Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1999-07-13
2002-09-17
Reamer, James H. (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C514S946000
Reexamination Certificate
active
06451815
ABSTRACT:
BACKGROUND
The term “multidrug resistance” (MDR) describes the phenomenon whereby certain cancerous tumor cells develop a resistance to broad classes of cytotoxic agents when exposed to an individual cytotoxic agent. In other words, after a certain period of treatment with a cytotoxic agent which initially shows efficacy in controlling the growth of the tumor, the tumor develops a resistance not only to the specific agent to which the tumor was exposed, but also to broad classes of structurally and functionally unrelated agents. It has recently been found that MDR tumor cells over express a particular membrane glycoprotein known as p-glycoprotein (“p” for permeability). This p-glycoprotein is a member of the superfamily of ATP-binding cassette (ABC) transporters. It is thought that the exposure of the MDR tumor cells to a cytotoxic agent causes the induction of this p-glycoprotein which mediates a reverse transport system located on the tumor cell membrane that pumps the cytotoxic agent, as well as the other broad classes of cytotoxic agents, out of the tumor cell thus providing mutiple drug resistance for the cell.
P-glycoprotein is not just found in tumor cells. It is also expressed in a variety of normal, non-cancerous, epithelial and endothelial cells including in such tissues as the adreneal cortex, in the brush border of the proximal renal tubule epithelium, on the lumenal surface of biliary hepatocytes, in pancreatic ductules, and in the mucosa of the small and large intestine. For purposes of describing the present invention, the presence of p-glycoprotein in the small and large intestine is of particular interest.
When substances are ingested, they are mixed with digestive substances secreted by the body and are ultimately combined in a mixture in the lumen of the intestine. The lumen of the intestine is in contact with certain special epithelial cells which form the mucosa of the intestine or the intestinal wall. Nutrients and other substances present in the intestinal lumen passively diffuse into these intestinal epithelial cells and later diffuse into the portal circulation which carries the nutrients via the blood stream on to the liver. Thus, nutrients and other substances are absorbed into the body and become bioavailable for use by other tissues in the body.
The intestinal epithelial cells, however, do not just operate as a vehicle for passive diffusion of nutrients and other ingested substances. In addition, there are various active transport mechanisms located in the outer membrane of the epithelial cells which actively transport various nutrients and other substances into the cell. It is now thought that one of the active transport mechanisms present in the intestinal epithelial cells is p-glycoprotein transport mechanism which facilitates the reverse transport of substances, which have diffused or have been transported inside the cell, back into the lumen of the intestine. It has been speculated that the p-glycoprotein present in the intestinal epithelial cells may function as a protective reverse pump which prevents toxic substances which have been ingested and diffused or transported into the epithelial cell from being absorbed into the circulatory system and becoming bioavailable. One of the unfortunate aspects of the function of the p-glycoprotein in the intestinal cell however is that it can also function to prevent bioavailability of substances which are beneficial, such as certain drugs which happen to be substates for the p-glycoprotein reverse transport system.
It has now been found that, surprisingly, the antihistamines of the present invention are coincidentally also targeted by the p-glycoprotein reverse transport system in intestinal epiothelial cells and therefore are not fully bioavailable. The present invention successfully provides a method for enhancing the bioavailablilty of these antihistamines.
SUMMARY IF THE INVENTION
The present invention relates to a method of enhancing the bioavailability of a piperidinoalkanol antihistamine of Formula I
wherein
R is hydrogen or C
1
-C
6
alkyl,
or a pharmaceutically acceptable salt or an individual optical isomer thereof, in a patient which comprises co-administering to said patient an effective antihistaminic amount of said piperidinoalkanol and an effective p-glycoprotein inhibiting amount of a p-glycoprotein inhibitor. The present invention further relates to a method of treating allergic reactions in a patient, which comprises co-administering to said patient an effective antihistaminic amount of antihistamine of Formula I and an effective p-glycoprotein inhibiting amount of a p-glycoprotein inhibitor. The present invention also relates composition comprising an effective antihistaminic amount of a piperidinoalkanol antihistamine of Formula I and an effective p-glycoprotein inhibiting amount of a p-glycoprotein inhibitor.
DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a method of enhancing bioavailability of a piperidinoalkanol antihistamine of Formula I
wherein
R is hydrogen or C
1
-C
6
alkyl,
or a pharmaceutically acceptable salt or an individual optical isomer thereof.
As used herein, the term “C
1
-C
6
alkyl” refers to a saturated hydrocarbyl radical of straight or branched chain configuration of from 1 to 6 carbon atoms. Specifically included within the scope of the term “C
1
-C
6
alkyl” are the hydrocarbyl radicals methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, isobutyl, tert-butyl, pentyl, hexyl, and the like. One skilled in the art would immediately recognize and appreciate that the compounds of Formula I possess a chiral center and as such exist in stereoisomeric forms. The present invention applies to the racemic mixture of these stereoisomeric forms as well as to the isolated individual stereoisomers. The individual stereoisomers can be isolated from the racemic mixture by separation techniques which are well known and appreciated in the art including chromatographic methods and selective crystallization techniques.
The compounds of Formula I may exist in their free form or as pharmaceutically acceptable salts. Pharmaceutically acceptable salts of the compounds of Formula I are those of any suitable inorganic or organic acid. Examples of suitable inorganic acids include hydrochloric, hydrobromic, sulfuric, and phosphoric acids. Examples of suitable organic acids include carboxylic acids, such as, acetic, propionic, glycolic, lactic, pyruvic, malonic, succinic, fumaric, malic, tartaric, citric, cyclamic, ascorbic, maleic, hydroxymaleic, dihydroxymaleic, benzoic, phenylacetic, 4-aminobenzoic, 4-hydroxybenzoic, anthranillic, cinnamic, salicylic, 4-aminosalicylic, 2-phenoxybenzoic, 2-acetoxybenzoic, mandelic acid, and sulfonic acids, such as, methanesulfonic, ethanesulfonic, and &bgr;-hydroxyethanesulfonic acid. Non-toxic salts of the compounds of Formula I formed with inorganic or organic bases are also included within the scope of this invention and include, for example, those of alkali earth metals, for example, calcium and magnesium, light metals of group IIIA, for example, aluminum, organic amines, such as, primary, secondary or tertiary amines, for example, cyclohexylamine, ethylamine, pyridine, methylaminoethanol, and piperazine. The salts of compounds of Formula I may be prepared by conventional means as, for example, by treating a compound of Formula I with an appropriate acid or base. The preferred pharmaceutically acceptable salt for compounds of Formula I is the hydrochloric acid salt.
Compounds of Formula I may be prepared as described in U.S. Pat. No. 4,254,129, which is hereby incorporated by reference in its entirety.
The preferred compound of Formula I is the compound (±)-4-[1-hydroxy-4-[4-(hydroxydiphenylmethyl)-1-piperidinyl]-butyl]-&agr;,&agr;-dimethyl benzeneacetic acid, which is also known as fexofenadine, and its individual stereoisomers. Fexofenadine, as the hydrochloric acid salt, has been recently approved by the United States Food and Drug Administration (FDA) for use as the active ingredient in the an
Giesing Dennis H.
Hurst Gail H.
Hwang Kin-Kai
Aventis Pharmaceuticals Inc.
Barney Charlotte L.
Lin Jiang
Reamer James H.
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