Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2001-09-27
2003-11-04
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S400000, C424S490000, C424S493000, C424S498000
Reexamination Certificate
active
06641844
ABSTRACT:
PRIOR ART
Inhalation anti-asthmatics are widely used in the treatment of reversible airway obstruction, inflammation and hyperresponsiveness.
Presently, the most widely used systems for inhalation therapy are the pressurised metered dose inhalers (MDIs) which use a propellant to expel droplets containing the pharmaceutical product to the respiratory tract.
However, despite their practicality and popularity, MDIs have some disadvantages:
i), droplets leaving the actuator orifice could be large or have an extremely high velocity resulting in extensive oropharyngeal deposition to the detriment of the dose which penetrates into the lungs;
ii) the amount of drug which penetrates the bronchial tree may be further reduced by poor inhalation technique, due to the common difficulty of the patient to synchronise actuation form the device with inspiration
iii) chlorofluorocarbons (CFCs), such as freons contained as propellants in MDIs, are disadvantageous on environmental grounds as they have a proven damaging effect on the atmospheric ozone layer.
Dry powder inhalers (DPIs) constitute a valid alternative to MDIs for the administration of drugs to airways. The main advantages of DPIs are:
i) being breath-actuated delivery systems, they do not require co-ordination of actuation since release of the drug is dependent on the patient own inhalation;
ii) they do not contain propellants acting as environmental hazards;
iii) the velocity of the delivered particles is the same or lower than that of the flow of inspired air, so making them more prone to follow the air flow than the faster moving MDI particles, thereby reducing upper respiratory tract deposition.
DPIs can be divided into two basic types:
i) single dose inhalers, for the administration of pre-subdivided single doses of the active compound;
ii) multidose dry powder inhalers (MDPIs), pre-loaded with quantities of active ingredient sufficient for multiple doses; each dose is created by a metering unit within the inhaler.
Drugs intended for inhalation as dry powders should be used in the form of micronised powder so they are characterized by particles of few micron particle size (&mgr;m). Said size is quantified by measuring a characteristic equivalent sphere diameter, known as aerodynamic diameter, which indicates the capability of the particles of being transported suspended in an air stream. Respirable particles are generally considered to be those with diameters from 0.5 to 6 &mgr;m, as they are able of penetrating into the lower lungs, i.e. the bronchiolar and alveolar sites, where absorption takes place. Larger particles are mostly deposited in the oropharyngeal cavity so they cannot reach said sites, whereas the smaller ones are exhaled.
Although micronisation of the active drug is essential for deposition into the lower lungs during inhalation, it is also known that the finer the particles, the stronger are the cohesion forces. Strong cohesion forces hinder the handling of the powder during the manufacturing process (pouring, filling). Moreover they reduce the flowability of the particles while favoring the agglomeration and/or adhesion thereof to the walls. In multidose DPI's, said phenomena impair the loading of the powder from the reservoir to the aerosolization chamber, so giving rise to handling and metering accuracy problems.
Said drawbacks are also detrimental to the respirable fraction of the delivered dose being the active particles unable to leave the inhaler and remaining adhered to the interior of the inhaler or leaving the inhaler as large agglomerates; agglomerated particles, in turn, cannot reach the bronchiolar and alveolar sites of the lungs. The uncertainty as to the extent of agglomeration of the particles between each actuation of the inhaler and also between inhalers and different batches of particles, leads to poor dose reproducibility as well.
In an attempt to improve both the handling and the efficiency, the dry powders for inhalation are generally formulated by mixing the micronised drug with a carrier material (generally lactose, preferably &agr;-lactose monohydrate) consisting of coarser particles. In such ordered mixtures, the micronised active particles, because of the electrostatic or Van der Waals interactions, 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.
Nevertheless, the use of a carrier is 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 carrier ones on inhalation, so compromising the availability of the drug to the respiratory tract. The surface of the carrier particles is, indeed, not smooth but has asperities and clefts, which are high energy sites on which the active particles are preferably attracted to and adhere more strongly; because of such strong, interparticle forces, they will be hardly leave the surface of the carrier particles and be dispersed in the respiratory tract.
Therefore the features of the carrier particles should be such as to give sufficient adhesion force to hold the active particles to the surface of the carrier particles during manufacturing of the dry powder and in the delivery device before use, but that force of adhesion should be low enough to allow the dispersion of the active particles in the respiratory tract.
The prior art discloses several approaches for manipulating the interparticle interactions between the drug and the carrier in ordered powder mixtures.
First, the carrier particles can be chosen according to their median particle size, taking into account the fact that a decrease in median particle size increases the adhesion force between drug and carrier particles.
GB 1,242,211 and GB 1,381,872 disclose pharmaceutical powders for the inhalatory use in which the micronised drug (0.01-10 &mgr;m) is mixed with carrier particles of sizes 30 to 80 &mgr;m and 80 to 150 &mgr;m, respectively; said mixtures can also contain a diluent of the same particle size as the micronised drug.
The deaggregation of the active ingredient from the carrier during inhalation can also be made more efficient by modifying the surface properties of the carrier and/or by addition of a fine fraction (<10 &mgr;m), preferably of the same material of the carrier (Podczeck F.
Aerosol Sci. Technol
. 1999, 31, 301-321; Lucas P. et al
Resp. Drug Deliv
. 1998, VI, 243-250).
GB 2,240,337 A discloses, for example, a controlled crystallization process for the preparation of carrier particles with smoother surfaces, and, in particular, characterized by a rugosity of less than 1.75 as measured by air permeametry; in practice their smoothness is readily apparent under electronic microscope examination. The use of said carrier particles allows to increase the respirable fraction of the drug (Kassem, Doctoral thesis of the London University, 1990).
EP 0,663,815 claims the use of carriers for controlling and optimizing the amount of delivered drug during the aerosolisation phase, consisting of suitable mixtures of particles of size >20 &mgr;m and finer particles (<10 &mgr;m) Staniforth et al. (WO 95/11666) combine both the aforementioned teachings (i.e. modification of the surface properties of the carrier and addition of a fine fraction) by exploiting the effects of a milling process, preferably carried out in a ball mill, referred to as corrasion (corrasion is a term used in geology and it describes either the effect of the wind on rocks and the filling of valley with stones during the ice age) Said process modifies the surface properties and it gets rid of the waviness of the carrier particles by dislodging any asperities in the form of small grains without substantially changing the size of the particles; the small grains, in turn, can be reattached to the surfaces of the particles either during the milling phase or after prev
Bilzi Roberto
Chiesi Paolo
Musa Rossella
Ventura Paolo
Chiesi Farmaceutici S.p.A.
Oh Simon J.
Spear James M.
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