Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Reexamination Certificate
1999-03-09
2001-01-09
Clardy, S. Mark (Department: 1616)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
Reexamination Certificate
active
06171619
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to spherical granules having a uniform grain size and a uniform density, which are suitable for controlled-release preparations.
DESCRIPTION OF THE RELATED ART
Recently, drug delivery systems (DDS) have been studied intensively and some of them are now put into actual use. The release control for oral dosage form is major one of such DDSs. The dosage forms utilizing the release control techniques are classified into two categories: single unit type and multiple unit type. These two dosage forms have inherent characteristics of their own. However, multiple unit type dosage is superior in view of ease of and high degree flexibility in drug design. There are many types of the multiple unit dosage form and most of them utilize plurality kinds of granules each imparted with predetermined diffusion properties as the constituents.
The granules of such multiple unit dosage form can generally be prepared by coating a medicinal ingredient (i.e., a pharmaceutically active ingredient) and a release control agent onto spherical granules with a grain size of about 200-1000 &mgr;m made of inert substances such as sucrose, starch and microcrystalline cellulose. As the spherical granules made of inert substances, commercial products sold under the trade name of, for example, “NONPAREIL” (Freund Industrial Co., Ltd.) and “Celpher” (Asahi Chemical Industry Co., Ltd.) are available, which are useful products as the raw materials for medicines. However, these products still have plenty of room for improvement.
That is, the spherical granules are required to have a coating layer on the surface which is capable of imparting a desired diffusion behavior to the medicinal ingredient. In addition, the spherical granules must satisfy many other requirements, including preciseness of the coating layer formation, less variation in lots of the spherical granules, ease of measuring and filling and no segregation during processing. The factors required for the spherical granules themselves which may affect the above-mentioned requirements include grain size, hardness, degree of abrasion wear, degree of spherisity, solubility and water-absorbing capacity. The factors required for the aggregates of the spherical granules include grain distribution, bulk density and angle of repose. In order to modify these factors, there are proposed several means.
With respect to the physical properties of the spherical granules such as hardness, degree of abrasion wear, solubility, water-absorbing capacity, the types of the constituent substances of the spherical granule is a predominant factor, and there have been made a number of studies on the constituents. For example, Japanese Unexamined Patent Publication No. 6-205959 proposes a composition comprising at least 95% by weight of lactose; Japanese Unexamined Patent Publication No. 4-283520 proposes a composition comprising 10-70% of crystalline cellulose having a mean polymerization degree of 60-375 and 10-90% of water-soluble additives; and Japanese Unexamined Patent Publication No. 7-173050 proposes a composition comprising at least 50% of crystalline cellulose having a mean polymerization degree of 60-375. Japanese Unexamined Patent Publication No. 5-229961 discloses a composition comprising mainly lactose and cellulose; and Japanese Patent Publication No. 7-2761 discloses a composition comprising at least 20% of microcrystalline cellulose. These compositions are closely correlated with the apparatus and the process employed for producing the spherical granules.
On the other hand, among the properties mentioned above, the universal properties independent on the types of the constituent substances include grain size and grain size distribution.
With respect to grain size, Japanese Patent Publication No. 7-2761, supra, discloses spherical granules in which at least 90% has a fraction falling through a 24 mesh (710 &mgr;m); and Japanese Unexamined Patent Publication No. 5-92918 discloses spherical granules which give a grain size of not greater than 500 &mgr;m when coated with a medicinal ingredient, both which are described to be good because they meet the requirements of the Japanese Pharmacopoeia and can reduce the variations in preparation.
With respect to grain size distribution, it is described in, for example, Mizunaga et al., “Summary of the lectures presented at the 7th Symposium on Preparation and Particle Design”, pp. 89-93, October 1990, that (although not referred to the spherical granules per se) granules comprising a medicinal ingredient and the like coated onto spherical granules, which are spherical in shape and have a sharp grain size distribution, are preferable in view of efficiency and reproducibility of the coating to the spherical granules.
However, in this publication, we cannot find any date showing the relationship between the grain size distribution and the coating efficiency or any description referring to what grain size distribution is preferable for pharmaceutical granule preparations.
There are several publications referring to the grain size distribution of the granulated spherical granules, such as a thesis for a degree cataloged in the National Diet Library by Funakoshi., “Compressive Molding and Granulation of Medicines”, Aug. 4, 1976, p.114; Sakamoto, “Summary of the lectures presented at the 7th Symposium on Preparation and Particle Design”, pp. 118-121, October 1990; B. Gajdos, Pharm. Ind., 45, No.7, pp.722-728, 1983; and Japanese Unexamined Patent Publication No. 62-269739. However, in these publications, such a sharp grain size distribution as required for the spherical granules of the present invention cannot be attained, and there is no description referring to the difference in density of the spherical granules and what result can be obtained by the use of the spherical granules for preparing pharmaceutical preparations.
As a method for producing spherical granules having a sharp grain size distribution, Japanese Unexamined Patent Publication No. 63-23731 discloses a process in which raw materials are charged into a rotary granulator successively and the resultant product is discharged continuously. Although this process has the advantage of continuous production, it is not clear what type of grain size distribution the granules actually have. In the specification of this publication, we can found only the portion “when the grain size distribution range (attained by such continuous discharge process) which is already extremely good should be more improve to, for example, 1.0-1.2 mm, . . . continuous feeding into a sizing apparatus may be available”, and there is no description referring to the grain size distribution. In addition, this process merely classifies the granules to desired grain sizes by sieving. However, sieving of spherical granules sometimes results in poor efficacy of classification under a certain grain size distribution of the raw powder materials and, consequently, results in production of a granules containing many fractions falling through the sieve and a poor yield, which being not suitable for practical application.
Japanese Unexamined Patent Publication No. 6-205959, supra, also discloses the incorporation of medicinal ingredients into the spherical granules. However, such medicinal ingredient-containing spherical granules also do not show a sharp grain size distribution.
As discussed above, in order to produce a controlled-release pharmaceutical preparation of multiple unit dosage form, it has already been practiced and studied on coating a medicinal ingredient and a release control agent onto spherical granules or incorporating a medicinal ingredient into spherical granules. However, it is hard to say that the conditions necessary for imparting an intended diffusion behavior to the spherical granules is well elucidated. Particularly with respect to the universal physical properties independent on the types of the components, any effective proposal has not been made.
In controlled-release preparations comprising spherical granules, it is considered to
Fusejima Yasutoyo
Kato Hisayoshi
Myo Nagayoshi
Takemura Yasuhiro
Clardy S. Mark
Foley & Lardner
Freund Industrial Co. Ltd.
George Konata M.
LandOfFree
Spherical granule, process for producing the same, and... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Spherical granule, process for producing the same, and..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Spherical granule, process for producing the same, and... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2466070