U.S. patent application number 16/387504 was filed with the patent office on 2019-08-08 for sustained release aminopyridine composition.
The applicant listed for this patent is Alkermes Pharma Ireland Limited. Invention is credited to Sean Cunningham, Seamus Mulligan, Michael Myers.
Application Number | 20190240206 16/387504 |
Document ID | / |
Family ID | 35460826 |
Filed Date | 2019-08-08 |
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United States Patent
Application |
20190240206 |
Kind Code |
A1 |
Cunningham; Sean ; et
al. |
August 8, 2019 |
SUSTAINED RELEASE AMINOPYRIDINE COMPOSITION
Abstract
A pharmaceutical composition which comprises a therapeuticallly
effective amount of a aminopyridine dispersed in a release matrix,
including, for example, a composition that can be formulated into a
stable, sustained-release oral dosage formulation, such as a tablet
which provides, upon administration to a patient, a therapeutically
effective plasma level of the aminopyridine for a period of at
least 12 hours, preferably 24 hours or more and the use of the
composition to treat various neurological diseases.
Inventors: |
Cunningham; Sean; (Athlone,
IE) ; Mulligan; Seamus; (Athlone, IE) ; Myers;
Michael; (Broadlands, VA) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Alkermes Pharma Ireland Limited |
Dublin |
|
IE |
|
|
Family ID: |
35460826 |
Appl. No.: |
16/387504 |
Filed: |
April 17, 2019 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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16116331 |
Aug 29, 2018 |
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16387504 |
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15863835 |
Jan 5, 2018 |
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16116331 |
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15606906 |
May 26, 2017 |
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15863835 |
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15294266 |
Oct 14, 2016 |
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15606906 |
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15058785 |
Mar 2, 2016 |
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15294266 |
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14025248 |
Sep 12, 2013 |
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15058785 |
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13585277 |
Aug 14, 2012 |
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14025248 |
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12626085 |
Nov 25, 2009 |
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13585277 |
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11010828 |
Dec 13, 2004 |
8007826 |
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12626085 |
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60560894 |
Apr 9, 2004 |
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60528760 |
Dec 11, 2003 |
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60528593 |
Dec 11, 2003 |
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60528592 |
Dec 11, 2003 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61K 31/44 20130101;
A61P 25/00 20180101; A61P 43/00 20180101; A61K 9/2054 20130101;
A61K 47/38 20130101; A61K 47/12 20130101; A61P 19/00 20180101; A61K
9/20 20130101; A61K 31/4409 20130101; A61K 47/14 20130101; A61K
47/44 20130101; A61P 25/28 20180101; A61K 9/2077 20130101 |
International
Class: |
A61K 31/4409 20060101
A61K031/4409; A61K 9/20 20060101 A61K009/20; A61K 47/12 20060101
A61K047/12; A61K 47/44 20060101 A61K047/44; A61K 47/14 20060101
A61K047/14; A61K 31/44 20060101 A61K031/44; A61K 47/38 20060101
A61K047/38 |
Claims
1. A sustained release tablet comprising: a sustained release
matrix and an aminopyridine, said tablet exhibiting a release
profile to obtain a C.sub.max:C ratio in vivo of about 1.0 to about
3.5 and a predetermined C.sub.avSS.
2. The sustained release tablet of claim 1 wherein said C.sub.max:C
is about 1.5 to about 3.0.
3. The sustained release tablet of claim 1 wherein said
predetermined C.sub.avSS is about 21 ng/ml.
4. The sustained release tablet of claim 1 wherein said
predetermined C.sub.avSS is about 31 ng/ml.
5. The sustained release tablet of claim 1 wherein said
predetermined C.sub.avSS is about 40 ng/ml.
6. The sustained release tablet of claim 1 wherein said C.sub.maxC
ratio is about 2.0 to about 3.0.
7. The sustained release tablet of claim 1 wherein said
aminopyridine is 4-aminopyridine.
8. The sustained release table of claim 1 wherein said sustained
release matrix is hydroxypropylmethylcellulose.
9. A method of treating a disease associated with a neurological
disorder, said method comprising; administering an aminopyridine on
a dosing regimen to obtain an in vivo C.sub.max:C ratio of 1.0 to
3.5 and a C.sub.avSS of about 15 ng/ml to about 35 ng/ml.
10. The method of claim 9 wherein said C.sub.max:C ratio is about
1.5 to about 3.0.
11. The method of claim 9 wherein said C.sub.max:C ratio is about
2.0 to about 3.0.
12. The method of claim 9 wherein said neurological disorder
comprises a spinal cord injury, Alzheimer's disease, multiple
sclerosis, or amyotrophic lateral sclerosis.
13. The method of claim 9 wherein said neurological disorder
comprises a spinal cord injury.
14. The method of claim 9 wherein said neurological disorder
comprises multiple sclerosis.
15. The method of claim 9 wherein said dosing regimen is comprised
of administering a tablet twice daily.
16. The method of claim 15 wherein said twice daily administration
comprises every twelve hours.
17. The method of claim 9 wherein said aminopyridine comprises
4-aminopyridine.
18. A therapeutic composition comprised of a release matrix and an
active aminopyridine, said aminopyridine being released from said
release matrix at a rate to maintain an in vivo C.sub.max:C ratio
of 1.0 to 3.5 and a C of about 15 ng/ml to about 35 ng/ml.
19. The therapeutic composition of claim 22 wherein said
C.sub.max:C.sub.z,999 ratio is about 15 to about 30.
20. The therapeutic composition of claim 22 wherein said
C.sub.max:C ratio is about 20 to about 30.
21. The therapeutic composition of claim 22 wherein the active
aminopyridine is 4-aminopyridine.
22. The therapeutic composition of claim 22 wherein the release
matrix is hydroxypropylmethylcellulose.
23. A sustained release composition comprising: a sustained release
matrix and an ammopyridine, wherein said composition provides a C
of about 15 ng/ml to about 35 ng/ml.
Description
CROSS REFERENCES
[0001] This application related to U.S. Provisional Application
Ser. No. 60/528,760, filed Dec. 11, 2003, U.S. Provisional
Application No. 60/560,894 filed Apr. 9, 2004, U.S. Provisional
Application No. 60/528,592 filed Dec. 11, 2003, 60/528,593 filed
Dec. 11, 2003, and PCT/US2004/008101 filed on Mar. 17, 2004, all of
which are incorporated herein by references in their entirety.
BACKGROUND
[0002] This invention related to a sustained release oral dosage
form of an aminopyridine pharmaceutical composition that can be
used to treat individuals affected with neurological disorders
wherein said pharmaceutical composition maximizes the therapeutic
effect, while minimizing adverse side effects.
[0003] The sustained release oral dosage form of the present
invention may be utilized to treat neurological disorders such as
spinal cord injuries, multiple sclerosis, Alzheimer's disease, and
ALS. Spinal cord injuries are one of the leading causes of
disability in young adults resulting in from partial to complete
paralysis of the lower extremities to partial to complete paralysis
from the level of spinal injury downward. In most extreme cases,
paralysis is complete from the C-1 cervical vertebra downward.
Oftentimes, however, the injury to the spinal cord does not consist
of an actual severing of the cord but rather consists of an injury
that interferes with signal transmission. Treatment alternatives
for promoting transmission along injured nerves of the spinal chord
have thus far met with limited success.
[0004] Multiple sclerosis (MS) is a degenerative and inflammatory
neurological disease which affects the central nervous system, more
specifically the myelin sheath. The condition of MS involves
demyelination of nerve fibers resulting in short-circuiting of
nerve impulses and thus slowing or blocking of transmission along
the nerve fibers, with associated disabling symptoms. Treatment
alternatives for promoting transmission along affected nerves have
thus far been limited.
[0005] Alzheimer's disease is a major cause of dementia in the
elderly. It may be described as a progressive pathological
deterioration in personality, memory and intellect consistent with
a generalized atrophy of corresponding brain centers. The emotional
state, behavior, cognitive function and thought processes of
sufferers are all adversely affected. A minor degrading in memory
which gradually becomes more apparent is the first indication of
the onset of the disease. Part of the disease process involves the
transmission of nerve signals and, as with MS, treatment
alternatives have thus far been limited.
[0006] Amyotrophic lateral sclerosis (ALS), commonly referred to as
Lou Gehrig's Disease, is a fatal neuromuscular disease
characterized by progressive muscle weakness resulting in
paralysis. ALS patients often suffer from symptoms including
tripping, stumbling, and failing, loss of muscle control and
strength in hands and arms, difficulty speaking, swallowing and/or
breathing, chronic fatigue, and muscle twitching and/or cramping.
ALS is characterized by both upper and lower motor neuron damage.
Symptoms of upper motor neuron damage include stiffness,
spasticity, muscle twitching (fasciculations), and muscle shaking
(clonus). Symptoms of lower motor neuron damage include muscle
weakness and muscle atrophy.
[0007] Potassium channel blockers are a class of compounds that
have been found to improve the conduction of nerve impulses. As a
result, they have become the focus of attention in the symptomatic
treatment of spinal cord injury, MS and Alzheimer's disease. One
sub-class of potassium channel blockers, aminopyridines have shown
promise in the treatment of neurological diseases. 4-aminopyridine
(4-AP), a mono-aminopyridine known as fampridine, has been found to
slow the potassium flow in nerve impulse transmission and, thereby,
shows effectiveness in restoring conduction in blocked and
demyelinated nerves.
[0008] Potassium channel blockers have also been found to improve
mental function in patients with Alzheimer's disease. This effect
is believed to be related to the potassium channel blocking action
which in turn enhances calcium influx into the neuron thus
prolonging nerve action potential and increasing transmitter
release. Mono- and di-aminopyridines constitute a particular
sub-class of potassium channel blockers that have showed promise in
treatment of Alzheimer's disease.
SUMMARY OF THE INVENTION
[0009] The present invention relates to a pharmaceutical
composition which contains one or more potassium channel blockers
and which can be used in the effective treatment of various
diseases, for example, spinal cord injury, multiple sclerosis,
Alzheimer's disease, and ALS. Embodiments of the present invention
are directed to compositions that include a matrix and a potassium
channel blocker. The potassium channel blockers may include
aminopyridines, for example, 4-aminopyridine, 3,4-diaminopyridine
and the like. The composition provides for sustained-release of the
aminopyridine from the matrix to maintain the efficacious and safe
plasma level of an aminopyridine. The aminopyridine dispersed in
the matrix is capable of providing, upon administration to a
patient, a desired release profile. The composition may be used to
establish in patients in need of such treatment, a therapeutically
effective blood plasma level of the aminopyridine for a period of
at least about 6 hours and preferably up to at least 24 hours in
the patient in a twice-daily administration while avoiding peaks
and troughs in the relapse of the aminopyridine. The composition
may include a mono- or di-aminopyridine, preferably 4-AP or 3,4-DAP
or a combination thereof, homogeneously dispersed in a
rate-controlling polymer matrix, preferably including a hydrophilic
polymer like hydroxypropylmethylcellulose (HPMC). The composition
of the present invention may also include one or more additional
active ingredients and/or one or more pharmaceutically acceptable
excipients. These compositions can be used to treat various
neurological diseases, for example, spinal cord injury, multiple
sclerosis, Alzheimer's disease, and ALS.
[0010] Another embodiment of the present invention is a stable
pharmaceutical composition which comprises a therapeutically
effective amount of an aminopyridine dispersed in a matrix that
provides a release profile of the aminopyridine to a patient that
has a desired C.sub.max to C ratio. The composition may be used to
establish and/or maintain in a patient, a therapeutically effective
level of the aminopyridine. Preferably the aminopyridine in the
composition is released over time so that a therapeutically
effective level of the aminopyridine in the patient can be achieved
with twice daily dosing of the composition. In a more preferred
embodiment, undesirable spikes or peaks in the release of the
amminopyridine are avoided.
[0011] Another embodiment of the present invention is a stable,
sustained-release oral dosage formulation of a composition which
includes an a therapeutically effective amount of a 4-aminopyridine
dispersed in a matrix that provides a release profile of
4-aminopyridine in the blood plasma of the patient extending over a
period of at least 6 hours, preferably at least 8 hours, and more
preferably, at least about 12 hours. In another embodiment, a
stable, sustained-release oral dosage formulation of a composition
includes an a therapeutically effective amount of a 4-aminopyridine
dispersed in a matrix that provides a therapeutically effective
blood plasma level of 4-aminopyridine in the patient extending over
about 24 hours.
[0012] Preferably, the oral dosage formulation of the composition
is a monolithic tablet formed by compression of the pharmaceutical
composition of the present invention. In preferred embodiments, the
oral dosage formulation includes a compressed tablet of a
therapeutically effective amount of 4-amminopyridine dispersed in
matrix which includes a hydrophilic polymer such as HPMC. The oral
dosage form of the present invention may also include one or more
pharmaceutically acceptable excipients.
[0013] The dispersion of 4-aminopyridine throughout the matrix
imparts chemical and physical stability to the composition while
providing a sustained-release profile. This enhanced dosage
stability is most notably observed in compositions and dosage forms
of the present invention having low concentrations of
4-aminopyridine, and stability is achieved while maintaining the
desired controlled-release profile. Specifically, the compressed
tablet formulation of the present invention exhibits superior
resistance to moisture absorption by ambient humidity and maintains
a uniform distribution of the 4-amminopyridine throughout the
tablet while providing a release profile of 4-aminopyridine that
permits establishment of a therapeutically effective concentration
of the potassium channel blocker with once daily or twice daily
dosing of the formulation. Preferably the therapeutically effective
concentration released by the formulation extends over at least 6
hours, preferably at least 8 hours, and more preferably to at least
12 hours. In addition, the homogeneity of the dosage form renders
it amenable to formation by simple and inexpensive manufacturing
processes as compared with the multi-layered structure of prior
sustained-release dosage formulations.
[0014] The compositions of the present invention may be used in the
treatment of a condition in a patient which includes establishing a
therapeutically effective concentration of a potassium channel
blocker in the patient in need thereof. The compositions may be
used for building up a level and or maintaining a therapeutically
effective concentration of an aminopyridine in the patient by twice
daily dosing. The dosages of the present compositions can made with
a lower concentration of the aminopyridine to facilitate restful
periods for the patient during the day. Where desirable, the
compositions of the present invention may be formulated to avoid
large peaks in initial release of the aminopyridine. The
compositions of the present invention when administered to a
patient in need thereof provide for the treatment of neurological
diseases that are characterized by a degradation of nerve impulse
transmission. Preferably, the compositions are a stable,
sustained-release tablet of a therapeutically effective amount of a
mono- or di-aminopyridine, dispersed in HPMC such that
therapeutically effective blood plasma level of the mono- or
di-aminopyridine is maintained in the patient for a period of at
least 6 hours, preferably at least 8 hours, and more preferably at
least about 10-12 hours in a once or twice daily
administration.
BRIEF DESCRIPTION OF THE DRAWINGS
[0015] FIG. 1 is a graph of mean plasma profiles associated with
the administration to a patient in both fasted and fed states of a
tablet form of 4-AP (fampridine) in accordance with the present
invention compared with the mean plasma profile associated with the
administration of an immediate release formulation of 4-AP in a
gelatin capsule.
[0016] FIG. 2 is a graph of mean plasma profiles associated with
the administration (fasted state) of a homogeneous dispersion of
4-AP (fampridine) in a matrix in a tablet form of in accordance
with the present invention compared with the mean plasma profile
associated with the administration of a layered controlled-release
capsule and an immediate release capsule formulations of 4-AP.
[0017] FIG. 3 is a graph of the mean change in walking sped
observed with the administration of a sustained release 4-AP
(fampridine) according to the present invention.
[0018] FIG. 4 is a graph of the mean change in LEMMT with the
administration of a sustained release 4-AP (fampridine) according
to the present invention.
[0019] FIG. 5 is a graph of the mean change in Ashworth score with
the administration of a sustained release 4-AP (fampridine)
according to the present invention.
DETAILED DESCRIPTION OF THE INVENTION
[0020] Before the present compositions and methods are described,
it is to be understood that this invention is not limited to the
particular molecules, compositions, methodologies or protocols
described, as these may vary. It is also to be understood that the
terminology used in the description is for the purpose of
describing the particular versions or embodiments only, and is not
intended to limit the scope of the present invention which will be
limited only by the appended claims.
[0021] The terms used herein have meanings recognized and known to
those of skill in the art, however, for convenience and
completeness, particular terms and their meanings are set forth
below.
[0022] It must also be noted that as used herein and in the
appended claims, the singular forms "a", "an", and "the" include
plural reference unless the context clearly dictates otherwise.
Thus, for example, reference to a "spheroid" is a reference to one
or more spheroid and equivalents thereof known to those skilled in
the art, and so forth. Unless defined otherwise, all technical and
scientific terms used herein have the same meanings as commonly
understood by one of ordinary skill in the art. Although any
methods and materials similar or equivalent to those described
herein can be used in the practice or testing of embodiments of the
present invention, the preferred methods, devices, and materials
are snow described. All publications mentioned herein are
incorporated by reference. Nothing herein is to be construed as an
admission that the invention is not entitled to antedate such
disclosure by virtue of prior invention.
[0023] "Buccal" refers to the cheek area in the mouth.
[0024] "Local administration" means direct administration by a
non-systemic route at or in the vicinity of the site of affliction,
disorder, or perceived pain.
[0025] The terms "patient" and "subject" mean all animals including
humans. Examples of patients or subjects include humans, cows,
dogs, cats, goats, sheep, and pigs.
[0026] The term "pharmaceutically acceptable salts, esters, amides,
and prodrugs" as used herein refers to those carboxylate salts,
amino acid addition salts, esters, amides, and prodrugs of the
compounds of the present invention which are, within the scope of
sound medical judgment, suitable for use in contact with the
tissues of patients without undue toxicity, irritation, allergic
response, and the like, commensurate with a reasonable benefit/risk
ratio, and effective for their intended use, as well as the
zwiiterionic forms, where possible, of the compounds of the
invention.
[0027] The term "prodrug" refers to compounds that are rapidly
transformed in vivo to yield the patent compounds of the above
formula, for example, by hydrolysis in blood. A thorough discussion
is provided in T. Higuchi and V. Stella, "Pro-drugs as Novel
Delivery Systems," Vol. 14 of the A.C.S, Symposium Series, and in
Bioreversible Carriers in Drug Design, ed. Edward B. Roche,
American Pharmaceutical Association and Pergamon Press, 1987, both
of which are incorporated herein by reference.
[0028] The term "salts" refers to the relatively nontoxic,
inorganic and organic acid addition salts of compounds of the
present invention. These salts can be prepared in situ during the
final isolation and purification of the compounds or by separately
reacting the purified compound in its free base form with a
suitable organic or inorganic acid and isolating the salt thus
formed. Representative salts include the hydrobromide,
hydrochloride, sulfate, bisulfate, nitrate, acetate, oxalate,
valerate, oleate, palmitate, stearate, laurate, borate, benzoate,
lactate, phosphate, tosylate, citrate, maleate, fumarate,
succinate, tartrate, naphthylate mesylate, glucoheptonate,
lactobionate and laurylsulphonate salts, and the like. These may
include cations based on the alkali and alkaline earth metals, such
as sodium, lithium, potassium, calcium, magnesium, and the like, as
well as non-toxic ammonium, tetramethylammonium,
tetramethylammonium, methlyamine, dimethlyamine, trimethlyamine,
triethlyamine, ethylamine, and the like. (See, for example, S. M.
Barge et al., "Pharmaceutical Salts," J. Pharm. Sci., 1977,
66:1-1.9 which is incorporated herein by reference).
[0029] "Slow or sustained release formulation" refers to a
formulation designed to release a therapeutically effective amount
of drug or other active agent such as a polypeptide or a synthetic
compound over an extended period of time, with the result being a
reduction in the number of treatments necessary to achieve the
desired therapeutic effect. In the matter of the present invention,
a slow release formulation would decrease the number of treatments
necessary to achieve the desired effect in terms of reduction in
pain or spasticity, or an improvement in motor or sensory function
in patients in need of such therapy, for example, in spinal cord
injured patients or in patients suffering from multiple sclerosis,
ALS or Alzheimer's disease. The slow or sustained release
formulations of the present invention achieve a desired
pharmacokinetic profile in a subject.
[0030] "Sublingual delivery" refers to the system delivery of drugs
or other agents through the mucosal membranes lining the floor of
the mouth.
[0031] A "therapeutically effective amount" is an amount sufficient
to decrease or prevent the symptoms associated with a medical
condition or infirmity or so normalize body functions in disease or
disorders that result in impairment of specific bodily functions.
As related to the present application, a therapeutically effective
amount is an amount sufficient to reduce the pain or spasticity
associated with the neurological disorder being treated, or an
amount sufficient to result in improvement of sexual, bladder or
bowel function in subjects having a neurological disorder which
impairs nerve conduction, which hinders normal sexual, bladder or
bowl functions.
[0032] "Treatment" refers to the administration of medicine or the
performance of medical procedures with respect to a patient, for
either prophylaxis (prevention) or cure the infirmity or malady in
the instance where the patient is afflicted.
[0033] In addition, the compounds of the present invention can
exist in unsolvated as well as solvated forms with pharmaceutically
acceptable solvents such as water, ethanol, and the like. In
general, the solvated forms are considered equivalent to the
unsolvated forms for the purposes of the present invention.
[0034] One aspect of the invention is a sustained-release
pharmaceutical composition comprising an aminopyridine dispersed in
a sustained release matrix such as a rate-controlling polymer. The
composition of the present invention is capable of providing, upon
administration to a patient, a release profile of the aminopyridine
extending over at least 6 hours, preferably least about 12 hours,
and more preferably at least 24 hours or more. Preferably the
aminopyridine concentration in the composition is a therapeutically
effective amount, and preferably the aminopyridine is dispersed
uniformly throughout the release matrix. A therapeutically
effective amount is an amount of a potassium channel blocker,
preferably an aminopyridine compound, that when administered to a
patient or subject, ameliorates a symptom of a neurological
disease.
[0035] When the compositions of the present invention are
administered to a patient, the concentration of the aminopyridine
in the patient's plasms over time (release profile) may extend over
a period of at least 6 hours, preferably over at lease 8 hours, and
more preferably over at about 12 hours. The compositions may
provide in single dose a mean maximum plasma concentration of
aminopyridine in the patient of from about 15 to about 180 ng/ml; a
mean T.sub.max from about 1 to about 6 hours, more preferably about
2 to about 5.2 hours after administration of the composition to the
patient.
[0036] In one embodiment, aminopyridine is administered to a
subject at a dose and for a period sufficient to allow said subject
to tolerate said dose without showing my adverse effects and
thereafter increasing the dose at selected intervals of time until
a therapeutic dose is achieved. In one embodiment the medicament is
administered to a subject at a dose and for a period sufficient to
allow said subject to tolerate said dose without showing any
adverse effects and thereafter increasing the dose of aminopyridine
at selected intervals of time until a therapeutic dose is achieved.
For example, at the commencement of treatment aminopyridine is
preferably administered at a dose less than 15 mg/day until a
tolerable state is reached. Suitably when said tolerable state is
reached, the dose administered may be increased by amounts of at
least 5-15 mg/day until said therapeutic dose is reached. The
method can include scheduling administration of doses of the
pharmaceutical so that the concentration of the aminopyridine in
the patient is at about the minimum therapeutically effective level
to ameliorate the neurological condition, yet relatively lower
compared to the maximum concentration in order to enhance restful
periods for the patient during the day. Preferably the method
provides for the treatment of neurological diseases characterized
by a degradation of nerve impulse transmission comprising the step
of administering to a patient a composition of the present
invention.
[0037] The formulations and compositions of the present invention
exhibit a specific, desired release profile which maximizes the
therapeutic effect while minimizing adverse side effects. The
desired release profile may be described in terms of the maximum
plasma concentration of the drag or active agent (C.sub.max) and
the plasma concentration of the drug or active agent at a specific
dosing interval (C.sub..tau.). A ratio of C.sub.max to
C.sub..tau.(C.sub.max:C.sub..tau.) may be calculated from the
observed C.sub.max and C. A dosing interval (.tau.) is the time
since the last administration of the drug or active agent. In the
present application, the dosing interval (.tau.) is twelve (12)
hours, therefore C is the concentration of the drug or active agent
at twelve (12) hours from the last administration,
[0038] Additionally, the formulations and compositions of the
present invention exhibit a desired release profile that may be
described in terms of the maximum plasma concentration of the drug
or active agent at steady state (C.sub.maxSS) and the minimum
plasma concentration of the drug or active agent at steady state
(C.sub.minSS). Steady state is observed when the rate of
administration (absorption) is equal to the rate of elimination of
the drug or active agent. A ratio of C.sub.maxSS to C.sub.minSS
(C.sub.maxSS:C.sub.minSS) may be calculated from the observed
C.sub.maxSS and C.sub.minSS. In addition, the formulations and
compositions of the present invention exhibit a desired release
profile that may be described in terms of the average maximum
plasma concentration of the drag or active agent at steady state
(C.sub.avSS).
[0039] Another embodiment is a sustained release tablet of a
sustained release matrix and an aminopyridine, said tablet exhibits
a release profile to obtain a C.sub.max:C ratio in vivo of 1.0 to
3.5, and more preferably a C.sub.max:C ratio of about 1.5 to about
3.0. In another preferred embodiment, the
C.sub.max:C.sub..tau.ratio is about 2.0 to about 3.0. The
aminopyridine may comprise 4-aminopyridine. The sustained release
matrix, may include for example, hydroxypropylmethylcellulose, or
other rate controlling matrices that are suitable for controlling
the release rate of an aminopyridine for use in the pharmaceutical
compositions of the present invention.
[0040] In a further embodiment, a sustained release tablet of a
sustained release matrix and an aminopyridine, wherein the tablet
exhibits an in vivo C.sub.max:C ratio of about 2.0 to about
3.0.
[0041] A method of treating a disease associated with a
neurological disorder is also provided. The method may include
administering an 4-aminopyridine on a dosing regimen to obtain an
in vivo ratio C.sub.max:C ratio of 1.0 to 3.5. In more preferred
embodiments, the C.sub.max:C ratio is about 1.5 to 3.0, and about
2.0 to about 3.0. Such neurological disorders include a spinal cord
injury, Alzheimer's disease, multiple sclerosis, ALS or the like.
The dosing regimen of the method of treating a neurological
disorder may comprise administering a tablet of said aminopyridine
twice daily dosing. Is a further embodiment, the twice-daily dosing
regiment of the aminopyridine may comprise every twelve hours.
[0042] Another embodiment is a method of treating a neurological
disorder comprising administering an aminopyridine to achieve an in
vivo C.sub.maxC ratio of 1.0 to 3.5, and more preferably the
C.sub.max:C ratio is about 1.5 to about 3.25. In another preferred
embodiment, the ratio of the method of treating a neurological
disorder is about 2.0 to about 3.0.
[0043] Another aspect is a therapeutic composition of a release
matrix and an active amminopyridine, wherein the aminopyridine is
released from the release matrix at a rate to maintain a
C.sub.max:C ratio of 1.0 to 3.5, and more preferably about 1.5 to
about 3.0. In another preferred embodiment, the C.sub.max:C ratio
of the therapeutic composition is about 2.0 to about 3.0.
[0044] Another embodiment is a sustained release tablet of a
sustained release matrix and an aminopyridine, said tablet exhibits
a release profile to obtain a C.sub.max:C ratio in vivo of 1.0 to
3.5 and a C.sub.avSS of about 15 ng/ml to about 35 ng/ml, and more
preferably a C.sub.max:C ratio of about 1.5 to about 3.0. In
another preferred embodiment, the C.sub.max:C ratio is about 2.0 to
about 3.0.
[0045] In another embodiment, a sustained release tablet comprising
a sustained release matrix and an aminopyridine, said tablet
exhibiting an in vivo C.sub.max:C ratio of about 2.0 to about 3.0
and a C.sub.avSS of about 15 ng/ml to about 35 ng/ml is
provided.
[0046] A further embodiment is a method of treating a disease
associated with a neurological disorder, said method comprising
administering an aminopyridine on a dosing regimen to obtain an in
vivo C.sub.max:C ratio of 1.0 to 3.5 and a C.sub.avSS of about 15
ng/ml to about 35 ng/ml.
[0047] A further aspect is a method of heating a disease associated
with a neurological disorder comprising administering an
aminopyridine to achieve an in vivo C.sub.max:C ratio of 1.0 to 3.5
and a C.sub.avSS about 15 ng/ml to about 35 ng/ml.
[0048] In a further aspect, a therapeutic composition comprised of
a release matrix and an active aminopyridine, said aminopyridine
being released from said release matrix at a rate to maintain an in
vivo C.sub.max:C ratio of 1.0 to 3.5 and a C.sub.avSS of about 15
ng/ml to about 35 ng/ml is provided.
[0049] In another embodiment, a method of treating a disease
associated with a neurological disorder, said method comprising
administering an aminopyridine on a dosing regimen to obtain an in
vivo C.sub.maxSS:C.sub.minSS ratio of 1.0 to 3.5 and a C.sub.avSS
of about 15 ng/ml to about 35 ng/ml is provided.
[0050] A further aspect is a sustained release composition
comprising a sustained release matrix and an aminopyridine, wherein
said composition provides a C.sub.avSS of about 15 ng/ml to about
35 ng/ml. In a further aspect, a sustained release tablet,
comprising a sustained release matrix and an aminopyridine, said
tablet exhibiting a C of about 20 ng/ml to about 35 ng/ml is
provided.
[0051] In another embodiment, a sustained release tablet composing
a sustained release matrix and an aminopyridine, said tablet
exhibiting a of about 30 ng/ml to about 55 ng/ml. In a further
embodiment, a sustained release tablet comprising a sustained
release matrix and an aminopyridine, said tablet exhibiting a
C.sub.maxSS of about 24 ng/ml to about 40 ng/ml is provided. In a
further embodiment, a sustained release tablet comprising sustained
release matrix and an aminopyridine, said tablet exhibiting a
C.sub.maxss of about 35 ng/ml to about 55 ng/ml is provided.
[0052] A further aspect is a method of treating a disease
associated with a neurological disorder comprising administering an
aminopyridine on a dosing regimen in vivo C.sub.maxSS:C.sub.minSS
ratio of 1.0 to 3.5, preferably an in vivo C.sub.maxSS:C.sub.minSS
ratio of about 1.5 to about 3.0, and more preferably about 2.0 to
about 3.0. The dosing regimen may consist of administering the
aminopyridine twice daily, snore preferably every twelve hours.
[0053] The amount of a pharmaceutically acceptable quality
aminopyridine, salt, solvated, or prodrug thereof included in the
pharmaceutical composition of the present invention will vary,
depending upon a variety of factors, including, for example, the
specific potassium channel blocker used, the desired dosage level,
the type and amount of rate-controlling polymer matrix used, and
the presence, types and amounts of additional materials included in
the composition. Preferably, the aminopyridine comprises from about
0.1 to about 13% w/w, more preferably from about 0.5 to about 6.25
% w/w. In as even more preferable embodiment of the present
invention the aminopyridine is present from about 0.5 to 4.75 % w/w
of the pharmaceutical composition. It has been found that for many
indications a weight (wt/wt %) above about 5% can result in
undesirable side effects. Accordingly, a weight percentage less
than about 4.75% is desired. The amount of aminopyridine, or a
derivative thereof, in the formulation varies depending on the
desired dose for efficient drug delivery, the molecular weight, and
the activity of the compound. The actual amount of the used drug
can depend on the patient's age, weight, sex, medical condition,
disease or any other medical criteria. The actual drug amount is
determined according to intended medical use by techniques known in
the art. The pharmaceutical dosage formulated according to the
invention may be administered once or more times per day,
preferably two or fewer times per day as determined by the
attending physician.
[0054] Typically, the 4-aminopyridine is formulated in tablets or
other pharmaceutical composition in amounts of about 0.5 mg to
about 80 mg, preferably from about 5 to about 50 mg of
4-aminopyridine. Preferably, the amount of an aminopyridine in the
composition is formulated to maintain therapeutic levels of the
aminopyridine in patient's blood up to about 80 ng/ml.
[0055] The matrix in which the aminopyridine is homogeneously
dispersed provides a sustained release of the aminopyridine into
the plasma of the patient. Polymeric matrices suitable for
controlling the release rate of aminopyridines for use in the
pharmaceutical compositions of the present invention include
hydrophilic polymers; hydrophobic polymers or mixtures of
hydrophilic and/or hydrophobic polymers that are capable of forming
sustained-release dosage formulation in combination with an
aminopyridine. Such matrices are also capable of preventing
degradation and loss of the aminopyridine from the composition.
Examples of suitable matrices either alone or in combination
include but are not limited to hydroxyalkylcelluloses, such as
hydroxypropylcellulose and HPMC, hydroxyethyl cellulose,
alkylcelluloses such as ethycellulose and methylcellulose,
carboxymethylcellulose; sodium carboxymethylcellulose, hydrophilic
cellulose derivatives, polyethylene oxide, polyethylene glycol,
polyvinylpyrrolidone; cellulose acetate, cellulose acetate
butyrate, cellulose acetate phthalate, cellulose acetate
trimellitate, polyvinylacetate phthalate,
hydroxypropylmethylcellulose phthalate,
hydroxypropylmethyl-cellulose acetate succinate; poly(alkyl
methacrylate); and poly(vinyl acetate). Examples of other suitable
polymers include, either alone or in combination,
carboxyvinylpolymers, poly(vinyl) alcohols), glucans,
scleroglucans, mannans, xanthans, and, in general, cellulose,
crosslinked polyvinylpyrrolidone, carboxymethyl starch, potassium
methacrylate-divinylbenzene copolymer, hydroxypropylcyclodextrin,
alpha, beta, gamma cyclodextrin or derivatives and other dextran
derivatives, natural gums, seaweed extract, plant exudate, agar,
agarose, algin, sodium alginate, potassium alginate, carrageenan,
kappa-carrageenan, lambda-carrageenan, fucoidan, furcellaran,
laminarin, hypnea, eucheuma, gum arabic, gum ghatti, gum karaya,
gum tragacanth, guar gum, locust bean gum, okra gum, quince
psyllium, flax seed, arabinogalactin, pectin, scleroglucan,
dextran, amylose, amylopectin, dextrin, acacia, karaya, guar, a
swellable mixture of agar and carboxymethyl cellulose, a swellable
composition comprising methyl cellulose mixed with a sparingly
cross-linked agar, a blend of sodium alginate and locust bean
gumpolymers or copolymers derived from acrylic or methacrylic acid
esters, copolymers of acrylic and methacrylic acid esters, zein,
waxes, shellac and hydrogenated vegetable oils.
[0056] In certain embodiments, the matrix is a rate-controlling
polymer such as but not limited to HPMC. HPMC is a
hydroxyalkylcellulose characterized by a polymeric backbone of
cellulose, a natural carbohydrate that contains a basic repeating
structure of anhydroglucose units, sad varying ratios of
hydroxypropyl and methyl substitution at the three available
substitution positions. The amount of substituent groups on the
anhydroglucose units can be designated by weight percent or by the
average number of substituent groups attached to the ring. For
example, if all three available positions on each unit are
substituted, the degree of substitution may be designated as 3
whereas if an average of two positions on each ring are reacted,
the degree of substitution is correspondingly designated as 2.
[0057] According to one method of manufacture, cellulose fibers are
heated with a caustic solution and then treated with methyl
chloride and propylene oxide to produce HPMC. The fibrous reaction
product is purified and ground to a fine, uniform powder.
Especially suitable HPMCs manufactured according to this process
are sold under the Methocel K designation, such as Methocel K100LV,
Methocel K15M, Methocel K4M and Methocel K100M, all available from
the Dow Chemical Co. Methocel K products are generally
characterized by a methoxyl degree of substitution of about 1.4, a
methoxyl percentage of about 22%, a hydroxypropyl molar
substitution of about 0.2, a hydroxypropyl percentage of about 8%,
and a particle size of 90%<100 mesh. In a preferred embodiment,
the rate-controlling polymer is HPMC sold under the name Methocel
K100LV.
[0058] Interaction between the matrix, excipients or other
additives and the potassium channel blocker through van der Waal
forces, hydrogen bonding, coordination, solvation, or complex
formation may also be desirable to control the release of the
potassium channel blocker from the composition and to prevent
evaporation and or degradation of the potassium channel blocker
within the composition.
[0059] In preferred embodiments, the rate-controlling polymer is
HPMC. In such embodiments, the HPMC preferably has a viscosity (2
wt % solution at 20.degree. C.) of about 100 to 100,000 cps, more
preferably 100 to 30,000 cps. Especially suitable HPMCs am Methocel
K types, such as Methocel O00LV, Methocel K15M, Methocel K4M and
Methocel K100M, available from the Dow Chemical Co. The
hydroxypropylmethylcelluloses used according to the invention
preferably have a molecular weight of about 80,000 to about
1,150,000, more preferably about 80,000 to about 600,000.
Especially suitable is a hydroxypropylmethylcellulose sold under
the name Klucel LF available from Aqualon and Nippon Soda Co.,
which has a molecular weight of 100,000. The poly(ethylene oxide)
used according to the invention preferably has a molecular weight
of about 100,000 to about 7,000,000, more preferably about 900,000
to about 7,000,000. An especially suitable poly(ethylene oxide) is
sold under the name Polyox WSR Coagulant available from the Dow
Chemical Co., which has a molecular weight of 5,000,000. The
ethylcelluloses used according to the invention preferably have a
viscosity of about 3 to about 110 cps, more preferably about 7 to
about 100 cps. In particularly preferred embodiments, the
rate-controlling polymer is the HPMC sold under the name Methocel
K100LV.
[0060] In another embodiment, the rate-controlling polymer is HPC.
HPCs used according to the invention preferably have a viscosity (2
wt % solution at 20.degree. C.) of about 10 to 100,000 cps, mote
preferably 100 to 30,000 cps, md a molecular weight of about 80,000
to about 1,150,000, more preferably about 80,000 to about 600,000.
An especially suitable HPC is sold under the name Klucel LP
available from Aqualon and Nippon Soda Co, which has a molecular
weight of about 95,000.
[0061] In another embodiment, the rate-controlling polymer release
matrix is poly(ethylene oxide) preferably having a molecular weight
of about 100,000 to about 7,000,000, more preferably about 900,000
to about 7,000,000. An especially suitable poly(ethylene oxide) is
sold under the name Polyox WSR Coagulant available from the Dow
Chemical Co. which has a molecular weight of about 5,000,000.
Suitable ethylcelluloses that may be used as the rate-controlling
polymer in accordance with the invention preferably have a
viscosity of about 3 to about 1.10 cps, more preferably about 7 to
about 100 cps.
[0062] The polymeric matrix of the drug delivery of the invention
may additionally also contain a hydrophobic polymer. Suitable
hydrophobic polymers are hydrophobic cellulose derivatives, such as
ethyl cellulose, fats, such as glycerol palmitostearate, waxes,
such as beeswax, glycowax, castrowax, caranubawax, glycerol
monostearate or stearylalcohol, hydrophobic polyacrlamide
derivatives and hydrophobic methacrylic acid derivatives.
[0063] A hydrophobic polymer may be included as part of a release
matrix, in order to modify the release kinetics. Preferably such a
hydrophobic polymer is used only in a mixture of hydrophilic and
hydrophobic polymers. In such a mixture, the hydrophobic polymer
controls the water penetration rate into the delivery system. For
example, incorporation of a hydrophobic polymer into the polymer
matrix and the ratio of hydrophilic to hydrophobic polymer thus
changes the erosion characteristics of the tablet. The hydrophobic
polymer shows down the water penetration into the tablet and thus
slows the tablet erosion.
[0064] The amount of the release matrix included in the
pharmaceutical composition of the present invention will vary
depending upon a variety of factors, including, for example, the
specific matrix used, its molecular weight, is hydrophilicity, the
type and amount of potassium channel blocker used, and the
presence, types and amounts of additional materials included in the
composition. Preferably, the rate-controlling polymer comprises
from about 20 to about 96 % w/w, mom preferably from about 20 to
about 10 % w/w, of the pharmaceutical composition. It is desirable
that the matrix permit release of the potassium channel blocker in
the lower gastrointestinal tract.
[0065] In general, when the viscosity grade of the matrix polymer
is higher, the release-rate of the drug is slower. The size, shape
and surface area of the tablet may also be modified to increase or
decrease the release rate of the aminopyridine from the tablet.
[0066] In preferred embodiments, the aminopyridine is milled prior
to dispersal in the rate-controlling polymer in order to ensure
proper particle size distribution. Milling of the aminopyridine may
be accomplished by any suitable means such as, for example, an air
jet mill, a micronizer, a hammer mill, a ball mill, a cone mill, or
other suitable type of mill. The milling is preferably accomplished
so that the particle size distributions permit satisfactory dosage
content uniformity and dissolution profiles. The particle size
distribution may be .+-.25% of the mean particle size use in the
formulation. In a preferred embodiment, the aminopyridine is milled
so that 90% of the particles ate smaller than about 1.5 mm, more
preferably smaller than about 1 mm, and even more preferably
smaller than about 300 .mu.m; 50% of the particles are smaller than
about 1 mm, more preferably smaller than about 600 .mu.m, and even
mom preferably smaller than about 150 .mu.m; and 10% of the
particles are smaller than about 500 .mu.more preferably smaller
than about 400 .mu.m, and even more preferably smaller than about
50 .mu.m.
[0067] Suitable screen sizes are from about #10 to about #400 mesh,
preferably #24 to #60 mesh. In certain embodiments, milling of the
aminopyridine may involve multiple passes of the material through
mesh screens at the same or different mill blade orientations. In
one embodiment, the milling process involves two passes of 4-AP
through a #24 mesh screen in a FitzMill.RTM. comminutor using two
different mill blade orientations.
[0068] The aminopyridine, in either milled or un-milled form, is
dispersed in the release matrix to form the pharmaceutical
composition such that the aminopyridine is distributed
substantially uniformly throughout the entirety of the matrix. The
dispersal of aminopyridine throughout the matrix may be
accomplished by any method capable of achieving substantial
homogeneity. Preferred dispersal methods include the use of
blenders, for example, planetary and cross-flow blenders. While
blending time will vary depending on a variety of factors,
including, for example, the specifics of the aminopyridine and
rate-controlling polymer used, substantially uniform distribution
is preferably realized within from about 10 to about 35 minutes of
blending.
[0069] The release matrix aminopyridine formulation is preferably
fabricated into tablets, capsules or grannies for oral use. The
rate of aminopyridine release from the tablets may be controlled by
the erosion mechanism of the release matrix from which
aminopyridine is released. In general, for producing a tablet on an
industrial scale, the drug and polymer are granulated alone or in
combination. Preferably the release of the aminopyridine from the
matrix of the pharmaceutical composition is relatively linear over
time. Preferably the matrix provides a release profile that gives a
therapeutically effective concentration of the aminopyridine in the
plasma of the patient permitting a once per day or twice per day
dosing. Preferably the sustained release aminopyridine formulation
for oral administration to patients includes from about 0.0001 mole
to about 0.0013 mole aminopyridine that provides a mean maximum
plasma concentration of aminopyridine from about 15 to about 180
ng/ml, a mean T.sub.max of about 2 to about 5 hours after
administration, and a mean minimum plasma concentration of from
about 10 to 60 ng/ml at about 8-24 hours after administration.
[0070] The formulations of the invention are prepared by procedures
known in the art, such as, for example, by the dry or wet method.
The method selected for manufacturing affects the release
characteristics of the finished tablet. In one method, for example,
the tablet is prepared by wet granulation in the presence of either
water or an aqueous solution of the hydrophilic polymer or using
other binder as a granulating fluid. In alternative, organic
solvent, such as isopropyl alcohol, ethanol and the like, may be
employed with or without water. The drug and polymer may be
granulated alone or in combination. Another method for preparation
of the tablet which may be used requires using a drug-polymer
dispersion in organic solvents in the presence or absence of water.
Where the aminopyridine or its derivative has very low solubility
in water it may be advantageous to reduce the particle size, for
example, by milling it into fine powder and in this way to control
the release kinetics of the drug and enhance its solubility.
[0071] The hardness of the tablets of the present invention may
vary, depending on a variety of factors, including, for example,
the relative amounts and specific types of ingredients used, the
tableting equipment employed, and the selected processing
parameters. The pressure used to prepare the tablets can influence
the release profile of the aminopyridine into the patient. The
pressure used to prepare the tablets of the present invention may
vary depending upon their surface area and the amount and particle
size of aminopyridine, additive, excipicnts, or binders included in
the tablet. The degree of hydration and solvation of the components
in the composition will also be important in determining the hard
ness of the tablets. Preferably the formed tablets have a hardness
in the range of from 80-400 N, and more preferably from 150 to 300
N.
[0072] Pellets or a combination of pellets in accordance with the
invention may also be filled into hard or soft gelatin capsules.
The pellets included in the capsule may have different amounts of
aminopyridine in the pellets and or different matrices. Various
amounts of the pellets may be used to tailor the total amount
aminopyridine delivered as well as to alter the release and
concentration profile of the aminopyridine in the patient.
[0073] The effects of various matrices, concentrations of
aminopyridine, as well as various excipients and additives to the
composition on the concentration of the channel blocker on the
dissolution rate may be monitored for example using a type H
dissolution apparatus according to U.S. Pharmacopoeia XXII, or USP
Apparatus II (Paddle Method). Clinical evaluations may be used to
study the effects on plasma levels of various release matrices,
concentrations of aminopyridine, as well as various excipients and
additives. Plasma aminopyridine concentrations may be used to
calculate pharmacokinetic data (release profiles) including
apparent absorption and elimination rates, area-under-the curve
(AUC), maximum plasma concentration (C.sub.max), time to maximum
plasma concentration (T.sub.max), absorption half-life
(T.sub.1/2(abs)), and elimination half-life (T.sub.1/2 (elim)).
Pharmacodynamic effects may be assessed based upon response tests,
such as muscle strength improvement or reduction in spaseticity for
patients with multiple sclerosis or spinal cord injury or other
tests as would be known to those skilled in the art. Plasma
aminopyridine concentration in blood plasma or cerebral spinal
fluid may be monitored using liquid chromatography/MS/MS assay
methods.
[0074] The drug delivery of the invention can utilize any suitable
dosage unit form. Specific examples of the delivery system of the
invention are tablets, tablets which disintegrate into granules,
capsules, sustained release microcapsules, spheroids, or any other
means which allow for oral administration. These forms may
optionally be coated with pharmaceutically acceptable coating which
allows the tablet or capsule to disintegrates in various portions
of the digestive system. For example a tablet may have an enteric
coating which prevents it from dissolving until it reaches the more
basic environment of the small intestine.
[0075] The dispersion of the aminopyridine throughout the release
matrix imparts enhanced stability characteristics in the dosage
formulation. This enhanced stability is achieved without loss of
the desired sustained-release profile. Preferably the release
profile, which may be measured by dissolution rate is linear or
approximately linear, preferably the release profile is measured by
the concentration of the aminopyridine in the plasma in the patient
and is such to permit twice daily (BID) dosing.
[0076] The pharmaceutical composition of the present invention can
include also auxiliary agents or excipients, for example, glidants,
dissolution agents, surfactants, diluents, binders including low
temperature melting binders, disintegrates and/or lubricants.
Dissolution agents increase the dissolution rate of the
aminopyridine from the dosage formulation and can function by
increasing the solubility of the aminopyridine. Suitable
dissolution agents include, for example, organic acids such as
citric acid, fumaric acid, tartaric acid, succinic acid, ascorbic
acid, acetic acid, malic acid, glutaric acid and adipic acid, and
may be used alone or in combination. These agents may also be
combined with salts of the acids, e.g, sodium citrate with citric
acid, in order to produce a buffer system.
[0077] Other agents that may alter the pH of the microenvironment
on dissolution and establishment of a therapeutically effective
plasma concentration profile of the aminopyridine include salts of
inorganic acids and magnesium hydroxide. Other agents that may be
used are surfactants and other solubilizing materials. Surfactants
that are suitable for use in the pharmaceutical composition of the
present invention include, for example, sodium lauryl sulphate,
polyethylene separates, polyethylene sorbitan fatty acid esters,
polyoxyethylene castor oil derivatives, polyoxyethylene alkyl
ethers, benzyl benzoate, cetrimide, cetyl alcohol, docusate sodium,
glyceryl monooleate, glyceryl monostearate, glyceryl
palmitostearate, lecithin, medium chain triglycerides,
monoethanolamine, oleic acid, poloxamers, polyvinyl alcohol and
sorbitan fatty acid esters.
[0078] Diluents that are suitable for use in the pharmaceutical
composition of the present invention include, for example,
pharmaceutically acceptable inert fillers such as microcrystalline
cellulose, lactose, sucrose, fructose, glucose dextrose, or other
sugars, dibasic calcium phosphate, calcium sulfate, cellulose,
ethylcellulose, cellulose derivatives, kaolin, mannitol, lactitol,
maltitol, xylitol, sorbitol, or other sugar alcohols, dry starch,
saccharides, dextrin, maltodextrin or other polysaccharides,
inositol or mixtures thereof. The diluent is preferably a
water-soluble diluent. Examples of preferred diluents include, for
example: microcrystalline cellulose such as Avicel PH112, Avicel
PH101 and Avicel PH102 available from FMC Corporation; lactose such
as lactose monohydrate, lactose anhydrous, and Pharmatose DCL 21;
dibasic calcium phosphate such as Emcompress available-from Penwest
Pharmaceuticals; mannitol; starch; sorbitol; sucrose; and glucose.
Diluents are carefully selected to match the specific composition
with attention paid to the compression properties. The diluent is
preferably used in an amount of about 10 to about 80% by weight,
preferably about 20 to about 50% by weight, of the
sustained-release composition.
[0079] Glidants are used to improve the flow and compressibility of
ingredients during processing. Suitable glidants include, for
example, colloidal silicon dioxide, a sab-micron fumed silica that
can be prepared by, for example, vapor-phase hydrolysis of a
silicon compound such as silicon tetrachloride. Colloidal silicon
dioxide is a sub-micron amorphous powder which is commercially
available from a number of sources, including Cabot Corporation
(under the tradename Cab-O-Sil); Degussa, Inc. (under the tradename
Aerosil); and E.I. DuPont & Co. Colloidal silicon dioxide is
also known as colloidal silica, fumed silica, light anhydrous
silicic acid, silicic anhydride, and silicon dioxide fumed, among
others. In one embodiment, the glidant comprises Aerosil 200.
[0080] Another agent that may be used is a surfactant, dissolution
agent and other solubilizing material. Surfactants that are
suitable for use in the pharmaceutical composition of the present
invention include, for example, sodium lauryl sulphate,
polyethylene stearates, polyethylene sorbitan fatty acid esters,
polyoxyethylene castor oil derivatives, polyoxyethylene alkyl
ethers, benzyl benzoate, cetrimide, cetyl alcohol, docusate sodium,
glyceryl monooleate, glyceryl monostearate, glyceryl
palmitostearate, lecithin, medium chain triglycerides,
monoethanolamine, oleic acid, poloxamers, polyvinyl alcohol and
sorbitan fatty acid esters. Dissolution agents increase the
dissolution rate of the aminopyridine and function by increasing
the solubility of the aminopyridine. Suitable dissolution agents
include, for example, organic acids such as citric acid, fumaric
acid, tartaric acid, succinic acid, ascorbic acid, acetic acid,
malic acid, glutaric acid and adipic acid, which may be used alone
or in combination. These agents may also be combined with salts of
the acids, e.g. sodium citrate with citric acid, in order to
produce a buffer system. Other agents that may be used to alter the
pH of the microenvironment on dissolution include salts of
inorganic acids and magnesium hydroxide.
[0081] The pellets or granulates may be compressed into tablets
using a binder and/or hardening agent commonly employed in tablets
such as microcrystalline cellulose sold under the Trade Mark
"AVICEL" or a co-crystallized powder of highly modified dextrins
(3% by weight) and sucrose sold under the Trade Mark "DI-PAC" in
such a way that the specific dissolution rate of the pellets is
maintained. Binders that are suitable for use in the pharmaceutical
composition of the present invention include, for example,
starches, ethyl cellulose, polyvinylpyrrolidone, acacia, guar gum,
hydroxyethylcellulose, agar, calcium carrageenan, sodium alginate,
gelatin, saccharides (including glucose, sucrose, dextrose and
lactose), molasses, extract of Irish moss, panwar gum, ghatti gum,
mucilage of isapol husk, carboxymethylcellulose, methylcellulose,
veegum, larch arbolactan, polyethylene glycols, waxes and mixtures
thereof. Suitable low temperature melting binders include, for
example, polyethylene glycols such as PEG 6000,cetostearyl alcohol,
cetyl alcohol, polyoxyethylene alkyl ethers, polyoxyethylene castor
oil derivatives, polyoxyethylene sorbitan fatty acid esters,
polyoxyethylene stearates, poloxamers, and waxes.
[0082] Disintegrants that are suitable for use in the
pharmaceutical composition of the present invention include, for
example, starches, sodium starch glycollate, crospovidone,
croscarmellose, microcrystalline cellulose, low substituted
hydroxypropyl cellulose, pectins, potassium
methacrylate-divinylbenzene copolymer, polyvinyl alcohol),
thylamide, sodium bicarbonate, sodium carbonate, starch
derivatives, dextrin, beta cyclodextrin, dextrin derivatives,
magnesium oxide, clays, bentonite and mixtures thereof.
[0083] The active ingredient of the present invention may be mixed
with excipients which are pharmaceutically acceptable and
compatible with the active ingredient and in amounts suitable for
use in the therapeutic methods described herein. Various excipients
may be homogeneously mixed with the aminopyridines of the present
invention as would be known to those skilled in the art. For
example, aminopyridines may be mixed or combined with excipients
such as but not limited to microcrystalline cellulose, colloidal
silicon dioxide, lactose, starch, sorbitol, cyclodextrin and
combinations of these.
[0084] Lubricants that are suitable for use in the pharmaceutical
composition of the present invention include agents that act on the
flowability of the powder to be compressed include but are not
limited to silicon dioxide such as Aerosil 200, talc; stearic acid,
magnesium stearate, calcium stearate, hydrogenated vegetable oils,
sodium benzoate, sodium chloride, leucine carbowax, magnesium
lauryl sulfate, and glyceryl monostearate.
[0085] To further improve the stability of the aminopyridine in the
sustained release composition, an antioxidant compound can be
included. Suitable antioxidants include, for example: sodium
metabisulfite; tocopherols such as .alpha., .beta.,
.delta.-tocopherol esters and .alpha.-tocopherol acetate; ascorbic
acid or a pharmaceutically acceptable salt thereof; ascorbyl
palmitate; alkyl gallates such as propyl gallate, Tenox PG, Tenox
s-1; sulfites or a pharmaceutically acceptable salt thereof; BHA;
BHT; and monothioglycerol.
[0086] In another embodiment, the pharmaceutical composition of the
present Invention comprises a rate-controlling polymeric matrix
comprising of a hydrogel matrix. For instance, an aminopyridine may
be compressed into a dosage formulation containing a
rate-controlling polymer, such as HPMC, or mixture of polymers
which, when wet, will swell to form a hydrogel. The rate of release
of the aminopyridine from this dosage formulation is sustained both
by diffusion from the swollen tablet mass and by erosion of the
tablet surface over time. The rate of release of the aminopyridine
may be sustained both by the amount of polymer per tablet and by
the inherent viscosities of the polymers used.
[0087] According to another aspect of the invention, there Is
provided a stable, sustained-release oral dosage formulation which
includes an effective amount a aminopyridine dispersed in a release
matrix, and which, upon administration to a patient or as part of a
therapy regiment, provides a release profile (of therapeutically
effective blood plasma level of the aminopyridine) extending for a
period of at least 6 hours, preferably at least 12 hours, and more
preferably at least 24 hours. In another embodiment, the stable,
controlled-release oral dosage form provides, upon administration
to a patient, a therapeutically effective blood plasma level of the
aminopyridine for a period of at least 6 hours, preferably at least
12 hours, and more preferably at least 24 hours.
[0088] The dosage formulation may assume any form capable of
delivering orally to a patient a therapeutically effective amount
of a aminopyridine dispersed in a rate-controlling polymer.
Preferably, the dosage formulation comprises a monolithic
tablet.
[0089] Tablet weight will also vary in accordance with, among other
things, the aminopyridine dosage, the type and amount of
rate-controlling polymer used, and the presence, types and amounts
of additional materials. Assuming 4-aminopyridine dosages of from
about 2 mg to about 120 mg; tablet weights can range from about 50
mg to about 1200 mg per tablet, and preferably from 250 to 500 mg,
and more preferably about 400 mg.
[0090] The dosage formulation of the present invention may comprise
also one or more pharmaceutical acceptable excipients as mentioned
above. In preferred embodiments, the dosage formulation will
comprise diluents and a lubricant in addition to the aminopyridine
unit dose and the rate-controlling polymer. A particularly
preferred diluents is microcrystalline cellulose sold under the
name A vicel PH101, and a particularly pretested lubricant is
magnesium stearate. When these materials are used, the magnesium
stearate component preferably comprises from about 0.2 to about
0.75 % w/w of the dosage formulation, and the macrocrystalline
cellulose along with the rate controlling polymer and aminopyridine
comprises the balance of the formulation. For example, a tablet
formulation including a aminopyridine x % w/w, a rate-controlling
polymer y % w/w, and macrocrystalline cellulose z %, the magnesium
stearate amount would be (100-(x+y+z) where
0.2%.ltoreq.(100-(x+y+z)).ltoreq.0.75% w/w. As would be known to
those skilled in the art, the amount of art additives such as
magnesium stearate may vary depending upon the shear rate used to
perform the mixing and the amount of such an additive may be
changed without limitation to obtain a satisfactory dissolution
rate or plasma level of the aminopyridine.
[0091] As used herein, the term "sustained-release" includes the
release of a aminopyridine from the dosage formulation at a
sustained rate such that a therapeutically beneficial blood level
below toxic levels of the aminopyridine is maintained over a period
of at least about 12 hours, preferably about 24 hours or more.
Preferably, the amount of the aminopyridine in the oral dosage
formulations according to embodiments of the present Invention
establish a therapeutically useful plasma concentration through BID
administration of the pharmaceutical composition.
[0092] If desired, the dosage formulations of this invention may be
coated with a sustained-release polymer layer so as to provide
additional sustained-release properties. Suitable polymers that can
be used to form this sustained release layer include, for example,
the release matrices listed above. As desired, the dosage
formulation of the invention can be provided also with a
light-protective and/or cosmetic film coating, for example,
film-formers, pigments, anti-adhesive agents and politicizes. Such
a film-former may consist of fast-dissolving constituents, such as
low-viscosity hydroxypropylmethylcelluose, for example, Methocel E5
or D14, or Pharmacoat 606 (Shin-Etsu), The film coating may also
contain excipients or enteric coatings customary in film-coating
procedures, such as, for example, light-protective pigments, for
example, iron oxide, or titanium dioxide, anti-adhesive agents, for
example, talc, and also suitable plasticizers such as, for example,
PEG 400, PEG 6006, diethyl phthalate or methyl citrate.
[0093] The compositions of the present invention may be used for
the treatment of neurological diseases characterized by a
degradation of nerve impulse transmission by administering to a
patient the oral dosage formulation of the present invention.
Preferably, the administration is twice daily dosage of a
therapeutically effective amount of an aminopyridine, even more
preferably, 4-AP dispersed in HPMC. The administration can also
include scheduling administration of doses of the pharmaceutical so
that the concentration of the aminopyridine in the patient is at
about the minimum therapeutically effective level to ameliorate the
neurological condition, yet relatively lower compared to the
maximum concentration in order to enhance restful periods for the
patient during the day. The compositions may be administered to a
subject at a dose and for a period sufficient to allow said subject
to tolerate said dose without showing any adverse effects and
thereafter increasing the dose of said active agent in the tablets
at selected intervals of time until a therapeutic dose is achieved
in the subject, For example, at the commencement of treatment the
active agent is preferably administered at a dose less than 15
mg/day until a tolerable state is reached. The dose administered
may then be increased by amounts of at least 5-15 mg/day until a
therapeutic dose is reached. For other diseases the amount of the
aminopyridine requited to reach a therapeutically effective amount
for treatment is described in U.S. Pat. No. 5,952,35 the contents
of which are incorporated herein by reference in their
entirety.
[0094] Compositions of the present invention where the potassium
channel blocker is a mono- or di-aminopyridine active agent are
particularly suitable for use in the treatment of a neurological
disease which is characterized by demyelmation of the central
nervous system. more especially multiple sclerosis. The momo- or
di-aminopyridine active agent in accordance with the invention is
also suitable for the treatment of Alzheimer's disease. Additional
features and embodiments of the present invention are illustrated
by the following non-limiting examples.
EXAMPLE 1
[0095] This example illustrates preparation of compositions of the
present invention and their release of an aminopyridine. Tablets in
accordance with the present invention having dosages of 5mg, 7.5mg
and 12.5 mg respectively were manufactured at 5 Kg scale. Materials
were used in the amounts shown in Table 1.
TABLE-US-00001 TABLE 1 % w/w % w/w % w/w Milled 4-AP 1.25 1.875
3.125 (#50 mesh) Methocel K100LV 60 60 60 Avicel PH101 38.15 37.525
36.275 Magnesium stearate 0.2 0.2 0.2 Aerosil 200 0.4 0.4 0.4
Equipment Tablet Horn Noak equipped with 13 .times. 8 mm oval
tooling Press press speed 42,000 tablets/hr Tablet Weight Range
386-404 388-410 388-406 (mg) (96.5-101.0%) (97.0-102.5%)
(97.0-101.5%) Tablet Hardness 200-262 179-292 150-268 Range (N)
Tablet Potency - 97.1 99.1 100.2 mg/tab. (% LC) Mean CU (mg/tab.)/%
5.0 mg/1.0% 7.4 mg/0.7% 12.4 mg/1.1% CV CU Discrete Samples 5.0
mg/1.2% 7.5 mg/1.8% 12.3/1.1% (mg/tab.)/% CV Dissolution (%/hr)
Mean (SD) Mean (SD) Mean (SD) 1 28.9 1.1 29.2 1.8 25.9 1.1 2 42.7
1.8 42.1 1.6 40.2 2.5 3 52.8 1.4 53.0 1.0 49.8 2.1 4 61.4 2.2 61.8
1.5 60.1 2.4 6 75.7 3.1 75.2 1.6 74.8 2.7 10 95.5 3.3 98.7 1.4 93.2
0.9
[0096] Prior to blending, 4-AP was milled through #50 mesh screen
using a Fitzmill.RTM. comminutor. The materials were added into a
Gral 25 bowl in the following order; half Methocel K100LV, Avicel
PH101, Aerosil 200, milled 4-AP and the remaining Methocel K100LV.
The mix was blended for 15 minutes at 175 rpm, then the magnesium
stearate was added and was further blended for 5 minutes at 100
rpm. Samples were taken from top and bottom positions for blend
potency analysis. Weight and hardness checks were performed every
IS minutes by the check-master E3049. Discrete tablet samples were
taken daring the compression process to evaluate intra batch
content uniformity.
EXAMPLE 2
[0097] This example illustrates that the pharmacokinetic profile of
fampridine in compositions of the present invention is altered by
administration in a sustained release tablet matrix compared to
immediate release and controlled release formulations.
[0098] There is a delay in absorption manifested by a lower peak
concentration, without any effect on the extent of absorption. When
given as a single 12.5 mg dose, the peak concentration is
approximately two-thirds lower as compared to peak values following
administration of the (IR) formulation; the time to reach peak
plasma levels was delayed by about 2 hours. FIG. 1 is a graph of
mean plasma profiles associated with the administration to a
patient in both fasted and fed states of a tablet form of 4-AP
(fampridine) in accordance with the present invention compared with
the mean plasma profile associated with the administration of an
immediate release (IR) formulation. As with the IR formulation,
food delayed the absorption of Fampridine-SR. The absorption of
fampridine was approximately 50% slower following ingestion of a
fatty meal, although due to the flatness of the absorption curve,
this may be exaggerated value. Extent of absorption did not differ,
as values for Cmax and AUC were comparable as summarized in Table
2.
TABLE-US-00002 TABLE 2 Pharmacokinetic Parameter Values (Mean .+-.
SD) in Studies Using Fampridine SR, CR, and IR Formulations: Single
Dose Studies in Healthy Adult Male Volunteers C.sub.MAX AUC
(0-.infin.) Study Number Dose (mg) Fed/Fasted (ng/mL) t.sub.MAX
(hours) (ng hr/mL) 0494006 12.5 SR Fed 28.7 .+-. 4.3 5.3 .+-. 0.8
257.0 .+-. 62.7 N = 12 (PD12265) Fasted 25.6 .+-. 3.8 2.8 .+-. 1.3
269.9 .+-. 44.4 12.5 IR Fasted 79.3 .+-. 16.3 0.9 .+-. 0.4 294.2
.+-. 55.6 (PD12266) 1194002 12.5 SR Fasted 28.5 .+-. 4.3 2.9 .+-.
2.4 285.9 .+-. 37.8 N = 12 (PD12907) 12.5 CR Fasted 37.7 .+-. 9.9
3.6 .+-. 0.9 300.0 .+-. 53.6 (4n806) 12.5 IR Fasted 83.5 .+-. 23.5
0.79 .+-. 0.3 274.0 .+-. 59.2 (PS644)
[0099] FIG. 2 is a graph of mean plasma profiles associated with
the administration of a tablet form of 4-AP (fampridine) in
accordance with the present invention compared with the mean plasma
profile associated with the administration of a sustained-release
capsule of the present invention and an immediate release
capsule.
EXAMPLE 3
[0100] This example details the plasma concentration of different
dosage tablets of a aminopyridine in compositions of the present
invention administered to patients with spinal cord injury.
Pharmacokinetic results are presented for the subset of 11 patients
who completed all dose levels. Maximal plasma concentrations and
AUC values increased with increasing dose, with a mean C.sub.max of
152.0 ng/ml, at the highest dose of 120 mg/day. The time of the
peak and the plasma elimination half-lives were independent of
dose. Mean T.sub.max ranged from 2.2 hours to 3.0 hours. The
T.sub.1/2 of fampridine ranged from 5.7 to 6.9 hours. Them were no
apparent differences between males and females. Data from this
study are summarized in Table 3.
TABLE-US-00003 TABLE 3 Pharmacokinetic Parameter Values (Mean .+-.
SD) Following Multiple Oral Doses of Fampridine-SR to 11 Patients
with SCI. Fampridine-SR Dosage C.sub.MAX T.sub.MAX AUC.sub.(0-12)
T.sub.1/2 (mg b.i.d.) (ng/mL) (hours) (ng hr/mL) (hours) 25 63.4
.+-. 11.9 2.2 .+-. 0.9 475.8 .+-. 65.5 6.4 .+-. 1.4 30 83.2 .+-.
20.5 2.4 .+-. 1.4 600.0 .+-. 128.0 6.7 .+-. 3.8 35 90.2 .+-. 14.4
2.4 .+-. 1.2 660.3 .+-. 137.7 6.9 .+-. 3.4 40 103.2 .+-. 19.4 2.6
.+-. 1.3 771.5 .+-. 135.3 6.6 .+-. 2.1 50 145.7 .+-. 27.9 3.0 .+-.
1.9 1047.6 .+-. 258.8 5.8 .+-. 1.9 60 152.0 .+-. 25.2 3.0 .+-. 2.0
1075.0 .+-. 163.0 5.7 .+-. 2.3
EXAMPLE 4
[0101] This example details the pharmacokinetic properties of
Fampridine-SR in tablets of the present invention administered to
patients with multiple sclerosis. Plasma samples were analyzed for
fampridine using a validated LC/MS/MS assay with a sensitivity of 2
ng/mL, Noncompartmental pharmacokinetic parameter values were
calculated using standard methodology.
[0102] This was an open-label, multi-center, dose proportionality
study of orally administered fampridine in patients with multiple
sclerosis. Single doses of fampridine were to be given in
escalating doses (5 mg, 10 mg, 15 mg, and 20 mg) with at least a
four-day interval between administration of each dose of drug.
Safety evaluations were to be performed during the 24 hour period
following administration of fampridine and blood samples were to be
taken at the following times to determine pharmacokinetic
parameters: hour 0 (pre-dose), hours 1-8, and hours 10,12, 14, 18,
and 24.
[0103] Twenty-three subjects received all 4 treatments, and one
subject received only 3 treatments; data from all treatments were
analyzed, Dose-dependent parameters (e.g., peak plasma
concentration and areas-under-the curve) were normalized to a 10 mg
dose for among-dose comparisons. Overall observed time of the peak
plasma concentration (mean and its 95% confidence interval) was
3.75 (3.52,3.98)h, observed peak plasms fampridine concentration
(normalized to a 10 mg dose) was 24.12 (23.8, 26.6) ng/ml,
area-under-the-concentration-time curve (normalized to a 10 mg
dose) was estimated to be 254 (238, 270) ng-h/ml, extrapolated
area-under-the-concentration-time curve (normalized to a 10 mg
dose) was 284 (266, 302) ng-h/ml, terminal rate constant equaled
0.14 (0.13, 0.15)h.sup.-1, terminal half-life was 5.47 (5.05, 5.89)
h and clearance divided by bioavailability (CL/F) was equal to 637
(600, 674) ml/mm.
[0104] Dizziness was the most common treatment-related adverse
event. Other treatment related adverse events included amblyopia,
asthenia, headache, and ataxia. There were clinically significant
changes in clinical laboratory values, ECG parameters, vital signs,
physical examination findings, or neurological examination findings
noted over the course of this study.
[0105] When the plasma concentrations of fampridine were normalized
to the 10.0 mg dose levels, there were no significant differences
between any pharmacokinetic parameter (AUC, C.sub.max, t.sub.1/2 )
in the 5-20 mg dose range. Fampridine was well tolerated at the
doses used in this study. Dose-normalized (to a 10 mg dose)
pharmacokinetic parameter values are summarized in Table 4.
TABLE-US-00004 TABLE 4 Dose-Normalized (at 10 mg) Pharmacokinetic
Parameter Values (Mean .+-. SEM) Following Single Oral
Administration of Fampridine-SR to Patients with MS. C.sub.MAX-
Dose norm t.sub.MAX AUC-norm t.sub.1/2 Cl/F (mg) (ng/mL) (hours)
(ng hr/mL) (hours) (mL/min) 5 26.2 .+-. 0.6 3.9 .+-. 0.2 244.2 .+-.
9.4 5.8 .+-. 0.5 619.8 .+-. 36.2 (n = 24) 10 25.2 .+-. 0.7 3.9 .+-.
0.3 252.2 .+-. 7.8 5.6 .+-. 0.4 641.4 .+-. 39.1 (n = 24) 15 24.6
.+-. 0.7 3.6 .+-. 0.3 263.0 .+-. 7.4 5.5 .+-. 0.4 632.4 .+-. 39.0
(n = 24) 20 24.6 .+-. 0.8 3.6 .+-. 0.3 255.6 .+-. 6.9 5.1 .+-. 0.3
653.9 .+-. 37.1 (n = 23)
EXAMPLE 5
[0106] This example describes the results of an open-label study to
assess the steady state pharmacokinetics of orally administered
fampridine (4-aminopyridine) compositions of the present invention
in subjects with Multiple Sclerosis. This study was an open-label
multiple dose study of Fampridine-SR intended to assess steady
state pharmacokinetics in 20 patients with MS who previously
completed the study summarized in Table 4. Fampridine-SR (40
mg/day) was administered as two 20 mg doses, given as one morning
and one evening dose for 13 consecutive days, with a single
administration of 20 mg on Day 14. Blood samples for
pharmacokinetic analysis were collected on Days 1, 7/8, and 14/15
at the following intervals: immediately prior to drug
administration (baseline), hourly for the first 8 hours, and 10,
12, and 24 hours post-dose. Additional blood samples were collected
14, 18, and 20 hours post-dose on Day 14, and 30 and 36 hours
post-dose on Day 15.
[0107] Pharmacokinetic parameter estimates following the first dose
in these patients in this study on Day 1 were comparable to those
determined when they participated in the study summarized in Table
4. No significant difference in T.sub.max was detected among the
four means (Single dose=3.76 h Day 1=3.78 h; Day 8=3.33 h; Day
15=3.25 h). C.sub.max and C.sub.max/C on Days 8 (C.sub.max=66.7
ng/ml) and 15 (C.sub.max=62.6 ng/ml) were significantly greater
than those of the single dose treatment and of Day 1
(C.sub.max=48.6 ng/ml), reflecting accumulation of the drug with
multiple dosing.
[0108] There was no significant difference among the four occasions
with regard to either T or C and no difference in
C.sub.max,C.sub.max/C, CL/F or AUC between Days 8 and 15. Further
AUC on Days 8 and 15 did not differ significantly from total AUC
with single dose treatment. Likewise, the estimates of CL/F on Days
8 and 15 and of X and T.sub.1/2on Day 15 did not differ
significantly from those with single dose.
[0109] Steady-state was attained by Day 7/8 as evidence by the lack
of differences in C.sub.max or AUC between Days 7/8 and 14/15;
there was no apparent unexpected accumulation. Likewise, the
estimates of Cl/F on Days 7/8 and 14/15 of and of T.sub.1/2on Day
14/15 did not differ significantly from those given a single dose.
On the final day of dosing, mean was 62.6 ng/mL, occurring 3.3
hours post-dose. The T.sub.1/2was 5.8 hours. These values are
similar to those observed in patients with chronic SCI receiving
similar doses of this formulation. These results are summarized in
Table 5.
TABLE-US-00005 TABLE 5 Pharmacokinetic Parameter Values (Mean and
95% CI) Following Multiple Oral Doses of Fampridine-SR (40 mg/day)
to 20 Patients with MS. Parameter C.sub.MAX t.sub.MAX
AUC.sub.(0-12) t.sub.1/2 Cl/F Day (ng/mL) (hours) (ng hr/mL)
(hours) (mL/min) Day 1 48.6 3.8 NE NE NE (42.0, 55.3) (3.2, 4.3)
Day 7/8 66.7 3.3 531 NE 700 (57.5, 76.0) (2.8, 3.9) (452, 610)
(557, 884) Day 62.6 3.3 499 5.8 703 14/15 (55.7, 69.4) (2.6, 3.9)
(446, 552) (5.0, 6.6) (621, 786)
[0110] Dizziness was the most common treatment-related adverse
event. Other treatment-related adverse events that occurred
included nausea, ataxia, Insomnia, and tremor. There were no
clinically significant changes in mean clinical laboratory values,
vital signs, or physical examination findings from baseline to last
visit. There were no apparent clinically significant changes in
corrected QT intervals or QRS amplitudes after administration of
fampridine.
[0111] Fampridine was well tolerated in subjects with multiple
sclerosis who receive twice daily doses (20 mg/dose) of fampridine
for two weeks. A significant increase was observed in C.sub.max,
and C.sub.maxC on Days 8 and 15 relative to those on Day 1 and with
single dose treatment, reflecting accumulation of fampridine with
multiple dosing. A lack of significant differences in C.sub.max,
C.sub.max/C or AUC between Days 8 and 15 suggest that near
steady-state is reached by Day 8. There was no evidence of
significant pharmacokinetics during a two-week period of multiple
dosing with fampridine.
EXAMPLE 6
[0112] This was an open-label, single dose, single-center study of
the pharmacokinetics and tolerability of escalating doses of orally
administered Fampridine-SE in fourteen (14) patients with chronic
incomplete SCI.
[0113] After fasting overnight, a single oral dose of Fampridine-SR
(10, 15, 20, or 25 mg) was to be administered. Each patient was to
receive each dose in an ascending fashion. Bach dose was to be
followed by a 7-day washout period. A single doss of Fampridine-SR
was to be administered orally on Day 1--10 mg, Day 8--15 mg, Day
15.degree.20 mg and Day 22--25 mg with 240 mL of tepid water at
approximately the same time on each treatment day. Patients were to
continue their fast for 4 hours after dosing and then a standard
meal was to fee served. Blood samples for pharmacokinetic analysis
were to be obtained at Hour 0 (immediately preceding study drug
administration) and 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 16, 20, and 24
hours after each dose. A baseline urine sample was to be collected
prior to dosing and urine was to be collected for 24 hours after
administration of the study drag at the following intervals; 0.1 to
4 hours; 4.1. to 8 hours; 8.1 to 12 hours; and 12.1 to 24
hours.
[0114] There was no detectable fampridine in any of the pre-dose
plasma samples. By visual inspection of plasma concentration-time
curves, concentrations were seen to rise for up to the first 4
hours post-dose and then to decline in a monophasic fashion. In
some patients, there was evidence of a second peak. Peak
concentrations increased proportionally with dose, with mean CMAX
27.7 ng/ml following a single dose of 10 mg and mean CMAX of 67.4
ng/ml, following a single dose of 25 mg. Peak concentrations
occurred 3 to 4 hours post-dose, regardless of dose level. AUC also
increased proportionally with increasing dose. The length of
sampling was adequate since AUC.sub.0-24 is at least 92% of
AUC.sub.0-8 . The mean T was independent of dose, approximately 6
hours. Pharmacokinetic parameter values by dose are summarized in
the Table 6 below.
TABLE-US-00006 TABLE 6 Mean (.+-. SD) pharmacokinetic parameters of
fampridine-SR following single dose administration Fampridine-SR
dose 10 mg 15 mg 20 mg 25 mg Parameter n = 14 n = 14 n = 14 n = 13*
C.sub.max (ng/mL) 27.7 .+-. 9.1 43.5 .+-. 11.2 54.9 .+-. 11.0 67.4
.+-. 13.3 t.sub.max (h) 3.2 .+-. 1.0 3.5 .+-. 1.2 3.5 .+-. 1.0 3.7
.+-. 1.2 AUC.sub.0-24h (ng * h/mL) 285.4 .+-. 96.8 423.0 .+-. 98.6
561.1 .+-. 117.6 715.6 .+-. 150.0 AUC.sub.0-.infin. (ng * h/mL)
311.8 .+-. 93.2 460.2 .+-. 100.2 604.3 .+-. 124.6 769.2 .+-. 154.4
K.sub.el (h.sup.-1) 0.13 .+-. 0.03 0.12 .+-. 0.03 0.12 .+-. 0.02
0.13 .+-. 0.03 t.sub.1/2 (h) 5.9 .+-. 1.5 5.9 .+-. 1.5 5.9 .+-. 1.4
5.8 .+-. 1.6 Cl/F (L/h) 34.8 .+-. 10.2 34.3 .+-. 8.9 34.7 .+-. 8.5
34.0 .+-. 8.3 V.sub.d/F (L) 299.8 .+-. 127.4 289.0 .+-. 93.7 289.9
.+-. 84.1 286.2 .+-. 123.2 *One patient was excluded from analysis,
as not all blood samples were collected. C.sub.max, maximum
observed plasma concentration; t.sub.max, time to reach C.sub.max;
AUC, area under the plasma concentration-time curve; K.sub.el,
elimination rate constant; t.sub.1/2, plasma half-life; Cl/F,
apparent total clearance; V.sub.d/F, apparent volume of
distribution.
[0115] Fampridine pharmacokinetic parameters following the oral
administration of single doses of fampridine-SR (10-25 mg) are
summarized in Table 6. Fampridine-SR was slowly absorbed (mean
t.sub.max occurring 3.2 to 3.7 hours postdose) and slowly
eliminated in a monophasic manner (mean t.sub.1/2.about.5.9 hours).
Mean t.sub.1/2, K,VF, and Cl/F were independent of dose over the
dose range (10-25 mg), while mean C.sub.max, AUC were linearly
related to dose, AUC.sub.0-24 h was at least 92% of AUC. Mean
C.sub.max for the lowest fampridine-SR dose (10 mg) was 27.7 ng/mL,
while mean C.sub.max for the highest dose (25 mg) was 67.4
ng/mL.
[0116] The plasma concentration profile following, administration
of Fampridine-SR was consistent with a sustained release of drug.
Peak concentrations of fampridine occurred on average 3 to 4 hours
post-dose, and concentrations declined with a plasma half-life of
approximately 6 hours. The results of this study indicate that
Fampridine-SR pharmacokinetics are linear over the single dose
range studied, 10 to 25 mg. Area under the curve (AUC) and peak
plasma concentration (CMAX) increased proportionally with dose.
[0117] Fampridine-SR was well-tolerated over the range of single
oral doses administered in this study. Dimness was the most
frequently reported adverse event. The next most common events were
hypotension, nausea, and paresthesia. There was no clear
relationship between dose level and frequency of adverse events,
except with the possibility of nausea, which only occurred at the
25 mg dose. There were no clinically significant changes in vital
signs during treatment.
[0118] The pharmacokinetic analysis of Fampridine-SR administered
once weekly showed dose proportionality across single oral doses of
10, 15, 20, and 25 mg. Mean peak fampridine concentration increased
linearly with dose from 27.7 ng/mL following a dose of 10 mg to
69.9 ng/mL following a dose of 25 mg. Absorption was prolonged with
peak concentrations occurring on average 3 to 4 hours postdose;
this was independent of dose. The mean T appeared independent of
dose, approximately 6 hours. Single oral doses of 10, 15, 20. and
25 mg of Fampridine-SR were well-tolerated, as assessed by adverse
event reporting, clinical laboratories, vital sign measurements,
physical examinations, and ECG Interpretation.
EXAMPLE 7
[0119] This example describes the results of an open-label,
multiple dose, single center study to assess the effects of
escalating doses of orally administered sustained release
fampridine (4-aminopyridine) in sixteen (16) patients with chronic
incomplete spinal cord injury (SCI). Sustained release tablets of
fampridine were administered 10 mg twice daily for 1 week, 15 mg
twice daily for 1 week, 20 mg twice daily for 1 week and 25 mg
twice daily for 1 week in sixteen patients with SCI.
[0120] Following administration of Fampridine-SR, fampridine was
slowly adsorbed, with peak concentration observed approximately
three hours post-dose, regardless of dose (p=0.227). Plasma levels
declined gradually with a half life of 6 to 7 hours, independent of
dose. Based on the mean trough concentrations, steady state was
achieved by Day 5. Steady state maximal, minimal, and average
plasma concentrations and AUC increased with Increasing dose. Total
clearance ranged between 9 and 10 ml/min/kg across dose groups.
Volume of distribution at steady state ranged from 2.01 L/kg in the
15 mg BID dose group to 2.11 L/kg in the 20 mg BID dose group. A
summary of the mean pharmacokinetic results is provided in Table
7.
[0121] Fampridine pharmacokinetic parameters following the oral
administration of multiple doses of fampridine-SR (10-25 mg BID)
are summarized in Table 7. Mean t.sub.max and t.sub.1/2 were
similar to values found in the single-dose study (compare to Table
6). Steady state was achieved by Day 5 (4 days of fampridine-SR
dosing) following twice-daily administration of fampridine-SR, Mean
t.sub.max, t.sub.1/2, VF, Cl/F, and mean residence time at steady
state (MRT.sub.SS) were independent of dosage following the
administration of fampridine-SR (10-25 mg BID). Mean plasma
concentrations (C, C, C) and AUC.sub.0-12h at steady state were
linearly related to dose over the dosage range (fampridine-SR 10-25
mg BID). Mean C at steady state for the lowest fampridine-SR dosage
(10 mg BID) was 32.2 ng/mL and was 87.2 ng/mL for the highest
fampridine-SR dosage (25 mg BID), Corresponding C values for the
lowest and highest dosages were 14.0 and 41.3 ng/mL.
TABLE-US-00007 TABLE 7 Mean (.+-. SD) pharmacokinetic parameters of
fampridine-SR following multiple dose administration Fampridine-SR
dose 10 mg BID 15 mg BID 20 mg BID 25 mg BID Parameter n = 15 n =
15 n = 14 n = 14 C.sub.maxss (ng/mL) 32.2 .+-. 8.9 46.7 .+-. 10.5
60.1 .+-. 15.0 87.2 .+-. 29.0 C.sub.minss (ng/mL) 14.0 .+-. 4.4
23.5 .+-. 9.1 27.3 .+-. 10.0 41.3 .+-. 15.2 C.sub.avss (ng/mL) 20.8
.+-. 5.7 31.0 .+-. 7.2 39.4 .+-. 9.3 53.3 .+-. 14.5 t.sub.max (h)
2.7 .+-. 1.0 3.2 .+-. 0.9 3.1 .+-. 1.2 2.6 .+-. 0.9 AUC.sub.0-12 h
(ng * h/mL) 249.3 .+-. 68.3 371.8 .+-. 86.8 472.3 .+-. 111.8 639.4
.+-. 173.9 K.sub.el (h.sup.-1) 0.14 .+-. 0.05 0.12 .+-. 0.03 0.13
.+-. 0.04 0.12 .+-. 0.05 t.sub.1/2 (h) 5.6 .+-. 1.8 6.0 .+-. 1.5
5.8 .+-. 2.1 7.6 .+-. 5.5 Cl/F (L/h/kg) 9.52 .+-. 2.85 9.35 .+-.
2.44 9.79 .+-. 2.03 9.15 .+-. 2.35 V.sub.ss/F (L/kg) 2.22 .+-. 0.79
2.01 .+-. 0.59 2.11 .+-. 0.51 2.09 .+-. 0.65 MRT.sub.ss (h) 5.18
.+-. 0.21 5.18 .+-. 0.30 5.15 .+-. 0.35 5.08 .+-. 0.31 Accumulation
factor 1.30 .+-. 0.18 1.34 .+-. 0.16 1.32 .+-. 0.22 1.53 .+-. 0.62
C.sub.maxss, maximum observed plasma concentration at steady state;
C.sub.minss, minimum observed plasma concentration at steady state;
C.sub.avss, average plasma concentration at steady state;
t.sub.max, time to reach C.sub.max; AUC, area under the plasma
concentration-time curve; K.sub.el, elimination rate constant;
t.sub.1/2, plasma half-life; Cl/F, apparent total clearance;
V.sub.ss/F, apparent volume of distribution at steady state;
MRT.sub.ss, mean residence time at steady state; BID, twice
daily.
[0122] Adverse events included pain, hypertonia, dizziness,
accidental injury, dyspepsia, asthenia, urinary tract infection and
euphoria. There was no clear relationship between frequency of
adverse events and dose level, however euphoria and dizziness were
observed more frequently in the 25 mg BID dose level.
[0123] Multiple oral doses of 10, 15, 20 and 25 mg BID of
Fampridine-SR were generally well-tolerated, as assessed by adverse
event reporting, clinical laboratories, vital signs, and physical
examinations. The pharmacokinetic analysis of Fampridine-SR showed
dose proportionality across multiple oral doses of 10, 15, 29, 25
mg BID each administered for 1 week. The results demonstrate that
fampridine pharmacokinetics am linear over the dose range studied.
Trough values indicated that steady state had been achieved by Day
5. Fampridine pharmacokinetics are dose-proportional: both AUC and
C.sub.max at doses of 10, 15, 20, and 25 mg BID, each administered
over the course of one week, were dose-proportional under both and
ANOVA model and a regression power model. Neither rate of
absorption (as reflected by the time of the peak concentration) nor
the rate of elimination (K) were dependent on dose.
EXAMPLE 8
[0124] This was a double-Mind, placebo-controlled, 20 week,
parallel-group study to evaluate safety, tolerability and activity
of oral fampridine-SR its subjects with Multiple Sclerosis. The
study was designed as follows: a two-week placebo run-in (single
blind); a two-week upward titration (10 mg bid, 15 mg bid or
placebo); a twelve-week stable treatment period (placebo, 10 mg
bid, 15 mg bid or 20 mg bid); a one-week downward titration (10 mg
bid, 15 mg bid or placebo) and a two-week post treatment follow-up.
A total of 206 patients were enrolled in the study.
[0125] The mean change in walking speed, the walking speed measured
per visit, the mean change in LEMMT, the LEMMT per visit, the
adverse events and serious adverse events associated with the study
were documented.
[0126] Results. The trial showed a strong positive trend across all
three dose groups compared to placebo in its primary endpoint,
improvement in walking speed, as measured by a timed 25-foot walk
as shown in FIG. 3. The trial also showed a statistically
significant improvement across dose groups in its secondary
endpoint, the Lower Extremity Manual Muscle Test (LEMMT), as shown
in FIG. 4. These results confirmed observations in earlier
double-blind trials that involved fewer subjects and shorter
treatment periods. Because most people with MS experience both
impairment in walking ability and weakened muscles, the Timed 25
Foot Walk is widely-used to assess MS patients`functional status.
The LEMMT is a standardized, 5-point manual assessment of strength,
applied to leg muscle groups. The study showed a statistically
significant difference across ail doses at up-titration and
follow-up for the 25 foot walk. The study also showed a
statistically significant improvement in LEMMT across all doses
during stable treatment. The study confirms the safety profile of
4-aminopyridine and preferable dosing of 10 to 15 milligrams twice
daily.
[0127] Fampridine-SR showed a strong positive trend in the
improvement of walking speed and significantly improved leg muscle
strength in people with multiple sclerosis (MS). The drug also
showed a reduction of muscle spasticity in people with chronic
spinal cord injury (SCI).
EXAMPLE 9
[0128] This was a group study to evaluate safety, tolerability and
activity of oral fampridine-SR in subjects with spinal cord injury
(SCI). The study was designed as follows: a two-week placebo run-in
(single blind); a two-week upward titration (10 mg bid, 15 mg bid
or placebo); a twelve-week stable treatment period (placebo, or 25
mg bid); a two-week downward titration (1.0 mg bid, 15 mg bid) and
a two-week post treatment follow-up. A total of 204 patients were
enrolled in the study, of which 166 completed.
[0129] The mean change in Ashworth scorn, the Ashworth scorn
measured per visit, the mean change in LEMMT, the LEMMT per visit,
the adverse events and serious adverse events associated with each
study were documented. The Ashworth is a validated, 5-point
clinician assessment of an individual's spasticity (the involuntary
tension, stiffness or contraction of muscles.)
[0130] Results. The study showed a statistically significant
improvement of Ashworth score using FDA-preferred analysis, as
shown in FIG. 5. The study also confirmed the safety profile of
4-aminopyridine.
[0131] Although the present invention has been described in
considerable detail with reference to certain preferred embodiments
thereof, other versions are possible. Therefore the spirit and
scope of the appended claims should not be limited to the
description and the preferred versions contain within tins
specification.
* * * * *