Note: Descriptions are shown in the official language in which they were submitted.
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COMPOSITIONS COMPRISING NANOPARTICULATE
NAPROXEN AND CONTROLLED RELEASE HYDROCODONE
CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of provisional Application No. 60/815,885,
filed June 23,
2006, and this application is a continuation-in-part of Application No.
11/372,857, filed March 10,
2006, is a continuation-in-part of Application No. 10/827,689, filed April
1,9, 2004, which is a
continuation of Application No. 10/354,483, filed January 30, 2003, now U.S.
Pat. No. 6,793,936,
which is a continuation of Application No. 10/331,754, filed December 30,
2002, now U.S. I'at. No.
6,902,742, which is a continuation of Application No. 09/850,425, filed May 7,
2001, now U.S. Pat.
No. 6,730,325, which is a continuation of Application No. 09/566,636, filed
May 8, 2000, now U.S.
Pat. No. 6,228,398, which is a continuation of Application No. PCT/US99/25632,
filed November 1,
1999, which claims the benefit of provisional Application No. 60/106,726,
filed November 2, 1998.
All of the above-identified applications are hereby incorporated by reference.
FIELD OF INVENTION
The present invention relates to compositions comprising nanoparticulate
naproxen, or a salt
or derivative thereof, in combination with a multiparticulate modified release
composition
comprising hydrocodone, or a salt or derivative thereof. In particular the
present invention relates
to compositions comprising nanoparticulate naproxen, or a salt or derivative
thereof, in
cornbination with a multiparticulate modified release composition that in
operation delivers
hydrocodone, or a salt or derivative thereof, in a bimodal or multimodal
manner. The present
invention further relates to solid oral dosage forms comprising such
multiparticulate controlled
release compositions as well as methods for delivering such compositions to a
patient in need
thereof.
BACKGROUND OF INVENTION
A. Background Regarding Oral Controlled Release Compositions
The effectiveness of pharmaceutical compounds in the prevention and treatment
of disease
states depends on a variety of factors including the rate and duration of
delivery of the compound
from the dosage form to the patient. The combination of delivery rate and
duration exhibited by a
given dosage form in a patient can be described as its in vivo release profile
and, depending on the
pharmaceutical compound administered, will be associated with a concentration
and duration of
the pharmaceutical compound in the blood plasma, referred to as a plasma
profile. As
pharmaceutical compounds vary in their pharmacokinetic properties such as
bioavailability, and
rates of absorption and elimination, the release profile and the resultant
plasma profile become
SUBSTITUTE SHEET (RULE 26)
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important elements to consider in designing effective drug therapies.
The release profiles of dosage forms may exhibit different rates and durations
of release
and may be continuous or pulsatile. Continuous release profiles include
release profiles in which
one or more pharmaceutical compounds are released continuously, either at a
constant or variable
rate, and pulsatile release profiles include release profiles in which at
least two discrete quantities
of one or more pharmaceutical compounds are released at different rates and/or
over different
time frames. For any given pharmaceutical compound or combination of such
compounds, the
release profile for a given dosage form gives rise to an associated plasma
profile in a patient.
Similar to the variables applicable to the release profile, the associated
plasma profile in a patient
may exhibit constant or variable blood plasma concentration levels of the
pharmaceutical
compounds in the dosage form over the duration of action and may be continuous
or pulsatile.
Continuous plasma profiles include plasma profiles of all rates and duration
which exhibit a single
plasma concentration maximum. Pulsatile plasma profiles include plasma
profiles in which at
least two higher blood plasma concentration levels of pharmaceutical compound
are separated by a
lower blood plasma concentration level. Pulsatile plasma profiles exhibiting
two peaks may be
described as "bimodal."
When two or more components of a dosage form have different release profiles,
the
release profile of the dosage form as a whole is a combination of the
individual release profiles.
The release profile of a two-component dosage form in which each component has
a different
release profile may described as "bimodal." For dosage forms of more than two
components in
which each component has a different release profile, the resultant release
profile of the dosage
form may be described as "multimodal." Depending on, at least in part, the
pharmacokinetics of
the pharmaceutical compounds that are used as well as the specific release
profiles of the
components of the dosage form, a bimodal or multimodal release profile may
result in either a
continuous or a pulsatile plasma profile in a patient. Conventional frequent
dosage regimes in
which an immediate release (IR) dosage form is administered at periodic
intervals typically gives
rise to a pulsatile plasma profile. In such cases, a peak in the plasma drug
concentration is
observed after administration of each IR dose with troughs (regions of low
drug concentration)
developing between consecutive administration time points. Such dosage regimes
(and their
resultant pulsatile plasma profiles) can have particular pharmacological and
therapeutic effects
associated with them that are beneficial for certain drug therapies. For
example, the wash out
period provided by the fall off of the plasma concentration of the active
ingredient between peaks
has been thought to be a contributing factor in reducing or preventing patient
tolerance to various
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types of drugs.
Many controlled release drug formulations are aimed at producing a zero-order
release of
the drug compound. Indeed, it is often a specific object of these formulations
to minimize the peak-
to-trough variation in plasma concentration levels associated with
conventional frequent dosage
regimes. For certain drugs, however, some of the therapeutic and
pharmacological effects intrinsic
in a pulsatile system may be lost or diminished as a result of the constant or
nearly constant plasma
concentration levels achieved by zero-order release drug delivery systems.
Thus, modified release
compositions or formulations which substantially mimic the release of frequent
IR dosage regimes,
while reducing the need for frequent dosing, is desirable. Similarly, modified
release compositions
or formulations which combine the benefits of at least two different release
profiles to achieve a
resultant plasma profile exhibiting phatinacokinetic values within
therapeutically effective
parameters is also desirable.
Shah et al., J Cont. Rel. (1989) 9:169-175 purports to disclose that certain
types of
hydroxypropyl methylcellulose ethers compressed into a solid dosage form with
a therapeutic agent
may produce a bimodal release profile. However, it is noted that while
polymers from one supplier
yielded a bimodal profile, the same polymers with almost identical product
specifications obtained
from a different source gave non-bimodal release profiles.
Giunchedi et al., Int. J. Pharm (1991) 77:177-181 discloses the use of a
hydrophilic matrix
multiple-unit formulation for the pulsed release of ketoprofen. Giunchedi et
al. teach that ketoprofen
is rapidly eliminated from the blood after dosing (plasma half-life 1-3 hours)
and consecutive
pulses of drug may be more beneficial than constant release for some
treatments. The multiple-unit
formulation disclosed comprises four identical hydrophilic matrix tablets
placed in a gelatin
capsule. Although the in vivo studies show two peaks in the plasma profile
there is no well defined
wash out period and the variation between the peak and trough plasma levels is
small.
Conte et al., Drug Dev. Ind. Pharm, (1989) 15:2583-2596 and EP 0 274 734
(Pharmidea Sri)
teach the use of a three layer tablet for delivery of ibuprofen in consecutive
pulses. The three layer
tablet is made up of a first layer containing the active ingredient, a barrier
layer (the second layer)
of semi-permeable material which is interposed between the first layer and a
third layer containing an
additional amount of active ingredient. The barrier layer and the third layer
are housed in an
impermeable casing. The first layer dissolves upon contact with a dissolving
fluid while the third
layer is only available after dissolution or rupture of the barrier layer. In
such a tablet the first
portion of active ingredient must be released instantly. This approach also
requires the provision of a
semi-permeable layer between the first and third layers in order to control
the relative rates of
delivery of the two portions of active ingredient. Additionally, rupture of
the semi-permeable layer
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leads to uncontrolled dumping of the second portion of the active ingredient
which may not be
desirable.
U.S. Pat. No. 5,158,777 (E. R. Squibb & Sons Inc.) discloses a formulation
comprising
captopril within an enteric or delayed release coated pH stable core combined
with additional
captopril which is available for immediate release following administration.
In order to form the pH
stable core, chelating agents such as disodium edetate or surfactants such as
polysorbate 80 are
used either alone or in combination with a buffering agent. The compositions
have an amount of
captopril available for immediate release following oral administration and an
additional amount of
pH stabilized captopril available for release in the colon.
U.S. Pat. Nos. 4,728,512, 4,794,001 and 4,904,476 (American Home Products
Corp.) relate
to preparations providing three distinct releases. The preparation contains
three groups of spheroids
containing an active medicinal substance: the first group of spheroids is
uncoated and rapidly
disintegrates upon ingestion to release an initial dose of medicinal
substance; the second group of
spheroids is coated with a pH sensitive coat to provide a second dose; and the
third group of
spheroids is coated with a pH independent coat to provide to third dose. The
preparation is designed
to provide repeated release of medicinal substances which are extensively
metabolized
presystemically or have relatively short elimination half-lives.
U.S. Pat. No. 5,837,284 (Mehta et al) discloses a methylphenidate dosage form
having
immediate release and delayed release particles. The delayed release is
provided by the use of
ammonio methacrylate pH independent polymers combined with certain fillers.
B. Background Regarding Hydrocodone
A typical example of a drug which may produce tolerance in patients is
hydrocodone.
Hydrocodone or dihydrocodeinone (marketed as Vicodin , Anexsia0, Dicodid ,
Hycodan0,
Hycomine0, Lorcet , LortabO, Norco , Hydroco0, Tussionex , and Vicoprofen ),
also known
as 4,5a-Epoxy-3-methoxy-l7-methylmorphinan-6-one tartrate (1:1) hydrate (2:5),
is an opiod derived
from either of the naturally occurring opiates codeine or thebaine. The
compound has the following
structure:
04p6o
Hydrocodone has the chemical formula C18H21N03, a molecular weight of 299.368,
and a
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half life of 4-8 hours.Hydrocodone is an orally active narcotic analgesic and
antitussive. Sales and
production of this drug have increased significantly in recent years, as have
diversion and illicit use.
Hydrocodone is commonly available in tablet, capsule and syrup form.
As a narcotic, hydrocodone relieves pain by binding to opioid receptors in the
brain and
spinal cord. It may be taken with or without food. When taken with alcohol, it
can intensify
drowsiness. It may interact with monoamine oxidase inhibitors, as well as
other drugs that cause
drowsiness. Common side effects include dizziness, lightheadedness, nausea,
drowsiness, euphoria,
vomiting, and constipation. Some less common side effects are allergic
reaction, blood disorders,
changes in mood, mental fogginess, anxiety, lethargy, difficulty urinating,
spasm of the ureter,
irregular or depressed respiration and rash.
Hydrocodone can be habit-forming , and can lead to physical and psychological
addiction.
In the U.S., pure hydrocodone and forms containing more than 15 ,,,g per
dosage unit are considered
Schedule II drugs. Those containing less than or equal to 15 mg per dosage
unit in combination with
acetaminophen or another non-controlled drug are called Hydrocodone Compounds
and are
considered Schedule III drugs. Hydrocodone can be found in combination with
other drugs such as
paracetamol (acetaminophen), aspirin, ibuprofen and homatropine methylbromide.
The presence of acetaminophen in hydrocodone-containing products deters many
drug
users from taking excessive amounts. However, some users will get around this
by extracting a
portion of the acetaminophen using hot/cold water, taking advantage of the
water-soluble element
of the drug. It is not uncommon for addicts to have liver problems from
consuming excessive
amounts of acetaminophen over a long period of time; taking 10,000 to 15,000
miligrams of
acetaminophen in a period of 24 hours typically results in severe
hepatoxicity, and doses in the
range of 15,000-20,0000 miligrams a day have been reported as fatal. It is
this factor that leads
many addicts to use only single entity opiates such as Oxycontin.
Daily consumption of hydrocodone should not exceed 40 milligrams in patients
not tolerant
to opiates. However, it clearly states in the 2006 PDR (Physicians Desk
Reference) that Norco 10,
containing 10 miligrams of hydrocodone and 325 miligrams of Apap, can be taken
at a dosage of up
to twelve tablets per day (120 miligrams of hydrocodone). Such high amounts of
hydrocodone are
only intended for opiate tolerant patients, and titration to such levels must
be monitored very
carefully. This restriction is only limited by the fact that twelve tablets,
each containing 325
miligrams of Apap, puts the patient right below the 24 hour FDA maximum of
4,000 mg of Apap.
Some specially compounded products are routinely given to chronic pain
patients in doses of up to
180 mg of hydrocodone per day. Tolerance to this drug can increase very
rapidly if abused.
Because of this, addicts often overdose from taking handfiills of pills, in
pursuit of the high they
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experienced very early on in their hydrocodone use. Symptoms of hydrocodone
overdosage
include respiratory depression, extreme somnolence, coma, stupor, cold and/or
clammy skin,
sometimes bradycardia, and hypotension. A severe overdose may involve
circulatory collapse,
cardiac arrest and/or death.
C. Background Regarding Naproxen
Naproxen, which is highly water insoluble, i.e., less than 10 mg/ml, has the
following
chemical structure:
CH3
CHCOOH
H3CO
Naproxen is a non-steroidal anti-inflammatory drug (NSAID) often used to
relieve the
inflammation, swelling, stiffness, and joint pain associated with rheumatoid
arthritis,
osteoarthritis (the most common form of arthritis), juvenile arthritis,
ankylosing spondylitis
(spinal arthritis), tendinitis, bursitis, and acute gout. In addition, it is
used to treat pain associated
with menstrual periods, migraine headaches, and other types of mild to
moderate pain.
Naproxen acts by suppressing the production of prostaglandins, which are
hormone-like
substances that act on local tissues to produce pain and inflammation. Its
pharmaceutical forms of
delivery include tablets, capsules, and liquids. Delivery characteristics and
forms are disclosed in,
for example, U.S. Patent Nos. 3,904,682; 4,009,197; 4,780,320; 4,888,178;
4,919,939; 4,940,588;
4,952,402; 5,200,193; 5,354,556; 5,462,747; and 5,480,650, all of which are
specifically
incorporated by reference. The synthesis of naproxen is described in U.S.
Patent Nos. 3,904,682
and 4,009,197.
Naproxen is a more potent pain reliever than aspirin, especially for menstrual
cramps,
toothaches, minor arthritis, and injuries accompanied by inflammation, such as
tendinitis. The
naproxen sodium salt is specifically indicated in the treatment of various
types of acute and very
high intensity pain because it induces a rapid and sustained remission. In
addition, it is possible to
obtain a good analgesic effect with few administrations, due to naproxen's
particular
pharmacokinetics. Tablet formulations of naproxen were approved for OTC ("over
the counter" as
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compared to prescription) marketing by the U.S. Food and Drug Administration
in 1994.
Because of naproxen's low solubility, it is generally formulated for oral
administration.
However, oral administration of naproxen frequently results in
gastrointestinal irritation. All
NSAIDs produce gastrointestinal symptoms to some degree upon oral
administration. Such
symptoms most commonly are constipation, gastric burns, diarrhea, stomatitis,
dyspepsia, nausea,
vomiting, upper abdominal pain, and heartburn. Oral administration may also
lead to an ulcer or
bleeding from the stomach or duodenum.
Gastrointestinal irritation resulting from oral administration of an NSAID can
be significant.
Numerous literature articles detail the severity of gastric irritation caused
by NSAID compositions.
For example, one report states that between 10,000 and 20,000 people in Canada
each year are
hospitalized with major gastro-intestinal bleeding caused by oral ingestion of
NSAIDs, with effects
resulting in death for at least 1,000 of these patients. See Marketplace,
October 24, 1996. Yet
another reference states that gastrointestinal complications of NSAID use may
be responsible for
over 10,000 deaths each year. See American Family Physician, March 1997.
D. Background Regarding Nanoparticulate Active Agent Compositions
Nanoparticulate active agent compositions, first described in U.S. Patent No.
5,145,684
("the '684 patent"), are particles consisting of a poorly soluble therapeutic
or diagnostic agent
having adsorbed onto or associated with the surface thereof a non-crosslinked
surface stabilizer.
Methods of making nanoparticulate active agent compositions are described in,
for
example, U.S. Patent Nos. 5,518,187 and 5,862,999, both for "Method of
Grinding
Pharmaceutical Substances;" U.S. Patent No. 5,718,388, for "Continuous Method
of Grinding
Pharmaceutical Substances;" and U.S. Patent No. 5,510,118 for "Process of
Preparing Therapeutic
Compositions Containing Nanoparticles."
Nanoparticulate active agent compositions are also described, for example, in
U.S. Patent
Nos. 5,298,262 for "Use of Ionic Cloud Point Modifiers to Prevent Particle
Aggregation During
Sterilization;" 5,302,401 for "Method to Reduce Particle Size Growth During
Lyophilization;"
5,318,767 for "X-Ray Contrast Compositions Useful in Medical Imaging;"
5,326,552 for "Novel
Formulation For Nanoparticulate X-Ray Blood Pool Contrast Agents Using High
Molecular
Weight Non-ionic Surfactants;" 5,328,404 for "Method of X-Ray Imaging Using
lodinated
Aromatic Propanedioates;" 5,336,507 for "Use of Charged Phospholipids to
Reduce Nanoparticle
Aggregation;" 5,340,564 for "Formulations Comprising Olin 10-G to Prevent
Particle Aggregation
and Increase Stability;" 5,346,702 for "Use of Non-Ionic Cloud Point Modifiers
to Minimize
Nanoparticulate Aggregation During Sterilization;" 5,349,957 for "Preparation
and Magnetic
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Properties of Very Small Magnetic-Dextran Particles;" 5,352,459 for "Use of
Purified Surface
Modifiers to Prevent Particle Aggregation During Sterilization;" 5,399,363 and
5,494,683, both for
"Surface Modified Anticancer Nanoparticles;" 5,401,492 for "Water Insoluble
Non-Magnetic
Manganese Particles as Magnetic Resonance Enhancement Agents;" 5,429,824 for
"Use of
Tyloxapol as a Nanoparticulate Stabilizer;" 5,447,710 for "Method for Making
Nanoparticulate X-
Ray Blood Pool Contrast Agents Using High Molecular Weight Non-ionic
Surfactants;" 5,451,393
for "X-Ray Contrast Compositions Useful in Medical Imaging;" 5,466,440 for
"Formulations of
Oral Gastrointestinal Diagnostic X-Ray Contrast Agents in Combination with
Pharmaceutically
Acceptable Clays;" 5,470,583 for "Method of Preparing Nanoparticle
Compositions Containing
Charged Phospholipids to Reduce Aggregation;" 5,472,683 for "Nanoparticulate
Diagnostic Mixed
Carbamic Anhydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic
System Imaging;"
5,500,204 for "Nanoparticulate Diagnostic Dimers as X-Ray Contrast Agents for
Blood Pool and
Lymphatic System Imaging;" 5,518,738 for "Nanoparticulate NSAID Formulations;"
5,521,218 for
"Nanoparticulate lododipamide Derivatives for Use as X-Ray Contrast Agents;"
5,525,328 for
"Nanoparticulate Diagnostic Diatrizoxy Ester X-Ray Contrast Agents for Blood
Pool and
Lymphatic System Imaging;" 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions
Containing Nanoparticles;" 5,552,160 for "Surface Modified NSAID
Nanoparticles;" 5,560,931 for
"Formulations of Compounds as Nanoparticulate Dispersions in Digestible Oils
or Fatty Acids;"
5,565,188 for "Polyalkylene Block Copolymers as Surface Modifiers for
Nanoparticles;" 5,569,448
for "Sulfated Non-ionic Block Copolymer Surfactant as Stabilizer Coatings for
Nanoparticle
Compositions;" 5,571,536 for "Formulations of Compounds as Nanoparticulate
Dispersions in
Digestible Oils or Fatty Acids;" 5,573,749 for "Nanoparticulate Diagnostic
Mixed Carboxylic
Anydrides as X-Ray Contrast Agents for Blood Pool and Lymphatic System
Imaging;" 5,573,750
for "Diagnostic Imaging X-Ray Contrast Agents;" 5,573,783 for "Redispersible
Nanoparticulate
Film Matrices With Protective Overcoats;" 5,580,579 for "Site-specific
Adhesion Within the GI
Tract Using Nanoparticles Stabilized by High Molecular Weight, Linear
Poly(ethylene Oxide)
Polymers;" 5,585,108 for "Formulations of Oral Gastrointestinal Therapeutic
Agents in
Combination with Pharmaceutically Acceptable Clays;" 5,587,143 for "Butylene
Oxide-Ethylene
Oxide Block Copolymers Surfactants as Stabilizer Coatings for Nanoparticulate
Compositions;"
5,591,456 for "Milled Naproxen with Hydroxypropyl Cellulose as Dispersion
Stabilizer;"
5,593,657 for "Novel Barium Salt Formulations Stabilized by Non-ionic and
Anionic Stabilizers;"
5,622,938 for "Sugar Based Surfactant for Nanocrystals;" 5,628,981 for
"Improved Formulations of
Oral Gastrointestinal Diagnostic X-Ray Contrast Agents and Oral
Gastrointestinal Therapeutic
Agents;" 5,643,552 for "Nanoparticulate Diagnostic Mixed Carbonic Anhydrides
as X-Ray
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Contrast Agents for Blood Pool and Lymphatic System Imaging;" 5,718,388 for
"Continuous
Method of Grinding Pharmaceutical Substances;" 5,718,919 for "Nanoparticles
Containing the R(-)
Enantiomer of Ibuprofen;" 5,747,001 for "Aerosols Containing Beclomethasone
Nanoparticle
Dispersions;" 5,834,025 for "Reduction of Intravenously Administered
Nanoparticulate
Formulation Induced Adverse Physiological Reactions;" 6,045,829
"Nanocrystalline Formulations
of Human Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic
Surface
Stabilizers;" 6,068,858 for "Methods of Making Nanocrystalline Formulations of
Human
Immunodeficiency Virus (HIV) Protease Inhibitors Using Cellulosic Surface
Stabilizers;"
6,153,225 for "Injectable Formulations of Nanoparticulate Naproxen;" 6,165,506
for "New Solid
Dose Form of Nanoparticulate Naproxen;" 6,221,400 for "Methods of Treating
Mammals Using
Nanocrystalline Formulations of Human Immunodeficiency Virus (HIV) Protease
Inhibitors;"
6,264,922 for "Nebulized Aerosols Containing Nanoparticle Dispersions;"
6,267,989 for "Methods
for Preventing Crystal Growth and Particle Aggregation in Nanoparticle
Compositions;" 6,270,806
for "Use of PEG-Derivatized Lipids as Surface Stabilizers for Nanoparticulate
Compositions;"
6,316,029 for "Rapidly Disintegrating Solid Oral Dosage Form," 6,375,986 for
"Solid Dose
Nanoparticulate Compositions Comprising a Synergistic Combination of a
Polymeric Surface
Stabilizer and Dioctyl Sodium Sulfosuccinate;" 6,428,814 for "Bioadhesive
Nanoparticulate
Compositions Having Cationic Surface Stabilizers;" 6,431,478 for "Small Scale
Mill;" 6,432,381
for "Methods for Targeting Drug Delivery to the Upper and/or Lower
Gastrointestinal Tract,"
6,592,903 for "Nanoparticulate Dispersions Comprising a Synergistic
Combination of a Polymeric
Surface Stabilizer and Dioctyl Sodium Sulfosuccinate," 6,582,285 for
"Apparatus for sanitary wet
milling;" 6,656,504 for "Nanoparticulate Compositions Comprising Amorphous
Cyclosporine;"
6,742,734 for "System and Method for Milling Materials;" 6,745,962 for "Small
Scale Mill and
Method Thereof;" 6,811,767 for "Liquid droplet aerosols of nanoparticulate
drugs;" 6,908,626 for
"Compositions having a combination of immediate release and controlled release
characteristics;"
6,969,529 for "Nanoparticulate compositions comprising copolymers of vinyl
pyrrolidone and vinyl
acetate as surface stabilizers;" and 6,976,647 for "System and Method for
Milling Materials," all of
which are specifically incorporated by reference. In addition, U.S. Patent
Publication No.
20020012675 Al, for "Controlled Release Nanoparticulate Compositions;" U.S.
Patent Publication
No. 20050276974 for "Nanoparticulate Fibrate Formulations;" U.S. Patent
Publication No.
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stabilizer;" U.S.
Patent Publication No. 20050233001 for "Nanoparticulate megestrol
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same for targeting nanoparticulate active agent delivery;" U.S. Patent
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for "Novel metaxalone compositions;" U.S. Patent Publication No. 20050042177
for "Novel
compositions of sildenafil free base;" U.S. Patent Publication No. 20050031691
for "Gel stabilized
nanoparticulate active agent compositions;" U.S. Patent Publication No.
20050019412 for " Novel
glipizide compositions;" U.S. Patent Publication No. 20050004049 for "Novel
griseofulvin
compositions;" U.S. Patent Publication No. 20040258758 for "Nanoparticulate
topiramate
formulations;" U.S. Patent Publication No. 20040258757 for " Liquid dosage
compositions of
stable nanoparticulate active agents;" U.S. Patent Publication No. 20040229038
for
"Nanoparticulate meloxicam formulations;" U.S. Patent Publication No.
20040208833 for "Novel
fluticasone formulations;" U.S. Patent Publication No. 20040195413 for "
Compositions and
method for milling materials;" U.S. Patent Publication No. 20040156895 for
"Solid dosage forms
comprising pullulan;" U.S. Patent Publication No. U.S. Patent Publication No.
U.S. Patent
Publication No. 20040156872 for "Novel nimesulide compositions;" U.S. Patent
Publication No.
20040141925 for "Novel triamcinolone compositions;" U.S. Patent Publication
No. 20040115134
for "Novel nifedipine compositions;" U.S. Patent Publication No. 20040105889
for "Low viscosity
liquid dosage forms;" U.S. Patent Publication No. 20040105778 for "Gamma
irradiation of solid
nanoparticulate active agents;" U.S. Patent Publication No. 20040101566 for
"Novel benzoyl
peroxide compositions;" U.S. Patent Publication No. 20040057905 for
"Nanoparticulate
beclomethasone dipropionate compositions;" U.S. Patent Publication No.
20040033267 for
"Nanoparticulate compositions of angiogenesis inhibitors;" U.S. Patent
Publication No.
20040033202 for "Nanoparticulate sterol formulations and novel sterol
combinations;" U.S. Patent
Publication No. 20040018242 for "Nanoparticulate nystatin formulations;" U.S.
Patent Publication
No. 20040015134 for "Drug delivery systems and methods;" U.S. Patent
Publication No.
20030232796 for "Nanoparticulate polycosanol formulations & novel polycosanol
combinations;"
U.S. Patent Publication No. 20030215502 for "Fast dissolving dosage forms
having reduced
friability;" U.S. Patent Publication No. 20030185869 for "Nanoparticulate
compositions having
lysozyme as a surface stabilizer;" U.S. Patent Publication No. 20030181411 for
"Nanoparticulate
compositions of mitogen-activated protein (MAP) kinase inhibitors;" U.S.
Patent Publication No.
20030137067 for "Compositions having a combination of immediate release and
controlled release
characteristics;" U.S. Patent Publication No. 20030108616 for "Nanoparticulate
compositions
comprising copolymers of vinyl pyrrolidone and vinyl acetate as surface
stabilizers;" U.S. Patent
Publication No. 20030095928 for "Nanoparticulate insulin;" U.S. Patent
Publication No.
20030087308 for "Method for high through put screening using a small scale
mill or
microfluidics;" U.S. Patent Publication No. 20030023203 for "Drug delivery
systems & methods;"
U.S. Patent Publication No. 20020179758 for "System and method for milling
materials; and U.S.
CA 02660649 2008-12-01
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Patent Publication No. 20010053664 for "Apparatus for sanitary wet milling,"
describe
nanoparticulate active agent compositions and are specifically incorporated by
reference.
In particular, U.S. Patent Nos. 5,518,738 for "Nanoparticulate NSAID
Formulations;"
5,552,160 for "Surface Modified NSAID Nanoparticles;" 5,591,456 for "Milled
Naproxen with
Hydroxypropyl Cellulose as Dispersion Stabilizer;" 6,153,225 for "Injectable
Formulations of
Nanoparticulate Naproxen;" and 6,165,506 for "New Solid Dose Form of
Nanoparticulate
Naproxen;" describe nanoparticulate naproxen and are incorporated by
reference. None of these
patents describe nanoparticulate naproxen in combination with controlled
release hydrocodone.
Amorphous small particle compositions are described, for example, in U.S.
Patent Nos.
4,783,484 for "Particulate Composition and Use Thereof as Antimicrobial
Agent;" 4,826,689 for
"Method for Making Uniformly Sized Particles from Water-Insoluble Organic
Compounds;"
4,997,454 for "Method for Making Uniformly-Sized Particles From Insoluble
Compounds;"
5,741,522 for "Ultrasmall, Non-aggregated Porous Particles of Uniform Size for
Entrapping Gas
Bubbles Within and Methods;" and 5,776,496, for "Ultrasmall Porous Particles
for Enhancing
Ultrasound Back Scatter." All of the aforementioned patents are hereby
incorporated by reference.
The problem with conventional hydrocodone formulations is that they can be
habit
forming. There is a need in the art for controlled release formulations that
may alleviate such side
effects. Moreover, there is a need in the art for new combination compositions
of controlled
release hydrocodone that provide alternatives to the existing combination
compositions. The
present invention satisfies these needs.
SUMMARY OF THE INVENTION
It is an object of the present invention to provide a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a
multiparticulate modified release
composition comprising at least two populations of hydrocodone-comprising
particles which,
upon administration to a patient, exhibit a bimodal or multimodal release
profile.
Another object of the invention is to provide a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a controlled
release hydrocodone
composition in which a first portion of the composition, i.e., a hydrocodone
or a salt or derivative
thereof, is released immediately upon administration and a second portion of
the hydrocodone, or
a salt or derivative thereof, is released rapidly after an initial delay
period in a bimodal manner.
It is another object of the invention to provide a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a
multiparticulate modified release
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composition comprising at least two populations of hydrocodone-comprising
particles which, upon
administration to a patient, exhibits a bimodal or multimodal release profile
that results in a plasma
profile within therapeutically effective pharmacokinetic parameters.
It is a further object of the invention to provide a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a
multiparticulate modified release
composition comprising at least two populations of hydrocodone-comprising
particles which, upon
administration to a patient, exhibits a pulsatile release profile, and/or a
pulsatile plasma profile.
It is still another object of the invention to provide a composition
comprising
nanoparticulate naproxen, or a salt or derivative thereof, in combination with
a multiparticulate
modified release composition comprising at least two populations of
hydrocodone-comprising
particles which, upon administration to a patient, (1) produces a plasma
profile substantially
similar to the plasma profile produced by the administration of two or more IR
dosage forms
given sequentially, and/or (2) substantially mimics the pharmacological and
therapeutic effects
produced by the administration of two or more IR dosage forms given
sequentially.
Conventional frequent dosage regimes in which an immediate release (IR) dosage
form is
administered at periodic intervals typically gives rise to a pulsatile plasma
profile. In this case, a
peak in the plasma drug concentration is observed after administration of each
IR dose with
troughs (regions of low drug concentration) developing between consecutive
administration time
points. Such dosage regimes (and their resultant pulsatile plasma profiles)
have particular
pharmacological and therapeutic effects associated with them. For example, the
wash out period
provided by the fall off of the plasma concentration of the active between
peaks has been thought to
be a contributing factor in reducing or preventing patient tolerance to
various types of drugs.
The present invention further relates to a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a controlled
release composition
comprising hydrocodone, or a salt or derivative thereof, which in operation
produced a
hydrocodone plasma profile that eliminates the "peaks" and "troughs" produced
by the
administration of two or more IR dosage forms given sequentially if such a
profile is beneficial.
This type of profile can be obtained using a controlled release mechanism that
allows for "zero-
order" delivery. Thus, it is a further object of the invention to provide a
composition comprising
nanoparticulate naproxen, or a salt or derivative thereof, in combination with
a controlled release
hydrocodone composition which in operation delivers hydrocodone, or a salt or
derivative
thereof, in a pulsatile manner or a zero-order manner.
Multiparticulate modified controlled release compositions similar to those
disclosed herein
are disclosed and claimed in the United States Patent Nos. 6,228,398 and
6,730,325 to Devane et
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al; both of which are incorporated by reference herein. All of the relevant
prior art in this field
may also be found therein.
Another object of the invention is to provide a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a controlled
release composition
which substantially reduces or eliminates the development of patient tolerance
to hydrocodone, or a
salt or derivative thereof.
Another object of the invention is to formulate the dosage in the form of
erodable
formulations, diffusion controlled formulations, or osmotic controlled
formulations.
Another object of the invention is to provide a controlled release composition
capable of
releasing a hydrocodone or a nanoparticulate naproxen in a bimodal or multi-
modal manner in
which a first portion of the active is released either immediately or after a
delay time to provide a
pulse of drug release and one or more additional portions of the hydrocodone
or a nanoparticulate
naproxen is released, after a respective lag time, to provide additional
pulses of drug release during
a period of up to twenty-four hours.
It is still a further object of the invention to provide a composition
comprising
nanoparticulate naproxen, or a salt or derivative thereof, in combination with
a multiparticulate
modified release composition comprising at least two populations of
hydrocodone-comprising
particles in which the amount of the one or more active ingredients in the
first population of
particles is a minor portion of the amount of the one or more active
ingredients in the composition,
and the amount of the one or more active ingredients in the one or more
additional population of
particles is a major portion of the amount of the one or more active
ingredients in the composition.
It is yet a further object of the invention to provide a solid dosage form
comprising the
composition comprising nanoparticulate naproxen, or a salt or derivative
thereof, in combination
with the multiparticulate modified release composition of the present
invention. A preferred
dosage form of the invention is a solid oral dosage form, although any
pharmaceutically acceptable
dosage form can be utilized.
Another aspect of the invention is directed to pharmaceutical compositions
comprising a
composition according to the invention and a pharmaceutically acceptable
carrier, as well as any
one or more of a number of desired excipients.
One embodiment of the invention encompasses a composition comprising
nanoparticulate
naproxen, or a salt or derivative thereof, in combination with a
multiparticulate modified release
composition comprising at least two populations of hydrocodone-comprising
particles, wherein
the pharmacokinetic profile of the nanoparticulate naproxen, or a salt or
derivative thereof, is not
affected by the fed or fasted state of a subject ingesting the naproxen
composition.
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In yet another embodiment, the invention encompasses a composition comprising
nanoparticulate naproxen, or a salt or derivative thereof, in combination with
a multiparticulate
modified release composition comprising at least two populations of
hydrocodone-comprising
particles, wherein administration of the nanoparticulate naproxen to a subject
in a fasted state is
bioequivalent to administration of the nanoparticulate naproxen to a subject
in a fed state.
In all of the embodiments above, the nanoparticulate naproxen particles have
an effective
average particle size of less than about 2000 nm, and preferable also comprise
at least one surface
stabilizer adsorbed on or are associated with the surface of the naproxen
particles.
This invention further discloses a method of making the nanoparticulate
naproxen
compositions. Such a method comprises contacting the naproxen particles with
at least one surface
stabilizer for a time and under conditions to reduce the effective average
particle size of the
naproxen particles to less than about 2000 nm.
The present invention is also directed to methods of treatment including but
not limited to,
the treatment of pain, comprising administering a dosage form comprising a
therapeutically
effective amount of the composition of the invention to provide bimodal or
multimodal release of
the hydrocodone comprised therein.
Other objects of the invention include provision of a once daily dosage form
of a
hydrocodone and a nanoparticulate naproxen which, in operation, produces a
plasma profile
substantially similar to the plasma profile produced by the administration of
two immediate
release hydrocodone dosage forms given sequentially and a method for
prevention and
treatment of pain conditions based on the administration of such a dosage
form.
The above objects are realized by a composition comprising a nanoparticulate
naproxen, or a
salt or derivative thereof, in combination with a controlled release
composition having a first
component comprising a first population of hydrocodone particles, and a second
component or
formulation comprising a second population of hydrocodone particles. The
hydrocodone-
comprising particles of the second component further comprise a modified
release constituent
comprising a release coating or release matrix material, or both. Following
oral delivery, the
composition in operation delivers a hydrocodone in a pulsatile or zero order
manner. In one
embodiment of the invention, the compositions of the invention delivers a
hydrocodone in a
pulsatile or zero order manner during a period of up to twenty-four hours.
The present invention utilizes controlled release delivery of hydrocodone, or
a salt or
derivative thereof, from a solid oral dosage formulation to allow dosage less
frequently than
before, and preferably once-a-day administration, increasing patient
convenience and compliance.
The mechanism of controlled release would preferably utilize, but not be
limited to, erodable
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formulations, diffusion controlled formulations and osmotic controlled
formulations. A portion of
the total dose may be released immediately to allow for rapid onset of effect.
The invention would
be useful in improving compliance and, therefore, therapeutic outcome for all
treatments requiring
a hydrocodone, including but not limited to, the treatment of pain conditions.
Preferred controlled release formulations are erodable formulations, diffusion
controlled
formulations and osmotic controlled formulations. According to the invention,
a portion of the total
dose may be released immediately to allow for rapid onset of effect, with the
remaining portion of
the total dose released over an extended time period. The invention would be
useful in improving
compliance and, therefore, therapeutic outcome for all treatments requiring a
hydrocodone.
Both the foregoing general description and the following brief description of
the figures and
the detailed description are exemplary and explanatory and are intended to
provide further
explanation of the invention as claimed. Other objects, advantages, and novel
features will be
readily apparent to those skilled in the art from the following detailed
description of the invention.
DESCRIPTION OF THE DRAWINGS
FIG. 1 shows single dose simulations of 10 mg hydrocodone formulations in
which 20% of
the hydrocodone is contained in the IR component.
FIG. 2 shows single dose simulations of 10 mg hydrocodone formulations in
which 20% of
the hydrocodone is contained in the IR component.
FIG. 3 shows steady state simulations of 10 mg hydrocodone formulations in
which
20% of the hydrocodone is contained in the IR component.
FIG. 4 shows steady state simulations of 10 mg hydrocodone formulations in
which
20% of the hydrocodone is contained in the IR component.
FIG. 5 shows single dose simulations of 10 mg hydrocodone formulations in
which 50% of
the hydrocodone is contained in the IR component.
FIG. 6 shows single dose simulations of 10 mg hydrocodone formulations in
which 50% of
the hydrocodone is contained in the IR component.
FIG. 7 shows steady state simulations of 10 mg hydrocodone formulations in
which 50%
of the hydrocodone is contained in the IR component.
FIG. 8 shows steady state simulations of 10 mg hydrocodone formulations in
which 50%
of the hydrocodone is contained in the IR component.
FIG. 9 shows single dose simulations of 20-160 mg/day hydrocodone formulations
(Option 1) in which 20% of the hydrocodone is contained in the IR component.
FIG. 10 shows steady state simulations of 20-160 mg/day hydrocodone
formulations
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(Option 1) in which 20% of the hydrocodone is contained in the IR component.
FIG. 11 shows single dose simulations of 20-80 mg BID hydrocodone formulations
(Option 3) in which 20% of the hydrocodone is contained in the IR component.
FIG. 12 shows steady state simulations of 20-80 mg BID hydrocodone
formulations
(Option 3) in which 20% of the hydrocodone is contained in the IR component.
FIG. 13 shows single dose simulations of 20-160 mg/day hydrocodone
formulations
(Option 1) in which 50% of the hydrocodone is contained in the IR component.
FIG. 14 shows steady state simulations of 20-160 mg/day hydrocodone
formulations
(Option 1) in which 50% of the hydrocodone is contained in the IR component.
FIG. 15 shows single dose simulations of 20-160 mg/day hydrocodone
formulations
(Option 3) in which 50% of the hydrocodone is contained in the IR component.
FIG. 16 shows steady state simulations of 20-160 mg/day hydrocodone
formulations
(Option 3) in which 50% of the hydrocodone is contained in the IR component.
DETAILED DESCRIPTION OF THE INVENTION
The compositions of the invention comprise (a) a composition comprising a
nanoparticulate
naproxen, or a salt or derivative thereof, and at least one surface
stabilizer; and (b) an oral controlled
release composition of a hydrocodone, or a salt or derivative thereof.
The purpose of the non-controlled release nanoparticulate naproxen compositoin
in
combination with the controlled release hydrocodone is at least twofold: (1)
to provide
increased analgesia via drug synergy; and (2) to limit the intake of
hydrocodone by causing
unpleasant and often unsafe side effects at higher than prescribed doses.
The present invention provides a method of treating a patient needing pain
relief
utilizing a composition according to the invention. The method comprises
administering a
therapeutically effective amount of a dosage form, such as a solid oral dosage
form,
comprising a nanoparticulate naproxen composition in combination with a
controlled
release hydrocodone composition, to provide a pulsed or bimodal or zero order
delivery of
the hydrocodone. Advantages of the present invention include reducing the
dosing
frequency required by conventional multiple IR dosage regimes while still
maintaining the
benefits derived from a pulsatile plasma profile or eliminating or minimizing
the "peak" to
"trough" ratio. This reduced dosing frequency is advantageous in terms of
patient
compliance to have a formulation which may be administered at reduced
frequency. The
reduction in dosage frequency made possible by utilizing the present invention
would
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contribute to reducing health care costs by reducing the amount of time spent
by health care
workers on the administration of drugs.
In one embodiment of the invention, the nanoparticulate naproxen composition,
in
accordance with standard pharmacokinetic practice, has a bioavailability that
is about 100%
greater, about 90% greater, about 80% greater, about 70% greater, about 60%
greater, about
50% greater, about 40% greater, about 30% greater, about 20% greater, or about
10% greater than
a conventional non-nanoparticulate naproxen dosage form.
The compositions of the 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.
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.
The 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.
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 agents
are 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
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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.
Liquid dosage forms for oral administration include pharmaceutically
acceptable
emulsions, solutions, suspensions, syrups, and elixirs. In addition to
hydrocodone and naproxen,
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.
Besides such inert diluents, the composition can also include adjuvants, such
as wetting
agents, emulsifying and suspending agents, sweetening, flavoring, and
perfuming agents.
"Therapeutically effective amount" as used herein with respect to a naproxen
and
hydrocodone dosage shall mean that dosage that provides the specific
pharmacological response for
which a hydrocodone or a naproxen is administered in a significant number of
subjects in need of
such treatment. It is emphasized that "therapeutically effective amount,"
administered to a
particular subject in a particular instance will not always be effective in
treating the conditions
described herein, even though such dosage is deemed a "therapeutically
effective amount" by those
skilled in the art. It is to be further understood that naproxen and
hydrocodone dosages are, in
particular instances, measured as oral dosages, or with reference to drug
levels as measured in
blood.
One of ordinary skill will appreciate that effective amounts of a naproxen and
a
hydrocodone can be determined empirically and can be employed in pure form or,
where such
forms exist, in pharmaceutically acceptable salt, ester, or prodrug form.
Actual dosage levels of a
naproxen and a hydrocodone in the compositions of the invention may be varied
to obtain an
amount of a naproxen and a hydrocodone that is effective to obtain a desired
therapeutic response
for a particular composition and method of administration. The selected dosage
lever therefore
depends upon the desired therapeutic effect, the route of administration, the
potency of the
administered naproxen, the desired duration of treatment, and other factors.
Dosage unit compositions may contain such amounts of such submultiples thereof
as may
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be used to make up the daily dose. It will be understood, however, that the
specific dose level for
any particular patient will depend upon a variety of factors: the type and
degree of the cellular or
physiological response to be achieved; activity of the specific agent or
composition employed;
the specific agents or composition employed; the age, body weight, general
health, sex, and diet
of the patient; the time of administration, route of administration, and rate
of excretion of the
agent; the duration of the treatment; drugs used in combination or
coincidental with the specific
agent; and like factors well known in the medical arts.
1. Controlled Release Hydrocodone
Component of the Compositions of the Invention
A. Definitions
As used herein, the term "enhancer" refers to a compound which is capable of
enhancing the
absorption and/or bioavailability of an active ingredient by promoting net
transport across the
gastrointestinal tract (GIT) in an animal, such as a human. Enhancers include
but are not limited to
medium chain fatty acids and salts, esters, ethers and derivatives thereof,
including glycerides and
triglycerides; non-ionic surfactants such as those that can be prepared by
reacting
ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a
sorbitan or glycerol fatty
acid ester; cytochrome P450 inhibitors, P-glycoprotein inhibitors and the
like; and mixtures
thereof.
The term "particulate" as used herein refers to a state of matter which is
characterized by the
presence of discrete particles, pellets, beads or granules irrespective of
their size, shape or
morphology. The term "multiparticulate" as used herein means a plurality of
discrete or aggregated
particles, pellets, beads, granules or mixture thereof, irrespective of their
size, shape or
morphology.
The term "modified release" as used herein with respect to the coating or
coating material
or used in any other context, means release which is not immediate release and
is taken to
encompass controlled release, sustained release and delayed release.
The term "time delay" as used herein refers to the duration of time between
administration of the composition and the release of the hydrocodone from a
particular
component.
The term "lag time" as used herein refers to the time between delivery of the
hydrocodone from one component and the subsequent delivery hydrocodone from
another
component.
The term "erodable" as used herein refers to formulations which may be worn
away,
diminished, or deteriorated by the action of substances within the body.
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The term "diffusion controlled" as used herein refers to formulations which
may spread as
the result of their spontaneous movement, for example, from a region of higher
to one of lower
concentration.
The term "osmotic controlled" as used herein refers to formulations which may
spread as
the result of their movement through a semipermeable membrane into a solution
of higher
concentration that tends to equalize the concentrations of the formulation on
the two sides of the
membrane.
B. Exemplary Embodiments
The composition according to the invention comprises at least two populations
of
hydrocodone, or a salt or derivative thereof, comprising particles which have
different in vitro
dissolution profiles.
The multiparticulate modified release composition and dosage forms made
therefrom
comprise at least two hydrocodone-comprising components. In one embodiment,
the release of the
hydrocodone, or a salt or derivative thereof, from the second and subsequent
components, if any, is
modified such that there is a lag time between the release of hydrocodone, or
a salt or derivative
thereof, from the first component and each subsequent component. The number of
pulses in the
release profile arising from such a composition in operation will depend on
the number of
hydrocodone-comprising components in the composition. For example, a
composition comprising
two hydrocodone-comprising components will give rise to two pulses in the
release profile, and a
composition comprising three hydrocodone-comprising components will give rise
to up to three
pulses in the release profile. In another embodiment, the release of the
active ingredients from
subsequent components is modified such that the release of hydrocodone from
the first component
and each subsequent component begins substantially upon administration but
over different periods
of time and/or at different rates.
For example, a controlled release composition can have a first component
comprising a
first population of a hydrocodone, or a salt or derivative thereof, and a
second component
comprising a second population of a hydrocodone, or a salt or derivative
thereof. The
hydrocodone-comprising particles of the second component are coated with a
modified release
coating. Alternatively or additionally, the second population of hydrocodone-
comprising
particles further comprises a modified release matrix material. Following oral
delivery, the
composition in operation delivers the hydrocodone, or a salt or derivative
thereof, in a pulsatile or
zero order manner.
In one embodiment of the invention, the controlled release composition
comprising
hydrocodone, or a salt or derivative thereof, in operation delivers the
hydrocodone in a bimodal or
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pulsatile or zero order manner. Such a composition in operation produces a
plasma profile which
substantially mimics that obtained by the sequential administration of two IR
hydrocodone doses.
The present invention further relates to a controlled release composition
comprising a
hydrocodone, or a salt or derivative thereof, which in operation produced a
plasma profile that
eliminates or minimizes the "peaks" and "troughs" produced by the
administration of two or more
IR dosage forms given sequentially if such a profile is beneficial. This type
of profile can be
obtained using a controlled release mechanism that allows for "zero-order"
delivery.
Any suitable dosage form can be used for the compositions of in the invention.
In one
embodiment, the invention provides solid oral dosage forms comprising a
composition
according to the invention.
The time release characteristics for the delivery of the hydrocodone, or a
salt or derivative
thereof, from each of the components may be varied by modifying the
composition of each
component, including modifying any of the excipients or coatings which may be
present.
In particular, the release of the hydrocodone, or a salt or derivative
thereof, may be
controlled by changing the composition and/or the amount of the modified
release coating on the
particles, if such a coating is present. If more than one modified release
component is present, the
modified release coating for each of these components may be the same or
different. Similarly,
when modified release is facilitated by the inclusion of a modified release
matrix material, release
of the hydrocodone, or a salt or derivative thereof, may be controlled by the
choice and amount of
modified release matrix material utilized. The modified release coating may be
present, in each
component, in any amount that is sufficient to yield the desired delay time
for each particular
component. The modified release coating may be preset, in each component, in
any amount that is
sufficient to yield the desired time lag between components.
The lag time or delay time for the release of the hydrocodone, or a salt or
derivative thereof,
from each component may also be varied by modifying the composition of each of
the components,
including modifying any excipients and coatings which may be present. For
example, the first
component may be an immediate release component wherein the hydrocodone, or a
salt or
derivative thereof, is released immediately upon administration.
Alternatively, the first component
may be, for example, a time-delayed immediate release component in which the
hydrocodone, or a
salt or derivative thereof, is released substantially in its entirety
immediately after a time delay. The
second component may be, for example, a time-delayed immediate release
component as just
described or, alternatively, a time-delayed sustained release or extended
release component in
which the hydrocodone, or a salt or derivative thereof, is released in a
controlled fashion over an
extended period of time.
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It will be understood that suitable hydrocodones also include all
pharmaceutically
acceptable salts, acids, esters, complexes or other derivatives of
hydrocodone, and may be
present either in the form of one enantiomer or as a mixture, racemic or
otherwise, of
enantiomers.
The hydrocodone in each component may be the same or different. In one
embodiment, the
first component comprises a first hydrocodone, or a salt or derivative
thereof, and the second
component comprises a second hydrocodone, or a salt or derivative thereof. In
another
embodiment, two or more hydrocodones may be incorporated into one or more
components.
Further, a hydrocodone present in one component of the composition may be
accompanied by, for
example, an enhancer compound or a sensitizer compound in another component of
the
composition, to modify the bioavailability or therapeutic effect of the
hydrocodone.
The amount of the hydrocodone comprised in the composition and in dosage forms
made
threfrom may be allocated evenly or unevenly across the different particle
populations
comprising the components of the composition and comprised in the dosage forms
made
therefrom. In one embodiment, the hydrocodone, or a salt or derivative
thereof, comprised in the
particles of the first component comprises a minor portion of the total amount
of hydrocodone, or a
salt or derivative thereof, in the composition or dosage form, and the amount
of the hydrocodone,
or a salt or derivative thereof, in the other components comprises a major
portion of the total
amount of hydrocodone, or a salt or derivative thereof, in the composition or
dosage form. In one
such embodiment comprising two components, about 20% of the total amount of
the hydrocodone,
or a salt or derivative thereof, is comprised in the particles of the first
component, and about 80%
of the total amount of the hydrocodone, or a salt or derivative thereof, is
comprised in the particles
of the second component.
The hydrocodone, or a salt or derivative thereof, is preferably present in the
composition and
in dosage forms made therefrom in an amount of from about 0.1 to about 1000
mg, from about 1
to about 160 mg, or from about 5 to about 80 mg. Depending at least in part on
the particular
hydrocodone, or a salt or derivative thereof, that are included in the
composition and dosage
forms, the hydrocodone, or a salt or derivative thereof, is present in an
amount of from about 5 to
about 80 mg, about 5 to about 60 mg, about 5 to about 40 mg, about 5 to about
20 mg, about 5 to
about 10 mg, about 10 to about 80 mg, about 10 to about 60 mg, about 10 to
about 40 mg, about
10 to about 20 mg, about 20 to about 80 mg, about 20 to about 60 mg, about 20
to about 40 mg,
about 40 to about 80 mg, about 40 to about 60 mg, or about 60 to about 80 mg.
When the active ingredient is hydrocodone, it is preferably present in the
composition and
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in dosage forms made therefrom in an amount of from about 5 to about 160 mg;
more preferably
the active ingredient is present in the first component in an amount of from
about 10 to about 80
mg.
The profile for the release of the hydrocodone, or a salt or derivative
thereof, from each
component of the composition may be varied by modifying the composition of
each component,
including modifying any of the excipients or coatings which may be present. In
particular the
release of the hydrocodone, or a salt or derivative thereof, may be controlled
by the choice and
amount of the modified release coating applied to the particles where such a
coating is present. If
more than one modified release component is present, the modified release
coating for each of
these components may be the same or different. Similarly, when the modified
release is
accomplished by means of a modified release matrix material, release of the
hydrocodone, or a salt
or derivative thereof, may be controlled by the choice and amount of modified
release matrix
material utilized.
For example, the modified release coating applied to the second population of
a
hydrocodone, or a salt or derivative thereof, causes a lag time between the
release of active from
the first population of active hydrocodone-comprising particles and the
release of active from the
second population of hydrocodone-comprising particles. Similarly, the presence
of a modified
release matrix material in the second population of hydrocodone-comprising
particles causes a lag
time between the release of hydrocodone from the first population of
hydrocodonecomprising
particles and the release of hydrocodone, or a salt or derivative thereof,
from the second population
of hydrocodone-comprising particles. The duration of the lag time may be
varied by altering the
composition and/or the amount of the modified release coating and/or altering
the composition
and/or amount of modified release matrix material utilized. Thus, the duration
of the lag time can
be designed to mimic a desired plasma profile.
In one embodiment, the first component may be an immediate release component
wherein
the hydrocodone, or a salt or derivative thereof, comprised therein is
released substantially
immediately upon administration. In another embodiment, the first component
may be a delayed
release component in which the hydrocodone, or a salt or derivative thereof,
is released
substantially immediately after a time delay. In either of such embodiments,
the second
component may be a modified release component in which the hydrocodone, or a
salt or derivative
thereof, is released over a period of time or substantially immediately after
a time delay.
In another embodiment, the controlled release composition comprise an
immediate release
component and at least one modified release component, the immediate release
component
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comprising a first population of hydrocodone-comprising particles and the
modified release
components comprising second and subsequent populations of hydrocodone-
comprising particles.
The second and subsequent modified release components may comprise a
controlled release
coating. Additionally or alternatively, the second and subsequent modified
release components
may comprise a modified release matrix material. In operation, administration
of such a multi-
particulate modified release composition having, for example, a single
modified release
component results in characteristic pulsatile plasma concentration levels of
the hydrocodone in
which the immediate release component of the composition gives rise to a first
peak in the plasma
profile and the modified release component gives rise to a second peak in the
plasma profile.
Embodiments of the invention comprising more than one modified release
component give rise to
further peaks in the plasma profile.
As will be appreciated by those skilled in the art, the exact nature of the
plasma profile will
be influenced by the combination of all of the factors described above. Thus
by variation
of the composition of each component thereof, including the amount and nature
of the
hydrocodone, or a salt or derivative thereof, and the modified release coating
or modified matrix
material, if any, numerous plasma profiles may result therefrom upon
administration to a patient.
Depending on the release profile of each component, the plasma profile
resulting therefrom may be
bimodal or multimodal, and may define well separated and clearly defined peaks
associated with
each component (e.g., when the lag time between immediate release and delayed
release
components is long) or superimposed peaks associated with each component
(e.g., in when the lag
time is short). For example, administration of a multiparticulate modified
release composition
having an immediate release component and a single modified release component
can result in a
plasma profile in which the immediate release component of the composition
gives rise to a first
peak in the plasma profile and the modified release component gives rise to a
second peak in the
plasma profile. Embodiments of the invention comprising more than one modified
release
component may give rise to further peaks in the plasma profile. Alternatively,
administration of a
multiparticulate modified release composition having an immediate release
component and one or
more modified release components can result in a bimodal or multimodal release
profile but a
plasma profile having a single peak or peaks fewer in number than the number
of components
contained in the composition.
The plasma profile produced from the administration of a single dosage unit of
the present
invention is advantageous when it is desirable to deliver two or more portions
of hydrocodone, or a
salt or derivative thereof, without the need for administration of two or more
dosage units.
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Additionally, in the case of some disorders it is particularly useful to have
such a bimodal plasma
profile. In embodiments which include drug compounds used for pain management,
such as for
example hydrocodone, the compositions and dosage forms of the present
invention may provide
continuous analgesia for up to 24 hours by providing minimum peak to trough
fluctuations in
plasma levels and reduce or eliminate side effects associated with such drug
compounds.
Any coating material which modifies the release of the hydrocodone, or a salt
or
derivative thereof, in the desired manner may be used in the practice of the
present invention. In
particular, coating materials suitable for use in the practice of the
invention include but are not
limited to polymer coating materials, such as cellulose acetate phthalate,
cellulose acetate
trimaletate, hydroxy propyl methylcellulose phthalate, polyvinyl acetate
phthalate, ammonio
methacrylate copolymers such as those sold under the Trade Mark Eudragit RS
and RL, poly
acrylic acid and poly acrylate and methacrylate copolymers such as those sold
under the
trademark Eudragit S and L, polyvinyl acetaldiethylamino acetate,
hydroxypropyl
methylcellulose acetate succinate, shellac; hydrogels and gel-forming
materials, such as
carboxyvinyl polymers, sodium alginate, sodium carmellose, calcium carmellose,
sodium
carboxymethyl starch, poly vinyl alcohol, hydroxyethyl cellulose, methyl
cellulose, gelatin, starch,
and cellulose based cross-linked polymers in which the degree of crosslinking
is low so as to
facilitate adsorption of water and expansion of the polymer matrix,
hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, crosslinked starch,
microcrystalline
cellulose, chitin, aminoacryl-methacrylate copolymer (Eudragit RS-PM, Rohm &
Haas), pullulan,
collagen, casein, agar, gum arabic, sodium carboxymethyl cellulose, (swellable
hydrophilic
polymers) poly(hydroxyalkyl methacrylate) (m. wt. -5k-5,000k),
polyvinylpyrrolidone (m. wt.
-10k-360k), anionic and cationic hydrogels, polyvinyl alcohol having a low
acetate residual, a
swellable mixture of agar and carboxymethyl cellulose, copolymers of maleic
anhydride and
styrene, ethylene, propylene or isobutylene, pectin (m. wt. -30k-300k),
polysaccharides such as
agar, acacia, karaya, tragacanth, algins and guar, polyacrylamides, Polyox
polyethylene oxides (m.
wt. -100k -5,000k), AquaKeep acrylate polymers, diesters of polyglucan,
crosslinked polyvinyl
alcohol and poly N-vinyl-2-pyrrolidone, sodium starch glycolate (e.g.,
Explotab ; Edward Mandell
C. Ltd.); hydrophilic polymers such as polysaccharides, methyl cellulose,
sodium or calcium
carboxymethyl cellulose, hydroxypropyl methyl cellulose, hydroxypropyl
cellulose, hydroxyethyl
cellulose, nitro cellulose, carboxymethyl cellulose, cellulose ethers,
polyethylene oxides (e.g.
Polyox , Union Carbide), methyl ethyl cellulose, ethylhydroxy ethylcellulose,
cellulose acetate,
cellulose butyrate, cellulose propionate, gelatin, collagen, starch,
maltodextrin, pullulan, polyvinyl
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pyrrolidone, polyvinyl alcohol, polyvinyl acetate, glycerol fatty acid esters,
polyacrylamide,
polyacrylic acid, copolymers of methacrylic acid or methacrylic acid (e.g.,
Eudragit , Rohm and
Haas), other acrylic acid derivatives, sorbitan esters, natural gums,
lecithins, pectin, alginates,
ammonia alginate, sodium, calcium, potassium alginates, propylene glycol
alginate, agar, and gums
such as arabic, karaya, locust bean, tragacanth, carrageens, guar, xanthan,
scleroglucan and
mixtures and blends thereof.
Excipients such as plasticisers, lubricants, solvents and the like may be
added to the
coating. Suitable plasticisers include for example acetylated monoglycerides;
butyl phthalyl butyl
glycolate; dibutyl tartrate; diethyl phthalate; dimethyl phthalate; ethyl
phthalyl ethyl glycolate;
glycerin; propylene glycol; triacetin; citrate; tripropioin; diacetin; dibutyl
phthalate; acetyl
monoglyceride; polyethylene glycols; castor oil; triethyl citrate; polyhydric
alcohols, glycerol,
acetate esters, gylcerol triacetate, acetyl triethyl citrate, dibenzyl
phthalate, dihexyl phthalate,
butyl octyl phthalate, diisononyl phthalate, butyl octyl phthalate, dioctyl
azelate,
epoxidized tallate, triisoctyl trimellitate, diethylhexyl phthalate, di-n-
octyl phthalate, di-i-octyl
phthalate, di-i-decyl phthalate, di-n-undecyl phthalate, di-n-tridecyl
phthalate, tri-2-ethylhexyl
trimellitate, di-2-ethylhexyl adipate, di-2-ethylhexyl sebacate, di-2-
ethylhexyl azelate, dibutyl
sebacate.
When the modified release component comprises a modified release matrix
material, any
suitable modified release matrix material or suitable combination of modified
release matrix
materials may be used. Such materials are known to those skilled in the art.
The term "modified
release matrix material" as used herein includes hydrophilic polymers,
hydrophobic polymers and
mixtures thereof which are capable of modifying the release of a hydrocodone,
or a salt or derivative
thereof, dispersed therein in vitro or in vivo. Modified release matrix
materials suitable for the
practice of the present invention include but are not limited to
microcrystalline cellulose, sodium
carboxymethylcellulose, hydroxyalkylcelluloses such as hydroxypropylmethyl-
cellulose and
hydroxypropylcellulose, polyethylene oxide, alkylcelluloses such as
methylcellulose and
ethylcellulose, polyethylene glycol, polyvinylpyrrolidone, cellulose acetate,
cellulose acetate
butyrate, cellulose acetate phthalate, cellulose acetate trimellitate,
polyvinylacetate phthalate,
polyalkylmethacrylates, polyvinyl acetate and mixture thereof.
A multiparticulate modified release composition according to the present
invention may be
incorporated into any suitable dosage form which facilitates release of the
hydrocodone, or a salt or
derivative thereof, in a bimodal or multimodal manner. Typically, the dosage
form may be a blend
of the different populations of a hydrocodone, or a salt or derivative
thereof,
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comprising particles which make up the immediate release and the modified
release components,
the blend being filled into suitable capsules, such as hard or soft gelatin
capsules. Alternatively, the
different individual populations of a hydrocodone, or a salt or derivative
thereof, comprising
particles may be compressed (optionally with additional excipients) into mini-
tablets which may
be subsequently filled into capsules in the appropriate proportions. Another
suitable dosage form
is that of a multilayer tablet. In such dosage forms, the first component of
the multiparticulate
modified release composition may be compressed into one layer with the second
component being
subsequently added as a second layer of the multilayer tablet. The populations
of hydrocodone, or
a salt or derivative thereof, comprising particles comprising the composition
of the invention may
further be included in rapidly dissolving dosage forms such as an effervescent
dosage form or a
fast-melt dosage form.
In one embodiment, the composition of the invention and the dosage forms made
therefrom release the hydrocodone, or a salt or derivative thereof, such that
substantially all
hydrocodone, or a salt or derivative thereof, comprised in the first component
is released prior to
release of a hydrocodone, or a salt or derivative thereof, from the second
component. For example,
when the first component comprises an IR component, release of the
hydrocodone, or a salt or
derivative thereof, from the second component may be delayed until
substantially all the
hydrocodone, or a salt or derivative thereof, in the IR component has been
released. Release of the
hydrocodone, or a salt or derivative thereof, from the second component may be
delayed as detailed
above by the use of a modified release coating and/or a modified release
matrix material.
Because the plasma profile produced by the controlled release hydrocodone
composition
upon administration can be substantially similar to the plasma profile
produced by the
administration of two or more IR hydrocodone dosage forms given sequentially,
the controlled
release composition of the present invention is particularly useful for
administering a
hydrocodone, or a salt or derivative thereof, for which patient tolerance may
be problematical.
This controlled release composition is therefore advantageous for reducing or
minimizing the
development of patient tolerance to the hydrocodone, or a salt or derivative
thereof, in the
composition.
When it is desirable to minimize patient tolerance by providing a dosage
regime which
facilitates wash-out of a first dose of hydrocodone, or a salt or derivative
thereof, from a patient's
system, release of the hydrocodone, or a salt or derivative thereof, from the
second component is
delayed until substantially all of the hydrocodone, or a salt or derivative
thereof, comprised in the
first component has been released, and further delayed until at least a
portion of the hydrocodone,
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or a salt or derivative thereof, released from the first component has been
cleared from the patient's
system. In one embodiment, release of the hydrocodone, or a salt or derivative
thereof, from the
second component of the composition is substantially, if not completely,
delayed for a period of
at least about two hours after administration of the composition.
In another embodiment, the composition of the invention and the dosage forms
made
therefrom release the hydrocodone, or a salt or derivative thereof, such that
the hydrocodone, or a
salt or derivative thereof, comprised in the first component is released
during the release of
hydrocodone, or a salt or derivative thereof, from the second component. In
one such embodiment,
release of the hydrocodone, or a salt or derivative thereof, from the second
component of the
composition occurs during and beyond the release of the hydrocodone, or a salt
or derivative
thereof, from the first component.
C. Other Types of Controlled Release Hydrocodone Compositions
As described herein, the invention includes various types of controlled
release systems by
which the hydrocodone, or a salt or derivative thereof, may be delivered in a
pulsatile or zero order
manner. These systems include, but are not limited to: films with the
hydrocodone, or a salt or
derivative thereof, in a polymer matrix (monolithic devices); the hydrocodone,
or a salt or
derivative thereof, contained by the polymer (reservoir devices); polymeric
colloidal particles or
microencapsulates (microparticles, microspheres or nanoparticles) in the form
of reservoir and
matrix devices; hydrocodone, or a salt or derivative thereof, contained by a
polymer containing a
hydrophilic and/or leachable additive e.g., a second polymer, surfactant or
plasticiser, etc. to give a
porous device, or a device in which the hydrocodone, or a salt or derivative
thereof, release may be
osmotically 'controlled' (both reservoir and matrix devices); enteric coatings
(ionise and dissolve at
a suitable pH); (soluble) polymers with (covalently) attached 'pendant'
hydrocodone, or a salt or
derivative thereof, molecules; devices where release rate is controlled
dynamically: e.g., the osmotic
pump.
The delivery mechanism of the invention will control the rate of release of
the drug. While
some mechanisms will release the hydrocodone, or a salt or derivative thereof,
at a constant rate
(zero order), others will vary as a function of time depending on factors such
as changing
concentration gradients or additive leaching leading to porosity, etc.
Polymers used in sustained release coatings are necessarily biocompatible, and
ideally
biodegradable. Examples of both naturally occurring polymers such as
Aquacoat (FMC Corporation, Food & Pharmaceutical Products Division,
Philadelphia, USA)
(ethylcellulose mechanically spheronised to sub-micron sized, aqueous based,
pseudo-latex
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dispersions), and also synthetic polymers such as the Eudragit (Rohm Pharma,
Weiterstadt.) range
of poly(acrylate, methacrylate) copolymers are known in the art.
1. Reservoir Devices
A typical approach to controlled release is to encapsulate or contain the
hydrocodone, or a
salt or derivative thereof, entirely (e.g., as a core), within a polymer film
or coat (i.e., microcapsules
or spray/pan coated cores).
The various factors that can affect the diffusion process may readily be
applied to reservoir
devices (e.g., the effects of additives, polymer functionality {and, hence,
sink-solution pH}
porosity, film casting conditions, etc.) and, hence, the choice of polymer
must be an important
consideration in the development of reservoir devices. Modeling the release
characteristics of
reservoir devices (and monolithic devices) in which the transport of the
hydrocodone, or a salt or
derivative thereof, is by a solution-diffusion mechanism therefore typically
involves a solution to
Fick's second law (unsteady-state conditions; concentration dependent flux)
for the relevant
boundary conditions. When the device contains dissolved hydrocodone, or a salt
or derivative
thereof, the rate of release decreases exponentially with time as the
concentration (activity) of the
agent (i.e., the driving force for release) within the device decreases (i.e.,
first order release). If,
however, the hydrocodone, or a salt or derivative thereof, is in a saturated
suspension, then the
driving force for release is kept constant (zero order) until the device is no
longer saturated.
Alternatively the release-rate kinetics may be desorption controlled, and a
function of the square
root of time.
Transport properties of coated tablets, may be enhanced compared to free-
polymer films, due
to the enclosed nature of the tablet core (permeant) which may enable the
internal build-up of an
osmotic pressure which will then act to force the permeant out of the tablet.
The effect of deionised water on salt containing tablets coated in
poly(ethylene glycol)
(PEG)-containing silicone elastomer, and also the effects of water on free
films has been
investigated. The release of salt from the tablets was found to be a mixture
of diffusion through
water filled pores, formed by hydration of the coating, and osmotic pumping.
KC1 transport through
films containing just 10% PEG was negligible, despite extensive swelling
observed in similar free
films, indicating that porosity was necessary for the release of the KC1 which
then occurred by
'trans-pore diffusion.' Coated salt tablets, shaped as disks, were found to
swell in deionised water
and change shape to an oblate spheroid as a result of the build-up of internal
hydrostatic pressure: the
change in shape providing a means to measure the 'force' generated. As might
be expected, the
osmotic force decreased with increasing levels of PEG content. The lower PEG
levels allowed water
to be imbibed through the hydrated polymer; whilst the porosity resulting from
the coating dissolving
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at higher levels of PEG content (20 to 40%) allowed the pressure to be
relieved by the flow of KC1.
Methods and equations have been developed, which by monitoring
(independently) the release of two different salts (e.g., KC1 and NaC1)
allowed the calculation of the
relative magnitudes that both osmotic pumping and trans-pore diffusion
contributed to the release of
salt from the tablet. At low PEG levels, osmotic flow was increased to a
greater extent than was
trans-pore diffusion due to the generation of only a low pore number density:
at a loading of 20%,
both mechanisms contributed approximately equally to the release. The build-up
of hydrostatic
pressure, however, decreased the osmotic inflow, and osmotic pumping. At
higher loadings of PEG,
the hydrated film was more porous and less resistant to outflow of salt.
Hence, although the osmotic
pumping increased (compared to the lower loading), trans-pore diffusion was
the dominant release
mechanism. An osmotic release mechanism has also been reported for
microcapsules containing a
water soluble core.
2. Monolithic Devices (Matrix Devices)
Monolithic (matrix) devices are possibly the most common of the devices for
controlling the
release of drugs. This is possibly because they are relatively easy to
fabricate, compared to reservoir
devices, and there is not the danger of an accidental high dosage that could
result from the rupture of
the membrane of a reservoir device. In such a device the hydrocodone, or a
salt or derivative thereof,
is present as a dispersion within the polymer matrix, and they are typically
formed by the
compression of a polymer/drug mixture or by dissolution or melting. The dosage
release properties
of monolithic devices may be dependent upon the solubility of the hydrocodone,
or a salt or
derivative thereof, in the polymer matrix or, in the case of porous matrices,
the solubility in the sink
solution within the particle's pore network, and also the tortuosity of the
network (to a greater extent
than the permeability of the film), dependent on whether the hydrocodone, or a
salt or derivative
thereof, is dispersed in the polymer or dissolved in the polymer. For low
loadings of drug, (0 to 5%
W/V) the hydrocodone, or a salt or derivative thereof, will be released by a
solution-diffusion
mechanism (in the absence of pores). At higher loadings (5 to 10% W/V), the
release mechanism
will be complicated by the presence of cavities formed near the surface of the
device as the
hydrocodone, or a salt or derivative thereof, is lost: such cavities fill with
fluid from the environment
increasing the rate of release of the drug.
It is common to add a plasticiser (e.g., a poly(ethylene glycol)), or
surfactant, or adjuvant (i.e.,
an ingredient which increases effectiveness), to matrix devices (and reservoir
devices) as a means to
enhance the permeability (although, in contrast, plasticiser may be fugitive,
and simply serve to aid
film formation and, hence, decrease permeability - a property normally more
desirable in polymer
paint coatings). It was noted that the leaching of PEG acted to increase the
permeability of (ethyl
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cellulose) films linearly as a function of PEG loading by increasing the
porosity, however, the films
retained their barrier properties, not permitting the transport of
electrolyte. It was deduced that the
enhancement of their permeability was as a result of the effective decrease in
thickness caused by
the PEG leaching. This was evinced from plots of the cumulative permeant flux
per unit area as a
function of time and film reciprocal thickness at a PEG loading of 50% W/W:
plots showing a linear
relationship between the rate of permeation and reciprocal film thickness, as
expected for a
(Fickian) solution-diffusion type transport mechanism in a homogeneous
membrane. Extrapolation
of the linear regions of the graphs to the time axis gave positive intercepts
on the time axis: the
magnitude of which decreased towards zero with decreasing film thickness.
These changing lag
times were attributed to the occurrence of two diffusional flows during the
early stages of the
experiment (the flow of the 'drug' and also the flow of the PEG), and also to
the more usual lag time
during which the concentration of permeant in the film is building-up.
Caffeine, when used as a
permeant, showed negative lag times. No explanation of this was forthcoming,
but it was noted that
caffeine exhibited a low partition coefficient in the system, and that this
was also a feature of aniline
permeation through polyethylene films which showed a similar negative time
lag.
The effects of added surfactants on (hydrophobic) matrix devices has been
investigated. It
was thought that surfactant may increase the hydrocodone, or a salt or
derivative thereof, release
rate by three possible mechanisms: (i) increased solubilisation, (ii) improved
'wettability' to the
dissolution media, and (iii) pore formation as a result of surfactant
leaching. For the system studied
(Eudragit RL 100 and RS 100 plasticised by sorbitol, Flurbiprofen as the
drug, and a range of
surfactants) it was concluded that improved wetting of the tablet led to only
a partial improvement in
drug release (implying that the release was diffusion, rather than
dissolution, controlled), although the
effect was greater for Eudragit RS than Eudragit RL, whilst the greatest
influence on release was
by those surfactants that were more soluble due to the formation of
'disruptions' in the matrix
allowing the dissolution medium access to within the matrix. This is of
obvious relevance to a study
of latex films which might be suitable for pharmaceutical coatings, due to the
ease with which a
polymer latex may be prepared with surfactant as opposed to surfactant-free.
Differences were
found between the two polymers - with only the Eudragit RS showing
interactions between the
anionic/cationic surfactant and drug. This was ascribed to the differing
levels of quaternary
ammonium ions on the polymer.
Composite devices consisting of a polymer/drug matrix coated in a polymer
containing no
drug also exist. Such a device was constructed from aqueous Eudragit latices,
and was found to
give zero order release by diffusion of the drug from the core through the
shell. Similarly, a polymer
core containing the drug has been produced, but coated this with a shell that
was eroded by the
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gastric fluid. The rate of release of the drug was found to be relatively
linear (a function of the rate
limiting diffusion process through the shell) and inversely proportional to
the shell thickness,
whereas the release from the core alone was found to decrease with time.
3. Microspheres
Methods for the preparation of hollow microspheres ('microballoons') with the
drug
dispersed in the sphere's shell, and also highly porous matrix-type
microspheres ('microsponges')
have been described. The microsponges were prepared by dissolving the drug and
polymer in
ethanol. On addition to water, the ethanol diffused from the emulsion droplets
to leave a highly
porous particle.
The hollow microspheres were formed by preparing a solution of
ethanol/dichloro-methane
containing the drug and polymer. On pouring into water, this formed an
emulsion containing the
dispersed polymer/drug/solvent particles, by a coacervation-type process, from
which the ethanol (a
good solvent for the polymer) rapidly diffused precipitating polymer at the
surface of the droplet to
give a hard-shelled particle enclosing the drug, dissolved in the
dichloromethane. At this point, a gas
phase of dichloromethane was generated within the particle which, after
diffusing through the shell,
was observed to bubble to the surface of the aqueous phase. The hollow sphere,
at reduced pressure,
then filled with water, which could be removed by a period of drying. (No drug
was found in the
water.) A suggested use of the microspheres was as floating drug delivery
devices for use in the
stomach.
4. Pendent devices
A means of attaching a range of drugs such as analgesics and antidepressants,
etc., by means
of an ester linkage to poly(acrylate) ester latex particles prepared by
aqueous emulsion
polymerization has been developed. These latices when passed through an ion
exchange resin such
that the polymer end groups were converted to their strong acid form could
'self-catalyse' the release
of the drug by hydrolysis of the ester link.
Drugs have been attached to polymers, and also monomers have been synthesized
with a
pendent drug attached. The research group have also prepared their own dosage
forms in which the
drug is bound to a biocompatible polymer by a labile chemical bond e.g.,
polyanhydrides prepared
from a substituted anhydride (itself prepared by reacting an acid chloride
with the drug:
methacryloyl chloride and the sodium salt of methoxy benzoic acid) were used
to form a matrix with
a second polymer (Eudragit RL) which released the drug on hydrolysis in
gastric fluid. The use of
polymeric Schiff bases suitable for use as carriers of pharmaceutical amines
has also been described.
5. Enteric films
Enteric coatings consist of pH sensitive polymers. Typically the polymers are
carboxylated
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and interact (swell) very little with water at low pH, whilst at high pH the
polymers ionise causing
swelling, or dissolving of the polymer. Coatings can therefore be designed to
remain intact in the
acidic environment of the stomach (protecting either the drug from this
environment or the stomach
from the drug), but to dissolve in the more alkaline environment of the
intestine.
6. Osmotically controlled devices
The osmotic pump is similar to a reservoir device but contains an osmotic
agent (e.g., the
active agent in salt form) which acts to imbibe water from the surrounding
medium via a semi-
permeable membrane. Such a device, called the 'elementary osmotic pump', has
been described.
Pressure is generated within the device which forces the active agent out of
the device via an orifice
(of a size designed to minimise solute diffusion, whilst preventing the build-
up of a hydrostatic
pressure head which has the effect of decreasing the osmotic pressure and
changing the dimensions
{volume} of the device). Whilst the internal volume of the device remains
constant, and there is an
excess of solid (saturated solution) in the device, then the release rate
remains constant delivering a
volume equal to the volume of solvent uptake.
7. Electrically stimulated release devices
Monolithic devices have been prepared using polyelectrolyte gels which swelled
when, for
example, an external electrical stimulus was applied, causing a change in pH.
The release could be
modulated, by the current, giving a pulsatile release profile.
8. Hydrogels
Hydrogels find a use in a number of biomedical applications, in addition to
their use in drug
matrices (e.g., soft contact lenses, and various 'soft' implants, etc.).
II. Nanoparticulate Naproxen Component of the Compositions of the Invention
The compositions of the invention comprise a nanoparticulate naproxen
composition. The
nanoparticulate naproxen composition comprises particles of naproxen having an
effective average
particle size of less than about 2000 nm and preferably at least one surface
stabilizer adsorbed on or
associated with the surface of the drug.
Advantages of the nanoparticulate naproxen compositions of the invention as
compared to
conventional, non-nanoparticulate or solubilized dosage forms of naproxen
include, but are not
limited to: (1) smaller tablet or other solid dosage form size; (2) smaller
doses of drug required to
obtain the same pharmacological effect; (3) increased bioavailability; (4)
substantially similar
pharmacokinetic profiles of the naproxen compositions when administered in the
fed versus the
fasted state; (5) bioequivalency of the naproxen compositions when
administered in the fed versus the
fasted state; (6) an increased rate of dissolution for the naproxen
compositions; and (7) the naproxen
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compositions can be used in conjunction with other active agents useful in the
prevention and
treatment of infective conditions.
The present invention also includes nanoparticulate naproxen 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 parental
injection (e.g., intravenous,
intramuscular, or subcutaneous), oral administration in solid, liquid, or
aerosol form, vaginal, nasal,
rectal, ocular, local (powders, ointments, or drops), buccal, intracisternal,
intraperitoneal, or topical
administrations, and the like.
A preferred dosage form of the invention is a solid dosage form, although any
pharmaceutically acceptable dosage form can be utilized. Exemplary solid
dosage forms include, but
are not limited to, tablets, capsules, sachets, lozenges, powders, pills, or
granules, and the solid dosage
form can be, for example, a fast melt dosage form, controlled release dosage
form, lyophilized
dosage form, delayed release dosage form, extended release dosage form,
pulsatile release dosage
form, mixed immediate release and controlled release dosage form, or a
combination thereof. A
solid dose tablet formulation is preferred.
The present invention is described herein using several definitions, as set
forth below and
throughout the application.
The term "effective average particle size," as used herein, means that at
least about 50% of the
nanoparticulate naproxen particles have a size of less than about 2000 nm, by
weight or by other
suitable measurement technique (e.g., such as by volume, number, etc.), when
measured by, for
example, sedimentation flow fractionation, photon correlation spectroscopy,
light scattering, disk
centrifugation, and other techniques known to those of skill in the art.
As used herein, "about" will be understood by persons of ordinary skill in the
art and will
vary to some extent depending upon the context in which it is used. If there
are uses of the term which
are not clear to persons of ordinary skill in the art given the context in
which it is used, "about" will
mean up to plus or minus 10% of the particular term.
As used herein with reference to stable naproxen particles, "stable" means
that the particles
do not appreciably flocculate or agglomerate due to interparticle attractive
forces or otherwise
increase in particle size. "Stable" connotes, but is not limited to one or
more of the following
parameters: (1) the particles do not appreciably flocculate or agglomerate due
to interparticle
attractive forces or otherwise significantly increase in particle size over
time; (2) the physical
structure of the particles is not altered over time, such as by conversion
from an amorphous phase to
a crystalline phase; (3) the particles are chemically stable; and/or (4) where
the naproxen or a salt or
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derivative thereof has not been subject to a heating step at or above the
melting point of the naproxen
particles in the preparation of the nanoparticles of the present invention.
The term "conventional" or "non-nanoparticulate active agent" shall mean an
active agent
which is solubilized or which has an effective average particle size of
greater than about 2000 nm.
Nanoparticulate active agents as defined herein have an effective average
particle size of less than
about 2000 nm.
The phrase "poorly water soluble drugs" as used herein refers to drugs having
a solubility in
water of less than about 30 mg/ml, less than about 20 mg/ml, less than about
10 mg/ml, or less than
about 1 mg/ml.
As used herein, the phrase "therapeutically effective amount" shall mean that
drug dosage
that provides the specific pharmacological response for which the drug is
administered in a significant
number of subjects in need of such treatment. It is emphasized that a
therapeutically effective
amount of a drug that is administered to a particular subject in a particular
instance will not always
be effective in treating the conditions/diseases described herein, even though
such dosage is deemed
to be a therapeutically effective amount by those of skill in the art.
A. Preferred Characteristics of the Nanoparticulate Naproxen Compositions of
the
Invention
1. Increased Bioavailability
The nanoparticulate naproxen formulations of the invention exhibit increased
bioavailability,
and require smaller doses as compared to prior conventional, non-
nanoparticulate naproxen
formulations.
2. Improved Pharmacokinetic Profiles
The invention also provides nanoparticulate naproxen, or a salt or derivative
thereof,
compositions having a desirable pharmacokinetic profile when administered to
mammalian subjects.
The desirable pharmacokinetic profile of the compositions comprising naproxen
includes but is not
limited to: (1) a C,,,a., for naproxen, when assayed in the plasma of a
mammalian subject following
administration, that is preferably greater than the Cmax for a non-
nanoparticulate formulation of the
same naproxen, administered at the same dosage; and/or (2) an AUC for
naproxen, when assayed in
the plasma of a mammalian subject following administration, that is preferably
greater than the AUC
for a non-nanoparticulate formulation of the same naproxen, administered at
the same dosage; and/or
(3) a T,,,a., for naproxen, when assayed in the plasma of a mammalian subject
following
administration, that is preferably less than the Tmax for a non-
nanoparticulate formulation of the
same naproxen, administered at the same dosage. The desirable pharmacokinetic
profile, as used
herein, is the pharmacokinetic profile measured after the initial dose of
naproxen or a salt or
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derivative thereof.
In one embodiment, a composition comprising a nanoparticulate naproxen
exhibits in
comparative pharmacokinetic testing with a non-nanoparticulate formulation of
the same naproxen,
administered at the same dosage, a T,,,,,x 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 40%, not greater than about 30%, not greater than about 25%, not greater
than about 20%, not
greater than about 15%, not greater than about 10%, or not greater than about
5% of the Tmax
exhibited by the non-nanoparticulate naproxen formulation.
In another embodiment, the composition comprising a nanoparticulate naproxen
exhibits in
comparative pharmacokinetic testing with a non-nanoparticulate formulation of
the same naproxen,
administered at the same dosage, a C,,,,,x which is at least about 50%, at
least about 100%, at least
about 200%, at least about 300%, at least about 400%, at least about 500%, at
least about 600%, at
least about 700%, at least about 800%, at least about 900%, at least about
1000%, at least about
1100%, at least about 1200%, at least about 1300%, at least about 1400%, at
least about 1500%, at
least about 1600%, at least about 1700%, at least about 1800%, or at least
about 1900% greater than
the Cmax exhibited by the non-nanoparticulate naproxen formulation.
In yet another embodiment, the composition comprising a nanoparticulate
naproxen exhibits
in comparative pharmacokinetic testing with a non-nanoparticulate formulation
of the same
naproxen, administered at the same dosage, an AUC which is at least about 25%,
at least about 50%,
at least about 75%, at least about 100%, at least about 125%, at least about
150%, at least about
175%, at least about 200%, at least about 225%, at least about 250%, at least
about 275%, at least
about 300%, at least about 350%, at least about 400%, at least about 450%, at
least about 500%, at
least about 550%, at least about 600%, at least about 650%, at least about
700%, at least about
750%, at least about 800%, at least about 850%, at least about 900%, at least
about 950%, at least
about 1000%, at least about 1050%, at least about 1100%, at least about 1150%,
or at least about
1200% greater than the AUC exhibited by the non-nanoparticulate naproxen
formulation.
In one embodiment of the invention, the Tmax of naproxen, when assayed in the
plasma of the
mammalian subject, is less than about 6 to about 8 hours. In other embodiments
of the invention, the
Tmax of naproxen is less than about 6 hours, 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, or less
than about 30 minutes
after administration.
The desirable pharmacokinetic profile, as used herein, is the pharmacokinetic
profile
measured after the initial dose of naproxen or a salt or derivative thereof.
The compositions can be
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formulated in any way as described herein and as known to those of skill in
the art.
3. The Pharmacokinetic Profiles of the Naproxen Compositions of the
Invention are not Affected by the Fed or Fasted State of the Subject
Ingesting the Compositions
The invention encompasses naproxen compositions wherein the pharmacokinetic
profile of
naproxen is not substantially affected by the fed or fasted state of a subject
ingesting the
composition. This means that there is no substantial difference in the
quantity of drug absorbed or
the rate of drug absorption when the nanoparticulate naproxen compositions are
administered in the
fed versus the fasted state.
Benefits of a dosage form, which substantially eliminates the effect of food,
include an
increase in subject convenience, thereby increasing subject compliance, as the
subject does not need to
ensure that they are taking a dose either with or without food. This is
significant, as with poor
subject compliance an increase in the medical condition for which the drug is
being prescribed may
be observed.
4. Bioequivalency of Naproxen Compositions of the Invention When
Administered in the Fed Versus the Fasted State
The invention also encompasses provides a nanoparticulate naproxen composition
in which
administration of the composition to a subject in a fasted state is
bioequivalent to administration of
the composition to a subject in a fed state.
The difference in absorption (AUC) or C,,,aX of the nanoparticulate naproxen
compositions of
the invention, when administered in the fed versus the fasted state,
preferably is less than about 60%,
less than about 55%, less than about 50%, less than about 45%, less than about
40%, less than about
35%, less than about 30%, less than about 25%, less than about 20%, less than
about 15%, less than
about 10%, less than about 5%, or less than about 3%.
In one embodiment of the invention, the invention encompasses compositions
comprising a
nanoparticulate naproxen, wherein administration of the composition to a
subject in a fasted state is
bioequivalent to administration of the composition to a subject in a fed
state, in particular as defined
by C,,,aX and AUC guidelines given by the U.S. Food and Drug Administration
and the
corresponding European regulatory agency (EMEA). Under U.S. FDA guidelines,
two products or
methods are bioequivalent if the 90% Confidence Intervals (CI) for AUC and
C,,,aX are between 0.80
to 1.25 (Tmax measurements are not relevant to bioequivalence for regulatory
purposes). To show
bioequivalency between two compounds or administration conditions pursuant to
Europe's EMEA
guidelines, the 90% CI for AUC must be between 0.80 to 1.25 and the 90% CI for
C,,,aR must between
0.70 to 1.43.
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5. Dissolution Profiles of the Naproxen Compositions of the Invention
The nanoparticulate naproxen compositions of the invention are proposed to
have
unexpectedly dramatic dissolution profiles. Rapid dissolution of an
administered active agent is
preferable, as faster dissolution generally leads to faster onset of action
and greater
bioavailability. To improve the dissolution profile and bioavailability of the
naproxen, it would be
useful to increase the drug's dissolution so that it could attain a level
close to 100%.
The naproxen compositions of the invention preferably have a dissolution
profile in which
within about 5 minutes at least about 20% of the composition is dissolved. In
other embodiments of
the invention, at least about 30% or at least about 40% of naproxen
composition is dissolved within
about 5 minutes. In yet other embodiments of the invention, preferably at
least about 40%, at least
about 50%, at least about 60%, at least about 70%, or at least about 80% of
the naproxen
composition is dissolved within about 10 minutes. Finally, in another
embodiment of the invention,
preferably at least about 70%, at least about 80%, at least about 90%, or at
least about 100% of the
naproxen composition is dissolved within about 20 minutes.
Dissolution is preferably measured in a medium which is discriminating. Such a
dissolution
medium will produce two very different dissolution curves for two products
having very different
dissolution profiles in gastric juices; i.e., the dissolution medium is
predictive of in vivo dissolution
of a composition. An exemplary dissolution medium is an aqueous medium
containing the
surfactant sodium lauryl sulfate at 0.025 M. Determination of the amount
dissolved can be carried
out by spectrophotometry. The rotating blade method (European Pharmacopoeia)
can be used to
measure dissolution.
6. Redispersibility Profiles of the Naproxen Compositions of the Invention
An additional feature of the naproxen compositions of the invention is that
the compositions
redisperse such that the effective average particle size of the redispersed
naproxen particles is less
than about 2 microns. This is significant, as if upon administration the
naproxen compositions of
the invention did not redisperse to a substantially nanoparticulate particle
size, then the dosage
form may lose the benefits afforded by formulating the naproxen into a
nanoparticulate particle
size.
This is because nanoparticulate active agent compositions benefit from the
small particle
size of the active agent; if the active agent does not redisperse into the
small particle sizes upon
administration, then "clumps" or agglomerated active agent particles are
formed, owing to the
extremely high surface free energy of the nanoparticulate system and the
thermodynamic driving
force to achieve an overall reduction in free energy. With the formation of
such agglomerated
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particles, the bioavailability of the dosage form may fall well below that
observed with the liquid
dispersion form of the nanoparticulate active agent.
Moreover, the nanoparticulate naproxen or a salt or derivative thereof
compositions of the
invention exhibit dramatic redispersion of the nanoparticulate naproxen
particles upon
administration to a mammal, such as a human or animal, as demonstrated by
reconstitution/redispersion in a biorelevant aqueous media such that the
effective average particle
size of the redispersed naproxen particles is less than about 2 microns. Such
biorelevant aqueous
media can be any aqueous media that exhibit the desired ionic strength and pH,
which form the basis
for the biorelevance of the media. The desired pH and ionic strength are those
that are representative
of physiological conditions found in the human body. Such biorelevant aqueous
media can be, for
example, aqueous electrolyte solutions or aqueous solutions of any salt, acid,
or base, or a
combination thereof, which exhibit the desired pH and ionic strength.
Biorelevant pH is well known in the art. For example, in the stomach, the pH
ranges from
slightly less than 2 (but typically greater than 1) up to 4 or 5. In the small
intestine the pH can range
from 4 to 6, and in the colon it can range from 6 to 8. Biorelevant ionic
strength is also well known
in the art. Fasted state gastric fluid has an ionic strength of about 0.1M
while fasted state intestinal
fluid has an ionic strength of about 0.14. See e.g., Lindahl et al.,
"Characterization of Fluids from
the Stomach and Proximal Jejunum in Men and Women," Pharm. Res., 14 (4): 497-
502 (1997).
It is believed that the pH and ionic strength of the test solution is more
critical than the
specific chemical content. Accordingly, appropriate pH and ionic strength
values can be obtained
through numerous combinations of strong acids, strong bases, salts, single or
multiple conjugate
acid-base pairs (i.e., weak acids and corresponding salts of that acid),
monoprotic and polyprotic
electrolytes, etc.
Representative electrolyte solutions can be, but are not limited to, HC1
solutions, ranging in
concentration from about 0.00 1 to about 0.1 M, and NaC1 solutions, ranging in
concentration from
about 0.00 1 to about 0.1 M, and mixtures thereof. For example, electrolyte
solutions can be, but are
not limited to, about 0.1 M HC1 or less, about 0.01 M HC1 or less, about 0.001
M HC1 or less,
about 0.1 M NaC1 or less, about 0.01 M NaC1 or less, about 0.001 M NaC1 or
less, and mixtures
thereof. Of these electrolyte solutions, 0.01 M HC1 and/or 0.1 M NaC1, are
most representative of
fasted human physiological conditions, owing to the pH and ionic strength
conditions of the
proximal gastrointestinal tract.
Electrolyte concentrations of 0.001 M HC1, 0.01 M HC1, and 0.1 M HC1
correspond to pH
3, pH 2, and pH 1, respectively. Thus, a 0.01 M HC1 solution simulates typical
acidic conditions
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found in the stomach. A solution of 0.1 M NaC1 provides a reasonable
approximation of the ionic
strength conditions found throughout the body, including the gastrointestinal
fluids, although
concentrations higher than 0.1 M may be employed to simulate fed conditions
within the human GI
tract.
Exemplary solutions of salts, acids, bases or combinations thereof, which
exhibit the desired
pH and ionic strength, include but are not limited to phosphoric
acid/phosphate salts + sodium,
potassium and calcium salts of chloride, acetic acid/acetate salts + sodium,
potassium and calcium
salts of chloride, carbonic acid/bicarbonate salts + sodium, potassium and
calcium salts of chloride,
and citric acid/citrate salts + sodium, potassium and calcium salts of
chloride.
In other embodiments of the invention, the redispersed naproxen particles of
the invention
(redispersed in an aqueous, biorelevant, or any other suitable media) have an
effective average
particle size of less than about less than about 1900 nm, less than about 1800
nm, less than about
1700 nm, less than about 1600 nm, less than about 1500 nm, less than about
1400 nm, less than
about 1300 nm, less than about 1200 nm, less than about 1100 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.
B. Nanoparticulate Naproxen Compositions
The invention provides compositions comprising naproxen particles and at least
one surface
stabilizer. The surface stabilizers preferably are adsorbed on, or associated
with, the surface of the
naproxen particles. Surface stabilizers especially useful herein preferably
physically adhere on, or
associate with, the surface of the nanoparticulate naproxen particles, but do
not chemically react with
the naproxen particles or itself. Individually adsorbed molecules of the
surface stabilizer are
essentially free of intermolecular cross-linkages.
The invention also includes naproxen 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 administration in solid, liquid, or aerosol form, vaginal,
nasal, rectal, ocular, local
(powders, ointments or drops), buccal, intracisternal, intraperitoneal, or
topical administration, and
the like.
1. Naproxen Particles
The compositions of the invention comprise particles of naproxen or a salt or
derivative
thereof. The particles can be in a crystalline phase, semi-crystalline phase,
amorphous phase, semi-
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amorphous phase, or a combination thereof.
2. Surface Stabilizers
Combinations of more than one surface stabilizers can be used in the
invention. Useful surface
stabilizers which can be employed in the invention include, but are not
limited to, known organic
and inorganic pharmaceutical excipients. Such excipients include various
polymers, low molecular
weight oligomers, natural products, and surfactants. Exemplary surface
stabilizers include nonionic,
ionic anionic, cationic, and zwitterionic surfactants or compounds.
Representative examples of surface stabilizers include hydroxypropyl
methylcellulose (now
known as hypromellose), hydroxypropylcellulose, polyvinylpyrrolidone, sodium
lauryl sulfate,
dioctylsulfosuccinate, gelatin, casein, lecithin (phosphatides), 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), polyoxyethylene castor oil
derivatives,
polyoxyethylene sorbitan fatty acid esters (e.g., the commercially available
Tweens such as e.g.,
Tween 20 and Tween 80 (ICI Speciality Chemicals)); polyethylene glycols
(e.g., Carbowaxs
3550 and 934 (Union Carbide)), polyoxyethylene stearates, colloidal silicon
dioxide, phosphates,
carboxymethylcellulose calcium, carboxymethylcellulose sodium,
methylcellulose,
hydroxyethylcellulose, hypromellose phthalate, noncrystalline cellulose,
magnesium aluminium
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), poloxamers
(e.g., Pluronics F68 and F108 , which are block copolymers of ethylene oxide
and propylene
oxide); poloxamines (e.g., Tetronic 908 , also known as Poloxamine 908 , 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 (T-
1508) (BASF Wyandotte Corporation), Tritons X-200 , which is an alkyl aryl
polyether sulfonate
(Rohm and Haas); Crodestas F-110 , which is a mixture of sucrose stearate and
sucrose distearate
(Croda, Inc.); p-isononylphenoxypoly-(glycidol), also known as Olin-OG or
Surfactant 10-G
(Olin Chemicals, Stamford, CT); Crodestas SL-40 (Croda, Inc.); and SA9OHCO,
which is
C18H37CH2(CON(CH3)-CH2(CHOH) 4(CH2OH) z(Eastman Kodak Co.); decanoyl-N-
methylglucamide; n-decyl (3-D-glucopyranoside; n-decyl (3-D-maltopyranoside; n-
dodecyl (3-D-
glucopyranoside; n-dodecyl (3-D-maltoside; heptanoyl-N-methylglucamide; n-
heptyl- (3-D-
glucopyranoside; n-heptyl (3-D-thioglucoside; n-hexyl (3-D-glucopyranoside;
nonanoyl-N-
methylglucamide; n-noyl (3-D-glucopyranoside; octanoyl-N-methylglucamide; n-
octyl- (3-D-
glucopyranoside; octyl (3-D-thioglucopyranoside; PEG-phospholipid, PEG-
cholesterol, PEG-
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cholesterol derivative, PEG-vitamin A, PEG-vitamin E, lysozyme, random
copolymers of vinyl
pyrrolidone and vinyl acetate, and the like.
Examples of useful cationic surface stabilizers include, but are not limited
to, polymers,
biopolymers, polysaccharides, cellulosics, alginates, phospholipids, and
nonpolymeric compounds,
such as zwitterionic stabilizers, poly-n-methylpyridinium, anthryul pyridinium
chloride, cationic
phospholipids, chitosan, polylysine, polyvinylimidazole, polybrene,
polymethylmethacrylate
trimethylammoniumbromide bromide (PMMTMABr), hexyldesyltrimethylammonium
bromide
(HDMAB), and polyvinylpyrrolidone-2-dimethylaminoethyl methacrylate dimethyl
sulfate.
Other useful cationic stabilizers include, but are not limited to, cationic
lipids, sulfonium,
phosphonium, and quarternary ammonium compounds, such as
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,
C12_1sdimethyl 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
(C12_
18)dimethylbenzyl ammonium chloride, N-alkyl (C14_1s)dimethyl-benzyl ammonium
chloride, N-
tetradecylidmethylbenzyl ammonium chloride monohydrate, dimethyl didecyl
ammonium chloride,
N-alkyl and (Ciz_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(C12_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, C12, C15, C17
trimethyl ammonium
bromides, dodecylbenzyl triethyl ammonium chloride,
polydiallyldimethylammonium chloride
(DADMAC), dimethyl ammonium chlorides, alkyldimethylammonium halogenides,
tricetyl methyl
ammonium chloride, decyltrimethylammonium bromide, dodecyltriethylammonium
bromide,
tetradecyltrimethylammonium bromide, methyl trioctylammonium chloride (ALIQUAT
336Tm),
POLYQUAT 10Tm, 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,
MIRAPOLTM and
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ALKAQUATTm (Alkaril Chemical Company), 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.
Such exemplary cationic surface stabilizers and other useful cationic surface
stabilizers are
described in J. Cross and E. Singer, Cationic Surfactants: 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).
Nonpolymeric surface stabilizers are any nonpolymeric compound, such
benzalkonium
chloride, a carbonium compound, a phosphonium compound, an oxonium compound, a
halonium
compound, a cationic organometallic compound, a quarternary phosphorous
compound, a
pyridinium compound, an anilinium compound, an ammonium compound, a
hydroxylammonium
compound, a primary ammonium compound, a secondary ammonium compound, a
tertiary
ammonium compound, and quarternary ammonium compounds of the formula
NR1R2R3R4(+). For
compounds of the formula NRiR2R3R4(+) :
(i) none of Ri-R.4 are CH3;
(ii) one of Ri-R4 is CH3;
(iii) three of Ri-R4 are CH3;
(iv) all of Ri-R4 are CH3;
(v) two of Ri-R4 are CH3, one of Ri-R4 is C6H5CH2, and one of Ri-R4 is an
alkyl chain
of seven carbon atoms or less;
(vi) two of Ri-R4 are CH3, one of Ri-R4 is C6H5CH2, and one of Ri-R4 is an
alkyl chain
of nineteen carbon atoms or more;
(vii) two of Ri-R4 are CH3 and one of Ri-R4 is the group C6H5(CH2)n, where
n>1;
(viii) two of Ri-R4 are CH3, one of Ri-R4 is C6H5CH2, and one of Ri-R4
comprises at least
one heteroatom;
(ix) two of Ri-R4 are CH3, one of Ri-R4 is C6H5CH2, and one of Ri-R4 comprises
at least
one halogen;
(x) two of Ri-R4 are CH3, one of Ri-R4 is C6H5CH2, and one of Ri-R4 comprises
at least
one cyclic fragment;
(xi) two of Ri-R4 are CH3 and one of Ri-R4 is a phenyl ring; or
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(xii) two of Ri-R4 are CH3 and two of Ri-R4 are purely aliphatic fragments.
Such compounds include, but are not limited to, behenalkonium chloride,
benzethonium
chloride, cetylpyridinium chloride, behentrimonium chloride, lauralkonium
chloride, cetalkonium
chloride, cetrimonium bromide, cetrimonium chloride, cethylamine
hydrofluoride,
chlorallylmethenamine chloride (Quaternium-15), distearyldimonium chloride
(Quaternium-5),
dodecyl dimethyl ethylbenzyl ammonium chloride(Quaternium-14), Quaternium-22,
Quaternium-
26, Quaternium-18 hectorite, dimethylaminoethylchloride hydrochloride,
cysteine hydrochloride,
diethanolammonium POE (10) oletyl ether phosphate, diethanolammonium POE
(3)oleyl ether
phosphate, tallow alkonium chloride, dimethyl dioctadecylammoniumbentonite,
stearalkonium
chloride, domiphen bromide, denatonium benzoate, myristalkonium chloride,
laurtrimonium
chloride, ethylenediamine dihydrochloride, guanidine hydrochloride, pyridoxine
HC1, iofetamine
hydrochloride, meglumine hydrochloride, methylbenzethonium chloride,
myrtrimonium bromide,
oleyltrimonium chloride, polyquaternium-1, procainehydrochloride, cocobetaine,
stearalkonium
bentonite, stearalkoniumhectonite, stearyl trihydroxyethyl propylenediamine
dihydrofluoride,
tallowtrimonium chloride, and hexadecyltrimethyl ammonium bromide.
The surface stabilizers are commercially available and/or can be prepared by
techniques
known in the art. Most of these surface stabilizers are known pharmaceutical
excipients and 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, 2000), specifically incorporated by reference.
3. Other Pharmaceutical Excipients
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. Such
excipients are known in the art.
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 PH101 and Avicel PH102,
microcrystalline cellulose,
and silicified microcrystalline cellulose (ProSolv SMCCTM)
Suitable lubricants, including agents that act on the flowability of the
powder to be
compressed, are colloidal silicon dioxide, such as Aerosil 200, talc, stearic
acid, magnesium
stearate, calcium stearate, and silica gel.
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
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(trademark of MAFCO), bubble gum flavor, and fruit flavors, and the like.
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.
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 PH101
and Avicel
PH102; lactose such as lactose monohydrate, lactose anhydrous, and Pharmatose
DCL21; dibasic
calcium phosphate such as Emcompress ; mannitol; starch; sorbitol; sucrose;
and glucose.
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.
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.
4. Nanoparticulate Naproxen Particle Size
The compositions of the invention comprise naproxen particles which have an
effective
average particle size of less than about 2000 nm (i.e., 2 microns), less than
about 1900 nm, less than
about 1800 nm, less than about 1700 nm, less than about 1600 nm, less than
about 1500 nm, less
than about 1400 nm, less than about 1300 nm, less than about 1200 nm, less
than about 1100 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.
By "an effective average particle size of less than about 2000 nm" it is meant
that at least
50% of the naproxen particles have a particle size of less than the effective
average, by weight or by
another suitable measurement technique (e.g., volume, number, etc.), i.e.,
less than about 2000 nm,
1900 nm, 1800 nm, etc., when measured by the above-noted techniques. In other
embodiments of
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the invention, at least about 60%, at least about 70%, at least about 80%, at
least about 90%, at least
about 95%, or at least about 99% of the naproxen particles have a particle
size of less than the
effective average, i.e., less than about 2000 nm, 1900 nm, 1800 nm, 1700 nm,
etc.
In the present invention, the value for D50 of a nanoparticulate naproxen
composition is the
particle size below which 50% of the naproxen particles fall, by weight.
Similarly, D90 is the
particle size below which 90% of the naproxen particles fall, by weight.
5. Concentration of Naproxen and Surface Stabilizers
The relative amounts of naproxen and one or more surface stabilizers can vary
widely. The
optimal amount of the individual components can depend,. for example, upon the
particular naproxen
selected, the hydrophilic lipophilic balance (HLB), melting point, and the
surface tension of water
solutions of the stabilizer, etc.
The concentration of naproxen can vary from about 99.5% to about 0.001 Io,
from about 95%
to about 0.1 Io, or from about 90% to about 0.5%, by weight, based on the
total combined dry
weight of naproxen and at least one surface stabilizer, not including other
excipients.
The concentration of the at least one surface stabilizer can vary from about
0.5% to about
99.999%, from about 5.0% to about 99.9%, or from about 10% to about 99.5%, by
weight, based on
the total combined dry weight of naproxen and at least one surface stabilizer,
not including other
excipients.
C. Methods of Making Nanoparticulate Naproxen Compositions
The nanoparticulate naproxen compositions can be made using, for example,
milling,
homogenization, precipitation, freezing, or template emulsion techniques.
Exemplary methods of
making nanoparticulate compositions are described in the '684 patent. Methods
of making
nanoparticulate compositions are also described in U.S. Patent No. 5,518,187
for "Method of
Grinding Pharmaceutical Substances;" U.S. Patent No. 5,718,388 for "Continuous
Method of
Grinding Pharmaceutical Substances;" U.S. Patent No. 5,862,999 for "Method of
Grinding
Pharmaceutical Substances;" U.S. Patent No. 5,665,331 for "Co-
Microprecipitation of
Nanoparticulate Pharmaceutical Agents with Crystal Growth Modifiers;" U.S.
Patent No. 5,662,883
for "Co-Microprecipitation of Nanoparticulate Pharmaceutical Agents with
Crystal Growth
Modifiers;" U.S. Patent No. 5,560,932 for "Microprecipitation of
Nanoparticulate Pharmaceutical
Agents;" U.S. Patent No. 5,543,133 for "Process of Preparing X-Ray Contrast
Compositions
Containing Nanoparticles;" U.S. Patent No. 5,534,270 for "Method of Preparing
Stable Drug
Nanoparticles;" U.S. Patent No. 5,510,118 for "Process of Preparing
Therapeutic Compositions
Containing Nanoparticles;" and U.S. Patent No. 5,470,583 for "Method of
Preparing Nanoparticle
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Compositions Containing Charged Phospholipids to Reduce Aggregation," all of
which are
specifically incorporated by reference.
The resultant nanoparticulate naproxen compositions or dispersions 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.
1. Milling to Obtain Nanoparticulate Naproxen Dispersions
Milling a naproxen to obtain a nanoparticulate dispersion comprises dispersing
the naproxen
particles in a liquid dispersion medium in which the naproxen is poorly
soluble, followed by
applying mechanical means in the presence of grinding media to reduce the
particle size of the
naproxen 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. A
preferred dispersion medium is water.
The naproxen particles can be reduced in size in the presence of at least one
surface
stabilizer. Alternatively, naproxen particles can be contacted with one or
more surface stabilizers
after attrition. Other compounds, such as a diluent, can be added to the
naproxen/surface stabilizer
composition during the size reduction process. Dispersions can be manufactured
continuously or in a
batch mode.
2. Precipitation to Obtain Nanoparticulate Naproxen Compositions
Another method of forming the desired nanoparticulate naproxen 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 the naproxen 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.
3. Homogenization to Obtain Nanoparticulate Naproxen Compositions
Exemplary homogenization methods of preparing active agent nanoparticulate
compositions
are described in U.S. Patent No. 5,510,118, for "Process of Preparing
Therapeutic Compositions
Containing Nanoparticles." Such a method comprises dispersing particles of a
naproxen in a liquid
dispersion medium, followed by subjecting the dispersion to homogenization to
reduce the particle
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size of a naproxen to the desired effective average particle size. The
naproxen particles can be
reduced in size in the presence of at least one surface stabilizer.
Alternatively, the naproxen 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 naproxen/surface stabilizer
composition, either
before, during, or after the size reduction process. Dispersions can be
manufactured continuously or
in a batch mode.
4. Cryogenic Methodologies to Obtain Nanoparticulate Naproxen
Compositions
Another method of forming the desired nanoparticulate naproxen composition is
by spray
freezing into liquid (SFL). This technology comprises an organic or
organoaqueous solution of
naproxen with stabilizers, which is injected into a cryogenic liquid, such as
liquid nitrogen. The
droplets of the naproxen solution freeze at a rate sufficient to minimize
crystallization and particle
growth, thus formulating nanostructured naproxen particles. Depending on the
choice of solvent
system and processing conditions, the nanoparticulate naproxen particles can
have varying particle
morphology. In the isolation step, the nitrogen and solvent are removed under
conditions that avoid
agglomeration or ripening of the naproxen particles.
As a complementary technology to SFL, ultra rapid freezing (URF) may also be
used to
created equivalent nanostructured naproxen particles with greatly enhanced
surface area. URF
comprises an organic or organoaqueous solution of naproxen with stabilizers
onto a cryogenic
substrate.
5. Emulsion Methodologies to Obtain Nanoparticulate Naproxen
Compositions
Another method of forming the desired nanoparticulate naproxen composition is
by template
emulsion. Template emulsion creates nanostructured naproxen particles with
controlled particle size
distribution and rapid dissolution performance. The method comprises an oil-in-
water emulsion that
is prepared, then swelled with a non-aqueous solution comprising the naproxen
and stabilizers. The
particle size distribution of the naproxen particles is a direct result of the
size of the emulsion
droplets prior to loading with the naproxen a property which can be controlled
and optimized in this
process. Furthermore, through selected use of solvents and stabilizers,
emulsion stability is achieved
with no or suppressed Ostwald ripening. Subsequently, the solvent and water
are removed, and the
stabilized nanostructured naproxen particles are recovered. Various naproxen
particles
morphologies can be achieved by appropriate control of processing conditions.
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In the following examples all percentages are weight by weight unless
otherwise stated. The
term "purified water" as used throughout the Examples refers to water that has
been purified by
passing it through a water filtration system. It is to be understood that the
examples are for
illustrative purposes only, and should not be interpreted as restricting the
spirit and scope of the
invention, as defined by the scope of the claims that follow. All references
identified herein,
including U.S. patents, are hereby expressly incorporated by reference.
EXAMPLE 1
The purpose of this example is to describe preparation of a multiparticulate
modified release
composition comprising a hydrocodone that can be used in the combination
compositions of the
invention.
Multiparticulate modified release hydrocodone compositions according to the
present
invention having an immediate release component and a modified release
component having a
modified release coating are prepared according to the formulations shown in
Tables 1 and 2.
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TABLE 1
Immediate Release Component Hydrocodone Solutions
Ingredient Amount, % (w/w)
(i) (ii) (iii) (iv) (v) (vi)
Hydrocodone Bitartrate 6.0 6.0 6.0 6.0 6.0 6.0
HPMC 2910 1.0 2.0 2.0 - - 1.5
Polyethylene G1yco16000 - - - 0.5 - -
Povidone K30 - - - - 5.0 -
Fumaric Acid - 6.0 - - - -
Citric Acid - - 6.0 - - -
Silicon Dioxide 1.5 1.0 1.0 - - 2.0
Talc 1.5 - - - - -
Purified Water 90.0 85.0 85.0 93.5 89.0 90.5
TABLE 2
Modified Release Component Hydrocodone Solutions
Ingredient Amount, % (w/w)
(i) (ii) (iii) (iv) (iv) (vi) (vii)
Eudragit RS 100 4.1 4.9 5.5 4.4 - 5.5 7.5
Eudragit RL 100 - 0.5 - 1.1 - - -
Eudragit L 100 1.4 - - - - - -
Ethocel - - - - 3.0 - -
Triethyl Citrate 1.5 1.6 - 1.1 - - 1.5
Dibutyl Sebacate - - - - 0.6 1.0 -
Silicon Dioxide 1.0 1.0 1.0 - 2.0 1.0 -
Talc 2.5 2.5 1.0 2.8 - 1.0 2.5
Acetone 34.0 34.0 15.0 35.6 - 14.0 33.5
Isopropyl Alcohol 50.0 50.0 72.5 50.0 94.4 72.5 50.0
Purified Water 5.5 5.5 5.0 5.0 - 5.0 5.0
In these exemplary hydrocodone formulations, the sugar spheres (30/35 mesh)
are provided
as inert cores that act as a carrier for the active ingredient and other
excipients present in the
formulation. The quality and size selected reflect the requirement to produce
multiparticulates with
a mean diameter in the size range 0.5-0.6 mm to facilitate the subsequent
coating and encapsulation
process. Hydroxypropylmethylcellulose (2910) (Methocal E6 Premium LV) is used
to prepare the
immediate-release coating solution that is coated onto the sugar spheres to
produce the IR beads
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and acts as a binding agent. Silicon Dioxide (Syloid 244FP) is an anti-
adherent that is used in the
preparation of the IR coating solution (Table 1) and the modified release
coating suspension (Table
2).
Ammonio methyacrylate copolymer Type B (Eudragit RS 100) is a rate-controlling
polymer
that imparts the controlled release properties to the formulation and exhibits
pH independent
release properties. Talc (Altaic 200) is used as an anti-adherent in the
modified-release coating
process to manufacture the modified release beads. Acetone and isopropyl
alcohol are the two
solvents in which the rate-controlling polymer is dissolved to produce the
coating suspension that is
applied to the IR beads to form the modified release beads. The resultant
coating suspension is
applied to the IR beads to form the modified release beads. Modified release
beads are dried in an
oven for 10-20 hours at 40-500C / 30-60% RH to remove residual solvents and to
obtain a moisture
content of about 3 -6 %. Suitable processing procedures are further detailed
in U.S. Patent No.
6,066,339 which is incorporated herein by reference in its entirety.
Table 3 shows the dissolution profiles for two multiparticulate modified
release formulations
prepared in accordance with Tables 1 and 2. These results indicate that about
20% of the hydrocodone
was released in the first hour and about 80% of the hydrocodone was released
over a period of about
11 hours.
TABLE 3
Dissolution Data for Compositions Containing an
IR Component and a Modified Release Component
Formulation
Time (hr) Fumaric Acid Non-Fumaric Acid
0 0 0
1 22 26
2 33 31
4 54 54
6 68 64
8 77 73
12 93 86
In vivo Study
A randomized, single-dose, parallel-group, placebo-controlled, active-
comparator study was
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performed to evaluate the safety, efficacy, and PK of hydrocodone formulations
in subjects
immediately following bunionectomy study. The study treatments were 10, 20,
30, 40 mg of
hydrocodone bitartarate, matching active comparator (10 mg hydrocodone/APAP)
or matching
placebo. During the 24-hour confinement periods, blood was collected at
baseline and at up to 17
additional time points, from 115 subjects (approx. 17 to 21 subjects per
group), to determine the
concentrations in plasma of hydrocodone. The following PK parameters were
calculated and are
presented in Tables 4-6.
Table 4
HC ER 10 mg HC ER 20 mg HC ER 30 mg HC ER 40 mg HC/APAP Placebo
Parameter Statistics N = 21 N = 19 N = 19 N = 17 N = 18 N = 21
Cmax (ng/mL) n 21 19 19 17 18 21
Mean 8.9 17.9 31.7 37.5 19.5 0,1
Std. Dev. 2.11 5.85 8.50 8.82 8.69 0.17
Median 9.1 16.3 30.1 34.1 20.2 0.0
Min/Max 5/15 10/27 16/46 28/62 9/45 0/1
Tmax (hr) n 21 19 19 17 18 3
Mean 6.3 6.0 6.3 6.1 2.7 8.2
Std. Dev. 1.46 1.80 1.88 1.62 1.66 13.70
Median 6.1 5.2 6.1 6.0 2.1 0.6
Min/Max 4/9 4/12 4/10 4/10 1/7 0/24
kel (1/hr) n 21 19 19 17 18 NC (a)
Mean 0.090 0.095 0.086 0.079 0.138 NC
Std. Dev. 0.0276 0.0289 0.0229 0.0211 0.0297 NC
Median 0.092 0.089 0.083 0.079 0.147 NC
Min/Max 0.02/0.13 0.05/0.16 0.05/0.13 0.05/0.13 0.06/0.18 NC
(a) NC = Not Calculated
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Table 5
HC ER 10 mg HC ER 20 mg HC ER 30 mg HC ER 40 mg HC/APAP Placebo
Parameter Statistics N=21 N = 19 N = 19 N = 17 N =18 N = 21
tl/2 (hr) n 21 19 19 17 18 NC
Mean 9.5 7.9 8.6 9.4 5.3 NC
Std. Dev. 8.25 2.44 2.32 2.40 1.64 NC
Median 7.6 7.8 8.4 8.8 4.7 NC
Min/Max 5/45 4/15 5/13 5/14 4/11 NC
AUCIast (ng*hr/mL) n 21 19 19 17 18 21
Mean 109.0 212.9 392.5 464.6 131.2 0.1
Std. Dev. 27.25 73.19 117.74 124.01 36.80 0.19
Median 104.2 196.2 367.0 471.0 129.9 0.0
Min/Max 73/179 130/377 177/671 321/712 80/162 011
AUCinf (ng*hr/mL) n 21 19 19 17 18 NC
Mean 136.9 255.6 480.7 596.2 137.6 NC
Std. Dev. 39.48 88.66 138.70 172.73 39.99 NC
Median 128.1 252.7 459.5 578.0 135.4 NC
Min/Max 80/217 151/468 226/756 375/992 83/189 NC
Table 6
HC ER 10 mg HC ER 20 mg HC ER 30 mg HC ER 40 mg HC/APAP Placebo
Ratio Using AUClast Statics N = 21 N = 19 N = 19 N = 17 N =18 N = 21
Hydromorphone/ n 21 19 19 17 18 3
hydrocodone Mean 0.000 0.001 0.002 0.003 0.001 0.000
Std. Dev. 0.0009 0.0038 0.0027 0.0050 0.0012 0.0000
Median 0.000 0.000 0.001 0.002 0.000 0.000
Min/Max 0.00/0.00 0.00/0.02 0.00/0.01 0.00/0.02 0.00/0.00 0.00/0.00
Norhydrocodone/ n 21 19 19 17 18 3
Hydrocodone Mean 0.366 0.360 0.327 0.362 0.448 0.000
Std. Dev. 0.1189 0.1215 0.1243 0.1310 0.2144 0.0000
Median 0.368 0.324 0.297 0.334 0.400 0.000
Min/Max 0.11/0.61 0.17/0.58 0.20/0.76 0.23/0.74 0.22/0.84 0.00/0.00
Hydrocodone Simulations
Studies of hydrocodone formulations of the present invention were conducted to
simulate the
profiles associated with twice-daily administration hydrocodone for both
single dose and steady
state. The target doses were 10, 20, 40 and 80 mg, and the targeted minimum
concentration was 5-
10 ng/ml. The formulations of the study were two-component dosage forms
comprising an
immediate release component and a modified release component in which the
hydrocodone was
allocated evenly (50/50) or unevenly (20/80) across the two components. Non-
compartmental
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parameters were used to find estimates of the unit input response and a one-
compartment model was
assumed for all simulations.
Non-compartmental parameters following a 10 mg oral dose of hydrocodone
administered to
five adult males are reported as shown in Table 7 below.
Table 7 - Non-Compartmental Parameters
Cmax 23.6 5.2 ng/ml
Tmax 1.3 0.3 hours
Thalf 3.8 0.3 hours
K10 and V/f were estimated to be 0.18 and 334.29L respectively. For the
absorption rate constant
k01, several profiles were simulated using different estimates of k01. The
secondary parameters
estimates were compared to identify an appropriate ka as set forth in Table 8
below.
Table 8 - Comparison of Absorption Rate Constant (ka).
ka=1 AUC 166.19
ka=1 KO1-HL 0.69
ka=1 K10-HL 3.85
ka=1 CL/F 60.17
ka=1 Tmax 2.09
ka=1 Cmax 20.53
ka=2 AUC 166.19
ka=2 KO1-HL 0.35 15
ka=2 K10-HL 3.85
ka=2 CL/F 60.17
ka=2 Tmax 1.32
ka=2 Cmax 23.57
ka=6 AUC 166.19
ka=6 KO1-HL 0.12
ka=6 K 10-HL 3.85
ka=6 CL/F 60.17 20
ka=6 Tmax 0.60
ka=6 Cmax 26.84
ka=2 appeared to be the best estimate of the absorption rate of the instant
release hydrocodone given
that the maximum concentration observed and the time to maximum concentration
were comparable
to previous data set forth above.
In conducting these simulations, three options were identified. Options 1 and
2 assumed a
first order release and option 3 a zero-order release. Plots of the plasma
concentrations of these
simulations are shown in Figs. 1 to 16.
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EXAMPLE 2
The purpose of this example is to describe preparation of a naproxen
composition that can be
used in the combination compositions of the invention.
To 670 g of deionized water, 30 g of hydroxypropylcellulose (Klucel Type EF;
Aqualon)
was dissolved using a continuous laboratory mixer. 300 g of naproxen was
dispersed into the HPC
solution until a homogeneous suspension was obtained. A laboratory scale media
mill filled with
polymeric grinding media was used in a continuous fashion until the mean
particle size was
approximately 200 nm as measured by laser light scattering technique, ex.
Microtrak UPA.
EXAMPLE 3
The purpose of this example is to describe preparation of a naproxen
composition that can be
used in the combination compositions of the invention.
To 575 g of deionized water was dissolved 25 g of polyvinylpyrrolidone
(K29/32; BASF
Corpl) using a continuous laboratory mixer. 400 g of naproxen was dispersed
into the PVP solution
until a homogenous suspension was obtained. It was processed through a
laboratory scale media
mill filled with polymeric grinding media in a continuous fashion until the
mean particle size was
approximately 200 nm as measured by laser light scattering technique, ex.
MicroTrak UPA.
EXAMPLE 4
The purpose of this example is to describe preparation of a naproxen
composition that can be
used in the combination compositions of the invention.
A nanoparticulate naproxen dispersion was prepared in a roller mill as
follows. A 250 ml
glass jar was charged with 120 ml of 1.0 mm pre-cleaned Zirconium oxide beads
(Zirbeads XR,
available from Zircoa Inc., having a nominal diameter of 1.0 mm), 60 g of an
aqueous slurry
containing 3 g naproxen (5% by weight), purchased from Sigma, St. Louis, Mo.,
particle size 20-30
microns, and 1.8 g(3 Io by weight) Pluronic F-68, purchased from BASF Fine
Chemicals, Inc., as
the surface stabilizer. The beads were pre-cleaned by rinsing in IN H2SO4
overnight followed by
several rinses with deionized water. The batch was rolled at 92 RPM for a
total of 120 hours. The
dispersion was stable when a portion was added to 0.1N HCI. The average
particle size measured by
photon correlation spectroscopy was 240-300 nm.
It will be apparent to those skilled in the art that various modifications and
variations can be
made in the methods and compositions of the present inventions without
departing from the spirit or
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scope of the invention. Thus, it is intended that the present invention cover
the modification and
variations of the invention provided they come within the scope of the
appended claims and their
equivalents.
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