Drug – bio-affecting and body treating compositions – Inorganic active ingredient containing – Aluminum – calcium or magnesium element – or compound containing
Reexamination Certificate
1997-04-02
2001-09-04
Bawa, Raj (Department: 1619)
Drug, bio-affecting and body treating compositions
Inorganic active ingredient containing
Aluminum, calcium or magnesium element, or compound containing
C424S046000
Reexamination Certificate
active
06284287
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a pharmaceutical formulation for administration by inhalation, the micronized active compound or the micronized active compound mixture being applied to an excipient without binders being used.
2. Background Information
Active compounds which are administered by inhalation must penetrate deep into the lungs in order to show topical or alternatively systemic action. In order to achieve this, the particles of the active compound must have a diameter which does not exceed approximately 5 &mgr;m-10 &mgr;m. Additionally, the active compound or the active compound mixture is administered to the patient with the aid of a specially made device, an inhaler. The active compound here must first be either predosed, for example in capsules or blister packs, or stored in a relatively large amount in the inhaler in order then to be removed from a measuring device by the inhalation process of the patient and redispersed into the fine primary particles with a dispersing device, for example a fluidizing chamber, carried along with the breath and thus made available to the lungs.
On account of the particle size a high specific surface area of the particles and a distribution of forces resulting therefrom, the very fine-grained active compounds used for this purpose have very pronounced adhesive and cohesive properties, which in turn has the result that the processing of such powders regarding process technology runs into difficulties. Such process technology steps are the mixing of the active compounds in active compound mixtures, the storage and the transport of the powders, the filling of capsules, blister packs or inhalers, and the dosage of the therapeutic amounts.
The agglomeration processes customary in pharmacy, e.g. granulation, cannot be employed because the particles are so strongly bound to one another thereby that respirable active compound particles are no longer present or can no longer be generated. Additionally, at present most of the pharmaceutically customary auxiliaries cannot be used in pharmaceutical forms for inhalation, as the toxicological behavior of these substances on pulmonary administration is still largely unknown.
In order to solve the problems mentioned, it was proposed, for example, in EP 0 398 631 to grind the active compound down to a mean particle diameter of 5 &mgr;m to 10 &mgr;m and then either to mix it with a solid, pharmaceutically customary excipient, this having a mean particle diameter of 30 &mgr;m to 80 &mgr;m, or else to prepare round agglomerates of the active compound particles (so-called soft pellets), these disintegrating into the primary particles again during inhalation. A process for the preparation of such soft pellets is also described (GB 1,569,612 and GB 1,520,247). In this process, the moisture content of the active compound must be adjusted before the preparation of the soft pellets. The soft pellets can be filled into capsules as described, for example, in DE 25 35 258 and GB 1,520,247. In vitro experiments showed that on emptying these capsules with the aid of an inhaler at least 50% of the filled material was emptied.
However, these soft pellets, prepared according to the abovementioned procedures, have a dispersing rate (=proportion of the respirable active compound particles after emptying, relative to the amount dispensed in the capsule), which may still not be satisfactory.
With a volume flow of 60 1/min, dispersing rates of 13.8-29.5% of the nominal dose were found for available systems in the cascade impinger (four-stage liquid impinger).
In another process (DE 22 29 981), the active compound is mixed with a pharmaceutically utilizable, water-soluble excipient, this excipient having a particle size of 80 &mgr;m to 150 &mgr;m.
The disadvantage here is the poor flow properties of the formulation.
DE 41 40 689 describes inhalation powders which consist of a physiologically acceptable auxiliary having a mean particle size of about 20 &mgr;m and a second component auxiliary having smaller particles of approximately 10 &mgr;m particle size.
This mixture can be filled into capsules and is inhaled using apparatuses which are described in DE 33 45 722. Here too the poor flow properties are a disadvantage.
EP 258 356 describes microparticles for inhalation purposes, which consist of a conglomerate of auxiliaries, for example lactose, xylitol and mannitol of a size between 30 &mgr;m and 150 &mgr;m. A problem in this process is the relatively complex preparation path in order to prepare auxiliary conglomerates having a specific particle size.
SUMMARY OF THE INVENTION
DE 28 51 489 A1 describes a formulation consisting of beclomethasone dipropionate whose particles to 90% by weight are smaller than 10 &mgr;m and of a powder excipient which consists of particles having an effective size of 90% by weight less than 400 &mgr;m and of at least 50% by weight greater than 30 &mgr;m. In addition to the active compound beclomethasone dipropionate, this formulation can additionally contain a bronchodilator of preferably the same particle size as beclomethasone dipropionate.
Designated bronchodilators are orciprenaline, terbutaline or salbutamol. Conversion to a pharmaceutical preparation is carried out by simple mixing.
WO 91/11179 A1 describes the use of excipient materials such as lactose, polysaccharides and others. As described, these excipient materials have a particle size of 5.0-1000 &mgr;m and a surface roughness of less than 1.75. Simple mixing of the excipient material with a pharmaceutical active compound leads to the powder preparation.
The object is thus, for the purposes of inhalation, to develop a powder which is simple to prepare, requires no complicated in-process controls of the moisture content of the active compounds and/or auxiliaries and has a high degree of redispersion. Furthermore, the formulation should have satisfactory flow properties and be easily disintegrable into respirable particles in the inhaler. Under identical conditions, at least 40% should be redispersed.
It has now surprisingly been found that by suitable mixing of the active compound or of the active compound mixture with a pharmaceutically utilizable excipient which has a mean particle size of 200 &mgr;m to 1000 &mgr;m, preferably between 300 &mgr;m and 600 &mgr;m, and a roughness of more than 1.75, the active compound particles having a particle size of 0.01 &mgr;m to 10 &mgr;m adhere to the excipient particles and thereby almost round excipient particles coated with active compound result. In the case of the formulation according to the invention, treatment, for example additional purification processes, of the excipient material employed can be dispensed with.
The particles of the excipient are commercially available or can be obtained by fractionation (sieve) into a specific grain size or grain size range.
The determination of the particle size of the excipient particles was carried out by measurement of scanning electron microscope photographs and/or by sieve analysis. The determination of the particle size of the active compound particles was carried out by measurement of scanning electron microscope photographs and/or by laser diffraction spectrometry.
This powder formulation can be prepared simply and economically and has significantly better flow properties both in comparison to the untreated active compound powder and to the soft pellets. The results in Table 1 show this. A lower bed height means better flow properties of the formulation.
The more similar the bulk and compacted volumes are, the better the flow properties. However, even the emptying and subsequent redispersion is better in comparison to the previously known formulations (mixtures, soft pellets according to GB 1 569 612 or GB 1 520 247 or untreated active compound powder), i.e. the residues in the inhaler are lower and the yield of respirable particles is higher.
The formulation can contain various active compounds, for example analgesics, antiallergics, antibiotics, anticholinergics, antihist
De Boer Anne
Sarlikiotis Werner
Asta Medica AG
Bawa Raj
Pillsbury & Winthrop LLP
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