Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
2000-11-06
2004-01-20
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S452000, C424S461000, C424S464000, C424S465000, C424S489000, C424S499000
Reexamination Certificate
active
06680069
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to low-substituted hydroxypropyl cellulose used as an additive for medicines, agrochemicals or food, a solid formulation (preparation) containing the same and a process for manufacturing the same.
2. Description of the Related Art
Solid formulations such as tablets and granules are used for medicines, agrochemicals, food and other industrial products. In general, they are used in the form of a granular formulation or a fine granule formulation which is prepared by mixing a principal component with an additive such as filler, a disintegrant, a binder or the like and tableting the mixture, or adding water and a binder to the mixture thereof, stirring or kneading it and then preparing particles therefrom.
Low-substituted hydroxypropyl cellulose (hereinafter also referred to as “L-HPC”) described in the Japanese Pharmacopoeia is used as both a disintegrant and a binder in these solid formulations (Japanese Patent Publication (JP-B) No. 48-38858/1973 (U.S. Pat. No. 3,852,421), Japanese Patent Publication (JP-B) No. 51-19017/1976, Japanese Patent Publication (JP-B) No. 57-53100/1982 (U.S. Pat. No. 4,091,205) and Japanese Patent Provisional Publication (JP-A) No. 7-324101/1995).
L-HPC is a kind of cellulose ethers and similar to hydroxypropyl cellulose (hereinafter also referred to as “HPC”) which is generally used as a binder. However, L-HPC has a different property. That is, an essential difference between HPC and L-HPC resides in a content of hydroxypropoxyl groups, and the value thereof is 53.4 to 77.5% in HPC but 5 to 16% in L-HPC. This value is determined by a method described in the Japanese Pharmacopoeia, and a range thereof is distinctly prescribed in a monograph of the Japanese Pharmacopoeia “low-substituted hydroxypropyl cellulose”.
However, those which have so far been commercially available as L-HPC have a loose bulk density of about 0.3 g/ml and is poor in a fluidity of powder, so that the following problems have existed. First, granules prepared by fluid bed granulation, have a lower bulk density than a L-HPC powder, so that the fluidity is reduced. When a hard capsule is charged with the above granules to prepare a capsule formulation, it becomes impossible to charge the capsule with the desired amount. Further, in a process for manufacturing tablets by tableting the granules, tableting at a high speed increases a weight deviation of the tablets because of a bulkiness and a poor fluidity thereof.
Further, a fundamental problem resides in that when a particularly large amount of L-HPC is added, fluid bed granulation itself becomes difficult. This is due to the fact that the powder absorbs moisture and swells during granulation to increase in a bulk and flowing is stopped or becomes inferior, so that the particle size distribution becomes quite uneven.
Further, there has been as well the problem that a formulation containing L-HPC is inferior in a feeling on a tongue.
SUMMARY OF THE INVENTION
An object of the present invention is to provide a low-substituted hydroxypropyl cellulose which allows the granules to be dense and rich in fluidity and can be increased in an amount thereof when a hard capsule is charged therewith, resulting in reduction of a weight deviation in making tablets at a high speed. In additon, it includes improvement of a feeling on a tongue of the resulting formulation and ease of problems in fluid bed granulation such as a stop of flow. It also includes providing a solid formulation (prepartion) containing the same and a process for manufacturing the same.
Intensive investigations by the present inventors in order to solve the problems described above have resulted in finding that use of low-substituted hydroxypropyl cellulose obtained by further pulverizing the low-substituted hydroxypropyl cellulose having a loose bulk density of 0.40 g/ml or more and a tapped bulk density of 0.60 g/ml or more, which is obtained in a first pulverization process, improves the fluidity and the feeling on the tongue, reduces a weight deviation in making tablets at a high speed, decreases problems such as a stop in flowing in the fluid bed granulation, and can ease the problem of the weight deviation even if a content of L-HPC is elevated in direct compression. Thus, they have come to complete the present invention.
That is, provided are a process for manufacturing a low-substituted hydroxypropyl cellulose, comprising:
a step for dipping a pulp in an alkaline solution to prepare an alkali cellulose,
a step for reacting said alkali cellulose with a hydroxypropylating agent such as propylene oxide to yield a product in a complete dissolution state thereof,
a step for neutralization with an acid to yield a precipitate,
a step for washing,
a step for drying, and
a step for pulverization to yield a powder having a volume-average particle diameter of less than 25 microns which is determined by a dry laser diffraction method, a loose bulk density of 0.29 g/ml or more and less than 0.40 g/ml, and a tapped bulk density of 0.55 g/ml or more, and the low-substituted hydroxypropyl cellulose. Further, provided is a solid formulation containing the low-substituted hydroxypropyl cellulose.
According to the present invention, the granules become dense and are rich in fluidity as compared with those obtained by using conventional L-HPC; when a hard capsule is charged with them, the amount thereof can be raised, and the weight deviation is reduced in making tablets at a high speed; in addition, the resulting formulation is improved in a feeling on a tongue.
Further, the problems in fluid bed granulation such as a stop of flow are reduced, and a problem of a weight deviation in a direct compression process is eased even if a content of L-HPC is elevated.
DETAILED DSCRIPTION OF THE PREFERRED EMBODIMENTS
The “loose bulk density” used in the present invention means a bulk density in a loosely filled state and is determined by evenly charging a cylindrical vessel having a diameter of 5.03 cm and a height of 5.03 cm (capacity: 100ml) with a sample through a sieve of 22 mesh (710 &mgr;m) of Japanese Industrial Standard (JIS) from an upper part thereof (23 cm above the vessel) and leveling the sample by cutting at the top face of the vessel for weighing it.
On the other hand, the “tapped bulk density” means a bulk density in a densely filled state by additional tapping on the above sample. Tapping is an operation in which the vessel charged with the sample is repeatedly dropped from a fixed height so as to obtain the sample in a densely filled state by applying light impact to the bottom thereof. In practice, after the sample is leveled by cutting at a top face of a vessel for weighing to obtain a loose bulk density, the vessel is fitted with a special-purpose cap supplied together with the powder tester by Hosokawa Micron Co., Ltd. Then, the sample is added up to the top bounds thereof and then 180 times of tapping are carried out at a tapping height of 1.8 cm. Subsequently, the cap is removed, and the sample is leveled by cutting at the top face of the vessel for weighing. The tapped bulk density is obtained as the bulk density in this state. These operations can be carried out by means of the powder tester (PT-D) manufactured by Hosokawa Micron Co., Ltd.
The L-HPC of the present invention can be produced by a method described below.
First, a pulp is dipped in an alkaline solution to prepare an alkali cellulose, and the obtained alkali cellulose is reacted with a hydroxypropylating agent such as propylene oxide. A process up to this stage is the same process as a conventional process for manufacturing L-HPC. In a step subsequent thereto, the product is placed into water or water adjusted to alkalinity and dissolved therein to prepare an almost homogeneous opaque slurry, and then neutralized with hydrochloric acid to recover deposited L-HPC. The recovered L-HPC is washed with water, dryed and pulverized.
In a conventional process, neutralization is partially carried out to obtain a semi-dissolution state by k
Myers Bigel & Sibley & Sajovec
Shin-Etsu Chemical Co. , Ltd.
Ware Todd D
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