U.S. patent application number 12/664503 was filed with the patent office on 2011-01-27 for baclofen solution for low-volume therapeutic delivery.
Invention is credited to Jay M. Meythaler, Stephen M. Tuel.
Application Number | 20110021469 12/664503 |
Document ID | / |
Family ID | 40156904 |
Filed Date | 2011-01-27 |
United States Patent
Application |
20110021469 |
Kind Code |
A1 |
Meythaler; Jay M. ; et
al. |
January 27, 2011 |
BACLOFEN SOLUTION FOR LOW-VOLUME THERAPEUTIC DELIVERY
Abstract
A high concentration baclofen solution is provided suitable for
therapeutic use in a medical setting. A high concentration solution
of baclofen in multivalent physiological ion solution such as
artificial cerebrospinal fluid is provided with concentrations of
baclofen of 10 mg/ml. Artificial cerebrospinal fluid is
particularly advantageous as a baclofen solvent. A medical package
is also provided for baclofen delivery to patients suffering from
spasticity.
Inventors: |
Meythaler; Jay M.; (Grosse
Pointe Farms, MI) ; Tuel; Stephen M.; (Silver Spring,
MD) |
Correspondence
Address: |
GIFFORD, KRASS, SPRINKLE,ANDERSON & CITKOWSKI, P.C
PO BOX 7021
TROY
MI
48007-7021
US
|
Family ID: |
40156904 |
Appl. No.: |
12/664503 |
Filed: |
June 13, 2008 |
PCT Filed: |
June 13, 2008 |
PCT NO: |
PCT/US08/66831 |
371 Date: |
October 6, 2010 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60943729 |
Jun 13, 2007 |
|
|
|
Current U.S.
Class: |
514/165 ;
514/282; 514/401; 514/406; 514/567 |
Current CPC
Class: |
A61K 31/192 20130101;
A61K 45/06 20130101; A61K 47/02 20130101; A61P 25/00 20180101; A61K
9/0019 20130101; A61K 31/195 20130101 |
Class at
Publication: |
514/165 ;
514/567; 514/282; 514/401; 514/406 |
International
Class: |
A61K 31/197 20060101
A61K031/197; A61P 25/00 20060101 A61P025/00; A61K 31/485 20060101
A61K031/485; A61K 31/4168 20060101 A61K031/4168; A61K 31/415
20060101 A61K031/415; A61K 31/60 20060101 A61K031/60 |
Claims
1. A solution comprising baclofen in a multivalent physiological
ion solution having a concentration of baclofen at or greater than
2 mg/ml.
2. The solution of claim 1 wherein said multivalent physiological
ion solution is artificial cerebrospinal fluid.
3. The solution of claim 1 wherein the concentration of baclofen is
greater than 2.0 mg/ml.
4. The solution of claim 1 where in the concentration of baclofen
is greater than 2.0 mg/ml and equal to or less than 10 mg/ml.
5. The use of the solution of claim 1 for delivery to a
patient.
6. The use of the solution of claim 5 wherein said delivery is
selected from the group comprising: intrathecal, intraventrical,
oral, intravenous, intra-arterial, intraperitoneal, epidural,
intramuscular, or subcutaneous delivery.
7. The use of the solution of claim 1 to medically treat a disease
or injury.
8. The use of claim 7 where in said disease or injury is selected
from the group comprising: spasticity, brain injury, cerebral
palsy, spinal cord injury, cervical injury, multiple sclerosis,
thoracic injuries, spinal pathology, or combinations thereof.
9. A medical package containing the solution of claim 1 along with
instructions for the use thereof to treat spasticity.
10. The medical package of claim 9 wherein said medical package
contains a single dose of baclofen.
11. A solution of baclofen comprising baclofen in a solution
consisting essentially of 130-160 mM NaCl, 2.7-3.9 mM KCl, 1-10 mM
CaCl.sub.2.2H.sub.2O, 0.5-10 mM MgCl.sub.2.6H.sub.2O and a
remainder water, having a concentration of baclofen of at or
between 2 mg/ml and 10 mg/ml inclusive.
12. The solution of claim 11 further comprising 0.5-1.0 mM
Na.sub.2HPO.sub.4 and 0.1-0.5 mM NaH.sub.2PO.sub.4.
13. The solution of claim 11 comprising 148 mM NaCl; 3 mM KCl; 1.4
mM CaCl.sub.2.2H.sub.2O; 0.8 mM MgCl.sub.2.6H.sub.2O; 0.8 mM
Na.sub.2HPO.sub.4.7H.sub.2O; 0.2 mM NaH.sub.2PO.sub.4.H.sub.2O.
14. The solution of claim 11 wherein the pH is at or between 5 and
8.
15. The solution of claim 11 further comprising 15-35 mM
HCO.sub.3.
16. The solution of claim 11 further comprising one or more pain
regulating agents selected from the group comprising morphine,
clondine, hydromorphine, hydrocodone, merperidine, celeroxib,
tramadol, oxycodone, acetometaphen, ketaprofen, ibuprofen, naproxen
sodium, aspirin, and combinations thereof.
17. The solution of claim 11 for intrathecal delivery to a patient
by manual or automatic injection apparatus.
18. The solution of claim 11 for delivery to a patient by a route
selected from the group comprising intraventrical, oral,
intravenous, intra-arterial, intraperitoneal, epidural,
intramuscular, subcutaneous, and combinations thereof.
19. The use of the solution of claim 11 to medically treat a
disease or injury selected from the group comprising spasticity,
brain injury, cerebral palsy, spinal cord injury, cervical injury,
multiple sclerosis, thoracic injuries, spinal pathology, and
combinations thereof.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority from U.S. Provisional
Application Ser. No. 60/943,729, filed on Jun. 13, 2007, the entire
contents of which are incorporated herein by reference as if
explicitly stated herein.
FIELD OF THE INVENTION
[0002] This invention relates to the field of high concentration
baclofen solutions in cerebrospinal fluid compatible solution
suitable for clinical and research intrathecal administration and
in particular to an artificial cerebrospinal fluid solution and
medical package suitable for clinical delivery to patients and use
in medical devices designed to deliver solution based baclofen to
patients.
BACKGROUND OF THE INVENTION
[0003] Baclofen is a muscle relaxant and anti-spastic. Baclofen is
useful for the alleviation of signs and symptoms of spasticity
resulting from multiple sclerosis, particularly for the relief of
flexor spasms and concomitant pain, clonus, and muscular rigidity.
Baclofen is an analog of the putative inhibitory neurotransmitter
gamma-aminobutyric acid (GABA). In studies with animals, baclofen
has been shown to have general CNS depressant properties as
indicated by the production of sedation with tolerance, somnolence,
ataxia, and respiratory and cardiovascular depression. Baclofen is
rapidly and extensively absorbed and eliminated. Absorption may be
dose dependent, being reduced with increasing doses. Baclofen is
excreted primarily by the kidney in unchanged form and there is
relatively large intersubject variation in absorption and/or
elimination.
[0004] The precise mechanism of action of baclofen as a muscle
relaxant and anti-spasticity agent is not fully understood.
Baclofen inhibits both monosynaptic and polysynaptic reflexes at
the spinal level, possibly by decreasing excitatory
neurotransmitter release from primary afferent terminals, although
actions at supraspinal sites may also occur and contribute to its
clinical effect. Baclofen is a structural analog of the inhibitory
neurotransmitter GABA, and may exert its effects by stimulation of
the GABA.sub.B receptor subtype. Bowery N G, et al., Nature, 1980;
283:92-94; Bowery N G, et al., Neuroscience, 1987; 20:365-383;
Bowery, N G, et al., Pharmacology Reviews, 2002; 54:247-264;
Meythaler J M. Use of intrathecally delivered medications for
spasticity and dystonia in acquired brain injury. Yaksh, editor.
Spinal Drug Delivery. Elsevier, N.Y. 1999, pp. 513-554;
LIORESAL.RTM. INTRATHECAL (baclofen injection) product insert.
[0005] Baclofen is a white to off-white, odorless or practically
odorless crystalline powder, with a molecular weight of 213.66
g/mol. It is slightly soluble in water, very slightly soluble in
methanol, and insoluble in chloroform. LIORESAL.RTM. INTRATHECAL
(baclofen injection) product insert.
[0006] Baclofen is currently the most effective treatment for
severe spasticity and spastic hypertonia. This debilitating
complication illustratively results from spinal cord injuries,
multiple sclerosis, stroke, traumatic brain injuries, cerebral
palsy and neurodegenerative diseases. Avellino A M, et al.,
Neuromodulation, 2000; 3:75-81. Spasticity is a debilitating
complication that commonly leads to functional impairment, pain,
and decreased personal independence. Id.
[0007] Oral baclofen therapy is approved. However, the oral therapy
is commonly insufficient to reduce spasticity, and many patients
are unresponsive. The high circulating concentrations of oral
baclofen required for clinical efficacy produce numerous side
effects including drowsiness, dizziness, weakness, ataxia, and
confusion.
[0008] Administration of baclofen to patients with spinal or distal
spasmodic conditions has proven to be a therapeutic challenge. Oral
administration of baclofen is limited in that the maximum
concentration of neural fluid baclofen is commonly insufficient to
alleviate the spastic result of underlying etiology. Commonly,
patients are unresponsive to oral baclofen administration or suffer
intolerable side effects such as drowsiness, dizziness, weakness,
ataxia, and confusion when efficacious levels of baclofen are
present. Avellino, A M and Loeser, J D, Neuromodulation, 2000;
3:75-81.
[0009] In response to the non-optimal response to oral baclofen,
programmable pump systems were developed that are implantable and
provide a continuous infusion of baclofen directly to the
cerebrospinal fluid. This method of delivery produces a more potent
anti-spastic effect with fewer and less severe side effects. The
pump is implanted subcutaneously whereby baclofen is transferred
though a catheter to the lumbar region where it is passed through a
Tuhoy needle directly into the cerebrospinal fluid. Albrigt, A L,
et al., Neurosurgery, 2005; 56:93-97.
[0010] Intrathecal delivery of baclofen is more efficacious than
oral delivery. However, it is not without complications. The most
common complications include pump failure, infection, or migration
of the catheter. Stempien, L, and Tsai, T, Am J Phys Med Rehabil,
2000; 79:536-41. However, cerebrospinal fluid (CSF) leaks are
common with intrathecal delivery, particularly in children with
cerebral palsy where an incidence rate of 6-15% is observed.
Similar complications are also observed in adults at a rate of
about 1%. Albrigt, A L, et al., Neurosurgery, 2005; 56:93-97. A
possible explanation for CSF leakage is increased fluid pressure
from the additional infusion volume from the pump or from occult
hydrocephalus.
[0011] Baclofen is delivered intrathecally in saline that is loaded
into the infusion pump by injection into a reservoir. The presence
of the saline itself leads to toxicity and other complications.
Injection of baclofen/saline solutions suffer neurotoxic
complications resulting from their differing pH, osmotic pressure,
membrane-active ion concentration, and CO.sub.2. Oka, K, et al.,
Neurosurgery, 1996; 38:733-736; Griffith H B, Endoneurosurgery:
Endoscopic intracranial surgery, in Symon L (ed): Advances and
Technical Standards in Neurosurgery. Wien, Springer-Verlag, 1986;
4:2-24; Griffith, H B, and Jamjoom A B, Br J Neurosurg, 1990;
4:95-100.
[0012] The use of directed intrathecal or intraventricular
administration of baclofen either by bolus injection or by
continuous or non-continuous infusion regulated by refillable,
implantable pump systems has drastically improved the clinical
feasibility of baclofen administration. However, baclofen has poor
solubility in aqueous solutions necessitating high volumes of
infused baclofen solution to achieve efficacious doses. Further,
the 2 mg/mL maximum saline concentration has been inadequate to
control the spasticity, hypertonia and symptoms of some patients.
An additional difficulty is that mixing a 2 mg/mL baclofen
injection with other drugs such as morphine or hydromorphone in
"cocktails" to aid in control of pain can dilute the baclofen
content to unacceptably low levels.
[0013] Baclofen is supplied as a solid powder form or tablet. Most
commonly baclofen is provided in a solution of baclofen, sodium
chloride, and water. These solutions generally do not require
preservatives or other stabilizers as dissolved baclofen has been
calculated to degrade less than 10% over a 10-year period when
maintained at near neutral pH and room temperature. Ahuja,
Analytical Profiles of Drug Substances, 1985; Vol. 14, New York:
Academic Press, pp. 527-548.
[0014] The practical solubility of baclofen in aqueous solutions
has been extensively investigated. The upper limit of aqueous
solubility has been estimated to be 4.3 mg/ml. (Ahuja, 1985.) This
was only achieved following long term dissolution of powder
baclofen requiring weeks or months and merely represents an
equilibrium suspension not suitable for intrathecal delivery.
Increased solubility has been achieved in aqueous saline solution
to as high as 12 mg/ml following extreme heating to as much as
100.degree. C. and intense agitation such as by sonication, or high
speed stirring. U.S. Patent Application Publication 2006/0009523.
The drawbacks of this method are that creating baclofen solutions
is time consuming and requires instrumentation not commonly found
in a clinical setting. Another method that has shown some success
is by initial dissolution in acid solution with pH levels below
3.87. Just prior to administration a base is added to bring the pH
to pharmaceutically acceptable levels. This back titration method
produces baclofen concentrations of nearly 10 mg/ml. U.S. Patent
Application Publication 2006/0009523. However, strong acids or
bases are required for the initial baclofen solvation that persist
as a component of the clinically delivered baclofen solution.
Unfortunately, saline solutions suffer neurotoxic complications
resulting from their differing pH, osmotic pressure,
membrane-active ion concentration, and CO.sub.2 making them
unsuitable for intrathecal delivery directly into the CSF. Oka, K,
et al., Neurosurgery, 1996; 38:733-736; Griffith H B:
Endoneurosurgery: Endoscopic intracranial surgery, in Symon L (ed):
Advances and Technical Standards in Neurosurgery. Wien,
Springer-Verlag, 1986; 4:2-24; Griffith, H B, and Jamjoom A B, Br J
Neurosurg, 1990; 4:95-100.
[0015] An alternative to saline or other aqueous solution for
baclofen administration is artificial cerebrospinal fluid (aCSF).
Differing forms of aCSF were previously used for in vivo
pharmacological studies of baclofen administration. Jackson, G L,
et al., Endocrinology, 2000; 141: 3940-3945; Goda, R. et al., J
Chromatogr B Analyt Technol Biomed Life Sci, 2004; 801:257-64.
However, the baclofen concentrations achieved in these and other
studies were less than 0.21 mg/ml.
[0016] Thus, there exists a need for an improved solution in both
concentration, stability, and compatibility with the CSF of
baclofen for intrathecal delivery for the treatment of
spasticity.
SUMMARY OF THE INVENTION
[0017] A solution of baclofen is provided wherein baclofen is
solubilized in a multivalent physiological ion solution such as
artificial cerebrospinal fluid at a concentration at or above 2
mg/ml and to 10 mg/ml. The pH of the inventive baclofen solution is
between 5 and 8. The high concentration baclofen solution is
suitable for delivery to a patient by a route including
intrathecal, intraventrical, oral, intravenous, intra-arterial,
intraperitoneal, epidural, intramuscular, or subcutaneous routes of
delivery.
[0018] The high concentration baclofen solution is suitable for
treating a disease or injury. Common diseases or injuries that are
treatable by the inventive solution are spasticity, brain injury,
cerebral palsy, spinal cord injury, cervical injury, multiple
sclerosis, thoracic injuries, and spinal pathology.
[0019] Further provided is a medical package including a single or
multidose ampule or ampules of inventive high concentration
baclofen solution along with instructions for the treatment of an
injury or disease such as spasticity.
[0020] The inventive high concentration baclofen solution is
provided in a solvent containing 130-160 mM NaCl, 2.7-3.9 mM KCl,
1-10 mM CaCl.sub.2.2H.sub.2O, 0.5-10 mM MgCl.sub.2.6H.sub.2O and a
remainder water. Preferred concentrations of ingredients are 148 mM
NaCl; 3 mM KCl; 1.4 mM CaCl.sub.2.2H.sub.2O; 0.8 mM
MgCl.sub.2.6H.sub.2O; 0.8 mM Na.sub.2HPO.sub.4.7H.sub.2O; 0.2 mM
NaH.sub.2PO.sub.4.H.sub.2O. The solution optionally also contains
0.5-1.0 mM Na.sub.2HPO.sub.4 and 0.1-0.5 mM NaH.sub.2PO.sub.4
and/or 15-35 mM HCO.sub.3. The pH of the inventive solutions is at
or between 5 and 8.
[0021] The inventive high concentration baclofen solution is
suitable to be used in combination with other therapeutics such as
one or more pain regulating agents that illustratively include
morphine, clondine, hydromorphine, hydrocodone, merperidine,
celeroxib, tramadol, oxycodone, acetometaphen, ketaprofen,
ibuprofen, naproxen sodium, aspirin, and combinations thereof.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0022] The present invention has utility as a therapeutic or
research baclofen solution for control of spastic or other
complications of underlying disease or injury. The present
invention allows for high concentrations of baclofen to be
administered to patients so as to increase the likelihood of
clinical benefit and allowing for simultaneous administration of
other clinical compounds such as pain modulators. It will also
allow for improved compatibility within the CSF.
[0023] A process is herein provided for increasing the solubility
of baclofen without resort to the procedure of U.S. Patent
Application Publication 2006/0009533 and in a solution more
biologically similar to the physiological environment of
cerebrospinal fluid. Moreover, the inventive procedure achieves
high baclofen concentrations in the without dependence on strong
acids or strong bases for initial solvation. As it was known in the
art that baclofen is modestly soluble in water or saline to a
concentration below 2 mg/mL, and studies indicated that low
solubility had been achieved in forms of artificial cerebrospinal
fluid, solid baclofen was dissolved in multivalent physiologic ion
solutions (MPI), and preferably aCSF at increasing final
concentrations. Surprisingly, MPI solution did not behave similar
to other aqueous solvent solutions when acting as a solvent for
baclofen. Baclofen rapidly dissolves in MPI solution at 0.1 to 2
mg/ml final concentration. More surprisingly, the solubility of
baclofen in MPI solution extended beyond the expected level of 2
mg/ml, and solubility of 6 mg/ml was rapidly achieved without the
need for sonication or excessive agitation as was required to
achieve the prior art saline solutions.
[0024] As used herein, the term multivalent physiological ion
solution (MPI) means any aqueous or non-aqueous liquid solution
containing at least one divalent cation of magnesium or calcium,
and at least one anion of carbonate or phosphate of a pH between 6
and 8.5. It is appreciated that other physiological ions such as
sodium, potassium, onium and chloride are optionally provided.
Preferably, the MPI solution is within 30% of isotonicity relative
to cerebrospinal fluid. MPI solution also optionally includes an
additive, illustratively, glucose, oncotic agents, plasma
extenders, and oxygen carrying components. Optionally, the
inventive MPI baclofen solution is saturated with 95% oxygen and 5%
carbon dioxide.
[0025] As used herein the term artificial cerebrospinal fluid
(aCSF) means any multivalent physiological ion solution designed to
mimic physiological cerebrospinal fluid. aCSF is illustratively a
MPI solution. aCSF illustratively contains 130-160 mM NaCl; 2.7-3.9
mM KCl; 1-10 mM CaCl.sub.2.2H.sub.2O; 0.5-10 mM
MgCl.sub.2.6H.sub.2O; 0.5-5 mM Na.sub.2HPO.sub.4.7H.sub.2O; 0.1-2
mM NaH.sub.2PO.sub.4.H.sub.2O. Preferably, aCSF is comprised of 148
mM NaCl; 3 mM KCl; 1.4 mM CaCl.sub.2.2H.sub.2O; 0.8 mM
MgCl.sub.2.6H.sub.2O; 0.8 mM Na.sub.2HPO.sub.4.7H.sub.2O; 0.2 mM
NaH.sub.2PO.sub.4.H.sub.2O. Additional or alternative components of
aCSF are illustratively 20-25 mM sodium carbonate, 0.5-1.5 mM
glucose, 200-450 mg/ml oncotic agent, or 5-20% oxygen carrying
component. The pH of aCSF is optionally at or between 3 and 10.
[0026] As used herein the term delivery means any administration of
baclofen to a mammal, other animal, or as used in in vitro
research.
[0027] As used herein the term patient means any animal.
Illustratively, the term patient means a mammal. Preferably, a
mammal illustratively includes humans, mice, rats, guinea pigs,
rabbits, dogs, cats, swine, bovine, monkey, baboon,
chimpanzees.
[0028] As used herein the term disease or injury means any
physiologically abnormal state. Illustrative examples of a disease
or injury are spasticity, brain injury, cerebral palsy, spinal cord
injury, cervical injury, multiple sclerosis, thoracic injuries, and
spinal pathology, or combinations thereof.
[0029] As used herein the term dose means any amount of active
therapeutic ingredient, such as baclofen or a pain regulating agent
delivered to a mammal, other animal, or as used in in vitro
research.
[0030] As used herein the term pain regulating agent is any agent
that serves to decrease, increase, or otherwise modulate pain.
Non-limiting examples include morphine, clondine, hydromorphine,
hydrocodone, merperidine, celeroxib, tramadol, oxycodone,
acetometaphen, ketaprofen, ibuprofen, naproxen sodium, and aspirin.
It is appreciated in the art that other chemical compounds are
similarly operable to modulate pain.
[0031] A MPI solution of the present invention includes at least
one divalent cation of magnesium or calcium, and at least one anion
of carbonate or phosphate of a pH between 6 and 8.5. Other
physiological ions such as sodium, potassium, onium and chloride
are optionally provided. Preferably, the MPI solution is within 30%
of isotonicity relative to cerebrospinal fluid. An MPI solution
also optionally includes an additive, illustratively, glucose,
oncotic agents, plasma extenders, and oxygen carrying components.
The identity of such additives is further detailed below.
Optionally, the inventive MPI baclofen solution is saturated with
95% oxygen and 5% carbon dioxide to mimic inventive physiologic gas
concentration. Most preferably, an inventive MPI solution is based
on artificial cerebrospinal fluid.
[0032] Artificial cerebrospinal fluid is composed generally of
physiological ions in a carbonate or phosphate buffered solution.
This solution illustratively contains 130-160 mM NaCl; 2.7-3.9 mM
KCl; 1-10 mM CaCl.sub.2.2H.sub.2O; 0.5-10 mM MgCl.sub.2.6H.sub.2O;
0.5-5 mM Na.sub.2HPO.sub.4.7H.sub.2O; 0.1-2 mM
NaH.sub.2PO.sub.4.H.sub.2O. Preferably, aCSF is comprised of 148 mM
NaCl; 3 mM KCl; 1.4 mM CaCl.sub.2.2H.sub.2O; 0.8 mM
MgCl.sub.2.6H.sub.2O; 0.8 mM Na.sub.2HPO.sub.4.7H.sub.2O; 0.2 mM
NaH.sub.2PO.sub.4.H.sub.2O. Additional or alternative components of
aCSF are illustratively 20-25 mM sodium carbonate, 0.5-1.5 mM
glucose, 200-450 mg/ml oncotic agent, or 5-20% oxygen carrying
component. U.S. Pat. No. 6,500,809. Oncotic agents are
illustratively proteins naturally found in plasma (e.g. the
albumin, globulin, and fibrinogen fractions), mixtures of such
proteins derived from human blood plasma (commonly called plasma
protein fraction), plasma extenders such as the dextrans (glucose
polymers of preferably 40,000 to about 80,000 average molecular
weight) and starch 2-hydroxyethyl ether (sold as Hespan by DuPont),
dextrins (cyclodextrin), carboxymethyl cellulose, polyethylene
glycol, glycogen, and pluronic acid. Oxygen carrying components
suitable in the instant invention include perfluorocarbon-based
products, cell-free hemoglobin, and liposome encapsulated
hemoglobin among others. Winslow, R M, Annual Review of Medicine,
1999; 50:337-353. Each of the above reagents are available by
clinical or research suppliers known in the art. The pH of the
above solutions is preferably at or between 3 and 10. More
preferably, the pH is at or between 5 and 8.
[0033] An inventive baclofen solution is provided that has higher
baclofen concentration than is achievable in saline, or other
aqueous solvents alone. In particular, baclofen concentrations are
greater than 2 mg/ml in an MPI solution. Preferably, concentrations
of baclofen are at or between 2 and 10 mg/ml inclusive in
artificial cerebrospinal fluid. More preferably, baclofen
concentrations are at or between 2 to 6.5 mg/ml in artificial
cerebrospinal fluid.
[0034] The high baclofen solubility in an MPI solution was
surprising given prior attempts to solubilize baclofen that
produced limiting concentrations of only 0.2 mg/ml in aCSF.
Jackson, G L, et al., Endocrinology, 2000; 141: 3940-3945; Goda, R.
et al., J Chromatogr B Analyt Technol Biomed Life Sci, 2004;
801:257-64. Moreover, the long unmet medical need for an increased
concentration of baclofen in a solution that does not itself
produce unwanted side effects counseled against dissolving baclofen
in aCSF to achieve high concentrations such as in the instant
invention. Ahuja, Analytical Profiles of Drug Substances, 1985;
Vol. 14, New York: Academic Press, pp. 527-548; Jackson, GL, et
al., Endocrinology, 2000; 141: 3940-3945; Goda, R. et al., J
Chromatogr B Analyt Technol Biomed Life Sci, 2004; 801:257-64.
Indeed, the knowledge in the art taught away from the present
invention in that baclofen was known to have an upper limit of
solubility in aqueous solvents of only 2 mg/ml. Ahuja, Analytical
Profiles of Drug Substances, 1985; Vol. 14, New York: Academic
Press, pp. 527-548. Further, the labor, time, and cost intensive
steps used by prior practitioners to increase baclofen solubility
suggested that a simple solution, such as the instant invention,
was untenable. U.S. Patent Application Publication 2006/0009523.
Thus, the 2-6.5 mg/ml baclofen solution of the present invention
was not considered in the art.
[0035] Baclofen suitable for use in the present invention is of any
stable appropriate form for addition to an MPI solution.
Preferably, baclofen is provided in tablet form such as supplied by
Novartis under the name LIORESAL, or in powder form as a racemic
mixture or as individual enantiomers from illustratively available
from Sigma-Aldrich Corp., St. Louis, Mo. Presently, baclofen is
commercially available for injection as a 2 mg/mL solution having a
pH of 5 to 7 and the following simple preservative-free formula
(LIORESAL INTRATHECAL package insert): Baclofen, 2 mg; Sodium
chloride, 9 mg; Water for injection, qs 1 mL.
[0036] The compositions and processes of the invention are
optionally used to treat mammalian subjects (e.g., sport or pet
mammals such as dogs, cats, and horses, and humans). Additionally,
the inventive compositions and processes are optionally used for,
but are not limited to research purposes such as in clinical or
preclinical in vivo animal studies involving mammals illustratively
including mice, rats, guinea pigs, rabbits, dogs, cats, swine,
bovine, monkey, baboon, chimpanzee, and humans. It is further
appreciated that the high concentration baclofen solutions are
uniquely suited for in vitro research studies.
[0037] Baclofen is illustratively used in the treatment of
intractable spasticity of the spine or brain etiology. Non-limiting
examples of disease states or injuries suitable for treatment with
the instant invention are spasticity, brain injury, cerebral palsy,
spinal cord injury, cervical injury, multiple sclerosis, thoracic
injuries, and spinal pathology.
[0038] The increased concentration of baclofen achieved in the
instant invention allows for subsequent dilution by the addition of
other components that are to be simultaneously infused with the
baclofen. Spasticity is a painful complication, and patients often
require pain regulating medications. Pain relieving medications
suitable for combination with the inventive baclofen solution are
illustratively morphine, clondine, hydromorphine, hydrocodone,
merperidine, celeroxib, tramadol, oxycodone, acetometaphen,
ketaprofen, ibuprofen, naproxen sodium, and aspirin. It is
appreciated in the art that other chemical compounds are similarly
suitable for co-administration with baclofen in the instant
invention.
[0039] The instant invention also provides a process of delivery of
the highly concentrated baclofen solution. The inventive solution
is illustratively delivered to the patient by intrathecal,
intraventrical, oral, intravenous, intra-arterial, intraperitoneal,
epidural, intramuscular, or subcutaneous delivery routes. There are
numerous methods of injection known in the art illustratively
including direct injection by the attending physician or other
caregiver and the use of a continuous infusion pump system. An
illustrative example of a pump system is that marketed under the
trade name ACCU-CHECK by Disetronic, Fishers, Ind. The infusion
pump is illustratively implantable, external, manual, or
automatically regulated. Illustratively, the pump or manual
infusion is by discontinuous administration.
[0040] In further embodiments, stable baclofen solutions of the
present invention are provided in a medical package of baclofen
solution illustratively suitable for injection, infusion, or other
route of administration including oral. In a preferred embodiment
the medical package contains a high concentration baclofen solution
in MPI solution and an optional second source of MPI solution
diluent that is optionally used to adjust the dosing volume or
concentration. The baclofen solution is preferably provided free of
pyrogens, antioxidants, preservatives or other potentially
neurotoxic additives. In a particular package, the baclofen
solution and diluent are provided in single dose ampules, however,
it is appreciated that a single ampule optionally contains partial
or multiple dose volumes and concentrations. In a preferred
embodiment the ampule is designed to operate in conjunction with an
implantable pump and contains sufficient baclofen solution such
that continuous infusion may be maintained for 3 months or longer.
Alternatively, the medical package is suitable for oral
administration in liquid, tablet, powder, capsule, suspension, or
other delivery form recognized in the art. In an alternative
embodiment the baclofen solution is provided in a preloaded syringe
that is suitable for manual injection or association with a syringe
pump or other apparatus for longer infusion or injection times.
Implantable infusion pumps generally designed for intrathecal
baclofen administration are commonly recharged by addition of
additional therapeutic by injection into a reservoir in the pump.
It is appreciated that the medical package of the instant invention
is suitable for recharging both implantable and external pumps, as
well as for direct delivery to the patient in the absence of a pump
such as for initial test dosing of baclofen. Common medical
packages for baclofen are described in U.S. Patent Application
Publication 2006/0009523. Preferably, a medical package includes
instructions for the use thereof to treat a disease or injury
resulting in spasticity.
[0041] Various aspects of the present invention are illustrated by
the following non-limiting examples. The examples are for
illustrative purposes and are not a limitation on any practice of
the present invention.
Example 1
[0042] Multivalent physiologic ion solution formation. A solution
(A) is produced with 8.66 g NaCl, 0.224 g KCl, 0.206 g
CaCl.sub.2.2H.sub.20 and 0.163 g MgCl.sub.2.6H.sub.20 dissolving in
500 mL of deionized water. A solution (B) is produced with 0.214 g
Na.sub.2HPO.sub.4.7H.sub.20 and 0.027 g NaH.sub.2PO.sub.4.H.sub.20
dissolving in 450 mL of water. The pH is adjusted to 6.0, 6.5, 7.0,
7.3, 7.6 and 8.0 as necessary with either NaOH or H.sub.3PO.sub.4
and dilution to final volume of 500 mL with deionized water. A
final multivalent physiologic ion solution is obtained by mixing
equal parts of Solution A and B. pH is tested and adjusted to the
desired final pH if necessary. All reagents are available from
sources known in the art. Illustratively, reagents are available
from Sigma-Aldrich Corp., St. Louis, Mo.
Example 2
[0043] Baclofen solubilization study in multivalent physiologic ion
solution. Baclofen raw material is weighed and 200.0.+-.3.0 mg is
added into each of six scintillation vials. To each vial is added
20.0 mL of the pH adjusted MPI of Example 1 (6.0, 6.5, 7.0, 7.3,
7.6 and 8.0). Solutions are warmed to 37.degree. C. in a water
bath. Each solution is manually mixed every minute during the first
five minutes and at five minute intervals thereafter for the entire
30 minute aliquot pull period. Visually clear solutions are
immediately obtained, but gentle stiffing or vortexing is applied
to the samples for several seconds to ensure complete
solubilization of the baclofen. Clear solutions present with no
visual particulate matter remaining. Approximately 5 mL aliquots
are pulled at 2, 5 and 30 minutes of incubation using a syringe
equipped with a 10 micron filter tip. The aliquots are analyzed by
high performance liquid chromatography (HPLC). For analyses, 2.0 mL
of each aliquot is transferred to a 20 mL volumetric flask
containing mobile phase to produce a maximum sample concentration
of 1.0 mg/mL. Additional linearity standards are optionally added.
Baclofen concentrations above 4 mg/ml are readily achieved.
Example 3
[0044] Baclofen solubilization in artificial cerebrospinal fluid.
Baclofen powder is titrated with pH 7.3 MPI per Example 2 that is
warmed to 37.degree. C. A light box is used to identify the
presence of precipitate. The volume added to the nearest 0.05 mLs.
Aliquots of approximately 5 mL are removed with a syringe equipped
with a 10 micron filter tip and analyzed by HPLC. Visually clear
solutions are immediately obtained, but gentle stiffing or
vortexing is applied to the samples for several seconds to ensure
complete solubilization of the baclofen. Baclofen concentrations
are achieved in aCSF at 2, 2.5, 3, 3.5, 4, 4.5, 5, 5.5 and 6 mg/ml.
Solutions with greater than 5 mg/ml final concentrations
infrequently require gentle agitation for 2 minutes or less. Clear
solutions are achieved with no visual particulate matter
remaining.
Example 4
[0045] Analyses of baclofen solutions to confirm concentrations.
Baclofen concentrations of Examples 2 and 3 are determined to
confirm soluble levels in MPI or aCSF in the inventive solutions.
Baclofen concentrations are quantified by LC/MS/MS using an Applied
Biosystems API 400 electrospray triple quadrupole mass
spectrometer. Lagarce, F, et al., Eur J Biopharm, 2005, 61:171-80.
Baclofen is separated on a C.sub.8 5 .mu.m 100.times.2.1 mm column
in which the mobile phase is composed of 60% H.sub.20/40%
acetonitrile at a solvent flow of 250 .mu.l/min following a 20
.mu.l sample injection. The transition between 214.1 and 151.2 is
used for quantification. All samples are confirmed with less than
5% variation from expected values.
Example 5
[0046] Analyses of baclofen solutions to confirm concentrations.
Alternatively, HPLC analyses of solutions prepared as in Example 2
or 3 are used to confirm baclofen concentrations in the visually
clear solution as described in U.S. Patent Application Publication
2006/0009523; Sitaram B R, et al., Int J Pharm, 1997; 153:13-24;
Gupta V D, and Parasrampuria J, Drug Develop Indust Pharm, 1998;
14:1623-1628; Johnson C E, et al., Am J Hosp Pharm, 1993;
50:2353-55; Allen L V, et al., Am J Health-Syst Pharm, 1996;
53:2179-2184. Solutions are filtered through a 0.22-micron filter
to remove any particulate matter. Baclofen is separated on a
C.sub.18 5 .mu.m 250.times.4.6 mm column with a mobile phase
gradient of 0.085 M ammonium phosphate (78.5%) and acetonitrile
(21.5%) to acetonitrile (100%) as previously described. Id.
Detection was by UV at 220 nm. In this system baclofen has a
retention time of 4.7 min and decomposition products are present at
3.3, 6.4, and 17 min. Baclofen concentrations are determined within
10% of expected values.
TABLE-US-00001 TABLE 1 HPLC Analytical Method Used Baclofen.sup.a
Column: Symmetry C.sub.18, 5 .mu.m, 250 .times. 4.6 mm i.d. Mobile
Phase: A. 0.085 M ammonium phosphate 78.5% and acetonitrile 21.5%
B. Acetonitrile 100% Flow Rate: Gradient, See Table 2. Detection:
UV 220 nm, 1.0 AUFS Retention Times: Baclofen 4.7 min Decomposition
products 3.3, 6.4, 17 min .sup.aPrecision: Mean .+-. S.D. (n = 10)
99.8 .+-. 1.0 .mu.g/mL, percent relative standard deviation was
1.0%. Standard curves range was baclofen 50 to 150 .mu.g/mL.
Correlation coefficients were >0.9999.
TABLE-US-00002 TABLE 2 HPLC Mobile Phase Gradical Table Time Flow A
B (min) (mL/min) (%) (%) 0 0.8 100 0 5 0.8 100 0 6 1.0 77 23 13 1.0
77 23 15 1.0 100 0 23 1.0 100 0 25 0.8 100 0
Example 6
[0047] Administration of high concentration baclofen solution
intrathecally. Patients presenting with spasticity who have
undergone subcutaneous placement of a programmable intrathecal
baclofen pump (Medtronic SyncroMed Infusion System; Medtronic, Inc,
Minneapolis, Minn.) are administered baclofen at appropriate dosage
levels by intrathecal delivery. The inventive baclofen solution is
optionally supplemented with a pain regulating medication such as
morphine at appropriate dosage levels and is simultaneously loaded
into the infusion pump for intrathecal delivery. Patients are
monitored in the hospital for two to four days while dose is
increased to achieve measurable spasticity reduction without
debilitating side effects. Additional follow up is at 1 month and
every three months subsequently. Avellino A M, et al.,
Neuromodulation, 2000; 3:75-81.
[0048] Administration of baclofen solution to mammals. Baclofen
solution of Example 2 or 3 is administered to adult rats
essentially as described by Seong, J Y, et al., Endocrinology,
1995; 136:2587-93. Briefly, adult female rats of 250 g mean body
weight and maintained under conditions of light on from 0700 h-1900
h, room temperature 23.degree. C., water and food available ad
libitum are ovarectomized and allowed to recover for two weeks. A
stainless steel cannula is inserted as described. Following
recovery of one week, rats are injected with baclofen at 1 mg/ml in
aCSF. Animals are studied for therapeutic and pharmacological
effects of Baclofen.
[0049] Alternatively, baclofen solution of Example 2 or 3 is
administered to Wistar rat brain by superfusion essentially as
described by Cesar, K, et al., Proc. Nat. Acad. Sci, USA, 2003;
100:16000-05. Briefly, a 0.4.times.10.sup.-2 mg/ml solution of
baclofen in aCSF is administered to anesthetized rats maintained to
basic physiologic parameters of pH, pO.sub.2, and pCO.sub.2 by
topical superfusion via an open cranial window prepared as
described. Electrophysiological and other parameters are recorded
prior to and following baclofen administration.
[0050] Administration of Baclofen to cats. Cats are administered
baclofen essentially as described in U.S. Pat. No. 5,149,713. Cats
weighing from 1.5 to 3.5 kg (n=4) are anaesthetized using
pentobarbital (from 30 to 40 mg/kg administered first i.p., and
then from 3 to 5 mg/kg administered i.v.) and then tracheotomised,
curarised and ventilated artificially. The various basic
haemodynamic parameters are recorded: arterial systolic and
diastolic pressures, cardiac frequency, cardiac output. The various
haemodynamic indices and parameters are also calculated (mean
arterial pressure, dP/dt, double product
frequency.times.pressure).
[0051] The core temperature of the animals is maintained at from
37.degree. to 37.5.degree. C. by means of an electric blanket. The
animals are placed in a stereotactic apparatus and then the defense
area is stimulated electrically by means of an electrode placed in
the grey matter, at coordinates A.sub.6L.sub.1H.sub.0. The stimuli
are supplied by a stimulator functioning in monopolar manner:
frequency 100 Hz, duration 3 msec., difference in potential 3 to 6
volts.
[0052] The positioning of the electrode is considered to be
satisfactory when the cardiac output and dP/dt are increased by
more than 20%.
[0053] The baclofen is administered via the femoral vein. The
animals are given 0.5 mg/kg or 1 mg/kg as the case may be The
various parameters are then recorded 15 minutes and 30 minutes
after the injection of baclofen.
Example 7
Clinical Study of Baclofen Administration in Humans
[0054] Baclofen administration in humans in conjunction with
Ziconotide is performed essentially as described in U.S. Pat. No.
7,268,109. The patient population includes male and female human
patients on a dose of intrathecal baclofen (either compounded
baclofen or LIORESAL.RTM.) ranging between 22 and 800 mg/day.
Patient has pain and sub optimal pain relief indicated by a minimum
VASPI of 40 mm at the Screening and Baseline Visit.
[0055] All patients must be on stable doses of LIORESAL.RTM.
(between 22 and 800 .mu.g/d), systemic opioids, and other
concomitant medications for at least 7 days prior to the baseline
visit. The contents of the SynchroMed.RTM. EL Infusion System are
removed and replaced with PRIALTT.TM. and LIORESAL.RTM.. The
LIORESAL.RTM. dose remains the same as during the last 7 days of
the screening period and throughout the first 9 weeks of the trial.
The initial dose of PRIALTT.TM. is 0.025 .mu.g/hr (0.6
.mu.g/d).
[0056] All patients must be on stable doses of LIORESAL.RTM.
(between 22 and 800 .mu.g/d), systemic opioids, and other
concomitant medications for at least 7 days prior to the Baseline
Visit. The contents of the SynchroMed.RTM. EL Infusion System are
removed and replaced with PRIALTT.TM. and LIORESAL.RTM..
[0057] The LIORESAL.RTM. dose remains the same as during the last 7
days of the screening period and throughout the first 9 weeks of
the trial. The initial dose of PRIALT.TM. is 0.025 .mu.g/hr (0.6
.mu.g/d). The pump flow rate is held constant and is at least 12
.mu.g/hr (288 mcl/d) to allow for clearance of the pump volume
within one or two days. Drug dosage is not to be adjusted by
changing the pump flow rate as this would change the rate of
infusion of both compounds.
[0058] Spasticity scales (Modified Ashworth Scale: 0-4 normal to
rigid tone; Spasm Scale 0-4 no spasms to greater than 10 per hr;
Penn Spasm Frequency Scale, Visual Analogue of Spasticity Scale or
VASS) is determined at each clinic visit.
[0059] Various modifications of the present invention, in addition
to those shown and described herein, will be apparent to those
skilled in the art of the above description. Such modifications are
also intended to fall within the scope of the appended claims.
[0060] Patents and publications mentioned in the specification are
indicative of the levels of those skilled in the art to which the
invention pertains. These patents and publications are incorporated
herein by reference to the same extent as if each individual
application or publication was specifically and individually
incorporated herein by reference.
[0061] The foregoing description is illustrative of particular
embodiments of the invention, but is not meant to be a limitation
upon the practice thereof. The following claims, including all
equivalents thereof, are intended to define the scope of the
invention.
[0062] The following references are each incorporated herein by
reference as if the contents of each reference were fully and
explicitly included.
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* * * * *