Drug – bio-affecting and body treating compositions – Plant material or plant extract of undetermined constitution...
Reexamination Certificate
2000-06-27
2001-10-23
Tate, Christopher R. (Department: 1651)
Drug, bio-affecting and body treating compositions
Plant material or plant extract of undetermined constitution...
C424S754000, C424S756000, C424S773000, C424S774000, C424S778000
Reexamination Certificate
active
06306444
ABSTRACT:
The present invention relates to a process for making flowable drug precursor products ready for pressing for the preparation of tablets, sugar-coated tablets and pellets from plant drugs, said precursor products being suitable for tabletting without additional interim steps, and the drug precursor products as such. In particular, it relates to a process which avoids the disadvantages of conventional wet granulation without having to resort to direct tabletting.
Conventional processes for making tablets from dried plant drugs are wet granulation on the one hand and direct tabletting on the other. Since direct tabletting requires the use of pre-treated or pre-granulated substances and excipients and carriers subjected to similar pre-treatment, wet granulation is usually chosen for cost reasons. In this process, the active ingredients, i.e. the dried plant drugs and optional excipients are humidified, mixed in the humid state, for example by kneading, stirring etc., and the mixture then subjected to granulation. In order to obtain a granulate suitable for tabletting, any water contained after wet granulation must be removed. The drying time in the classical process of tray drying is approx. 15 hours during which time the plant drugs are exposed to oxidation by oxygen in the air. The drying temperature of the material is between 65° C. and 75° C., which may disadvantageously influence the active ingredients contained therein. In addition, the long drying time and the use of non-sterile plant material often result in the development of undesirable germs such as mould cultures, because their growth is favoured by such system conditions.
On the other hand, the limits for the germ count of plant drugs containing such materials have been determined in DAB 98 (German Pharmacopoeia, 10
th
edition). Even though they would be appropriate for use under chemical and pharmaceutical aspects, the drugs must often be discarded, because they do not comply with the strict requirements of the pharmacopoeias. In order to stay within the germ count limit, DE-A-195 47 973, for example, has proposed to sterilise plant drugs before wet granulation by a specific process in a vacuum drying system comprising a multi-blade stirrer under reduced pressure conditions and thus to reduce the initial germ count of the material used for wet granulation. The smaller the initial germ count, the smaller the germ count of the granulate obtained after the main drying step and suitable for tabletting. However, this process does not reduce the drying time so that the exposure to oxygen in the air remains unchanged.
Even the shorter drying process by means of a fluidised-bed apparatus requires between 7 and 8 hours with incoming air being preheated to 65° C. At the same time, large volumes affair are required (3,000 to 5,000 cm
3
/h). Thus, fluidised-bed shift-batch production-requires between 21,000 and 40,000 cm
3
of pre-heated air. On the other hand, it has been proven that air and particularly heated air has a detrimental influence on the contents of flavonoids, essential oils, polyphenols and unsaturated fatty acids which are especially susceptible to oxidation by oxygen contained in the air. Therefore, intensive exposure is undesirable. In addition, even drying by the fluidised-bed system cannot prevent proliferation of aerobic germs in view of the lengthy drying time of 7 to 8 hours, so that this process also encounters the above-mentioned problems.
For direct tabletting, the second process known in the prior art for making tablets from dried plant drugs, the individual tablet components, i.e. the drug material and the carriers or excipients, respectively, must be provided in a form suitable for direct tabletting, e.g. as a granulate, and require lengthy mixing in this form. Since, in addition to the active ingredients, the finished tablets sometimes may contain up to 20 different substances which must be introduced at a strictly defined location in the production process to insure that the newly added ingredients remain stable in the granulate, direct tabletting is a comparatively complicated method. Therefore, granulation is a lengthy and costly process in the pharmaceutical industry which binds time, energy and technical personnel to an undesirable extent.
Therefore, it is the objective of the present invention to provide a fast and simple process which permits preparation of a flowable drug precursor product ready for pressing without requiring a lot of time, energy and staff, but which is effective with regard to the product compatibility of the individual ingredients and excipients, does not negatively influence the plant ingredients and achieves an adequate germ count.
The objective of the invention is achieved by a process for making a flowable drug precursor product ready for pressing comprising humidifying dried plant drug material in a vacuum drying device together with the desired additives, carriers and/or excipients, which device comprises a multi-blade stirrer having its own drive and extending through a cylindrical mixing and drying chamber, said device optionally being provided with a filter, a back-purge means, a solvent condenser with an after-cooler and a collection vessel, a back-condenser and/or a process, control and regulation unit, and drying the humid mixture at a jacket temperature of the device of 20 to 50° C., preferably 20 to 40° C. and most preferably 30° C., a product temperature between 20 and 40° C., preferably 20° C. to 30° C. and most preferably 20 to 25° C. and a pressure of 20 to 500 mbar, preferably 50 to 200 mbar and most preferably 50 to 100 mbar to obtain the precursor product.
Examples for commercial vacuum drying devices which may be used in the process according to the invention are the ITUT-INOX® universal dryers, e.g. the types ITUT 20, ITUT 50, ITUT 100 or ITUT 2000.
The desired components of the finished tablet or the drug preparation, respectively, may be introduced into the process either simultaneously or consecutively. By simultaneously mixing and drying the components with the aid of the multi-blade stirrer, much less humidity needs to be added to the wet granulate than in the conventional wet granulation process. Preferably, humidification is effected by adding water or a water/solvent mixture in an amount of 0.01 to 0.05 ml/g solids, preferably 0.02 to 0.04 ml/g solids. Preferred solvents are lower alcohols such as methanol, ethanol, propanol or glycol and glycerol, ketones such as acetone, or ethers such as diethyl ether, glyme and diglyme. Water or water/alcohol mixtures are preferred. In addition, highly dispersed silica in an amount of 1 to 10%, preferably 3 to 6%, based on the total amount is preferably added.
Owing to the lower degree of humidification, it is possible to decrease the drying time to 30 minutes to 2 hours, preferably 1 to 1,5 hours. Since, in addition to the decrease in drying time which results in a considerable reduction in the germ count, the drying temperature and the air blown in may be reduced, the flowable, ready-for-pressing precursor products according to the invention have a higher content of active ingredients in comparison with wet granulates prepared by conventional methods. This is due to the fact that the undesirable effects of air drying may be eliminated. The process according to the invention provides the additional advantage that the time for making the granulate may be reduced significantly, the production process is simplified and that far less personnel is required.
FIG. 1
shows a time comparison between classical wet granulation, fluidised-bed granulation and vacuum granulation according to the invention as well as direct tabletting. This illustration shows that the process according to the invention is comparable to direct tabletting with regard to the time advantage. Direct tabletting, however, is far more complicated and places much higher requirements on the purity and physical characteristics of the starting materials used. On the whole, the process according to the invention thus offers advantages vis-a-vi
Bionorica Arzneimittel GmbH
Ratner & Prestia
Tate Christopher R.
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