Once-weekly oral administration of aripiprazole

a technology of aripiprazole and once-weekly oral administration, which is applied in the direction of drug composition, metabolism disorder, nervous disorder, etc., can solve the problems of time-consuming and expensive supervised administration, patients may consider once-a-day oral administration dosage regime too frequent for many patients, etc., to reduce the indirect human cost of drugs, improve patient convenience and compliance, and increase adverse events

Inactive Publication Date: 2014-02-13
ZYSIS
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]Put another way, the compositions of the invention allow greater quantities of aripiprazole to be administered in one dose without significantly increasing adverse events compared to the current once daily conventional IR dosing regimen. Any reduction in dosing frequency is thought to bring material improvements in patient convenience and compliance.
[0018]Reduction in dosing frequency offers significant pharmacoeconomic advantages over the current dosin...

Problems solved by technology

There are a number of disadvantages associated with the dosage regimen for aripiprazole described above for treating schizophrenia, bipolar disease and other CNS conditions.
T...

Method used

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  • Once-weekly oral administration of aripiprazole
  • Once-weekly oral administration of aripiprazole
  • Once-weekly oral administration of aripiprazole

Examples

Experimental program
Comparison scheme
Effect test

example 1

Aripiprazole Compositions

[0285]30 mg direct compression (DC) and wet granulation (WG) controlled release tablets were manufactured as described below.

[0286]Direct Compression Tablets

[0287]The ingredients set out in Table 1 below were blended together in a planetary mixer for 5 minutes. The blend was compressed on a rotary tabletting machine, using 7.0 mm diameter round n / c punches. The tablet breaking strength was 2.5 kp to 3.5 kp.

TABLE 1Direct Compression CompositionDJ / 1 / 27 / ADCIngredient%tablet mgbatch gAripiprazole2030100Methocel K4M3552.5175Avicel PH 2004466220Sodium Stearyl Fumarate11.55100150500

[0288]Wet Granulation Tablets

[0289]The ingredients set out in Table 2 below except for sodium stearyl fumarate were blended together in planetary mixer for 5 minutes prior to wet granulation with purified water. The moist powders were dried in a fluid bed drier at an inlet temperature of 70° C. for 15 minutes. The dried granule had a loss on drying value of 2.5% w / w. The granules were si...

example 2

In Vitro Release Experiments

[0291]The release profiles of Aripiprazole from the DC and WG tablets described in Example 1 were studied in pH 4.0 phosphate buffer and 0.1M HCl, as described in more detail below.

[0292]Dissolution System

Dissolution medium0.05M Phosphate Buffer (pH 4.0)or 0.1M Hydrochloric AcidApparatusUSP II (Paddles)Volume900 mlSpeed100 rpmTemperature37° C.

[0293]7 litres 0.05M Phosphate buffer (pH 4.0) was prepared by dissolving 47.8 g potassium phosphate in 6.75 litres of water, then adding portions of 60% orthophosphoric acid solution to obtain a pH of 4.0 (+ / −0.05). The solution was made up to 7 litres with water and the pH adjusted as necessary with sodium hydroxide or phosphoric acid).

[0294]The 0.1M HCl was prepared by diluting 3.5 litres of 0.2M hydrochloric acid to 7 litres with purified water.

[0295]Dissolution Procedure

[0296]Aliquots were taken from each dissolution vessel at the indicated (e.g. hourly) hourly intervals. The UV absorbance of each aliquot at 215...

example 3

Pharmacokinetic Modelling

[0303]Multiexponential functions were fitted to the published plasma concentration-time profiles of immediate-release (IR) aripiprazole after repeated once-daily oral doses of 5, 10, 15 and 20 mg (Mallikaarjun S, Salazar D, Braner S, “Pharmacokinetics, tolerability and safety of aripiprazole following multiple oral dosing in normal healthy volunteers”, J. Clin. Pharmacol., 2004; 44:179-187).

[0304]The function (representing first-order absorption with two-compartment disposition) was of the form:

C(t)=A·e−α(t)+B·e−β(t)+C·e−k01(t)

where A, B, α, β and k01 are constants, C=−(A+B) and C(t) is the plasma concentration at time, t.

[0305]The published model (Mallikaarjun et al, see above) was used to simulate plasma concentrations of aripiprazole after various dose regimens of the IR formulation. In addition, various dose regimens of a sustained-release (SR) formulation were simulated assuming that the release was zero-order for examples ranging from 10 h to 18 h. Th...

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Abstract

An orally deliverable pharmaceutical composition provides controlled release of aripiprazole. The composition includes a therapeutically effective amount of aripiprazole and at least one pharmaceutically acceptable excipient. The compositions of the invention may exhibit one or more of the release profiles defined in the specification.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a division of co-pending U.S. patent application Ser. No. 12 / 443,036, filed Mar. 26, 2009, which in turn was a Section 371 U.S. National Stage application of International Application No. PCT / GB2007 / 003677, filed Sep. 26, 2007, which was published in the English language on Apr. 3, 2008, under International Publication No. WO / 2008 / 038003 A2, the disclosures of each of which are hereby incorporated herein by reference.BACKGROUND OF THE INVENTION[0002]The invention relates to pharmaceutical formulations comprising aripiprazole. More particularly, the invention relates to orally deliverable pharmaceutical compositions for the controlled release of aripiprazole.[0003]Aripiprazole is 7-[4-[4-(2,3-dichlorophenyl)piperazin-1-yl]butoxy]-3,4-dihydro-1H-quinolin-2-one and has the following structure:[0004]Aripiprazole appears to mediate its antipsychotic effects primarily by partial agonism at the D2 receptor. Partial agonism at...

Claims

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Application Information

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IPC IPC(8): A61K47/38A61K45/06A61K31/496
CPCA61K47/38A61K45/06A61K31/496A61K9/2054A61P1/00A61P11/06A61P19/10A61P25/00A61P25/08A61P25/14A61P25/16A61P25/18A61P25/20A61P25/22A61P25/24A61P25/28A61P25/30A61P43/00A61P3/10A61K9/20
Inventor WILDING, IANPENDLETON, RUSSELL
Owner ZYSIS
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