Compounds and compositions for delivering active agents

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

1997-03-18

2002-02-05

Spear, James M. (Department: 1615)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Capsules

C424S464000, C424S465000, C424S452000, C424S455000, C424S489000

Reexamination Certificate

active

06344213

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to compounds for delivering active agents, and particularly biologically or chemically 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 or chemically 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 or chemically 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 or chemically 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
Compositions which are useful in the delivery of active agents are provided. These compositions include at least one active agent, and eferably a biologically or chemically active agent, and at least one of the following compounds I-CXXIII, or salts thereof.
I

II

III

IV

V

VI

VII

VIII

IX

X

XI

XII

XIII

XIV

XV

XVI

XVII

XVIII

XIX

XX

XXI

XXII

XXIII

XXIV

XXV

XXVI

XXVII

XXVIII

XXIX

XXX

XXXI

XXXII

XXXIII

XXXIV

XXXV

XXXVI
A

Compound
n
m
X
XXXVII
0
0
4-Cl
XXXVIII
3
0
H
XXXIX
3
1
4-CH
3
XL
3
1
2-F
XLI
3
1
2-CH
3
XLII
3
0
3-CF
3
XLIII
3
4
H
XLIV
3
0
3-Cl
XLV
3
0
3-F
XLVI
3
0
3-CH
3
XLVII
0
0
2-CF
3
XLVIII
1
2
H
XLIX
3
2
2-F
L
3
0
3,4-OCH
2
O—
LI
3
0
2-COOH
LII
1
0
2-OH
LIII
3
0
2,6-dihydroxy
LIV
2
0
2-OH
LV
0
0
2,4-difluoro
LVI
2
0
2,6-dihydroxy
LVII
0
0
4-CF
3
LVIII
3
0
3-NMe
2
LIX
2
0
3-NMe
2
LX
3
0
2,6-dimethyl
LXI
3
0
2-NO
2
LXII
3
0
2-CF
3
LXIII
3
0
4-n-Pr
LXIV
3
0
2-NH
2
LXV
3
0
2-OCH
3
LXVI
3
0
3-NO
2
LXVII
3
0
3-NH
2
LXVIII
2
0
2-NO
2
LXIX
2
0
2-NH
2
LXX
3
0
2-OCF
3
LXXI
2
0
2-OCH
3
LXXII
2
0
2-OCF
3
B

Compound
n
X
LXXIII
3
4-CF
3
LXXIV
1
2-F
LXXV
1
4-CF
3
LXXVI
3
3,4-dimethoxy
LXXVII
0
3-OCH
3
LXXVIII
3
3-OCH
3
LXXIX
3
2,6-difluoro
LXXX
3
4-CH
3
LXXXI
1
4-OCH
3
LXXXII
2
2-F
LXXXIII
0
2-F
LXXXIV
2
4-OCH
3
LXXXV
0
2-OCH
3
LXXXVI
2
2-OCH
3
LXXXVII
0
4-CF
3
LXXXVIII
3
3-F
LXXXIX
3
2-OCH
3
C

Compound
n
m
X
XC
3
0
2-carboxycyclohexyl
XCI
3
3
cyclohexyl
XCII
3
0
2-adamantyl
XCIII
3
0
1-morpholino
D

Compound
m
XCIV
0
XCV
3
E

Compound
X
XCVI
OH
XCVII
═O
F

Compound
n
XCVIII
0
XCIX
2
C

CI

CII

CIII

CIV

CV

CVI

CVII

CVIII

CIX

CX
G

Compound
n
m
X
CXI
6
0
2-OH
CXII
7
3
H
CXIII
7
0
2-I
CXIV
7
0
2-Br
CXV
7
0
3-NO
2
CXVI
7
0
3-N(CH
3
)
2
CXVII
7
0
2-NO
2
CXVIII
7
0
4-NO
2
CXIX
9
0
2-OH
H

Compound
X
CXX
1-morpholino
CXXI
O-t-Butyl
CXXII
CH(CH
2
Ph)NC(O)O-t-Bu
CXXIII
2-hydroxyphenyl
It has been discovered that organic acid compounds, and their salts, having an aromatic amide group, having a hydroxy group substituted in the ortho position on the aromatic ring, and a lipophilic chain with from about 4 carbon atoms to about 20 atoms in the chain are useful as carriers for the delivery of active agents. In a preferred form the lipophilic chain can have from 5 to 20 carbon atoms.
Compositions comprising the carrier compounds discussed above and active agents have been shown effective in delivering active agents to selected biological systems. These compositions include at least one active agent which is preferably a biologically or chemically active agent, and at least one carrier compound having the formula:
2-HO—Ar—CONR
8
—R
7
—COOH
wherein Ar is a substituted or unsubstituted phenyl or naphthyl;
R
7
is selected from the group consisting of C
4
to C
20
alkyl, C
4
to C
20
alkenyl, phenyl, naphthyl, (C
1
to C
10
alkyl)phenyl, (C
1
to C
10
alkenyl)phenyl, (C
4
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
8
is selected from the group consisting of hydrogen, C
1
to C
4
alkyl, C
1
to C
4
alkenyl, hydroxy, and C
1
to C
4
alkoxy;
R
7
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
9
or any combination thereof;
R
9
is hydrogen, C
1
to C
4
alkyl or C
1
to C
4
alkenyl;
R
7
is optionally interrupted by oxygen, nitrogen, sulfur or any combination thereof;
with the proviso that the compounds are not substituted with an amino group in the position alpha to the acid group, or salts thereof.
The preferred R
7
groups are of C
4
to C
20
alkyl and C
4
to C
20
alkenyl. The most preferred R
7
groups are C
5
to C
20
alkyl and C
5
to C
20
alkenyl.
A preferred carrier compound can have the formula:
wherein R
7
is defined above.
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 vehi

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