Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Cosmetic – antiperspirant – dentifrice
Patent
1991-09-30
1993-10-19
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Cosmetic, antiperspirant, dentifrice
424447, 4352401, 4352402, 4352403, 43524031, C12N 502, C12N 506, C12N 508
Patent
active
052543420
DESCRIPTION:
BRIEF SUMMARY
m comprising: (1) a carrier molecule selected from the group consisting of transferrin receptor ligands to which an active agent of interest may be conjugated; and (2) a transport enhancing agent (e.g., monensin or BFA) which enhances transendothelial or transepithelial transport of the transferrin receptor ligand/active agent conjugate via the TfR's.
BRIEF DESCRIPTION OF THE DRAWINGS
The invention may be better understood with reference to the accompanying drawings, in which:
FIGS. 1A and 1B illustrate the levels of transcytosis of .sup.125 I-Tf and HRP achieved in filter-grown MDCK cells, respectively;
FIGS. 2A and 2B illustrate the results of pulse-chase experiments monitoring processing of cell-associated .sup.125 I-Tf with and without addition of bufeldin A (BFA), respectively;
FIG. 3 illustrates changes in the specific binding of .sup.125 I-Tf to the basal and apical membranes upon treatment with BFA;
FIGS. 4A-4C illustrate the results of experiments to determine the effects of BFA on TfR-mediated uptake of .sup.59 Fe, FIG. 4A showing uptake from the apical membrane, 4B uptake from the basolateral membrane and 4C transcytosis in the basal-to-apical direction;
FIGS. 5A and 5B illustrate the results of experiments to determine the effects of monensin and NH.sub.4 Cl on the transcytosis of HRP-SS-Tf (FIG. 5A) and HRP (FIG. 5B);
FIGS. 6A and 6B illustrate the results of experiments to determine the effects of BFA on the transcytosis of HRP-SS-Tf and HRP, respectively; and
FIG. 7 illustrates the elution pattern of transcytosed TF-SS-HRP and a control standard in Sephacryl S-200 gel chromatography.
DETAILED DESCRIPTION OF THE INVENTION
The present invention involves the use of non-specific and specific-membrane binding ligands as well as the use of agents which can perturb intracellular protein sorting processes to significantly increase the transport of a macromolecular protein across the cells via endocytotic and transcytotic mechanisms.
During the last decade, most of the studies on drug transepithelial transport have been carried out at tissue and organ levels. For example, various types of intestinal samples, such as everted intestine preparations, intestinal ring slices and mucosal sheets have been used. Because of such factors as cellular heterogeneity, complexity in geometric structure, inaccessibility of the serosal side of the epithelium, and limited viability of epithelial cells in the isolated tissues, it is very difficult to use these methods for specific mechanistic studies on transepithelial transport of the drugs.
Purified brush border membrane vesicles, basolateral membrane vesicles and isolated intestinal epithelial cells have also been used to study drug transport. Although membrane vesicles offer an excellent model to study transport properties of solutes without the interference of cellular metabolism, they may not be suitable for studies on the endocytosis and transcytosis of macromolecules because of lack of membrane internalization. In addition, results from these membrane vesicles may not correlate well with those from viable cells. Isolated intestinal epithelial cell is a very good model to study the cellular binding, uptake and transport of drugs, but it suffers from short viability; therefore, the practical use of this type of cell is limited.
Cultured filter-grown epithelial cells, on the other hand, show many advantages as a model system. For example, the viability of the cell can be maintained for almost as long as it is needed, and studies on the interaction between peptides/proteins and cells can be carried out readily without the potential interference from other mucosal structures which are normally found in tissue samples. In addition, filter-grown epithelial cells allow easy access to both apical and basal side of the cell. The experimental data obtained is generally more reliable and easy to interpret, because of the relative homogeneity of the cell population. Other desirable properties, such as high sensitivity, reproducibility, and small sample requirements, a
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Shen Wei-Chiang
Wan Jiansheng
Azpuru Carlos
Page Thurman K.
University of Southern California
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