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Sustained release aminopyridine composition

a technology of aminopyridine and composition, which is applied in the direction of drug compositions, biocide, heterocyclic compound active ingredients, etc., can solve the problems of affecting the effect of treatment, and promoting the transmission of spinal cord nerves, so as to achieve enhanced dosage stability, chemical and physical stability, and superior resistance to moisture absorption

Inactive Publication Date: 2010-10-28
ALKERMES PHARMA IRELAND LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention is about a pharmaceutical composition that contains a potassium channel blocker called aminopyridine. The composition can be used to treat various neurological diseases such as spinal cord injury, multiple sclerosis, Alzheimer's disease, and ALS. The composition is made by dispersing the aminopyridine in a matrix and can be administered as a once- or twice-daily dosage form. The composition provides a therapeutically effective level of the aminopyridine in the patient's blood plasma for at least 6 hours, preferably at least 8 hours, and more preferably at least 12 hours. The composition is stable and can be easily manufactured. Overall, the invention provides a new and effective treatment for various neurological diseases.

Problems solved by technology

Treatment alternatives for promoting transmission along injured nerves of the spinal cord have thus far met with limited success.
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.
The emotional state, behavior, cognitive function and thought processes of sufferers are all adversely affected.
Part of the disease process involves the transmission of nerve signals and, as with MS, treatment alternatives have thus far been limited.
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.
Symptoms of lower motor neuron damage include muscle weakness and muscle atrophy.

Method used

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  • Sustained release aminopyridine composition
  • Sustained release aminopyridine composition
  • Sustained release aminopyridine composition

Examples

Experimental program
Comparison scheme
Effect test

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 5 mg, 7.5 mg and 12.5 mg respectively were manufactured at 5Kg scale. Materials were used in the amounts shown in Table 1.

TABLE 1% w / w% w / w% w / wMilled 4-AP1.251.8753.125(#50 mesh)Methocel K 100LV606060Avicel PH10138.1537.52536.275Magnesium stearate0.20.20.2Aerosil 2000.40.40.4Equipment TabletHorn Noak equipped with 13 × 8 mm oval toolingPresspress speed 42,000 tablets / hrTablet Weight386-404388-410388-406Range (mg)(96.5-101.0%)(97.0-102.5%)(97.0-101.5%)Tablet Hardness200-262179-292150-268Range (N)Tablet Potency -97.199.1100.2mg / tab. (% LC)Mean CU (mg / tab.) / 5.0 mg / 1.0%7.4 mg / 0.7%12.4 mg / 1.1%% CVCU Discrete Samples5.0 mg / 1.2%7.5 mg / 1.8%12.3 / 1.1%(mg / tab.) / % CVDissolution (% / hr)Mean(SD)Mean(SD)Mean(SD) 128.91.129.21.825.91.1 242.71.842.11.640.22.5 352.81.453.01.049.82.1 461.42.261.81.560.12.4 675.73.1...

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...

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 Cmax 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 Tmax ranged from 2.2 hours to 3.0 hours. The T1 / 2 of fampridine ranged from 5.7 to 6.9 hours. There were no apparent differences between males and females. Data from this study are summarized in Table 3.

TABLE 3Pharmacokinetic Parameter Values (Mean ± SD) FollowingMultiple Oral Doses of Fampridine-SR to 11 Patients with SCI.Fampridine-SRDosageCMAXTMAXAUC(0-12)T1 / 2(mg b.i.d.)(ng / mL)(hours)(ng hr / mL)(hours)25 63.4 ± 11.92.2 ± 0.9 475.8 ± 65.56.4 ± 1.430 83.2 ± 20.52.4 ± 1....

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Abstract

A pharmaceutical composition which comprises a therapeutically 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.

Description

CROSS REFERENCES[0001]This application is a divisional of U.S. application Ser. No. 11 / 010,828 filed Dec. 13, 2004, which claims priority to U.S. Provisional Application 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, U.S. Provisional Application No. 60 / 528,593 filed Dec. 11, 2003, and International Application No. PCT / US2004 / 008101 filed on Mar. 17, 2004, all of which are incorporated herein by reference in their entirety.BACKGROUND[0002]This invention relates 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 i...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/00A61K31/4409A61P25/28A61P19/00A61P25/00A61K9/22A61K9/52A61K9/20A61K31/44
CPCA61K9/2054A61K31/44A61K9/2077A61K47/44A61K47/14A61K47/38A61K31/4409A61P19/00A61P25/00A61P25/28A61P43/00A61K47/12A61K9/20
Inventor CUNNINGHAM, SEANMULLIGAN, SEAMUSMYERS, MICHAEL
Owner ALKERMES PHARMA IRELAND LTD
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