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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

The patent text describes a method for making particles of antimuscarinic agents that are easier to inhale and can be administered in smaller doses. This method involves using a process called SAS precipitation, which can create particles with smoother surfaces and shapes, and can also improve the delivery of these drugs with an acicular crystal habit. This can lead to faster onset of action and reduce the amount of drug needed. This technology is useful for developing new pharmaceutical products.

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 ranges, generally results in highly charged, very cohesive material which causes severe downstream handling and processing issues.
In addition, amorphous hygroscopic domains varying in content between batches of product tend to be formed which can lead to particle recrystallisation and growth upon uptake of water.
As might be expected, being a random operation, milling produces irregular shaped and sized particle as a result of uncontrolled particle fracture and breakage.
A further problem with milling is that a disturbed particle size distribution is generally obtained.
Such material will not aerosolise readily and easily.

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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