Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing
Reexamination Certificate
2001-05-22
2002-10-15
Dees, Jose′ G. (Department: 1619)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
C424S045000, C424S400000, C424S489000
Reexamination Certificate
active
06464958
ABSTRACT:
The administration of drugs through inhalation has been used for many years and is the mainstay of treatment of diseases which limit airflow, such as asthma and chronic bronchitis.
Furthermore, a number of inhalatory formulations have been marketed for some years, for the administration of steroidal antiinflammatory, decongestant and antiallergic agents for the topical treatment of rhinitis and/or sinusitis.
One of the advantages of the inhalatory route over the systemic one is the possibility of delivering the drug directly at the action site, so avoiding any systemic side-effects. Said way of administration allows to achieve a more rapid clinical response and a higher therapeutic index.
Among the different classes of drugs which are usually administered by inhalation for the treatment of respiratory diseases, glucocorticosteroids such as beclomethasone dipropionate (BDP), dexamethasone, flunisolide, budesonide, fluticasone propionate are of great importance. They can be administered in the form of a finely divided, i.e. micronised, powder, formulated as suspension in an aqueous phase containing any necessary surfactants and/or cosolvents; when intended to be administered in the form of metered doses of aerosol spray, they should also contain a low-boiling propellant.
The effectiveness of the administration form depends on the deposition of an adequate amount of particles at the action site. One of most critical parameters determining the proportion of inhalable drug which will reach the lower respiratory tract of a patient is the size of the particles emerging from the device. In order to ensure an effective penetration into the bronchioli and alveoli and hence ensure a high respirable fraction, the mean aerodynamic diameter (MMAD) of the particles should be lower than 5-6 microns (&mgr;m). For nasal administration, particles with higher MMAD are required.
Other important characteristics for a correct administration and therefore for the therapeutic efficacy, are the size distribution and the homogeneous dispersion of the particles in the suspension.
A poor control of said parameters might favour the formation of loose agglomerates (curds) or, if the curds become compacted and fuse, cakes of suspended particles which, in turn, may impair the possibility of re-suspending the product easily and providing uniform dosing either during the filling of the containers and during the use.
The first object of the present invention is to provide a process for the preparation of particles suspensions for use in pharmaceutical formulations for aerosol inhalation, said particles being characterised by optimised particle size and distribution for obtaining compositions with high therapeutic efficacy.
In a first embodiment of the invention, the process is carried out by using a turboemulsifier, optionally followed by a treatment with a high pressure homogeniser.
Accordingly, said process includes a first step wherein an aqueous solution which constitutes the carrier is dispersed in a turboemulsifier apparatus. A typical turboemulsifier suitable for the treatment comprises a containment vessel equipped with magnetic stirring and a high potency turbine system which is used for homogenising the suspension. The apparatus can also be fitted with a heating steam jacket as well as a vacuum system.
The carrier optionally contains wetting agents, surfactants, viscosity-increasing agents, preservatives, stabilising agents, isotonicity agents and/or buffers and can optionally be sterilised. In a second step, one or more micronised active ingredients, obtained after conventional milling, are added to the aqueous phase and dispersed in the same turboemulsifier vessel by applying very high speed (2000-3000 r.p.m., preferably 2500-2600) for 15-20 min. In has been found that said conditions are necessary in order to effectively disperse the micronised particles of the active ingredient in such a way as to prevent agglomeration during storage. Moreover, it has been more surprisingly found that the particles during said treatment are subjected to a further mild milling which reduces the sizes of the crystals of larger diameter so removing the fractions with higher particle size distribution.
Optionally the process can be carried out under vacuum in order to skim off the suspension.
In a more preferred embodiment of the invention, the drug, dispersed in the aqueous phase, is subjected to an additional homogenisation treatment under high-pressure to further reduce the mean size of the suspended particles. A typical apparatus used for this treatment, such as the Microfluidizer®, includes a high pressure pump which can supply pressures up to 1500 bar and one or more interaction chambers. During the process, the sample is introduced as a stream, then forced at the operating pressure through the interaction chambers where the stream is accelerated to extremely high velocities and subjected to three main forces: i) shear (sliding of particles across one another, tearing); ii) impaction (collisions; crushing); iii) cavitation (collapsing of cavities or bubbles of the surrounding liquid phase; an increased change in velocity with a decreased change in pressure).
The degree of reduction of the solid particles size and the resulting distribution particle curve can be optimised by controlling the following variables i) the type and size of the interaction chamber; ii) the operating pressure; iii) the time of processing and the number of cycle the material is going through.
The effect of the process is also dependent on physico-chemical characteristics of the ingredient subjected to the treatment. According to the hardness of its crystalline lattice, different pressure and processing times can be requested to achieve the desired results.
It has now been found that, in case of steroids, it is possible to tighten the distribution particle curve in such a way as that the mean diameter of at least 90% of the particles is lower than or equal to 5 &mgr;m by keeping the operating pressures between 500 and 1000 bar. In particular, particles optimised for pulmonary delivery are obtained using an interaction chamber with sharp edges and maintaining the operating pressure between 600 and 800 bar. Overprocessing at higher pressure should be avoided as it may result in particle-size growth and curds formation. Said surprising results were achieved by submitting the suspension to only one cycle of treatment and therefore for a very short period, making the process very convenient and attractive from an industrial point of view.
The process of the invention is efficiently carried out at room temperature which constitutes a considerable advantage in case of potentially thermolabile molecules such as steroids. On the other hand, the temperature does not significantly increase during the treatment. Furthermore, said specific range of pressures turned out to be suitable for reducing the particle size of the suspended active ingredient without requiring a significant increment in the amount of surfactants. It is general knowledge indeed that the total surface area of the active ingredient increases upon micronisation making sometimes necessary to change the formula of the suspension. Therefore, the breaking of the particles has to be controlled to the degree allowed by the chosen composition.
At the end of the treatment of the invention, particles of particle size distribution within well-defined parameters as well as a good dispersion of the suspended particles are obtained. The resulting formulation is physically stable and it can be easily re-suspended after at least one year of storage.
In order to prevent an increment in the viscosity of the suspension and the formation of even loose aggregates during storage which may puzzle the patient before the use, the process can be preferably carried out by operating at 600-700 bar and by employing an additional interaction chamber arranged in series with respect to the former.
The most widely experienced applications of high-pressure homogenisation regard solid-in-liquid dispersion of paint, p
Bernini Eva
Brambilla Gaetano
Chiesi Paolo
Garzia Raffaella
Malvolti Chiara
Chiesi Farmaceutici S.p.A.
Dees Jose′ G.
Haghighatian Mina
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