Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Capsules
Reexamination Certificate
1996-07-15
2001-10-30
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Capsules
C424S457000, C424S494000, C424S496000, C424S497000, C514S772300, C514S781000, C514S782000, C514S784000
Reexamination Certificate
active
06309666
ABSTRACT:
BACKGROUND OF THE INVENTION
The present invention relates to a pharmaceutical preparation which can release contents of a capsule at a lower part of the digestive tract and more particularly to a pharmaceutical preparation in the form of a coated capsule by which contents of a capsule can be selectively delivered to a desired site, e.g. the large intestine, and quickly released thereat.
Selective delivery of a medicament to the large intestine has been desired in drug therapies, for instance, a local therapy for inflammatory disease in the digestive tract such as ulcerative colitis or Crohn's disease, or an oral administrative therapy with a medicament of a peptide which is apt to be decomposed chemically or enzymatically in the digestive tract, with a medicament of which the absorption site is limited, or with other medicament.
In order to efficiently realize the site-selective delivery of a medicament to the large intestine, it is necessary to design a pharmaceutical preparation taking into account the physical and physiological environment in the human digestive tract and the residence time of the pharmaceutical preparation in the digestive tract. With respect to the physical and physiological environment in the digestive tract, it is recognized that the value of pH in the stomach is usually 1.8 to 4.5 in a healthy human and that the value of pH in the intestines is 6.5 to 7.5. According to the results of the widespread research of Davis et al., the residence time of a pharmaceutical preparation in the human stomach is 0.5 to 10 hours. Further not only is the inter-individual variation of the residence time large, but also the residence time is considerably influenced, for example, by feeding, the size of the pharmaceutical preparation to be administered and the like. On the other hand, the passage time of a pharmaceutical preparation through the small intestine is generally recognized to be 3±1 hours and the inter- and intra-individual variation is relatively small (Journal of Controlled Release, 2, 27-38 (1985)).
With respect to a method by which a medicament can be selectively released at the large intestine, hitherto various researches have been done. There have been proposed a pharmaceutical preparation which is obtained by coating a sustained release pharmaceutical preparation with an enteric coating (Annals of the New York Academy of Science, 618, 428-440 (1991)), a pharmaceutical preparation utilizing a technique for controlling the starting time of the release (Chemical & Pharmaceutical Bulletin, 40, 3036-3041 (1992), European Patent Publication No. 0425699 and Japanese Unexamined Patent Publication No. 256166/1994), a pharmaceutical preparation in the form of tablet which is obtained by coating insulin with an azopolymer soluble at the large intestine (Saffran et al, Science, 233, 1081-1084 (1986)) and the like, as well as pharmaceutical preparations using known techniques such as an enteric pharmaceutical preparation and a sustained release pharmaceutical preparation.
However, every conventional method has a problem such as insufficient site-selectivity, poor practicality due to peculiarity of the material to be used or complicated process for manufacturing a preparation.
For instance, as the enteric pharmaceutical preparation starts to release a medicament abruptly at the upper part of the small intestine, a selective delivery of the medicament can not be achieved.
When using the sustained release pharmaceutical preparation, a considerable amount of a medicament is released while the pharmaceutical preparation stays in the stomach and passes through the small intestine because the medicament is continuously released.
Furthermore, attempts have been made to suppress the release of a medicament in the stomach by coating a sustained release pharmaceutical preparation with an enteric coating. However, the problem that the medicament is released during the passage of the pharmaceutical preparation through the small intestine, has not entirely been solved by the above-mentioned enteric-coated sustained release pharmaceutical preparation.
The conventional pharmaceutical coated preparation requires optimization of, for example, a combination of a medicament and a coating agent, a coating amount, a kind of a solvent for a coating liquid, a spraying condition, a drying condition and the like, for every medicament to be used. In the case of a medicament which is easily decomposed by heating or by a solvent to be used, the optimization requires much labor.
Furthermore, there are some cases where the obtained optimum conditions are not always applicable to another medicament, in fact, the cases where the conditions are not applicable are numerous compared with cases where applicable. Therefore, it is hard to say that the conventional pharmaceutical preparation is excellent in a wide use.
Additionally, before coating, the conventional pharmaceutical coated preparation essentially requires processes such as granulation process, shieving process and tabletting process. Thus, it takes more time, labor and cost.
An object of the invention is to provide a pharmaceutical preparation which is excellent in a site-selective delivery. In particular the object of the invention is to provide a pharmaceutical preparation whereby medicaments, pharmaceutical preparations, functional substances or the like contained in a hard capsule can be delivered to any desired site of the lower part of the digestive tract.
A still further object of the invention is to provide a pharmaceutical preparation in the form of a coated capsule wherein any kind of medicaments etc. can be commonly or widely used without a special formulation.
These and the other objects of the present invention will become apparent from the description hereinafter.
SUMMARY OF THE INVENTION
It has now been found that (i) a hard capsule containing an acidic substance which is firstly coated with a substance soluble at low pH and further coated with an enteric substance, can quickly release contents of the hard capsule at any desired site between the upper part of the small intestine and the lower part of the large intestine according to the kind of the acidic substance and the kind of and the amount of the substance soluble at low pH, and (ii) only if using such a capsule, there can be obtained a pharmaceutical preparation whereby any kind of a medicament, a pharmaceutical preparation, a functional substance or the like can be delivered and quickly released at any desired site between the upper part of the small intestine and the lower part of the large intestine in the digestive tract.
In accordance with the present invention, there is provided a pharmaceutical preparation in the form of a coated capsule which can release contents of a capsule at a lower part of the digestive tract comprising (a) a hard capsule containing at least an acidic substance, (b) a polymer film soluble at low pH which is formed on a surface of said hard capsule, and (c) an enteric coating film which is formed on a surface of said polymer film soluble at low pH.
The pharmaceutical preparation of the present invention relates to a hard capsule for delivering the contents to the lower part of the digestive tract. That is, the pharmaceutical preparation of the present invention has the following characteristics: When a pharmaceutical preparation stays in the stomach, an enteric coating film protects the pharmaceutical preparation. Successively when the preparation transits from the stomach to the upper part of the small intestine, the enteric coating film dissolves and starts to disappear. Then, the digestive juice gradually penetrates through a low pH-soluble polymer film and a hard capsule to enter the hard capsule, and thereby an acidic substance is dissolved. The solution having low pH which is produced by the dissolution of the acidic substance, dissolves the hard capsule and the low pH-soluble polymer film, resulting in disappearance thereof. Then, the contents of the hard capsule such as medicaments, pharmaceutical preparations and functio
Hatano Harumi
Ishibashi Takashi
Ito Takahiro
Mizobe Masakazu
Yoshino Hiroyuki
Browdy and Neimark
Spear James M.
Tanabe Seiyaku Co. Ltd.
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