Modified amino acids for drug delivery

Details Modified amino acids for drug delivery Modified amino acids for drug delivery

1995-06-02

2001-01-30

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Particulate form

C424S451000, C424S464000, C514S553000, C514S561000

Reexamination Certificate

active

06180140

ABSTRACT:

The present invention relates to compositions suitable for drug delivery, and in particular to compositions in which modified amino acids or peptides are used as carriers for biologically active agents including, but not limited, to bioactive peptides and the like. The modified amino acids or peptides can form non-covalent mixtures or microspheres with biologically-active agents and 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 often are severely limited by chemical and physical barriers imposed by the body. Oral delivery of many biologically-active agents would be the route of choice if not for the presence of chemical and physico-chemical barriers such as extreme and Varying pH in the gastrointestinal (GI) tract, exposure to powerful digestive enzymes, and impermeability of gastrointestinal membranes to the active ingredient. Among the numerous pharmacological agents which are not suitable for oral administration are biologically-active peptides such as calcitonin and insulin. Examples of other compounds which are affected by the physico-chemical barriers are polysaccharides and mucopolysaccharides, including, but not limited to, heparin, heparinoids, antibiotics and other organic substrates. These agents are rapidly destroyed in the gastrointestinal tract by acid hydrolysis, enzymes, or the like.
Prior methods for orally administering vulnerable pharmacological agents have relied on 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 co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitor, diisopropylfluorophosphate (DFF) and trasylol) to avoid 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. The broader use of the aforementioned methods, however, as drug delivery systems are precluded for reasons which include: (1) the use of 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) difficulty in manufacturing; and (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 such microspheres as well as methods for their preparation and use. The proteinoid microspheres of the '673 patent are useful for encapsulating a number of active agents.
There is a need in the art for a simple and inexpensive delivery system which is easily prepared and which can deliver a broad range of biologically-active agents.
SUMMARY OF THE INVENTION
Compositions for delivering biologically-active agents incorporating modified amino acids as carriers are provided. The compositions comprise;
(A) at least one biologically active agent, and
(B) (a) at least one acylated amino acid;
(b) at least one peptide comprising at least one acylated amino acid; or
(c) a combination of (a) and (b);
wherein said acylated amino acid is acylated by
(i) a C
3
-C
10
cycloalkyl acylating agent, said agent optionally being substituted with C
1
-C
7
alkyl, C
2
-C
7
alkenyl, C
1
-C
7
alkoxy, hydroxy, phenyl, phenoxy, or —CO
2
R, wherein R is hydrogen, C
1
-C
4
alkyl or C
2
-C
4
alkenyl; or
(ii) a C
3
-C
10
cycloalkyl substituted C
1
-C
6
alkyl acylating agent.
In an alternative embodiment, these compositions are used in oral dosage unit forms. The compositions or oral dosage unit forms can be orally administered to animals.


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