Surgery – Respiratory method or device – Means for mixing treating agent with respiratory gas
Reexamination Certificate
1997-08-04
2001-10-30
Weiss, John G. (Department: 3761)
Surgery
Respiratory method or device
Means for mixing treating agent with respiratory gas
C128S203120, C366S309000
Reexamination Certificate
active
06308704
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to a method for mixing cohesive finely divided powders, such as finely divided powdered medicaments having a particle size less than about 10 &mgr;m, and consisting of more than one substance in order to obtain a homogeneous mixture.
BACKGROUND OF THE INVENTION
Powder mixing or blending is an operation to make two or more powdered substances to form a homogeneous mixture. The operation of mixing finely divided powders consisting of two or more substances is extremely difficult as the particles are subjected to various interparticle forces and such powder can not be set in motion without an external force such as mechanical agitation, ultra sound, electrical forces or similar.
Finely-divided powders are commonly used in inhalation therapy where the size of the particles and the homogeneity of mixtures of substances are of utmost importance. Due to the fact that inhalation therapy is becoming a more and more important therapy not only in the therapy for diseases in the bronchial area but also in therapy against other diseases, the mixing of interacting powders, where a fine, cohesive ingredient may adhere to coarser carrier particles, has become a subject of increased interest during recent years. However, little work has been done regarding the situation where all the ingredients are finely divided, e.g. have a particle size smaller than 10 &mgr;m.
For finely-divided powders having a high proportion of particles with particle size smaller than about 10 &mgr;m, interparticle adhesive forces, such as van der Waal forces, make the powders cohesive, leading to the formation of irregular aggregates. This formation of aggregates makes the mixing of two or more such cohesive powders much more complicated and difficult than the mixing of powders with a particle size greater than 10 &mgr;m. Therefore, if a homogeneous mixture is required, a breakdown of the aggregates must be achieved during the mixing process.
In solid/solid mixing one of the most important requirements is to ensure uniformity of the content, which is particularly relevant for clinical effectiveness when using low dosage cohesive powder mixtures, such as for example those containing 1-2% of the active ingredient. The major problem encountered in powder mixing of finely divided powders is the inability of the commonly used mixers to break down the aggregates formed in the powder. The so-called low-power mixers are not able to breakdown the aggregates formed in the cohesive powders into their primary particles, which means that the aggregates are still present and do not permit the relative movement between particles to occur, something which is necessary if a homogeneous mixture is to be achieved. The critical step of the mixing of low dosage cohesive powder mixtures is the breakdown of the aggregates. Thus, in order to obtain a homogeneous mixture naturally formed aggregates must be repeatedly broken down. To enable the aggregates to breakdown into its primary particles a sufficiently high energy must be applied to the system.
PRIOR ART
Among the vast number of references on mixing only a few discuss the problems involving cohesive powder mixtures (particularly those with all the components being cohesive).
The following main references are of special interest:
“Powder Mixing—A Literature Survey” by M. H. Cooke et al., Powder Technology 15 (1976), 1-20, which gives a general background to the special problems involved in the technical area of mixing powders.
“Mixing in the Process Industries”, edited by N. Harnby, M. F. Edwards and A. W. Nienow, Butterworths, London (1990), 375 p.
“Recent Developments in Solids Mixing” by L. T. Fan et al., Powder Technology, 61 (1990), 255-287.
JP 62,124,201 (priority date 1985) describes a process where a cohesive fine powder is sieved and mixed with a noncohesive powder in a V-type mixer. However, the fine powder was added externally to the coarse material.
Some work has also been done using rotatory and vibratory ball mills as an efficient method of mixing fine powders (I. Krycer et al., Int. J. Pharmaceutics, 6 (1980), 119-129; Powder Techn. 27 (1980), 137-141). The high energy applied in this type of milling will disrupt the crystal lattice of the particles thereby influencing the chemical and physical stability of the crystals and making the crystals more sensitive to humidity. On prolonged milling, aggregation of the minor constituent with the diluent occurs leading to cohesion and formation of an ordered mixture. Further comminution results in a fragmentation and reaggregation without loss of mixture homogeneity. However, nothing is said about the stability of the product mixture obtained.
According to N. Harnby et al. in “Mixing in the Process Industries” p. 90 a mixer for mixing cohesive powders is likely to need high shearing or impaction characteristics and could well be a particle comminuter rather than a conventional mixer. Bulk circulation of powder can be effected in fluidized beds, tumbler mixers or convective mixers and is useful when powders, which are not too cohesive, are to be mixed. The break-down of aggregates is usually accomplished by a stirring device, such as for example an impeller, which rotates at a high speed. Therefore, runner mills have been recommended where shearing mixing occurs.
The equipment employed by Orr and Shotton (Chem, Eng. No 269 (1973), 12-19 (Mixing of cohesive powders) was a Lödige Morton M4E mixer and a Y-cone mixer. The Y-cone was mounted on an Eureka rotatory machine so as to rotate about a horizontal axis.
The comprehensive review by Fan et al., referred to above, on recent developments in solids mixing covers the classification of mixing equipment, the characterisation of mixtures and the rates and mechanisms of mixing processes as well as the design and scale-up of mixers. Herein is also given a comprehensive list of references of prior work.
The commonly used equipment is further described in “Chemical Engineers' Handbook” (5th ed.) by R. H. Perry and C. H. Chilton, Tokyo, p. 21-30.
Many investigations using different methods of mixing have been performed e.g. fluidized-bed mixers. As pointed out by Fan et al. the design of mixers or blenders for particulate solids has mainly been carried out by trial and error due to the complexity of the behavior of solids when mixing and particularly with very cohesive powders.
The breakdown of aggregates and attrition are well-known phenomena and are performed by impaction (peripherical speed of the rotating internal device) or a shearing and compressing action. The attrition may produce other disturbances (size reduction etc) on batch ingredients.
The most common type of equipment for mixing in which aggregate breakers are used is the tumbler. Several different types of tumblers are available in which separate internal rotating devices for breaking down the aggregates are provided in order to minimize segregation. The form and shape of such rotating devices vary, but no reference has been found describing the use of a net in association with the use of stirring devices. The tumbler itself can not be used if an effective breakdown of the aggregates is required.
THE INVENTION
The present invention relates to another form of mixing equipment and method for the breakdown of aggregates during the mixing of cohesive particles.
The formulations in inhalation therapy require substances having a particle size being less than 10 &mgr;m. When two or more substances having this particle size are to be used in an inhalation formulation a mixing step is required. Due to the inherent properties such as for example cohesivness and aggregate formation of these powders, conventional mixing equipment is not applicable. The present invention provides a simple and effective method and apparatus for mixing finely-divided powders.
It is therefore an object of the present invention to provide a method of mixing at least two cohesive finely divided powders such as finely divided powdered medicaments having a particle size less than about 10 &mgr;m, which method comp
Astra Aktiebolag
Fish & Richardson P.C.
Srivastava V.
Weiss John G.
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