Plastic and nonmetallic article shaping or treating: processes – With severing – removing material from preform mechanically,... – To form particulate product
Reexamination Certificate
2000-08-23
2003-10-14
Eashoo, Mark (Department: 1732)
Plastic and nonmetallic article shaping or treating: processes
With severing, removing material from preform mechanically,...
To form particulate product
C264S17800F, C424S465000
Reexamination Certificate
active
06632389
ABSTRACT:
The present invention relates to a process for producing pellets which comprise active compounds and are based on thermoplastic polymers by melt extrusion and underwater pelletizing and also relates to corresponding pellets and their use.
Underwater pelletizing is generally known as an effective pelletizing method for thermoplastic materials for the industrial production of plastic pellets.
Corresponding apparatuses and processes are described, for example, in DE-A 2646309, U.S. Pat. No. 4,264,553 or U.S. Pat. No. 5,143,673. In these the hot plastic melt is transported from an extruder via a perforated disk directly into a liquid cooling medium, in this case water. The exiting plastic strands are divided into pellets by a cutting apparatus mounted at the perforated disk and are transported away by the generally recirculated water, separated off and dried. By means of this liquid-cooled process it is possible to produce very small particle sizes uniformly, continuously and on an industrial scale down to the submillimeter range. By using cooling media having a high heat capacity and a high heat transfer, such as water, the still-plastic pellets are rapidly cooled, do not stick together and may be produced in very uniform shape and size.
In comparison, using die-face cutting with air cooling for pelletizing the extruded strands is considerably more difficult because of the slow and poor heat transfer.
Formulations which contain active compounds, for example comprising vitamins as active compound, are administered, to maintain the health of humans and animals, in parallel to food intake or are added to the diet as additive. A large proportion of the formulations of vitamins, vitaminoids or other food supplements manufactured is required for animal nutrition. Since the feedstuffs used there are supplied as ground material having a mean particle size of 0.3-0.5 mm, added feed additives—to prevent separation—should have roughly the same size and uniformity. Uniform particle size is also of particular importance for producing pellets for drugs, since the dissolution behavior and thus the bioavailability are dependent on the particle size. The previously used drug pellets, feed supplements or feed additives are therefore usually produced in complex and expensive grinding, pelletizing and spraying processes.
Preparations which contain active compounds and are produced by melt extrusion are generally known. Extrusion of melts of water-soluble polymers, which melts contain active compounds, preferably copolymers of vinylpyrrolidone, is disclosed, for example, by EP-A 240904 and EP-A 240906. EP-A 240 906 also describes the melt extrusion of active-compound-containing mixtures, copolymers of methyl methacrylate and acrylic acid, copolymers of vinyl acetate and crotonic acid, and also ethylene/vinyl acetate copolymers. They are shaped via injection molding or extrusion with subsequent shaping of the still-plastic strand, for example by die-face cutting to form pellets or shaping to form tablets. In all said examples shaping is performed in air. The pharmaceutical forms thus produced are generally water-soluble.
Thus, for example, DE-A 19536387 also describes melt extrusion and shaping of vitamin-containing products. Water-soluble, thermoplastic hydroxypropylcelluloses are used as matrix. In the examples, inter alia, melts of vitamin C or &bgr;-carotene together with hydroxypropylcellulose are pressed by shaping calenders to form tablets. In addition, die-face cutting of the water-soluble matrix to form pellets is mentioned.
Although such water-soluble formulations can be produced using melt extrusion and subsequent pelletizing in air, it is a disadvantage that frequently, owing to the poor heat transfer, the required (small) particle size, uniformity and large-scale feasibility cannot be achieved in this manner.
It is an object of the present invention to develop an inexpensive and simple production process for formulations which contain active compounds, for example drugs or feed additives, which dissolve or disperse on their own in water or in the gastrointestinal tract.
We have found that this object is achieved, surprisingly, if mixtures which comprise active compounds are melt-extruded with polymers which are water-insoluble in a certain pH range and are water-soluble in another pH range.
Accordingly, a process was found for producing pellets which comprise biologically active substances in which the biologically active substances are homogeneously dispersed in a matrix based on at least one thermoplastic polymer, which polymer has in aqueous medium a pH-dependent solubility, by homogeneous mixing of the starting materials in the melt and subsequent extrusion and shaping, which comprises the shaping being performed in a cooling medium in which the pellets are not soluble or dispersible.
To carry out the process of the invention, the starting materials are mixed to form a homogeneous melt. This can be done, for example, by introducing a physical premix of solid starting materials into a suitable extruder or kneader, melting the mixture with the use of mechanical and thermal energy, and transporting the hot, still-plastic melt through a perforated disk or a nozzle plate directly into a liquid cooling medium. If the formulation also comprises liquid constituents, it is advisable to add these separately via a metering pump. If thermally labile active compounds are used, it can also be advisable firstly to prepare a melt of the thermoplastic polymers and, if desired, other formulation aids, and only then to add the active compound. The melting is preferably performed in a screw machine, in particular in a double-screw extruder, which is preferably corotating. The process of the invention is preferably carried out in the absence of solvents. In the event that it should be necessary to add to the mixture one or more of the starting materials in the form of a solution, the solvents used here can be removed in the downstream extruder zones by applying a vacuum. The extruded, still-thermoplastic mass then no longer contains solvent.
The starting materials can be melted, depending on composition of the mixture, at from 50 to 300° C., preferably from 70 to 250° C.
The exiting plastic strands are divided into pellets by a cutting apparatus mounted at the perforated disk or nozzle plate, and are transported away by the preferably recirculated cooling medium, separated off and dried. Suitable cooling media are, for example, liquid hydrocarbons such as paraffins or aromatic hydrocarbons, or preferably water. If water is used as cooling medium, according to the invention the pH of the water is set using acids or bases such that the matrix comprising the active compounds does not dissolve or disperse itself therein. According to the invention this is intended to mean that no more than 1 g/l of the pellets may be dissolved or dispersed in water.
By using cooling media having a high heat capacity and a high heat transfer, such as water, the still-plastic pellets are rapidly cooled, do not stick together and may be produced in very uniform shape and size. Preference is given to pellets produced having mean particle sizes of from 0.1 to 5, preferably from 0.3 to 3, mm.
The process of the invention is suitable in principle for producing pellets comprising biologically active substances in which one or more biologically active substances is/are homogeneously dispersed in a matrix based on thermoplastic polymers. Homogeneously dispersed can also mean according to the invention that the biologically active substances are present molecularly dispersed in the matrix, that is are what are termed “solid solutions”.
Biologically active substances which can be used are generally all substances which are to be released in the gastrointestinal tract of humans and animals. These can be, for example, active drug compounds, vitamins, vitaminoids, carotenoids, enzymes, hormones, amino acids or “nutraceuticals”, that is to say food supplements and dietetic compositions.
In addition, it is also possible to formulate active p
Berndl Gunther
Ernst Andreas
Kessler Thomas
BASF - Aktiengesellschaft
Eashoo Mark
Keil & Weinkauf
Shipsides Geoffrey P.
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