Method to obtain microparticles

Details Method to obtain microparticles Method to obtain microparticles

2000-10-23

2004-06-22

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S486000

Reexamination Certificate

active

06753014

ABSTRACT:

FIELD OF INVENTION
The present invention provides a method of obtaining microparticles by a spray freezing technique. More specifically the present invention relates to a method by which spherical microparticles containing one or more pharmaceutically active substances can be prepared.
BACKGROUND OF THE INVENTION
The strategy for pharmaceutical formulation of a given drug depends on different factors. Ultimately, these factors emanate from 1) the therapeutic needs, 2) the physical chemical properties of the drug, and 3) the influence of the biological environment where the formulation will release its contents. Thus, both technical and biopharmaceutical considerations will contribute to a successful therapy.
However, improved drug administration may also be achieved by so called modified release of the drug, which has been discussed extensively in the literature, e g R L Langer and D L Wise (Eds) “
Medical Applications of Controlled Release
”, vols I, II (1984), CRC Press Inc, Boca Raton.
Several approaches to achieve different types of modified release are described in the references above. Of special importance to the present invention is modified release achieved by formulating the active substance with a suitable carrier material in the form of microparticles. Such a formulation then contains multiparticulate discrete delivery units, each of which can be coated if necessary with, e g a suitable pH sensitive, semipermeable or other polymeric film. Several advantages can be obtained with this type of formulation compared with more conventional delivery means. Thus, the small size of the
FIELD OF INVENTION
The present invention provides a method of obtaining microparticles by a spray freezing technique. More specifically the present invention relates to a method by which spherical microparticles containing one or more pharmaceutically active substances can be prepared.
BACKGROUND OF THE INVENTION
The strategy for pharmaceutical formulation of a given drug depends on different factors. Ultimately, these factors emanate from 1) the therapeutic needs, 2) the physical chemical properties of the drug, and 3) the influence of the biological environment where the formulation will release its contents. Thus, both technical and biopharmaceutical considerations will contribute to a successful therapy.
However, improved drug administration may also be achieved by so called modified release of the drug, which has been discussed extensively in the literature, e g R L Langer and D L Wise (Eds) “
Medical Applications of Controlled Release
”, vols I, II (1984), CRC Press Inc, Boca Raton.
Several approaches to achieve different types of modified release are described in the references above. Of special importance to the present invention is modified release achieved by formulating the active substance with a suitable carrier material in the form of microparticles. Such a formulation then contains multiparticulate discrete delivery units, each of which can be coated if necessary with, e g a suitable pH sensitive, semipermeable or other polymeric film. Several advantages can be obtained with this type of formulation compared with more conventional delivery means. Thus, the small size of the microparticles assures a fast and predictable emptying from the stomach, which is of special importance in the presence of food. Further, the particles will spread over a larger area in the whole GI-tract compared with a conventional monolithic (single-unit) formulation. This will result in a safer therapy when the active substance has local irritating side effects. Controllable plasma levels of absorbed drug can also be obtained. The microparticle formulation will also have a longer residence time in the colon which makes 24 hrs extended release formulations possible. From a technological point of view, microparticles are more suitable for coating and handling since a technical fault during the process may be serious for single unit formulations but less so for micropellets. Also, microparticle formulations are more easily manufactured and prepared in different doses than standard tablet systems.
PRIOR ART
An ideal method for the preparation of microparticles where the drug is homogeneously distributed within a polymeric matrix, should be simple, reproducible, rapid and minimally dependent on the solubility characteristics of the drug. A high product yield and a high degree of retention of the active substance in the final microparticles should also be obtained.
Several different techniques are available for making microparticles (<1 mm), e g spray-drying, extrusion-spheronization, spray-chilling, emulsion solvent evaporation/extraction and coating of nonpareil spheres, among others. A recent review was presented by Conti et al in STP Pharma Sci 7, 331 (1997) where the technical aspects of coacervation, spray-drying, emulsion solvent extraction, and emulsion solvent evaporation were discussed.
However, all existing techniques suffer from one or more drawbacks. Thus, many drugs are sensitive to heat and therefore will deteroriate which restricts the use of spray-drying or spray-chilling.
In extrusion spheronization and in coating of non-pareils particles it has been difficult to achieve acceptable microparticles in the size range of 50-400 &mgr;m. Pellets made by these methods contain significant amounts of inert excipients. This may make the pelletization of high-dose drugs by these methods a difficult task.
Finally, in emulsification solvent evaporation, an emulsion has to be made and the drug to be incorporated is preferably lipophilic, which restricts the drugs which can be used. Another drawback is the toxicity of the solvent used, usually methylene chloride, which can remain in the microparticles after drying.
However, despite the many different approaches there has not been disclosed a technique that can produce both smaller microparticles but also particles of more uniform size. It is important to avoid, e g segregation and dose variation during further processing into capsules or tablets. Further, the existing techniques do not incorporate several desirable aspects such as the possibility to produce spherical microparticles of different size ranges that are homogeneous, have a high drug content and sufficient mechanical strength (to e g withstand coating processes) into one single technique.
A spray-freezing technique has been used for the processing and granulation of ceramic materials to achieve homogeneous distribution of additives within granules to be compacted. For the processing of slurries containing silicon-nitride, sintering additives and a binder, spherical free-flowing granules have been prepared by spray-freezing and subsequent freeze-drying. The homogenity of the slurry was retained in the granules and thus in the final sintered product (Nyberg et al, Euro-Ceramics II 1, 447 (1993)). Suspensions of silicon carbide and additives were processed in this way to give granules for compaction (U.S. Pat. No. 4,526,734). The increased homogenity compared with traditional granulation techniques resulted in better mechanical properties of a whisker reinforced ceramic (EP 0 584 051). The process is also feasible for making homogeneous powder blends for ceramic superconductors (Japanese unexamined patent application no. 59-102433).
Normally pharmaceutical materials are lyophilized by freeze-drying in a bulk process in which the solution/suspension to be freezed is placed in vials or on trays in a freeze-drier, where freezing and subsequent sublimation of the dry solvent take place. The dried product is a powder cake.
The rapid freezing provided by spray-freezing ensures that no concentration gradients exist in the resulting frozen particles and degradation of biological material is prevented. This approach has been used to achieve precise metering and dispensing (M J Akers and D J Schmidt, BioPharm 28, (April 1997)); where the frozen particles were in the form of large lumps of size 1-9 mm. Freezing of droplets in a moving bath of Freon 12 (−20° C.), which medium conflicts with environmen

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