Stock material or miscellaneous articles – Coated or structually defined flake – particle – cell – strand,... – Particulate matter
Reexamination Certificate
2002-04-16
2004-08-24
Kiliman, Leszek (Department: 1773)
Stock material or miscellaneous articles
Coated or structually defined flake, particle, cell, strand,...
Particulate matter
C428S407000, C424S045000, C424S046000, C424S434000, C424S435000, C424S489000, C424S493000, C514S002600, C514S003100, C514S021800, C514S023000, C514S167000, C514S523000, C514S165000, C514S456000
Reexamination Certificate
active
06780508
ABSTRACT:
SUMMARY OF THE INVENTION
The invention relates to carrier particles (the carrier) for use in the preparation of powdery mixtures for inhalation intended for the pulmonary administration of micronized drugs by means of a dry powder inhaler and the method for their preparation.
According to a first aspect, the invention relates to a novel carrier, consisting of a crystalline substance in powder form, in the size range from tens to hundreds of microns, whose particles have a perfectly smooth surface.
A second aspect of the invention relates to a method for smoothing the surface of said particles. The method claimed is able to make the surface of the particles of the carrier smooth, without any roughness, or hollows, clefts and sharp edges, which represent sites of high surface energy to which the drug particles might adhere, without being removed in the aerosol clouds production stage.
The claimed method further permits to improve the uniformity of the surface characteristics of commercially available substances, which are commonly employed as carriers for inhalation powders, whose characteristics are generally rather variable.
Finally, a third aspect of the invention comprises carrier particles that are obtained with the said smoothing method, the surface of which is coated or partially coated with a suitable additive. By virtue of the claimed method the particles of the additive are not released from the carrier particles during inhalation and so do not reach the smaller branching of the pulmonary tree where absorption occurs.
The powders for inhalation obtained by mixing the smooth carrier particles (with or without coating) with a micronized drug give rise to a particularly high respirable fraction of drug.
PRIOR ART
Drugs intended for inhalation therapy, carried out by the administration of dry powders, are characterized by a particle size of a few microns. The particle size is quantified by measuring a characteristic equivalent sphere diameter, known as aerodynamic diameter, which expresses the ability of the particles to be transported as a suspension in an air stream (aerosolization). In general, particles with an aerodynamic diameter of less than 6.4 microns are regarded as respirable, i.e. capable of penetrating into the lungs.
The administration of these drugs in the form of micronized powder requires the use of suitable dry powder inhalers (DPIs).
DPIs in turn can be divided into two basic types:
i) single dose inhalers, for the administration of single subdivided doses of the active compound;
ii) multidose dry powder inhalers (MDPIs), preloaded with quantities of active principles sufficient for longer treatment cycles.
Although micronization of the drug particles is essential for penetration to the deepest branchings of the pulmonary tree during inhalation, it is also known that the finer are the particles, the stronger are the cohension forces. In multidose inhalers, said effects hamper the loading of the doses of powder from the reservoir system to the aerosolization chamber, since the cohesion forces reduce free flowing of the particles and promote their agglomeration and/or their adhesion to the walls. The aforementioned effects therefore impair the efficiency and reproducibility of the delivered dose and are detrimental to the respirable fraction.
Multidose inhalers work properly when so-called free-flowing powders are used, generally formulated by mixing the micronised drug with a carrier material (generally lactose, preferably &agr;-lactose monohydrate) consisting of coarser particles, approximately equal or greater than 100 microns. In such mixtures, the micronised active particles mainly adhere to the surface of the carrier particles whilst in the inhaler device; on the contrary, during inhalation, a redispersion of the drug particles from the surface of the carrier particles occurs allowing the formers to reach the absorption site into the lungs.
Mixing with the carrier also facilitates the introduction and withdrawal of the inhalation preparation, in a regular dose, from the reservoir of a multidose inhaler or its dosage in single-dose containers. Mixing of the micronized drug with the coarse carrier therefore leads to the production of a mixture in which the micronized drug is distributed uniformly on the carrier particles as a result of the interactions, usually of an electrostatic nature, which establish between the drug particles and the carrier particles. Said interactions lead to the production of a so-called ordered mixture. It is extremely important for the interactions to be weak and reversible, so that, since transport in the air stream and the respirability of the powder depend on the particle size, only the micronized drug particles will be able to be deposited in the lungs, whereas the coarser carrier particles will be deposited, because of their mass, in the upper airways. Due to the weak interactions between the two components of the mixture, breathing-in through the inhaler causes separation of the micronized drug particles from the coarse carrier particles and therefore inhalation of the smaller particles and deposition of the coarser particles in the oropharyngeal cavity. Accordingly, it is of great applicative interest to find new carriers for inhalers and new techniques for the production of drug-carrier mixtures easy to handle and able to generate a high respirable fraction.
The use of a carrier is indeed not free of drawbacks in that the strong interparticle forces between the two ingredients may prevent the separation of the micronised drug particles from the surface of the coarse carriers ones on inhalation, so compromising the availability of the drug to the respiratory tract.
In the prior art there are many examples of processes for modifying the surface conditions of the carrier with the aim of reducing the strength of the interactions between the particles during inhalation, without causing pre-separation of the drug particles in the inhaler.
Ganderton (BG 2 240 337) reports that the surface conditions of the particles, in particular their rugosity, are critical for the behaviour of the carrier during inhalation and claims pharmaceutical carriers, such as lactose, consisting of particles whose rugosity is controlled by a cristallization process. The rugosity of the said particles is evaluated using measurements of surface area, based on gas permeametry. The surface area value measured by this technique, relative to the theoretical surface area value, provides a numerical index of rugosity called Ganderton scale.
It is known anyway that measurements based on the said parameter (gas permeametry) only provide reliable data in the case of powders consisting of particles with diameter below 45 &mgr;m (subsieve range). In fact, by using such method, no difference between the lactose before and after the smoothing treatment can be detected in the case of particles with a mean diameter of about 100 &mgr;m. Moreover the values obtained are not reliable (≈2.5) as demonstrated in Example 1.
In any case, the method of the prior art makes it possible only to reduce the surface rugosity of the carrier particles, as they can have a degree of surface rugosity up to 1.75, determined according to the permeametry method.
Staniforth (WO 95/11666) claims a milling process preferably carried out in a ball mill, called corrasion (for analogy with the effect of wind on rocks), which alters the surface characteristics of the carrier by removing asperities in the form of small grains; these grains in turn can become attached to the clefts of the surface area of the particles, so saturating the high-energy sites. As a result of this preliminary treatment of the carrier, the micronized drug particles are deposited preferentially on lower-energy sites and so are subject to weaker forces of interparticle adhesion.
It is also known from the literature that various types of commercial lactose can have a moderate degree of surface rugosity.
In Kawashima et al. (Int J Pharm 172, 1998, 179-188) examples are given of crystalline lactose with rugosity between
Bettini Ruggero
Caponetti Giovanni
Catellani Pier Luigi
Colombo Paolo
Ventura Paolo
Chiesi Farmaceutici S.p.A.
Kiliman Leszek
LandOfFree
Powder particles with smooth surface for use in inhalation... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Powder particles with smooth surface for use in inhalation..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Powder particles with smooth surface for use in inhalation... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3345325