Coating processes – Medical or dental purpose product; parts; subcombinations;... – Particulate or unit-dosage-article base
Reexamination Certificate
2000-08-23
2004-04-20
Beck, Shrive P. (Department: 1762)
Coating processes
Medical or dental purpose product; parts; subcombinations;...
Particulate or unit-dosage-article base
C427S002150, C427S002160, C427S002190, C427S002210, C427S212000, C427S213000, C427S213300, C427S213310, C427S421100, C427S372200, C427S379000
Reexamination Certificate
active
06723372
ABSTRACT:
The invention relates to a process for the production of encased, spherical granular grains, especially for compositions with prostane derivatives.
PRIOR ART
Prostane derivatives and their product are described in detail in EP 0 011 591 (date of application: Oct. 18, 1979). The prostane derivatives are compounds that are derived from prostacyclin (PGl
2
). They contain a methylene group at the position of the 9-ether-oxygen atom in prostacyclin. Prostane derivatives are used for treating various diseases, whereby the cardiovascular and thromboaggregation-inhibiting action is clearly emphasized. The use of prostane derivatives as medication is described in detail in European Publication EP 0 011 591. In the publications EP 0 055 208, EP 0 099 538 and EP 0 119 949, carbacyclin derivatives are cited that have indications similar to the above-mentioned prostane derivatives. Other prostane derivatives are described in publication EP 0 084 856, which was proposed for the use in the inhibition of thrombocyte-aggregation, lowering of the systemic blood pressure or treatment of gastric ulcers. Iloprost is the most important prostane derivative.
Iloprost oral (pharmaceutical active ingredient: 5-(E)-(1S,5S,6R)-7-hydroxy-6[(E)-(3S,4RS)-3-hydroxy-4-methyl-1-octen-6-inyl]bicyclo[3.3.0]octen-3-ylidene pentanoic acid) is a timed-release capsule. Timed-release capsules include the multiparticulate dosage form (multiple units). They consist of a hard gelatin capsule, which is filled with many small timed-release elements (in the case of iloprost oral: coated pellets [=spherical granular grains]). After peroral administration, the hard gelatin capsule is dissolved quickly in the stomach, and the individual timed-release elements are released. Regardless of how full the stomach is, from there they move on into the intestine. At the same time, the active ingredient that is contained is continuously released. Diffusion pellets represent the most important group of the coated multiparticulate dosage forms.
As coating materials for peroral timed-release dosage forms, polymers have gained tremendous importance. The polymer types that are used are primarily ethyl cellulose or poly(meth)acrylic acid ester. The polymers can be used either as an organic solution or dispersed inaqueous phase. Since they are more environmentally friendly, more reliable and more economical in handling, aqueous polymer dispersions are increasingly used in the industry. The best-known trade names are Aquacoat ECD 30®, Surelease® or Eudragit® NE 30 D, RL 30 D and RS 30 D. In the paint suspensions that are used for the coating process, additional additives are contained that are necessary for production and application reasons and help determine the properties of the film agent.
In a processing manner, the encasing process of pellets is carried out with a polymer membrane in fluidized-bed devices. By a stream of air, the pellets are arranged in a fluidized bed or a boiling bed, on which the polymer dispersion with the added additives is sprayed depending on the type of device in countercurrent or co-current flow (top or bottom spraying) from a spraying device (one or more spray nozzles). By the motion in the fluidized bed, the fine-particle dispersion is dispersed on the surface of the pellets. At the same time, the dispersing agent evaporates water by the drying stream of air, and the latex particles approach a spherical packing that becomes tighter and tighter. Then, an increasing penetration of the particles below one another takes place. This process is referred to as coalescence. In the final stage of this process, an almost homogenous, water-insoluble film develops. The film that now surrounds the pellet acts as a diffusion barrier for the pharmaceutical substance that is found in the core and results in a delayed release of pharmaceutical substance.
The production of iloprost oral is performed in two essential steps. In the first step, active ingredient-containing crude pellets are produced via an extrusion/spheronization process. The crude pellets consist of 90% lactose and 10% Avicel PH 101 as adjuvants and contain iloprost-&bgr;-cyclodextrin clathrate as an active ingredient. The content is 0.05 or 0.1 mg of iloprost per 65 or 130 mg of pellets [active ingredient content about 0.08% (w/w)]. In a second step, the crude pellets are then coated with a coating suspension that is based on Eudragit NE 30 D and additives in a fluidized-bed device.
At the beginning of the development, the crude pellets were sprayed in a fluidized-bed device (WSG), type GPCG-3 (Glatt Company)) or Strea type (Aeromatic Company) on a laboratory scale (both top-spraying processes) in principle with the qualitatively identical coating suspension, which is still used even now. As a target value for the paint layer, the resulting active ingredient-release profile was used (determined from the amount of active ingredient released after, e.g., 1, 2 and 3 hours), which was studied in the dissolution test according to USP, device
1
(basket). The pellets that were produced were used for first kinetic and clinical studies. A problem from the start was the fact that in this formulation, the release of active ingredient slowed down somewhat over the storage time. The first sizeable batches (production scale) were coated in WSG aeromatic MP4 (Aeromatic Company). Just as in the smaller laboratory devices, the spraying application took place by a countercurrent process (top spraying). In this case, it was sprayed from a spray nozzle from above in opposite direction to the incoming stream of air on the pellets located in the fluidized bed. In each case, 75 kg of active ingredient-containing crude pellets with 16.5 kg of paint suspension were ultimately sprayed in Aeromatic MP4.
The transfer of the process from the laboratory scale to the Aeromatic MP4 then revealed that the release of active ingredient slowed down over the storage time and for this reason, the batches first produced with amounts of coating larger than 16.5 kg were soon no longer able to meet the specification. This phenomenon that was noted for this formulation is described in the poster publication by T. C. WAGNER and S. KEITEL, The Effect of Dispersion Concentration and Curing Temperature on Drug Release of Pellets Coated with Eudragit NE 30 D, Proc. 1st World Meeting APGI/APV, Budapest, May 9-11, 1995. To this end, the effect of subsequent heat treatment (stoving—“curing”) on the release of active ingredients was studied for the first time. For the production scale, however, no attempt at stoving was generally made, since no drying ovens were available; the exact extent of this problem was still not known and in addition basic concerns problem was still not known and in addition basic concerns existed due to the thermal instability of the active ingredient. For this reason, for production an amount of coating had to be applied that led to a post-production active ingredient-release profile that did not fall within the specification. After about four weeks of storage time at room temperature, the release had slowed, and the WSF-profile was in the upper third of the specification. Over the storage time, however, a further slowing occurred.
In the publication of F. W. GOODHART et al. (1984), An Evaluation of Aqueous Film-forming Dispersions for Controlled Release, in Pharmaceutical Technology, Vol. pp. 65-71, processes are described in which the stoving takes place for scientific purposes. The idea is to grasp the principles underlying the phenomena. The effect, to increase the stability, is not mentioned.
In the publication of Shun Por Li et al. (1989) Preparation and In Vitro Evaluation of a Controlled Release Drug Delivery System of Theophylline Using an Aqueous Acrylic Resin Dispersion, in Drug Development and Industrial Pharmacy, Vol. 15(8), pp. 1231-1242, a stoving is described in which the active ingredient theophylline is encased with poly(meth)acrylic acid ester. The stoving is carried out at 40° C. for 24 hours. The stability is increa
Beck Shrive P.
Kolb Michener Jennifer
Millen White Zelano & Branigan P.C.
Schering Aktiengesellschaft
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