Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Patent
1995-10-23
1998-06-16
Page, Thurman K.
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
424464, 424451, A61K 914
Patent
active
057666334
DESCRIPTION:
BRIEF SUMMARY
FIELD OF THE INVENTION
The present invention relates to compositions suitable for oral drug delivery, and in particular to compositions in which modified amino acids and modified amino acid derivatives are used as carriers for sensitive agents such as bioactive peptides and the like. The modified amino acids or derivatives can form non-covalent mixtures with biologically-active agents which are suitable for oral administration to animals. Methods for the preparation and for the administration of such compositions are also disclosed.
BACKGROUND OF THE INVENTION
Conventional means for delivering biologically-active agents, including, but not limited to, pharmaceutical and therapeutic agents, to animals are often severely limited by chemical barriers and physical barriers imposed by the body. Oral delivery of many biologically-active agents would be the route of choice if not for chemical and physico-chemical barriers such as the extreme and varying pH in the gastro-intestinal (GI) tract, exposure to powerful digestive enzymes, and the impermeability of gastro-intestinal membranes to the active agent. Among the numerous agents which are not typically suitable for oral administration are biologically-active peptides such as calcitonin and insulin. Examples of other compounds which are affected by these physico-chemical barriers are polysaccharides and particularly mucopolysaccharides, including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents are rapidly destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, or the like.
Prior methods for orally administering vulnerable pharmacological agents have relied on the co-administration of adjuvants (e.g., resorcinols and non-ionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to increase artificially the permeability of the intestinal walls; and on the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. See, for instance, U.S. Pat. No. 4,239,754; Patel et al. (1976) FEBS Letters Vol. 62, page 60; and Hashimoto et al. (1979) Endocrinol. Japan, Vol. 26, page 337. However, broad spectrum use of the aforementioned drug delivery systems is precluded for reasons including: (1) the need to use toxic amounts of adjuvants or inhibitors; (2) the lack of suitable low MW cargoes; (3) the poor stability and inadequate shelf life of the systems; (4) the difficulties in manufacturing the systems; (5) the failure of the systems to protect the active ingredient; and (6) the failure of the systems to promote absorption of the active agent.
More recently, microspheres of artificial polymers or proteinoids of mixed amino acids have been described for delivery of pharmaceuticals. For example, U.S. Pat. No. 4,925,673 describes drug containing microsphere constructs as well as methods for their preparation and use. These proteinoid microspheres are useful for delivery of a number of active agents.
There is still a need in the art for simple and inexpensive delivery systems which are easily prepared and which can deliver a broad range of biologically-active agents.
SUMMARY OF THE INVENTION
Compositions for orally delivering biologically-active agents incorporating modified amino acids, amino acid derivatives, peptides and peptide derivatives as carriers are provided. These compositions comprise ##STR1## wherein: R.sup.3 is C.sub.1 to C.sub.24 alkyl, C.sub.1 to C.sub.24 alkenyl, phenyl, naphthyl, (C.sub.1 to C.sub.10 alkyl)phenyl, (C.sub.1 to C.sub.10 alkenyl)phenyl, (C.sub.1 to C.sub.10 alkyl)naphthyl, (C.sub.1 to C.sub.10 alkenyl)naphthyl, phenyl(C.sub.1 to C.sub.10 alkyl), phenyl(C.sub.1 to C.sub.10 alkenyl), naphthyl(C.sub.1 to C.sub.10 alkyl) and naphthyl (C.sub.1 to C.sub.10 alkenyl); C.sub.4 alkenyl, C.sub.1 to C.sub.4 alkoxy, --OH, --SH, --CO.sub.2 R.sup.5.sub.1, cycloalkyl, cycloalkeny
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Barantsevitch Evgueni N.
Leone-Bay Andrea
Milstein Sam J.
Paton Duncan R.
Sarubbi Donald J.
Benston, Jr. William E.
Emisphere Technologies Inc.
Page Thurman K.
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