Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-01-30
1998-01-20
Criares, Theodore J.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424499, A61K 914, A61K 950
Patent
active
057098840
DESCRIPTION:
BRIEF SUMMARY
This is a 371 application of PCT/SE94/00780 filed Aug. 25, 1994.
FIELD OF THE INVENTION
The present invention relates to a process for providing a fine-grained substance or substance mixture, which can be produced, stored and used while maintaining the aerodynamic properties required for inhalation of such a substance or substance mixture and which has improved physicochemical properties in the dry state, thereby facilitating the technical handling and significantly increase the medical value of the substance or substance mixture used.
BACKGROUND OF THE INVENTION
There are presently several effective drugs available for the treatment of patients with asthma or other respiratory disorders. It has been recognized that these drugs should be given by the inhaled route whenever possible. The ideal delivery system for inhalable drugs would be a user- and environment-friendly multidose inhaler giving accurate doses of a stable formulation with good aerodynamic behaviour of the particles.
During the past few years, there have been frequent demonstrations of the fact that the appropriate selection of the most suitable crystalline modification significantly can influence the clinical results of a given chemical substance. The chemical and physical stability of a solid in a particular dosage form can be improved by presenting the substance(s) in the appropriate crystal form. The solid state phase transformation of the substance in a dosage form can dramatically alter the pharmaceutical properties of the formulation. The solid state phase of the administered substance(s) can influence such important factors as bioavailability and physicochemical stability (specific surface area, particle size etc). Chemical stability in solid state and hygroscopicity are often closely related to the crystallinity.
Solid state transformations may occur during mechanical processing e.g. micronization. In a micronization process of solids, disruption or activation of the crystalline structure often leads to varying degrees of disorder through the formation of defects or amorphous regions. Such regions are often more sensitive to external effects e.g. moisture. It is necessary to establish the conditions whereby different forms of a substance might be converted to a single stable form thus eliminating differences in solid state properties and subsequent different physicochemical and pharmaceutical properties.
The increasing production and use of fine powders in the pharmaceutical industry has highlighted the need of reliable methods for assessing their physicochemical and technical handling. Mixing of cohesive powders will be influenced by the interparticulate forces between particles of the same species and also between particles of different species. Since fine powders agglomerate, the mixture will often be inhomogeneous, particularly the minor component will show a skewed distribution. One reason could be that the agglomerates of the minor component are not completely dispersed into their component particles; see further Chem. Eng. (1973), 12-19. Cohesive powders are thus very difficult to mix to a homogenous mixture in an accurate way, especially when one component is present only as a small fraction.
Substances will often be obtained in an amorphous state or a metastable crystalline form when spray drying, freeze drying, rapid solvent quenching or when using controlled precipitation, where both crystalline and amorphous forms can be prepared. The use of an amorphous form or metastable crystalline form is often limited due to its thermodynamic instability. It is therefore a desire to convert the amorphous form or the metastable crystalline form to the more stable crystalline state. For crystalline substances, a diminution operation step will give amorphous regions of the particle making the particle more sensitive to moisture and chemical degradation. The present invention deals with such physical changes, or more importantly, to anticipate them and the means by which these solid state phenomena can be handled.
The rearrangement
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Briggner Lars-Erik
Trofast Eva Ann-Christin
Astra Aktiebolag
Criares Theodore J.
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