Improvements Relating To Inhalable Particles

a technology of inhalable particles and powder formulations, which is applied in the direction of powder delivery, medical preparations, pharmaceutical active ingredients, etc., can solve the problems of inability to direct prepare the particle sizes required for unhelpful crystalline habits, and inability to achieve the effect of effective drug deposition in the central and deep lung compartments, easy inhalation, and reduced dosag

Inactive Publication Date: 2017-03-02
CRYSTEC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0017]It has been found that SAS precipitation of antimuscarinic agents can provide particles that are more readily inhalable than milled particles.
[0018]Without wishing to be bound by theory, it appears that SAS precipitation leads to antimuscarinic...

Problems solved by technology

The preparation of inhalable or insufflable powder formulations comprising an antimuscarinic agent, in particular tolterodine, poses particular challenges.
One issue faced in this area is that of unhelpful crystalline habits.
For example, organic solvent particle precipitation/crystallisation of tolterodine L-tartrate leads to lengthy needle shaped (acicular) crystals, with the consequence that direct preparation of the particle sizes required for effective drug deposition in central and deep lung compartments is not possible by conventional crystallisation.
This approach, whilst producing particles in respirable r...

Method used

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  • Improvements Relating To Inhalable Particles
  • Improvements Relating To Inhalable Particles
  • Improvements Relating To Inhalable Particles

Examples

Experimental program
Comparison scheme
Effect test

examples 1 to 33

Tolterodine L-Tartrate / Examples C1 to C5

[0096]Experiments were conducted with the object of forming advantageously inhalable or insufflable particles of Tolterodine L-tartrate using supercritical anti-solvent (SAS) precipitation.

[0097]Tolterodine L-tartrate forms acicular (needle-like) crystals. Acicular particles grow extremely fast in one dimension. This presents particular challenges in the context of precipitation of inhalable or insufflable particles. Specific particle formation conditions for providing readily inhalable or insufflable particles, in particular particles with D50 and D90 percentiles between 1 to 4 μm and 2 to 10 μm and volume mean diameter<7 μm, more preferably <5 μm respectively were investigated.

[0098]The method used to generate particles of inhalable tolterodine L-tartrate was a SAS (Supercritical Anti-Solvent) process

[0099]For each example, tolterodine L-tartrate was dissolved in methanol.

[0100]A stream of the solution of tolterodine L-tartrate was contacte...

example 34

Hydroxymethyl Tolterodine

[0137]A further experiment was conducted to prepare inhalable particles of hydroxymethyl tolterodine.

[0138]Hydroxymethyl tolterodine was precipitated, in the general manner of Examples 1 to 33, from acetonitrile solution (50.0 mg / ml) using a carbon dioxide temperature of 40° C., a carbon dioxide pressure of 85 bar, a carbon dioxide density of 0.353, a hydroxymethyl tolterodine solution flow of 0.32 g / min and carbon dioxide flow of 36 g / min. The product was a fine, free flowing powder that had D50 and D90 percentiles of 1.2 μm and 3.1 μm and volume mean diameter 1.5 μm respectively. The sample was amorphous by PXRD.

example 35

Batch Consistency

[0139]The results of reproducibility of seven batches of tolterodine L-tartrate produced using the same conditions as in Example 1 are shown in FIG. 6 in the form of a particle size distribution curve. Particle size analysis of the product was carried out using a Sympatec Helos Particle Size Analyser using an aerosolisation pressure of 4 bar.

[0140]Particles possessed a median diameter of D50=1.4 μm with a percentiles diameter of D90=3.3 μm and a volume mean diameter (VMD)=1.7 μm. These data demonstrate the excellent reproducibility under the conditions of Example 1 process and confirm the suitability of the particle size distribution for respiratory drug delivery applications.

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Abstract

A powder formulation, or pharmaceutical composition comprising or consisting of particles of an antimuscarinic agent, said particles being obtainable by supercritical anti-solvent (SAS) precipitation and having a D50 of 4 μm or less and a D90 of 10 μm or less. Methods of forming the formulation and composition are also disclosed, as are uses of the composition.

Description

FIELD OF THE INVENTION[0001]This invention relates to powder formulations comprising an antimuscarinic agent, and to methods of forming such powder formulations.[0002]In particular, though not exclusively, this invention relates to powder formulations comprising tolterodine, such as pharmaceutical powder compositions for administration by inhalation or insufflation, the use of such compositions as medicaments, as well as methods of treatment involving administration of the compositions. The compositions may be useful in particular for the treatment of urinary disorder, asthma, a group of breathing disorders termed Chronic Obstructive Pulmonary Disease (COPD), and allergic rhinitis.BACKGROUND TO THE INVENTION[0003]U.S. Pat. No. 5,382,600 discloses (substituted) 3,3-diphenylpropylamines useful for treating urinary incontinence. In particular, it discloses 2-[(1R)-3-(diisopropylamino)-1-phenylpropyl)-4-methylphenol, also known as N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpro...

Claims

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Application Information

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IPC IPC(8): A61K9/00A61K31/137
CPCA61K31/137A61K9/0075
Inventor LEDGER, DANIEL MARKDAINTREE, LINDA SHARONYORK, PETER
Owner CRYSTEC
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