Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Implant or insert
Reexamination Certificate
2000-11-27
2001-12-25
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Implant or insert
C424S435000, C424S436000, C424S422000
Reexamination Certificate
active
06333046
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a transmucous absorption enhancer. More particularly, this invention relates to a transmucous absorption enhancer for promoting an absorption of a physiologically active agent via a mucosa of an intestinal tract and rectal, vaginal, nasal and oral cavities and the like. Specifically, the invention relates to a transmucous absorption enhancer having a sustained effect and an absorption-promoting effect which was obtained by combining a glycyrrhizic acid salts which is used as a therapeutic agent against a chronic hepatitis, an allergic injury, an inflammation and a gastric ulcer and also as an agent for promoting an absorption via a nasal mucosa but exhibits no absorption-promoting effect in a cultured cell assay system with a medium-chain fatty acid salts or a bile acid salt, and also by specifying the amounts to be combined.
DESCRIPTION OF THE RELATED ART
A conventional oral formulation undergoes a disintegration and a dissolution generally before it reaches a large intestine after being taken orally. As a result, a physiologically active polypeptide which is degraded readily in a gastrointestinal tract can not exert a pharmacological effect reliably after an oral intake. Accordingly, such physiologically active peptide has conventionally been developed in a dosage form of a nasal, vaginal or rectal formulation of a physiologically active peptide. However, such dosage form can not be used conveniently, and a dosage form for an oral administration is still desired.
In order to formulate a physiologically active polypeptide into a dosage form for an oral administration, it is required that such polypeptide is not degraded in a gastrointestinal tract. On the other hand, a large intestine is a hopeful candidate of an absorption site of a peptide agent since it has a lower protease activity when compared with a small intestine. Nevertheless, a large intestine has a finer interstice of the cells when compared with a small intestine, due to which it usually involves a difficulty in absorbing a highly hydrophilic peptide agent. Accordingly, various attempts have been made to improve the absorption via a mucosa of a large intestine, including a method using a absorption enhancer. A absorption enhancer is employed widely in a nasal, vaginal or rectal formulation or in an oral formulation for the purpose of promoting a transmucous absorption. Examples of such absorption enhancer which have been reported are a bile acid salt having a surfactant property (JP-A-59-130820), an ionic or non-ionic surfactant (JP-A-4-247034), as well as a substance which promotes the absorption via a nasal or rectal mucosa, such as a chelating agent, a medium-chain fatty acid salts (U.S. Pat. No. 4,476,116), an alkaline metal glycyrrhizinate (JP-A-2-42027), and the like.
On the other hand, one of the assay systems for evaluating the absorption of an agent via an intestinal tract is a method using a Caco-2 cell which is a human large intestine cancer-derived cell line. When a Caco-2 cell is cultured as a monolayer for about 3 weeks on a double-chambered porous polycarbonate membrane, it exhibits a morphological and biochemical polarity of a membrane such as the formation of a villus or a tight connection, and thus is known to be a cell line capable of being used for evaluating the absorption of an agent in an intestinal tract (Hidalgo, I.J. et al., Gastroenterology, 96:736-749, 1989). Once a tight connection is formed to make a cell interstice finer, a transepitherial electrical resistance (TEER) is established between the top and the bottom of a cell monolayer, and a Caco-2 cell has a stronger intercellular connection and an extremely lower permeation through an interstice when forming such tight connection than when present as an in vivo intestine. It is also known that the results of a study on a drug permeability using a Caco-2 cell are correlated highly with the results of an in vivo study (Yamashita,setal., Pharm. Res. 14 (4) :486-491, 1997). Due to the reasons described above, a Caco-2 cell is used widely as a mean for performing an in vitro investigation of an effect of a absorption enhancer f or promoting absorption by dilating the interstice of the cells (Tomita, Metal., Pharm. Res., 5:341-346, 1980, Sawada, T et al., Pharm. Res., 8:1365-1371, 1991).
SUMMARY OF THE INVENTION
While a large number of studies have been made for developing a absorption enhancer, a substantial use has not actually been made, since a conventional absorption enhancer has an only insufficiently sustained effect.
Thus, an objective of the present invention is to provide a transmucous absorption enhancer capable of sustaining the effect of the absorption enhancer and allowing an agent (especially a physiologically active peptide) to be absorbed more efficiently via a mucosa (especially a large intestine mucosa).
Accordingly, in order to achieve the objectives described above, as the first aspect of the invention, a transmucous absorption enhancer comprising a medium-chain fatty acid salts and a glycyrrhizic acid salts is provided. In a preferred embodiment, the ratio of said medium-chain fatty acid salts and said glycyrrhizic acid salts is 1:2 to 1:100.
As the second aspect of the invention, a transmucous absorption enhancer comprising a bile acid salts and a glycyrrhizic acid salts is provided. In a preferred embodiment, the ratio of said bile acid salts and said glycyrrhizic acid salts is 1:1 to 1:100.
Preferably, in any of the aspects of the invention, said glycyrrhizic acid salts is a monoammonium glycyrrhizinate or an alkaline metal glycyrrhizinate (e.g., dipotassium or sodium salt, tripotassium or sodium salt), said medium-chain fatty acid salts is an alkaline metal salt of capric acid, caprylic acid and caproic acid (e.g., sodium or potassium salt), and said bile acid salt is sodium cholate, sodium glycocholate, sodium taurocholate, sodium deoxycholate or sodium cenodeoxycholate.
REFERENCES:
patent: 4835142 (1989-05-01), Suzuki et al.
patent: 4952560 (1990-08-01), Kigasawa et al.
patent: 5182258 (1993-01-01), Chiou
patent: 5578567 (1996-11-01), Cardinaux et al.
Azuma Hidekazu
Imai Teruko
Ohtake Hiroshi
Otagiri Masaki
Sakai Michinori
Bennett Rachel M.
Hisamitsu Pharmaceutical Co. Inc.
Page Thurman K.
Wenderoth , Lind & Ponack, L.L.P.
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