U.S. patent application number 16/749435 was filed with the patent office on 2020-12-24 for continuous administration of l-dopa, dopa decarboxylase inhibitors, catechol-o-methyl transferase inhibitors and compositions for same.
The applicant listed for this patent is NeuroDerm, Ltd.. Invention is credited to Mara Nemas, Oron Yacoby-Zeevi.
Application Number | 20200397730 16/749435 |
Document ID | / |
Family ID | 1000005064655 |
Filed Date | 2020-12-24 |
United States Patent
Application |
20200397730 |
Kind Code |
A1 |
Yacoby-Zeevi; Oron ; et
al. |
December 24, 2020 |
Continuous Administration of L-Dopa, Dopa Decarboxylase Inhibitors,
Catechol-O-Methyl Transferase Inhibitors and Compositions for
Same
Abstract
Provided herein, in part, is a method of treating a neurological
or movement disorder in a patient in need thereof, comprising
subcutaneously administering to said patient a pharmaceutically
acceptable composition comprising levodopa and optionally carbidopa
and optionally entacapone or tolcapone, or pharmaceutically
acceptable salts thereof, wherein said composition is administered
substantially continuously, and compositions that can be used in
the disclosed methods.
Inventors: |
Yacoby-Zeevi; Oron; (Moshav
Bitsaron, IL) ; Nemas; Mara; (Rehovot, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
NeuroDerm, Ltd. |
Rehovot |
|
IL |
|
|
Family ID: |
1000005064655 |
Appl. No.: |
16/749435 |
Filed: |
January 22, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15209423 |
Jul 13, 2016 |
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16749435 |
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13885518 |
Oct 29, 2013 |
9421267 |
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PCT/IL11/00881 |
Nov 15, 2011 |
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15209423 |
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61524064 |
Aug 16, 2011 |
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61413637 |
Nov 15, 2010 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 9/0014 20130101;
A61K 47/22 20130101; A61K 31/195 20130101; A61K 31/198 20130101;
A61K 31/12 20130101; A61K 31/122 20130101; A61K 47/18 20130101;
A61K 47/26 20130101; A61K 31/197 20130101; A61K 47/20 20130101;
A61K 9/08 20130101; A61K 31/277 20130101; A61K 9/0019 20130101;
A61K 31/133 20130101; A61K 47/183 20130101 |
International
Class: |
A61K 31/198 20060101
A61K031/198; A61K 9/00 20060101 A61K009/00; A61K 31/195 20060101
A61K031/195; A61K 31/122 20060101 A61K031/122; A61K 31/133 20060101
A61K031/133; A61K 31/197 20060101 A61K031/197; A61K 31/277 20060101
A61K031/277; A61K 47/18 20060101 A61K047/18; A61K 47/20 20060101
A61K047/20; A61K 47/22 20060101 A61K047/22; A61K 9/08 20060101
A61K009/08; A61K 31/12 20060101 A61K031/12; A61K 47/26 20060101
A61K047/26 |
Claims
1. A pharmaceutically acceptable composition having a pH of about
9.1 to about 9.8 at 25.degree. C., comprising: active components
comprising carbidopa and at least about 4% by weight levodopa;
arginine and optionally meglumine.
2. The pharmaceutically acceptable composition of claim 1, wherein
the molar ratio of active components to the arginine is about 1:1.8
to about 1:3.5.
3. The pharmaceutically acceptable composition of claim 1,
comprising about 4% to about 12% by weight levodopa.
4. The pharmaceutically acceptable composition of claim 1,
comprising about 1% to about 6% by weight carbidopa.
5. The pharmaceutically acceptable composition of claim 1,
comprising meglumine.
6. The pharmaceutically acceptable composition of claim 5, wherein
the molar ratio of active components to the arginine is about 1:1.1
to about 1:1.9, and the molar ratio of active components to the
meglumine is about 1:0.3 to about 1:1.5.
7. The pharmaceutically acceptable composition of claim 5, wherein
the molar ratio of active components to the meglumine is about
1:0.3 to about 1:1.2.
8. The pharmaceutically acceptable composition of claim 5, wherein
the composition comprises about 2.0% to about 11% by weight
meglumine.
9. The pharmaceutically acceptable composition of claim 1,
comprising about 10% to about 35% by weight arginine.
10. The pharmaceutically acceptable composition of claim 1, further
comprising an agent that inhibits the formation of oxidation
products.
11. The pharmaceutically acceptable composition of claim 10,
wherein the agent is selected from ascorbic acid, Na-ascorbate,
L-cysteine, N-acetylcysteine (NAC), glutathione (GSH),
Na.sub.2-EDTA, Na.sub.2-EDTA-Ca, or combinations thereof.
12. The pharmaceutically acceptable composition of claim 10,
wherein said agent is ascorbic acid or a pharmaceutically
acceptable salt thereof.
13. The pharmaceutically acceptable composition of claim 1, further
comprising sodium bisulfate.
14. A pharmaceutically acceptable composition comprising levodopa,
arginine and optionally meglumine; and further comprising ascorbic
acid or a pharmaceutically acceptable salt thereof.
15. The pharmaceutically acceptable composition of claim 14,
wherein the ascorbic acid salt is selected from ascorbate, sodium
ascorbate, calcium ascorbate, potassium ascorbate, ascorbyl
palmitate, or ascorbyl stearate.
16. The pharmaceutically acceptable composition of claim 14,
comprising about 0.5% to about 1%, by weight ascorbic acid or a
pharmaceutically acceptable salt thereof.
17. The pharmaceutically acceptable composition of claim 14,
wherein the molar ratio of levodopa to the arginine is about
1:2.3.
18. The pharmaceutically acceptable composition of claim 17,
comprising about 4% to about 12% by weight levodopa.
19-25. (canceled)
26. A transdermal patch suitable for administering a
pharmaceutically acceptable composition according to claim 1.
27. A method of treating a neurological or movement disorder in a
patient in need thereof, the method comprising the steps of: (a)
substantially continuously administering to said patient a
composition of claim 1, wherein the composition is administered
subcutaneously, intraduodenally or intravenously; and (b) orally
administering levodopa and/or carbidopa and optionally entacapone
or tolcapone.
28-30. (canceled)
31. The method of claim 27, wherein the composition is administered
subcutaneously using one or more infusion pumps and/or transdermal
and/or dermal patches.
32. (canceled)
33. The method of claim 27, wherein the rate of administering the
composition is about 1.0.+-.0.5 ml/hour during the day or during
patient activity, and about 0 to about 0.5 ml/hour at night or at
rest.
34. The method of claim 27, wherein the disorder is Parkinson's
disease.
35. A pharmaceutically acceptable formulation comprising about 2.5
to about 7% by weight levodopa, about 0 to about 2% by weight
carbidopa, about 5 to about 18% by weight arginine, and about 0.25%
to about 3% by weight ascorbic acid or a pharmaceutically
acceptable salt thereof.
36-47. (canceled)
Description
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. patent
application Ser. No. 15/209,423, filed Jul. 13, 2016, which is a
continuation of U.S. patent application Ser. No. 13/885,518, filed
Oct. 29, 2013 (now U.S. Pat. No. 9,421,267), which is the National
Stage filing under 35 U.S.C. .sctn. 371 of International Patent
Application No. PCT/IL2011/000881, filed Nov. 15, 2011, which
claims the benefit of and priority to U.S. Provisional Application
No. 61/413,637, filed Nov. 15, 2010, and U.S. Provisional
Application No. 61/524,064, filed Aug. 16, 2011, each of which is
hereby incorporated by reference in its entirety.
TECHNICAL FIELD
[0002] The present invention provides pharmaceutical compositions
useful for treatment of neurological or movement disorders such as
Parkinson's disease, and a method for treatment such disorders by
substantially continuously subcutaneous administration of said
compositions.
BACKGROUND
[0003] Parkinson's disease is a degenerative condition
characterized by reduced concentration of the neurotransmitter
dopamine in the brain. Levodopa (L-dopa or
L-3,4-dihydroxyphenylalanine) is an immediate metabolic precursor
of dopamine that, unlike dopamine, is able to cross the blood-brain
barrier, and is most commonly used for restoring the dopamine
concentration in the brain. For the past 40 years, levodopa has
remained the most effective therapy for the treatment of
Parkinson's disease.
[0004] However, levodopa has a short half life in plasma that, even
under best common current standard of care, results in pulsatile
dopaminergic stimulation. Long-term therapy is therefore
complicated by motor fluctuations and dyskinesia that can represent
a source of significant disability for some patients. A therapeutic
strategy that could ultimately deliver levodopa/dopamine to the
brain in a more continuous and physiologic manner would provide the
benefits of standard levodopa with reduced motor complications and
is much needed by patients suffering from Parkinson's disease and
other neurological or movement disorders (Olanow CW; Mov. Dis.
2008, 23(Suppl. 3):S613-S622). Sustained-release oral levodopa
formulations have been developed, but, at best, such preparations
have been found to be no more efficacious than standard tablets.
Continuous administration of levodopa by intraduodenal
administration or infusion has also been attempted by using
ambulatory pumps or patches. Such treatments, especially
intraduodenal, are extremely invasive and inconvenient.
[0005] The metabolic transformation of levodopa to dopamine is
catalyzed by the aromatic L-amino acid decarboxylase enzyme, a
ubiquitous enzyme with particularly high concentrations in the
intestinal mucosa, liver, brain and brain capillaries. Due to the
possibility of extracerebral metabolism of levodopa, it is
necessary to administer large doses of levodopa leading to high
extracerebral concentrations of dopamine that cause nausea in some
patients. Therefore, levodopa is usually administered concurrently
with oral administration of a dopa decarboxylase inhibitor, such as
carbidopa or benserazide, which reduces by 60-80% the levodopa dose
required for a clinical response, and thus prevents certain of its
side effects by inhibiting the conversion of levodopa to dopamine
outside the brain. Various oral formulations together with
inhibitors of enzymes associated with the metabolic degradation of
levodopa are well known, for example, decarboxylase inhibitors such
as carbidopa and benserazide, catechol-O-methyl transferase (COMT)
inhibitors such as entacapone and tolcapone, and monoamone oxidase
(MAO)-A or MAO-B inhibitors such as moclobemide, rasagiline or
selegiline or safinamide. Currently available oral drugs include
SINEMET.RTM. and SINEMET.RTM. CR sustained-release tablets that
include carbidopa or levodopa; STALEVO.RTM. tablets containing
carbidopa, entacapone and levodopa; and MADOPAR.RTM. tablets
containing levodopa and benserazide. There is an on-going and
urgent need for methods and compositions that can effect continuous
stimulation of L-dopa to more effectively treat movement disorders
such as Parkinson's disease. Nevertheless, no stable liquid
formulation having e.g., an effective concentration in a volume
suitable for use for subcutaneous or transdermal delivery has ever
been achieved.
SUMMARY OF INVENTION
[0006] This disclosure generally relates, in part, to a
pharmaceutically acceptable composition comprising 1) active
components comprising carbidopa and at least about 4% by weight
levodopa; and arginine and optionally meglumine. Such compositions
may have a pH of about 9.1 to about 9.8 at 25.degree. C.
[0007] In some embodiments, a disclosed composition having arginine
may have a molar ratio of active components to the arginine is
about 1:1.8 to about 1:3.5, or about 1:2.3. In an exemplary
embodiment, a disclosed composition may include about 4% to about
12% by weight or more of levodopa and/or may include 1% to about 6%
by weight carbidopa, e.g. about 1% to about 2% by weight
carbidopa.
[0008] When meglumine is present in a disclosed composition, the
molar ratio of active components to the arginine may be, for
example, about 1:1.1 to about 1:1.9, and the molar ratio of active
components to the meglumine may about 1:0.3 to about 1:1.5, e.g.,
the molar ratio of active components to the meglumine may about
1:0.3 to about 1:1.2, or for example, about 1:0.4, or about 1:1.1.
Such contemplated compositions may include about 2.0% to about 11%
by weight meglumine. Contemplated compositions as above for example
may include 10% to about 35% by weight arginine.
[0009] Disclosed compositions may further comprise an agent that
inhibits the formation of oxidation products, for example, such an
agent may selected from the group consisting of: ascorbic acid,
Na-ascorbate, L-cysteine, N-acetylcysteine (NAC), gluthatione
(GSH), Na.sub.2-EDTA, Na.sub.2-EDTA-Ca, and combinations thereof.
For example, the pharmaceutically acceptable composition disclosed
herein may further include, in an exemplary embodiment, ascorbic
acid or a pharmaceutically acceptable salt thereof. In another or
further embodiment, disclosed compositions may include sodium
bisulfate.
[0010] Contemplated herein, for example, is a pharmaceutically
acceptable composition comprising levodopa, arginine and optionally
meglumine; and ascorbic acid or a pharmaceutically acceptable salt
thereof, e.g. the composition may have about 4% to about 12% by
weight levodopa The ascorbic acid salt may selected, for example,
from the group consisting of: ascorbate, sodium ascorbate, calcium
ascorbate, potassium ascorbate, ascorbyl palmitate, and ascorbyl
stearate. For example, a disclosed pharmaceutically acceptable
composition may include the ascorbic acid or a pharmaceutically
acceptable salt thereof is sodium ascorbate, e.g., about 0.25% by
weight or more ascorbic acid or a pharmaceutically acceptable salt
thereof, about 0.2% to about 3% by weight ascorbic acid or a
pharmaceutically acceptable salt thereof, or about 0.5% to about 1%
by weight ascorbic acid or pharmaceutically acceptable salts
thereof. In some embodiments, a contemplated pharmaceutically
acceptable composition may have a molar ratio of levodopa to the
arginine is about 1:1.8 to about 1:3.5, e.g., about 1:2.3.
[0011] Such contemplated compositions may further comprise
carbidopa in some embodiments, for example, 1% to about 2% by
weight carbidopa. In such an embodiment, the molar ratio of the
levodopa and the carbidopa together, to the arginine, may be about
1:1.8 to about 1:3.5, e.g. about 1:2.3. Such a pharmaceutically
acceptable composition may have a pH of about 9.1 to about 9.8 at
25.degree. C.
[0012] Contemplated compositions and formulations disclosed herein
may be, for example, liquid at room temperature. In some
embodiments, a disclosed pharmaceutically acceptable composition
may further comprise entacapone or tolcapone.
[0013] Disclosed pharmaceutically acceptable formulations may be
stable for at least two weeks at 25.degree. C..+-.5.degree. C.,
and/or for example, may be stable for at least two months at
-20.degree. C..+-.5.degree. C.
[0014] In an embodiment, a transdermal patch is contemplated herein
suitable for administering a disclosed pharmaceutically acceptable
composition.
[0015] Also provided herein is a method of treating a neurological
or movement disorder in a patient in need thereof, e.g.,
Parkinson's disease, comprising administering to said patient a
composition disclosed herein, e.g. a liquid composition of levodopa
and/or carbidopa. Also provided herein, in one embodiment, is a
method for treatment of a disease or disorder such as a
neurological disorder, or a disorder characterized by reduced
levels of dopamine in a patient's brain, and/or for example a
disorder such as Parkinson's disease, wherein the method includes
administration (e.g. substantially continuous administration) of a
disclosed composition. In an embodiment, continuous administering
may include transdermal, intradermal, subcutaneous, intravenous,
intrathecal, epidural, intracranial, or intraduodenal
administration, e.g. may include the use of an infusion pump. Such
methods may further comprise orally administering levodopa and/or
carbidopa and optionally entacapone or tolcapone.
[0016] Disclosed compositions may be administered subcutaneously
and/or e.g. substantially continuously. Such subcutaneous
administration may comprise the use of one or more infusion pumps
and/or transdermal and/or dermal patches. For example, a disclosed
method may include a rate of administering a disclosed composition
at least about 0.01 ml/hour to about 0.2 ml/h, or at least about
0.07 ml/hour, or for example, about 0.15 ml/hour during the day or
during patient activity, and about 0 to about 0.075 0.25 ml/hour at
rest or sleep. Alternatively, a disclosed composition may be
administered intraduodenally or intravenously.
[0017] In some embodiments, a method that includes subcutaneously
administering comprises the use of one or more infusion pumps,
e.g., with a rate of administering the composition is about 0.20
ml/hour to about 2.0 ml/h, for example, about 1.0.+-.0.5 ml/hour,
or about 1.25.+-.0.5 ml/hour during the day or during patient
activity, and about 0 to about 0.5 ml/hour at night or at rest.
[0018] Also provided herein is a pharmaceutically acceptable
composition comprising (i) carbidopa, at least 4% by weight
levodopa, arginine and optionally meglumine; or (ii) levodopa,
arginine, optionally meglumine, and ascorbic acid or a
pharmaceutically acceptable salt thereof, for use in treatment of a
neurological or movement disorder. In one embodiment, the
neurological or movement disorder is Parkinson's disease.
[0019] A pharmaceutically acceptable formulation is disclosed
herein, in an embodiment, comprising about 2.5 to about 7% by
weight levodopa, about 0 to about 2% by weight carbidopa, about 5
to about 18% by weight arginine, and about 0.25% to about 3% by
weight ascorbic acid or a pharmaceutically acceptable salt
thereof.
[0020] In an embodiment, a pharmaceutically acceptable formulation
comprising about 8 to about 12% by weight levodopa, about 1 to
about 3% by weight carbidopa, about 15 to about 35% weight arginine
is contemplated. In another embodiment, a pharmaceutically
acceptable formulation comprising about 8 to about 12% by weight
levodopa, about 1 to about 3% by weight carbidopa, and about 12 to
about 15% weight arginine, and about 3% to about 10% by weight
meglumine is provided. Such compositions may further include about
0.25-3% by weight ascorbic acid.
[0021] Also provided herein is a pharmaceutically acceptable liquid
composition comprising arginine and at least about 7% by weight
entacapone or tolcapone, e.g. at least about 8%, or at least about
10%, or about 7% to about 12% by weight entacapone or tolcapone.
For example, a disclosed composition may have entacapone or
tolcapone and the arginine with a molar ratio of about 1:0.5 to
about 1:2.5, for example about 1:1 to about 1:1.5. Such liquid
compositions may have a pH of about 6 to about 9 at 25.degree. C.,
and/or may be substantially stable at 25.degree. C. for 48 hours or
more.
[0022] Provided herein, in an embodiment, is a process for
preparing a stable liquid solution comprising levodopa and/or
carbidopa, and arginine, comprising:
[0023] providing levodopa and/or carbidopa, and arginine to form a
powder mixture;
[0024] adding water to said powder mixture to form a
suspension;
[0025] heating said suspension at a temperature of about 40.degree.
C. to about 90.degree. C. to form a solution; and
[0026] cooling said solution to provide the stable liquid
composition. In some embodiments, wherein heating said suspension
further comprises stirring the suspension.
[0027] This disclosure relates at least in part to the discovery
that arginine can form a salt of carbidopa, and/or levodopa and/or
entacapone, or tolcapone, that can be used to form a stable, liquid
formulation that is suitable for e.g., continuous subcutaneous,
transdermal, intradermal, intravenous and/or intraduodenal
administration. Such disclosed compositions are capable of
substantially continuously administering carbidopa, entacapone,
tolcapone and/or levodopa to a patient in need thereof. For
example, disclosed herein are compositions that relate to the
disclosed discovery that substantially continuously administering a
dopa decarboxylase inhibitor such as carbidopa, together with
substantially continuously administering levodopa and optionally
entacapone or tolcapone, may stimulate L-dopa substantially
continuously and thus e.g., extend the effectiveness of a levodopa
oral dosing regimen and/or reduce the daily dosage of levodopa or
eliminate the need for oral levodopa, while effectively treating a
movement and/or neurological disorder such as Parkinson's
disease.
BRIEF DESCRIPTION OF THE FIGURES
[0028] FIGS. 1A and 1B depict the effect of carbidopa on the
stability of levodopa In Vitro and Ex Vivo: FIG. 1A. 6% weight
levodopa and arginine solution with various concentrations (2, 1.5,
1, 0.5%) of carbidopa or no carbidopa were tested for physical
stability in vitro. The results show that carbidopa prevented dark
yellow color formation in the presence of air, in a dose related
manner (small vials at the right hand side), and in the absence of
air (with N.sub.2 in the head space) 0.5% carbidopa was sufficient
to inhibit this color formation (large vials in the left hand side
of the figure). FIG. 1B. 7% weight percent levodopa and arginine
solution, with or without 2% carbidopa by weight, continuously
administered in to the subcutaneous tissue of a 5.times.5 cm fresh,
full-thickness pig skin. The right hand side depicts the inhibition
of oxidation with the use of a levodopa formulation that includes
carbidopa.
[0029] FIG. 2 depicts that the presence of 1% carbidopa in a
levodopa solution reduces the severity and extent of local levodopa
dependent subcutaneous toxicity in the pig.
[0030] FIGS. 3A-3C depict the effect of carbidopa on the
pharmacokinetics of levodopa in the pig. FIG. 3A: the plasma
concentration of levodopa following continuous subcutaneous
administration of 6% levodopa with various amounts of carbidopa.
FIG. 3B: The correlation between plasma steady state concentration
of levodopa, obtained following continuous subcutaneous
administration of levodopa/carbidopa formulations and the
formulation concentration of carbidopa. FIG. 3C. The correlation
between plasma steady state concentration of carbidopa following
continuous subcutaneous administration of levodopa/carbidopa
formulations and the formulation concentration of carbidopa.
[0031] FIGS. 4A-4D show the effect of various agents on oxidation
of levodopa in the subcutaneous tissue of pig skin samples,
ex-vivo, following subcutaneous administration of
levodopa/carbidopa formulations.
[0032] FIG. 5A depicts the effect of continuous subcutaneous (SC)
entacapone (200 mg/24 h) and/or carbidopa (CD) (40 mg/24 h) on the
plasma concentrations of levodopa (ng/ml) following oral
Administration of Sinemet (100/25 levodopa/carbidopa) in pigs.
[0033] FIG. 5B depicts the effect of continuous SC CD (40 mg/24 h)
and/or levodopa (LD) (140 mg/24 h) administration on the plasma
concentrations of levodopa following oral administration of Sinemet
(100/25) in pigs.
[0034] FIG. 6 shows the effect of carbidopa on the local
subcutaneous toxicity of levodopa following 24 h-continuous
subcutaneous administration, at 0.16 ml/h, in pigs.
DETAILED DESCRIPTION OF THE INVENTION
[0035] Disclosed herein, in an embodiment, is a liquid composition
that includes an arginine salt of levodopa (e.g., arginine and
levodopa), and optionally carbidopa, that is stable at room
temperature. Such disclosed compositions may facilitate continuous
delivery of an effective amount of levodopa, carbidopa, and/or
other active agents such as entacapone or tolcapone to a patient in
a minimally invasive fashion. Further, disclosed formulations have
a pH that is suitable for e.g., transdermal, subcutaneous,
intravenous, intrathecal, epidural, intracranial or intraduodenal
administration.
[0036] For example, provided herein are formulations and methods
capable of obtaining substantially constant inhibition of COMT
activity upon administration, thereby increasing the half life of
administered levodopa and substantially reducing the pulsatility of
levodopa plasma levels to avoid low trough levels of plasma
levodopa.
[0037] Further, provided herein are formulations of levodopa and
optionally carbidopa that unexpectedly allow for stable dissolution
of higher concentrations (e.g., greater than 2% by weight) of
levodopa at e.g. an acceptable pH, for e.g., substantially
continuous subcutaneous or transdermal administration. Such
formulations may also be suitable for intravenous, intradermal,
oral or intraduodenal administration. For example, provided herein
are formulations and methods capable of obtaining substantially
constant plasma levodopa concentrations and substantially reducing
the pulsatility of levodopa plasma levels to avoid low trough
levels of plasma levodopa.
[0038] A treatment strategy of continuous levodopa and carbidopa
(and/or entacapone or tolcapone) administration in accordance with
the present invention may simulate L-dopa substantially
continuously. For example, therapies and/or methods of the present
invention may extend a levodopa oral dosing regimen to about 2 to
about 3 times/day, and/or reduce daily dose of levodopa, and/or
reduce or even eliminate oral dosing of levodopa and carbidopa.
Compositions
[0039] Provided herein, in an embodiment, is a liquid formulation
comprising an arginine salt of levodopa, or a liquid formulation
comprising arginine and levodopa. In an embodiment, provided herein
is a liquid formulation that includes levodopa and arginine in a
molar ratio of about 1:1.5 to about 1:2.5, or about 1:2 to about
1:2.3 levodopa:arginine, or, for example, when such a liquid
composition further comprises carbidopa in a molar ratio of about
1:2 to about 1.3.5, or about 1:1.8 to about 1:3.5
carbidopa:arginine.
[0040] Such levodopa and arginine formulations or solutions may
have a pH that is pharmaceutically acceptable for subcutaneous
administration, e.g. a pH of about 8 to about 10, for example,
about 9.1 to about 9.8, e.g., 9.2 to 9.6 at 25.degree. C. A
disclosed formulation having levodopa and arginine may include at
least about 7%, 8%, 9%, or more by weight levodopa, e.g., may
include about 10%, 20% or more by weight levodopa. In some
embodiments, a disclosed formulation may include about 2.5 to about
10 weight percent levodopa, 4 to about 7 weight percent levodopa,
or about 7.5 to about 12 weight percent levodopa, or about 5% to
about 30%, or about 10 to about 20 weight percent levodopa, and may
further include about 9 to about 20 weight percent arginine or
about 9 to about 30 weight percent arginine, e.g. about 10 to about
18 weight percent arginine, about 10 to about 20% or about 15 to
about 30% or more by weight arginine or about 12, 13, 14, or 15
weight percent arginine. For example, arginine may be present in
contemplated formulations at a molar ratio of about 1.5:1 to about
3:1, e.g. 1.8:1 to about 3.5:1, ratio of arginine:total active
ingredients (which may include e.g., levodopa, carbidopa,
etc.).
[0041] For example, disclosed herein is a pharmaceutically
acceptable composition, having a pH of about 9.1 to about 9.8 at
25.degree. C., that includes the active components levodopa and
carbidopa (e.g. about 4% by weight or more levodopa), and arginine
and/or meglumine. For example, contemplated compositions having
levodopa and arginine may further comprise carbidopa, for example,
may further include at least about 1%, at least about 2%, at least
about 4% by weight carbidopa, for example about 2% to about 4% by
weight carbidopa. For example, provided herein is a composition
comprising arginine and about 2% to about 12% by weight levodopa or
more (e.g. about 4% to about 10%, about 4% to about 7%, about 5% to
about 10%, or about 6% to about 11% by weight levodopa, or about 5%
to about 20% by weight levodopa) and about 1% to about 6%, about 1%
to about 2% (e.g. about 1.25 or about 1.5%), or about 2% to about
5% or about 2% to about 4% by weight carbidopa. When administered
subcutaneously and/or dermally, such compositions having levodopa
and carbidopa may result in minimal local tissue damage, e.g., as
compared to subcutaneous or dermal administration of a composition
that includes levodopa (e.g., a levodopa/arginine composition)
alone. Further, such levodopa and arginine compositions, when
further including carbidopa, may have more stability (e.g. may not
form unwanted oxidation products over time as compared to a
composition having levodopa and arginine alone).
[0042] In another embodiment, disclosed formulations may include an
amino sugar such as meglumine, which may, for example, replace some
or all of the arginine present in the formulations. For example,
disclosed here is a formulation comprising levodopa and/or
carbidopa and meglumine. Also contemplated herein is a meglumine
salt of levodopa and a meglumine salt of carbidopa. In an
embodiment, a composition comprising arginine and having active
agents such as levodopa and carbidopa, wherein the molar ratio of
active agents to arginine is less than about 1:2; to improve the
stability of such compositions, this exemplary composition may
further comprise meglumine, e.g., with a ratio of active agents to
meglumine of about 1:0.3 to about 1.1.5. For example, provided
herein is a composition having levodopa or carbidopa (or a
combination) as active components, arginine, and meglumine, wherein
the molar ratio of active components to arginine is about 1:1.1 to
about 1:1.9 (e.g. 1:1.3) and the molar ratio of active components
to meglumine of about 1:0.3 to about 1:1.2 (e.g. about 1:0.4,
1:0.5, 1:0.8, 1:1.1). Contemplated compositions can include
levodopa (e.g. about 4 to about 10% by weight or more), carbidopa
(e.g. about 0.5 to about 3% by weight, e.g. about 1 or 2% by
weight), about 9% to about 16 by weight arginine, and about 2% to
about 10% by weight meglumine.
[0043] Also provided herein, in an embodiment, is a formulation
comprising levodopa, arginine, and/or carbidopa, and optionally for
example an agent that inhibits the formation of oxidation products.
Such a formulation may be liquid at room temperature, with a pH of
about 9.1 to 9.8. For example, provided herein is a composition
that includes ascorbic acid or salt thereof.
[0044] In an embodiment, a disclosed composition may further
comprise one or more agents that inhibit the formation of oxidation
products. Such agent may be e.g., tyrosinase inhibitors and/or
o-quinone scavengers and/or Cu.sup.++ chelators and/or
antioxidants. In some embodiments, carbidopa may act as an agent
that inhibits the formation of oxidation products. For example,
contemplated formulations may include o-quinone scavengers such as,
but not limited to, N-acetyl cysteine, gluthatione, ascorbic acid,
Na-ascorbate, and/or L-cysteine. In an embodiment, formulations may
include an agent chosen from one or more of tyrosinase inhibitors
such as captopril; methimazole, quercetin, arbutin, aloesin,
N-acetylglucoseamine, retinoic acid, .alpha.-tocopheryl ferulate,
MAP (Mg ascorbyl phosphate), substrate analogues (e.g., sodium
benzoate, L-phenylalanine), Cu.sup.++ chelators for example,
Na.sub.2-EDTA, Na.sub.2-EDTA-Ca, DMSA (succimer), DPA
(D-penicillamine), trientine-HCl, dimercaprol, clioquinol, sodium
thiosulfate, TETA, TEPA, curcumin, neocuproine, tannin, and/or
cuprizone. Other contemplated anti-oxidants that may form part of a
disclosed formulation include sulfite salts (e.g., sodium hydrogen
sulfite or sodium metabisulfite), di-tert-butyl methyl phenols,
tert-butyl-methoxyphenols, polyphenols, tocopherols and/or
ubiquinones, including but not limited to caffeic acid.
[0045] In a particular embodiment, provided herein are compositions
that include levodopa, carbidopa, arginine, optionally meglumine,
and an ascorbic acid or pharmaceutically acceptable salt thereof.
For example, contemplated compositions may further include
ascorbate, sodium ascorbate, potassium ascorbate, calcium
ascorbate, ascorbyl stearate, and/or ascorbyl palmitate. For
example, a composition may include about 0.5 percent by weight or
more (e.g., about 0.5 to about 3 percent by weight, or about 0.2 to
about 2 percent or about 0.5 to about 1 percent by weight, e.g.
about 0.75% by weight ascorbic acid or salt thereof.
[0046] Provided herein, in an embodiment, is a pharmaceutically
acceptable formulation that includes entacapone (or tolcapone), and
arginine, that allows for substantially continuous administration
of entacapone or tolcapone. For example, provided herein, for
example, is a stable liquid formulation that includes entacapone or
tolcapone and may be suitable for substantially continuous
administration to a patient. Further, such formulations may have a
physiologically acceptable pH, for example, about 6 to about 9.5,
or about 6.5 to about 8.5, or about 7 to about 8.
[0047] For example, entacapone (or tolcapone) and arginine may be
dissolved in an aqueous solution, (e.g., having a pH of about 6 to
9, e.g., from about 6.5 to about 8.5, e.g., from about 7 to 8 at
25.degree. C. or at 30.degree. C. Alternatively, entacapone (free
base) (or tolcapone (free base) and a basic amino acid salt (e.g.
arginine and/or lysine) are dissolved together in a liquid (e.g. an
aqueous liquid) to form a disclosed liquid formulation. Disclosed
liquid formulations may include about 2% by weight entacapone or
tolcapone, about 4% by weight entacapone or tolcapone, or about 2%
to about 12% by weight entacapone or tolcapone, for example, may
include about 7% by weight or more, about 8% by weight or more, or
about 10% by weight or more entacapone or tolcapone, for example,
may include about 3% to about 20% by weight or more entacapone or
tolcapone, e.g., about 5% to about 8% by weight, about 8% to about
12% by weight entacapone or tolcapone. For example, a liquid
formulation may include entacapone, and a basic amino acid (such as
arginine) in molar ratio of about 1:0.5 to about 1:2.5, or about
1:1 to about a 1:2, e.g., about 1:1 or 1:1.5. Such liquid
formulations may further comprise carbidopa, for example, at least
about 2% by weight or at least about 4% by weight carbidopa, e.g.
about 2% to about 6% or more by weight carbidopa. In another
embodiment, such liquid formulations may further comprise levodopa,
for example, at least about 2%, 3%, 4%, 5%, 6%, or 7% by weight
levodopa, e.g. about 2.5% to about 12% by weight levodopa. In an
exemplary embodiment, a composition that includes tolcapone or
entacapone may further include an excipient such as an .alpha.,
.beta. or .gamma.cyclodextrin or derivative.
[0048] Disclosed liquid formulations (e.g. a liquid composition
comprising levodopa, carbidopa, entacapone tolcapone, or
combinations of two or more) and arginine (and/or meglumine), e.g.,
a disclosed formulation comprising levodopa and arginine) may be
stable for 24 hours, for 48 hours, for 7 days, or more at .degree.
25 C. For example, an exemplary liquid formulation may include
about a 1:1 molar ratio of entacapone:arginine (or
tolcapone:arginine), with about 5% to about 15%, or about 6% to
about 12%, or 6% to about 10% by weight entacapone. Such an
entacapone, arginine liquid formulation may be more stable, in some
embodiments, at 7 days as compared to a liquid composition that
includes a lysine or histidine salt of entacapone. In an
embodiment, a disclosed formulation comprising levodopa and
arginine may be stable for at least one week, or at least two weeks
or more at room temperature, e.g. at 20.degree. C. to 30.degree.
C., e.g. at 25.degree. C. In an embodiment, a disclosed formulation
comprising levodopa and arginine may be stable for at least one
month, or at least two months at temperature below freezing e.g. at
-10.degree. C. and/or at -20.degree. C., at -18.degree. C., or
e.g., at -20 to -80.degree. C. The term "stable" in this context
means that a formulation does not significantly precipitate out of
solution and/or one or more active agents does not degrade
significantly for a substantial amount of time.
[0049] In some embodiments, disclosed liquid formulations or
compositions are liquid solutions, i.e. are substantially
homogenous liquid mixtures. Such liquid mixtures may comprise water
and/or other pharmaceutically acceptable excipients. In another
embodiment, disclosed liquid compositions may be substantially
non-aqueous.
[0050] In some embodiments, a disclosed liquid formulation will be
stable for a period of 1 day, 2 days, 3 days, 1 week, or 1 month or
more at room temperature. In an embodiment of the invention, a
disclosed liquid formulation further comprise a pharmaceutically
acceptable excipient such as e.g., N-methylpyrrolidone (NMP), or
polyvinylpyrrolidone (PVP), EDTA (or salts thereof) cysteine,
N-acetylcysteine and/or sodium bisulfate.
[0051] For example, in one embodiment, provided herein is a stable
liquid formulation that comprises about 4% to about 12% by weight
levodopa, and/or carbidopa (e.g. about 1% to about 6% by weight, or
about 2% to about 6% by weight) and/or entacapone or tolcapone
(e.g. about 7% to about 12% by weight) and about 1 to about 40%
arginine, about 0 to about 10% NMP, about 0 to about 5% PVP, and/or
about 0 to about 3.5% of one or more water soluble antioxidants, by
weight.
[0052] The invention further provides a stable lyophilized powder
comprising an arginine salt of levodopa, carbidopa or entacapone,
or a combination of two or more of levodopa, carbidopa or
entacapone. In one embodiment, such stable lyophilized powder may
comprise about 20-99% of the levodopa or entacapone salt, about
0-60% NMP, about 0-15% PVP, and about 0-10% of one or more water
soluble anti oxidants. The lyophilized powder can be reconstituted
into a liquid formulation by addition of water alone or water with
NMP, and may include or not include antioxidants.
[0053] In some embodiments, provided herein is a formulation
suitable for continuous subcutaneous administration, e.g.,
comprising about 4 to about 7% by weight levodopa, about 1 to about
2% by weight carbidopa, and about 10 to about 18% weight percent
arginine. Such formulations may further include, in some
embodiments, about 1% weight percent ascorbic acid (or a
pharmaceutically acceptable salt thereof), and/or optionally about
0.2% weight percent Na.sub.2EDTA-Ca.
[0054] In another embodiment, a formulation suitable for
intraduodenal or intravenous administration is provided comprising
at least about 8% by weight levodopa (e.g. 8% to about 12%), at
least about 1.5% by weight carbidopa (e.g. about 1.5% to about 3%),
and at least about 15% arginine by weight (e.g. about 15% to about
30% by weight, or about 15% to about 20% by weight). Such
formulations may include about 1% by weight ascorbic acid and about
0.2% by weight Na.sub.2EDTA-Ca. Also provided herein is a
formulation suitable for intraduodenal or intravenous
administration, comprising at least about 8% by weight levodopa
(e.g. 8% to about 12%), at least about 1.5% by weight carbidopa
(e.g. about 1.5% to about 3%), at least about 10% arginine or about
12% arginine by weight (e.g. about 10% to about 15% by weight, or
about 12% to about 15% by weight), at least about 3% by weight
meglumine (e.g. about 3% to about 8%, or about 3% to about 5%), and
optionally about 1% by weight ascorbic acid (or salt therefore),
and/or optionally about 0.2% Na.sub.2EDTA-Ca for continuous
intraduodenal or intravenous administration. Such formulations may
include water.
[0055] Liquid formulations of the invention may be designed for
continuous administration of entacapone, tolcapone, carbidopa
and/or levodopa a patient in need thereof. For example, a patient
may be substantially continuously administered (e.g.
subcutaneously, transdermally, intraduodenally, intradermally, or
intravenously) a formulation that includes a disclosed entacapone
composition that includes arginine and entacapone, while carbidopa,
a carbidopa salt, or a composition comprising carbidopa is also
substantially continuously administered e.g. a different device, or
in a separate compartment in the same device, in a separate
composition via the same device, or in the same composition, and/or
optionally levodopa and/or carbidopa is orally administered at
discrete intervals, e.g., 2, 3, 4, or 5 times a day.
[0056] As used herein in the specification, the term "a composition
comprising levodopa" or "levodopa composition" contemplates
formulations that comprise levodopa, optionally together with a
decarboxylase inhibitor, a catechol-O-methyl transferase (COMT)
inhibitor, and/or a MAO-A or MAO-B inhibitor. For example, a
composition comprising levodopa includes a dosage formulation that
comprises levodopa (or a salt thereof) and optionally another drug,
where the dosage formulation may be an immediate release,
controlled release, dual release or multiple release formulation
suitable for oral administration.
[0057] The term "decarboxylase inhibitor" refers to a dopa
decarboxylase inhibitor, e.g., a drug that inhibits the peripheral
metabolism of levodopa to dopamine by aromatic L-amino acid
decarboxylase such as carbidopa and benserazide.
[0058] A movement disorder refers to a nervous system condition
that causes abnormal voluntary or involuntary movements, or slow,
reduced movements.
[0059] A neurological disorder is a disorder of the body's nervous
system.
[0060] The term "pharmaceutically acceptable carrier" or
"pharmaceutically acceptable excipient" as used herein 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 use of such media and agents for
pharmaceutically active substances is well known in the art. The
compositions may also contain other active compounds providing
supplemental, additional, or enhanced therapeutic functions.
[0061] Pharmaceutically or pharmacologically acceptable" include
molecular entities and compositions that do not produce an adverse,
allergic or other untoward reaction when administered to an animal,
or a human, as appropriate. For human administration, preparations
should meet sterility, pyrogenicity, general safety and purity
standards as required by e.g, the U.S. FDA Office of Biologics
standards.
[0062] The term "pharmaceutical composition" as used herein refers
to a composition comprising at least one active agent as disclosed
herein formulated together with one or more pharmaceutically
acceptable carriers.
[0063] The term "physiologically acceptable pH" is understood to
mean a pH of e.g., a composition that facilitates administration of
the composition to a patient without significant adverse effects,
e.g. a pH of about 4 to about 9.8, (for example, about 4.+-.0.3 to
about 9.5.+-.0.3.)
[0064] COMT inhibitors refer to inhibitors that inhibit the
degradation of levodopa to 3-methyldopa by catechol-O-methyl
transferase and prolong the action of levodopa, such as such as
entacapone or tolcapone. For example, compositions comprising
levodopa contemplated herein may also include a decarboxylase
inhibitor (carbidopa or benserazide) and entacapone, e.g. "triple
therapy".
[0065] MAO-A or MAO-B inhibitors prevent the breakdown of dopamine
by monoamine oxidases, e.g., moclobemide, rasagiline, selegiline or
safinamide, e.g., rasagiline.
Kits and Devices
[0066] Contemplated herein, in part, is a transdermal patch
suitable for transdermal or subcutaneous administration of an
active agent that comprises a composition as disclosed herein, for
example, may include a composition including levodopa and
carbidopa, and arginine, as disclosed herein, and optionally a
composition that comprises carbidopa and/or levodopa. Such patches
may have one or more compartments which may have the same or
different compositions, for example, one compartment may have a
disclosed formulation and another a different disclosed
formulation, or a different active formulation. A transdermal patch
refers to any device that is capable of delivering one or more of
the active agents forming a disclosed composition through the skin
or mucous membrane into the bloodstream of a patient.
[0067] Also contemplated herein is a kit comprising: a) a first
formulation comprising a disclosed composition comprising carbidopa
and arginine, wherein said first formulation is suitable for
continuous (e.g dermal or subcutaneous) administration; optionally
b) a second formulation comprising levodopa or an arginine salt of
levodopa, wherein the second formulation is suitable for continuous
administration; optionally c) a third formulation comprising
entacapone and arginine, wherein the third formulation is suitable
for continuous administration, and/or optionally d) a fourth
formulation comprising tolcapone and arginine, wherein the fourth
formulation is suitable for continuous administration, optionally
e) a fifth composition comprising levodopa and optionally
carbidopa, wherein said fifth formulation is suitable for
subcutaneous administration; and/or optionally f) a sixth
composition comprising levodopa and/or optionally carbidopa,
wherein said sixth formulation is suitable for oral administration;
and g) instructions for administration of at least one of
formulations a)-f). The formulations a)-e) may be suitable for
continuous administration by any suitable route such as
transdermally, intravenously, subcutaneously, intradermally,
intramuscularly or intraduodenally.
[0068] In an embodiment, the first formulation comprises a
disclosed carbidopa salt and is suitable for administration
subcutaneously. The sixth formulation of a contemplated kit may
include levodopa, a levodopa salt, or a composition comprising
levodopa, and may be presented as any suitable oral dosage such as,
but not limited to, pills, tablets, dispersible tablets, capsules,
liquid, and the like. In an embodiment, the fourth formulation may
be in the form of an immediate release, controlled release or dual
release oral formulation that comprises both levodopa and
benserazide, or both levodopa and carbidopa. Such oral formulation
in the form of pills, tablets, or the like, may comprise a ratio of
carbidopa or benserazide to levodopa of about 1:10 to 1:4,
preferably from about 1:4 to 1:1. Other contemplated second
formulations include formulations, e.g., tablets that include
levodopa, carbidopa, and entacapone (or tolcapone), or e.g. a
tablet that includes levodopa arginine salt and/or carbidopa
arginine.
[0069] A contemplated kit may include a levodopa arginine salt
(and/or carbidopa arginine salt), or a liquid composition having
levodopa, carbidopa, and/or entacapone (or a combination) and
arginine. Such composition may be liquid or a lyophilized powder
that can be reconstituted into a liquid formulation, or, for
example, may form part of a transdermal patch, and may be designed
for continuous administration by any suitable route such as, but
not limited to, transdermally, intravenously, subcutaneously,
intradermally, intramuscularly or intraduodenally.
[0070] In another embodiment, the kit comprises a first liquid
formulation comprising carbidopa and arginine (and optionally
levodopa and/or entacapone or tolcapone) suitable for, but not
limited to, transdermal, intravenous, subcutaneous, intradermal,
intramuscular, intraduodenal continuous administration, and a
second formulation in the form of an immediate release, controlled
release or dual release oral formulation comprising levodopa and
carbidopa and/or a second liquid formulation comprising entacapone
and arginine (or tolcapone and arginine), suitable for, but not
limited to, transdermal, intravenous, subcutaneous, intradermal,
intramuscular, intraduodenal continuous administration.
[0071] In some embodiments, disclosed liquid compositions (e.g.
comprising levodopa, arginine and optionally carbidopa), may be
provided in e.g. a pre-filled cartridge suitable for use by a
patient or physician. For example, provided herein is a kit
comprising a prefilled cartridge wherein a disclosed liquid
formulation is disposed within the cartridge (e.g., a pre-filled
cartridge having a single dose or a dose suitable for a single
administration to a patient of a levodopa and arginine solution
(and optionally carbidopa)), and optionally instructions for
use.
Preparation of Compositions
[0072] Disclosed formulations or compositions may be prepared by
mixing arginine and/or meglumine in amounts as disclosed above with
levodopa and/or carbidopa, and optionally anti oxidant(s) e.g., to
form a powder mixture. Water may be added to the mixture to form a
suspension. The suspension may be heated to about e.g., at about 40
to about 100.degree. C., or at about 60 to 90.degree. C., e.g.,
72.+-.5.degree. C.) e.g., by adding pre-heated water and/or by
placing the mixture in a hot (e.g. 72.+-.5.degree. C.) water bath
(e.g. for about 3, about 5, about 10 minutes or more (e.g. up to
about 10 minutes)), to form a solution, with optional stirring, and
cooling the solution to form the composition. N.sub.2 may be
provided the head space of the container. For example, the mixture
can then be removed from the hot water bath, and cooled to room
temperature, and adding, e.g., immediately thereafter, an optional
anti-oxidant(s) under N.sub.2 atmosphere and subsequent stirring. A
preparation such as that above, e.g., where levodopa, carbidopa,
and arginine are mixed together as powders first, and a suspension
formed with water and then heated may result in a more stable
solution as compared to a preparation that includes a step wise
preparation of individual water suspensions of ingredients and
later combination.
[0073] Disclosed formulations can be sterilized, e.g., using 0.2
.mu.M filters such as filters with nylon or PVDF membranes. In some
embodiments, the preparation of disclosed formulations has fewer
undesirable by-products (e.g. toxic by-products) or contaminants
(for example, hydrazine) when carbidopa and levodopa are present at
the same time and/or when prepared using certain antioxidants (e.g.
ascorbic acid or salts thereof) rather than others (e.g. sodium
bisulfite). In another embodiment, the preparation of disclosed
formulations has fewer undesirable by-products when pre-heated
water is added as disclosed above, as compared to a formulation
prepared without the addition of pre-heated water. In another
embodiment, the levodopa and/or carbidopa may not dissolve unless
the preparation procedure disclosed is used. Such disclosed
preparations as above may provide a more stable formulation as
compared to a formulation prepared without adding hot water or
heating.
Methods of Treatment
[0074] In a further aspect, the present invention provides a method
for treatment of a disease or disorder, such as a neurological or
movement disorder, comprising substantially continuously
administering a disclosed composition, and/or administering
composition comprising levodopa (e.g. orally administering a
levodopa composition or subcutaneously administering such as a
disclosed levodopa composition), and optionally co-administering
substantially continuously to a patient in need a therapeutically
effective amount of a composition comprising a decarboxylase
inhibitor or a salt thereof (e.g. comprising carbidopa and
arginine), optionally together with substantially continuously
administering a composition such as disclosed herein, comprising a
therapeutically effective amount of a COMT inhibitor (e.g a
entacapone composition comprising entacapone and arginine, or a
tolcapone composition comprising tolcapone and arginine). In some
embodiments, a provided method may comprise substantially
continuously administering a composition that includes both e.g.
carbidopa and entacapone or tolcapone, or may comprise
substantially continuously administering two separate compositions
(e.g., one having entacapone or tolcapone, one having carbidopa
and/or levodopa), such as the compositions disclosed herein. As
shown in the Examples, patients administered levodopa together with
continuous administration of carbidopa and entacapone may result in
higher plasma levels of levodopa as compared to the plasma levels a
person of skill in art would expect from continuous administration
of carbidopa or entacapone alone.
[0075] For example, provided herein are methods of treating
neurological or movement disorders that include oral administration
of a composition comprising levodopa and/or carbidopa, (and
optionally, oral administration of a composition comprising a COMT
inhibitor), and also includes subcutaneous administration of a
carbidopa composition such as disclosed herein, or composition that
includes both levodopa and/or carbidopa, such as disclosed herein
(and where subcutaneous administration of levodopa and carbidopa
may be as separate compositions or compositions that include both
levodopa and carbidopa). Such methods can also include subcutaneous
administration of levodopa and/or a COMT inhibitor, which may be in
different formulations or in the formulation.
[0076] Also provided herein are methods of treating neurological or
movement disorders that include subcutaneous or dermal,
substantially continuous administration of a composition (e.g. a
liquid composition) comprising levodopa and optionally carbidopa
(and may include optionally substantially administering a
composition comprising carbidopa), even without discrete (e.g.
oral) administration of levodopa, which may be sufficient to
maintain therapeutic plasma levels of levodopa. In an embodiment,
contemplated methods may include substantially continuously
administering levodopa and carbidopa, (in the same composition or
separate compositions), e.g. with levodopa:carbidopa weight ratios
of about 10:1 to about 1:1. In an embodiment, contemplated methods
may include substantially continuously administering levodopa with
or without carbidopa and/or oral COMT inhibitors.
[0077] In some embodiments, compositions comprising levodopa (e.g.
a disclosed liquid composition) may be administering at a rate of
about 0.07 ml/hour, or e.g., about 0.01 ml/hour to about 0.2
ml/hour. Such rates may be constant throughout the day and night or
varied according to patient's need, for example, may reflect a
patient resting or sleeping schedule and waking or higher activity
level schedule. For example, liquid compositions such as those
disclosed herein (e.g including levodopa) may be administered at a
rate of about 0.15 ml/hour in the morning (e.g. for about 2-3 hours
before waking), about 0.1 ml/hours during the daytime or activity
time, (e.g. for about 10 to about 12 hours), and/or about 0.035
ml/hour at rest or at night. In another embodiment, liquid
composition such as those disclosed herein (e.g., disclosed
compositions comprising levodopa) may be administered, e.g.,
intraduodenally, at a rate of about 1.0 ml/hour during the daytime
or activity time (e.g. for about 2-3 hours before waking and for
about 10 to about 12 hours thereafter), and 0 to about 0.5 ml/hour
at rest or at night. In another embodiment, liquid compositions
such as disclosed herein (e.g. comprising levodopa and arginine),
may be administered at a rate of about 1.25 ml/hour (e.g. about
1.25.+-.0.5 ml/hour during the daytime or activity time (e.g. for
about 2-3 hours before or after waking and for about 10 to about 14
hours thereafter) and 0 to about 0.5 ml/hour (e.g. about
0.5.+-.0.25 ml/hour) at rest or night.
[0078] Contemplated administration of e.g., carbidopa, entacapone,
tolcapone, and/or levodopa, following the disclosed methods,
typically can be carried out over a defined time period (usually
weeks, months or years depending upon the combination selected).
Contemplated therapies are intended in part to embrace
administration of multiple therapeutic agents in a manner wherein a
dopa decarboxylase inhibitor and optionally a COMT inhibitor (e.g.
entacapone or tolcapone) is administered substantially continuously
while levodopa is administered at discrete intervals, as well as
administration of contemplated therapeutic agents, or at least two
of the therapeutic agents (e.g. levodopa and carbidopa, and
optionally entacapone or tolcapone, or levodopa and entacapone or
tolcapone) in a substantially simultaneous manner, which may be
administered in the same composition or e.g., simultaneously
administered but as different compositions. Administration can be
effected by any appropriate route including, but not limited to,
oral routes, intravenous routes, intramuscular routes, intradermal
routes, subcutaneously, transdermally, and direct absorption
through mucous membrane tissues.
[0079] In some embodiments, levodopa can be administered by the
same route or by different routes as compared to administration of
e.g. a contemplated carbidopa formulation. For example, carbidopa
may be administered subcutaneously, e.g., substantially
continuously, while levodopa may be administered orally, e.g. at
discrete intervals. In an embodiment, a disclosed liquid carbidopa
composition (e.g. having carbidopa and arginine) and a liquid
entacapone composition (e.g. having entacapone and arginine) is
administered substantially continuously, while an oral composition
that includes levodopa (and may also include one or more other
active agents such as a dopa decarboxylase inhibitor and/or a COMT
inhibitor) is administered at discrete intervals. Alternatively,
for example, both levodopa and carbidopa may be administered
subcutaneously or transdermally. Disclosed compositions may be
administered substantially continuously over 12 hours, 1 day, 1
week, or more.
[0080] The disease or disorder characterized by reduced levels of
dopamine in the brain contemplated herein are neurological or
movement disorders including restless leg syndrome, Parkinson's
disease, secondary parkinsonism, Huntington's disease, Shy-Drager
syndrome and conditions resulting from brain injury including
carbon monoxide or manganese intoxication. Methods for treating
such disorders in a patient in need thereof are provided, for
example, by administering (e.g., subcutaneously) a disclosed
composition. In one embodiment, the disease to be treated is
Parkinson's disease.
[0081] In an embodiment, substantially continuously administering
using e.g. a liquid formulation may be via a pump for subcutaneous
infusion (insulin pump) at an average rate of about 10-250
.mu.l/hour, or about 160.+-.40 .mu.l/hour continuously for 24
hours; about 200.+-.50 .mu.l/hour continuously for 16 hours (during
waking hours) and at night (e.g. for 8 hours, about 0 to 80
.mu.l/hour or via a transdermal patch. In an embodiment,
substantially continuously administering intravenously or
intraperitonealy using e.g. a liquid formulation may be at an
average rate of about 0.2-2 ml/hour, or about 1.+-.0.5 ml/hour
continuously for 24 hours; about 1.0.+-.0.5 ml/hour continuously
for 16 hours (during waking hours) and at night (e.g. for 8 hours,
about 0 to 0.5 ml/hour via a pump or transdermal patch, or
combination of delivery devices that are suitable for e.g.
subcutaneous, intravenous, intrathecal, or via the duodenum.).
[0082] The invention now being generally described, it will be more
readily understood by reference to the following examples which are
included merely for purposes of illustration of certain aspects and
embodiments of the present invention, and are not intended to limit
the invention in any way.
EXAMPLES
Example 1: Preparation of Solutions/Formulation for Subcutaneous
Administration
[0083] A. A 2% Carbidopa solution/formulation was prepared by
adding pre-heated 0.1% Na-bisulfite solution to carbidopa [ASSIA
Ltd.]. Arginine [MERCK] was added to obtain a final molar ratio of
1:1.2 CD (carbidopa):arg(argininine). The mixture was stirred at
60.degree. C. until complete dissolution was obtained. Heating was
stopped and the preparation was allowed to cool down to room
temperature pH of 8.5. Solution was filtered using a sterile 0.22
.mu.M PVDF membrane.
[0084] B. A 10% tolcapone solution/formulation was prepared as
follows: a solution containing 10% tolcapone was prepared by adding
the respective amount of H.sub.2O to tolcapone [Synfine Research],
slowly adding arginine while stirring to obtain a final molar ratio
of 1:1. The mixture is stirred until complete dissolution is
obtained. After cooling down, the pH of the solution was 7.8.
[0085] C. A solution containing 10% entacapone was prepared by
adding the respective amount of H.sub.2O to entacapone [Suven Life
Sciences], stirring at 30-35.degree. C. and slowly adding arginine
to obtain a final molar ratio of 1:1. The mixture is stirred until
complete dissolution is obtained. After cooling down, the pH of the
solution was 6.9. The pH of less concentrated solutions (6%) was
7.8. After preparation, such entacapone solution can be diluted to
a 2%, 3% or 4% by weight formulation.
[0086] Entacapone did not dissolve (at concentrations >1%) with
other amino acids such as histidine and glutamic acid or in buffers
at various pHs.
[0087] D. A 7% levodopa/2% carbidopa solution was prepared by
adding pre-heated 0.1% Na-bisulfite solution to arginine. Levodopa
was added to obtain a final molar ratio of 1:2 LD:arg. The mixture
was stirred at 75-80.degree. C. until complete dissolution was
obtained. After cooling down to 60.degree. C., carbidopa and
arginine were added to obtain a final molar ratio of 1:1.2
CD(carbidopa):arg(arginine). The mixture was stirred at 60.degree.
C. until complete dissolution was obtained. After cooling, about
12.5% more arginine was added to the solution. The pH of the
solution was about 9.2.
[0088] E. A 7% weight percent. Levodopa solution was prepared by
adding pre-heated 0.1% Na-bisulfite solution to arginine. Levodopa
was added to obtain a final molar ratio of 1:2 LD:arg. The mixture
was stirred at 75-80.degree. C. until complete dissolution was
obtained. After cooling down, the pH of the solution was about
9.4.
Example 2: Formulation Preparation Procedure
[0089] Levodopa (LD) and carbidopa (CD) formulations can be
prepared as follows. However, as shown in Table A, the method of
preparation has significant impact on the resulting composition's
physical and chemical stability.
[0090] Method #1(L-Arg solution): L-Arg and Na-Bis (Na-bisulfate)
were dissolved in water. The solution was added to the LD and CD
powders. The mixture was heated with stirring for 13 min at
75.degree. C. until fully dissolved. LD/CD solution kept at room
temperature (RT) for 10 min to cool down.
[0091] Method #2 (all powders together): All powders (LD, CD and
L-Arg) were weighed and water with Na-Bis was added. Suspension was
heated with stirring for 13 min at 75.degree. C. until fully
dissolved. LD/CD solution kept at RT for 10 min to cool down.
[0092] Method #3 (same as #2 without Na-Bis pre-heating): All
powders (LD, CD and L-Arg) were weighed together and water was
added. Suspension was heated with stirring for 13 min at 75.degree.
C. until fully dissolved. LD/CD solution kept at RT for 10 min to
cool down.
[0093] Method #4 (preparation in steps): LD and the respective
amount of L-Arg were weighed; water and Na-Bis solution were added.
The suspension was heated for 7 min at 75.degree. C. until fully
dissolved followed by 7 min at RT. CD and the respective amount of
L-Arg were weighed, and added to the LD-arg solution at 60.degree.
C. until fully dissolved. Finally, extra L-Arg was added.
[0094] Method #5 (same as #4 without Na-Bis pre-heating): LD and
the respective amount of L-Arg were weighed; water was added. The
suspension was heated for 7 min at 75.degree. C. until fully
dissolved followed by 7 min at RT. CD and the respective amount of
L-Arg were weighed, and added to the LD-arg solution at 60.degree.
C. until fully dissolved. Finally, extra L-Arg was added.
[0095] After cooling down, all formulations from all methods were
divided in to 3 vials, and water, Na-Bis solution or Na-Bis-Arg
solution was added to each vial. The physical and chemical
stability were evaluated and are presented in Table A1 and A2:
TABLE-US-00001 TABLE A1 Physical stability: First test Second test
Stability Stability 24 48 72 24 48 Method hours hours hours hours
hours 1 Water +++ NR NR ++ NR Na-Bis solution +++ ++ Na-Bis
solution +++ ++ titrated with L-Arg 2 Water + ++ NR - +/- Na-Bis
solution - + - +/- Na-Bis solution - +/- - +/- titrated with L-Arg
3 Water - - + - Very few Na-Bis solution - - + (more - particles
than at the 13,15) bottom Na-Bis solution - - + - titrated with
L-Arg 4 Water + NR NR + NR Na-Bis solution + + Na-Bis solution +/-
+ titrated with L-Arg 5 Water ++ NR NR + NR Na-Bis solution ++ +
Na-Bis solution ++ + titrated with L-Arg - No precipitate +
Precipitate
[0096] The formulations were sampled for HPLC analysis at the end
of the preparation and after 5 days of stability at RT. The
recovery after 5 days at RT was calculated compared to T=0.
TABLE-US-00002 TABLE A2 Chemical Stability First test Second test
LD CD LD CD recovery recovery recovery recovery after 5 after 5
after 5 after 5 Method days (%) days (%) days (%) days (%) 1 Water
90.6 98.0 89.5 100.4 Na-Bis solution 90.6 98.6 87.0 101.3 Na-Bis
solution 90.8 98.0 88.9 99.9 titrated with L-Arg 2 Water 98.4 98.2
99.1 100.1 Na-Bis solution 98.2 98.1 99.4 100.5 Na-Bis solution
99.0 98.5 98.9 99.5 titrated with L-Arg 3 Water 99.7 97.5 .sup.
95.5[1] 96.5 Na-Bis solution 99.2 97.7 .sup. 97.7.sup.(a) 99.1
Na-Bis solution 99.5 98.1 .sup. 94.9.sup.(a) 96.2 titrated with
L-Arg 4 Water 97.7 97.5 96.3 99.3 Na-Bis solution 96.0 95.8 94.9
97.6 Na-Bis solution 97.7 97.9 96.3 100.0 titrated with L-Arg 5
Water 97.9 96.3 98.1 100.9 Na-Bis solution 98.2 98.0 98.2 102.2
Na-Bis solution 97.4 96.7 98.3 100.6 titrated with L-Arg [1]The
recovery values were lower at the second test compared to the first
test, due to technical problem which occurred during the sampling.
.sup.(a)The recovery values were lower at the second test compared
to the first test, due to technical problem which occurred during
the sampling.
[0097] The results in Table A1 and A2 clearly show that the method
of formulation preparation has a significant impact on its physical
and chemical stability. The formulation of Method #3 shows
significantly more stability.
Example 3: Effect of Arginine on Long Term Stability of Levodopa
and Levodopa/Carbidopa Compositions
[0098] Liquid formulations with levodopa, carbidopa and arginine
were prepared using the procedure outlined in Example 2, and
comparative studies on formulations with a different concentration
of arginine and/or an amino sugar (e.g., meglumine), and/or a sugar
(e.g. dextrose), and/or a base (NaOH), or another basic amino acid
(e.g. lysine, histidine) were prepared. The results are shown in
Table B.
[0099] Table B indicate that arginine forms stable solutions with
high concentrations of levodopa and carbidopa (>2.5%) at molar
ratios <1:2.5, whereas with other basic amino acids LD does not
even dissolve under these conditions. At molar ratios of LD/CD to
arginine 1:<2, the solutions do not have long term stability,
unless meglumine or another counterion is used, and meglumine may
be used to reduce the molar ratio of arginine to LD/CD.
TABLE-US-00003 TABLE B Amino Acid (AA) Other LD/CD Molar Molar
Physical Conc. Conc. ratio Conc. ratio stability (%) Name (%)
(APL:Arg) Name (%) (APL:CI) Dissolution at RT 10/0 Lys 8.5 1:2.5 --
-- -- No NA 5/0 Lys 9.25 1:2.5 -- -- -- No NA 3.3/0.sup. Lys 6.2
1:2.5 -- -- -- No NA 3/0 Lys 5.6 1:2.5 -- -- -- Partial NA
2.5/0.sup. Lys 4.6 1:2.5 -- -- -- Yes 2 days 5/0 His 9.8 1:2.5 --
-- -- No NA 2.5/0.sup. His 4.9 1:2.5 -- -- -- No NA 1.25/0 His 2.5
1:2.5 -- -- -- Yes 14 days 9/0 Arg 8.2 1:1.sup. -- -- -- No NA
4.7/0.sup. Arg 4.0 1:1.sup. -- -- -- No NA 9.5/0.sup. Arg 15.9
1:1.9 -- -- -- Yes 2 days 4.8/1.4 Arg 11.0 1:2.0 -- -- -- Yes
.gtoreq.2 months 4.8/1.4 Arg 12.1 1:2.2 -- -- -- Yes .gtoreq.2
months 4.8/1.4 Arg 12.7 1:2.4 -- -- -- Yes .gtoreq.2 months 5.4/1.5
Arg 13.5 2.1 -- -- -- Yes .gtoreq.2 months 5.4/1.5 Arg 14.8 2.3 --
-- -- Yes .gtoreq.2 months .sup. 6/1.5 Arg 14.8 2.1 -- -- -- Yes
.gtoreq.1 month .sup. 6/1.5 Arg 16.0 2.3 -- -- -- Yes .gtoreq.2
months 7/2 Arg 17.8 2.2 -- -- -- Yes .gtoreq.1 month .sup. 7/1.5
Arg 14.1 1:1.8 Dex 5.0 -- Yes Color change .sup. 8/1.5 Arg 15.7
1:1.9 Dex 5.0 -- Yes Color change 10/1.5 Arg 19.2 1:1.9 Dex 5.0 --
Yes Color change .sup. 6/1.5 Arg 9.3 1:1.5 NaOH 4.6 1:0.5 Yes
.gtoreq.3 months 5/0 -- -- -- Meg 5.0 1:1.sup. No NA 5/0 -- -- --
Meg 5.9 1:1.2 No NA 5/0 -- -- -- Meg 10.8 1:2.2 Yes NA .sup. 8/1.5
Arg 15.7 1:1.9 Meg 3.2 1:0.4 Yes .gtoreq.4.5 months .sup. 8/1.5 Arg
12.2 1:1.5 Meg 7.9 1:1.sup. Yes .gtoreq.4.5 months 10/1.5 Arg 19.2
1:1.9 Meg 4.0 1:0.4 Yes .gtoreq.4.5 months 10/1.5 Arg 14.6 1:1.5
Meg 9.9 1:1.sup. Yes .gtoreq.4.5 months .sup. 7/1.5 Arg 14.1 1:1.9
Meg 2.8 1:0.4 Yes .gtoreq.4.5 months .sup. 7/1.5 Arg 10.7 1:1.5 Meg
6.9 1:1.sup. Yes .gtoreq.4.5 months -- Lys--Lysine; His--Histidine;
Arg--Arginine; Dex--Dextrose; Meg--Meglumine.
[0100] Liquid formulations were prepared by weighing all powders
(LD, CD and L-Arg) and the addition of water pre-heated to
73.+-.3.degree. C. Suspension was put in a water bath at
73.+-.3.degree. C. and stirred for 10 min until fully dissolved.
LD/CD solution was kept at RT for 10 min to cool down. Then,
ascorbic acid was added. Solutions were divided in to glass vials
and kept at +25.degree. C. and at -20.degree. C. for the indicated
period of time. Prior to analyses, frozen vials were placed at RT
until fully thawed. Formulations were then mixed and subjected to
stability analyses.
[0101] Tables C indicate the effect of 1-arginine on physical and
chemical long term stability at +25.degree. C. and at -20.degree.
C.
[0102] Liquid formulations were prepared by weighing all powders
(LD, CD and L-Arg) and the addition of water pre-heated to
73.+-.3.degree. C. Suspension was put in a water bath at
73.+-.3.degree. C. and stirred for 10 min until fully dissolved.
LD/CD solution was kept at RT for 10 min to cool down. Then,
ascorbic acid was added. Solutions were divided in to glass vials
and kept at +25.degree. C. and at -20.degree. C. for the indicated
period of time. Prior to analyses, frozen vials were placed at RT
until fully thawed. Formulations were then mixed and subjected to
stability analyses.
TABLE-US-00004 TABLE C1 L-Arg Physical Stability (% from T = 0) at
RT conc. stability 5 days 2 months Formulation (%) at RT LD CD LD
CD 6/1.5% LD/CD 13.5 6 days 100.0 97.5 (1% Na-Asc) 14.2 At least
100.8 96.7 14.8 7 days 99.6 96.6 16.0 99.5 96.6 4.8/1.4% LD/CD 11.0
At least 99.4 97.3 100.1 93.7 (1% Na-Asc) 11.6 2 months 98.9 97.4
100.6 96.2 12.1 99.1 97.0 100.3 94.3 12.7 99.4 97.2 99.0 92.4
TABLE-US-00005 TABLE C2 Stability (% from T = 0) 2 weeks at -20
.+-. 5.degree. C. L-Arg Immediately 24 hours conc. Physical after
thawing at RT Formulation (%) stability LD CD LD CD 6/1.5% LD/CD
13.5 At least 24 99.7 98.4 100.0 99.1 (1% Na-Asc) 14.2 hr after
99.8 98.1 101.0 99.4 at -20.degree. C. 14.8 thawing 100.0 98.9 99.9
98.9 16.0 99.9 98.8 100.3 99.3
TABLE-US-00006 TABLE C3 L-Arg Physical stability (at RT)
Formulation conc. (%) 1% Na-Asc 1% Asc 6/1.5% LD/CD 14.8 At least 3
weeks At least 3 days 15.8 16.8 5.4/1.5% LD/CD 12.3 At least 3 days
13.5 14.8
TABLE-US-00007 TABLE C4 Physical L-Arg stability Stability (% from
T = 0) at RT conc. (after 2 1 weeks 2 weeks 1 month Formulation (%)
month at RT) LD CD LD CD LD CD 5.4/1.5% LD/CD 13.5 + 101.4 100.4
101.7 98.4 98.8 103.1 (1% Asc) 14.8 + 101.4 101.4 102.0 100.1 99.0
104.2 6/1.5% LD/CD 14.8 + 101.8 101.5 101.6 99.6 99.0 104.2 (1%
Asc) 16.0 - 101.1 100.4 102.8 100.6 99.4 104.2 7/2% LD/CD 17.8 +
101.7 101.0 102.7 99.7 98.7 103.1 (1% Asc) 7/2% LD/CD - 100.6 NA
101.9 99.2 98.4 103.6 (1% Na-Asc)
TABLE-US-00008 TABLE C5 Physical Stability (% from T = 0) Stability
(% from T = 0) L-Arg Stability 2 weeks at -20 .+-. 5.degree. C. 5
weeks at -20 .+-. 5.degree. C. conc. (11 days after immediately
after thawing immediately after thawing Formulation (%) thawing) LD
CD LD CD 5.4/1.5% LD/CD 13.5 + 102.3 99.5 99.4 104.3 (1% Asc) 14.8
- 102.7 101.3 99.6 104.6 6/1.5% LD/CD 14.8 - 102.6 101.1 99.1 104.2
(1% Asc) 16.0 - 103.2 100.9 99.2 104.3 7/2% LD/CD 17.8 + 102.8
101.0 99.2 104.3 (1% Asc) 7/2% LD/CD - 102.9 101.0 99.4 104.4 (1%
Na-Asc)
TABLE-US-00009 TABLE C6 LD/CD conc. L-Arg conc. (%) Physical
Stability at 25.degree. C. 12/3% 24.4 Considerable precipitate on
Day 5 29.6 Slight precipitate on Day 5 32.1 No precipitate on Day
7
[0103] Tables C1-C6 indicate that there is a correlation between
the molar ratio of arginine to LD/CD and stability where generally
compositions having more arginine, have longer stability:
LD/CD:arginine solutions (at molar ratios of 1:.gtoreq.2.1) are
stable for at least 1 month at RT and at -20.+-.5.degree. C. The
solutions are stable even at very high solid concentrations (total
of >45%).
[0104] Formulations containing 6/1.5% and 5.4/1.5% LD/CD and
varying L-Arg concentrations were titrated with Acetic acid (100%)
or Lactic acid (85%) to investigate the effect of pH and L-arginine
concentration on the physical stability of the solutions. Table D
indicates the results.
TABLE-US-00010 TABLE D pH L-Arginine Asc/ pH Lactic after pH 4 24
(%) Na-Asc before (%) Lactic drop hours hours 6/1.5% 14.8 Na-Asc
9.53 1.1 9.25 -0.28 OK + LD/CD 9.53 1.7 9.16 -0.37 + + 9.53 2.3
9.02 -0.51 ++ + 14.8 Asc 9.41 0.85 9.24 -0.17 OK + 9.42 1.3 9.14
-0.28 + + 9.41 1.7 9.06 -0.35 + + 15.8 Na-Asc 9.52 1.1 9.33 -0.19
OK OK 9.50 1.7 9.21 -0.32 OK + 9.53 2.3 9.08 -0.45 + + 15.8 Asc
9.44 0.85 9.27 -0.17 OK OK 9.45 1.3 9.19 -0.26 OK + 9.45 1.7 9.11
-0.34 + + 16.8 Na-Asc 9.56 1.1 9.36 -0.20 OK OK 9.56 1.7 9.23 -0.33
OK OK 9.56 2.3 9.09 -0.47 OK + 16.8 Asc 9.46 0.85 9.30 -0.16 OK OK
9.46 1.3 9.20 -0.26 OK OK 9.47 1.7 9.11 -0.36 OK + L-Arginine Asc/
pH Lactic Acetic pH pH 2 3 10 (%) Na-Asc before (%) (%) after drop
days days days 5.4/1.5% 12.3 Na-Asc 9.41 0.36 -- 9.35 -0.06 OK + +
LD/CD 9.43 1.0 -- 9.18 -0.25 ++ + + 9.43 -- 0.35 9.29 -0.14 OK + +
12.3 Asc 9.28 0.36 -- 9.20 -0.08 ++ + + 9.29 1.0 -- 9.05 -0.24 ++
++ ++ 9.29 -- 0.35 9.14 -0.15 ++ ++ ++ 13.5 Na-Asc 9.50 0.36 --
9.38 -0.12 OK OK OK 9.48 1.0 -- 9.25 -0.23 + + + 9.49 -- 0.35 9.35
-0.14 OK OK OK 13.5 Asc 9.32 0.36 -- 9.25 -0.07 + + + 9.33 1.0 --
9.11 -0.22 ++ ++ ++ 9.34 -- 0.35 9.20 -0.14 + + + 14.8 Na-Asc 9.51
0.36 -- 9.43 -0.08 OK OK OK 9.51 1.0 -- 9.28 -0.23 OK OK OK 9.51 --
0.35 9.38 -0.13 OK OK OK 14.8 Asc 9.36 0.36 -- 9.29 -0.07 OK OK OK
9.37 1.0 -- 9.13 -0.24 + /- + + 9.36 -- 0.35 9.23 -0.13 OK OK OK
OK--no precipitate; +/- very few particles; + slight precipitate;
++ considerable precipitate
[0105] Table E shows the physical and chemical stability 3 weeks
post-preparation of the 6/1.5/14.8% LD/CD/Arg formulation used for
the stability tests shown in Table D.
TABLE-US-00011 TABLE E Physical Stability Asc/Na-Asc stability (%
of T = 0) Formulation (1%) (at RT) LD CD 6/1.5% LD/CD, Asc
.gtoreq.3 weeks 103.1 98.9 14.8% L-Arg Na-Asc 101.1 97.4
[0106] Table D indicate that ascorbic acid reduces the pH by
0.1-0.15 units as compared to Na-ascorbate and that other organic
acids can further reduce the pH of the formulations. But the
physical stability test results indicate that formulations are not
generally stable at pH<9.15.+-.0.5. Formulations with
Na-ascorbate appear more stable than formulations with ascorbic
acid at a given L-arginine concentration. Thus, it is suggested
that excess of acid may cause precipitation in the absence of
adequate amount of L-Arg.
Example 4: Stability of Levodopa Formulations with Carbidopa
In-Vitro and Ex-Vivo
[0107] The effect of carbidopa on levodopa formulations was
investigated. Levodopa (LD) formulations were prepared with 0, 0.5,
1, 1.5 & 2% by weight carbidopa (CD) and a constant
concentration of arginine. Physical and chemical stabilities were
evaluated, as shown in Table F:
TABLE-US-00012 TABLE F Stability (% from T = 0) Physical 3 days 15
days Formulation N.sub.2+/- stability LD CD LD CD 7% LD w/o CD +
Stable 99.2 NA 103.4 NA - Stable 98.1 NA -- NA 0.5% CD + Stable
98.6 94.7 104.1 108.1 - Stable 98.7 95.6 -- -- 1% CD + Stable 98.9
95.2 102.5 104.4 - Slight 97.9 94.0 -- -- precipitate 1.5% CD + 7
days 98.1 94.2 103.7 104.8 - 99.6 96.0 -- -- 2% CD + 4 days 98.9
94.5 102.9 103.3 - 98.3 94.8 -- --
[0108] The experimental results shown in FIG. 1A (see figures)
indicate that carbidopa prevented dark yellow color formation in
the presence of air, in a dose related manner. In the absence of
air (with N.sub.2 in the head space) 0.5% CD was sufficient to
inhibit this color formation. It is suggested that CD inhibits
oxidation of LD in vitro. The experimental results shown in Table F
indicate that carbidopa does not have a significant effect on the
chemical stability of levodopa. It also shows that the ratio
between arginine and the total active ingredients is important to
prevent precipitation, i.e., the physical stability of the
formulation depended on the relative concentration of arginine
[0109] In an additional experiment, LD formulations were prepared
with 0, 0.5, 1 & 2% CD and respective concentrations of
arginine. Physical and chemical stability were evaluated, and
results are shown in Table G:
TABLE-US-00013 TABLE G Chemical Stability at RT (% of t0) Physical
1 month after stability at RT L-Arg 3 days thawing 1 month after
Formulation (%) LD CD LD CD thawing LD 6% LD/0% CD 13.5 102.3 -- 6%
LD/0% CD 13.5 102.3 6% LD/0.5% CD 14.2 103.3 100.4 6% LD/0.5% CD
14.2 103.3 6% LD/1% CD 14.8 103.5 101.3 6% LD/1% CD 14.8 103.5 6%
LD/2% CD 16.5 103.3 101.6 6% LD/2% CD 16.5 103.3
[0110] In the presence of adequate concentrations of L-arginine,
all formulations ex-vivo were stable for at least a month at RT
following thawing, as shown in Table G.
[0111] The effect of carbidopa on the stability of levodopa
formulations is shown in FIG. 1B. A 7% LD-arginine solution, with
or without 2% CD, was continuously administered at 0.08
ml/h.times.18 h, 37.degree. C. into a 5.times.5 cm fresh,
full-thickness pig skin. The right hand side of FIG. 1B indicates
the lack of black by-products formation, suggesting that CD
inhibits oxidation of LD ex vivo and may also inhibit the formation
of o-quinones and melanin.
Example 5: Stability of Carbidopa Formulations with Levodopa
[0112] The effect of levodopa on the stability of carbidopa was
investigated. Table H indicates results.
TABLE-US-00014 TABLE H T = 0 T = 4 days at 25.degree. C. LD CD LD
CD Recovery of CD Formulation (mg/g) (mg/g) (mg/g) (mg/g) (% of t0)
6% LD/2% CD 60.3 19.4 Air 63.2 18.9 97.4 N.sub.2 62.9 19.0 97.9 2%
CD N/A 19.5 Air N/A 15.9 81.5 N.sub.2 N/A 19.0 97.4 T = 0 Retention
time (srea of impurity) Formulation 3.38 3.54 4.2 4.85 5.2 5.52
5.77 12.10 13.35 13.60 14.60 6% LD/2% CD NA NA 1.08 3.15 1.67 0.34
0.86 NA 1.48 0.95 1.63 2% CD 1.30 0.25 NA 1.79 NA NA 0.95 0.35 NA
1.45 3.83 CD vs. CD/LD 0.6 1.1 1.5 2.3 T = 4 days at 25.degree. C.
Retention Time (Area of Impurity) 3.15 3.32 4.12 4.82 5.65 11.92
12.10 12.27 12.70 13.53 14.55 6% LD/2% CD Air 12.23 1.00 2.10 3.57
1.94 0.79 0.69 0.89 1.34 1.34 16.82 N.sub.2 8.09 0.82 1.48 3.63
1.61 0.44 0.53 0.56 0.56 1.08 11.82 2% CD Air NA 1.59 NA 9.49 1.18
NA NA NA 7.54 24.04 70.22 N.sub.2 NA 1.65 NA 6.63 1.07 0.23 NA NA
0.50 3.62 25.45 CD vs. CD/LD Air 1.6 2.7 0.6 5.6 17.9 4.2 N.sub.2
2.0 1.8 0.7 0.5 0.9 3.4 2.2
[0113] Table H indicates that CD was less sensitive to oxidation
and degradation and was more stable in the presence of LD: The area
of impurities at R.T. 4.82, 5.65, 12.7, 13.53 and 14.55 were
significantly increased under aerobic conditions when LD was not
present, and the area of impurities at R.T. at 4.82 and 13.53 were
increased even in the absence of oxygen. It appears that LD may
protect CD from degradation.
Example 6: Toxicity and Pharmocokinetics of Levodopa Formulations
with Carbidopa
[0114] The effect of carbidopa on levodopa local toxicity was
investigated in pigs: Solutions containing 6% LD and 0, 0.5 or 1%
CD with the respective amount of arginine (13.5, 14.2 or 14.8%,
respectively) were continuously administered SC to pigs at 0.16
ml/h.times.24 h. Each formulation was administered to 2 pigs. Skin
samples were collected 8.+-.1 days thereafter. FIG. 2 shows that
the presence of 1% carbidopa reduces the severity and extent of
levodopa dependent toxicity, in-vivo.
[0115] The effect of carbidopa on the pharmacokinetics of levodopa
and carbidopa were investigated. Solutions containing 6% LD and 0,
0.5, 1 or 2% CD and the respective amount of arginine (13.5, 14.2,
14.8 or 16.5% respectively) were continuously administered SC to
pigs at 0.16 ml/h.times.24 h. FIGS. 3A-3C show that CD has a
significant effect on the pharmacokinetics of LD. This effect was
dose dependent and linear between .+-.0.3 and .+-.1.2% CD, as in
example 6.
Example 7: Effect of Tyrosinase Inhibitors
[0116] The effect of tyrosinase inhibitors, substrate analogues,
Cu.sup.++ chelators and O-quinone scavengers on oxidation on
levodopa (LD) following continuous subcutaneous administration of
levodopa/carbidopa formulations at 37.degree. C. in to the
subcutaneous tissue of pig skin, was studied ex-vivo.
[0117] Full thickness pig skin samples (including the subcutaneous
tissue) were placed on top of a 100 ml glass bottle filled to the
top with warm PBS, in an incubator set at 37.degree. C. The skin
was directly in contact with the PBS, and the skin and bottle were
then covered with parafilm to protect the inner side of the skin
from air as much as possible. The formulations were administered
subcutaneously using a 22G butterfly and an infusion pump set at
0.08 ml/h.
[0118] A list of various potential levodopa stabilizers and
oxidation/degradation/metabolism inhibitors are listed in Table I.
The effect of representatives from each group and combinations
there off were tested ex vivo and is shown in FIGS. 4A-4D.
[0119] The number of each skin sample corresponds to the numbered
formulation that was administered as per Table J below:
TABLE-US-00015 TABLE I Cu.sup.++ chelators Clinical use Chemical
Min. Max. pH name MW Solubility dose dose compatibility EDTA
calcium 374 Soluble 500 mg/m2 0.17% disodium EDTA 372 Soluble NA
0.2% disodium DMSA (succimer) 182 Soluble 10 mg/kg .times. 3 NI pKa
3, 3.9 DPA (D- 149 Soluble 125 mg .times. 1 NA pKa 8 & 10.5
penicillamine) Trientine ? Soluble 250 mg .times. 2 NA (HCl)
Dimercaprol 124 0.275% 2.5 mg .times. 4 NA pKa 10.4 Clioquinol 305
<0.1% 125 mg .times. 2 NA Sodium NA 0.2% thiosulfate TETA NA NA
TEPA NA NA Curcumin NA NA Neocuproine NA NA Tannin NA NA Cuprizone
NA NA Substrate analogues Chemical Name MW Solubility pH
compatibility Sodium benzoate Pka 4.2 L-phenylalanine Tyrosinase
inhibitors Min required Generic name MW Solubility concentration
Captopril 217 Soluble 0.04 mg/ml Methimazole 114 Soluble Quercetin
302 Arbutin Aloesin N-acetylglucoseamine Retinoic Acid a-tocopheryl
ferulate MAP(Mg ascorbyl phosph) O-quinone scavengers Clinical use
pH Generic name MW Solubility Dose compatibility L-Cysteine 121
Soluble 0.1% pKa 8, 10 Ascorbic acid 176 Soluble 1.0% pKa 4, 11
Gluthatione (GSH) 0.5% pKa 8, 10 NI--Not indicated; NA--Not
applicable
TABLE-US-00016 TABLE J # Composition 1 7% LD, 0.02% Na-bisulfite 2
7% LD, 2% CD 3 7% LD, 1% Na-ascorbate 4 7% LD, 0.1% Cysteine 5 7%
LD, 0.2% Na.sub.2 EDTA 6 7% LD, 0.2% EDTA-Ca--Na.sub.2 7 7% LD,
0.2% methimazole 8 7% LD, 0.2% D-penicillamine 9 7% LD, 0.2%
Captopril 10 7% LD, 0.2% EDTA-Ca--Na2, 0.2% captopril, 1%
Na-ascorbate 11 5.4% LD, 0.02% Na-bisulfite 12 5.4% LD, 1.5% CD 13
5.4% LD, 1.5% CD, 1% Na-ascorbate 14 5.4% LD, 1.5% CD, 1%
Na-ascorbate, 0.2% EDTA-Ca--Na.sub.2 15 5.4% LD, 1.5% CD, 1%
Na-ascorbate, 0.2% captopril 16 5.4% LD, 1.5% CD, 1% Na-ascorbate,
0.2% methimazole 17 5.4% LD, 1.5% CD, 0.2% captopril 18 5.4% LD,
1.5% CD, 0.2% captopril, 0.2% EDTA-Ca--Na.sub.2 19 5.4% LD, 1.5%
CD, 0.2% methimazole 20 5.4% LD, 1.5% CD, 0.2% methimazole, 0.2%
EDTA-Ca--Na.sub.2 21 7% LD, 0.02% Na-bisulfite 22 7% LD, 2% CD 23
7% LD, 2% CD, 0.2% Ascorbate 24 7% LD, 2% CD, 1% Ascorbate 25 7%
LD, 2% CD, 0.2% ascorbate, 0.2% captopril 26 7% LD, 2% CD, 1%
Ascorbate, 0.2% Captopril 27 7% LD, 2% CD, 0.2% Ascorbate, 0.2%
Na2-EDTA 28 5.4% LD, 1.5% CD 29 5.4% LD, 1.5% CD, 0.2% Ascorbate 30
5.4% LD, 1.5% CD, 1% Ascorbate 31 7% LD, 0.02% Na-bisulfite 32 7%
LD, 2% CD 33 7% LD, 2% CD, 0.5% ascorbate 34 7% LD, 2% CD, 0.5%
ascorbate, 0.2% captopril 35 7% LD, 2% CD, 1% ascorbate 36 7% LD,
2% CD, 1% ascorbate, 0.2% captopril 37 7% LD, 2% CD, 1% ascorbate,
0.2% captopril, 0.2% Na.sub.2EDTA 38 7% LD, 2% CD, 1% ascorbate, 0
2% captopril, 0.2% Ca--Na.sub.2EDTA
[0120] FIGS. 4A-4C indicate that ascorbate, at a concentration of
.gtoreq.0.5%, was sufficient to inhibit color change of levodopa
and carbidopa in pig skin samples. Other compounds tested were less
effective.
Example 8 Effect of Tyrosinase Inhibitors on Subcutaneous Toxicity
In-Vivo
[0121] The effect of tyrosinase inhibitors on subcutaneous toxicity
following 24 h-continuous subcutaneous administration of LD/CD in
Pigs was studied for 6 to 11 days after administration. Results are
shown in Table K:
TABLE-US-00017 TABLE K Histological Score Formulation Inflammation
Necrosis LD/CD (5.4/1.5%) + 1% ascorbate 2.2 2.0 LD/CD (5.4/1.5%) +
1% ascorbate, 2.6 2.5 0.2% Ca--Na.sub.2-EDTA LD/CD (5.4/1.5%) + 1%
ascorbate, 2.5 2.6 0.2% Ca--Na.sub.2-EDTA, 0.2% captopril Score Key
0 No lesions 1 Minimal inflammation/necrosis 2 Mild
inflammation/necrosis 3 Moderate inflammation/necrosis 4 Severe
inflammation/necrosis
[0122] Under the experimental conditions employed, captopril and/or
Ca-Na.sub.2EDTA did not have a supplementary effect, as compared to
1% ascorbate alone, in the protection from local toxicity.
Example 9: Plasma Levels of Levodopa Following Subcutaneous
Administration
[0123] In this experiment, the purpose was to determine the plasma
levels of LD (levodopa) following continuous subcutaneous
administration of carbidopa, levodopa or entacapone and
combinations thereof with oral LD/CD in pigs.
[0124] Landrace.times.Large White female pigs weighing about 22 kg
were treated, starting on Day 1 at 15:00 as per table 1, with oral
LD/CD 100/25 and with the respective test formulations, containing
carbidopa, levodopa or entacapone and combinations thereof,
formulated with arginine, as described above, and administered
continuously subcutaneously via a dermal patch (Omnipod.RTM.) at a
rate of 0.08 ml/h.
[0125] Table L indicates the treatment protocol of each group. The
formulations were prepared as in Example 1 and 2.
TABLE-US-00018 TABLE L Treatment None CD CD + E E LD + CD LD group
n 3 3 3 2 2 1 SC route of No SC 2% carbidopa 2% carbidopa + 10%
entacapone 7% levodopa + 7% levodopa administration treatment 10%
entacapone 2% carbidopa Oral treatment 100/25
levodopa/carbidopa
[0126] Blood samples were collected following the 3.sup.rd oral
dose at pre-determined time points and plasma levels of levodopa,
carbidopa and 3-OMD were analyzed by HPLC-ECD.
[0127] FIGS. 5A and 5B indicate the mean levodopa plasma
concentrations following oral administration of Sinemet (oral
100/25 LD/CD) with continuous SC administration of FIG. 5A)
Entacapone (200 mg/24 h).+-.CD (40 mg/24 h) or FIG. 5B) Levodopa
(140 mg/24 h).+-.CD (40 mg/24 h) in pigs (all subcutaneous
formulations included arginine, as above).
[0128] Results show that there is a synergistic effect between
entacapone (200 mg/24 h) and CD (40 mg/24 h) on the plasma PK of
levodopa (ng/ml) when co-administered continuously subcutaneously,
as compared to the calculated LD plasma PK obtained after adding
the plasma concentrations of LD following the continuous SC
administration of CD and entacapone each alone (FIG. 1A and Table
2, C vs. B+D). Results also show that there is an additive effect
between levodopa (140 mg/24 h) and CD (40 mg/24 h) on the plasma PK
of levodopa (ng/ml) when co-administered continuously
subcutaneously, as compared to the calculated LD plasma PK obtained
after adding the plasma concentrations of LD following the
continuous SC administration of CD and LD each alone (FIG. 1B and
Table 2, E vs. D+F). Moreover, the results suggest that continuous
SC administration of LD and CD may be sufficient to maintain
constant, continuous levodopa plasma concentrations even in the
absence of oral LD/CD administration (FIG. 5B dotted line and Table
M `E minus A`). Table M presents trough concentrations of plasma
levodopa 61/2 and 8 h Post-Oral LD/CD administration.
TABLE-US-00019 TABLE M SC treatment (LD + CD)-None LD + CD E + CD
Times, None E E + CD CD LD + CD calculated LD calculated calculated
point (h) A B C D E E - A F D + F B + D 6.5 51 179 1695 998 1226
1174 322 1320 1177 8 0 0 1474 868 1227 1227 413 1281 868
E--entacapone; CD--carbidopa: LD--levodopa; NA--not Available
[0129] FIG. 6 shows tissue biopsies from the application site of
the levodopa-carbidopa arginine combination formulation and the
levodopa/arginine formulation. No visible tissue irritation or
damage was apparent in the levodopa-carbidopa arginine formulation.
The site administered with levodopa-arginine formulation appears to
have some blackening of tissue. Without being limited by any
theory, it is thought that having carbidopa and arginine together
with levodopa (arginine) formulation protects the local tissue from
local damage of levodopa by preventing oxidation of levodopa into
irritant by products, and that carbidopa is a potent
anti-oxidant.
EQUIVALENTS
[0130] While specific embodiments of the subject invention have
been discussed, the above specification is illustrative and not
restrictive. Many variations of the invention will become apparent
to those skilled in the art upon review of this specification. The
full scope of the invention should be determined by reference to
the claims, along with their full scope of equivalents, and the
specification, along with such variations.
[0131] Unless otherwise indicated, all numbers expressing
quantities of ingredients, reaction conditions, and so forth used
in the specification and claims are to be understood as being
modified in all instances by the term "about." Accordingly, unless
indicated to the contrary, the numerical parameters set forth in
this specification and attached claims are approximations that may
vary depending upon the desired properties sought to be obtained by
the present invention.
INCORPORATION BY REFERENCE
[0132] The entire contents of all patents, published patent
applications, websites, and other references cited herein are
hereby expressly incorporated herein in their entireties by
reference.
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