Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Food or edible as carrier for pharmaceutical
Reexamination Certificate
1998-09-30
2002-07-23
Spear, James M. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Food or edible as carrier for pharmaceutical
C424S451000, C424S464000, C424S489000, C424S400000, C514S800000, C514S802000, C514S807000, C514S808000, C514S783000, C514S784000, C514S822000
Reexamination Certificate
active
06423334
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a composition and method for enhancing transport across gastrointestinal tract (GIT) cell layers in an animal. More particularly, the present invention provides an enteral composition which enhances the uptake of a drug across the GIT comprising a non-ionic vegetable oil GIT absorption enhancer, most particularly Babassu oil or a derivative of Babassu oil.
BACKGROUND OF THE INVENTION
While the vast majority of drugs are intended for systemic action, most drug formulations are designed for enteral or peroral administration primarily for ease of administration and patient compliance. However, the systemic availability of hydrophilic and or macromolecular drugs, particularly peptides, administered enterally or perorally is often too low to have any therapeutic affect. Limiting factors which can decrease overall peroral bioavailability of a drug include low solubility or chemical instability in the GIT, high gastrointestinal and or hepatic metabolism and poor intestinal membrane permeability. Low peroral bioavailability of a drug is typically undesirable and can lead to significant intra- and inter patient variability in drug bioavailability and therefore therapeutic performance.
The mammalian small intestine is composed of “fingerlike” villi and crypts that are covered by a continuous layer of polarized, columnar epithelial cells. This epithelium, consisting of a heterogeneous group of cells, forms the interface between the external environment (the intestinal lumen) and the interstitial space. The most common epithelial cell is the enterocyte or the absorptive cell. This cell type is responsible for the majority of the absorption of both nutrients and drugs which occurs in the small intestine. It is highly polarized with distinct apical and basolateral membranes which are separated by tight junctions. The actin-rich tight junctions in conjunction with looser desmosomes maintain the continuity of the epithelium. Efficient regulation of the opening and closure of the tight junctions is a key event in the control of macromolecular movement across the epithelium.
Enterocytes have active transport mechanisms that drive the absorption of nutrients, electrolytes and water (occurs predominantly over the surface of the villus) and the secretion of electrolytes and water (occurs mainly in the crypts). The apical membrane has uniform microvilli measuring approximately 1 &mgr;m in height in which disaccharides and peptidases reside. This membrane also expresses receptor mediated transport systems (e.g., cobalamin) together with ion, monosaccharide, amino acid, peptide and fatty acid transporters. The basolateral membrane, in contrast, has smooth contours with no sugar and peptide hydrolayses. The Na
+
/K
+
ATPase pump is localized in the basolateral membrane and permits the vectorial movement of ions and solutes.
The epithelial cells lining the lumenal side of the GIT are a major barrier to drug delivery following oral administration. However, there are four recognized transport pathways which can be exploited to facilitate drug delivery and transport: the transcellular, paracellular, carrier-mediated and transcytotic transport pathways. The ability of a drug, such as a conventional drug, a peptide, a protein, a macromolecule or a nano or microparticulate system, to “interact” with one or more of these transport pathways may result in increased delivery of that drug from the GIT to the underlying circulation.
Certain drugs utilize transport systems for nutrients which are located in the apical cell membranes (carrier mediated route). Macromolecules may also be transported across the cells in endocytosed vesicles (transcytosis route). However, many drugs are transported across the intestinal epithelium by passive diffusion either through cells (transcellular route) or between cells (paracellular). Most orally administered drugs are absorbed by passive transport. Drugs which are lipophilic permeate the epithelium by the transcellular route whereas drugs that are hydrophilic are restricted to the paracellular route.
Paracellular pathways occupy less than 0.1% of the total surface area of the intestinal epithelium. Further, tight junctions, which form a continuous belt around the apical part of the cells, restrict permeation between the cells by creating a seal between adjacent cells. Thus, oral absorption of hydrophilic drugs such as peptides. can be severely restricted. Other barriers to absorption of drugs may include hydrolyzing enzymes in the lumen brush border or in the intestinal epithelial cells, the existence of the aqueous boundary layer on the surface of the epithelial membrane which may provide an additional diffusion barrier, the mucus layer associated with the aqueous boundary layer and the acid microclimate which creates a proton gradient across the apical membrane. Therefore, new strategies for delivering drugs across the GIT cell layers are needed, particularly for hydrophilic drugs including peptides and proteins, and macromolecular drugs.
Numerous potential absorption enhancers have been identified. For instance, medium chain glycerides have demonstrated the ability to enhance the absorption of hydrophilic drugs across the intestinal mucosa (
Pharm. Res
. Vol 11:1148-54 (1994)). However, the importance of chain length and/or composition is unclear and therefore their mechanism of action remains largely unknown. Sodium caprate has been reported to enhance intestinal and colonic drug absorption by the paracellular route (
Pharm. Res
. 10:857-864 (1993);
Pharm. Res
. 5:341-346 (1988)). U.S. Pat. No. 4,545,161 discloses a process for increasing the enteral absorbability of heparin and heparinoids by adding non-ionic surfactants such as those that can be prepared by reacting ethylene oxide with a fatty acid, a fatty alcohol, an alkylphenol or a sorbitan or glycerol fatty acid ester. U.S. Pat. No. 5,229,130 discloses a composition which increases the permeability of skin to a transdermally administered pharmacologically active agent formulated with one or more vegetable oils as skin permeation enhancers.
Often, however, the enhancement of, drug absorption correlates with damage to the intestinal wall. Consequently, limitations to the widespread use of GIT enhancers is frequently determined by their potential toxicities and side effects. Additionally and especially with respect to peptide, protein or macromolecular drugs, the “interaction” of the GIT enhancer with one of the transport pathways should be transient or reversible, such as a transient interaction with or opening of tight junctions so as to enhance transport via the paracellular route.
SUMMARY OF THE INVENTION
The present invention satisfies the above needs by providing a composition having a non-ionic vegetable oil GIT absorption enhancer for increasing the enteral absorbability of drugs, especially oral absorbability of hydrophilic and macromolecular drugs. The non-ionic vegetable oil GIT absorption enhancer is capable of enhancing the uptake of a drug from the gastrointestinal tract so as to allow therapeutically effective amounts of the drug to be transported across the GIT of an animal such as a human without significant toxic side effects.
The non-ionic vegetable oil GIT absorption enhancer of this invention is capable of transiently interacting with at least one transport pathway, preferably the paracellular or transcellular pathway so as to increase the transport of a drug between or through cells in the GIT. In one embodiment of this invention, the non-ionic vegetable oil GIT absorption enhancer of this invention is capable of opening tight junctions in the GIT, thereby increasing the transport of a drug from the GIT of an animal into the systemic system via the paracellular pathway. In another embodiment of this invention, the non-ionic vegetable oil GIT absorption enhancer of this invention is capable of increasing the transport of a drug via the transcellular pathway.
Preferred non-ionic vegetable oil GIT absorption enhancers according to th
Brayden David J.
Dee Jacqueline M.
Caesar Rivise Bernstein Cohen & Pokotilow Ltd.
Elan Corporation, plc
Spear James M.
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