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Modified release formulation

Inactive Publication Date: 2016-05-12
NOVARTIS AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides drug products with modified drug substance release properties. The invention provides a modified release formulation of AFQ056 that can release the drug over a controlled period of time, resulting in a controlled release rate in ethanol containing media as compared to a purely aqueous media. The drug substance has a particle size distribution of x10≦50 μm, x50≦100 μm, and x90≦200 μm. The drug product can be in the form of a single unit dosage form with AFQ056 present in an amount of about 25 mg to about 250 mg. The pharmaceutical composition can also include other excipients such as hypromellose, lactose monohydrate, sodium starch glycolate, and colloidal silicon dioxide. The invention also provides a method of treating patients with Parkinson's disease and exhibiting L-dopa induced dyskinesia by administering an effective amount of a pharmaceutical composition of the present invention.

Problems solved by technology

One of the major problems associated with long-term L-dopa treatment is the development of L-dopa induced motor complications such as dyskinesias (LIDs).
Results also revealed that a significant proportion of patients did not achieve and maintain the target dose throughout the study, presumably due to tolerability issues such as dizziness.
Advantages of modified release formulations are the prolonged blood plasma levels of drug compared to an immediate release formulation.
If the formulation releases the drug at a rate that is faster than the intended controlled release rate (often referred to as dose dumping), there is a risk of overdosing with potential severe consequences for the patient.

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1

[0075]The following formulations (tablet core compositions) of AFQ056 are made:

TABLE 1IR-CapsForm AForm BForm C[mg / dose][mg / dose][mg / dose][mg / dose]AFQ056100.00100.00100.0099.00Lactose monohydrate100.0022.0022.0021.78Microcrystalline20.00———CelluloseSodium Starch16.2512.5012.5012.375glycolateHypromellose10.0042.8069.5071.775Colloidal Silicon1.250.901.000.99DioxideMagnesium stearate2.501.802.001.98Total250.00180.00207.00207.90IR-CapsForm AForm BForm C[%][%][%][%]AFQ05640.0055.5648.3147.62Hypromellose4.0023.7833.5734.52Lactose monohydrate40.0012.2210.6310.48Microcrystalline8.40———CelluloseSodium Starch6.506.946.045.95glycolateMagnesium stearate1.001.000.970.95Colloidal Silicon0.500.500.480.48Dioxide

[0076]Since previous oral formulations have exhibited an increased exposure upon concomitant intake of a high-fat meal, the extent of which has been found to be formulation-dependent, this study is designed to assess the food-effect (by administration of a high fat breakfast) on the PK of th...

example 2

[0090]The tablet core is formulated using common excipients for such pharmaceutical dosage forms. Release of the drug substance from the tablet core occurs through an erosion and diffusion mechanism, and is controlled by the hypromellose (type 2208) content of the formulated product. A pharmacokinetic study is performed using different 100 mg modified release tablet formulations in order to evaluate the impact of delaying release of the active ingredient.

[0091]The same ratio of excipients in the 100 mg tablet core is used to create the additional dosage strengths. The lower dosage strengths e.g. 25 mg, 50 mg and 75 mg use lactose monohydrate as compensation for drug substance in order to maintain the tablet weight and size. The tablet cores of dosage strengths less than or equal to 100 mg are compressed to round tablets possessing a diameter of 8 mm.

[0092]For the higher dosage strengths e.g. 150 mg, 200 mg and 250 mg, the tablet weight and size are increased. The same formulation pr...

example 3

[0094]Particle size distribution is an important factor in dissolution of the modified release forms of the present invention. The following experiments are performed to in order to determine how particle size effects dissolution at various time points.

[0095]FIG. 11 graphically depicts the percentage of AFQ056 dissolved after 45 minutes versus particle size at x90. As can be discerned from the figure, particle size distribution is a key factor in dissolution rate and thus the performance of the MR Form. The drug substance has a particle size distribution of x10≦50 μm, x50≦100 μm and x90≦200 μm.

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Abstract

Drug products in the form of modified release formulations comprising the drug substance (-)-(3aR,4S,7aR)-4-Hydroxy-4m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester (AFQ056), as well as processes for making such drug products are provided. The drug products are useful in treating patients with Parkinson's disease and exhibiting L-dopa induced dyskinesia.

Description

BACKGROUND OF THE INVENTION[0001]The drug substance AFQ056 is a subtype-selective, non-competitive antagonist at the metabotropic glutamate receptor 5 (mGluR5). Glutamate is the main excitatory neurotransmitter in the nervous system and as such is involved in a variety of physiological and pathophysiological functions. Excessive glutamatergic transmission has been shown to play a role in both movement disorders and psychiatric conditions and the pharmacological use of glutamate receptor antagonists has shown efficacy in these indications.[0002]The systemic chemical name for AFQ056 is (-)-(3aR,4S,7aR)-Octahydro-4-hydroxy-4-[(3-methylphenyl)ethynyl]-1H-indole-1-carboxylic acid methyl ester, and is also known as (-)-(3aR,4S,7aR)-4-Hydroxy-4m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. AFQ056 has the molecular formula C19H23NO3 and the following structural formula:[0003]AFQ056 drug substance is a white to practically white powder, which is hardly soluble in water but s...

Claims

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Application Information

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IPC IPC(8): A61K31/404A61K9/16A61J3/02A61K9/20A61J3/10A61K47/38A61K9/50
CPCA61K31/404A61K47/38A61K9/1652A61K9/50A61J3/02A61K9/5089A61K9/1682A61J3/10A61K9/2072A61K9/2004A61K9/28A61K31/4045A61P25/00A61P25/04A61P25/14A61P25/16A61P25/24A61P25/28A61P25/30A61P25/32A61P25/34A61P25/36
Inventor THOMA, HUBERTGALLI, BRUNOSPICKERMANN, DIRKPUTZBACH, KARSTENMOLL, KLAUS-PETERUFER, MIKEGRANDEURY, ARNAUDGLANTZMANN, JEAN-MARIEMUELLER-ZSIGMONDY, MARTIN
Owner NOVARTIS AG
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