Drug – bio-affecting and body treating compositions – Effervescent or pressurized fluid containing – Organic pressurized fluid
Reexamination Certificate
2001-10-11
2003-07-01
Azpuru, Carlos (Department: 1615)
Drug, bio-affecting and body treating compositions
Effervescent or pressurized fluid containing
Organic pressurized fluid
C424S434000, C424S435000, C424S489000, C424S493000
Reexamination Certificate
active
06585959
ABSTRACT:
The invention relates to a new process for preparing powdered preparations for inhalation.
BACKGROUND OF THE INVENTION
treating a number of complaints, particularly respiratory diseases, it is useful to administer the active substance by inhalation. In addition to the administration of therapeutically active compounds in the form of metered aerosols and inhalable solutions, the use of inhalable powders containing active substance is of particular importance.
With active substances which have a particularly high efficacy, only small amounts of the active substance are needed per single dose to achieve the desired therapeutic effect. In such cases, the active substance has to be diluted with suitable excipients in order to prepare the inhalable powder. Because of the large amount of excipient, the properties of the inhalable powder are critically influenced by the choice of excipient.
In powder mixture technology, it is conventional to use mixing processes based on the dilution method. All the active substance is used and then excipient is added in proportions of 1:1, 1:2 or 1:4 and they are mixed together. More excipient is then added to the resulting mixtures in comparable proportions. This procedure is usually repeated until all the excipient has been added. The drawback of this type of procedure is that in some cases there are problems of homogeneity. These arise particularly with mixtures in which the substances have a widely varying spectrum of particle sizes. This is particularly apparent in powder mixtures in which the substance having the smaller particle size distribution, the active substance, makes up only a very small proportion of the total amount of powder.
The problem of the present invention is therefore to provide a process which can be used to produce inhalable powders characterised by a high degree of homogeneity in the sense of a uniformity of content.
DETAILED DESCRIPTION OF THE INVENTION
It was found that, surprisingly, the problem outlined above can be solved by means of a process in which the substance with the smaller particle size distribution can be added to the substance with the coarser particle size distribution by a layered mixing process.
The process according to the invention for preparing inhalable powders is characterised in that N+m substantially equal portions of the substance having a larger particle size distribution and N equal portions of the substance having a smaller particle size distribution are placed in alternate layers in a suitable mixing vessel and after they have all been added the 2N+m layers of the two components are mixed together using a suitable mixer, a portion of the substance having the larger particle size being put in first, while N is an integer >0, preferably >5, and m denotes 0 or 1.
Preferably, the individual fractions are added in layers through a suitable screening apparatus. If desired, once the mixing process is finished, the entire powder mixture can be subjected to one or more additional screening processes. In the process according to the invention, N is naturally dependent inter alia on the total quantity of powder mixture to be produced. When producing smaller batches, the desired effect of high homogeneity in the sense of uniformity of content can be achieved with a smaller N. In principle, it is preferable according to the invention if N is at least 10 or more, more preferably 20 or more, better still 30 or more. The greater N is and, as a result, the greater the total number of layers of the powder fractions formed, the more homogeneous the powder mixture becomes in the sense of uniformity of content.
The number m may represent 0 or 1 within the scope of the process according to the invention. If m denotes 0 the last fraction added to the mixing apparatus, preferably screened into it, in a layer is the last portion of the substance with a smaller particle size distribution. If m represents the number 1, the last fraction added to the mixing apparatus, preferably screened into it, in a layer is the last portion of the substance with a larger particle size distribution. This may prove advantageous inasmuch as, when m=1, any residues of the last fraction of the substance with the finer particle size distribution still remaining in the screening unit can be carried into the mixing unit by means of the last portion of excipient.
Within the scope of the present invention, unless otherwise defined, the substance with the smaller particle size distribution, which is very finely ground and is present in the resulting powder formulation in a very small proportion by mass, represents the active substance. Within the scope of the present invention, unless otherwise defined, the substance with the larger particle size distribution, which is coarsely ground and is present in the resulting powder formulation in a large proportion by mass, represents the excipient.
The present invention relates in particular to a process for preparing inhalable powders containing less than 5%, preferably less than 2%, most preferably less than 1% of active substance mixed with a physiologically acceptable excipient. A preferred process according to the invention is a process for preparing inhalable powders containing 0.04 to 0.8%, most preferably 0.08 to 0.64%, better still 0.16 to 0.4% of active substance mixed with a physiologically acceptable excipient.
The active substance used according to the invention preferably has an average particle size of 0.5 to 10 &mgr;m, preferably 1 to 6 &mgr;m, most preferably 2 to 5 &mgr;m. The excipient which may be used in the process according to the invention preferably has an average particle size of 10 to 100 &mgr;m, preferably 15 to 80 &mgr;m, most preferably 17 to 50 &mgr;m. Particularly preferred according to the invention are processes for preparing inhalable powders wherein the excipient has an average particle size of 20-30 &mgr;m.
The two components are preferably added through a screening granulator with a mesh size of 0.1 to 2 mm, most preferably 0.3 to 1 mm, even more preferably 0.3 to 0.6 mm.
Preferably, the first portion of the N+m portions of the excipient is put in first, and then the first portion of the N portions of the active substance is placed in the mixing container. Whereas within the scope of the process according to the invention the individual components are normally added in roughly equal portions, it may be advantageous in some cases if the first of the N+m portions of excipient which is put into the mixing apparatus has a larger volume than the subsequent portions of excipient. Preferably, the two components are added alternately through a screening unit and in more than 20, preferably more than 25, most preferably more than 30 layers. For example, with a desired total amount of powder of 30-35 kg containing 0.3-0.5% of active substance, for example, and using common excipients, the two components can be screened in in about 30 to 60 layers each (N=30-60). The upper limit of 60 layers mentioned above is given purely from the point of view of economy of the process. It should not be regarded in any way as restricting the number of possible layers according to the invention. As will be clearly apparent to anyone skilled in the art, the process can equally well be carried out with N>60 to achieve the desired effect of the maximum possible homogeneity of the powder mixture.
In some cases the excipient may also consist of a mixture of coarser excipient with an average particle size of 15 to 80 &mgr;m and finer excipient with an average particle size of 1 to 9 &mgr;m, wherein the proportion of finer excipient in the total quantity of excipient may be 1 to 20%. If the inhalable powders which may be produced using the process according to the invention contain a mixture of coarser and finer excipient fractions, it is preferable according to the invention to prepare inhalable powders wherein the coarser excipient has an average particle size of 17 to 50 &mgr;m, most preferably 20 to 30 &mgr;m, and the finer excipient has an average p
Boeck Georg
Walz Michael
Azpuru Carlos
Boehringer Ingelheim Pharma KG
Datlow Philip I.
Raymond Robert P.
Stempel Alan R.
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