Compounds and compositions for delivering active agents

Details Compounds and compositions for delivering active agents Compounds and compositions for delivering active agents

2002-02-21

2003-12-16

Page, Thurman K. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S455000, C424S400000, C424S491000

Reexamination Certificate

active

06663887

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds for delivering active agents, and particularly biologically active agents such as, for example, bioactive peptides and the like. These compounds are used as carriers to facilitate the delivery of a cargo to a target. The carriers are modified amino acids and are well suited to form non-covalent mixtures with biologically-active agents 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 active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which delivery occurs, the environment of the target for delivery, or the target itself.
Biologically active agents are particularly vulnerable to such barriers. For example in the delivery to animals of pharmacological and therapeutic agents, barriers are imposed by the body. Examples of physical barriers are the skin and various organ membranes that must be traversed before reaching a target. Chemical barriers include, but are not limited to, pH variations, lipid bi-layers, and degrading enzymes.
These barriers are of particular significance in the design of oral delivery systems. Oral delivery of many biologically active agents would be the route of choice for administration to animals if not for biological, chemical, and physical barriers such as varying pH in the gastro-intestinal (GI) tract, powerful digestive enzymes, and active agent impermeable gastro-intestinal membranes. Among the numerous agents which are not typically amenable to oral administration are biologically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopolysaccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents are rapidly rendered ineffective or are destroyed in the gastro-intestinal tract by acid hydrolysis, enzymes, or the like.
Earlier 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-hexadecylpolyethylene ether) to increase artificially the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (e.g., pancreatic trypsin inhibitors, diisopropylfluorophosphate (DFF) and trasylol) to inhibit enzymatic degradation.
Liposomes have also been described as drug delivery systems for insulin and heparin. See, for example, U.S. Pat. No. 4,239,754; Patel et al. (1976),
FEBS Letters,
Vol. 62, pg. 60; and Hashimoto et al. (1979),
Endocrinology Japan,
Vol. 26, pg. 337.
However, broad spectrum use of such drug delivery systems is precluded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) suitable low molecular weight cargos, i.e. active agents, are not available; (3) the systems exhibit poor stability and inadequate shelf life; (4) the systems are difficult to manufacture; (5) the systems fail to protect the active agent (cargo); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote absorption of the active agent.
More recently, microspheres of artificial polymers of mixed amino acids (proteinoids) have been used to deliver pharmaceuticals. For example, U.S. Pat. No. 4,925,673 describes drug-containing proteinoid microsphere carriers as well as methods for their preparation and use. These proteinoid microspheres are useful for the delivery of a number of active agents.
There is still a need in the art for simple, inexpensive delivery systems which are easily prepared and which can deliver a broad range of active agents.
SUMMARY OF THE INVENTION
Compounds useful in the delivery of active agents are provided. These compounds include
or salts thereof.
Compositions comprising at least one biologically active agent and at least one of the compounds above are also provided. Further contemplated by the present invention are dosage unit forms that include these compositions.
Also contemplated is a method for preparing these compositions which comprises mixing at least one active agent with at least one compound as described above, and optionally, a dosing vehicle.
In an alternative embodiment, these non-toxic compounds are orally administered to animals as part of a delivery system by blending or mixing the compounds with an active agent prior to administration.
DETAILED DESCRIPTION OF THE INVENTION
The specific compounds of the present invention or salts thereof such as, for example, sodium salts, may be used to deliver various active agents through various biological, chemical, and physical barriers. These compounds are particularly suited for delivering active agents which are subject to environmental degradation. The compounds and compositions of the subject invention are particularly useful for delivering or administering biologically-active agents to any animals such as birds; mammals, such as primates and particularly humans; and insects.
Other advantages of the present invention include the use of easy to prepare, inexpensive raw materials. The compositions and the formulation methods of the present invention are cost effective, simple to perform, and amenable to industrial scale up for commercial production.
Amino acids, poly amino acids, and peptides, in modified form, may be used to deliver active agents including, but not limited to, biologically active agents such as for example, pharmacological and therapeutic agents.
An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids.
Poly amino acids are either peptides or two or more amino acids linked by a bond formed by other groups which can be linked, e.g. an ester, anhydride, or an anhydride linkage. Special mention is made of non-naturally occurring poly amino acids and particularly non-naturally occurring hetero poly amino acids, i.e. polymers of mixed amino acids.
Peptides are two or more amino acids joined by a peptide bond. Peptides can vary in length from dipeptides with two amino acids to poly peptides with several hundred amino acids. See
Chambers Biological Dictionary,
editor Peter M. B. Walker, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of di-peptides, tri-peptides, tetra-peptides, and penta-peptides.
The terms modified amino acids, modified poly amino acids, and modified peptides are meant to include amino acids which have been modified or poly amino acids and peptides in which at least one amino acid has been modified by acylating at least one free amine group with an acylating agent which reacts with at least one of the free amine groups present.
Modified Amino Acids
Several of the compounds of the present invention are broadly represented by one of formula XLVI or XLVII below:
Ar—Y—(R
1
)
n
—OH  XLVI
wherein Ar is a substituted or unsubstituted phenyl or naphthyl;
Y is
or —SO
2
—, R
1
has the formula
wherein:
R
2
is C
1
to C
24
alkyl, C
1
to C
24
alkenyl, phenyl, naphthyl, (C
1
to C
10
alkyl) phenyl, (C
1
to C
10
alkenyl) phenyl, (C
1
to C
10
alkyl) naphthyl, (C
1
to C
10
alkenyl) naphthyl, phenyl (C
1
to C
10
alkyl), phenyl (C
1
to C
10
alkenyl), naphthyl (C
1
to C
10
alkyl), and naphthyl (C
1
to C
10
alkenyl);
R
2
is optionally substituted with C
1
to C
4
alkyl, C
1
to C
4
alkenyl, C
1
to C
4
alkoxy, —OH, —SH and —CO
2
R
4
or any combination thereof;
R
4
is hydrogen, C
1
to C
4
alkyl or C
1
to C
4
alkenyl;
R
2
is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof; and
R
3
is hydrogen, C
1
to C
4
alkyl or C
1
to C
4
alkenyl; or
wherein: R
5
is (i) C
3
-C
10
cycloalkyl, optionally substituted with C
1
-C
7
alkyl, C
2
-C
7
alkenyl, C
1
-C
7
alkoxy, hydroxy, phenyl, phenoxy or —CO
2
R
8
, wherein R
8
is hydrogen, C
1
-C
4
alkyl, or C
2
-C
4
alke

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