WO2004082684A1 - Stable oral formulations of aminopyridines and uses thereof - Google Patents

Abstract

A pharmaceutical composition which comprises a therapeutically effective amount of a potassium channel blocker 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 potassium channel blocker for a period of at least 12 hours, preferably 24 hours or more and the use of the composition to treat various neurological diseases.

Description

STABLE ORAL FORMULATIONS OF AMINOPYWDINES AND USES THEREOF

CROSS REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefit and priority of U.S. Provisional Application Serial Number 60/453,734 filed March 17, 2003, U.S. Provisional Application Serial Number 60/528,593 filed December 11, 2003, U.S. Provisional Application Serial Number 60/528,760 filed December 11, 2003, and U.S. Provisional Application Serial Number 60/528,592 filed December 11 , 2003, the contents of each being incorporated herein by reference in their entirety.

BACKGROUND

[0002] Spinal cord injuries are one of the leading causes of disability in young adults. The extent of such injuries can range from partial paralysis of the lower extremities to extreme cases where paralysis is complete from the C-l cervical vertebra downward. Oftentimes the injury to the spinal cord is one that that interferes with signal transmission. Treatment alternatives for promoting transmission along injured nerves of the spinal cord have thus far met with limited success.

[0003] 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 a 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. [0004] 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.

[0005] Amyotrophic lateral sclerosis (ALS), commonly referred to as Lou Gebrig'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 falling, 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.

[0006] Potassium channel blockers are 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) has been found to slow the potassium flow in nerve impulse transmission and, thereby, shows effectiveness in restoring conduction in blocked and demyelinated nerves. 4-AP has been administered orally in multiple daily doses over 2-5 days to MS patients with mild to marked improvements being noted and minimal side effects. Mono- and di-aminopyridines are potassium channel blockers that have 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.

[0007] Potassium channel blockers, such as the mono and di-aminopyridines have been formulated and used as intravenous compositions. Immediate release (IR) formulations of potassium channel blockers like 4-aminopyridine for oral administration have been developed. One immediate release composition consisted of 4-AP powder in a gelatin-based capsule. In some cases the administration of such IR capsules to patients resulted in high 4-AP plasma levels for short periods of time and were poorly tolerated by some patients. A controlled-release (CR) capsule dosage form of 4-AP was developed as disclosed in U.S. Patent No. 5,370,879 to Masterson et. al. While this controlled-release capsule yielded longer half-life and lower peak blood plasma levels of 4-AP following administration, the dosage forms were found to be unstable, to be susceptible to degradation by ambient humidity, and to leach 4-aminopyridine.

SUMMARY OF THE INVENTION [0008] The present invention relates to stable pharmaceutical compositions that contain one or more potassium channel blockers dispersed in a release matrix that may be used in the treatment of various conditions or diseases, for example, spinal cord injury, MS and Alzheimer's disease. Embodiments of the present invention are directed to compositions that include a release matrix and a potassium channel blocker combined into a stable oral dosage form. The composition provides for sustained-release of the potassium channel blocker from the release matrix, and maintains the efficacy, stability, and formulation of the composition. The composition may be used to establish in patients in need of a potassium channel blocker, a therapeutically effective blood plasma level of the potassium channel blocker for a period of at least about 6 hours, preferably at least about 12, and more preferably up to at least 24 hours in the patient with a once or twice daily administration. The potassium channel blocker in the pharmaceutical may include aminopyridines, for example a mono- or di-aniinopyridine, preferably 4-aminopyridine, 3,4-diaminopyridinβ, or a combination thereof. The potassium channel blocker is dispersed in a release matrix, preferably homogeneously dispersed in a rate- controlling polymer or release matrix. Preferably the release matrix includes the hydrophilic polymer hydroxypropylmethylcellulose (HPMC) alone or in combination with other release matricies. More preferably the release matrix includes hydroxypropylmethylcellulose from about 20 to about 80 %w/w of the composition and the potassium channel blocker in the matrix is 4-aminopyridine that is 4.75 %w/w or less of the dosage form. 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 and conditions in need of potassium channel blockers for improved nerve conduction, spinal cord injury, Multiple Sclerosis and Alzheimer's disease.

[0009] One embodiment of the present invention is a stable, sustained-release oral dosage formulation of a composition which includes an amount of a potassium channel blocker dispersed in a matrix that provides a therapeutically effective amount of the potassium channel blocker in the blood plasma of the patient extending over a period of at least 6 hours, preferably at least 8 hours, and more preferably least about 10-12 hours. The stable pharmaceutical composition includes a therapeutically effective amount of a potassium channel blocker dispersed in a matrix with optional excipients that provides a release profile of the potassium channel blocker to a patient that has a desired C_max to C_τ ratio. The composition may be used to establish and or maintain in a patient, a therapeutically effective level of the potassium channel blocker. Preferably the potassium channel blocker in the composition is released over time so that a therapeutically effective level of the potassium channel blocker in the patient can be achieved with once daily or twice daily dosing of the composition. Undesirable spikes or peaks in the release of the potassium channel blocker from the stable oral dosage form are avoided and the release profile of potassium channel blocker in the blood plasma of a patient to whom the formulation has been administers is characterized by a release profile with a C_max/C_τ at τ=12 hours of from about 1 to about 3.6. In preferred embodiments, the pharmaceutical composition comprises a mono - or di-aminopyridine, more preferably 4-AP, dispersed in hydroxypropylmethylcellulose (HPMC). The pharmaceutical composition of the present invention may include also one or more pharmaceutically acceptable excipients, lubricants, diluents, or glidants.

[0010] One embodiment of the present invention is a stable pharmaceutical composition that is a tablet which includes an amount, and preferably a therapeutically effective amount, of one or more potassium channel blockers such as 4-aminopyridine dispersed in a release matrix. The composition may be used to establish and or maintain in a patient, a therapeutically effective level of the potassium channel blocker in the blood plasma of the patient characterized by a release profile with a C_max/C_τ at τ=12 hours of about 1 to about 3.6, and preferably a C_max/C_τ at

τ=12 hours of about 2 to about 3. Preferably the potassium channel blocker in the composition is released over time so that a therapeutically effective level of the potassium channel blocker in the patient can be achieved with once daily or twice daily dosing of the composition. Undesirable spikes or peaks in the blood plasma concentration of the potassium channel blocker in the stable oral dosage forms of the present invention administered to a patient are avoided. In preferred embodiments, the pharmaceutical composition comprises a mono- or di-aminopyridine, more preferably 4-AP, dispersed in hydroxypropyl-methylcellulose (HPMC). The pharmaceutical composition of the present invention may also comprise one or more pharmaceutically acceptable excipients such as but not limited to diluents, glidants, and lubricants.

[0011] One embodiment of the present invention is a pharmaceutical that includes an amount of a potassium channel blocker dispersed, and preferably an aminopyridine homogeneously dispersed, in a release matrix with a lubricant and formed into a stable oral dosage. The stable oral dosage provides a dissolution profile of the potassium channel blocker in an aqueous media such that about 15% to 32.5 % of the potassium channel blocker is released into the aqueous media from the release matrix after about 1 hour; about 45% to 65% of the potassium channel blocker is released from the matrix after about 4 hours, and at least about 78% of the potassium channel blocker is released from the matrix after about 10 hours. Preferably the release matrix includes hydroxypropylmethylcellulose from about 20 to about 80 %w/w of the composition. Preferably the potassium channel blocker in the matrix is 4-aminopyridine and is 4.75 %w/w or less of the tablet.

[0012] One embodiment of the present invention is a stable, sustained-release oral dosage formulation of a composition includes a therapeutically effective amount of a potassium channel blocker dispersed in a matrix with optional excipients that provides a therapeutically effective blood plasma level of the potassium channel blocker in a patient extending over a period of at least 6 hours, preferably at least 12 hours, and more preferably to least about 24 hours.

[0013] One embodiment of the present invention is a stable oral dosage formulation of a potassium channel blocker in a release matrix with optional excipients that can be made by the acts including dispersing a therapeutic amount of a potassium channel blocker with a release matrix and optionally excipients, such as a lubricant, and pressing the combination into a stable oral dosage form. Preferably the potassium channel blocker is an aminopyridine such as 4- aminopyridine, 3,4-diaminopyridine, or combinations thereof homogeneously dispersed in the release matrix which includes HMPC. Stable oral dosage forms prepared by this method providing a release profile of the potassium channel blocker in the blood plasma of a patient characterized by a C_max/C_τ at τ=12 hours of between about 1 and about 3.6, and more preferably

a release profile with a a C_max/C_τ at τ=12 hours from about 2 to about 3. Preferably, the oral dosage formulation of the composition is a monolithic tablet formed by compression of the pharmaceutical composition of the present invention, hi preferred embodiments, the oral dosage formulation includes a compressed tablet of a therapeutically effective amount of a potassium channel blocker such as a mono- or di-aminopyridine, 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.

[0014] The dispersion of the potassium channel blocker throughout the release matrix imparts chemical and physical stability to the composition while providing a sustained-release profile of the potassium channel blocker. Enhanced dosage stability is most notably observed in compositions and dosage forms of the present invention having low concentrations of the potassium channel blocker, 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 potassium channel blocker throughout the tablet while providing a release profile of the potassium channel blocker that permits establishment of a therapeutically effective concentration of the potassium channel blocker in a patient with once daily or twice daily dosing of the stable oral dosage formulation. Preferably the therapeutically effective concentration of the potassium channel blocker or aminopyridine released by the formulation extends over at least 6 hours, preferably at least 8 hours, and more preferably to at least 10-12 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.

[0015] The compositions of the present invention may be administered to patients and used in the treatment of a condition in a patient which includes establishing a therapeutically effective concentration of a potassium channel blocker or an aminopyridine in the patient in need thereof. The compositions may be used for building up a level and or maintaining a therapeutically effective concentration of the potassium channel blocker or aminopyridine in the patient by once daily or twice daily dosing. The dosages of the present compositions can made with a lower concentration of the potassium channel blocker to facilitate restful periods for the patient during the day. The compositions of the present invention are formulated to avoid large peaks in initial release of the potassium channel blocker or aminopyridine. The compositions of the present invention when administered to a patient in need thereof, provide for the treatment of conditions such as but not limited to neurological diseases that are characterized by a degradation of nerve impulse transmission. Preferably the stable oral dosage forms used in the treatment are a stable, sustained-release tablet of a therapeutically effective amount of a mono—or di- aminopyridine, dispersed in a release matrix including HPMC such that therapeutically effective blood plasma level of the mono- or di-aminopyridine is maintained in the patient suffering from a neurological condition for a period of at least 6 hours, preferably at least 8 hours, more preferably at least about 10-12 hours, and most preferably at least about 24 with a once or twice daily administration.

[0016] Preferably the method of treating a patient includes administering to a patient a stable oral dosage form, which can be a tablet, of an aminopyridine or potassium channel blocker homogenously dispersed in a release matrix with an optional excipients such as a lubricant. The stable oral dosage provides a release profile of the aminopyridine in the blood plasma of the patient characterized by a C_max/C_τ at τ=12 hours of between 1 and 3.6, and more preferably a

C_max/C_τ at τ=12 hours of from about 2 to about 3. Preferably when the aminopyridine is 4- aminopyridine, the amount of 4-AP is 4.75 %w/w or less of the mass of the stable oral dosage form.

BRIEF DESCRIPTION OF THE DRAWINGS

[0017] FIG. 1 is a graph of mean blood plasma profiles associated with the administration to patients (n=12) in both fasted and fed states of a tablet form of 4-aminopyridine dispersed in a release matrix in accordance with the present invention compared with the mean plasma profile associated with the administration of an immediate release formulation of 4- aminopyridine.

[0018] FIG. 2 is a graph of mean blood plasma profiles associated with the administration (fasted state) of a homogeneous dispersion of 4-AP in a release matrix in a tablet form 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 formulation of 4-AP. DETAILED DESCRIPTION OF THE INVENTION [0019] 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.

[0020] 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 "granule" is a reference to one or more granules 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 now 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.

[0021] One aspect of the invention is a pharmaceutical composition including a potassium channel blocker dispersed in a release matrix such as a hydrophillic polymer with acceptable excipients and formed into a stable oral dosage. The composition of the present invention is capable of providing, upon administration to a patient, a therapeutic concentration of the potassium channel blocker in the blood plasma of the patient that a extends over at least 6 hours, preferably least about 12 hours, and more preferably at least 24 hours or more. Preferably the amount potassium channel blocker in the composition is a therapeutically effective amount, and preferably the potassium channel blocker is dispersed uniformly and homogeneously throughout the release matrix.

[0022] A therapeutically effective amount of a potassium channel blocker or aminopyridine compound in a stable oral dosage of the present invention is an amount of the potassium channel blocker or aminopyridine in a stable oral dosage form that when administered to a patient, ameliorates a condition or ameliorates the symptom of a neurological disease. The stable oral dosage form to achieve the therapeutically effective amount may be but is not limited to one or more tablets or capsules. A therapeutically effective amount is an amount sufficient to decrease or prevent the symptoms associated with a medical condition or infirmity or to normalize body functions in disease or disorders that result in impairment of specific bodily functions. Preferably a therapeutically effective amount of a potassium channel blocker or aminopyridine in a stable oral dosage can be an amount sufficient to improve nerve signal transmission, 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.

[0023] The term "stable" when used to describe the oral formulations of the present invention refers to oral administration forms of potassium channel blocker dispersed in a release matrix with one or more optional excipients such that the form maintains the release profile of potassium channel blocker under suitable test conditions, for example blood plasma or dissolution profiles in aqueous media, following exposure to humidity and temperature, especially conditions know to degrade controlled release dosage formulations of 4- aminopyridine.

[0024] Potassium channel blockers are compounds which at relatively low levels, for example 0.09 to 10 ng/ml concentration in blood plasma, are effective at blocking fast, voltage- dependent K⁺ channels in neurons. Aminopyridines are a class of potassium channel blockers and include but are not limited to monosubstituted pyridines, such as 2-aminopyridine, 3- aminopyridine, and preferably 4-aminopyridine, as well as diaminopydirines such as 3,4- diaminopyridine.

[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] Pharmaceutically acceptable salts, esters, amides, and prodrugs as used herein refers to those carboxylate salts, amino acid addition salts, esters, amides, zwitterionic forms, where possible, and prodrugs of the potassium channel blocker and aminopyridines used in the stable oral dosages 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. The term "salts" refers to the relatively non-toxic, 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 but are not limited to the bromide, chloride, 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.

[0027] The term "prodrug" refers to compounds that are rapidly transformed in vivo, for example by hydrolysis in blood, to yield the parent potassium channel blockers or aminopyridines. A thorough discussion is provided in T. Higuchi and N. 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] 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, hi general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the present invention.

[0029] Mono or di-aminopyridines are particularly suitable potassium channel blockers for use in the treatment of a neurological disease which is characterized by demyelination of the central nervous system, more especially multiple sclerosis degenerative neurological diseases such as Alzheimer's disease, and conditions involving neurological impairment such as spinal cord injury. These aminopyridines may be combined with each other, other potassium channel blockers and dispersed in the release matrix. When the potassium channel blocker is a mono- aminopyridine, a particularly preferred mono-arninopyridine is 4-aminopyridine (4-AP). When the potassium channel blocker is a di-aminopyridine, a particularly preferred di-aminopyridine is 3,4-diaminopyridine (3,4-DAP).

[0030] When the compositions of the present invention are administered to a patient, the therapeutically effective concentration of the potassium channel blocker in the patient's blood plasma over time may extend over a period of at least 6 hours, preferably over at least 12 hours, and more preferably over at least 24 hours. The compositions may provide in single administration a mean maximum blood plasma concentration of a potassium channel blocker like 4-aminopyridine in the patient of from about 15 to about 180 ng/ml and a mean minimum blood plasma concentration of the potassium channel blocker 8-14 hours following administration in the patient of less than about 60 ng/ml and preferably from about 10 to about 60 ng/ml.

[0031] The potassium channel blocker, such as a mono or di-aminopyridine dispersed in a release matrix with an optional excipient like a lubricant and formed into a stable oral dosage form, can be administered to a subject at a dose and for a period sufficient to allow the subject to tolerate the dose without showing any adverse effects and thereafter increasing the dose at selected intervals of time until a therapeutic dose of the potassium channel blocker in the blood plasma of the patient is achieved. For example, at the commencement of treatment the active agent or potassium channel blocker, such as 4-aminopyridine, is preferably administered as a stable oral dosage form with an amount of 4-aminopyridine in the dosage of less than 15 mg/day until a tolerable state is reached. Suitably when the tolerable state is reached, the amount of 4- aminopyridine in the stable oral dosage administered may be increased by amounts of at least 5- 15 mg/day until the therapeutic effective dose is reached. The method can include scheduling administration of doses of the pharmaceutical so that the concentration of the potassium channel blocker 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. [0032] The amount of a pharmaceutically acceptable quality potassium channel blocker, salt, solvate, or prodrug thereof included in the stable oral dosage pharmaceutical composition of the present invention will vary, depending upon a variety of factors, including but not limited to the specific potassium channel blocker used, the desired dosage level, the type and amount of rate-controlling polymer or release matrix used, and the presence, types and amounts of additional excipients such as but not limited to diluents, glidants, and lubricants included in the composition. Preferably, the potassium channel blocker, and more preferably 4-aminopyridine, comprises from about 0.1 to about 13%w/w, more preferably from about 0.5 to about 6.25 %w/w, and even more preferably from about 0.5 to 4.75 %w/w of the pharmaceutical composition. Most preferably a weight percentage of 4.75% or less or 4-aminopyridine is desired. The stable potassium channel blocker formulation for oral administration to patients can be one or more tablets that includes from about 0.0001 mole to about 0.0013 mole potassium channel blocker as a dosage. The amount of potassium channel blocker, or a derivative thereof, in the formulation can vary depending on the desired dose for efficient drug delivery, the molecular weight, and the activity of the compound. The actual amount of the potassium channel blocker or aminopyridine in the stable oral dosage can also depend on the patient's age, weight, sex, medical condition, disease or any other medical criteria. The actual amount of potassium channel blocker or aminopyridine in the stable oral dosage of the present invention can be 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.

[0033] Where the potassium channel blocker is 4-aminopyridine, a stable oral dosage form can be formulate to include an amount of 4-aminopyridine of from about 0.5 g to about 80 mg, preferably from about 2 to about 40 mg in the stable oral dosage. For adults, the daily dose of a potassium channel blocker like 4-aminopyridine may be about 50 milligrams per day, however some patients may receive up to about 120 milligrams of such channel blockers daily. Preferably; the amount of 4-aminopyridine in the composition is formulated to maintain therapeutic levels of the potassium channel blocker in patient's blood up to about 80 ng/ml.

[0034] The potassium channel blocker dispersed, and preferably homogeneously dispersed, in the release matrix of the present invention provides a dissolution profile in aqueous media, for example using USP Apparatus II (Paddle Method) at 50 rpm and 37 °C, such that about 15% to 32.5 % of the potassium channel blocker is released from the stable oral dosage after about 1 hour; about 45% to 65% of the potassium channel blocker is released from the stable oral dosage after about 4 hours, and at least about 78% of the potassium channel blocker is released from the stable oral dosage after about 10 hours.

[0035] The stable oral dosage formulations of the present invention exhibit a specific, desired release profile which maximizes the therapeutic effect while minimizing adverse side effects from short duration, high concentrations of the potassium channel blocker in the blood plasma. The desired release profile may be described in terms of the maximum blood plasma concentration of the potassium channel blocker or aminopyridine (C_max) and the blood plasma concentration of the drug or active agent at a specific time (CT) which may be used as a dosing interval in a therapeutic method of treatment. A ratio of C_max to C_τ (C_max/C_r) may be calculated from the observed C_max and C_τ. The interval (T) is the time since the administration of the potassium channel blocker or aminopyridine in the stable oral dosage to the patient. For example, the interval (T) can be 12 hours, therefore C_τ is the concentration of the potassium channel blocker or aminopyridine at 12 hours following administration to the patient. [0036] For example, as illustrated by the data in FIG. 1, a stable oral composition of the present invention avoids the undesirable spike or peak in the release of the potassium channel blocker, 4-AP, in the blood plasma. The immediate release capsule gives a C_max concentration of about 70 ng/ml of 4-aminopyridine following administration and the release profile is characterized by C_max to C_τ ratio at τ=12 hours that is about 16. In comparison, the stable oral dosage tablet form of the present invention when administered to patients in the fed and fasted states resulted in a C_max of less than 30 and a C_maχ to C_T ratio at τ=12 hours of about 2.3 in the

fed state and a C_max to C_τ ratio at τ=12 hours of 3.6 in the fasted state.

[0037] As illustrated by the data in FIG. 2, the release profile of a potassium channel blocker, 4-AP, in a stable oral formulation of the present invention is characterized by a C_max concentration of about 23 ng/ml and a C_maχ to C_T ratio at τ=12 hours of about 2.3. This contrasts

to the C_max to C_τ ratio at τ=12 hours of about 11.7 for the immediate release capsule formulation. A controlled release capsule, which is susceptible to moisture and leaching the 4-AP had a C_max concentration of the 4-AP in the blood plasma of just over 30 ng/ml and a C_max to C_T ratio at τ=12 hours of about 3.7.

[0038] A stable oral dosage in the form of a tablet of an aminopyridine dispersed in a release matrix with optional excipients, has an in vivo release profile of the aminopyridine in the blood plasma where the C_max/C_τ at τ=12 hours is about 1.0 to 3.6, preferably the C_max/C_τ at τ=12

hours ratio is about 1.5 to about 3.0 and even more preferably the C_max/C_τ at τ=12 hours is about 2.0 to about 3.0. The aminopyridine dispersed in the stable tablet may comprise 4- aminopyridine, 3,4-diaminopyridine or a combination thereof. 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.

[0039] The stable oral dosage forms of the present invention may be used in a method of treating a neurological disorder. The method can includes administering a stable oral dosage in the form of a tablet of an aminopyridine dispersed in a release matrix with optional excipients which exhibits an in vivo release profile of the aminopyridine in the blood plasma where the C_max/C_τ ratio is 1.0 to 3.6 at τ=12 hours, preferably the C_max/C_τ at τ=12 hours is about 1.5 to

about 3.0, and even more preferably the C_maχ/C_τ at τ=12 hours is about 2.0 to about 3.0. The aminopyridine of the present method may include 4-aminopyridine, 3,4-diaminopyridine or a combination thereof.

[0040] Stable oral dosage forms of the present invention may be in the form of a tablet with an aminopyridine homogeneously dispersed in a release matrix with optional excipients which exhibits an in vivo release profile of the aminopyridine in the blood plasma. The stable oral dosage formulations provide a concentration of aminopyridine in the blood plasma of a patient characterized by a C_max/C_. at τ=12 hours of 1.0 to 3.6, preferably a C_max/C_τ at τ=12 hours

about 1.5 to about 3.0, and more preferably a C_max/C_τ at τ=12 hours of about 2.0 to about 3.0. The aminopyridine of the present method may include 4-aminopyridine, 3,4-diaminopyridine or a combination thereof. The matrix may include for example, hydroxypropylmethylcellulose, or other rate controlling matrices that are suitable for controlling the release rate of an aminopyridine or other potassium channel blocker for use in the pharmaceutical compositions of the present invention.

[0041] The release matrix of the stable oral dosage in which the potassium channel blocker is dispersed, preferably homogeneously dispersed, provides a sustained release of the potassium channel blocker into the patient. The release matrix of the stable oral dosage provides a therapeutic amount of the potassium channel blocker in the plasma of a patient for at least 12 hours and preferably provides a release profile of the potassium channel blocker in the blood plasma of a patient characterized by a C_maχ/C_τ at τ=12 hours of between 1 and 3.6 and most

preferably a C_max/C_τ at τ=12 hours of between 2 and 3. Polymeric release matrices suitable for providing a sustained release rate of channel blocker(s) for use in the pharmaceutical compositions of the present invention include hydrophilic polymers or mixtures of hydrophilic and/or hydrophobic polymers that are capable of forming a stable sustained-release dosage formulation in combination with a potassium channel blocker and optional excipients. These matrices are also capable of preventing degradation and loss of the potassium channel blocker 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, hydroxypropylmethyl-cellulose phthalate, hydroxypropylmethyl-cellulose acetate succinate; poly(alkyl methacrylate); and poly(vinyl acetate). Examples of other suitable polymers include, either alone or in combination, include 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, gu 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.

[0042] In certain embodiments, the sustained release 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 anhydro glucose units, and 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.

[0043] According to one method of manufacture of a hydroxyalkylcellulose, 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.

[0044] Interaction between the release 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 reduce or prevent moisture absorption, evaporation and or degradation of the potassium channel blocker within the composition.

[0045] In preferred embodiments, the rate-controlling polymer is HPMC. In such embodiments, the HPMC preferably has a viscosity (2 wt % solution at 20 °C.) of about 100 to 100,000 cps, more preferably 100 to 30,000 cps. Especially suitable HPMCs are Methocel K types, such as Methocel K100LV, 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. Another hydroxypropylmethylcellulose sold under the name Klucel LF available from Aqualon and Nippon Soda Co., which has a molecular weight of 100,000 may also be used as a release matrix. Where poly(ethylene oxide) is used as a release matrix, it 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.

[0046] In another embodiment, the pharmaceutical composition of the present invention comprises a rate-controlling polymeric matrix comprising of a hydrogel matrix. For instance, a potassium channel blocker 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 potassium channel blocker 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 potassium channel blocker may be sustained both by the amount of polymer per tablet and by the inherent viscosities of the polymers used.

[0047] 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 can inhibit the penetration of water into the tablet and can be used to control the rate of tablet erosion. Suitable hydrophobic polymers are hydrophobic cellulose derivatives, such as ethyl cellulose, fats, such as glycerol palmitostearate, waxes, such as beeswax, glycowax, castrowax, carnaubawax, glycerol monostearate or stearylalcohol, hydrophobic polyacrlamide derivatives and hydrophobic methacrylic acid derivatives.

[0048] The amount of the release matrix included in the pharmaceutical composition of the present invention to achieve the desired release profile of the potassium channel blocker dispersed therein 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 of the release matrix from about 20 to about 96 %w/w, more preferably from about 20 to about 80 %w/w, of the pharmaceutical composition. It is desirable that the matrix permit release of the potassium channel blocker in the lower gastrointestinal tract. 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 potassium channel blocker from the tablet.

[0049] In preferred embodiments, the potassium channel blocker is milled prior to dispersal in the rate-controlling polymer in order to ensure proper particle size distribution. Milling of the potassium channel blocker may be accomplished by any suitable means such as, for example, an air jet mill, fritzmill, 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 potassium channel blocker is milled so that 90% of the particles are smaller than about 1.5 mm, more preferably smaller than about 1 mm, and even more preferably smaller than about 300 μm.

[0050] Suitable screen sizes for processing the milled potassium channel blocker are from about #10 to about #400 mesh, preferably #24 to #60 mesh. In certain embodiments, milling of the potassium channel blocker 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® comminutor using two different mill blade orientations.

[0051] The potassium channel blocker, in either milled or un-milled form, can be dispersed in the release matrix, along with optional excipients and diluents, to form the pharmaceutical composition such that the potassium channel blocker is distributed in a substantially uniform manner throughout the entirety of the matrix. The dispersal of potassium channel blocker throughout the matrix may be accomplished by any method capable of achieving substantial homogeneity of the combination. For purposes of the claims and specification, the term homogeneously dispersed means that the concentration of the potassium channel blocker in any given portion of a tablet or capsule when mixed with, for example, a release matrix, excipients, or additive is preferably within about ±20 % w/w, more preferably within about 10% w/w, and even more preferably within about ±5 % w/w or less of its average concentration in the tablet or capsule. Preferred dispersal methods include the use of blenders, for example, planetary, cross-flow, and v- blenders. While blending time will vary depending on a variety of factors, including, for example, the specifics of the potassium channel blocker and rate- controlling polymer used, substantially uniform distribution is preferably realized within from about 10 to about 55 minutes of blending.

[0052] The formulations of the invention are prepared or formed 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 binders as a granulating fluid. Alternatively, an organic solvent, such as isopropyl alcohol, ethanol and the like, may be employed with or without water. The potassium channel blocker and release matrix 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 potassium channel blocker 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 of the drug and enhance its solubility. Alternatively potassium channel blockers such as the mono- or di-aminopyridine active agent can be made in the form of quaternary ammonium-type salts to alter their solubility.

[0053] The stable oral dosage may assume any form capable of delivering orally to a patient a therapeutically effective amount of a potassium channel blocker dispersed in a rate- controlling polymer release matrix and optional excipients. The release matrix, excipients, and potassium channel blocker in the stable oral formulation can be fabricated or formed into tablets, tablets which disintegrate into granules, capsules, sustained release microcapsules, spheroids, or any other means which allow for oral administration. Pellets or a combination of pellets in accordance with the invention may also be filled into hard or soft gelatin capsules to prepare stable oral dosages. The pellets included in the capsule may have different amounts of potassium channel blocker in the pellets and or different matrices. Various amounts of the pellets may be used to tailor the total amount potassium channel blocker delivered as well as to alter the release and concentration profile of the potassium channel blocker in the patient. 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. The rate of potassium channel blocker release from the tablets may be controlled by the erosion mechanism of the release matrix in which potassium channel blocker is dispersed, hi general, for producing a tablet, the drug and polymer are granulated alone or in combination. Preferably the release of the potassium channel blocker from the matrix of the pharmaceutical composition is relatively linear over time. Preferably the stable oral dosage form provides a release profile that gives a therapeutically effective concentration of the potassium channel blocker in the blood plasma of the patient permitting a once per day or twice per day dosing. Preferably, the dosage formulation comprises a monolithic tablet. In preferred embodiments, the oral dosage formulation comprises a compressed tablet of a therapeutically effective amount of a mono- or di-aminopyridine, more preferably 4-AP or 3,4- DAP, dispersed in the release matrix HPMC.

[0054] 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 potassium channel blocker 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 potassium channel blocker, additive, excipients, 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 about 150 to about 300 N.

[0055] The effects of various matrices, concentrations of potassium channel blocker, as well as various excipients and additives to the composition on the concentration of the channel blocker in prepared stable oral dosages 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) at 50 rpm and 37 °C. Clinical evaluations may also be used to study the effects of various release matrices, concentrations of potassium channel blocker, as well as various excipients and additives on the amount and release profile over time of potassium channel blocker into a patient's blood plasma, other bodily fluid, or tissue. The therapeutic effect of a composition may be assessed based upon the results of response tests, such as muscle strength improvement or reduction in spascticity for patients with MS or SCI or other tests as would be known to those skilled in the art. Potassium channel blocker concentration in blood plasma or cerebral spinal fluid may be monitored using liquid chromatography/MS/MS assay methods.

[0056] 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, disintegrants and/or lubricants. 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 potassium channel blockers of the present invention as would be known to those skilled in the art. Preferably the potassium channel blockers are mixed or combined with excipients such as but not limited to microcrystalline cellulose, colloidal silicon dioxide, and magnesium stearate.

[0057] The dosage formulation of the present invention may include one or more pharmaceutically acceptable excipients as mentioned above. In preferred embodiments, the dosage formulation will comprise diluents and a lubricant in addition to the potassium channel blocker unit dose and the rate-controlling polymer. Particularly preferred excipients include microcrystalline cellulose sold under the name Avicel PH101, and magnesium stearate. When these materials are used, the magnesium stearate component preferably comprises from about 0.1 to about 0.75 %w/w of the dosage formulation, and the microcrystalline cellulose along with the rate controlling polymer and potassium channel blocker comprises the balance of the formulation. For example, a tablet formulation including a potassium channel blocker x % w/w, a rate-controlling polymer y % w/w, and microcrystalline cellulose z %, the magnesium stearate amount would be (100-(x+y+z)) where 0.1% (100-(x+y+z)) <0.75% w/w. As would be known to those skilled in the art, the amount of an 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 potassium channel blocker.

[0058] Dissolution agents modify, increase or decrease, the dissolution rate of the potassium channel blocker from the dosage formulation and can function by increasing the solubility of the potassium channel blocker. 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. Other agents that may alter the pH of the microenvironment on dissolution and establishment of a therapeutically effective plasma concentration profile of the potassium channel blocker include salts of inorganic acids and magnesium hydroxide. [0059] 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. 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.

[0060] 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 PHI 12, 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 stable oral dosage formulation.

[0061] Glidants are used to improve the flow and compressibility of ingredients during processing. Suitable glidants include, for example, colloidal silicon dioxide, a sub-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 in an amount of less than about 2% w/w of the stable oral formulation.

[0062] 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.

[0063] 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, poly(vinyl alcohol), thylamide, sodium bicarbonate, sodium carbonate, starch derivatives, dextrin, beta cyclodextrin, dextrin derivatives, magnesium oxide, clays, bentonite and mixtures thereof.

[0064] 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, and preferably a colloidal 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. '

[0065] To further improve the stability of the mono- or di-aminopyridine in the sustained release composition, an antioxidant compound can be included. Suitable antioxidants include, for example: sodium metabisulfite; tocopherols such as α, β, δ-tocopherol esters and α-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.

[0066] 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 plasticizers. Such a film-former may consist of fast-dissolving constituents, such as low- iscosity 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 6000, diethyl phthalate or triethyl citrate.

[0067] Tablet weight will also vary in accordance with, among other things, the potassium channel blocker dosage, the type and amount of rate-controlling polymer used as a release matrix, and the presence, types and amounts of additional excipients materials. Tablet weights can range from about 50 mg to about 1200 mg per tablet, preferably from 250 to 600 mg, and more preferably from about 325 to about 500 mg. The tablets may be formulated such that a potassium channel blocker, for example 4-aminopyridine, comprises from about 0.1 to about 13%w/w, more preferably from about 0.5 to about 6.25 %w/w, and even more preferably from about 0.5 to 4.75 %w/w of the tablet weight.

[0068] As used herein, the term "sustained-release" includes the release of a potassium channel blocker from a stable oral dosage formulation at a sustained rate such that a therapeutically beneficial blood level of the potassium channel blocker is maintained over a period of at least about 12 hours, preferably about 24 hours or more. Preferably, the amount of the potassium channel blocker in the oral dosage formulations according to embodiments of the present invention establish a therapeutically useful plasma concentration through QD or BID administration of the pharmaceutical composition. Most preferably a stable oral dosage in the form of a tablet of an aminopyridine dispersed in a release matrix with optional excipients, has an in vivo release profile of the aminopyridine where the C_max/C_τ at τ=12 hours is 1.0 to 3.6,

preferably the C_maX/C_τ at τ=12 hours ratio is about 1.5 to about 3.0 and even more preferably the

C_n._ax/C_τ at τ=12 hours is about 2.0 to about 3.0.

[0069] According to another aspect of the invention, there is provided a stable, sustained- release oral dosage formulation which includes an effective amount a potassium channel blocker dispersed in a release matrix, and which, upon administration to a patient or as part of a therapy regiment, provides a therapeutically effective blood plasma level of the potassium channel blocker 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 potassium channel blocker for a period of at least 6 hours, preferably at least 12 hours, and more preferably at least 24 hours.

[0070] The compositions of the present invention may be used for the treatment of conditions in need of a potassium channel blocker or aminopyridine such as but not limited to 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 a once (QD) or twice (BID) daily dosage of a therapeutically effective amount of a mono- or di-aminopyridine, even more preferably, 4-AP or 3,4-DAP, dispersed in an HPMC release matrix. The administration can also include scheduling administration of doses of the pharmaceutical so that the concentration of the potassium channel blocker 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 the subject to tolerate said dose without showing any adverse effects and thereafter increasing the dose of the active agent in the dosage form, preferably one or more tablets, at selected intervals of time until a therapeutic dose of the potassium channel blocker 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 conditions or diseases the amount of the aminopyridine or potassium chaimel blocker required to reach a therapeutically effective amount for treatment is described in U.S. Pat. No. 5, 952,357 the contents of which are incorporated herein by reference in their entirety.

[0071] 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 demyelination of the central nervous system, more especially multiple sclerosis. The mono- 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.

EXAMPLE1

[0072] This example illustrates preparation of compositions of the present invention and their release of a potassium channel blocker. Tablets in accordance with the present invention having dosages of 5mg, 7.5mg and 12.5mg respectively were manufactured at 5Kg scale. Materials were used in the amounts shown in Table 1.

TABLE 1

[0073] Prior to blending, 4-AP was milled through #50 mesh screen using a Fitzmill comminutor. The materials were added into a Gral 25 bowl in the following order: half Methocel KIOOLV, Avicel PH101, Aerosil 200, milled 4-AP and the remaining Methocel KIOOLV. 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 15 minutes by the check-master E3049. Discrete tablet samples were taken during the compression process to evaluate infra batch content uniformity. The dissolution profiles of the tablets, summarized in Table 1, show a sustained-release over a ten-hour period.

[0074] Tablets in accordance with the present invention are compared with an immediate-release form of 4-AP each having dosages of 15mg as shown in Table 2.

TABLE 2

[0075] As shown in the dissolution data presented in Table 2, the use of a rate-controlling polymer, such as the HPMC sold under the name Methocel KIOOLV, in varying proportions with microcrystalline cellulose demonstrates a dissolution profile that provides for an extended release of 4-AP over a 10-hour period as shown above. By comparison, the combination of crospovidone and microcrystalline cellulose to form a tablet of 4-AP at a comparable unit dose demonstrates a dramatically different dissolution profile and fails to provide for the type of sustained-release profile available from tablets made in accordance with the present invention.

EXAMPLE 2 [0076] This example illustrate the stability of the composition of the present invention during exposure to various storage conditions. Tablets formed from the pharmaceutical composition of the present invention exhibit excellent physical chemical stability characteristics following storage at 25°C at 60% relative humidity (RH). Stability studies have been undertaken with reference to the FDA Draft Guidance for Industry entitled "Stability Testing of Drug Substances & Drug Products," June 1998 which is incorporated herein by reference. Tablets and other pharmaceutical compositions of the present invention which meet these requirements are considered to be stable for purposes of the present invention. Stability data for samples stored at 25°C at 60% RH for 12 months and also at accelerated 40°C at 75% RH conditions for six months is provided in Table 3.

TABLE 3

Pkd = Packaged Exp = Exposed

[0077] Stability data generated for bulk and packaged tablets is provided in Table 4 that includes 12 month, long-term stability data for tablet batches packaged in simulated bulk holding conditions, and 18 month and 46 week stability data for tablets packaged in HDPE bottles with desiccant. The bulk tablets are de-bossed, and the packaged drug product does not contain filler.

Pkd = Packaged

Exp = Exposed

25°C+60%RH = 25°C ± 2°C + 60% ± 5%RH

30°C+60%RH = 30°C ± 2°C + 60% ± 5%RH

40°C+75%RH = 40°C ± 2°C + 75% ± 5%RH

25°C = 25°C ± 2°C

The packaging details for the stability studies are as follows:

[0078] Study 1 : White opaque 120cc HDPE bottles with a closure of a white metal cap (38mm-400) with continuous threads and a knurled flat top. The cap liner board is made of reprocessed materials overlaid with skim manila pulp lining on one surface and 1 mil of white pigmented HDPE extrusion coated on the skim manila surface. The inner seal is 2 mil thick pressure sensitive coating of ethylene vinyl acetate base on approximately 0.020" to 0.029" thick film of extruded polystyrene foam printed safety seal. The bottle contains 100 unit doses per pack without filler or desiccant.

[0079] Study 2: Amber 60cc (2.39oz) glass (height 3.000", diameter 1.766") bottles containing 50 units per bottle with polyester pharmaceutical coil and a sorb-it desiccant capsule capped with 33mm CRC child proof white polypropylene caps with Tekniseal closure liner.

[0080] Study 3: 6 liter HDPE standard neck keg with red screw top closure which is lined with a single polyethylene bag containing 5 x 200g tablets in individual polyethylene bags and 1 x 50g silica gel desiccant sachet. [0081] Study 4: 6 liter HDPE standard neck keg with red screw top closure which is lined with a single polyethylene bag containing 4 x 230g tablets in individual polyethylene bags and 1 x 50g silica gel desiccant sachet.

[0082] Study 5: Samples are packaged in 30cc HDPE W/M round white bottles with 28mm white polypropylene caps lined with polypropylene Tekniseal closure liner and heat sealed Innerseal. Each bottle contains n=8 unit doses and lg desiccant cannister is included. No filler is included.

[0083] Study 6: Samples are packaged in 30cc HDPE W M round white bottles with 28mm white polypropylene caps lined with polypropylene Tekniseal closure liner and heat sealed Innerseal. Each bottle contains n=16 unit doses and lg desiccant cannister is included. No filler is included.

[0084] The data as provided and discussed show that tablets made from the pharmaceutical compositions of the present invention exhibit excellent physical and chemical stability characteristics following storage at 25°C+60% RH.

[0085] 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 this specification.

Claims

CLAIMSWhat is claimed:

1. A pharmaceutical comprising:

a therapeutic amount of an aminopyridine homogeneously dispersed with a release matrix and lubricant and formed into a stable oral dosage.

2. The pharmaceutical of claim 1 wherein the aminopyridine is a potassium channel blocker.

3. The pharmaceutical of claim 1 wherein the release matrix includes hydroxypropylmethylcellulose from about 20% to about 80 %w/w of the stable oral dosage.

4. The pharmaceutical of claim 1 wherein the aminopyridine is 4-aminopyridine and is 4.75

%w/w or less of the stable oral dosage.

5. The pharmaceutical of claim 1 wherein said stable oral dosage provides a therapeutic amount of said aminopyridine in the plasma of a patient for at least 12 hours.

6. The pharmaceutical of claim 1 wherein the stable dosage provides a release profile of said aminopyridine in the plasma of a patient characterized by a a C_n.ax/C _τ at τ=l 2 hours of between about 1 and about 3.6.

7. A pharmaceutical comprising:

an amount of an aminopyridine homogeneously dispersed with a release matrix and lubricant and formed into a stable tablet, said tablet provides a release profile of said aminopyridine in the plasma of a patient characterized by a a C_maχ/C_. at τ=12 hours of between about 1 and about 3.6.

8. The pharmaceutical of claim 7 wherein the aminopyridine is 4-aminopyridine, 3,4- diaminopyridine, or combinations thereof.

9. The pharmaceutical of claim 7 wherein the release matrix includes hydroxypropylmethylcellulose from about 20 to about 80 %w/w of the tablet.

10. The pharmaceutical of claim 7 wherein the aminopyridine is 4-aminopyridine and is 4.75

%w/w or less of the tablet.

11. The pharmaceutical of claim 7 including colloidal silicon dioxide.

12. The pharmaceutical of claim 7 wherein the tablet has a hardness of between 80 and 300

Newtons.

13. The pharmaceutical of claim 7 wherein the aminopyridine is milled through a #24-#60 mesh screen.

14. A pharmaceutical comprising:

an amount of an aminopyridine homogenously dispersed in a release matrix with a lubricant and formed into a stable oral dosage that provides a dissolution profile of said aminopyridine in an aqueous media such that about 15% to 32.5 % of the potassium channel blocker is released from the release matrix after about 1 hour; about 45% to 65% of the potassium channel blocker is released from the matrix after about 4 hours, and at least about 78% released after about 10 hours.

15. The composition of claim 14 wherein the release matrix includes hydroxypropylmethylcellulose from about 20 to about 80 %w/w of the composition.

16. The composition of claim 14 wherein the aminopyridine is 4-aminopyridine and is 4.75

%w/w or less of the dosage.

17. A method of treating a patient comprising:

administering to a patient, a stable oral dosage form of an aminopyridine homogenously dispersed in a release matrix with a lubricant, said stable oral dosage provides a release profile of said aminopyridine in the plasma of a patient characterized by a C_max/C_. at τ=12 hours of between 1 and 3.6.

18. The method of claim 17 wherein the aminopyridine is 4-aminopyridine and is less than 4.75

%w/w of the tablet.

19. The method of claim 17 wherein said oral dosage is a tablet.

20. A method of making an oral dose formulation comprising:

combining a therapeutic amount of an aminopyridine with a release matrix and a lubricant and forming said combination into a stable oral dosage, said stable oral dosage providing a release profile of said aminopyridine in the blood plasma of a patient characterized by a C_max/C_τ at τ=12 hours of between 1 and 3.6.