U.S. patent application number 16/161940 was filed with the patent office on 2019-05-16 for levodopoa and carbidopa intestinal gel and methods of use.
The applicant listed for this patent is AbbVie Inc.. Invention is credited to Rajkumar Conjeevaram, Alexandru DEAC, Ye HUANG, Sean E. MACKEY, Randy A. MENGES, Jayne Zimmerman.
Application Number | 20190142777 16/161940 |
Document ID | / |
Family ID | 55410198 |
Filed Date | 2019-05-16 |
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United States Patent
Application |
20190142777 |
Kind Code |
A1 |
Conjeevaram; Rajkumar ; et
al. |
May 16, 2019 |
Levodopoa and Carbidopa Intestinal Gel and Methods of Use
Abstract
The present disclosure relates to (a) an improved pharmaceutical
composition comprising a levodopa active agent and a carbidopa
active agent (b) methods of producing the pharmaceutical
composition and (c) methods of treating Parkinson's disease and
associated conditions comprising administering the pharmaceutical
composition to a subject with Parkinson's disease.
Inventors: |
Conjeevaram; Rajkumar; (Lake
Bluff, IL) ; DEAC; Alexandru; (Skokie, IL) ;
HUANG; Ye; (Gurnee, IL) ; MACKEY; Sean E.;
(Grayslake, IL) ; MENGES; Randy A.; (Lake Villa,
IL) ; Zimmerman; Jayne; (Deerfield, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
AbbVie Inc. |
North Chicago |
IL |
US |
|
|
Family ID: |
55410198 |
Appl. No.: |
16/161940 |
Filed: |
October 16, 2018 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15001392 |
Jan 20, 2016 |
10117843 |
|
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16161940 |
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62272922 |
Dec 30, 2015 |
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62105565 |
Jan 20, 2015 |
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Current U.S.
Class: |
424/400 ;
424/489; 514/565 |
Current CPC
Class: |
A61K 31/198 20130101;
A61K 47/32 20130101; A61K 9/10 20130101; A61K 9/0019 20130101; A61P
25/16 20180101; A61K 47/38 20130101; A61K 45/06 20130101; A61K
9/0053 20130101; A61K 47/10 20130101; A61K 31/198 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 45/06 20060101 A61K045/06; A61K 9/00 20060101
A61K009/00; A61K 47/10 20060101 A61K047/10; A61K 9/10 20060101
A61K009/10; A61K 47/38 20060101 A61K047/38; A61K 47/32 20060101
A61K047/32 |
Claims
1. A pharmaceutical composition for intraduodenal administration
comprising: (a) a levodopa active agent in an amount of about 4.0
weight/weight percent of the total composition; (b) a carbidopa
monohydrate active agent in an amount of about 1.0 weight/weight
percent of the total composition; (c) one or more acrylic
acid-based polymer suspending agents; and (d) water, wherein the
pharmaceutical composition has: (i) a high shear viscosity of no
more than about 4500 cps at 22.degree. C. and 24.1 s.sup.-1; (ii) a
low shear viscosity of no less than about 45000 cps at 5.degree. C.
and 1 s.sup.-1; and (iii) a ratio of low shear viscosity to high
shear viscosity of not less than 10.
2-5. (canceled)
6. The pharmaceutical composition according to claim 1, wherein the
one or more acrylic acid-based polymer suspending agents is
Carbopol.RTM..
7. The pharmaceutical composition according to claim 1, wherein the
concentration of water is in an amount of from about zero percent
to about 95 weight/weight percent of the total composition.
8. (canceled)
9. (canceled)
10. The pharmaceutical composition according to claim 1, wherein
the pharmaceutical composition does not experience degradation into
DHPA at a rate faster than 0.06 w/w % per week.
11. The pharmaceutical composition according to claim 1, wherein
the pharmaceutical composition does not experience degradation into
DHPPA at a rate faster than 0.06 w/w % per week.
12. The pharmaceutical composition according to claim 1, wherein
the pharmaceutical composition does not experience degradation
producing hydrazine at a rate faster than 0.75 .mu.g/g per
week.
13. The pharmaceutical composition according to claim 1, wherein
the pharmaceutical composition is present in a lower O.sub.2
permeable primary or secondary container.
14. A pharmaceutical dosage form comprising the pharmaceutical
composition of claim 1 in a disposable drug reservoir having an
oxygen impermeable enclosure disposed therein, wherein the oxygen
impermeable enclosure is purged with an inert gas and an oxygen
scavenger is added.
15. The pharmaceutical dosage form according to claim 14, wherein
the pharmaceutical dosage form is suitable for use in a continuous
infusion pump capable of delivering the composition in a
therapeutically effective manner.
16. A method of preparing a pharmaceutical composition for
intraduodenal administration comprising: (a) a levodopa active
agent in an amount of about 4.0 weight/weight percent of the total
composition; (b) a carbidopa monohydrate active agent in an amount
of about 1.0 weight/weight percent of the total composition; (c)
one or more polymer-based suspending agents; and (d) water, wherein
the pharmaceutical composition has: (i) a high shear viscosity of
no more than about 4500 cps at 22.degree. C. and 24.1 s.sup.-1;
(ii) a low shear viscosity of no less than about 45000 cps at
5.degree. C. and 1 s.sup.-1; and (iii) a ratio of low shear
viscosity to high shear viscosity of not less than 10, wherein the
method comprises: adding a levodopa active agent and a carbidopa
monohydrate active agent to water to form a slurry; adding the
slurry to one or more polymer-based suspending agents to form a
suspension; and subjecting the suspension to N.sub.2 sparging.
17. The method according to claim 16, further comprising loading
the suspension into a lower oxygen permeability container.
18. The method according to claim 16, wherein, prior to forming the
suspension, the levodopa active agent has a particle size
distribution of: (i) D50 less than or equal to about 5 .mu.m; (ii)
D90 less than or equal to about 11 .mu.m; and (iii) D100 less than
or equal to about 22 .mu.m; and the carbidopa active agent has a
particle size distribution of: (i) D50 less than or equal to about
3 .mu.m; (ii) D90 less than or equal to about 7 .mu.m; and (iii)
D100 less than or equal to about 21 .mu.m.
19. The method according to claim 16, wherein the one or more
polymer-based suspending agents is selected from the group
consisting of hydroxypropylcellulose, hydroxymethylcellulose, and
sodium carboxymethyl cellulose.
20. The method according to claim 16, wherein the one or more
polymer-based suspending agent is an acrylic acid-based
polymer.
21-25. (canceled)
26. A method of treating Parkinson's disease in a patient in need
thereof, wherein the method comprises intraduodenal administration
to the patient a pharmaceutical composition comprising: (a) a
levodopa active agent in an amount of about 4.0 weight/weight
percent of the total composition; and (b) a carbidopa monohydrate
active agent in an amount of about 1.0 weight/weight percent of the
total composition; (c) one or more polymer-based suspending agents;
and (d) water, wherein the pharmaceutical composition has: (i) a
high shear viscosity of no more than about 4500 cps at 22.degree.
C. and 24.1 s.sup.-1; (ii) a low shear viscosity of no less than
about 45000 cps at 5.degree. C. and 1 s.sup.-1; and (iii) a ratio
of low shear viscosity to high shear viscosity of not less than
10.
27. The method according to claim 26, wherein the method comprises
substantially continuous administration of the pharmaceutical
composition for a period of at least about 16 hours.
28-31. (canceled)
32. The method according to claim 26, wherein the one or more
polymer-based suspending agent is selected from the group
consisting of hydroxypropylcellulose, hydroxymethylcellulose, and
sodium carboxymethyl cellulose.
33. (canceled)
34. The method according to claim 26, wherein the one or more
polymer-based suspending agent is an acrylic acid-based polymer
35. A kit comprising the pharmaceutical composition of claim 1.
36. A kit comprising the pharmaceutical dosage form of claim 14.
Description
PRIORITY STATEMENT
[0001] This U.S. patent application is a divisional application
claiming priority to U.S. patent application Ser. No. 15/001,392,
filed Jan. 20, 2016, which claims the benefit of U.S. Provisional
application 62/105,565 filed 20 Jan. 2015 and 62/272,922 filed 30
Dec. 2015. The entire contents of each patent application recited
herein are hereby incorporated by reference.
FIELD OF THE INVENTION
[0002] The present disclosure relates to (a) an improved
pharmaceutical composition comprising levodopa and carbidopa and
(b) methods of treating Parkinson's disease and associated
conditions comprising administering the pharmaceutical composition
to a subject with Parkinson's disease.
BACKGROUND OF THE INVENTION
[0003] Parkinson's disease is a chronic and progressive
neurodegenerative condition characterized by reduced levels in the
brain of the neurotransmitter dopamine (i.e.,
3,4-dihydroxyphenethylamine). Administration of L-dopa currently is
the most effective therapy for treating a patient with Parkinson's
disease. L-dopa, which unlike dopamine can cross the blood-brain
barrier, is enzymatically converted in the brain to dopamine
resulting in an increase in dopamine levels:
##STR00001##
[0004] The conversion of L-dopa to dopamine is catalyzed by
aromatic L-amino acid decarboxylase, a ubiquitous enzyme that
promotes central as well as peripheral metabolism of L-dopa to
dopamine. A relatively large dose of L-dopa is required to achieve
therapeutically effective dopamine levels in the brain.
Administration of such large L-dopa doses results in elevated
peripheral dopamine levels that can cause nausea in some patients.
To overcome these problems, L-dopa generally is co-administered
with a peripheral aromatic L-amino acid decarboxylase inhibitor
such as carbidopa (i.e.,
(2S)-3-(3,4-dihydroxy-phenyl)-2-hydrazino-2-methylpropanoic
acid):
##STR00002##
Co-administration of carbidopa with L-dopa inhibits the peripheral
metabolism of L-dopa to dopamine, which significantly reduces the
L-dopa dose required for a therapeutically effective response and
reduces the associated side effects.
[0005] Even when L-dopa and carbidopa are co-administered, however,
it is difficult to consistently maintain the desired dopamine
levels in the brain due to the relatively short half-life of L-dopa
in plasma. In addition, the tolerance of many patients to
variability in dopamine levels in the brain decreases as the
disease progresses. One approach that has been effective in
reducing variability of dopamine levels is the continuous
intestinal delivery of an adjustable dose of an L-dopa/carbidopa
gel known by its commercial name, DuoDopa.RTM.. DuoDopa.RTM. is a
suspension of L-dopa/carbidopa monohydrate (4:1 ratio of L-dopa to
carbidopa monohydrate) in an aqueous gel. The gel is delivered to
the proximal small intestine through a jejunal tube inserted
through a percutaneous endoscopic gastrostomy port. DuoDopa.RTM. is
packaged in disposable drug reservoirs ("DDRs") and continuously
administered via a software-controlled ambulatory infusion pump.
Although L-dopa and carbidopa have been co-administered to treat
Parkinson's disease for several decades, a pharmaceutical
composition suitable for use in a newer generation of lighter,
smaller infusion pumps that deliver gel compositions to the
intestine is not currently commercially available.
[0006] The current composition of the DuoDopa.RTM. L-dopa/carbidopa
intestinal gel is a gel for continuous intestinal administration.
For long-term administration, the gel is administered with a
portable pump directly into the duodenum or upper jejunum via a
percutaneous endoscopic gastrostomy tube with an inner
intestinal/jejunal tube. Each 1 ml of Duodopa.RTM. contains 20 mg
levodopa and 5 mg carbidopa monohydrate. Despite the current
commercial success of DuoDopa.RTM., the product is subject to
limitations in product preparation, including (1) risk of
sedimentation of drug particles during storage and administration,
(2) chemical instability of carbidopa, which leads to hydrazine
formation.
[0007] Accordingly, there is a continuing need for improved
formulations and methods that can provide continuous and consistent
dopamine levels in the brain to effectively treat movement
disorders such as Parkinson's disease. The present disclosure
provides such improved formulations and methods.
SUMMARY OF THE INVENTION
[0008] In one aspect, the present disclosure relates to a
pharmaceutical composition comprising a levodopa active agent and a
carbidopa active agent for intraduodenal administration wherein the
levodopa active agent is provided in an amount of about 4
weight/weight percent (w/w %) of the composition and carbidopa
(e.g., carbidopa monohydrate) is provided in an amount of about 1
weight/weight percent of the composition wherein the levodopa and
carbidopa are suspended in an aqueous carrier. The pharmaceutical
composition has a desired viscosity suitable for storage under
refrigerated conditions and/or delivery (e.g., delivered via a
pump) at room temperature (e.g., .about.20.degree. C. to
.about.25.degree. C.).
[0009] In another aspect, the present disclosure relates to a
method of treating Parkinson's disease in a patient in need
thereof, wherein the method comprises administering to the patient
a pharmaceutical composition comprising a levodopa active agent and
a carbidopa active agent for intraduodenal administration wherein
the levodopa active agent and carbidopa active agent (e.g.,
carbidopa monohydrate) are provided in an amount of from about 4
weight/weight percent and 1 weight/weight percent of the
composition, respectively, suspended in an aqueous carrier. The
pharmaceutical composition has a desired viscosity suitable for
storage under refrigerated conditions and/or delivery (e.g.,
delivered via a pump) at room temperature (e.g., .about.20.degree.
C. to .about.25.degree. C.).
[0010] In another aspect, the present disclosure relates to methods
of manufacturing a pharmaceutical composition of the invention, in
particular a high concentration pharmaceutical composition as
disclosed, for example, in Example 1 and FIG. 1 below.
[0011] These and additional embodiments of the invention are
further described herein.
[0012] Further benefits of the present disclosure will be apparent
to one skilled in the art from reading this patent application. The
embodiments of the disclosure described in the following paragraphs
are intended to illustrate the invention and should not be deemed
to narrow the scope of the invention.
BRIEF DESCRIPTION OF THE DRAWINGS
[0013] FIG. 1 is a manufacturing process flowchart for producing an
exemplary pharmaceutical formulation of the invention.
[0014] FIG. 2 shows the L-Dopa blood level time-concentration
profile in mini-pigs of an exemplary pharmaceutical composition of
the invention as against two comparators, all given in a six-hour
continuous infusion.
[0015] FIG. 3 shows the carbidopa blood level time-concentration
profile in mini-pigs of an exemplary pharmaceutical composition of
the invention as against two comparators, all given in a six-hour
continuous infusion.
[0016] FIG. 4 shows average levodopa plasma concentrations in 12
human subjects at various time points post administration.
[0017] FIG. 5 shows average carbidopa plasma concentrations in 12
human subjects at various time points post administration.
[0018] FIG. 6 shows the dissolution rate at which levodopa and
carbidopa dissolve in a pH 4.5 media.
[0019] FIG. 7 shows the dissolution rate at which levodopa and
carbidopa dissolve in a pH 6.8 media.
[0020] FIG. 8 charts the decomposition of low and high
concentration gel formulations into 3,4-dihydroxyphenylacetone
(DHPA) over the course of 15 weeks storage at 2-8.degree. C.
[0021] FIG. 9 charts the decomposition of low and high
concentration gel formulations into
2-methyl-3-(3,4-dihydroxyphenyl) propanoic acid (DHPPA) over the
course of 15 weeks storage at 2-8.degree. C.
[0022] FIG. 10 charts the decomposition of low and high
concentration gel formulations into hydrazine over the course of 15
weeks storage at 2-8.degree. C.
[0023] FIG. 11 shows the effects of oxygen scavengers in different
packages on the accumulation of DHPA (panel A) and DHPPA (panel B)
degradation products. The abbreviations in the legend have the
following significations: 1.times.=2 w/w % levodopa, 0.5 w/w %
carbidopa; 2.times.=4 w/w % levodopa, 1.0 w/w % carbidopa;
EVA=container closure bag made from EVA/EVOH/EVA material;
Smiths=PVC bag used in Smiths Medical cassette reservoir;
OW+Scav=with oxygen scavenger inside overwrapped aluminum foil
pouch.
DETAILED DESCRIPTION OF THE INVENTION
[0024] This written description uses examples to disclose the
invention, including the best mode, and also to enable any person
skilled in the art to practice the invention, including making and
using any of the disclosed pharmaceutical compositions, kits,
pharmaceutical dosage forms, and performing any of the disclosed
methods or processes. The patentable scope of the invention is
defined by the claims, and may include other examples that occur to
those skilled in the art. Such other examples are intended to be
within the scope of the claims if they have elements that do not
differ from the literal language of the claims, or if they include
equivalent elements.
I. DEFINITIONS
[0025] Section headings as used in this section and the entire
disclosure are not intended to be limiting.
[0026] Where a numeric range is recited, each intervening number
within the range is explicitly contemplated with the same degree of
precision. For example, for the range 6 to 9, the numbers 7 and 8
are contemplated in addition 15 to 6 and 9, and for the range 6.0
to 7.0, the numbers 6.0, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8,
6.9 and 7.0 are explicitly contemplated. In the same manner, all
recited ratios also include all sub-ratios falling within the
broader ratio.
[0027] The singular forms "a," "an," and "the" include plural
referents unless the context clearly dictates otherwise.
[0028] The term "and/or" as used in a phrase such as "A and/or B"
herein is intended to include "A and B", "A or B", "A", and
"B".
[0029] The term "about" generally refers to a range of numbers that
one of skill in the art would consider equivalent to the recited
value (i.e., having the same function or result). In many
instances, the term "about" may include numbers that are rounded to
the nearest significant figure.
[0030] Unless the context requires otherwise, the terms "comprise,"
"comprises," and "comprising" are used on the basis and clear
understanding that they are to be interpreted inclusively, rather
than exclusively, and that Applicant intends each of those words to
be so interpreted in construing this patent, including the claims
below.
[0031] The terms "improve" and "improving" have their plain and
ordinary meaning to one skilled in the art of pharmaceutical or
medical sciences and specifically include ameliorating the effects
of Parkinson's disease, or decreasing or lessening a symptom or
side effect of Parkinson's disease.
[0032] The term "patient" includes mammals and humans, particularly
humans.
[0033] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" refers to any and all
solvents, dispersion media, preservatives, antioxidants, coatings,
isotonic and absorption delaying agents, and the like, that are
compatible with pharmaceutical administration. The term "aqueous
carrier" refers to a pharmaceutically acceptable carrier in which
the solvent is water.
[0034] The term "pharmaceutically acceptable salt" refers to a salt
of a compound that is pharmaceutically acceptable and that
possesses the desired pharmacological activity of the parent
compound. Such salts include: (1) acid addition salts, formed with
inorganic acids such as hydrochloric acid, hydrobromic acid,
sulfuric acid, nitric acid, phosphoric acid, and the like; or
formed with organic acids such as acetic acid, propionic acid,
hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic
acid, lactic acid, malonic acid, succinic acid, malic acid, maleic
acid, fumaric acid, tartaric acid, citric acid, benzoic acid,
3-(4-hydroxybenzoyl)benzoic acid, cinnamic acid, mandelic acid,
methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic
acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid,
4-chlorobenzenesulfonic acid, 2-naphthalenesulfonic acid,
4-toluenesulfonic acid, camphorsulfonic acid,
4-methyl-bicyclo[2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic
acid, 3-phenylpropionic acid, trimethylacetic acid, tertiary
butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic
acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic
acid, and the like; and (2) salts formed when an acidic proton
present in the parent compound either is replaced by a metal ion,
e.g., an alkali metal ion, an alkaline earth ion, or an aluminum
ion; or coordinates with an organic base such as ethanolamine,
diethanolamine, triethanolamine, N-methylglucamine,
dicyclohexylamine, and the like.
[0035] The terms "reduce" and "reducing" have their plain and
ordinary meanings to one skilled in the art of pharmaceutical or
medical sciences and specifically include diminishing or decreasing
the number of occurrences, the duration, or the intensity, of a
Parkinson's disease symptom or side effect, such as dyskinesias or
hallucinations.
[0036] The term "therapeutically effective amount" means an amount
of a compound that, when administered to a patient suffering from
or susceptible to Parkinson's disease or an associated condition is
sufficient, either alone or in combination with additional
therapies, to effect treatment for Parkinson's disease or the
associated condition. The "therapeutically effective amount" will
vary depending, for example, on the compound, pharmaceutical
composition or pharmaceutical dosage form, the condition treated
and its severity, and the age and weight of the patient to be
treated.
[0037] The terms "treat" and "treating" have their plain and
ordinary meaning to one skilled in the art of pharmaceutical or
medical sciences and specifically include improving the quality of
life or reducing the symptoms or side effects of Parkinson's
disease.
II. PHARMACEUTICAL COMPOSITIONS
[0038] The present disclosure relates to a pharmaceutical
composition comprising a levodopa active agent and a carbidopa
active agent for intraduodenal administration wherein the levodopa
active agent and carbidopa active agent are present in a
therapeutically effective amount suspended in an aqueous carrier,
characterized in that the levodopa active agent and the carbidopa
active agent in the carrier has a high shear viscosity of no more
than about 4500 cps at room temperature (e.g., .about.20.degree. C.
to .about.25.degree. C., such as .about.22.degree. C.) and a low
shear viscosity of no less than about 45000 cps under refrigerated
storage conditions (for example, at about 2.degree. C. to about
8.degree. C., such as 5.degree. C.). Additionally or alternatively,
the pharmaceutical composition--i.e., the aqueous carrier with the
levodopa active agent and carbidopa active agent suspended
therein--can have a ratio of low shear viscosity to high shear
viscosity of not less than about 10. In particular, the aqueous
carrier with the levodopa active agent and carbidopa active agent
suspended therein can have a high shear viscosity of no more than
about 4500 cps at room temperature (e.g., .about.20.degree. C. to
.about.25.degree. C., such as .about.22.degree. C.) and a low shear
viscosity of no less than about 45000 cps under refrigerated
storage conditions (for example, at about 2.degree. C. to about
8.degree. C., such as 5.degree. C.) and a ratio of low shear
viscosity to high shear viscosity of not less than about 10. The
pharmaceutical compositions may have the aforementioned low shear
viscosity and high shear viscosity throughout shelf life. As used
herein, "shelf life" includes at least about 2 weeks, for example,
at least about 5 weeks, at least about 10 weeks, at least about 15
weeks, or at least about 20 weeks. For example, the pharmaceutical
composition can have a high shear viscosity of about 4300-4400 cps
(at .about.22.degree. C.) and a low shear viscosity of about 49600
cps (at .about.5.degree. C.) throughout its shelf life.
[0039] Both low shear and high shear viscosity can be measured by
routine methods known in the art. For purposes of measuring
viscosity of the compositions and formulations disclosed herein,
low shear viscosity should be measured in a sample of .about.9 mL
at a temperature of .about.5.degree. C. and a shear rate of
.about.0.1 sec.sup.-1. If the viscosity is measured in, e.g., a
BROOKFIELD Model LV viscometer (for example in sample chamber
SC4-13R with temperature probe and water jacket assembly SC4-45Y),
then the test should be conducted with an SC4-31 model spindle.
Where other equipment is used, a spindle of corresponding
dimensions and specifications can be substituted accordingly.
[0040] High sheer viscosity should be measured in a sample of
.about.16 mL at a temperature of .about.22.degree. C. and a shear
rate of .about.24.1 sec.sup.-1. If the viscosity is measured in,
e.g., a BOHLIN model 88 BV rotational viscometer, then the test
should be conducted with a C25 cylinder/spindle system. Where other
equipment is used, a spindle of corresponding dimensions and
specifications can be substituted accordingly.
[0041] In various aspects, the therapeutically effective amount of
a levodopa active agent and a carbidopa active agent (e.g.,
carbidopa monohydrate) present in the pharmaceutical composition
may be about 4.0 and 1.0 weight/weight percent of the composition,
respectively.
[0042] As previously noted, the inherently low aqueous solubility
of L-dopa and carbidopa at physiologically acceptable pH for
infusion presents a significant technical challenge to the
development of improved pharmaceutical compositions and methods of
treatment. Such challenges include, for example, difficulties in
achieving formulation stability within the required pH limitations.
These challenges are further complicated by the requirement that
the pharmaceutical compositions and methods of treatment provide
pharmacokinetically-appropriate and pharmacokinetically-consistent
control of dopamine levels in the patient's brain.
[0043] In one embodiment, the pharmaceutical composition comprises
a levodopa active agent in an amount of about 4.0 weight/weight
percent of the total composition; a carbidopa active agent (e.g.,
carbidopa monohydrate) in an amount of about 1.0 weight/weight
percent of the total composition; at least one suspending agent;
and a liquid vehicle (for example, water). In various embodiments,
the liquid vehicle can make up from about zero weight/weight
percent to about 95 weight/weight percent of the total composition,
for example from about 10 weight/weight percent to about 70
weight/weight percent, or from about 40 weight/weight percent to
about 60 weight/weight percent of the total composition.
[0044] In one embodiment, the levodopa active agent is levodopa and
pharmaceutically acceptable salts or hydrates thereof, such as
levodopa monohydrate. Levodopa is preferably present in the
composition in an amount of from about 1.0 to 5.0 weight/weight
percent in the total composition. In a preferred embodiment the
pharmaceutical composition comprises about 4.0 weight/weight
percent of a levodopa active agent. In one embodiment, the levodopa
active agent can be processed into microparticles or microspheres
or the like, for example as described in Example 1 below, for
inclusion in the present pharmaceutical compositions.
[0045] In one embodiment, the carbidopa active agent is carbidopa
and pharmaceutically acceptable salts or hydrates thereof, such as
carbidopa monohydrate. The carbidopa active agent is preferably
present in the composition in an amount of from about 0.25 to 1.25
weight/weight percent in the total composition. In a preferred
embodiment the pharmaceutical composition comprises about 1.0
weight/weight percent of a carbidopa active agent. The preferred
form of carbidopa active agent to be administered is carbidopa
monohydrate. In one embodiment, the carbidopa active agent can be
processed into microparticles or microspheres or the like, for
example as described in Example 1 below, for inclusion in the
present pharmaceutical compositions.
[0046] The levodopa active agent and carbidopa active agent may be
present in the pharmaceutical composition in any suitable ratio,
for example, the ratio of levodopa active agent to carbidopa active
agent (e.g., carbidopa monohydrate) in the present pharmaceutical
compositions may be about 4:1. For example, the pharmaceutical
composition can comprise about 4 weight/weight percent of levodopa
active agent and 1 weight/weight percent carbidopa active agent
(e.g., carbidopa monohydrate). In one embodiment, the
pharmaceutical composition comprises a liquid or viscous liquid
comprising about 200 mg levodopa and about 50 mg carbidopa (e.g.,
carbidopa monohydrate) per each 5.0 mL volume. In one embodiment,
the levodopa active agent and the carbidopa active agent are
processed into microparticles or microspheres or the like, for
example as described in Example 1 below, for inclusion in the
present pharmaceutical compositions.
[0047] The ratio of levodopa active agent, or of the combination of
levodopa active agent to carbidopa active agent, to a suspending
agent is from about 3 to about 1 w/w % to about 1 to about 30 w/w
%, with a generally preferred range from about 2 to about 1 w/w %
to about 1 to about 10 w/w %. Such readily available suspending
agents are well known in the art and can include polymer-based
suspending agents, such as, but not limited to, carbohydrate-based
suspending agents and acrylic acid-based polymers (e.g., Carbomer,
Carbopol.RTM.). Exemplary carbohydrate-based suspending agents
include, but are not limited to hydroxypropylcellulose,
hydroxymethylcellulose, and sodium carboxymethyl cellulose (NaCMC).
Acrylic acid-based polymers may be cross-linked, for example,
cross-linked with polyalkenyl ethers or divinyl glycol. In
particular, the suspending agent may be sodium carboxymethyl
cellulose (NaCMC) or Carbopol.
[0048] For the present compositions, one or more suspending agents
can be used to obtain the ratios of levodopa active agent, or of
the combination of levodopa active agent to carbidopa active agent,
to suspending agent as set forth above.
[0049] However, when a surfactant is used, it may be best to add
the surfactant or surfactants following addition of levodopa active
agent and carbidopa active agent and suspending agent as taught
herein.
[0050] It should be understood that each component comprising the
compositions of the present invention must be pharmaceutically
acceptable and utilized in a non-toxic concentration.
[0051] In one embodiment, the pharmaceutical composition is a
viscous liquid composition. In one aspect, the pharmaceutical
composition comprises water and is suitable for infusion.
[0052] In another embodiment, the pharmaceutical composition is an
aqueous pharmaceutical composition having a levodopa active agent
concentration of at least about 5 mg/mL. In one aspect, the
levodopa active agent concentration is at least about 10 mg/mL. In
another aspect, the levodopa active agent concentration is at least
about 20 mg/mL. In another aspect, the levodopa active agent
concentration is at least about 30 mg/mL. In another aspect, the
levodopa active agent concentration is at least about 35 mg/mL. In
another aspect, the levodopa active agent concentration is at least
about 40 mg/mL. In another aspect, the levodopa active agent
concentration is at least about 45 mg/mL. In another aspect, the
levodopa active agent concentration is at least about 50 mg/mL. In
another aspect, the levodopa active agent concentration is at least
about 100 mg/mL. In another aspect, the levodopa active agent
concentration is at least about 150 mg/mL. In another aspect, the
levodopa active agent concentration is at least about 200
mg/mL.
[0053] In another embodiment, the pharmaceutical composition is an
aqueous pharmaceutical composition having a carbidopa active agent
(e.g., carbidopa monohydrate) concentration of at least about 5
mg/mL. In one aspect, the carbidopa active agent concentration is
at least about 10 mg/mL. In another aspect, the carbidopa active
agent concentration is at least about 20 mg/mL. In another aspect,
the carbidopa active agent concentration is at least about 30
mg/mL. In another aspect, the carbidopa active agent concentration
is at least about 50 mg/mL. In another aspect, the carbidopa active
agent concentration is at least about 100 mg/mL. In another aspect,
the carbidopa active agent concentration is at least about 150
mg/mL. In another aspect, the active agent carbidopa concentration
is at least about 200 mg/mL.
[0054] The pharmaceutical compositions of the present disclosure
optionally comprise one or more additional pharmaceutically
acceptable excipients. The term "excipient" refers to any
substance, not itself a therapeutic agent, used as a carrier or
vehicle for delivery of a therapeutic agent to a subject or added
to a pharmaceutical composition to improve its handling or storage
properties or to permit or facilitate formation of a unit dose of
the composition.
[0055] Excipients include, for example, antioxidants, agents to
adjust the pH and osmolarity, preservatives, thickening agents,
colorants, buffering agents, bacteriostats, and stabilizers. A
given excipient, if present, generally will be present in an amount
of about 0.001% to about 95%, about 0.01% to about 80%, about 0.02%
to about 25%, or about 0.3% to about 10%, by weight.
[0056] In one embodiment, the pharmaceutical compositions
optionally comprise an antioxidant. Suitable antioxidants for use
in the pharmaceutical compositions include, for example, butylated
hydroxytoluene, butylated hydroxyanisole, potassium metabisulfite,
cysteine, and the like.
[0057] In one embodiment, the pharmaceutical compositions
optionally comprise a buffering agent. Buffering agents include
agents that reduce pH changes. Suitable classes of buffering agents
for use in various embodiments of the present invention comprise a
salt of a Group IA metal including, for example, a bicarbonate salt
of a Group IA metal, a carbonate salt of a Group IA metal, an
alkaline or alkali earth metal buffering agent, an aluminum
buffering agent, a calcium buffering agent, a sodium buffering
agent, or a magnesium buffering agent. Suitable buffering agents
further include carbonates, phosphates, bicarbonates, citrates,
borates, acetates, phthalates, tartrates, succinates of any of the
foregoing, for example, sodium or potassium phosphate, citrate,
borate, acetate, bicarbonate and carbonate.
[0058] In one embodiment, the composition has a pH from about 3.5
to about 8. In one aspect, the pH is from about 3.5 to about 7.5.
In another aspect, the pH is from about 4.0 to about 7.5. In
another aspect, the pH is from about 5.0 to about 7.5. In another
aspect, the pH is from about 5.5 to about 7.5. In another aspect,
the pH is from about 6.0 to about 7.5.
[0059] In various embodiments, the pharmaceutical composition may
be present in a container. Suitable containers include containers
(e.g., a bag) with lower oxygen permeability (e.g., oxygen
transmission rate of .about.0.95 cc/(100 in.sup.2*day)) or which
are oxygen impermeable. These low oxygen permeability barriers may
be incorporated into the primary container of a secondary outer
container. Non-limiting examples of suitable containers include DDR
(Disposable Drug Reservoirs) bags, such as an EVA/EVOH/EVA bag.
[0060] In still other embodiments, the present disclosure relates
to a ready-to-use vial or cartridge or container or enclosure
suitable for liquid pharmaceutical dosage formulation containment.
Such container may serve the function of holding a liquid
formulation containing one or more active ingredients. The vials
can also serve as storage for powder forms of the active
ingredients such that the vial can be in a ready to use format
wherein reconstitution with an aqueous vehicle results in a
ready-to-withdraw or ready-to-load injection to the patient.
[0061] In another embodiment, a pharmaceutical dosage form is
provided. The pharmaceutical dosage form may comprise the
pharmaceutical composition described herein in a DDR having an
oxygen impermeable enclosure disposed therein, wherein the oxygen
impermeable enclosure is purged with an inert gas (e.g., N.sub.2).
An oxygen scavenger (e.g., ferrous or non-ferrous based, canister
or sachet) may also be added. The pharmaceutical dosage form may
suitable for use in a continuous infusion pump capable of
delivering the composition in a therapeutically effective manner. A
suitable oxygen impermeable enclosure can include, for example, a
foil bag or a bag having an EVA-EVOH film layer.
III. METHODS OF PREPARING A PHARMACEUTICAL COMPOSITION
[0062] The present disclosure further relates to methods of
preparing the pharmaceutical compositions described herein. In
various aspects, the methods of preparing the pharmaceutical
composition describe herein can comprise providing a levodopa
active agent and a carbidopa active agent in suitable amounts so
that the levodopa active agent and carbidopa active agent are
present in therapeutically effective amounts in the pharmaceutical
composition. The levodopa active agent and carbidopa active agent
may be added to water to produce a slurry. The slurry may be added
to one or more suspending agents (e.g., NaCMC) as described herein
to form a suspension. The suspension may or may not undergo N.sub.2
sparging to reduce the oxygen level. Particularly, the suspension
may be subjected to N.sub.2 sparging. Optionally, the suspension
may be degassed to remove any entrapped nitrogen or air from the
suspension. The suspension may then be loaded into lower oxygen
permeability or oxygen impermeable containers as described herein.
Optionally, an oxygen scavenger may be added to the suspension as
well. The combination of N.sub.2 sparging of the suspension and use
of lower oxygen permeability containers advantageously can result
in a pharmaceutical composition with increased chemical stability
by reducing both the initial solubilized O.sub.2 present in the
composition and the amount of O.sub.2 ingress into the composition
during storage.
[0063] Additionally, when the suspension is subjected to N.sub.2
sparging and/or the container has low oxygen permeability, the
pharmaceutical composition may not experience degradation into DHPA
at a rate faster than 0.04 w/w % per week of refrigerated storage
conditions. (The percent is relative to the label amount of
carbidopa.) Additionally or alternatively, when the suspension is
subjected to N.sub.2 sparging and/or the container has low oxygen
permeability, the pharmaceutical composition may not experience
degradation into DHPPA at a rate faster than 0.04 w/w % per week of
refrigerated storage conditions. (The percent is relative to the
label amount of carbidopa.) Additionally or alternatively, when the
suspension is subjected to N.sub.2 sparging and/or the container
has low oxygen permeability, the pharmaceutical composition may not
degrade producing hydrazine at a rate faster than 0.6 .mu.g/g per
week per week of refrigerated storage, where .mu.g/g denotes .mu.g
of hydrazine per gram of gel-suspension.
[0064] In various aspects, the levodopa active agent (e.g., prior
to forming the suspension) may have a particle size distribution
where: [0065] (i) D50 may be less than or equal to about 5 .mu.m,
less than or equal to about 3 .mu.m, or less than or equal to about
1 .mu.m; [0066] (ii) D90 may be less than or equal to about 11
.mu.m, less than or equal to about 9 .mu.m, less than or equal to
about 7 .mu.m, less than or equal to about 5 .mu.m or less than or
equal to about 3 .mu.m; and [0067] (iii) D100 may be less than or
equal less than or equal to about 22 .mu.m, less than or equal to
about 21 .mu.m, less than or equal to about 19 .mu.m, less than or
equal to about 17 .mu.m, less than or equal to about 15 .mu.m, less
than or equal to about 13 .mu.m or less than or equal to about 11
.mu.m. In particular, the levodopa active agent may have a particle
size distribution of: (i) D50 less than or equal to about 5 .mu.m;
(ii) D90 less than or equal to 11 .mu.m; and (iii) D100 less than
or equal to 22 .mu.m.
[0068] Additionally, the carbidopa active agent (e.g., prior to
forming the suspension) may have a particle size distribution
where: [0069] (i) D50 may be less than or equal to 3 .mu.m; [0070]
(ii) D90 may be less than or equal to 7 .mu.m, or less than or
equal to 5 .mu.m; and [0071] (iii) D100 may be less than or equal
to 21 .mu.m, less than or equal to 19 .mu.m, less than or equal to
17 .mu.m, less than or equal to 15 .mu.m, less than or equal to 13
.mu.m, less than or equal to 11 .mu.m, less than or equal to 9
.mu.m. In particular, the carbidopa active agent may have a
particle size distribution of: (i) D50 less than or equal to about
3 .mu.m; (ii) D90 less than or equal to 7 .mu.m; and (iii) D100
less than or equal to 21 .mu.m. The levodopa active agent and/or
the carbidopa active may be milled or micronized to achieve such a
particle size distribution.
[0072] Advantageously, the levodopa active agent and the carbidopa
active agent with the above described particle size distributions
may successfully form a suspension and maintain physical stability
of the suspension throughout the pharmaceutical composition's shelf
life even when the levodopa active agent and the carbidopa active
agent are present at higher concentrations in the composition. For
example, physical stability may be maintained even when the
pharmaceutical composition comprises about 4 weight/weight percent
of levodopa active agent and 1 weight/weight percent carbidopa
active agent (e.g., carbidopa monohydrate).
[0073] In another embodiment, pharmaceutical compositions as
described herein prepared by the methods described herein are
provided. In particular, a levodopa active agent and a carbidopa
active agent may be provided in suitable amounts so that the
levodopa active agent and carbidopa active agent are present in
therapeutically effective amounts in the pharmaceutical
composition. The levodopa active agent and the carbidopa active
agent provided have a particle size distribution as described
above. The levodopa active agent and carbidopa active agent are
added to water to produce a slurry. The slurry is added to a
suspending agent (e.g., NaCMC) as described herein or a mixture of
suspending agents to form a suspension, and the suspension can
undergo N.sub.2 sparging to reduce the oxygen level. The suspension
can be loaded into lower oxygen permeability or oxygen impermeable
containers as described herein. Optionally, an oxygen scavenger may
be added to the suspension as well.
IV. METHODS OF TREATMENT
[0074] The present disclosure further relates to methods of
treating Parkinson's disease and associated conditions comprising
administering a therapeutically effective amount of a
pharmaceutical composition comprising a high concentration levodopa
active agent and carbidopa active agent to a patient. A
pharmaceutical composition comprising a high concentration levodopa
active agent and carbidopa active agent can comprise, for example,
a liquid or viscous liquid comprising about 200 mg levodopa and
about 50 mg carbidopa monohydrate per each 5.0 mL volume.
[0075] In one embodiment, the present disclosure relates to a
method of treating a condition in need of treatment, wherein the
method comprises administering to the patient a therapeutically
effective amount of a pharmaceutical composition of the present
disclosure.
[0076] In one embodiment, the condition treated by administering
the pharmaceutical composition is Parkinson's disease.
[0077] In another embodiment, the condition treated by
administering the pharmaceutical composition is impaired motor
performance in a patient with Parkinson's disease (i.e., a method
of improving motor performance in a patient with Parkinson's
disease).
[0078] In another embodiment, the pharmaceutical composition is
administered to treat motor fluctuations in a patient with
Parkinson's disease.
[0079] In another embodiment, the pharmaceutical composition is
administered to treat dyskinesia in a patient with Parkinson's
disease.
[0080] In another embodiment, the present pharmaceutical
compositions are administered via intestinal administration. They
can be administered (or "infused") directly into the intestine,
such as the small intestine (e.g., duodenum or the jejunum) by a
permanent tube inserted via percutaneous endoscopic gastrostomy,
for example, with an outer transabdominal tube and an inner
intestinal tube. In one aspect, the first compound and the second
compound are administered via a tube inserted by radiological
gastrojejunostomy. In another aspect, the present pharmaceutical
compositions are administered via a temporary nasoduodenal tube
that is inserted into the patient, for example to initially to
determine if the patient responds favorably to the treatment method
before the permanent tube is inserted.
[0081] In embodiments where one or more of the present
pharmaceutical compositions are administered via intestinal
administration, administration can be carried out using a portable
pump, such as the pump sold under the trade name, CADD-Legacy
Duodopa.RTM. pump. Specifically, a cassette, pouch, vial or
cartridge comprising the first compound and the second compound can
be attached to the pump to create the delivery system. The delivery
system is then connected to the nasoduodenal tube, the
transabdominal port, the duodenal tube, or the jejunum tube for
intestinal administration.
[0082] In one embodiment, the method comprises administering one or
more of the present pharmaceutical compositions to the patient
substantially continuously over a period of at least about 12
hours. In additional aspects, the present pharmaceutical
compositions can be administered substantially continuously over a
period of about 16 hours, about 24 hours, about 36 hours, about 48
hours, about 3 days, about 4 days, about 5 days, about 6 days,
about one week, or longer.
[0083] In one embodiment, the dosing of the present pharmaceutical
composition administered to the patient is adjusted to optimize the
clinical response achieved by a patient, which means, for example,
maximizing the functional ON-time during the day by minimizing the
number and duration of OFF-time episodes (i.e., bradykinesia) and
minimizing ON-time with disabling dyskinesia.
[0084] In one embodiment, the daily dose of levodopa active agent
administered to the patient according to methods of the present
disclosure may be, for example, about 20 to about 5000 mg, about 20
mg to about 4000 mg, about 20 mg to about 3000 mg, about 20 mg to
about 2000 mg, or about 20 mg to about 1000 mg per day. In various
aspects, the patient may receive, for example, about: 20, 30, 40,
50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180,
190, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310,
320, 330, 340, 350, 360, 370, 380, 390, 400, 410, 420, 430, 440,
450, 460, 470, 480, 490, 500, 510, 520, 530, 540, 550, 560, 570,
580, 590, 600, 610, 620, 630, 640, 650, 660, 670, 680, 690, 700,
710, 720, 730, 740, 750, 760, 770, 780, 790, 800, 810, 820, 830,
840, 850, 860, 870, 880, 890, 900, 910, 920, 930, 940, 950, 960,
970, 980, 990, 1000, 1010, 1020, 1030, 1040, 1050, 1060, 1070,
1080, 1090, 1100, 1110, 1120, 1130, 1140, 1150, 1160, 1170, 1180,
1190, 1200, 1210, 1220, 1230, 1240, 1250, 1260, 1270, 1280, 1290,
1300, 1310, 1320, 1330, 1340, 1350, 1360, 1370, 1380, 1390, 1400,
1410, 1420, 1430, 1440, 1450, 1460, 1470, 1480, 1490, 1500, 1510,
1520, 1530, 1540, 1550, 1560, 1570, 1580, 1590, 1600, 1610, 1620,
1630, 1640, 1650, 1660, 1670, 1680, 1690, 1700, 1710, 1720, 1730,
1740, 1750, 1760, 1770, 1780, 1790, 1800, 1810, 1820, 1830, 1840,
1850, 1860, 1870, 1880, 1890, 1900, 1910, 1920, 1930, 1940, 1950,
1960, 1970, 1980, 1990, 2000, 2010, 2020, 2030, 2040, 2050, 2060,
2070, 2080, 2090, 2100, 2110, 2120, 2130, 2140, 2150, 2160, 2170,
2180, 2190, 2200, 2210, 2220, 2230, 2240, 2250, 2260, 2270, 2280,
2290, 2300, 2310, 2320, 2330, 2340, 2350, 2360, 2370, 2380, 2390,
2400, 2410, 2420, 2430, 2440, 2450, 2460, 2470, 2480, 2490, 2500,
2600, 2700, 2800, 2900, 3000, 3100, 3200, 3300, 3400, 3500, 3600,
3700, 3800, 3900, 4000, 4100, 4200, 4300, 4400, 4500, 4600, 4700,
4800, 4900, or 5000 mg of levodopa active agent per day.
[0085] In one embodiment, the daily dose of the carbidopa active
agent administered to the patient according to methods of the
present disclosure may be, for example, 0 to about 625 mg, 0 mg to
about 500 mg, 0 mg to about 375 mg, 0 mg to about 250 mg, or 0 mg
to about 125 mg per day. In various aspects, the patient may
receive, for example, about: 20, 30, 40, 50, 60, 70, 80, 90, 100,
110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230,
240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360,
370, 380, 390, 400, 410, 420, 430, 440, 450, 460, 470, 480, 490,
500, 510, 520, 530, 540, 550, 560, 570, 580, 590, 600, 610, 620,
630, 640, 650, 660, 670, 680, 690, 700, 710, 720, 730, 740, 750,
760, 770, 780, 790, 800, 810, 820, 830, 840, 850, 860, 870, 880,
890, 900, 910, 920, 930, 940, 950, 960, 970, 980, 990, 1000, 1010,
1020, 1030, 1040, 1050, 1060, 1070, 1080, 1090, 1100, 1110, 1120,
1130, 1140, 1150, 1160, 1170, 1180, 1190, 1200, 1210, 1220, 1230,
1240, or 1250 mg of carbidopa active agent per day.
[0086] In some embodiments, an amount of levodopa active agent and
carbidopa active agent are administered such that in combination
they are sufficient to achieve an L-dopa plasma level in the
patient of at least about 100 ng/mL. In one aspect, the L-dopa
plasma level is at least about 200 ng/mL. In another aspect, the
L-dopa plasma level is at least about 200 ng/mL. In another aspect,
the L-dopa plasma level is at least about 300 ng/mL. In another
aspect, the L-dopa plasma level is at least about 400 ng/mL. In
another aspect, the L-dopa plasma level is at least about 500
ng/mL. In another aspect, the L-dopa plasma level is at least about
600 ng/mL. In another aspect, the L-dopa plasma level is at least
about 700 ng/mL. In another aspect, the L-dopa plasma level is at
least about 800 ng/mL. In another aspect, the L-dopa plasma level
is at least about 900 ng/mL. In another aspect, the L-dopa plasma
level is at least about 1,000 ng/mL. In another aspect, the L-dopa
plasma level is at least about 1,500 ng/mL. In another aspect, the
L-dopa plasma level is at least about 2,000 ng/mL. In another
aspect, the L-dopa plasma level is at least about 3,000 ng/mL. In
another aspect, the L-dopa plasma level is at least about 4,000
ng/mL. In another aspect, the L-dopa plasma level is at least about
5,000 ng/mL.
[0087] In some embodiments, an amount of the levodopa active agent
and carbidopa active agent are administered such that in
combination they are sufficient to achieve an L-dopa plasma level
from about 10 ng/mL to about 8,000 ng/mL. In one aspect, the L-dopa
plasma level is from about 25 ng/mL to about 6,000 ng/mL. In
another aspect, the L-dopa plasma level is from about 50 ng/mL to
about 4,000 ng/mL. In another aspect, the L-dopa plasma level is
from about 100 ng/mL to about 2,000 ng/mL. In another aspect, the
L-dopa plasma level is from about 25 ng/mL to about 1,200 ng/mL. In
another aspect, the L-dopa plasma level is from about 10 ng/mL to
about 500 ng/mL. In another aspect, the L-dopa plasma level is from
about 25 ng/mL to about 500 ng/mL.
[0088] In some embodiments, the above-described L-dopa
concentration ranges are maintained for at least about: a 1 hour
interval, a 2 hour interval, a 3 hour interval, a 4 hour interval,
a 5 hour interval, a 6 hour interval, a 7 hour interval, an 8 hour
interval, a 9 hour interval, a 10 hour interval, an 11 hour
interval, a 12 hour interval, an 18 hour interval, or a 24 hour
interval.
[0089] In some embodiments, an amount of the levodopa active agent
and carbidopa active agent are administered such that in
combination they are sufficient to maintain a carbidopa plasma
level less than about 500 ng/mL. In one aspect, the carbidopa
plasma level is less than about 250 ng/mL. In another aspect, the
carbidopa plasma level is less than about 100 ng/mL. In another
aspect, the carbidopa plasma level is less than about 50 ng/mL. In
another aspect, the carbidopa plasma level is less than about 25
ng/mL.
[0090] In some embodiments, an amount of the levodopa active agent
and carbidopa active agent are administered such that in
combination they are sufficient to maintain a carbidopa plasma
level from about 1 to about 10 ng/mL. In one aspect, the carbidopa
plasma level is from about 1 to about 25 ng/mL. In another aspect,
the carbidopa plasma level is from about 1 to about 50 ng/mL. In
another aspect, the carbidopa plasma level is from about 1 to about
100 ng/mL. In another aspect, the carbidopa plasma level is from
about 1 to about 250 ng/mL. In another aspect, the carbidopa plasma
level is from about 5 to about 250 ng/mL. In another aspect, the
carbidopa plasma level is from about 5 to about 100 ng/mL. In
another aspect, the carbidopa plasma level is from about 10 to
about 250 ng/mL. In another aspect, the carbidopa plasma level is
from about 10 to about 100 ng/mL. In another aspect, the carbidopa
plasma level is from about 25 to about 250 ng/mL. In another
aspect, the carbidopa plasma level is from about 25 to about 100
ng/mL.
[0091] In some embodiments, the above-described carbidopa
concentration ranges are maintained for at least about: a 1 hour
interval, a 2 hour interval, a 3 hour interval, a 4 hour interval,
a 5 hour interval, a 6 hour interval, a 7 hour interval, an 8 hour
interval, a 9 hour interval, a 10 hour interval, an 11 hour
interval, a 12 hour interval, an 18 hour interval, or a 24 hour
interval.
[0092] In additional embodiments, the levodopa active agent and the
carbidopa active agent administered may have a particle size
distribution of as described above.
[0093] In various embodiments, the pharmaceutical composition may
be present in a container as described above and prior to
administration to the patient, the gel-suspension may or may not be
subjected to N.sub.2 sparging. When the gel-suspension is subjected
to N.sub.2 sparging and the container has low oxygen permeability,
the pharmaceutical composition may not experience degradation
producing DHPA at a rate faster than 0.04 w/w % per week of
refrigerated storage. (The percent is relative to the label amount
of carbidopa.) Additionally or alternatively, when the container is
subjected to N.sub.2 sparging, the pharmaceutical composition may
not experience degradation producing DHPPA at a rate faster than
0.04 w/w % per week of refrigerated storage. (The percent is
relative to the label amount of carbidopa.) Additionally or
alternatively, when the container is subjected to N.sub.2 sparging,
the pharmaceutical composition may not degrade producing hydrazine
at a rate faster than 0.6 .mu.g/g per week of refrigerated storage,
where .mu.g/g denotes .mu.g of hydrazine per gram of
gel-suspension.
V. CO-ADMINISTRATION OF ADDITIONAL THERAPEUTIC AGENTS
[0094] The methods of treatment of the present disclosure
optionally can further comprise administration of one or more
therapeutic agents for the treatment of Parkinson's disease in
addition to administration of the levodopa active agent and
carbidopa active agent. In one embodiment, the additional
therapeutic agent(s) is selected from the group consisting of
decarboxylase inhibitors other than a carbidopa active agent (e.g.,
benserazide), catechol-0-methyl transferase ("COMT") inhibitors
(e.g., entacapone and tolcapone), and monoamine oxidase A ("MAO-A")
or monoamine oxidase B ("MAO-B") inhibitors (e.g., moclobemide,
rasagiline, selegiline, and safinamide). In one aspect, the
additional therapeutic agent(s) is selected from the group
consisting of decarboxylase inhibitors other than a carbidopa
active agent. In another aspect, the additional therapeutic
agent(s) is selected from the group consisting of COMT inhibitors.
In another aspect, the additional therapeutic agent(s) is selected
from the group consisting of MAO-A inhibitors. In another aspect,
the additional therapeutic agent(s) is selected from the group
consisting of MAO-B inhibitors.
[0095] In a similar manner, the pharmaceutical compositions of the
present disclosure optionally can further comprise one or more
additional therapeutic agents for the treatment of Parkinson's
disease as described above.
VI. KITS
[0096] The present disclosure also relates to kits comprising one
or more pharmaceutical dosage forms comprising a carbidopa active
agent; kits comprising one or more pharmaceutical dosage forms
comprising a levodopa active agent; and kits comprising one or more
pharmaceutical dosage forms comprising both a levodopa active agent
and carbidopa active agent. In the kit, the pharmaceutical dosage
forms may be present, separately or together, in a lower O.sub.2
permeability bag. The pharmaceutical dosage forms may comprise a
high concentration of a levodopa active agent and a carbidopa
active agent, for example, a levodopa active agent in an amount of
about 4.0 weight/weight percent of the total composition; and a
carbidopa monohydrate active agent in an amount of about 1.0
weight/weight percent of the total composition. The kit optionally
can comprise one or more additional therapeutic agents and/or
instructions, for example, instructions for using the kit to treat
a patient having Parkinson's disease or an associated
condition.
VII. EXAMPLES
[0097] The following non-limiting examples are provided to further
illustrate the present disclosure. Abbreviations used in the
examples below include the following: [0098] "Cmax" means maximum
observed plasma concentration. [0099] "Tmax" means time to maximum
observed plasma concentration. [0100] "AUC" means area under the
plasma concentration-time curve. [0101] "t.sub.1/2" means
biological half-life, i.e., the time required for half the quantity
of a drug or other substance administered to a living organism to
be metabolized or eliminated by normal biological processes.
Example 1: Preparation of Pharmaceutical Composition
[0102] A high concentration ("HC") levodopa active agent/carbidopa
active agent pharmaceutical composition was prepared as shown in
FIG. 1 and as described below:
[0103] 1.1 Gel Preparation
[0104] Pre-work was performed in the lab to establish the ratio of
NaCMC 700 to NaCMC 2000 needed to achieve a certain viscosity. The
viscosity was measured with a rotational viscometer at two points:
22.degree. C. at 24.1 1/s (also called the "high shear viscosity");
and at 5.degree. C. at 0.1 1/s (also called the "low shear
viscosity"). The proper amounts of NaCMC 2000 and NaCMC 700 were
then dispensed and added to a hopper, after which the NaCMC was fed
into the homogenizer tank and mixed at a high shear. The gel was
then degassed and visually inspected to ensure that the NaCMC
dissolved. This was also the time that the gel is sampled for
viscosity measurements.
[0105] 1.2 Gel Sparging
[0106] Gel was sparged with nitrogen to remove the majority of
oxygen prior to adding the API (Levodopa and Carbidopa). Oxygen
concentration was monitored throughout the process via an inline
oxygen probe.
[0107] 1.3 First Slurry Preparation
[0108] Half of Levodopa and Carbidopa was added to water in a
separate vessel and was mixed using one overhead impeller and one
bottom driven impeller. This method is considered low shear.
Alternatively the overhead impeller can be replaced with a
homogenizer for achieving high shear mixing. The slurry was used to
wet and delump the API. After the process was finished, the slurry
was transferred to the homogenizer tank.
[0109] 1.4 Gel Suspension Preparation
[0110] This is where the API from the slurry and the NaCMC gel was
mixed, under high shear, to achieve a homogeneous suspension.
Nitrogen was sparged into the tank to reduce the oxygen level that
was initially introduced with the slurry transfer.
[0111] 1.5 Second Slurry Preparation
[0112] The other half of Levodopa and Carbidopa was added to water
and mixed similar to the process in step 1.3.
[0113] 1.6 Gel Suspension Preparation
[0114] The API from the second slurry was mixed with the rest of
the gel suspension at the same conditions as in step 1.4. Nitrogen
was sparged into the tank to reduce the oxygen level that was
initially introduced with the slurry transfer.
[0115] 1.7 Degassing
[0116] The gel suspension was degassed to remove any entrapped
nitrogen or air from the gel.
[0117] 1.8 Filling
[0118] The filling lines were first flushed with nitrogen before
gel suspension was pushed through. 55-61 g of gel suspension was
filled into disposable drug reservoirs (DDRs). Fill weight was
checked at routine intervals via a balance. Oxygen reading was
taken at the filling nozzle (for the two case studies, the reading
was taken at the discharge end).
[0119] 1.9 Packaging
[0120] DDRs were labeled and packaged into a kit that holds 7 DDRs.
The kit protects the formulation from light. The kits were then
sent to the freezer.
TABLE-US-00001 TABLE 1 Formulation of High Concentration (HC) and
Low Concentration (LC) Pharmaceutical Composition Component HC w/w
% LC w/w % Levodopa Micronized 4 2 Carbidopa Monohydrate 1 0.5
Micronized NaCMC 2000 2.92* 2.92* NaCMC 700 Purified Water 92.08
94.58 *Represents total NaCMC. The ratio of one NaCMC grade to the
other can be varied to achieve the desired viscosity. **Density of
HC formulation was approximately 1.03 g/ml and LC formulation is
approximately 1.02 g/ml
TABLE-US-00002 TABLE 2 LC Specifications and HC Tentative Ranges
for Drug Product and API Attributes HC Tentative Drug Product
Attributes LC Specs Range High Shear Viscosity 2000-3500 cps
.ltoreq.4500 cps (22.degree. C. and 24.1 1/s) Low Shear Viscosity
>21000 cps >45000 cps (5.degree. C. and 0.1 1/s) pH 5.5-7.5
Oxygen Concentration Ambient Low Batch Size 500 Kg
Example 2: High Concentration Pharmaceutical Composition
Stability
[0121] 2.1--A high concentration (HC) formulation was made on the
commercial scale equipment to improve the nitrogen sparging process
time and mixing efficiency. The overall manufacturing process was
the same as in Example 1. A high viscosity was chosen, relative to
the HC formulation viscosity range, to ensure good physical
stability. The batch was filled into prototype DDR (Disposable Drug
Reservoirs) bags (without the housing) and placed on stability. The
bags are made with a 0.3 mm thick EVA/EVOH/EVA multilayer film.
This batch maintained its chemical and physical stability
throughout the 15 week stability study.
TABLE-US-00003 TABLE 3 Raw Material and Finished Material
Attributes Suspension Attributes Value High Shear Viscosity (24.1
1/s, 22.degree. C.) 43000 cps Low Shear Viscosity (0.1 1/s,
5.degree. C.) 49600 cps pH 6.4* Oxygen Concentration 0.45* mg/L
Batch Size 500 Kg *Values were measured in process
[0122] 2.2--Analytical Results
[0123] Batch Content Uniformity--100 mL of the pharmaceutical
composition was filled into cassettes at the beginning, middle, and
end of the filling run which represents bottom, middle, and top of
the tank, respectively. These cassettes were then assayed and the
results represent the content uniformity of the batch.
TABLE-US-00004 TABLE 4 Batch Content Uniformity Results (API
concentration) Cassettes Levodopa % Carbidopa % Beginning 1 94.9
94.6 Beginning 2 101.9 101.6 Beginning 3 99.5 99.0 Beginning 4 98.7
98.4 Beginning 5 99.7 99.4 Middle 1 101.8 101.6 Middle 2 99.7 99.3
Middle 3 99.1 99.0 Middle 4 96.0 95.8 Middle 5 101.2 100.9 End 1
101.3 101.0 End 2 101.6 101.4 End 3 101.6 101.3 End 4 101.7 101.5
End 5 101.8 101.6
[0124] 2.3--Formulation Attributes on Stability
[0125] Filled DDR bags were frozen and stored at -20.degree. C.
after manufacture. Bags for testing were then placed at 5.degree.
C. for a 15 week stability study. Samples were evaluated at 0, 8,
and 15 weeks. In addition, a portion of the samples were
subsequently placed at 30.degree. C. in 75% relative humidity (%
RH), after they spent either 8 or 15 weeks at 5.degree. C., with
testing at 24 and 48 hours. Assay, impurities, pH, and viscosity
were all tested. Results are summarized in Table 5 below.
TABLE-US-00005 TABLE 5 Assay, Impurities, pH, and Viscosity
Throughout a 15 Weeks Stability Study Levodopa Carbidopa % DHPA per
% DHPPA per Condition Assay (%) Assay (%) Carbidopa Carbidopa
5.degree. C.: 0 weeks 102.3 100.5 0.14 0.06 5.degree. C.: 8 weeks
104.3 102.7 0.44 0.42 5.degree. C.: 8 weeks 102.4 100.9 0.46 0.41
30.degree. C.: 24 hrs 5.degree. C.: 8 weeks 103 101.4 0.50 0.47
30.degree. C.: 48 hrs 5.degree. C.: 15 weeks 102.1 99.8 0.60 0.60
5.degree. C.: 15 weeks 102.5 100 0.74 0.80 30.degree. C.: 24 hrs
5.degree. C.: 15 weeks 102.2 99.7 0.74 0.79 30.degree. C.: 48 hrs
Viscosity (cps) Viscosity (cps) Hydrazine (.mu.g) at 22.degree. C.
and at 5.degree. C. and Condition per gel (g) pH 24.1 sec.sup.-1
0.1 sec.sup.-1 5.degree. C.: 0 weeks 2.10 6.4 4400 49600 5.degree.
C.: 8 weeks 6.63 6.4 4500 57400 5.degree. C.: 8 weeks 7.43 6.3 4500
59900 30.degree. C.: 24 hrs 5.degree. C.: 8 weeks 9.90 6.4 4500
54200 30.degree. C.: 48 hrs 5.degree. C.: 15 weeks 9.20 6.3 4400
58300 5.degree. C.: 15 weeks 10.90 6.3 4400 59000 30.degree. C.: 24
hrs 5.degree. C.: 15 weeks 11.10 6.3 4500 55200 30.degree. C.: 48
hrs
[0126] 2.4--Uniformity of Dispensed Content of Samples on
Stability
[0127] The uniformity of dispensed content (UDC) method was used to
obtain API concentration in the gel as it is dosed. This simulates
what a patient would be receiving per every 5 g of gel delivered by
the pump, and ensures that a patient will be receiving consistent
amounts of drug throughout the consumption of one DDR. The test was
performed at each time point throughout the 15 week stability.
Particle size distributions of the APIs used for the study were
within the particle size limits mentioned herein. Results are
summarized in Tables 6 (levodopa) and 7 (carbidopa) below.
TABLE-US-00006 TABLE 6 Uniformity of Dispensed Content of Levodopa
Samples on Stability 5.degree. C.: 8 5.degree. C.: 8 5.degree. C.:
15 5.degree. C.: 15 weeks weeks weeks weeks Dispensed 5.degree. C.:
0 5.degree. C.: 8 30.degree. C.: 30.degree. C.: 5.degree. C.: 15
30.degree. C.: 30.degree. C.: Fraction weeks weeks 24 hrs 48 hrs
weeks 24 hrs 48 hrs 1 102.1 103.0 103.5 103.3 101.6 100.7 102.6 2
102.1 102.0 102.8 102.6 99.8 100.6 101.4 3 100.0 103.4 103.3 103.1
98.7 100.6 102.2 4 101.9 103.4 103.3 103.7 99.0 101.6 101.9 5 101.6
103.1 102.0 102.8 98.9 101.9 102.0 6 101.6 103.6 104.0 99.7 103.1
100.9 102.0 7 101.9 103.6 104.1 103.7 101.7 97.3 102.4 8 101.2
104.0 104.5 103.7 101.9 102.7 102.6 9 100.1 104.1 104.0 104.3 102.2
102.4 102.5 10 99.6 103.7 104.4 103.7 102.1 104.1 102.0
TABLE-US-00007 TABLE 7 Uniformity of Dispensed Content of Carbidopa
Samples on Stability 5.degree. C.: 8 5.degree. C.: 8 5.degree. C.:
15 5.degree. C.: 15 weeks weeks weeks weeks Dispensed 5.degree. C.:
0 5.degree. C.: 8 30.degree. C.: 30.degree. C.: 5.degree. C.: 15
30.degree. C.: 30.degree. C.: Fraction weeks weeks 24 hrs 48 hrs
weeks 24 hrs 48 hrs 1 102.0 102.5 102.4 101.4 100.4 98.5 99.7 2
102.0 100.9 101.3 101.3 98.6 98.8 99.1 3 99.5 102.0 101.5 101.2
96.9 98.1 99.5 4 101.0 101.7 101.5 101.7 97.0 99.4 99.2 5 100.5
101.6 100.1 100.5 96.8 99.4 99.4 6 100.8 102.0 101.6 97.7 99.5 98.3
99.3 7 100.9 102.0 101.8 101.8 98.1 94.7 99.3 8 100.3 101.9 101.7
101.3 99.2 99.8 99.3 9 99.3 101.9 101.8 101.7 98.7 99.3 99.4 10
98.4 101.7 101.7 101.5 99.3 100.8 99.1
Example 3--Therapeutic Effect of Pharmaceutical Composition in
Mini-Pigs
[0128] High concentration L-dopa/carbidopa intestinal gel was
compared with a low concentration L-dopa/carbidopa intestinal gel
and tested in the following manner: A group of four minipigs each
was administered LC L-dopa/carbidopa intestinal gel, HC
L-Dopa/carbidopa intestinal gel, or L-dopa/carbidopa in a Carbopol
carrier in a cross-over study design. Each of four mini-pigs was
administrated with one formulation at the first day of a week,
followed by 1-week washout period before the second formulation was
administered. The third formulation was administered to the same
mini-pigs after another week of washout period.
Total Dose: 11.07 mg/kg levodopa dose over 6.5 hrs.; 20 mg/mL
Groups: LC; HC; Carbopol
[0129] Bolus dose: 2.53 mg/kg over 30 min Bolus dose Infusion dose:
8.54 mg/kg over 6 hrs.
[0130] Bolus Infusion Rate: [0131] LC=0.253 mL/kg/hr (For example:
10 kg pig=2.53 mL/hr pump rate) [0132] HC=0.127 mL/kg/hr (For
example: 10 kg pig=1.27 mL/hr pump rate) [0133] Carbopol=0.127
mL/kg/hr (For example: 10 kg pig=1.27 mL/hr pump rate)
[0134] 6 hr Infusion Rate: [0135] LC=0.071 mL/kg/hr (For example:
10 kg pig=0.71 mL/hr pump rate) [0136] HC=0.0355 mL/kg/hr (For
example: 10 kg pig=0.355 mL/hr pump rate) [0137] Carbopol=0.0355
mL/kg/hr (For example: 10 kg pig=0.355 mL/hr pump rate). Plasma
sampling Time points: 0.5, 1, 1.5, 2, 4, 6, 8, 9, 10, 12 h
[0138] The results of the study confirm that the high concentration
levodopa/carbidopa intestinal gel demonstrates comparable
C.sub.max, T.sub.max and AUC values to the LC formulation when
administered under half hour bolus and 6 hour infusion conditions,
as shown in FIGS. 2 and 3. Cassettes of levodopa at 11.07 mg/kg and
of carbidopa monohydrate at 2.77 mg/kg were dosed at 80 .mu.L/kg
(LC gel) or 40 .mu.L/kg (HC gel and Carbopol control).
Bioavailability of levodopa is summarized in Table 8 below. The
half lives in Table 8 are calculated as harmonic means.
TABLE-US-00008 TABLE 8 Levodopa plasma concentration Mean Parameter
Pig 1 Pig 2 Pig 3 Pig 4 (SEM) C.sub.max (.mu.g/mL) 3.36 2.84 2.30
2.25 2.69 (0.26) LC gel T.sub.max (h) 6.5 0.5 0.5 0.5 2.0 (1.5) AUC
23.7 19.1 10.4 10.2 15.9 (3.35) (.mu.g h/mL) t.sub.1/2 (h) 1.0 0.9
0.9 2.2 1.1 C.sub.max (.mu.g/mL) 4.23 3.09 1.70 2.45 2.87 (0.53) HC
gel T.sub.max (h) 6.5 4.0 0.5 0.5 2.9 (1.5) AUC 27.6 21.8 9.88 12.3
17.9 (4.13) (.mu.g h/mL) t.sub.1/2 (h) 1.3 1.1 1.0 1.3 1.2
C.sub.max (.mu.g/mL) 3.03 3.39 1.95 2.62 2.75 (0.31) Carbopol
T.sub.max (h) 6.5 1.0 0.5 0.5 2.1 (1.5) AUC 20.6 22.1 9.56 13.4
16.4 (2.97) (.mu.g h/mL) t.sub.1/2 (h) 1.2 1.0 0.9 1.0 1.0
Bioavailability of carbidopa is summarized in Table 9 below.
TABLE-US-00009 TABLE 9 Carbidopa plasma concentration Mean
Parameter Pig 1 Pig 2 Pig 3 Pig 4 (SEM) C.sub.max (ng/mL) 92 132 20
17 65 (28) LC gel T.sub.max (h) 0.5 0.5 0.5 0.5 0.5 (0) AUC (ng
h/mL) 374 348 18 23 191 (99) C.sub.max (ng/mL) 192 151 40 36 105
(39) HC gel T.sub.max (h) 0.5 0.5 0.5 0.5 0.5 (0) AUC (ng h/mL) 751
393 41 47 308 (169) C.sub.max (ng/mL) 204 369 28 32 158 (81)
Carbopol T.sub.max (h) 0.5 0.5 1.0 0.5 0.63 (0.13) AUC (ng h/mL)
578 660 36 38 328 (169)
Example 4: Further Bioavailability Studies in Human Subjects
[0139] To further test the bioavailability of the LC and HC
formulations discussed in Example 3 above, a total of 12 subjects
participated in an open label, single dose, randomized crossover
study to test the bioavailability of the LC and HC formulations.
Each subject received a single dose of levodopa (200 mg) and
carbidopa monohydrate (50 mg) on the mornings of Day 1 and Day 4
under fasting conditions. Subjects were randomly assigned in equal
numbers to the two sequences of commercially prepared LC
formulation of and commercially prepared HC formulation. Each dose
was administered over a 30 minute period via nasojejunal tube
connected to a portable infusion pump. Patients receiving the LC
formulation received a 10.0 mL dose. Patients receiving the HC
formulation received a 5.0 mL dose, so that equal amounts of drug
were delivered regardless of whether LC or HC formulation was
administered. Subjects were confined for approximately 6 days
(Check-in Day to Day 5). Serial blood samples for levodopa,
carbidopa, and 3-O-methyldopa assays were collected after dosing on
Day 1 and Day 4. Times for collection include 0 hour (prior to
dose), at 5, 10, 15, 30, 45 minutes after the start of infusion,
and at 1, 1.5, 2, 3, 4, 6, 8, 12, and 24 hours after the start of
infusion. Bioavailability for levodopa is summarized in Table 10
below and in FIG. 4.
TABLE-US-00010 TABLE 10 Levodopa plasma concentration from test
subjects (N = 12) Pharmacokinetic 200 mg Levodopa in LC 200 mg
Levodopa in HC Parameters gel (% CV) gel (% CV) C.sub.max (ng/mL)
2100 (35) 2100 (25) T.sub.max (h) 0.85 (18) 0.81 (33) AUC.sub.t (ng
h/mL) 4000 (18) 3930 (21) AUC.sub..infin. (ng h/mL) 4080 (17) 4010
(20) t.sub.1/2.sup.a (h) 1.69 (12) 1.85 (32)
[0140] Bioavailability for carbidopa is summarized in Table 11
below and in FIG. 5.
TABLE-US-00011 TABLE 11 Carbidopa plasma concentration from test
subjects (N = 12) Pharmacokinetic 50 mg Carbidopa in LC 50 mg
Carbidopa in HC Parameters gel (% CV) gel (% CV) C.sub.max (ng/mL)
242 (79) 220 (45) T.sub.max (h) 3.0 (31) 2.5 (42) AUC.sub.t (ng
h/mL) 956 (35) 910 (45) AUC.sub..infin. (ng h/mL) 1100 (30) 1070
(39) t.sub.1/2.sup.a (h) 1.82 (14) 1.76 (18)
[0141] These tests show that the HC formulation was equal to the LC
formulation for levodopa C.sub.max, AUC.sub.t and AUC.sub..infin.
and for carbidopa AUC.sub.t and AUC.sub..infin.. The 90% confidence
interval for equal carbidopa C.sub.max is slightly beyond the 0.8
to 1.25 range. However, this is not a clinically relevant factor
because dosing for efficacy is determined by the levodopa content,
and not carbidopa. Studies show that peripheral dopa decarboxylase
is saturated by carbidopa at approximately 70-100 mg a day, and
advanced Parkinson's disease patients on levodopa/carbidopa gel
treatment would surpass these daily carbidopa doses for saturation.
The relative bioavailability of the LC and HC formulations for
levodopa and carbidopa are summarized in Table 12 below.
TABLE-US-00012 TABLE 12 Bioequivalency of LC and HC gel
formulations Relative bioavailability Central value Point 90%
Parameter HC LC estimate Confidence C.sub.max (ng/mL) 2040 1980
1.028 (0.859, 1.231) Levodopa AUC.sub.t (ng h/mL) 3860 3890 0.991
(0.922, 1.065) AUC.sub..infin. (ng h/mL) 3940 3970 0.993 (0.926,
1.065) C.sub.max (ng/mL) 198 205 0.963 (0.739, 1.253) carbidopa
AUC.sub.t (ng h/mL) 835 903 0.925 (0.831, 1.029) AUC.sub..infin.
(ng h/mL) 887 965 0.919 (0.824, 1.025)
[0142] In summary, the amount of drug delivered was similar for
both formulations. Doses delivered for both formulations were
similar (.about.6% difference). Levodopa and carbidopa exposures
were very similar for both formulations. Levodopa exposure
variability was low to moderate (17-35% CV) for both the LC and HC
formulations. Both the LC and HC formulations were equivalent for
levodopa. The LC and HC formulations were equivalent for carbidopa
except for the C.sub.max which is not clinically significant.
[0143] FIGS. 6 & 7 show that the LC and HC formulations have
similar dissolution rates at pH 4.5 and 6.8, which supports the
bioequivalency results summarized above. These dissolution trials
were conducted by adding equal doses of drug formulations to
beakers containing 500 mL of 50 mM sodium acetate buffer at pH 4.5
(.+-.0.05) or pH 6.8 (.+-.0.05). Each sample was maintained at
37.degree. C. with agitation at 50 RPM during the procedure.
Samples were drawn at 5, 10, 15, 20, 30, 45, and 60 minutes post
addition of drug. The concentration of drug dissolved in the
samples was measured by HPLC on a PHENOMENEX KINETEX C8 column
(100.times.4.6 mm, 5 .mu.m with SecurityGuard Cartridge) at
30.degree. C. The mobile phase was 88:12 10 mM sodium heptane
sulfonic acid (HAS) in 0.2% H.sub.3PO.sub.4: acetonitrile. The
sample was eluted through the column at a rate of .about.3.0 mL/min
and measured by UV spectrophotometry (OD.sub.280).
Example 5: Sedimentation and Storage Stability
[0144] Stokes' Law can be used to assess particle sedimentation and
thus the physical stability of the HC formulation. Stokes' Law
considers three forces acting on a particle situated in a
continuous viscous fluid: buoyancy force, drag force, and
gravitational force. When the forces are balanced and there is no
net acceleration, the particle reaches a terminal or settling
velocity given by:
v=(d.sup.2(.rho..sub.1-.rho..sub.2)g)/18.eta.=(2r.sup.2(.rho..sub.1-.rho-
..sub.2)g)/9.eta.
where v is the settling velocity; d is the particle diameter and r
is the particle radius; .rho..sub.1 is the density of the dispersed
phase and .rho..sub.2 is the density of the dispersion medium; g is
the gravity constant; .eta. is the viscosity of the fluid at
rest.
[0145] There are two factors that can be controlled in the HC
formulation to modulate physical stability: particle size of
levodopa and carbidopa monohydrate and viscosity of the
gel-suspension. Levodopa and carbidopa monohydrate particle sizes
are well controlled by the micronization process within the
particle size limits mentioned herein. However, the viscosity can
be adjusted by modifying the ratio of carmellose sodium viscosity
grades. The viscosity of the fluid at rest is approximated by the
low shear viscosity method. The minimum low shear viscosity
necessary to achieve the desired physical stability is 44,590 cps
based on this example, as shown in Tables 13 and 14.
TABLE-US-00013 TABLE 13 Acceptance Values for Levodopa Lot 1 Lot 2
Lot 3 Lot 4 Lot 5 Lot 6 Interval LS Viscosity 32,393 36,692 39,692
44,590 45,590 45,790 (cps) Release AV 4.9 5.0 6.1 4.1 3.7 3.9 15
weeks AV 26.1 31.2 20.6 4.7 2.8 3.1 at 5.degree. C. Result Fail
Fail Fail Pass Pass Pass
TABLE-US-00014 TABLE 14 Acceptance Values for Carbidopa Lot 1 Lot 2
Lot 3 Lot 4 Lot 5 Lot 6 Interval LS Viscosity 32,393 36,692 39,692
44,590 45,590 45,790 (cps) Release AV 3.6 4.7 3.8 5.2 5.3 4.4 15
weeks AV 10 8.4 6.4 0.7 1.8 1.9 at 5.degree. C. Result Fail Fail
Fail Pass Pass Pass
[0146] The criterion for "acceptable" physically stable was the
absence of significant sedimentation for at least 15 weeks under
refrigerated storage conditions (e.g., 5.degree. C.). The physical
stability was assessed by drawing 5 ml samples from the DDR for a
total of 10 samples and then analyzing them for levodopa and
carbidopa content using a high pressure liquid chromatography
(HPLC) system with guard column: Agilent, Zorbax Eclipse XDB-C8,
4.6.times.12.5 mm, 5 .mu.m (Agilent, part number 820950-926) with
Agilent Hardware kit High Press, (Agilent, Part number 820999-901)
or equivalent; and analytical column: Zorbax Eclipse XDB-C8,
150.times.4.6 mm, 5 .mu.m (Agilent part no. 993967-906). The
chromatographic conditions are shown in Table 15.
TABLE-US-00015 TABLE 15 Chromatographic Conditions for
Levodopa/Carbidopa Concentration Test Flow Rate ~1.2 mL/min.
Injection Volume 5 .mu.L Autosampler Temp. 5.degree. C. Column
Temp. ~30.degree. C. Sample Diluent 0.1M phosphoric acid in water
Mobile phase A 10 mM sodium heptane sulfonic acid in 0.2%
phosphoric acid Mobile phase B Acetonitrile % Time (min.) % Mobile
phase A Mobile phase B Isocratic Profile 0 88 12 Run Time
Approximately 12 to 15 minutes
[0147] A sample was defined as physically stable if the Acceptance
Value (AV), defined by Equation 2, was no more than 15 for both
levodopa and carbidopa.
AV=|M-X|+ks Equation 2.
[0148] The definition of each variable in Equation 2 is shown in
Table 16.
TABLE-US-00016 TABLE 16 Definition of Variables Used in Calculating
the Acceptance Value Variable Definition Conditions Value X Mean of
individual contents (X.sub.1, X.sub.2, . . . , X.sub.n), expressed
as a percentage of the label claim X.sub.1, X.sub.2, Individual
contents of the . . . , X.sub.n units tested, expressed as a
percentage of the label claim n Sample size (# of units in sample)
k Acceptability constant If n = 10, then k = 2.4 If n = 30, then k
= 2.0 s Sample standard deviation [ i = 1 n ( .chi. 1 - X _ ) 2 n -
1 ] 1 2 ##EQU00001## RSD Relative standard 100s/X deviation (the
sample standard deviation expressed as a percentage of the mean) M
Reference value to be If 98.5% .ltoreq. X .ltoreq. M = X (AV = ks)
(case 1) applied where T .ltoreq. 101.5 101.5% If X < 98.5% M =
98.5% (AV = 98.5 - X + ks) If X > 101.5% M = 101.5% (AV = X -
101.5 + ks) M Reference value to be If 98.5 .ltoreq. X .ltoreq. T M
= X (AV = ks) (case 2) applied where T > 101.5 If X < 98.5% M
= 98.5% (AV = 98.5 - X + ks) If X > T M = T % (AV = X - T +
ks)
Example 6: Effect of Oxygen
[0149] The high concentration formulation can be purged of oxygen
during manufacturing and stored in containers with low oxygen
permeation. This significantly decreases the rate of degradation
compared to a formulation manufactured and stored in ambient oxygen
conditions. Depending on the packaging, the disposable drug
reservoirs can have very low oxygen content at the time of filling.
These DDRs consist of a hard shell outer, an inner package, and
tubings/connectors. The inner bag serves to maintain the O.sub.2
content of the final drug product gel. The EVA/EVOH/EVA bag has a
very low O.sub.2 permeability (oxygen transmission rate for the
EVA/EVOH/EVA sheet film was approximately 0.95 cc/(100
in.sup.2*day). FIG. 11 charts the accumulation of DHPA breakdown
product when LC and HC gel formulations are left for 15 weeks 0.3
mm thick EVA/EVOH/EVA bags at 2-8.degree. C. Moreover, N.sub.2
sparging can be used in the manufacture process to purge oxygen.
The combination of N.sub.2 sparging and low O.sub.2 permeability
EVA/EVOH/EVA bag ensures a very low overall O.sub.2 content.
[0150] To test the effects of this low 02 packaging, samples of LC
gel formulation were not sparged with N.sub.2 and were packaged in
polyvinyl chloride (PVC) bags. Samples of HC gel formulation were
sparged with N.sub.2 and packaged in EVA/EVOH/EVA bags. Both sets
of bags were monitored for the development of DHPA, DHPPA, and
hydrazine degradation products over time. The results of these
tests are shown in FIGS. 8-10 below. DHPA and DHPPA were analyzed
using HPLC system with analytical column: Waters, X-Bridge, C8, 3.5
.mu.m particles, 4.6.times.150 mm column (catalogue 186003055) or
equivalent with a stationary phase of octylsilane chemically bonded
to totally porous silica particles (USP L7); and guard column:
Phenomenex Security Guard Cartridge PFP 4.times.3.0 mm (catalogue
AJ0-4290) or equivalent, security guard cartridge holder,
Phenomenox, (catalogue AJO-6071) or equivalent. HPLC settings for
the DHPA and DHPPA tests are shown in Table 17 below.
TABLE-US-00017 TABLE 17 Chromatographic Conditions for DHPA/DHPPA
Test Wavelength 220 nm Flow Rate 1.3 .+-. 0.2 mL/min Injection
Volume 20 .mu.L Autosampler Temp. 8 .+-. 2.degree. C. Column Temp.
30 .+-. 1.degree. C. Sample Diluent 0.1M Phosphoric acid in water
Mobile phase A 10% phosphate buffer, 10% 0.1M sodium heptane
sulfonic acid and 80% water Mobile phase B 10% phosphate buffer,
10% 0.1M sodium heptane sulfonic acid, 20% Acetonitrile and 60%
water % Time (min.) % Mobile phase A Mobile phase B Gradient
Profile 0 85 15 18.3 25 75 19.0 25 75 20.0* 85 15 27.0* 85 15
*Gradient equilibration time
[0151] Hydrazine was analyzed using HPLC with a Grace Scientific
column, Grom-Sil 120 ODS-5, 250.times.4.6 mm, 5 .mu.m (Part No.
GS0D50512S2505) or equivalent after the sample was eluted from SPE
column: Chromabond.RTM. HR-X (15 mL/1000 mg) by Macherey-Nagel,
Part No. 730941. HPLC settings for the hydrazine tests are shown in
Table 18 below.
TABLE-US-00018 TABLE 18 Chromatographic Conditions for Hydrazine
Test Wavelength 313 nm Flow Rate 1.0 mL/min Injection Volume 30
.mu.L Autosampler 5.degree. C. Temp. Column Temp. 40.degree. C.
Sample Diluent 50 mM sulfuric acid in water; 1% solution of
benzaldehyde in methanol; 100 mM solution of sodium borate in water
Mobile phase A Purified water Mobile phase B Acetonitrile Isocratic
Profile 30% A, 70% B Run Time 18 minutes
[0152] Degradation can also be slowed by adding oxygen scavengers
(e.g. either ferrous or non-ferrous based, canister or sachet) and
placing into a low O.sub.2 permeability secondary container. The
effects of oxygen scavengers in different packages on the
accumulation of DHPA and DHPPA degradation products are illustrated
in FIG. 11 below.
[0153] Although the invention has been described with respect to
specific embodiments and examples, it should be appreciated that
other embodiments utilize the concept of the present invention are
possible without departing from the scope of the invention. The
present invention is defined by the claimed elements, and any and
all modifications, variations, or equivalents that fall within the
true spirit and scope of the underlying principles.
VIII. FURTHER EMBODIMENTS
Embodiment 1
[0154] A pharmaceutical composition comprising a levodopa active
agent and a carbidopa active agent for intraduodenal administration
wherein the levodopa active agent and the carbidopa active agent
are suspended in an aqueous carrier, characterized in that the
levodopa active agent and the carbidopa active agent in the carrier
has a high shear viscosity of no more than about 4500 cps at room
temperature and a low shear viscosity of no less than about 45000
cps under refrigerated conditions and a ratio of low shear
viscosity to high shear viscosity of not less than 10.
Embodiment 2
[0155] The pharmaceutical composition according to Embodiment 1,
wherein the pharmaceutical composition comprises: a levodopa active
agent in an amount of about 4.0 weight/weight percent of the total
composition; a carbidopa monohydrate active agent in an amount of
about 1.0 weight/weight percent of the total composition; a liquid
vehicle (e.g., in an amount of from about zero percent to about 95
weight/weight percent of the total composition and/or selected from
the group consisting of water), and wherein the aqueous carrier
comprises a suspending agent (e.g., one or more polymer-based
suspending agent, such as an acrylic acid-based polymer or a
polymer selected from the group consisting of
hydroxypropylcellulose, hydroxymethylcellulose, and sodium
carboxymethyl cellulose).
Embodiment 3
[0156] The pharmaceutical composition according to Embodiment 1 or
2, wherein the pharmaceutical composition does not experience
degradation into DHPA at a rate faster than 0.04 w/w % per
week.
Embodiment 4
[0157] The pharmaceutical composition according to any one of the
previous Embodiments, wherein the pharmaceutical composition does
not experience degradation into DHPPA at a rate faster than 0.04
w/w % per week.
Embodiment 5
[0158] The pharmaceutical composition according to any one of the
previous Embodiments, wherein the pharmaceutical composition does
not experience degradation producing hydrazine at a rate faster
than 0.6 .mu.g/g per week.
Embodiment 6
[0159] The pharmaceutical composition according to any one of the
previous Embodiments, wherein the pharmaceutical composition is
present in a lower O.sub.2 permeable primary or secondary
container.
Embodiment 7
[0160] A pharmaceutical dosage form comprising the pharmaceutical
composition of any one of the previous Embodiments in a disposable
drug reservoir having an oxygen impermeable enclosure disposed
therein, wherein the oxygen impermeable enclosure is purged with an
inert gas and an oxygen scavenger is added, and optionally, wherein
the pharmaceutical dosage form is suitable for use in a continuous
infusion pump capable of delivering the composition in a
therapeutically effective manner.
Embodiment 8
[0161] A method of preparing the pharmaceutical composition
according to any one of Embodiments 1-6, wherein the method
comprises: adding a levodopa active agent and a carbidopa active
agent to water to form a slurry; adding the slurry to one or more
suspending agents (e.g., an acrylic acid-based polymer or a polymer
selected from the group consisting of hydroxypropylcellulose,
hydroxymethylcellulose, and sodium carboxymethyl cellulose) to form
a suspension; subjecting the suspension to N.sub.2 sparging; and
optionally, loading the suspension into a lower oxygen permeability
container.
Embodiment 9
[0162] The method according to Embodiment 8, wherein, prior to
forming the suspension, the levodopa active agent has a particle
size distribution of: (i) D50 less than or equal to about 5 .mu.m;
(ii) D90 less than or equal to about 11 .mu.m; and (iii) D100 less
than or equal to about 22 .mu.m; and the carbidopa active agent has
a particle size distribution of: (i) D50 less than or equal to
about 3 .mu.m; (ii) D90 less than or equal to about 7 .mu.m; and
(iii) D100 less than or equal to about 21 .mu.m.
Embodiment 10
[0163] The pharmaceutical composition according to any one of
Embodiments 1-6 prepared by: adding a levodopa active agent and a
carbidopa active agent to water to form a slurry; adding the slurry
to one or more suspending agents (e.g., an acrylic acid-based
polymer or a polymer selected from the group consisting of
hydroxypropylcellulose, hydroxymethylcellulose, and sodium
carboxymethyl cellulose) to form a suspension; subjecting the
suspension to N.sub.2 sparging; and optionally, loading the
suspension into a lower oxygen permeability container.
Embodiment 11
[0164] The pharmaceutical composition according to Embodiment 10,
wherein, prior to forming the suspension, the levodopa active agent
has a particle size distribution of: (i) D50 less than or equal to
about 5 .mu.m; (ii) D90 less than or equal to about 11 .mu.m; and
(iii) D100 less than or equal to about 22 .mu.m; and the carbidopa
active agent has a particle size distribution of: (i) D50 less than
or equal to about 3 .mu.m; (ii) D90 less than or equal to about 7
.mu.m; and (iii) D100 less than or equal to about 21 .mu.m.
Embodiment 12
[0165] A method of treating Parkinson's disease in a patient in
need thereof, wherein the method comprises administering to the
patient a pharmaceutical composition comprising a levodopa active
agent and a carbidopa active agent for intraduodenal
administration, wherein the levodopa active agent and carbidopa
active agent are provided in a therapeutically effective manner for
the patient and, suspended in an aqueous carrier, characterized in
that the levodopa active agent and the carbidopa active agent in
the carrier has a high shear viscosity of no more than about 4500
cps at room temperature and a low shear viscosity of no less than
about 45000 cps under refrigerated conditions and a ratio of low
shear viscosity to high shear viscosity of not less than 10 and
optionally, wherein the pharmaceutical composition is administered
in a pharmaceutical dosage form according to Embodiment 7.
Embodiment 13
[0166] The method according to Embodiment 12, wherein the method
comprises substantially continuous administration of the
pharmaceutical composition for a period of at least about 16 hours
or for a period of at least about 24 hours.
Embodiment 14
[0167] The method according to Embodiment 12 or 13, wherein the
pharmaceutical composition comprises: a levodopa active agent in an
amount of about 4.0 weight/weight percent of the total composition;
and a carbidopa monohydrate active agent in an amount of about 1.0
weight/weight percent of the total composition.
Embodiment 15
[0168] The method according to any one of Embodiments 12-14,
wherein the aqueous carrier comprises one or more polymer-based
suspending agent (e.g., an acrylic acid-based polymer or a polymer
selected from the group consisting of hydroxypropylcellulose,
hydroxymethylcellulose, and sodium carboxymethyl cellulose).
Embodiment 16
[0169] A kit comprising the pharmaceutical composition of any one
of Embodiments 1-6 or the pharmaceutical dosage form of Embodiment
7.
* * * * *