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Sustained release pharmaceutical compositions

a technology of pharmaceutical compositions and suspensions, which is applied in the direction of drug compositions, heterocyclic compound active ingredients, biocide, etc., can solve the problems of high initial drug concentration and failure to maintain, and achieve high viscosity, low viscosity, and high viscosity.

Inactive Publication Date: 2005-05-05
WYETH LLC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides controlled release dosage formulations of a compound of Formula I, which can be used to treat various conditions. The dosage formulations are designed to release the compound at a controlled rate, which can increase or decrease the maximum therapeutic concentration of the compound in a mammal over time. This controlled release can provide a more effective and safe treatment compared to an instant release formulation. The dosage formulations can be in the form of microparticles, tablets, or spheroids, and can be used orally or through other routes of administration. The compound can be released at a rate effective to increase or decrease the area under the plasma concentration curve relative to an instant release formulation. Overall, the invention provides a more effective and safe treatment for various conditions by providing controlled release dosage formulations of a compound of Formula I.

Problems solved by technology

The administration of aplindore results in high initial drug concentrations.
Such an “immediate release” pattern can pose difficulties, which include failure to maintain optimal exposure levels over time, and unpleasant side effects from having too large initial dose.

Method used

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  • Sustained release pharmaceutical compositions
  • Sustained release pharmaceutical compositions
  • Sustained release pharmaceutical compositions

Examples

Experimental program
Comparison scheme
Effect test

example 1

Sustained Release Aplindore Fumarate Pellets Prepared Using Extrusion / Spheronization and SR Coating

[0107] Batches were made by blending drug with Microcrystalline Cellulose (Avicel PH102) and granulating with water to form a wet mass. The wet mass was extruded through a 1.0 mm screen and spheronized on a small Caleva system. The formulations and the dissolution data in 0.1 N HCl for the uncoated pellets are presented in Table 1. The Avicel matrix does not retard the release of aplindore and essentially all of the drug is released from the uncoated pellets in 30 minutes.

TABLE 1Formulation and Dissolution of Uncoated PelletsComposition12Aplindore (% listed as free5.0%10.0%base)Avicel PH 10295.0%90.0%Dissolution (Hrs)% Dissolved% Dissolved0.1 N HCl0.2576.9185.900.591.1290.30194.7991.07294.1390.86

[0108] The spheres prepared by extrusion / spheronization were coated with Eudragit RS / RL and Surelease to control the release of aplindore. The formulation and the dissolution profiles are sh...

example 2

Sustained Release Aplindore Fumarate Pellets Prepared By Sustained Release Coating of Layered Sugar Spheres

[0109] Aplindore fumarate sustained-release pellets were also prepared by layering the active drug on sugar spheres. The formulation and the dissolution data are given in Table 3. Composition 5 was tested for in vivo release in monkeys. The data is included in Table 4.

TABLE 3Formulation and dissolution of sustained release coated aplindorelayered sugar spheres.Composition5% W / WSpheroids coreSugar spheres 25 / 30 mesh100Drug coating (5% as free base)aplindore fumarate44.4HPMC 6 cps55.6Controlled release CoatingEudragit RS10045.5Triethylcitrate9.1Talc45.5Dissolution Time(Hr)% Dissolved 0.1 N HCl 0.250.9 0.53.77 113.71 231.1pH 6.8 phosphate 18.15 221.27 438.37 863.891279.02

[0110]

TABLE 4Summary Aplindore Bioavailability Parameters in MonkeysAUC% RelativeCom-(ng * hr / CmaxTmaxBio-positionDescriptionmL)(ng / mL)(hr)availability6Instant Release1290166.82.5100capsule3Surelease coated369....

example 3

Sustained Release Tablets Prepared Using Co-Compression Method

[0111] The use of a co-compressed tablet was investigated for the purpose of having a zero-order or nearly zero-order release profile. Different release profiles could be obtained by varying the amounts of drug and polymer (HPMC) in the core tablet and in the outer compressed coat, as well as the total tablet weight. All tablets were made individually on the Carver press using standard round tooling. The formulations and the dissolution data are given in Table 5. In vivo absorption data in Monkeys for Composition 8 are included in Table 4.

TABLE 5Formulations for Aplindore Fumarate Co-CompressedTablets (Tablet-in-Tablet):8INGREDIENTS:InnerOuterAplindore (as base)5.0005.000Lactose, Spray dried25.80068.250Avicel, PH 10125.80068.250Methocel K4M Prem CR36.00048.000Methocel K100 Prem LV7.00059.500Mg-stearate0.4001.000Total100.000250.000Dissolution (Hrs)% DissolvedpH 6.8 phosphate buffer 0.255.50 0.508.47 112.98 112.98 219.70...

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Abstract

The present invention provides controlled release dosage formulations of compounds having the Formula: or pharmaceutically acceptable salts thereof, and in particular, aplindore. The dosage forms are useful, inter alia, for reducing side effects from administration of such compounds.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS [0001] This application claims priority to U.S. provisional application Ser. No. 60 / 515,315 filed Oct. 29, 2003, which is incorporated herein by reference in its entirety.FIELD OF THE INVENTION [0002] This invention relates to sustained release formulations of dopaminergic compounds, including S-2-[(Benzylamino)-methyl]-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (aplindore) and pharmaceutically acceptable salts thereof. BACKGROUND OF THE INVENTION [0003] Compounds having the 2-(Aminomethyl)-2,3,8,9-7H-4-dioxino[2,3-e]-indol-8-one structure have been reported to have significant activity at the dopamine receptor, as well as the ability to modulate dopamine synthesis. See U.S. Pat. No. 5,756,532, incorporated by reference herein in its entirety for all purposes. These compounds are useful in the treatment and prevention of a variety of dopaminergic disorders including schizophrenia, schizoaffective disorder, symptoms of Parkinson's dise...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K9/14A61K9/16A61K9/20A61K9/22A61K9/50A61K31/407
CPCA61K9/2054A61K31/407A61K9/2866A61P25/00A61P25/16A61P25/18A61P43/00A61K9/48A61K9/20
Inventor BENJAMIN, ERIC J.DULIN, WENDY A.LIN, YANNINGZHUANG, KAI
Owner WYETH LLC
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