U.S. patent application number 11/631602 was filed with the patent office on 2008-10-16 for infusion and injection solution of levodopa.
This patent application is currently assigned to Dizlin Medical Design AB. Invention is credited to Nil Dizdar Segrell.
Application Number | 20080255235 11/631602 |
Document ID | / |
Family ID | 32867227 |
Filed Date | 2008-10-16 |
United States Patent
Application |
20080255235 |
Kind Code |
A1 |
Segrell; Nil Dizdar |
October 16, 2008 |
Infusion and Injection Solution of Levodopa
Abstract
An infusion or injection solution of Levodopa containing at
least 10 mg/mL of Levodopa, or at least 5 mg/mL of Levodopa
together with at least 0.5 mg/mL of at least one inhibitor of a
Levodopa-metabolising enzyme is disclosed. The solution further
contains a buffer, a physiologically acceptable sugar, such as
glucose, a physiologically acceptable acid, such as hydrochloric
acid, and optionally a stabilizer, and has a pH of lower than or
equal to 6. There are also described a disposable syringe
containing an infusion or injection solution of Levodopa,
optionally together with a Levodopa-metabolising enzyme, and an
infusion pump cassette containing an infusion or injection solution
of Levodopa optionally together with a Levodopa-metabolising
enzyme.
Inventors: |
Segrell; Nil Dizdar;
(Linkoping, SE) |
Correspondence
Address: |
BACON & THOMAS, PLLC
625 SLATERS LANE, FOURTH FLOOR
ALEXANDRIA
VA
22314-1176
US
|
Assignee: |
Dizlin Medical Design AB
Vastervik
SE
|
Family ID: |
32867227 |
Appl. No.: |
11/631602 |
Filed: |
July 8, 2005 |
PCT Filed: |
July 8, 2005 |
PCT NO: |
PCT/SE05/01135 |
371 Date: |
January 2, 2008 |
Current U.S.
Class: |
514/567 |
Current CPC
Class: |
A61K 47/26 20130101;
A61K 47/02 20130101; A61P 25/00 20180101; A61P 25/16 20180101; A61K
47/12 20130101; A61K 31/198 20130101; A61K 9/0019 20130101; A61P
25/14 20180101 |
Class at
Publication: |
514/567 |
International
Class: |
A61K 31/195 20060101
A61K031/195 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 12, 2004 |
SE |
0401842-0 |
Claims
1-16. (canceled)
17. An infusion or injection solution of Levodopa containing a1) at
least 10 mg/mL of Levodopa, or a2) at least 5 mg/mL of Levodopa
together with at least 0.5 mg/mL of at least one inhibitor of a
Levodopa-metabolising enzyme, b) a buffer, c) a physiologically
acceptable sugar, and d) a physiologically acceptable acid, the pH
of the solution being lower than or equal to 6.
18. The infusion or injection solution according to claim 17,
wherein the physiologically acceptable sugar is glucose.
19. The infusion or injection solution according to claim 17,
wherein the pH of the solution is in the range of 3 to 6.
20. The infusion or injection solution according to claim 17,
wherein the solution further comprises a stabilizer.
21. The infusion or injection solution according to claim 17,
wherein the volume of the solution is adapted for a single or
continuous intravenous and/or subcutaneous and/or intrathekal
administration.
22. The infusion or injection solution according to claim 17,
wherein the inhibitor of a Levodopa-metabolising enzyme is selected
from the group consisting of dopa decarboxylase (DDC) inhibitors,
catechol-o-methyltransferase (COMT) inhibitors, and monoamino
oxidase (MAO-B) inhibitors.
23. The infusion or injection solution according to claim 22,
wherein the DDC-inhibitor is
L-2-hydrazino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
(carbidopa).
24. The infusion or injection solution according to claim 22,
wherein the DDC-inhibitor is
2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propionohydrazide
(benserazide).
25. The infusion or injection solution according to claim 22,
wherein the COMT inhibitor is
(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propane
amide (entacapone).
26. The infusion or injection solution according to claim 22,
wherein the MAO-B inhibitor is
(R)--N,.alpha.-dimethyl-N-(2-propynyl)phenethyl amine
(selegiline).
27. The infusion or injection solution according to claim 17,
wherein the physiologically acceptable acid is hydrochloric
acid.
28. The infusion or injection solution according to claim 17,
wherein the physiologically acceptable acid is acetic acid.
29. A disposable syringe containing a therapeutically effective
amount of an infusion or injection solution of Levodopa dissolved
in a physiologically acceptable acid, containing a buffer, a
physiologically acceptable sugar and having a pH of lower than or
equal to 6.
30. The disposable syringe according to claim 29, further
comprising at least one inhibitor of a Levodopa-metabolising enzyme
in an amount that together with an amount of Levodopa gives a
therapeutically effective amount of the solution.
31. An infusion pump cassette containing a therapeutically
effective amount of an infusion or injection solution of Levodopa
dissolved in a physiologically acceptable acid, containing a
buffer, a physiologically acceptable sugar and having a pH of lower
than or equal to 6.
32. The infusion pump cassette according to claim 31, further
comprising at least one inhibitor of a Levodopa-metabolising enzyme
in an amount that together with an amount of Levodopa gives a
therapeutically effective amount of the solution.
Description
[0001] The present invention relates to an infusion or injection
solution of Levodopa which optionally comprises at least one
inhibitor of a Levodopa-metabolising enzyme. The invention also
relates to a disposable syringe as well as an infusion pump
cassette containing a therapeutically effective amount of an
infusion or injection solution of Levodopa, optionally further
containing at least one inhibitor of a Levodopa-metabolising
enzyme.
BACKGROUND
[0002] Parkinson's Disease (PD) is very common and is contracted by
approximately 15 out of 10,000 people in the Western world. The age
of debut is usually between 55 and 60 years. The disease is
characterised by rigidity and tremors caused by a massive loss of
nigrostratial neurones and subsequently a lack of dopamine
[3,4-dihydroxyphenylethylamine] (1). The symptoms of Parkinson's
Disease appear upon a loss of approximately 80% of dopamine
neurones.
[0003] Tyrosine hydroxylase is the enzyme which transforms tyrosine
into Levodopa [Levodopa=3-(3,4-dihydroxiphenyl)-L-alanine] (2),
which then is metabolised into dopamine by dopadecarboxylase (DDC)
both in the brain and in the peripheral circulation. Dopamine is
metabolised into 3,4-dihydroxyphenylacetic acid (DOPAC),
3-methoxytyramine and Homovanilic acid (HVA) by the two enzymes
monoamino oxidase (MAO) and catechol-o-methyltransferase (COMT)
(3).
[0004] Levodopa is still the most important treatment for
Parkinson's disease and intermittent oral Levodopa treatment
achieves good relief of the symptoms at early stages of the
disease. In spite of the massive loss of neurones there still is an
adequate storage capacity, which makes possible an even release of
dopamine into the synaptic spatium during interval dosage. Levodopa
given orally is, however, metabolised to 90% in the first passage
before reaching the brain. Bioavailability can be increased by
simultaneous administration of DDC-inhibitors, such as carbidopa
[L-2-hydrazino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid] or
benserazide
[2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propionohydrazide],
which both compete with Levodopa for the metabolising DDC-- and
thus allow more of the administered Levodopa to reach the brain
before it is metabolised into dopamine.
[0005] Levodopa is a neutral amino acid, which must pass the
blood-brain barrier before it reaches the central nervous system.
This transport is energy consuming. The half-life of Levodopa is
short, 30 to 60 minutes. Under the influence of the enzyme
dopadecarboxylase (DDC), the greater part of Levodopa is
metabolised into dopamine. This enzyme is found in a number of
organs but above all in muscles, red blood cells and in the skin
where it is an important component in the formation of melanin
pigment (5). Upon the intake of Levodopa alone, more than 90% is
metabolised before it reaches the brain (6).
[0006] In order to increase the bioavailability of Levodopa, and
reduce its secondary effects on the system, Levodopa is therefore
given in combination with a decarboxylase inhibitor (benserazide or
carbidopa) in the same oral dosage form. In both the intestine and
the blood-brain barrier Levodopa has to compete for the enzyme
transport with other amino acids from, for example, protein-rich
meals (7). The absorption of Levodopa takes place primarily in the
proximal third part of the small intestine (8). Variations in the
emptying of the ventricle can, therefore, result in large
variations in the serum concentration in the same patient despite
intake of the same amount of Levodopa. The inhibition of
dopadecarboxylase does not, however, increase the half-life for
Levodopa very greatly, which points to the metabolising of Levodopa
being shunted to the smaller COMT pathway. This leads to the
formation of the metabolite 3-0-methyldopa (OMD) which because of
its long half-life (9) is accumulated in plasma and reaches
manifestly higher levels as compared to Levodopa (10). The
metabolite OMD is also a neutral amino acid and can therefore
compete with Levodopa for the passage over the two barriers.
[0007] Pharmacokinetic and pharmacodynamic problems concerning
Levodopa treatment arise after approximately five years of
treatment in the form of fluctuations--from dyskinesia (involuntary
movements) to akinesia (totally inhibited movements). When clinical
fluctuations begin a distinct parallel can be seen between the
decreasing plasma concentrations and the declining clinical
response to the Levodopa dose administered. Yet, at an advanced
stage in the disease rapid "on-off" fluctuations can be seen
without any visible relation to the plasma concentration of
Levodopa. This can be explained by there being a certain delay of
about 90 minutes in the concentration levels between plasma and the
central nervous system (CNS), where the CNS concentration is
directly correlated to clinical status.
[0008] After suffering from the disease for 5-10 years, the storage
capacity of the patient has, however, decreased somewhat due to the
continuous loss of neurones, and "wearing off" problems occur. At
this stage the storage capacity for dopamine is not adequate until
the next dose is due, and Levodopa must therefore be administered
at shorter intervals.
[0009] At a later stage of the disease, fluctuations occur too with
both dyskinesia and bradykinesia (partially inhibited movements) in
spite of increasingly frequent doses of dopamine, and sometimes
seemingly with no relation to the intake of medicine. This is
assumed to be caused by hypersensitivity of the postsynaptic
dopamine receptors, resulting in a narrowing of the therapeutic
window. This entails a much smaller difference between effective
dose and overdose.
[0010] Levodopa belongs to the group of neutral amino acids and is
absorbed by oral administration only in the proximal third of the
small intestine via competitive active transport. It has been shown
that approximately 10% of the total dose enters the blood
circulation. By avoiding protein-rich meals during the daytime, and
in close proximity to the individual times of dosage, it is
possible to facilitate Levodopa absorption from the intestine and
to a certain degree relieve clinical fluctuations. There is not
always a direct correlation between the serum concentration of
Levodopa and clinical fluctuations. This is probably due to the
fact that the passage over the blood-brain barrier also takes place
through active transport and even there competes with other neutral
amino acids. An overview of the analysis methods for Levodopa has
been published (11)
[0011] Experimentally it has been possible to show in animals that
hypersensitivity of the postsynaptic dopamine receptors takes place
upon interval stimulation, as well as it being possible to achieve
hyposensitivity with continuous stimulation of these receptors with
Levodopa. Such treatment of human patients should bring about a
widening of the therapeutic window and a decrease in the clinical
fluctuations (12), a treatment strategy that has not been possible,
due to the insolubility of Levodopa in aqueous solutions at
approximately neutral pH.
[0012] Oral dosage forms of Levodopa for treatment of Parkinson's
disease have been used since the 1960ies and the progress of the
disease and the treatment thereof follows the description above. In
order to improve the treatment of the patients new treatment
approaches have been developed such as dopamine agonists and enzyme
inhibitors. However, these have not been able to solve all the
problems encountered with the traditional Levodopa treatment.
[0013] A new Levodopa formulation comprising carbidopa in the form
of a viscous gel, Duodopa.RTM., has recently become available from
NeoPharma AB, Uppsala, Sweden, for treatment of Parkinson's
disease. This treatment is given directly to the duodenum with a
nasoduodenal probe or with a percutaneous probe. With this system a
continuous administration of Levodopa is possible but the
limitations of the gastric transport barrier remains.
[0014] There are at present no commercially available
pharmaceutical preparations for intravenous, subcutaneous or
intrathekal administration due to the poor solubility of Levodopa
at neutral pH. Large quantities of Levodopa-containing liquid would
be required to give a therapeutic effect at a near neutral pH, and
further, Levodopa auto-oxidises rapidly. However, the Swedish
patent 512 655 describes the preparation of a Levodopa infusion
solution containing 5 mg/mL Levodopa as the only active ingredient.
The Levodopa is dissolved in HCl and diluted with glucose, but at
higher concentrations than 5 mg/mL the Levodopa precipitates. For a
daily dosage of e.g. 600 mg Levodopa, a patient would need 120 mL
of said infusion solution per day. It would be desirable to have an
infusion solution or injection solution that is therapeutically
effective in lower daily volumes.
DESCRIPTION OF THE INVENTION
[0015] The present invention provides an infusion or injection
solution that is therapeutically effective in lower daily volumes.
This is achieved by first dissolving the Levodopa in a
physiologically acceptable acid and then adding an organic buffer
and small portions of a physiologically acceptable sugar, such as
glucose, at a time, ensuring that no precipitation of Levodopa
occurs. The higher the concentration of Levodopa in the solution,
the more slowly the addition of a sugar solution should be.
[0016] As mentioned in the background, the bioavailability of
Levodopa can be increased by simultaneous administration of an
inhibitor of a Levodopa-metabolising enzyme. Therefore, the
concentration of Levodopa in the infusion or injection solution of
the invention can be as low as 5 mg/mL of Levodopa as long as the
solution also comprises at least 0.5 mg/mL of at least one
inhibitor of a Levodopa-metabolising enzyme.
[0017] Thus, the present invention is directed to an infusion or
injection solution of Levodopa containing
a1) at least 10 mg/mL of Levodopa, or a2) at least 5 mg/mL of
Levodopa together with at least 0.5 mg/mL of at least one inhibitor
of a Levodopa-metabolising enzyme, b) a buffer, c) a
physiologically acceptable sugar, and d) a physiologically
acceptable acid, the pH of the solution being lower than or equal
to 6.
[0018] Thus, when a solution containing 10 mg/mL of Levodopa
according to the invention is administered to a patient requiring
600 mg Levodopa per day, the total volume can be cut into half
compared to the prior art 5 mg/mL of Levodopa solution, resulting
in a daily volume of only 60 mL. This reduction in volume will
enable the use of smaller infusion pump cassettes--or alternatively
larger doses in the cassettes. The same applies for other
administration means, such as syringes.
[0019] Examples of the buffer in the solution of the invention are
2-amino-2-hydroxymethyl-1,3-propane diol (Trometamol) and
tris(hydroxymethyl)aminomethane (Tris).
[0020] In an embodiment of the invention the solution further
comprises a stabilizer, such as sodium pyrosulphite,
[0021] In a preferred embodiment of the invention, the volume of
the solution is adapted for a single or continuous intravenous
and/or subcutaneous and/or intrathekal administration. Currently,
in addition to traditional needles, infusion pumps are used for
administration of solutions to patients, and these are also
possible to use with the infusion or injection solution of Levodopa
of the invention.
[0022] In current studies the PCA pump CADD system from Smiths
Medical Sverige AB, Sollentuna, Sweden, is used for administering
the Levodopa infusion solution according to the invention. This
system can be used both for infusion with the infusion solution in
cassettes (maximum 100 mL) and with the infusion solution in a
bottle connected with an adapter to the pump system. For
subcutaneous infusion the Disetronic pump system from Disetronic
Medical Systems AB, Sweden, can be used. The advantage with this
system is the small size of the pump and the possibilities using it
during different activities without interference. Maximum infusion
solution is 20 mL. For intrathekal infusion the Medtronic pump
system from Medtronic AB, Jarfalla, Sweden, can be used. The pump
is placed subcutaneously and refilled regularly by medical
staff.
[0023] In another embodiment of the invention the physiologically
acceptable sugar is selected from dextran, e.g. dextran 70, 60 or
40, mannitol and glucose, and glucose is presently preferred.
[0024] In yet another embodiment, the pH of the infusion or
injection solution of the invention is in the range of 3 to 6.
[0025] In a further embodiment of the invention the amount of
Levodopa in a2) is selected from the range 5 mg/mL to 25 mg/mL and
the amount of the inhibitor of a Levodopa-metabolising enzyme is
selected from the range 0.5 mg/mL to 6.25 mg/mL.
[0026] In still another embodiment of the invention, the inhibitor
of a Levodopa-metabolising enzyme in the infusion or injection
solution is selected from the group consisting of dopa
decarboxylase (DDC) inhibitors, catechol-o-methyltransferase (COMT)
inhibitors, and enzymes monoamino oxidase (MAO-B) inhibitors.
[0027] In a preferred embodiment the DDC-inhibitor is
L-2-hydrazino-3-(3,4-dihydroxyphenyl)-2-methylpropanoic acid
(carbidopa) or
2-amino-3-hydroxy-N'-(2,3,4-trihydroxybenzyl)propionohydrazide
(benserazide).
[0028] In another preferred embodiment the COMT inhibitor is
(E)-2-cyano-3-(3,4-dihydroxy-5-nitrophenyl)-N,N-diethyl-2-propane
amide (entacapone).
[0029] In yet another preferred embodiment the MAO-B inhibitor is
(R)--N,.alpha.-dimethyl-N-(2-propynyl)phenethyl amine
(selegiline).
[0030] The physiologically acceptable acid comprised by a preferred
infusion or injection solution of Levodopa according to the
invention is hydrochloric acid or acetic acid.
[0031] Acid solutions are often used for intravenous infusion. pH
below 3 is known to give vessel irritations and trombophlebitis.
Glucose solutions can however have a low pH (3.5) without any side
effects. Weak acids as hydrochloric acid and acetic acid are
tolerated for intravenous infusion in pH above 3. Levodopa is
easily soluble at low pH. However it is crystallized at higher pH
although the crystallization doesn't appear instantly.
[0032] Another aspect of the invention is directed to a disposable
syringe containing a therapeutically effective amount of an
infusion or injection solution of Levodopa dissolved in a
physiologically acceptable acid, containing a buffer and a
physiologically acceptable sugar and having a pH of lower than or
equal to 6. The therapeutically effective amount is decided
empirically based on the condition of the patient, or a standard
dose is recommended by the manufacturer, and it is preferably made
up of a solution having a concentration of at least 10 mg/mL of
Levodopa, and the physiologically acceptable sugar is preferably
selected from dextran, e.g. dextran 70, 60 or 40, mannitol or
glucose, preferably glucose, and the solution having a pH of lower
than or equal to 6, is preferably a solution having a pH in the
range of 3 to 6.
[0033] In an alternative embodiment of this aspect of the invention
the infusion or injection solution in the disposable syringe
further comprises at least one inhibitor of a Levodopa-metabolising
enzyme in an amount that together with an amount of Levodopa gives
a therapeutically effective amount of the solution. In this case,
the therapeutically effective amount is preferably made up of a
solution having at least 5 mg/mL of Levodopa together with at least
0.5 mg/mL of at least one inhibitor of a Levodopa-metabolising
enzyme, such as Levodopa in the range of 5 mg/mL to 25 mg/mL and
the amount of inhibitor(s) of a Levodopa-metabolising enzyme in the
range 0.5 mg/mL to 6.25 mg/mL.
[0034] A syringe of the invention will typically hold 1 to 10 mL of
an infusion or injection solution according to the invention.
Still another aspect of the invention is directed to an infusion
pump cassette containing a therapeutically effective amount of an
infusion or injection solution of Levodopa, dissolved in a
physiologically acceptable acid, containing a buffer, a
physiologically acceptable sugar, and having a pH of lower than or
equal to 6. The therapeutically effective amount is decided
empirically based on the condition of the patient, or a standard
dose is recommended by the manufacturer, and it is preferably made
up of a solution having a concentration of at least 10 mg/mL of
Levodopa, and the physiologically acceptable sugar is preferably
selected from dextran, e.g. dextran 70, 60 or 40, mannitol or
glucose, preferably glucose, and the solution having a pH of lower
than or equal to 6, is preferably a solution having a pH in the
range of 3 to 6.
[0035] In an alternative embodiment of this aspect of the invention
the infusion pump cassette further comprises at least one inhibitor
of a Levodopa-metabolising enzyme in an amount that together with
an amount of Levodopa gives a therapeutically effective amount of
the solution. In this case, the therapeutically effective amount is
preferably made up of a solution having at least 5 mg/mL of
Levodopa together with at least 0.5 mg/mL of at least one inhibitor
of a Levodopa-metabolising enzyme, such as Levodopa in the range of
5 mg/mL to 25 mg/mL and the amount of inhibitor(s) of a
Levodopa-metabolising enzyme in the range 0.5 mg/mL to 6.25
mg/mL.
[0036] The size and shape of the cassette will vary depending on
the actual infusion pump system that will be used for the
administration of the infusion or injection solution of the
invention.
[0037] The invention will now be illustrated by description of
examples of the preparation of the infusion or injection solution
and use thereof, but it should be understood that the disclosures
are not intended to limit the scope of the invention.
Highly Concentrated Levodopa Solutions Optionally Containing
Carbidopa
[0038] Addex.RTM.-Tham that is used in the preparation of the
infusion solutions, is a concentrated infusion solution sold by
Fresenius Kabi AB, Uppsala Sweden. The active ingredient is
Trometamol, 2-amino-2-hydroximethylpropan-1,3-diol
(Tris-Hydroximethyl-AminoMetan), also named TRIS or THAM, and it is
an organic buffer. THAM functions as a proton acceptor, i.e. a weak
base.
TABLE-US-00001 Stock solution 1 of Levodopa 100 mg/mL Levodopa 10 g
HCl 1 mole/L 31 g Sodium pyrosulfite 1 g Water for injection add to
100 mL
[0039] The Levodopa is dissolved in the HCl solution in a 100 mL
flask. The sodium pyrosulfite is weighed into a 10 mL injection
vial and 2 mL of sterile water is added for dissolution. Water in
an amount of 50 mL is added to the flask containing Levodopa,
followed by addition of the sodium pyrosulfite solution. The
mixture is poured into a 100 mL measuring flask and water for
injection is added up to the 100 mL mark. The resulting solution is
sterile filtered into a 100 mL injection flask. A Sterivex
GV-filter 0.22 .mu.m was used.
TABLE-US-00002 Levodopa 10 mg/mL - solution Levodopa, 40 mL of the
100 mg/mL stock solution 1 Addex-Tham 5.5-6 mL Glucose 50 mg/mL add
to 200 mL
[0040] Addex-Tham was added to the Levodopa solution. Glucose, 50
mg/mL, was added slowly in portions of approximately 10 mL with
stirring up to a total volume of 200 mL. The pH of the solution was
3.5-4 and the shelf-life was >3 days.
TABLE-US-00003 Stock solution 2 of Levodopa 50 mg/mL + Carbidopa
Levodopa 5 g Carbidopa 0.5 g HCl 1 mole/L 36 g Sodium pyrosulfite
0.5 g Water for injection add to 100 mL
[0041] The Levodopa is dissolved in the HCl solution in a 100 mL
flask. The sodium pyrosulfite is weighed into a 10 mL injection
vial and 2 mL of sterile water is added for dissolution. Water in
an amount of 50 mL is added to the flask containing Levodopa,
followed by addition of the sodium pyrosulfite solution. The
mixture is poured into a 100 mL measuring flask and water for
injection is added up to the 100 mL mark. The resulting solution is
sterile filtered into a 100 mL injection flask. A Sterivex
GV-filter 0.22 .mu.m was used.
TABLE-US-00004 Levodopa 5 mg/mL - solution containing Carbidopa 0.5
mg/mL Levodopa, 20 mL of the 50 mg/mL stock solution 2 Addex-Tham 3
mL Glucose 50 mg/mL add to 200 mL
[0042] Addex-Tham was added to the Levodopa solution. Glucose, 50
mg/mL, was added up to a total volume of 200 mL.
The pH of the solution was 3.5-4 and the shelf-life was >3
days.
TABLE-US-00005 Levodopa 10 mg/mL - solution containing Carbidopa 1
mg/mL Levodopa 40 mL of the 50 mg/mL stock solution 2 Addex-Tham
5.5-6 mL Glucose 50 mg/mL add to 200 mL
[0043] Addex-Tham was added to the Levodopa stock solution 2.
Glucose, 50 mg/mL, was added slowly in portions of approximately 10
mL with stirring up to a total volume of 200 mL. The pH of the
solution was 3.5-4 and the shelf-life was >3 days.
Experiments with Levodopa Solutions of the Invention
Solubility
[0044] Levodopa can be dissolved in HCl up to 100 mg/mL without any
precipitation. To raise the pH with glucose in a way according to
the invention and still get a stabile solution, it is possible to
obtain 10 mg/mL Levodopa, and with 2 mg/mL Carbidopa addition 20
mg/mL Levodopa. A precipitate appears at 30 mg/mL Levodopa in the
presence of 3 mg/mL Carbidopa.
Preparation of Levodopa Solution
[0045] The steps of producing the solutions of the invention are
made rather quickly up to the addition of glucose. Initially,
approximately half of the volume of the glucose solution is added,
followed by a drop by drop addition of the rest of the volume at
approximately 10 min intervals and constant stirring until the pH
is acceptable (e.g. pH 3-6).
Stability
[0046] A solution of 5 mg/mL Levodopa and 0.5 mg Carbidopa has been
heated to 60.degree. C. and left to stand for 36 hours, and then at
room temperature for 1 week, without any sign of discoloration or
precipitation.
Mannitol Compared to Glucose
[0047] Mannitol can be used instead of glucose in the Levodopa
solutions of the invention, but it is much more unstable and a
precipitate is formed in a few hours.
Different Applications of the Infusion Solution of the
Invention
[0048] Previously, individual studies have shown that fluctuations
with alternating dyskinesia and bradykinesia decline and can even
disappear during on-going treatment by oral and intravenous
levodopa administration (12). As yet, no studies exist on the
long-term effects of continuous intravenous treatment with Levodopa
with prior art solutions. Nor has the subsequent, traditional oral
treatment need for Levodopa been investigated.
[0049] In preliminary studies we have now been able to show that
both bradykinesia and above all dyskinesia decline during
intravenous treatment with Levodopa and this effect remains even
after five months. The patients have also been able to manage on
reduced oral Levodopa treatment with lower doses and
monotherapy.
Treatment Options
[0050] Intravenous Levodopa infusion or injection continuously or
intermittently during 12 hours for 10 days is an effective
treatment of clinical fluctuations. The effect is due to a widening
of the therapeutic interval for Levodopa. The treatment has also a
long-lasting effect of at least 5 months.
[0051] Infusion to subcutaneous tissue could avoid the appearance
of clinical fluctuations both because of lower daily Levodopa dose
and because of the continuous administration.
[0052] The method is very suitable for diagnostic intravenous
Levodopa test. No other diagnostic method equal in merit is
available.
A New Method for Levodopa Treatment
[0053] The Levodopa solutions according to the invention can be
given as an infusion or injection into different tissues or to the
blood. Several advantages can be seen: [0054] Reduced volume
compared to previously described Levodopa-solutions, due to a
higher concentration of 10 mg/mL or from 5 mg/mL when the solution
also contains at least one inhibitor of a Levodopa-metabolising
enzyme in an amount of 0.5 mg/mL or more. [0055] Prolonged
durability of the effect with at least 5 months. [0056] Addition of
inhibitor of a Levodopa-metabolising enzyme is at a concentration
of 0.5 mg/mL or more, such as dopadecarbolyxyase inhibitor, into
the Levodopa solution which enables simultaneous administration of
the two active ingredients to even an unconscious patient. [0057]
No interference from the gastric transport barrier. [0058] Quick
and simple regulation of the Levodopa concentrations by direct
infusion or injection to blood or tissues. [0059] Reduced
post-treatment daily oral Levodopa dose, with a subsequent decrease
of the risk of side effects. [0060] Dynamic physiologic release of
the signal substance dopamine by infusion or injection to tissues,
which has similarities to the "normal" situation.
[0061] These advantages separate the use of the Levodopa solutions
of the invention from prior art oral Levodopa preparations.
[0062] Another advantage is that the use of the Levodopa solutions
of the invention doesn't need any surgical intervention since it
can be given as an infusion through a standard needle
(Venflon.RTM.), which is used for all types of intravenous
infusions.
[0063] Infusion or injection to the subcutaneous tissue, of the
abdomen, is given trough a needle of a syringe, which can be placed
by the patient. The same infusion or injection method that is used
for treatment with the dopamine agonist Apomorfin and for treatment
with Insulin can be used with the infusion or injection solution of
the invention.
[0064] The ease of self-administration of the Levodopa solutions of
the invention by the patient from a syringe that can be carried by
the patient as a disposable "emergency syringe" in case the patient
senses that a condition with bradykinesia or akinesia is on its
way, will help some patients to a more mobile life. In this case,
the infusion or injection solution will possibly not need to
contain the inhibitor of a Levodopa-metabolising enzyme. Therefore,
the invention comprises a disposable syringe containing a
therapeutically effective amount of an infusion or injection
solution of Levodopa solved in a physiologically acceptable acid,
containing a buffer, glucose and having a pH in the range of 3 to 6
and optionally further containing an inhibitor of a
Levodopa-metabolising enzyme.
[0065] The Levodopa solution of the invention is significantly
improved by the addition of at least one inhibitor of a
Levodopa-metabolising enzyme, e.g. dopadecarbolyxyase inhibitor,
into the solution. This simplifies the treatment and oral treatment
with dopadecarbolyxyase inhibitor becomes unnecessary. The
increased concentration of Levodopa decreases the volume necessary
for infusion or injection of the daily Levodopa dose enabling the
use of smaller infusion pump and a subsequent increased mobility
for the patient. The treatment can be given both in ward and as
policlinic treatment.
[0066] Thus, the Levodopa solutions of the invention can be
delivered in ready-to-use cassettes adapted for the infusion pump
used by the patient.
Test of a Patient's Therapeutic Response to Levodopa Treatment.
[0067] Parkinson's disease (PD) is diagnosed by clinical symptoms
in combination with therapeutic response to treatment with
Levodopa. Until now, only oral treatment has been provided to the
patients. This means that the therapeutic response of the patient
has been seen after a treatment period of 2-3 months. The
therapeutic response is often discrete, and a certain positive
effect is hard to evaluate, especially when the difference from day
to day is very small.
[0068] The Levodopa solution of the invention, with or without the
inhibitor of a Levodopa-metabolising enzyme, enables intravenous
administration of Levodopa and makes it possible to register a
positive response within one to two days!
[0069] The following test procedure may be used:
a. A predetermined dose of Levodopa is administered to the patient
intravenously. b. The dose is successively increased e.g. starting
from 6 mL per hour and increasing by 1 mL every 30 minutes of a
solution containing 5 mg/mL of Levodopa--or half the amounts of a
solution containing 10 mg/mL Levodopa. c. A positive response is
seen as an effect on clinical symptoms. d. A test for determining
the plasma concentration of Levodopa is taken (see e.g. Ref. 11,
13, 14 or 15) and this value can be used for establishing the
therapeutic threshold value. e. The infusion velocity is increased
further until side effects are noticed. f. A new plasma
concentration value is taken, and the interval between therapeutic
threshold value and side effect value is called therapeutic
interval.
[0070] The magnitude of the therapeutic interval can be used for
diagnostic purposes, and for evaluating any previously given
Levodopa therapy.
[0071] Thus, intravenous Levodopa test is suitable for
1) de novo patients with suspected PD, 2) for evaluating dose
regimen in already diagnosed patients, 3) for diagnostic test in
patients where the PD diagnosis is disputable, 4) for test of
patients evaluated for Deep Brain Stimulation (DBS)-operations.
Preliminary Results
Continuous Infusion of Levodopa
[0072] Continuous infusion of Levodopa has been given to PD
patients during 12 hours a day for 10 days. The daily dosage of
Levodopa was 608 mg and the infusion rate was 51 mg/h. Fifty % of
the patients received traditional oral administration of Carbidopa
and 50% received Benserazide.
[0073] A preliminary compilation of results from seventeen patients
has shown a pronounced decrease in clinical fluctuations of the
patients with alternating dyskineasia and bradykinesia. This has
given the patients a clearly improved quality of life with
increased selfsufficiency for several months after the treatment
period. The preliminary results can be illustrated by the following
case:
[0074] A 65 year old woman who had had Parkinson's disease for 20
years with very grave dyskinesia, which disabled her totally for
five hours a day, was admitted. Between the dyskinetic periods she
was also troubled by severe bradykinesia for a total of seven hours
per day. The patient was, during both these conditions, totally
dependent on help with hygiene, dressing and feeding. During the
greater part of the day she was in a wheel chair apart from one
hour in the morning when she could move about with the help of a
Zimmerframe. During the infusion treatment the dyskinesia
disappeared almost completely and was seen only on very rare
occasions when attempts to increase the rate of infusion were made.
Some rigidity remained during the entire period of infusion but was
not completely disabling. The patient partially needed help with
hygiene and dressing but ate by herself and walked with the
Zimmerframe. At follow-up six months later the patient could walk
without any means of assistance indoors, but used the wheel chair
outdoors for reasons of self-confidence. She managed dressing and
hygiene herself and could even manage lighter household chores. The
patient had, at the check-up, some remaining rigidity but accepted
this as it was not disabling. She had not suffered from dyskinesia
since the infusion.
[0075] The other patients showed, as did the patient described
above, a clear improvement in the symptoms of Parkinson's disease
during and after the treatment with continuous intravenous
Levodopa. Individual variations did occur and this pilot study is
not comprehensive enough to securely assess the length of the
effect of treatment. The preliminary results did, however, indicate
a distinctly improved clinical picture during approximately six
months. A greater number of patients must, however, be treated
before reliable conclusions can be drawn. The results from the
analysis of Levodopa in plasma showed a widening of the therapeutic
interval but even here there was not a uniform distribution in the
material. The study showed that treatment with intravenous infusion
of Levodopa lowered the required oral dosages during the subsequent
course of treatment. The calculated mean values of the test group
of seventeen patients gave a pre-treatment dosage of 1003 mg/day
and a post-treatment dosage of 773 mg/day. The combination of oral
Levodopa in standard and in sustained release preparation had even
been tried out by several patients before the infusion treatment,
but without effect. The infusion also eliminated the rapid shifts
from severe dyskinesia to total akinesia. The long-term effect was
stable at follow-up 6-10 months after the concluded infusion. Last,
but not least, the treatment brings about a greatly improved
quality of life.
Intravenous Levodopa Treatment in Intensive Care Units and in
Surgery
[0076] Patients with PD undergoing surgical operation or patients
with critical illnesses treated in intensive care units are often
not suitable for oral medication. Intravenous treatment with
Levodopa makes it possible to ascertain these patients a normal
motor function and more effective and faster mobilisation. Patients
with PD are sometimes considered not to be suitable for surgery,
because of postoperative rehabilitation difficulties. Peroperative
intravenous Levodopa treatment increases the therapeutic
possibilities in these cases.
Subcutaneous Infusion
[0077] Tests have been made with subcutaneous infusion. They showed
a fast distribution of Levodopa to the blood with measurable
concentrations and a positive clinical effect for the patient.
[0078] One patient has been treated subcutaneously, with continuous
infusion of Levodopa, for 3 consecutive days. This resulted in a
good clinical effect and measurable blood concentrations of
Levodopa in bloodsamples taken once every hour.
[0079] The patient was further treated intravenously another day,
with continuous Levodopa infusion.
[0080] The patient responded in a dose dependant manner on the
subcutaneous infusions, but some fluctuations of the Levodopa blood
concentrations occurred during the day of the intravenous
infusions.
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