Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
2000-01-24
2001-07-24
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S493000, C424S439000, C424S451000, C424S496000, C424S497000, C427S002180, C427S002150, C427S212000, C427S213000, C427S214000, C427S242000
Reexamination Certificate
active
06264989
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to spherical single-substance particles having good surface smoothness and low abrasiveness and a method for producing the same. More specifically, the present invention relates to spherical particles comprising a sugar alcohol, sodium chloride, vitamin C or the like, which is useful for coating granulation in the preparation of medicines and foodstuffs and to a method of the production thereof.
RELATED BACKGROUND ART
Spherical particles used as raw materials of pharmaceuticals have been mainly used as seeds of sustained-release preparations and enteric coated preparations. Examples of such spherical particles for pharmaceutical use include “Sugar Spheres” made mainly of sucrose/corn starch, which is prescribed in the “National Formulary (NF)”; and purified sucrose spheres (e.g., “Nonpareil-103”, a tradename of Freund Industrial Co., Ltd.), sucrose/starch spheres (e.g., “Nonpareil-101”, a tradename of Freund Industrial Co., Ltd.) and microcrystalline cellulose spheres (e.g., “Celphere” made by Asahi Chemical Industry Co., Ltd.), which are prescribed in the Japanese Pharmaceutical Excipients (JPE 1998).
All of the substances serving as the raw materials of such spherical particles have physiochemical properties suited for the formation of spherical shapes. For example, a series of commercial products sold under the aforementioned tradename “Nonpareil®”, which have cores made of granulated sugar having an octahedral to dodecahedral monoclinic crystalline structure, are suitable for the sphere formation, because they can also effectively act as binders in the form of aqueous solutions. Commercial product sold under the aforementioned tradename “Celphere®”, which is a spherical particle without a core, can also be formed into spheres readily, because the raw component crystalline cellulose thereof has a short fibrous form.
The commercial product “Nonpareil-103®”, for example, is known to be produced by charging granulated sugar as a core into a centrifugal tumbling apparatus (e.g., “CF-Granulator” manufactured by Freund Industrial Co., Ltd.; hereinafter, simply referred to as “CF apparatus”), dispersing sucrose microparticles or powders over the granulated sugar core while spraying an aqueous sucrose solution as a binder on the core to thereby coat the granulated sugar with sucrose, and then granulating the resultant coated granulated sugar into spheres. Thus, the product “Nonpareil-103®” can be said to consist of 100% sucrose, since granulated sugar has the same chemical composition as that of sucrose.
The commercial product “Nonpareil-101®” is known to be produced by charging granulated sugar as a core into CF apparatus, dispersing microparticles or powders of a sucrose/starch mixture over the granulated sugar core while spraying an aqueous solution of a sucrose/starch mixture as a binder on the core to thereby coat the granulated sugar with the sucrose/starch mixture, and then granulating the resultant coated granulated sugar into spheres. In the product “Nonpareil-103®”, the content ratio of sucrose to starch is 65-85%:35-15%.
Another type of spherical particle granulated from a core and the method for the production thereof is disclosed in Japanese Patent Application Laid-open No. 5-229961, in which the spherical particle comprises a mixture of a water-soluble substance (e.g., lactose) and a water-insoluble substance (e.g., cellulose) and has a particle diameter of 0.1-1 mm.
These spherical particles can be used for pharmaceutical preparation. However, many medicinal agents often react with the raw substances of the spherical particles to cause a brown discoloration such as Maillard reaction. Therefore, upon use with such medicinal agents, complicated tests are required for confirming the compatibility of the raw substances of the spherical particles with the medicinal agents.
Lactose has been focused on as a raw material of a spherical particle for pharmaceutical preparation, because it is less reactive with various medicinal agents and therefore has a low tendency to cause Maillard reaction with the medicinal agents. For example, Japanese Patent Application Laid-open No. 6-205959 discloses a lactose spherical particle and a method for producing it, in which the finished spherical particle comprising at least 95% lactose and has a longer diameter/shorter diameter ratio of 1.2 or lower, and as an aggregate, exerts a bulk density of 0.7 g/mL or larger and an angle of repose of 35 degree or less.
DISCLOSURE OF THE INVENTION
In the case of lactose which is less reactive with medicinal agents, however, one has not succeeded as yet in producing spherical particles of lactose alone with high sphericity and low abrasiveness in the industrial scale, because lactose itself has no function as a binder.
For example, in the method disclosed in Japanese Patent Application Laid-open No. 5-229961, when lactose is combined with crystalline cellulose at a mixing ratio of at least 95% lactose, particles can be obtained which macroscopically appear spherical. However, when the surface of the individual spherical particles is observed under a scanning electron microscope, lactose powder particles are clung to the surface unevenly. Therefore, when such spherical particles are further coated with a medicinal agent to produce a sustained-release preparation, such unevenness undesirably leads to greater abrasiveness, resulting in unavoidable reduction in yields (i.e., coating efficiency and granulating efficiency).
Likewise, with respect to the method disclosed in Japanese Patent Application Laid-open No. 6-205959, the present inventors have also found such a disadvantage that the lactose content of 95% or greater causes the phenomenon of microscopic surface roughness of the finished spherical particles.
The disadvantages as mentioned above are also true for substances other than lactose, as illustrated in the drawings attached. For example, in the case of a sugar alcohol, sodium chloride and vitamin C, it was impossible to prepare smooth-surfaced spherical particles consisting essentially of the single substance.
Accordingly, an object of the present invention is to provide a novel spherical particle consisting essentially of a single substance and a method for producing the spherical particles, which can overcome the drawbacks associated with the prior art spherical particles comprising sucrose (or a sucrose/starch mixture), crystalline cellulose, a lactose/crystalline cellulose mixture or the like. Another object of the present invention is to provide a food and a pharmaceutical preparation comprising the spherical particles.
The present inventors have further studied on improving the surface smoothness and reducing the abrasiveness of spherical particles consisting essentially of a single substance. As a result, the inventors have succeeded in the establishment of a method in which moist spherical single-substance particles granulated in the aforementioned CF apparatus are sprayed with an aqueous solution of the single substance in a fluidized bed and dried to conduct the fixation treatment of the surface of the spherical particles. This success led to the accomplishment of the present invention.
The present invention encompasses the following aspects and embodiments.
(1) A spherical particle comprising a granulated particle containing at least 95 wt % of a water-soluble single substance which has a viscosity of 10 mPa.s or less as determined in the form of a saturated aqueous solution, the spherical particle having an aspect ratio of 1.2 or less and, as an aggregate, having a bulk density of 0.65 g/mL or more and an angle of repose of 35 degree or less.
(2) A spherical particle comprising a granulated crystalline particle containing at least 95 wt % of a water-soluble single substance which has a viscosity of 10 mPa.s or less as determined in the form of a saturated aqueous solution, the spherical particle having an aspect ratio of 1.2 or less and, as an aggregate, having a bulk density of 0.65 g/mL or more, an angle of repose of 35 degree o
Fujii Toshiro
Kato Hisayoshi
Myo Nagayoshi
Suzuki Yusuke
Tanai Ikuo
Di Nola -Baron Liliana
Foley & Lardner
Freund Industrial Co. Ltd.
Spear James M.
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