Plastic and nonmetallic article shaping or treating: processes – Forming articles by uniting randomly associated particles – Stratified or layered articles
Reexamination Certificate
2001-02-26
2003-12-30
Theisen, Mary Lynn (Department: 1732)
Plastic and nonmetallic article shaping or treating: processes
Forming articles by uniting randomly associated particles
Stratified or layered articles
C264S141000, C264S300000
Reexamination Certificate
active
06669879
ABSTRACT:
The present invention relates to a process for producing solid dosage forms by forming a plastic mixture of at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives, and shaping the plastic mixture to the solid dosage forms using a mold.
The production of solid dosage forms by extrusion and subsequent calendering of an active ingredient-containing melt is disclosed, for example in DE-A-17 66 546 and U.S. Pat. No. 4,880,585. This process is based on the embedding of an active ingedient in a melt of a carrier, for example fatty substances or water-soluble, thermoplastic polymers. The melt is produced by melting the mixture of active ingredient, polymer and, where appropriate, other ancillary substances, for example in an extruder, and shaping as melt in a subsequent shaping calender to tablets, which harden by cooling.
Solid dosage forms ordinarily contain not only the carrier substance but also one or more ancillary substances. On the hand, these ancillary substances are often indispensable in order to control the release of the active ingredient, to prevent decomposition of the active ingredient due to light and/or oxidation, to mask an unpleasant taste of the active ingredient, to make the dosage forms colored for easier identification etc. On the other hand, ancillary substances are usually necessary in order to ensure satisfactory industrial processability of the dosage forms during production, during subsequent processing steps etc.
The required ancillary substances are usually incorporated into the tablet composition, i.e. in the finished dosage forms, they are uniformly distributed in the volume of the dosage forms. However, most of the ancillary substances employed display their effect only on the surface of the dosage forms. This means that only the portion of the ancillary substances located in the outermost surface layer and a few micrometers below that contributes to the required effect. In order to have a sufficient concentration at the surface, it is therefore necessary for these ancillary substances to be incorporated in relatively high concentration into the tablet composition. Most of the ancillary substance in the tablet volume remains without effect, which makes the production of the tablets unnecessarily costly. There may also be unwanted interactions of the ancillary substance with the active ingredient or with the substances forming the matrix.
In addition, the freedom of formulating the tablet composition is restricted because it is possible to use only active ingredients and ancillary substances which are compatible with one another.
On the other hand, it is known to coat tablets in the last step of manufacture with a thin layer of, for example, water-soluble polymers. Film-coated tablets are produced in this way. If a coating was required over the tablets produced by melt calendering, it was necessary to apply this coating in a separate step after cooling of the tablets. This took place in a conventional way, for example by spraying on in rotating drums, by dipcoating or in a fluidized bed etc. The conventional processes for applying coating layers all require a comparatively large energy input because the solvents used in the spray solutions must be removed again rapidly after spraying onto the tablets. In addition, a coating process usually takes several hours because the spraying rate cannot be set as high as desired.
WO 96/19963 describes a process for producing coated tablets by melt calendering, in which the active ingredient-containing melt is introduced between two sheets of the coating material into the calender molding rolls. This process is, however, suitable only for ancillary substances which can easily be produced in the form of a sheet.
DE-A-44 46 467 describes a process for producing lenticular tablets by melt calendering. It is pointed out in this publication that molding rolls provided with a release agent can be used. An example of a suitable release agent is a silicone paint. This suggests that the molding rolls are lined only once with the release agent and there is no transfer of the release agent from the molding rolls to the mixture to be tableted.
It is an object of the present invention to provide a process for producing solid dosage forms by melt extrusion, in which a modification of the surface properties of the solid dosage forms is possible in a simple and cost- and material-saving manner.
We have found that this object is achieved by applying an agent which modifies the surface properties in finely divided form to the surface of the plastic mixture during the shaping. The outer surface of the plastic mixture which is created by the shaping to solid dosage forms is in this way provided with an agent which modifies the surface properties.
The present invention therefore relates to a process for producing solid dosage forms by forming a plastic mixture of at least one polymeric binder, at least one active ingredient and, where appropriate, conventional additives, and shaping the plastic mixture to the solid dosage forms using a mold, wherein an agent which modifies the surface properties is applied in finely divided form to the surface of the plastic mixture during the shaping. The process according to the invention is preferably carried out continuously. It is essential for the process according to the invention that a continuous supply of agent which modifies the surface properties is ensured. It is also important that the agent which modifies the surface properties is applied at a time at which the plastic mixture has not yet completely solidified.
The term “shaping” may comprise the steps of preforming and definitive shaping. “Preforming” means every procedure in which the ratio of the surface area to the volume of the plastic mixture already substantially approximates to that of the finished dosage form. The preformed plastic mixture is preferably exposed to negligible shear forces during the definitive shaping, so that surface elements are not mixed into the interior.
Preforming is regarded as being, for example, the extrusion of the plastic mixture to give a ribbon or a sheet. It is thus possible within the scope of the present invention to apply the agent which modifies the surface properties to the surface of the preformed plastic mixture, e.g. of the ribbon or sheet, which is subsequently subjected to the definitive shaping.
The process according to the invention makes a considerable saving of ancillary substances possible without losses of efficacy because the dosage forms obtained according to the invention contain the ancillary substances predominantly or exclusively on their surface, while the concentration of ancillary substances over the volume of the dosage forms can be reduced, or the composition to be tableted can be kept free of ancillary substances.
The agent which modifies the surface properties is applied in finely divided form. This means that the agent is in powdered or liquid form and not in compact form, e.g. as sheet. The agent which modifies the surface properties can be applied in the form of a powder, a solution, a suspension, emulsion or dispersion. Where carrier liquids are required to produce a solution, suspension, emulsion or dispersion, these can be chosen to be volatile or else involatile.
Agents which modify the surface properties mean for the purpose of the invention all pharmaceutically suitable ancillary substances which alter the physical and/or chemical properties of the dosage forms which are caused wholly or partly by surface effects, e.g. color, pourability, separation characteristics, surface slip, sievability, permeability for vapors and/or gases, transparency, lipophilicity/hydrophilicity, redox potential, surface tension etc. They comprise ancillary substances normally incorporated into the tablet composition, and those whose use is made possible by the present invention for the first time.
Depending on the nature of the agent used to modify the surface properties, it is embedded or partly dissolved in the surface of the pl
Rosenberg Jörg
Spengler Reinhard
Abbott Laboratories
Keil & Weinkauf
Theisen Mary Lynn
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