healthy adult males, the 7.5
mg tablets have a mean Cmax of 1.05 .mu.g/mL, a Tmax of 4.9 hrs,
and a t1/2 of 20.1 hours. Under steady state fed conditions in
elderly males and females, the 15 mg tablets have a Cmax of 2.3 and
3.2 .mu.g/mL, respectively, a Tmax of 5 and 6 hrs, respectively,
and a t1/2 of 21 and 24 hrs, respectively. See The Physicians' Desk
Reference, 56th Ed., pp. 1054 (2002).
[0013] Meloxicam is useful in relieving the signs and symptoms of
rheumatoid arthritis, lower back pain, and acute pain, e.g.
treatment of post surgical pain, treatment of pain resulting from
battle field wounds, and migraine headaches. Meloxicam may be
especially effective for treatment of all types of pain associated
with inflammation. In general meloxicam is effective for treatment
of moderate to moderately severe acute pain as would be understood
by a skilled practitioner.
[0014] NSAIDs, like meloxicam, are useful in pain management
because NSAIDs provide an analgesic effect without the sedation and
addictive properties of narcotic analgesics. Furthermore, the long
t.sub.1/2 of meloxicam makes it useful for long-lasting relief
which is not provided by narcotic analgesics. However, due to their
typically long onset of action, conventional NSAIDs, including
conventional meloxicam, are frequently inappropriate for management
of acute pain.
[0015] Because meloxicam is practically insoluble in water,
attaining sufficient bioavailability of this drug is problematic.
Prior art methods of increasing the bioavailability of meloxicam
include increasing its solubility by forming a cyclodextrin complex
of the drug (see U.S. Pat. No. 6,284,269) or by forming a salt of
meloxicam with an inorganic or organic base (U.S. Pat. Appln. Pub.
No. US 2002/0035107 A1).
[0016] The skilled person knows that for any particulate
composition to be approved by the FDA for intravenous (I.V.) or
intramuscular (I.M.) administration, the composition must meet the
standards set forth in General Chapter 788 of the United States
Pharmacopoeia ("USP<788>"). Specifically, in the United
States, any particulate matter injectable solution must comply with
the particle size and number requirements of USP<788>. That
is, under the approved "Light Obscuration" test set forth in
USP<788>, known as "Method 1," there must be: (i) no more
than 6,000 particles in a particulate composition that are greater
than 10 .mu.m in size and (ii) no more than 600 particles that are
greater than 25 .mu.m in size. Under "Method 2," the Microscopy
test, a particulate composition must contain (i) no more than 3,000
particles in a particulate composition that are greater than 10
.mu.m in size and (ii) no more than 300 particles that are greater
than 25 .mu.m in size. The theorized large particles represent the
presence of aggregates of individual particles which clump
together.
[0017] Because poorly water soluble active agents are difficult to
solubilize in an aqueous based mammal environment, it can be
difficult to formulate many poorly water soluble drugs for
injectable formulations as conventional poorly water soluble drug
formulations can contain particles of drug which do not meet the
standards set forth in USP<788>. This is problematic, as an
injectable formulation may be highly desirable over an alternative
dosage form. For example, drugs taken orally may cause significant
first pass liver damage, which can be avoided or minimized using an
injectable dosage form. Particularly for pain medication,
injectable dosage forms may be highly desirable due to the fast
onset of activity.
BRIEF SUMMARY OF THE INVENTION
[0018] The present invention is directed to a method of treating
moderate to moderately severe acute pain with a composition
comprising meloxicam. In an exemplary embodiment, method of
treatment includes administering an injectable dosage form
comprising meloxicam, polyvinylpyrrolidone, NaDOC, and sucrose to a
patient in need thereof. In an embodiment of the invention, the
composition provides meaningful pain relief for up to 24 hours when
administered to a patient in need thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
[0019] The invention is best understood from the following detailed
description when read in connection with the accompanying
drawings.
[0020] FIG. 1 is a particle size distribution plot of an exemplary
embodiment of a formulation of the present invention stored at
25.degree. C. and 40.degree. C. for up to 30 days.
[0021] FIG. 2 is a particle size distribution plot of an exemplary
embodiment of a formulation of the present invention stored at
5.degree. C., 25.degree. C. and 40.degree. C. for up to 60
days.
[0022] FIG. 3 is a plot of the percentage of patients without first
perceptible pain relief over time to first perceptible pain
relief.
[0023] FIG. 4 is a plot of the percentage of patients without
meaningful pain relief over time to meaningful pain relief.
[0024] FIG. 5 is a plot of the percentage of patients without
rescue medication over time.
DETAILED DESCRIPTION OF THE INVENTION
[0025] The United States Food and Drug Administration (FDA) has
defined bioequivalence as, "the absence of a significant difference
in the rate and extent to which the active ingredient or active
moiety in pharmaceutical equivalents or pharmaceutical alternatives
becomes available at the site of drug action when administered at
the same molar dose under similar conditions in an appropriately
designed study." (FDA, 2003) In other words, the FDA considers two
products bioequivalent if the 90% CI of the relative mean
C.sub.max, AUC.sub.(0-t) and AUC.sub.(0-.infin.) of the test
formulation to reference formulation should be within 80.00% to
125.00%.
[0026] The present invention is directed to compositions comprising
nanoparticulate meloxicam. The compositions comprise
nanoparticulate meloxicam and at least one surface stabilizer
adsorbed on the surface of the drug. The nanoparticulate meloxicam
particles, which have an effective average particle size of less
than about 2000 nm, surprisingly exhibit superior Tmax profiles as
compared to conventional prior meloxicam formulations.
[0027] As taught in the '684 patent, not every combination of
surface stabilizer and active agent will result in a stable
nanoparticulate composition. It was surprisingly discovered that
stable nanoparticulate meloxicam formulations can be made. As
described in more detail below, preferred surface stabilizers
include polyvinylpyrrolidone (e.g., Kollidon.RTM. 12 PF,
Kollidon.RTM. 17 PF), docusate sodium, block polymers of
polyethylene glycol and polypropylene glycol, poloxamers (e.g.,
Pluronics F68.RTM. and F108.RTM., which are block copolymers of
ethylene oxide and propylene oxide), polyethylene sorbitan
monooleate (Polysorbate 80), sodium Deoxycholate, lecithin,
lysozyme, and mixtures thereof. Docusate sodium is particularly
useful as a surface stabilizer in combination with one or more
other surface stabilizers.
[0028] As described in Example 3 below, many of these surface
stabilizers are particularly suited for injectable nanoparticulate
meloxicam formulations. This is significant, and surprising, as for
injectable formulations it is critical that very small meloxicam
particles be obtained. Moreover, the composition must be stable,
with very little or no particle size growth observed, as injectable
formulations having large particles can cause embolism.
[0029] Nanoparticulate meloxicam formulations suitable parenteral
injection (e.g., intravenous, intramuscular, or subcutaneous) for
the treatment of acute pain are highly superior to conventional
meloxicam formulations because they have much faster onset of
action due to the nanoparticulate size of the active agent.
[0030] In addition to exhibiting dramatically superior Tmax
profiles, the nanoparticulate meloxicam formulations preferably
also exhibit improved pharmacokinetic profiles as compared to
conventional meloxicam formulations, resulting in faster onset of
action and smaller effective doses as compared to prior
conventional meloxicam formulations.
[0031] Conventional formulations of meloxicam are inappropriate for
management of acute pain due to delayed onset of action, as such
meloxicam formulations have a Tmax of 4-6 hours, which is more than
five times as long as most narcotic analgesic drugs. See The
Physician's Desk Reference, 56th Ed., pp. 446 and 1054. Unlike
conventional meloxicam formulations, nanoparticulate meloxicam
formulations, which exhibit faster onset of action, are useful in
treating acute pain where fast pain relief is required.
[0032] Additionally, any drug, including meloxicam, can have
adverse side effects. Thus, lower doses of meloxicam which can
achieve the same or better therapeutic effects as those observed
with larger doses of conventional meloxicam are desired.
[0033] Nanoparticulate formulations of meloxicam also provide a
longer duration of pain relief as compared to traditional narcotic
analgesic drugs. While traditional narcotics provide fast onset of
action, the duration of pain relief is short. Nanoparticulate
meloxicam formulations combine the fast onset of traditional
narcotics with the duration of pain relief of conventional NSAIDs.
The long half-life of meloxicam, approximately 20 hours as compared
to 2-3 hours for most narcotics, confers a long duration of action
and thus requires less frequent dosing.
[0034] Additionally, nanoparticulate meloxicam formulations do not
possess the sedative and addictive properties of narcotic
analgesics. Meloxicam does not cause drowsiness and is not
addictive, making it a preferred analgesic when ambulation is
important or when treatment is protracted and chemical dependency
could result from continued use of narcotic analgesics.
[0035] Nanoparticulate formulations can be prepared for oral
administration for treatment of, for example, migraine headaches.
The use of oral nanoparticulate formulations also provide much
faster onset of action as compared to conventional orally dosed
meloxicam formulations.
[0036] In addition, the invention encompasses compositions
comprising nanoparticulate meloxicam, one or more surface
stabilizers, and one or more non-meloxicam active agents, either
conventional or nanoparticulate. Methods of using such combination
compositions are also encompassed by the invention. For example,
additional analgesic drugs can be used in combination with
nanoparticulate meloxicam, such as one or more COX-2 inhibitors,
NSAIDs, or narcotics. Other exemplary types of active agents which
can be used in combination with nanoparticulate meloxicam are
described below. If the non-meloxicam active agent is in
nanoparticulate form, then such a non-meloxicam active agent also
has one or more surface stabilizers adsorbed onto the surface of
the active agent. The surface stabilizer(s) adsorbed onto the
surface of the non-meloxicam active agent can be the same as or
different from the surface stabilizer(s) adsorbed onto the surface
of the nanoparticulate meloxicam.
[0037] In general, such non-meloxicam active agents do not include
vasomodulators, such as those described in U.S. Published Patent
Application No. 20020077328.
[0038] In yet another embodiment of the invention, a first
meloxicam formulation providing the pharmacokinetic profile
required herein is co-administered with at least one other
meloxicam formulation that generates a different pharmacokinetic
profile, specifically one exhibiting slower absorption into the
bloodstream and therefore a longer Tmax, and typically a lower
Cmax. For example, the second meloxicam formulation can have a
conventional particle size, which produces a longer Tmax, and
typically a lower Cmax. Alternatively, a second, third, or fourth
meloxicam formulation can differ from the first, and from each
other, in the effective average particle sizes of each composition.
The different particle sizes produce different Tmaxs. The
combination of fast pain relief provided by the first formulation
and longer-lasting pain relief provided by the second (or third,
fourth, etc.) formulation can reduce the dose frequency required.
Preferably where co-administration of a "fast-acting" formulation
and a "longer-lasting" formulation is desired, the two formulations
are combined within a single composition, for example a
dual-release composition.
[0039] A. Compositions
[0040] The invention provides compositions comprising
nanoparticulate meloxicam particles and at least one surface
stabilizer. The surface stabilizers are adsorbed on the surface of
the meloxicam particles. Surface stabilizers useful herein
physically adhere on the surface of the nanoparticulate meloxicam
but do not chemically react with the meloxicam particles or itself.
Individually adsorbed molecules of the surface stabilizer are
essentially free of intermolecular cross-linkages.
[0041] The invention also provides compositions of nanoparticulate
meloxicam in combination with one or more conventional or
nanoparticulate non-meloxicam drugs.
[0042] The present invention includes nanoparticulate meloxicam
compositions together with one or more non-toxic physiologically
acceptable carriers, adjuvants, or vehicles, collectively referred
to as carriers. The compositions can be formulated for parenteral
injection (e.g., intravenous, intramuscular, or subcutaneous), oral
(in solid, liquid, or aerosol form), vaginal, nasal, rectal,
ocular, local (powders, ointments or drops), buccal,
intracisternal, intraperitoneal, or topical administration, and the
like. Such compositions can also comprise one or more conventional
or nanoparticulate non-meloxicam drugs.
[0043] The present invention provides compositions of meloxicam
with a desirable pharmacokinetic profile when administered to
mammalian subjects. Preferably, the T.sub.max of a 7.5 mg orally
administered dose of nanoparticulate meloxicam, when assayed in the
plasma of a mammalian subject following administration of an
initial dose, is less than about 5 hours, less than about 4 hours,
less than about 3 hours, less than about 2 hours, less than about 1
hour, less than less than about 50 minutes, less than about 45
minutes, less than about 40 minutes, less than about 35 minutes,
less than about 30 minutes, less than about 20 minutes, less than
about 15 minutes, less than about 10 minutes, or less than about 5
minutes.
[0044] In addition, preferably the C.sub.max of a 7.5 mg orally
administered dose of nanoparticulate meloxicam, when assayed in the
plasma of a mammalian subject following administration of an
initial dose, is greater than about 1 .mu.g/mL, greater than about
3 .mu.g/mL, greater than about 5 .mu.g/mL, greater than about 10
.mu.g/mL, or greater than about 15 .mu.g/mL.
[0045] The desirable pharmacokinetic profile, as used herein, is
the pharmacokinetic profile measured after the initial dose of
meloxicam. The compositions can be formulated in any way as
described below.
[0046] A preferred nanoparticulate meloxicam formulation of the
invention exhibits in comparative pharmacokinetic testing with a
standard commercial formulation of meloxicam, such as MOBIC.RTM.
from Boehringer Ingelheim Pharmaceuticals, Inc., a Tmax not greater
than about 90%, not greater than about 80%, not greater than about
70%, not greater than about 60%, not greater than about 50%, not
greater than about 30%, not greater than about 25%, not greater
than about 20%, not greater than about 15%, or not greater than
about 10% of the Tmax exhibited by a standard commercial meloxicam
formulation, e.g., MOBIC.RTM. tablets.
[0047] In addition, an exemplary oral nanoparticulate meloxicam
formulation of the invention exhibits in comparative
pharmacokinetic testing with a standard commercial formulation of
meloxicam, such as MOBIC.RTM. from Boehringer Ingelheim
Pharmaceuticals, Inc., a Cmax which is greater than about 20%,
greater than about 40%, greater than about 60%, greater than about
80%, greater than about 100%, greater than about 140%, greater than
about 180%, greater than about 200%, greater than about 240%,
greater than about 280%, greater than about 300%, greater than
about 340%, greater than about 380%, or greater than about 400% of
the Cmax exhibited by a standard commercial meloxicam formulation,
e.g., MOBIC.RTM. tablets.
[0048] Any nanoparticulate meloxicam formulation giving the desired
pharmacokinetic profile is suitable for administration according to
the present methods.
[0049] 1. Meloxicam Particles
[0050] As used herein the term meloxicam, which is the active
ingredient in the composition, is used to mean meloxicam
(4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2-H-1,2-benzothiazine-3-carb-
oxamide 1,1-dioxide) or any salt thereof. Meloxicam can be present
in a crystalline phase, an amorphous phase, or a mixture
thereof.
[0051] Nanoparticulate meloxicam compositions are contemplated to
be useful in treatment and/or prevention of a wide range of
conditions and disorders mediated by COX-2, including but not
limited to, disorders characterized by inflammation, pain, and/or
fever. Such compositions are especially useful as anti-inflammatory
agents, such as in treatment of arthritis, with the additional
benefit of having significantly less harmful side effects than
compositions of conventional NSAIDs that lack selectivity for COX-2
over COX-1. In particular, such compositions have reduced potential
for gastrointestinal toxicity and gastrointestinal irritation
including upper gastrointestinal ulceration and bleeding, reduced
potential for renal side effects such as reduction in renal
function leading to fluid retention and exacerbation of
hypertension, reduced effect on bleeding times including inhibition
of platelet function, and possibly a lessened ability to induce
asthma attacks in aspirin-sensitive asthmatic subjects, by
comparison with compositions of conventional NSAIDs.
[0052] Thus, nanoparticulate meloxicam compositions of the
invention are particularly useful as an alternative to conventional
normanoparticulate NSAIDs where such NSAIDs are contraindicated,
for example in patients with peptic ulcers, gastritis, regional
enteritis, ulcerative colitis, diverticulitis, or with a recurrent
history of gastrointestinal lesions; gastrointestinal bleeding;
coagulation disorders including anemia such as hypoprothrombinemia,
hemophilia, or other bleeding problems; kidney disease; or in
patients prior to surgery or patients taking anticoagulants.
[0053] Because of the rapid onset of therapeutic effect observed
with the compositions of the invention, these compositions have
particular advantages over prior conventional formulations for
treatment of acute COX-2 mediated disorders, especially for relief
of pain, for example in headache, including sinus headache and
migraine.
[0054] Meloxicam is also useful in treating and/or preventing, for
example, arthritic disorders, gastrointestinal conditions,
inflammatory conditions, pulmonary inflammation, opthalmic
diseases, central nervous systems disorders, pain,
inflammation-related cardiovascular disorders, angiogenesis-related
disorders, benign and malignant tumors, adenomatous polyps,
disorders of the female reproductive system such as endometriosis,
osteoporosis, dysmenorrhea, premature labor, asthma,
eosinophil-related disorders, pyrexia, bone resorption,
nephrotoxicity, hypotension, arthrosis, joint stiffness, kidney
disease, liver disease including hepatitis, acute mastitis,
diarrhea, colonic adenomas, bronchitis, allergic neuritis,
cytomegalovirus infectivity, apoptosis including HIV-induced
apoptosis, lumbago; skin-related conditions such as psoriasis,
eczema, acne, burns, dermatitis, and ultraviolet radiation damage
including sunburn; allergic rhinitis, respiratory distress
syndrome, and endotoxin shock syndrome. Nanoparticulate meloxicam
is also useful as an immunosuppressive agent.
[0055] Exemplary forms of arthritic disorders which can be treated
include, but are not limited to, osteoarthritis, rheumatoid
arthritis, spondyloarthropathies, gouty arthritis, juvenile
arthritis, gout, ankylosing spondylitis, systemic lupus
erythematosus, bursitis, tendinitis, myofascial pain, carpal tunnel
syndrome, fibromyalgia syndrome, infectious arthritis, psoriatic
arthritis, reiter's syndrome, and scleroderma.
[0056] Exemplary gastrointestinal conditions or ulcerative diseases
which can be treated include, but are not limited to, inflammatory
bowel disease, Crohn's disease, gastritis, irritable bowel
syndrome, ulcerative colitis, gastric ulcer, pathological but
non-malignant conditions such as hemangiomas, including infantile
hemaginomas, angiofibroma of the nasopharynx, and avascular
necrosis of bone.
[0057] Exemplary inflammation conditions which can be treated
include, but are not limited to, migraine headaches, periarteritis
nodosa, thyroiditis, aplastic anemia, Hodgkin's disease,
sclerodoma, rheumatic fever, type I diabetes, neuromuscular
junction disease including myasthenia gravis, white matter disease
including multiple sclerosis, sarcoidosis, nephrotic syndrome,
Behcet's syndrome, polymyositis, gingivitis, nephritis,
hypersensitivity, swelling occurring after injury including brain
edema, myocardial ischemia, post-operative inflammation including
that following ophthalmic surgery such as cataract surgery or
refractive surgery, and the like.
[0058] Exemplary pulmonary inflammation conditions which can be
treated include, but are not limited to, inflammation associated
with viral infections and cystic fibrosis, and in bone resorption
such as that associated with osteoporosis. Exemplary opthalmic
diseases or conditions which can be treated include, but are not
limited to, retinitis, conjunctivitis, retinopathies, uveitis,
ocular photophobia, acute injury to the eye tissue, corneal graft
rejection, ocular neovascularization, retinal neovascularization
including neovascularization following injury or infection,
diabetic retinopathy, macular degeneration, retrolental
fibroplasia, glaucoma, and neovascular glaucoma. Exemplary central
nervous system disorders which can be treated include, but are not
limited to, cortical dementias including Alzheimer's disease,
neurodegeneration, and central nervous system damage resulting from
stroke, ischemia, and trauma. Exemplary pain conditions which can
be treated include, but are not limited to, low back and neck pain,
postoperative pain, pain resulting from battle field wounds, dental
pain, muscular pain, pain resulting from cancer, headaches,
including sinus headache and migraine, menstrual cramps, and pain
associated with inflammation.
[0059] According to a preferred embodiment, the compositions of the
invention are useful for treating moderate to moderately severe
acute pain and/or prescribed for the management of severe pain as
an adjunct therapy to opiod analgesics and may allow a reduction in
the opiod dose and corresponding adverse events associated with
opiod use. When the meloxicam composition of the present invention
is formulated into an injectable dosage form and administered to a
patient in need thereof, the composition of the invention provides
a time to first perceptible pain relief. Time to first perceptible
pain relief is the time from administration of the drug to the
point at which the patient first perceives a change in their pain
intensity (as discussed in Example 10). The time to perceptible
pain relief ranges from about less than 1 minute, from about 1 to
30, 2 to 25, 5 to 20, 10 to 20 and 12 to 18 minutes. In other
words, an injectable form of the present invention, when
administered to a patient in need thereof, provides a time to first
perceptible pain relief in about 30, 25, 20, 18, 16, 15, 14, 13,
12, 11, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1 or less than 1 minute.
[0060] According to another embodiment, when the meloxicam
composition of the present invention is formulated into an
injectable dosage form and administered to a patient in need
thereof, the composition of the invention provides a time to
meaningful pain relief. Time to meaningful pain relief is the time
from administration of the drug to the point at which the patient
first perceives a meaningful reduction in pain intensity (as
discussed in Example 10). The time to first meaningful pain relief
ranges from about less than 25, from 25 to 300, 75 to 250, 100 to
200, and 115 to 125 minutes. In other words, an injectable form of
the present invention, when administered to a patient in need
thereof, provides a time to meaningful pain relief in about 300,
275, 250, 225, 200, 195, 185, 175, 165, 155, 150, 125, 100, 75, 50,
25, or less than 25 minutes.
[0061] According to yet another embodiment, when the meloxicam
composition is formulated into an injectable dosage form and
administered to a patient in need thereof, the composition of the
invention provides meaningful pain relief for an extended period of
time, such as, a period of up to 24 hours. According to other
exemplary embodiments, the expended period of time that patients
experience meaningful pain relief ranges from about 120 to 1440,
180 to 1320, 240 to 1260, 300 to 1200, 360 to 1140, 480 to 1080,
540 to 1020, 600 to 960, 660 to 900, or 720 to 840 minutes. In
other words, an injectable form of the present invention, when
administered to a patient in need thereof, provides a meaningful
pain relief for up to about 120, 180, 240, 300, 360, 420, 480, 540,
600, 660, 720, 780, 840, 900, 960, 1020, 1080, 1140, 1200, 1260,
1320, or 1440 minutes. In a preferred embodiment, an exemplary
method for treating moderate to moderately severe acute pain
comprises administering to a patient in need thereof, an
intravenous dosage form comprising 15 mg, 30, mg, or 60 mg, of
meloxicam which provides a duration of analgesic effect for up to
1440 minutes (i.e., 24 hours).
[0062] Exemplary inflammation-related cardiovascular disorders
which can be treated or prevented using the compositions of the
invention include, but are not limited to, vascular diseases,
coronary artery disease, aneurysm, vascular rejection,
arteriosclerosis, atherosclerosis including cardiac transplant
atherosclerosis, myocardial infarction, embolism, stroke,
thrombosis including venous thrombosis, angina including unstable
angina, coronary plaque inflammation, bacterial-induced
inflammation including Chlamydia-induced inflammation, viral
induced inflammation, and inflammation associated with surgical
procedures such as vascular grafting including coronary artery
bypass surgery, revascularization procedures including angioplasty,
stent placement, endarterectomy, or other invasive procedures
involving arteries, veins, and capillaries.
[0063] In a preferred embodiment, meloxicam is useful for treating
inflammation and pain in post-surgical settings. For example, one
post surgical setting is post dental procedures, like extractions
or molar insertions or bridge-work. Another surgical setting is
post surgical soft tissue procedures, like abdominal surgeries
involving appendectomies or gall bladder removals. Yet another
post-surgical setting includes procedures related to bone
manipulations, like hip, knee and shoulder surgeries.
[0064] Exemplary angiogenesis-related disorders include, but are
not limited to, inhibition of tumor angiogenesis. Such compositions
are useful in treatment of neoplasia, including metastasis, benign
and malignant tumors, and neoplasia including cancer, such as
colorectal cancer, brain cancer, bone cancer, epithelial
cell-derived neoplasia (epithelial carcinoma) such as basal cell
carcinoma, adenocarcinoma, gastrointestinal cancer such as lip
cancer, mouth cancer, esophageal cancer, small bowel cancer,
stomach cancer, colon cancer, liver cancer, bladder cancer,
pancreas cancer, ovary cancer, cervical cancer, lung cancer, breast
cancer, skin cancer such as squamous cell and basal cell cancers,
prostate cancer, renal cell carcinoma, and other known cancers that
effect epithelial cells throughout the body. Neoplasias for which
compositions of the invention are contemplated to be particularly
useful are gastrointestinal cancer, Barrett's esophagus, liver
cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate
cancer, cervical cancer, lung cancer, breast cancer and skin
cancer. The nanoparticulate meloxicam compositions of the invention
can also be used to treat fibrosis that occurs with radiation
therapy.
[0065] The compositions of the invention can be used to treat
subjects having adenomatous polyps, including those with familial
adenomatous polyposis (FAP). Additionally, such compositions can be
used to prevent polyps from forming in patients at risk of FAP.
[0066] Because the meloxicam compositions of the invention inhibit
prostanoid-induced smooth muscle contraction by inhibiting
synthesis of contractile prostanoids, the compositions can be used
in the treatment of dysmenorrhea, premature labor, asthma, and
eosinophil-related disorders.
[0067] The compositions of the invention are also useful in
treating indications where anti-inflammatory agents,
anti-angiogenesis agents, antitumorigenic agents, immunosuppressive
agents, NSAIDs, COX-2 inhibitors, analgesic agents, anti-thrombotic
agents, narcotics, or antifebrile agents are typically used.
[0068] 2. Non-Meloxicam Active Agents
[0069] The nanoparticulate meloxicam compositions of the invention
can additionally comprise one or more non-meloxicam active agents,
in either a conventional or nanoparticulate form. The non-meloxicam
active agents, if present in nanoparticulate form, are present in a
crystalline phase, a semi-crystalline, an amorphous phase, or a
mixture thereof.
[0070] Such active agents can be, for example, an active,
therapeutic, or diagnostic agent. A therapeutic agent can be a
pharmaceutical agent, including biologics such as proteins,
peptides, and nucleotides, or a diagnostic agent, such as a
contrast agent, including x-ray contrast agents. The active agent
can be selected from a variety of known classes of drugs,
including, for example, proteins, peptides, nucleotides,
anti-obesity drugs, nutraceuticals, dietary supplements,
carotenoids, corticosteroids, elastase inhibitors, anti-fungals,
oncology therapies, anti-emetics, analgesics, cardiovascular
agents, anti-inflammatory agents, such as NSAIDs and COX-2
inhibitors, anthelmintics, anti-arrhythmic agents, antibiotics
(including penicillins), anticoagulants, antidepressants,
antidiabetic agents, antiepileptics, antihistamines,
antihypertensive agents, antimuscarinic agents, antimycobacterial
agents, antineoplastic agents, immunosuppressants, antithyroid
agents, antiviral agents, anxiolytics, sedatives (hypnotics and
neuroleptics), astringents, beta-adrenoceptor blocking agents,
blood products and substitutes, cardiac inotropic agents, contrast
media, corticosteroids, cough suppressants (expectorants and
mucolytics), diagnostic agents, diagnostic imaging agents,
diuretics, dopaminergics (antiparkinsonian agents), haemostatics,
immunological agents, lipid regulating agents, muscle relaxants,
parasympathomimetics, parathyroid calcitonin and biphosphonates,
prostaglandins, radio-pharmaceuticals, sex hormones (including
steroids), anti-allergic agents, stimulants and anoretics,
sympathomimetics, thyroid agents, vasodilators, and xanthines.
[0071] A description of these classes of active agents and a
listing of species within each class can be found in Martindale's
The Extra Pharmacopoeia, 31st Edition (The Pharmaceutical Press,
London, 1996), specifically incorporated by reference. The active
agents are commercially available and/or can be prepared by
techniques known in the art.
[0072] Exemplary nutraceuticals and dietary supplements are
disclosed, for example, in Roberts et al., Nutraceuticals: The
Complete Encyclopedia of Supplements, Herbs, Vitamins, and Healing
Foods (American Nutraceutical Association, 2001), which is
specifically incorporated by reference. A nutraceutical or dietary
supplement, also known as phytochemicals or functional foods, is
generally any one of a class of dietary supplements, vitamins,
minerals, herbs, or healing foods that have medical or
pharmaceutical effects on the body. Exemplary nutraceuticals or
dietary supplements include, but are not limited to, lutein, folic
acid, fatty acids (e.g., DHA and ARA), fruit and vegetable
extracts, vitamin and mineral supplements, phosphatidylserine,
lipoic acid, melatonin, glucosamine/chondroitin, Aloe Vera, Guggul,
glutamine, amino acids (e.g., iso-leucine, leucine, lysine,
methionine, phenylanine, threonine, tryptophan, and valine), green
tea, lycopene, whole foods, food additives, herbs, phytonutrients,
antioxidants, flavonoid constituents of fruits, evening primrose
oil, flax seeds, fish and marine animal oils, and probiotics.
Nutraceuticals and dietary supplements also include bio-engineered
foods genetically engineered to have a desired property, also known
as "pharmafoods."
[0073] Nanoparticulate meloxicam compositions useful in methods of
the present invention can be used in combination therapies with
opioids and other analgesics, including narcotic analgesics, Mu
receptor antagonists, Kappa receptor antagonists, non-narcotic
(i.e., non-addictive) analgesics, monoamine uptake inhibitors,
adenosine regulating agents, cannabinoid derivatives, Substance P
antagonists, neurokinin-1 receptor antagonists and sodium channel
blockers, among others.
[0074] Preferred combination therapies comprise a composition
useful in methods of the invention with one or more compounds
selected from aceclofenac, acemetacin, e-acetamidocaproic acid,
acetaminophen, acetaminosalol, acetanilide, acetylsalicylic acid
(aspirin), S-adenosylmethionine, alclofenac, alfentanil,
allylprodine, alminoprofen, aloxiprin, alphaprodine, aluminum
bis(acetylsalicylate), amfenac, aminochlorthenoxazin,
3-amino-4-hydroxybutyric acid, 2-amino-4-picoline, aminopropylon,
aminopyrine, amixetrine, ammonium salicylate, ampiroxicam,
amtolmetin guacil, anileridine, antipyrine, antipyrine salicylate,
antrafenine, apazone, bendazac, benorylate, benoxaprofen,
benzpiperylon, benzydamine, benzylmorphine, bermoprofen,
bezitramide, .alpha.-bisabolol, bromfenac, p-bromoacetanilide,
5-bromosalicylic acid acetate, bromosaligenin, bucetin, bucloxic
acid, bucolome, bufexamac, bumadizon, buprenorphine, butacetin,
butibufen, butophanol, calcium acetylsalicylate, carbamazepine,
carbiphene, carprofen, carsalam, chlorobutanol, chlorthenoxazin,
choline salicylate, cinchophen, cinmetacin, ciramadol, clidanac,
clometacin, clonitazene, clonixin, clopirac, clove, codeine,
codeine methyl bromide, codeine phosphate, codeine sulfate,
cropropamide, crotethamide, desomorphine, dexoxadrol,
dextromoramide, dezocine, diampromide, diclofenac sodium,
difenamizole, difenpiramide, diflunisal, dihydrocodeine,
dihydrocodeinone enol acetate, dihydromorphine, dihydroxyaluminum
acetylsalicylate, dimenoxadol, dimepheptanol, dimethylthiambutene,
dioxaphetyl butyrate, dipipanone, diprocetyl, dipyrone, ditazol,
droxicam, emorfazone, enfenamic acid, epirizole, eptazocine,
etersalate, ethenzamide, ethoheptazine, ethoxazene,
ethylmethylthiambutene, ethylmorphine, etodolac, etofenamate,
etonitazene, eugenol, felbinac, fenbufen, fenclozic acid, fendosal,
fenoprofen, fentanyl, fentiazac, fepradinol, feprazone,
floctafenine, flufenamic acid, flunoxaprofen, fluoresone,
flupirtine, fluproquazone, flurbiprofen, fosfosal, gentisic acid,
glafenine, glucametacin, glycol salicylate, guaiazulene,
hydrocodone, hydromorphone, hydroxypethidine, ibufenac, ibuprofen,
ibuproxam, imidazole salicylate, indomethacin, indoprofen,
isofezolac, isoladol, isomethadone, isonixin, isoxepac, isoxicam,
ketobemidone, ketoprofen, ketorolac, p-lactophenetide, lefetamine,
levorphanol, lofentanil, lonazolac, lomoxicam, loxoprofen, lysine
acetylsalicylate, magnesium acetylsalicylate, meclofenamic acid,
mefenamic acid, meperidine, meptazinol, mesalamine, metazocine,
methadone hydrochloride, methotrimeprazine, metiazinic acid,
metofoline, metopon, mofebutazone, mofezolac, morazone, morphine,
morphine hydrochloride, morphine sulfate, morpholine salicylate,
myrophine, nabumetone, nalbuphine, 1-naphthyl salicylate, naproxen,
narceine, nefopam, nicomorphine, nifenazone, niflumic acid,
nimesulide, 5'-nitro-2'-propoxyacetanilide, norlevorphanol,
normethadone, normorphine, norpipanone, olsalazine, opium,
oxaceprol, oxametacine, oxaprozin, oxycodone, oxymorphone,
oxyphenbutazone, papavereturn, paranyline, parsalmide, pentazocine,
perisoxal, phenacetin, phenadoxone, phenazocine, phenazopyridine
hydrochloride, phenocoll, phenoperidine, phenopyrazone, phenyl
acetylsalicylate, phenylbutazone, phenyl salicylate, phenyramidol,
piketoprofen, piminodine, pipebuzone, piperylone, piprofen,
pirazolac, piritramide, piroxicam, pranoprofen, proglumetacin,
proheptazine, promedol, propacetamol, propiram, propoxyphene,
propyphenazone, proquazone, protizinic acid, ramifenazone,
remifentanil, rimazolium metilsulfate, salacetamide, salicin,
salicylamide, salicylamide o-acetic acid, salicylsulfuric acid,
salsalte, salverine, simetride, sodium salicylate, sufentanil,
sulfasalazine, sulindac, superoxide dismutase, suprofen,
suxibuzone, talniflumate, tenidap, tenoxicam, terofenamate,
tetrandrine, thiazolinobutazone, tiaprofenic acid, tiaramide,
tilidine, tinoridine, tolfenamic acid, tolmetin, tramadol,
tropesin, viminol, xenbucin, ximoprofen, zaltoprofen, and
zomepirac. See The Merck Index, 12th Edition (1996), Therapeutic
Category and Biological Activity Index, lists therein headed
"Analgesic", "Anti-inflammatory", and "Antipyretic").
[0075] Particularly preferred combination therapies comprise use of
a nanoparticulate meloxicam composition of the invention with an
opioid compound, more particularly where the opioid compound is
codeine, meperidine, morphine, or a derivative thereof.
[0076] The compound to be administered in combination with a
nanoparticulate meloxicam composition of the invention can be
formulated separately from said composition or co-formulated with
said composition. Where a meloxicam composition is co-formulated
with a second drug, for example an opioid drug, the second drug can
be formulated in immediate-release, rapid-onset, sustained-release,
or dual-release form.
[0077] In an embodiment of the invention, particularly where the
COX-2 mediated condition is headache or migraine, the
nanoparticulate meloxicam composition is administered in
combination therapy with a vasomodulator, preferably a xanthine
derivative having vasomodulatory effect, more preferably an
alkylxanthine compound.
[0078] Combination therapies wherein an alkylxanthine compound is
co-administered with a nanoparticulate meloxicam composition as
provided herein are embraced by the present embodiment of the
invention whether or not the alkylxanthine is a vasomodulator and
whether or not the therapeutic effectiveness of the combination is
to any degree attributable to a vasomodulatory effect. The term
"alkylxanthine" herein embraces xanthine derivatives having one or
more C1-4 alkyl substituents, preferably methyl, and
pharmaceutically acceptable salts of such xanthine derivatives.
Dimethylxanthines and trimethylxanthines, including caffeine,
theobromine, and theophylline, are especially preferred. Most
preferably, the alkylxanthine compound is caffeine.
[0079] Exemplary COX-2 inhibitors which can be formulated in
combination with the nanoparticulate meloxicam composition of the
invention include, but are not limited to, celecoxib, rofecoxib
(Vioxx.RTM.), meloxicam (MOBIC.RTM., co-marketed by Abbott
Laboratories, Chicago, Ill., and Boehringer Ingelheim
Pharmaceuticals, Inc.), valdecoxib (G.D. Searle & Co.),
parecoxib (G.D. Searle & Co.), MK-966 (Merck, in Phase III
studies), etoricoxib (MK-663; Merck, in Phase II studies), SC-236
(chemical name of
4-[5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)]benzenesulfona-
mide; G.D. Searle & Co., Skokie, Ill.); NS-398
(N-(2-cyclohexyloxy-4-nitrophenyl)methane sulfonamide; Taisho
Pharmaceutical Co., Ltd., Japan); SC-58125 (methyl sulfone
spiro(2.4)hept-5-ene I; Pharmacia/Searle & Co.); SC-57666
(Pharmacia/Searle & Co.); SC-58635 (celexcoxib;
Pharmacia/Searle & Co.); SC-558 (Pharmacia/Searle & Co.);
SC-560 (Pharmacia/Searle & Co.); etodolac (Lodine.RTM.,
Wyeth-Ayerst Laboratories, Inc.); DFU
(5,5-dimethyl-3-(3-fluorophenyl)-4-(4-methylsulfonyl)phenyl
2(5H)-furanone); MK-476, L-745337, L-761066, L-761000, L-748780,
and L-748731 (all Merck & Co.); DUP-697
(5-Bromo-2-(4-fluorophenyl)-3-(4-(methylsulfonyl)phenyl; DuPont
Merck Pharmaceutical Co.); PGV 20229
(1-(7-tert.-butyl-2,3-dihydro-3,3-dimethylbenzo(b)furan-5-yl)-4-cycloprop-
ylbutan-1-one) (Procter & Gamble Pharmaceuticals); T-614
(3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one;
Toyama Corp., Japan); BF 389 (Biofor, USA); PD 136005, PD 142893,
and PD 145065 (all Parke-Davis/Warner-Lambert Co.); flurbiprofen
(Ansaid.RTM.; Pharmacia & Upjohn); nimesulide (NIM-03,
Mesulid.RTM.; Hisamitsu, Japan); nabumetone (Relafen.RTM.;
SmithKline Beecham, plc); flosulide (CGP 28238; Novartis/Ciba
Geigy); piroxicam (Feldene.RTM.; Pfizer); dicofenac (Voltaren.RTM.
and Cataflam.RTM., Novartis); COX-189 (Novartis); D 1367 (Celltech
Chiroscience, plc); R 805 (4 nitro 2 phenoxymethane sulfonanilide);
R 807 (3 benzoyldifluoromethane sulfonanilide, diflumidone);
JTE-522 (Japan Tobacco, Japan); FK-3311
(4'-Acetyl-2'-(2,4-difluorophenoxy)methanesulfonanilide; Fujisawa,
Japan); FK 867 (Fujisawa, Japan); FR 115068 (Fujisawa, Japan); GR
253035 (Glaxo Wellcome); RWJ 63556 (Johnson & Johnson); RWJ
20485 (Johnson & Johnson); ZK 38997 (Schering); S 2474
((E)-(5)-(3,5-di-tert-butyl-4-hydroxybenzylidene)-2-ethyl-1,2-isothiazoli-
dine-1,1-dioxide indomethacin; Shionogi & Co., Ltd., Japan); CL
1004 (Parke-Davis); RS 57067 (Hoffmann La Roche); RS 104894
(Hoffmann La Roche); SC 41930 (Monsanto); SB 205312 (SmithKline
Beecham); SKB 209670 (SmithKline Beecham, plc); and Ono 1078 (Ono
Pharmaceutical Co., Japan).
[0080] 3. Surface Stabilizers for Nanoparticles
[0081] The meloxicam particles of the present invention have at
least one surface stabilizer adsorb on the surface thereof. Surface
stabilizers useful herein physically adhere on or associate with
the surface of the nanoparticulate meloxicam but do not chemically
react with the meloxicam particles. The surface stabilizers are
present in an amount sufficient to substantially prevent
aggregation or agglomeration of the meloxicam particles during
formation and/or administration of the meloxicam formulation.
[0082] Exemplary surface stabilizers include, but are not limited
to, known organic and inorganic pharmaceutical excipients, as well
as peptides and proteins. Such excipients include various polymers,
low molecular weight oligomers, natural products, and surfactants.
Useful surface stabilizers include nonionic surface stabilizers,
anionic surface stabilizers, cationic surface stabilizers, and
zwitterionic surface stabilizers. Combinations of more than one
surface stabilizer can be used in the invention.
[0083] Representative examples of surface stabilizers include, but
are not limited to, to foregoing alone or in combination:
hydroxypropyl methylcellulose (HPMC); dioctyl sodium succinate
(DOSS); sodium lauryl sulfate (SLS) a.k.a. sodium dodecyl sulfate
(SDS); hydroxypropyl cellulose grade HPC-SL (viscosity of 2.0 to
2.9 mPas, aqueous 2% WN solution, 20 DEG C, Nippon Soda Co., Ltd.);
polyvinylpyrrolidone (PVP) such as Kollidone.RTM. K12 sold by BASF
a.k.a. Plasdone.RTM. C-12 sold by ISP Technologies, Inc. (USA),
Kollidone.RTM. K17 sold by BASF a.k.a. Plasdone.RTM. C-17 sold by
ISP Technologies, Inc. (USA), Kollidone.RTM. K29/32 sold by BASF
a.k.a. Plasdone.RTM. C-29/32 sold by ISP Technologies, Inc. (USA);
sodium deoxycholate; block copolymers based on ethylene oxide and
propylene oxide commonly known as poloxamers which are sold under
the Pluronic.RTM. name by BASF (sold under the trade name
Lutrol.RTM. in EU) and include Pluronic.RTM. F 68 a.k.a. poloxamer
188, Pluronic.RTM. F 108, a.k.a. poloxamer 338, Pluronic.RTM. F 127
a.k.a poloxamer 407; benzalkonium chloride a.k.a.
alkyldimethylbenzylammonium chloride; copolymers of
vinylpyrrolidone and vinyl acetate commonly known as copovidone
sold under the tradename Plasdone.RTM. S-630 by ISP Technologies,
Inc. (USA); lecithin; distearyl palmitate glyceryl; polyoxyethylene
sorbitan fatty acid esters commonly known as polyoxyethylene 20
sorbitan monolaurate a.k.a. "polysorbate 20", polyoxyethylene 20
sorbitan monopalmitate a.k.a. "polysorbate 40," polyoxyethylene 20
sorbitan monooleate a.k.a. "polysorbate 80" sold under the trade
names Tween.RTM. 20, Tween.RTM. 40 and Tween.RTM. 80, respectively,
by ICI Americas; albumin; lysozyme; gelatin; macrogol 15
hydroxystearate sold as Solutol.RTM. 15 by BASF; tyloxapol, and
polyethoxylated castor oils sold under the trade name
Cremophor.RTM. EL by BASF.
[0084] Other surface stabilizers include, but are not limited to,
hydroxypropylcellulose, random copolymers of vinyl pyrrolidone and
vinyl acetate, casein, dextran, gum acacia, cholesterol,
tragacanth, stearic acid, benzalkonium chloride, calcium stearate,
glycerol monostearate, cetostearyl alcohol, cetomacrogol
emulsifying wax, sorbitan esters, polyoxyethylene alkyl ethers
(e.g., macrogol ethers such as cetomacrogol 1000); polyethylene
glycols (e.g., Carbowaxes 3550.RTM. and 934.RTM. (Union Carbide)),
polyoxyethylene stearates, colloidal silicon dioxide, phosphates,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
methylcellulose, hydroxyethylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol
(PVA), 4-(1,1,3,3-tetramethylbutyl)-phenol polymer with ethylene
oxide and formaldehyde (also known as tyloxapol, superione, and
triton); poloxamines (e.g., Tetronic 908.RTM., also known as
Poloxamine 908.RTM., which is a tetrafunctional block copolymer
derived from sequential addition of propylene oxide and ethylene
oxide to ethylenediamine (BASF Wyandotte Corporation, Parsippany,
N.J.); Tetronic 1508.RTM. (T-1508) (BASF Wyandotte Corporation),
Tritons X-200.RTM., which is an alkyl aryl polyether sulfonate
(Dow); Crodestas F-1100, which is a mixture of sucrose stearate and
sucrose distearate (Croda Inc.); p-isononylphenoxypoly-(glyc-idol),
also known as Olin-10G.RTM. or Surfactant 10-G.RTM. (Olin
Chemicals, Stamford, Conn.); Crodestas SL-40.RTM. (Croda, Inc.);
and SA.sub.9OHCO, which is
C.sub.18H.sub.37CH.sub.2C(O)N(CH.sub.3)--CH.sub.2(CHOH).sub.4(CH.sub.20H)-
.sub.2 (Eastman Kodak Co.); decanoyl-N-methylglucamide; n-decyl
.beta.-D-glucopyranoside; n-decyl .beta.-D-maltopyranoside;
n-dodecyl .beta.-D-glucopyranoside; n-dodecyl .beta.-D-maltoside;
heptanoyl-N-methylglucamide; n-heptyl-.beta.-D-glucopyranoside;
n-heptyl .beta.-D-thioglucoside; n-hexyl .beta.-D-glucopyranoside;
nonanoyl-N-methylglucamide; n-noyl .beta.-D-glucopyranoside;
octanoyl-N-methylglucamide; n-octyl-.beta.-D-glucopyranoside; octyl
.beta.-D-thioglucopyranoside; PEG-phospholipid, PEG-cholesterol,
PEG-cholesterol derivative, PEG-vitamin A, PEG-vitamin E, and the
like.
[0085] Additional examples of useful surface stabilizers include,
but are not limited to, polymers, biopolymers, polysaccharides,
cellulosics, alginates, phospholipids, poly-n-methylpyridinium
chloride, anthryul pyridinium chloride, cationic phospholipids,
chitosan, polylysine, polyvinylimidazole, polybrene,
polymethylmethacrylate trimethylammonium bromide (PMMTMABr),
hexyldecyltrimethylammonium bromide (HDMAB), and
polyvinylpyrrolidone-2-dimethylamino ethyl methacrylate dimethyl
sulfate.
[0086] Still further examples of useful stabilizers include, but
are not limited to, cationic lipids, sulfonium, phosphonium, and
quarternary ammonium compounds, stearyltrimethylammonium chloride,
benzyl-di(2-chloroethyl)ethylammonium bromide, coconut trimethyl
ammonium chloride or bromide, coconut methyl dihydroxyethyl
ammonium chloride or bromide, decyl triethyl ammonium chloride,
decyl dimethyl hydroxyethyl ammonium chloride or bromide,
C.sub.12-15dimethyl hydroxyethyl ammonium chloride or bromide,
coconut dimethyl hydroxyethyl ammonium chloride or bromide,
myristyl trimethyl ammonium methyl sulphate, lauryl dimethyl benzyl
ammonium chloride or bromide, lauryl dimethyl (ethenoxy)4 ammonium
chloride or bromide, N-alkyl (C.sub.12-18)dimethylbenzyl ammonium
chloride, N-alkyl (C.sub.14-18)dimethyl-benzyl ammonium chloride,
N-tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl
didecyl ammonium chloride, N-alkyl and (C.sub.12-14) dimethyl
1-napthylmethyl ammonium chloride, trimethylammonium halide,
alkyl-trimethylammonium salts and dialkyl-dimethylammonium salts,
lauryl trimethyl ammonium chloride, ethoxylated
alkyamidoalkyldialkylammonium salt and/or an ethoxylated trialkyl
ammonium salt, dialkylbenzene dialkylammonium chloride,
N-didecyldimethyl ammonium chloride, N-tetradecyldimethylbenzyl
ammonium, chloride monohydrate, N-alkyl(C.sub.12-14) dimethyl
1-naphthylmethyl ammonium chloride and dodecyldimethylbenzyl
ammonium chloride, dialkyl benzenealkyl ammonium chloride, lauryl
trimethyl ammonium chloride, alkylbenzyl methyl ammonium chloride,
alkyl benzyl dimethyl ammonium bromide, C.sub.12, C.sub.15,
C.sub.17 trimethyl ammonium bromides, dodecylbenzyl triethyl
ammonium chloride, poly-diallyldimethylammonium chloride (DADMAC),
dimethyl ammonium chlorides, alkyldimethylammonium halogenides,
tricetyl methyl ammonium chloride, decyltrimethylammonium bromide,
dodecyltriethylammonium bromide, tetradecyltrimethylammonium
bromide, methyl trioctylammonium chloride (sold under the
ALIQUAT.RTM. 336 trade name of the Henkel Corporation),
Polyquaternium-10, tetrabutylammonium bromide, benzyl
trimethylammonium bromide, choline esters (such as choline esters
of fatty acids), benzalkonium chloride, stearalkonium chloride
compounds (such as stearyltrimonium chloride and Di-stearyldimonium
chloride), cetyl pyridinium bromide or chloride, halide salts of
quaternized polyoxyethylalkylamines, alkyl pyridinium salts;
amines, such as alkylamines, dialkylamines, alkanolamines,
polyethylenepolyamines, N,N-dialkylaminoalkyl acrylates, and vinyl
pyridine, amine salts, such as lauryl amine acetate, stearyl amine
acetate, alkylpyridinium salt, and alkylimidazolium salt, and amine
oxides; imide azolinium salts; protonated quaternary acrylamides;
methylated quaternary polymers, such as poly[diallyl
dimethylammonium chloride] and poly-[N-methyl vinyl pyridinium
chloride]; and cationic guar.
[0087] Additional exemplary surface stabilizers are described in
detail in the Handbook of Pharmaceutical Excipients, published
jointly by the American Pharmaceutical Association and The
Pharmaceutical Society of Great Britain, the Pharmaceutical Press,
2005. The surface stabilizers are commercially available and/or can
be prepared by techniques known in the art. Presentations of
exemplary surface stabilizers are given in McCutcheon, Detergents
and Emulsifiers, Allied Publishing Co., New Jersey, 2004 and Van
Os, Haak and Rupert, Physicochemical Properties of Selected
Anionic, Cationic and Nonionic Surfactants, Elsevier, Amsterdam,
1993; Analytical and Biological Evaluation (Marcel Dekker, 1994);
P. and D. Rubingh (Editor), Cationic Surfactants: Physical
Chemistry (Marcel Dekker, 1991); and J. Richmond, Cationic
Surfactants: Organic Chemistry, (Marcel Dekker, 1990); all of which
are incorporated by reference.
[0088] 4. Other Pharmaceutical Excipients
[0089] Pharmaceutical compositions according to the invention may
also comprise one or more binding agents, filling agents,
lubricating agents, suspending agents, sweeteners, flavoring
agents, preservatives, buffers, wetting agents, disintegrants,
effervescent agents, and other excipients depending on the final
dosage form of the commercial product. Such excipients are known in
the art.
[0090] Examples of filling agents are lactose monohydrate, lactose
anhydrous, and various starches; examples of binding agents are
various celluloses and cross-linked polyvinylpyrrolidone,
microcrystalline cellulose, such as Avicel.RTM. PH101 and
Avicel.RTM. PH102, microcrystalline cellulose, and silicified
microcrystalline cellulose (ProSolv SMCC.TM.).
[0091] Suitable lubricants, including agents that act on the
flowability of a powder to be compressed, are colloidal silicon
dioxide, such as Aerosil.RTM. 200, talc, stearic acid, magnesium
stearate, calcium stearate, and silica gel.
[0092] Examples of sweeteners are any natural or artificial
sweetener, such as sucrose, xylitol, sodium saccharin, cyclamate,
aspartame, and acsulfame. Examples of flavoring agents are
Magnasweet.RTM. (trademark of MAFCO), bubble gum flavor, mint
flavor, and fruit flavors, and the like.
[0093] Examples of preservatives are potassium sorbate,
methylparaben, propylparaben, benzoic acid and its salts, other
esters of parahydroxybenzoic acid such as butylparaben, alcohols
such as ethyl or benzyl alcohol, phenolic compounds such as phenol,
or quarternary compounds such as benzalkonium chloride.
[0094] Suitable diluents include pharmaceutically acceptable inert
fillers, such as microcrystalline cellulose, lactose, dibasic
calcium phosphate, saccharides, and/or mixtures of any of the
foregoing. Examples of diluents include microcrystalline cellulose,
such as Avicel.RTM. PH101 and Avicel.RTM. PH102; lactose such as
lactose monohydrate, lactose anhydrous, and Pharmatose.RTM. DCL21;
dibasic calcium phosphate such as Emcompress.RTM.; mannitol;
starch; sorbitol; sucrose; and glucose.
[0095] Suitable disintegrants include lightly crosslinked polyvinyl
pyrrolidone, corn starch, potato starch, maize starch, and modified
starches, croscarmellose sodium, cross-povidone, sodium starch
glycolate, and mixtures thereof.
[0096] Examples of effervescent agents are effervescent couples
such as an organic acid and a carbonate or bicarbonate. Suitable
organic acids include, for example, citric, tartaric, malic,
fumaric, adipic, succinic, and alginic acids and anhydrides and
acid salts. Suitable carbonates and bicarbonates include, for
example, sodium carbonate, sodium bicarbonate, potassium carbonate,
potassium bicarbonate, magnesium carbonate, sodium glycine
carbonate, L-lysine carbonate, and arginine carbonate.
Alternatively, only the sodium bicarbonate component of the
effervescent couple may be present.
[0097] 5. Meloxicam Particle Size
[0098] In exemplary embodiments of the invention, compositions
comprising meloxicam nanoparticles are defined by a particle size
distribution. The particle size distribution is characterized by an
effective average particle size. Nanoparticle meloxicam composition
s of the invention have an effective particle size of less than
about 2000 nm (i.e., 2 microns), less than about 1500 nm, less than
about 1000 nm, less than about 900 nm, less than about 800 nm, less
than about 700 nm, less than about 600 nm, less than about 500 nm,
less than about 400 nm, less than about 300 nm, less than about 250
nm, less than about 200 nm, less than about 150 nm, less than about
100 nm, less than about 75 nm, or less than about 50 nm, as
measured by light-scattering methods, microscopy, or other
appropriate methods.
[0099] The distribution of medicament particles is also
characterized by D.sub.value. The nomenclature "D" followed by a
number, e.g., D.sub.50, is the particle size at which 50% of the
particles in a particle size distribution are smaller and 50% of
the particles are larger, when measured on a weight or volume
basis. In another example, the D.sub.90 of a particle size
distribution is the particle size below which 90% of particles
fall, and which conversely, only 10% of the particles are of a
larger particle size, when measured on a weight or volume basis.
The D.sub.90 of the distribution of medicament particles according
to an embodiment of the invention is 2000 nm (2 .mu.m), 1900 nm,
1800 nm, 1700 nm, 1600 nm, 1500 nm, 1400 nm, 1300 nm, 1200 nm, 1100
nm, 1000 nm (1 .mu.m), 900 nm, 800 nm, 700 nm, 600 nm, 500 nm, 400
nm, 300 nm, 200 nm, 150 nm, 100 nm, 75 nm, and 50 nm.
[0100] If the composition additionally comprises one or more
non-meloxicam nanoparticulate active agents, then such active
agents have an effective average particle size of less than about
2000 nm (i.e., 2 microns), less than about 1500 nm, less than about
1000 nm, less than about 900 nm, less than about 800 nm, less than
about 700 nm, less than about 600 nm, less than about 500 nm, less
than about 400 nm, less than about 300 nm, less than about 250 nm,
less than about 200 nm, less than about 150 nm, less than about 100
nm, less than about 75 nm, or less than about 50 nm, as measured by
light-scattering methods, microscopy, or other appropriate
methods.
[0101] 6. Concentration of Nanoparticulate Meloxicam, Surface
Stabilizers, and Optional One or More Active Agents
[0102] The concentration of meloxicam can vary from about 99.5% to
about 0.001%, from about 95% to about 0.1%, and from about 90% to
about 0.5%, by weight, based on the total combined weight of the
meloxicam and at least one surface stabilizer, not including other
excipients.
[0103] In a given unit dosage form, according to certain
embodiments of the invention, the dosage form comprises range of
2.5 to 120 mg, such as 2.5, 5, 7.5, 15, 30, 60, 75, 90, 105, or 120
mg of meloxicam.
[0104] The concentration of the at least one surface stabilizer can
vary from about 0.01% to about 99.5%, from about 0.1% to about 95%,
and from about 0.5% to about 90%, by weight, based on the total
combined dry weight of the meloxicam and at least one surface
stabilizer, not including other excipients.
[0105] 7. Methods of Making Nanoparticulate Formulations
[0106] The nanoparticulate meloxicam compositions can be made
using, for example, milling, homogenization, or precipitation
techniques. Exemplary methods of making nanoparticulate
compositions are described in the '684 patent. Methods of making
nanoparticulate compositions are also described in U.S. Pat. No.
5,518,187 for "Method of Grinding Pharmaceutical Substances;" U.S.
Pat. No. 5,718,388 for "Continuous Method of Grinding
Pharmaceutical Substances;" U.S. Pat. No. 5,862,999 for "Method of
Grinding Pharmaceutical Substances;" U.S. Pat. No. 5,665,331 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,662,883 for
"Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents
with Crystal Growth Modifiers;" U.S. Pat. No. 5,560,932 for
"Microprecipitation of Nanoparticulate Pharmaceutical Agents;" U.S.
Pat. No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions Containing Nanoparticles;" U.S. Pat. No. 5,534,270 for
"Method of Preparing Stable Drug Nanoparticles;" U.S. Pat. No.
5,510,118 for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles;" and U.S. Pat. No. 5,470,583 for "Method
of Preparing Nanoparticle Compositions Containing Charged
Phospholipids to Reduce Aggregation," all of which are specifically
incorporated by reference.
[0107] One or more non-meloxicam active agents can also be reduced
in size at the same time as meloxicam, to produce a nanoparticulate
meloxican and nanoparticulate non-meloxicam active agent
composition. A non-meloxicam active agent, which is either
conventional or nanoparticulate sized, can also be added to the
nanoparticulate meloxicam composition after size reduction.
[0108] In yet another embodiment of the invention, nanoparticulate
meloxicam compositions of the invention can be made in which the
formulation comprises multiple nanoparticulate meloxicam
compositions, each of which has a different effective average
particle size. Such a composition can be made by preparing the
individual nanoparticulate meloxicam formulations using, for
example, milling, precipitation, or homogenization techniques,
followed by combining the different compositions to prepare a
single dosage form.
[0109] B. Methods of Making Nanoparticulate Meloxicam
Compositions
[0110] 1. Milling to Obtain Nanoparticulate Meloxicam
Dispersions
[0111] Milling meloxicam to obtain a nanoparticulate dispersion
comprises dispersing meloxicam particles in a liquid dispersion
medium in which meloxicam is poorly soluble, followed by applying
mechanical means in the presence of rigid grinding media to reduce
the particle size of meloxicam to the desired effective average
particle size. The dispersion medium can be, for example, water,
safflower oil, ethanol, t-butanol, glycerin, polyethylene glycol
(PEG), hexane, or glycol.
[0112] The meloxicam particles can be reduced in size in the
presence of at least one surface stabilizer. Alternatively, the
meloxicam particles can be contacted with one or more surface
stabilizers after attrition. Other compounds, such as a diluent,
can be added to the meloxicam/surface stabilizer composition during
the size reduction process. Dispersions can be manufactured
continuously or in a batch mode. The resultant nanoparticulate
meloxicam dispersion can be utilized in solid or liquid dosage
formulations, such as liquid dispersions, gels, aerosols,
ointments, creams, controlled release formulations, fast melt
formulations, lyophilized formulations, tablets, capsules, delayed
release formulations, extended release formulations, pulsatile
release formulations, mixed immediate release and controlled
release formulations, etc.
[0113] 2. Precipitation to Obtain Nanoparticulate Meloxicam
Compositions
[0114] Another method of forming the desired nanoparticulate
meloxicam composition is by microprecipitation. This is a method of
preparing stable dispersions of poorly soluble active agents in the
presence of one or more surface stabilizers and one or more colloid
stability enhancing surface active agents free of any trace toxic
solvents or solubilized heavy metal impurities. Such a method
comprises, for example: (1) dissolving meloxicam in a suitable
solvent; (2) adding the formulation from step (1) to a solution
comprising at least one surface stabilizer; and (3) precipitating
the formulation from step (2) using an appropriate non-solvent. The
method can be followed by removal of any formed salt, if present,
by dialysis or diafiltration and concentration of the dispersion by
conventional means. The resultant nanoparticulate meloxicam
dispersion can be utilized in solid or liquid dosage formulations,
such as liquid dispersions, gels, aerosols, ointments, creams,
controlled release formulations, fast melt formulations,
lyophilized formulations, tablets, capsules, delayed release
formulations, extended release formulations, pulsatile release
formulations, mixed immediate release and controlled release
formulations, etc.
[0115] 3. Homogenization to Obtain Meloxicam Nanoparticulate
Compositions
[0116] Exemplary homogenization methods of preparing active agent
nanoparticulate compositions are described in U.S. Pat. No.
5,510,118, for "Process of Preparing Therapeutic Compositions
Containing Nanoparticles." Such a method comprises dispersing
meloxicam particles in a liquid dispersion medium, followed by
subjecting the dispersion to homogenization to reduce the particle
size of the meloxicam to the desired effective average particle
size. The meloxicam particles can be reduced in size in the
presence of at least one surface stabilizer. Alternatively, the
meloxicam particles can be contacted with one or more surface
stabilizers either before or after attrition. Other compounds, such
as a diluent, can be added to the meloxicam/surface stabilizer
composition either before, during, or after the size reduction
process. Dispersions can be manufactured continuously or in a batch
mode. The resultant nanoparticulate meloxicam dispersion can be
utilized in solid or liquid dosage formulations, such as liquid
dispersions, gels, aerosols, ointments, creams, controlled release
formulations, fast melt formulations, lyophilized formulations,
tablets, capsules, delayed release formulations, extended release
formulations, pulsatile release formulations, mixed immediate
release and controlled release formulations, etc.
[0117] C. Methods of Using Meloxicam Formulations of the Current
Invention
[0118] The meloxicam compositions of the present invention can be
administered to a subject via any conventional means including, but
not limited to, orally, rectally, ocularly, parenterally (e.g.,
intravenous, intramuscular, or subcutaneous), intracisternally,
pulmonary, intravaginally, intraperitoneally, locally (e.g.,
powders, ointments or drops), or as a buccal or nasal spray. As
used herein, the term "subject" is used to mean an animal,
preferably a mammal, including a human or non-human. The terms
patient and subject may be used interchangeably.
[0119] The present invention provides a method of rapidly
increasing the plasma levels of orally administered meloxicam in a
subject. Such a method comprises administering to a subject an
effective amount of an orally administered composition comprising
nanoparticulate meloxicam.
[0120] Compositions suitable for parenteral injection may comprise
physiologically acceptable sterile aqueous or nonaqueous solutions,
dispersions, suspensions or emulsions, and sterile powders for
reconstitution into sterile injectable solutions or dispersions.
Examples of suitable aqueous and nonaqueous carriers, diluents,
solvents, or vehicles including water, ethanol, polyols
(propyleneglycol, polyethylene-glycol, glycerol, and the like),
suitable mixtures thereof, vegetable oils (such as olive oil) and
injectable organic esters such as ethyl oleate. Proper fluidity can
be maintained, for example, by the use of a coating such as
lecithin, by the maintenance of the required particle size in the
case of dispersions, and by the use of surfactants.
[0121] The nanoparticulate compositions may also contain adjuvants
such as preserving, wetting, emulsifying, and dispensing agents.
Prevention of the growth of microorganisms can be ensured by
various antibacterial and antifungal agents, such as parabens,
chlorobutanol, phenol, sorbic acid, and the like. It may also be
desirable to include isotonic agents, such as sugars, sodium
chloride, and the like. Prolonged absorption of the injectable
pharmaceutical form can be brought about by the use of agents
delaying absorption, such as aluminum monostearate and gelatin.
[0122] Solid dosage forms for oral administration include, but are
not limited to, capsules, tablets, pills, powders, and granules. In
such solid dosage forms, the active agent is admixed with at least
one of the following: (a) one or more inert excipients (or
carriers), such as sodium citrate or dicalcium phosphate; (b)
fillers or extenders, such as starches, lactose, sucrose, glucose,
mannitol, and silicic acid; (c) binders, such as
carboxymethylcellulose, alignates, gelatin, polyvinylpyrrolidone,
sucrose, and acacia; (d) humectants, such as glycerol; (e)
disintegrating agents, such as agar-agar, calcium carbonate, potato
or tapioca starch, alginic acid, certain complex silicates, and
sodium carbonate; (f) solution retarders, such as paraffin; (g)
absorption accelerators, such as quaternary ammonium compounds; (h)
wetting agents, such as cetyl alcohol and glycerol monostearate;
(i) adsorbents, such as kaolin and bentonite; and (j) lubricants,
such as talc, calcium stearate, magnesium stearate, solid
polyethylene glycols, sodium lauryl sulfate, or mixtures thereof.
For capsules, tablets, and pills, the dosage forms may also
comprise buffering agents.
[0123] Liquid dosage forms for oral administration include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, softgels, gummies, and elixirs. In addition to the active
agent, the liquid dosage forms may comprise inert diluents commonly
used in the art, such as water or other solvents, solubilizing
agents, and emulsifiers. Exemplary emulsifiers are ethyl alcohol,
isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol,
benzyl benzoate, propyleneglycol, 1,3-butyleneglycol,
dimethylformamide, oils, such as cottonseed oil, groundnut oil,
corn germ oil, olive oil, castor oil, and sesame oil, glycerol,
tetrahydrofurfuryl alcohol, polyethyleneglycols, fatty acid esters
of sorbitan, or mixtures of these substances, and the like.
[0124] Besides such inert diluents, the composition can also
include adjuvants, such as wetting agents, emulsifying and
suspending agents, sweetening, flavoring, and perfuming agents.
[0125] Ocular dosage forms of the nanoparticulate meloxicam of the
invention preferably do not include cross-linked
carboxyl-containing polymers, used as excipients, as described in
U.S. Pat. No. 5,192,535. Such excipients can be undesirable.
EXAMPLES
[0126] The following examples are given to illustrate the present
invention. It should be understood, however, that the invention is
not to be limited to the specific conditions or details described
in these examples.
Example 1
[0127] This example identifies and exemplary method to prepare a
nanoparticulate meloxicam dispersion suitable for injection.
[0128] A slurry of 20% (w/w) meloxicam and 4% (w/w) polyvinyl
pyrrolidone were milled in a NanoMill.RTM. milling system (Elan
Drug Delivery, Inc., King of Prussia, Pa.; see e.g., U.S. Pat. No.
6,431,478 for "Small Scale Mill").
Example 2
[0129] Aqueous dispersions of 5 wt. % meloxicam and 1 wt. %
stabilizer (see Table 1, below) were charged into a NanoMill.RTM.
milling system (Elan Drug Delivery, Inc., King of Prussia, Pa.; see
e.g., U.S. Pat. No. 6,431,478 for "Small Scale Mill").
[0130] Particle size analysis of the resultant milled dispersions
was performed using a Horiba LA-910 particle size analyzer (Horiba
Instruments, Irvine, Calif.). The results are shown below in Table
1. In the table below, the value for D50 is the particle size below
which 50% of the active agent particles fall. Similarly, D90 is the
particle size below which 90% of the active agent particles
fall.
TABLE-US-00001 TABLE 1 Mean D50 D90 Stabilizer (nm) (nm) (nm)
Optical Microscopy* poloxamer 188 133 110 226 Stable poloxamer 388
129 108 219 Stable polyvinylpyrrolidone k-12 98 90 125 Stable
polyvinylpyrrolidone k-17 98 95 135 Stable Polysorbate 80 227 227
322 Stable Sodium Deoxycholate 119 101 198 Stable Lecithin 190 169
271 Mild aggregation at initial Lysozyme 95 89 117 Moderate
aggregation at initial; Stable at 24 hours
[0131] All formulations were taken at initial time except for
Lecithin and Lysozyme. For those samples, the "initial particle
size" was measured at 24 hr post milling.
[0132] The results demonstrate that meloxicam can be formulated
into stable nanoparticulate compositions suitable for IV
administration with each of the surface stabilizers shown in Table
1, as all of the formulations have a particle size suitable for
injectable compositions. Nanoparticulate compositions shown in
Table 1 had mean particles sizes ranging from 95 to 227 nm, with
D50 and D90 sizes ranging from 89 nm to 227 nm and 117 nm to 322
nm, respectively.
Example 3
[0133] The purpose of this example was to test the stability of a
nanoparticulate meloxicam formulation comprising mannitol.
[0134] A slurry of 10% (w/w) meloxicam, 2.5% (w/w)
polyvinylpyrrolidone, 0.75% (w/w) NaDOC and 10% (w/w) mannitol was
milled to obtain a nanopartiuclate dispersion of meloxicam. The
nanoparticulate meloxicam dispersion was diluted to 5% meloxicam,
1.25% polyvinylpyrrolidone, 0.375% NaDOC, 5% mannitol and 15%
sucrose with a 30% sucrose solution. The formulation was stored at
5.degree. C. for 3 months. The resulting nanoparticulate meloxicam
formulation did not show any significant particle agglomeration or
aggregation.
Example 4
[0135] The purpose of this example was to test in vivo the
meloxicam compositions.
[0136] Four male and four female Beagle dogs were fasted overnight.
In addition, each dog was fasted for four (4) hours post dose. Each
dog received three different meloxicam formulations, which are
described in more detail below. Formulation #1 was a liquid
dispersion of nanoparticulate meloxicam particles; Formulation #2
was a lyophilized table of nanoparticulate meloxicam particles; and
Formulation #3 was a MOBIC.RTM. 7.5 mg tablet (Boehringer Ingelheim
Pharmaceuticals, Inc.).
[0137] Formulation #1 (liquid dispersion): 8.0 g meloxicam was
milled with a solution containing 1.6 g Poloxamer 407 and 70.4 g
water. The mean (weight average) final meloxicam particle size was
111 nm, as measured on a Horiba LB-910 particle size analyzer
(Horiba Instruments, Irvine, Calif.). 5 grams of the meloxicam
dispersion was then added to 45 grams of water to give a final
concentration of 1% meloxicam.
[0138] Formulation #2 (lyophilzed wafers): A "fast melt"
lyophilized dosage form was prepared from a nanoparticulate
dispersion of meloxicam to study the relationship between the
lyophilization and reconstitution process and the pharmacokinetic
data. 8.0 g meloxicam was added to a solution containing 2.4 g
polyvinylpyrrolidone, 1.6 g docusate sodium, and 68 g water. The
mean particle size of the meloxicam dispersion following milling
was 101 nm, as measured on a Horiba LA-910 particle size analyzer.
Mannitol, pullulan and glycerol were added to the dispersion and
placed in a lyophilizer to produce the final lyophilized wafer
dosage form. After 2.5 months the reconstituted mean particle size
of the meloxicam particles was 111 nm.
[0139] Formulation #3 (tablet): MOBIC.RTM. Tablets (Boehringer
Ingelheim), 7.5 mg.
[0140] Dog Study Protocol
[0141] In Phase 1, each dog received a single oral gavage dose of
7.5 mg meloxicam (Formulation #1), followed by an approximately 10
mL tap water flush of the gavage tube.
[0142] In Phase 2, after a 7-day washout period, the same eight
dogs received a 7.5 mg dose of meloxicam as a single lyophilized
wafer (Formulation #2).
[0143] In Phase 3, after a 7-day washout period, the same 8 dogs
received a single 7.5 mg tablet of MOBIC.RTM. (lot #251586N)
(Formulation #3).
[0144] Results
[0145] Blood samples were collected and processed to plasma at the
conclusion of each phase as follows: Blood samples (approximately 1
mL) were drawn at specified time points (blood collected predose
and at 0.167, 0.333, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 6, 8, 12, 16,
24, and 48 hours postdose). The Cmax, Tmax, and AUC for the three
different formulations are shown below in Table 2.
TABLE-US-00002 TABLE 2 Formulation Cmax (.mu.g/mL) Tmax (hours) AUC
1 (liquid dispersion) 3.499 0.750 118.225 2 (lyophilized wafer)
3.420 1.292 106.642 3 (MOBIC .RTM.) 2.768 3.375 99.870
[0146] Both the liquid dispersion of nanoparticulate meloxicam
(Formulation #1) and the lyophilized wafer of nanoparticulate
meloxicam (Formulation #2) showed a faster onset time and a larger
Cmax than the commercial MOBIC.RTM. tablet. In addition, the
smaller particle sizes of the nanoparticulate meloxicam
formulations resulted in faster dissolution, thereby producing a
much shorter Tmax (0.75 and 1.3 hours, respectively, for
Formulations #1 and #2, as compared to 3.4 hours for Formulation
#3). See FIG. 1.
Example 5
[0147] The formulation of Example 3 was evaluated in a single-dose,
crossover study following intravenous administration to humans. The
safety, tolerability, and pharmacokinetics were compared to
commercially available oral meloxicam tablets, 7.5 mg and 15 mg
MOBIC.RTM. tablets, NDA 020938 approval date 13 Apr. 2000
(Boehringer Ingelheim).
[0148] As reported on the 27 Jun. 2008 label for MOBIC.RTM.
tablets, meloxicam oral suspension doses of 7.5 mg/5 mL and 15
mg/10 mL have been found to be bioequivalent to meloxicam 7.5 mg
and 15 mg capsules, respectively. Meloxicam capsules have been
shown to be bioequivalent to Mobic.RTM. (meloxicam) tablets. See
table 1 of the MOBIC.RTM. tablet label reproduced below.
TABLE-US-00003 TABLE 3 1 Single Dose and Steady State
Pharmacokinetic Parameters for Oral 7.5 mg and 15 mg Meloxicam
(Mean and % CV).sup.1 Steady State Healthy Single Dose male Elderly
Elderly Renal Hepatic Pharma- adults males females failure
insufficiency cokinetic (Fed).sup.2 (Fed).sup.2 (Fed).sup.2
(Fasted) (Fasted) Parameters 7.5 mg.sup.3 15 mg 15 mg 15 mg 15 mg
(% CV) tablets capsules capsules capsules capsules N 18 5 8 12 12
C.sub.max 1.05 (20) 2.3 (59) 3.2 (24) 0.59 (36) 0.84 (29)
[.mu.g/mL] t.sub.max [h] 4.9 (8) 5 (12) 6 (27) 4 (65) 10 (87)
t.sub.1/2 [h] 20.1 (29) 21 (34) 24 (34) 18 (46) 16 (29) CL/f 8.8
(29) 9.9 (76) 5.1 (22) 19 (43) 11 (44) [mL/min] V.sub.z/f.sup.4 [L]
14.7 (32) 15 (42) 10 (30) 26 (44) 14 (29) .sup.1The parameter
values in the Table are from various studies .sup.2not under high
fat conditions .sup.3MOBIC tablets .sup.4V.sub.z/f = Dose/(AUC
K.sub.el) indicates data missing or illegible when filed
[0149] A single-dose, randomized, 2-treatment, 3-cohort (n=7), open
label crossover study of 3 dose levels (15 mg, 30 mg, and 60 mg) of
meloxicam of the present invention administered intravenously and
commercially available meloxicam (MOBIC.RTM. tablets) administered
orally was conducted. An exemplary method of administrating an
embodiment of the present invention is intravenous (IV) injection,
such as, but not limited to, slow intravenous (IV) push over 2
minutes or less.
[0150] Cohort 1 received 15 mg, cohort 2 received 30 mg, and cohort
3 received 60 mg of meloxicam according to the present invention.
Blood plasma drug concentrations and safety evaluations were
obtained at various times following dosing, up to 72 hours
postdose.
[0151] The following table displays the mean pharmacokinetic
parameters of an exemplary meloxicam composition following a single
dose exposure in healthy volunteers and the commercially available
meloxicam MOBIC.RTM. tablet for each cohort. Within each cohort,
the elimination rate and half life of the meloxicam were similar
and expected. Table 4 is a summary of pharmacokinetic parameters of
mean AUC.sub.last, and mean AUC.sub.inf for cohort 1, 2, and 3.
TABLE-US-00004 TABLE 4 Dosage Amount of AUC Exemplary embodiment of
Meloxicam (mg) (ng * hr/mL) Statistic the present invention MOBIC
.RTM. Tablet Cohort 1: 15 last Mean (SD) 46094.8 (14565.8) 42949.2
(11662.8) inf. Mean (SD) 57314.4 (27233.2) 53988.8 (23207.7) Cohort
2: 30 last Mean (SD) 92575.9 (18456.0) 88340.6 (16547.1) inf. Mean
(SD) 107508.7 (34443.0) 104400.0 (30656.2) Cohort 3: 60 last Mean
(SD) 156042.6 (24041.4) 146677.3 (21925.3) inf. Mean (SD) 171229.0
(34439.1) 163854.7 (32916.7)
Example 6
[0152] The purpose of this example was to evaluate the analgesic
efficacy of a single intravenous (IV) dose of the meloxicam
formulations made in accordance with Example 3 with varying dose
amount (15 mg, 30 mg, and 60 mg).
[0153] A randomized, single-dose study was completed in a post
dental surgical setting. The study was conducted on subjects who
underwent surgical removal of at least two, third molars with at
least one mandibular impaction. Following dental surgery, subjects
were randomly assigned treatment: placebo, 15 mg meloxicam IV, 30
mg meloxicam IV, 60 mg meloxicam IV, or MOTRIN.RTM. IB (ibuprofen)
400 mg. MORTIN.RTM. IB was given as 2, 200 mg tablets orally (400
mg total). Subjects were dosed within 5 hours and only when their
pain intensity (PI) rating was moderate to severe on a 4-point
Likert Scale (with categories of none, mild, moderate, or severe).
Efficacy measurements were made regularly up to a 24 hour time
period.
[0154] Pain intensity (PI) and pain relief (PR) were recorded at
10, 20, 30, and 45 mins, 1, 1.5, 2, 3, 4, 5, 6, 8, 20, 12, 18, and
24 hours after dosing. Time of onset was determined using a
two-stopwatch technique. Stopwatches were started when the subjects
received their study medication. Subjects were instructed to stop
the first stopwatch when pain relief was initially perceptible
(PI), and stop the second stopwatch when pain relief was considered
meaningful (PR). The duration of analgesia is represented by the
time interval between administration of the study drug and
administration of the rescue drug, if requested. If no rescue drug
was requested, pain relief was recorded for up to 24 hours post
administration.
[0155] FIG. 3 is a plot of the percentage of patients without first
perceptible pain relief over time to first perceptible pain relief
for those patients who were given the placebo, MOTRIN.RTM. IB
(ibuprofen) 400 mg, 15 mg meloxicam IV, or 60 mg meloxicam IV.
After 20 minutes, greater than 80% of the patients given either the
15 mg meloxicam IV or 60 mg meloxicam IV reported first perceptible
pain relief.
[0156] FIG. 4 is a plot of the percentage of patients without
meaningful pain relief over time to meaningful pain relief for
those patients who were given the placebo, MOTRIN.RTM. IB
(ibuprofen) 400 mg, 15 mg meloxicam IV, or 60 mg meloxicam IV.
After 2 hrs, greater than 60% of the patients given either the 15
mg meloxicam IV or 60 mg meloxicam IV reported meaningful pain
relief.
[0157] FIG. 5 is a plot of the percentage of patients without first
rescue medication over time to when the patient received the rescue
medication for those patients who were given the placebo,
MOTRIN.RTM. IB (ibuprofen) 400 mg, 15 mg meloxicam IV, or 60 mg
meloxicam IV. More than 80% of patients given the 60 mg meloxicam
IV did not request rescue medication for up to 24 hours (1440
min.). Also more than 40% of patients given the 15 mg meloxicam IV
did not request rescue medication for up to 24 hours (1440 min.).
In other words, patients who received either the 15 mg meloxicam IV
or 60 mg meloxicam IV experienced efficacious pain relief for up to
24 hours.
* * * * *