Compounds and compositions for delivering active agents

Abstract

Carrier compounds and compositions therewith which are useful in the delivery of active agents are provided. Methods of administration and preparation are provided as well.

Description

FIELD OF THE INVENTION

[0001] The present invention relates to compounds for delivering active agents, and particularly biologically or chemically active agents. These compounds are used as carriers to facilitate the delivery of a cargo to a target. The carrier compounds are well suited to form non-covalent mixtures with biologically-active agents for oral administration to animals. Methods for the preparation administration of such compositions are also disclosed.

BACKGROUND OF THE INVENTION

[0002] 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.

[0003] For example in the delivery to animals of biologically active or chemically active 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.

[0004] 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 gastrointestinal 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.

[0005] 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.

[0006] 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.

[0007] 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.

[0008] 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.

[0009] 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

[0010] Compounds and compositions which are useful in the delivery of active agents are provided. These compositions include at least one active agent, preferably a biologically or chemically active agent, and at least one of the following compounds 1-193, or salts thereof.

1   1
6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid
2   2
8(2-aminobenzoylamino)caprylic acid
3   3
8(2-trifluoromethoxy)benzoylamino caprylic acid
4   4
N-(2-hydroxybenzoyl)isonipecotic acid
5   5
4-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid
6   6
4-(4-(pentafluorobenzoyl)aminophenyl)butyric acid
7   7
4-(4-(3-anisoyl)aminophenyl)butyric acid
8   8
8-(3-anisoyl)aminocaprylic acid
9   9
4-(4-(phenoxyacetyl)aminophenyl)butyric acid
10  10
4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid
11  11
8-(2-nitrobenzenesulfonyl)aminocaprylic acid
12  12
6-(4-(salivyloyl)aminophenyl)hexanoic acid
13  13
8-(2-methoxybenzoyl)amino caprylic acid
14  14
2-[4-Salicyloylamino)phenyl]ethyl methyl sulfone
15  15
1-Salicyloyl-2-succinyl hydrazide
16  16
3-(4-(2,5-dimethoxycinnamoyl)aminophenyl)propionic acid
17  17
4-(4-(2,5-dimethoxycinnamoyl)aminophenyl)butyric acid
18  18
1-salicyloyl-2-glutaryl hydrazide
19  19
Succinyl-4-aminosalicylic acid
20  20
8-(Phenoxyacetylamino)caprylic acid
21  21
8-(2-pyrazinecarbonyl)aminocaprylic acid
22  22
4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid
23  23
6-(4-(N-2-Nitrobenzoyl)aminophenyl)hexanoic acid
24  24
6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid
25  25
4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid
26  26
4(2-Nitrobenzoyl)aminophenylsuccinic acid
27  27
8-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid
28  28
29  29
8-(Benzylcarbonylamino)caprylic acid
30  30
8-(phenylcarbonylamino)caprylic acid
31  31
2-[4-(2-Methoxybenzoylamino)phenyl]ethyl H2PO4
32  32
1-salicyloyl-2-suberyl hydrazide
33  33
4-(4-benzyloxycarbonylaminophenyl)butyric acid
34  34
4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid
35  35
9-Salicyloylaminononanionic acid
36  36
4-(4-phenyloxycarbonylaminophenyl)butyric acid
37  37
3-(2-methoxybenzoylamino)-1-propanol
38  38
8-(2-Hydroxynicotinoyl)aminocaprylic acid
39  39
6-(2-methoxybenzoyl)amino nicotinic acid
40  40
salicyloylglycine
41  41
4-(1-(2-pyrimidyl)piperazinoyl)butyric acid
42  42
8-(chromone-3-carbonyl)aminocaprylic acid
43  43
8-(vinylbenzoyl)aminocaprylic acid
44  44
4-(4-(chromone-3-carbonyl)aminophenyl)butyric acid
45  45
8-cinnamoylaminocaprylic acid
46  46
6-(N-salicyloylamino)valeric acid
47  47
9-(2-hydroxybenzoamido)nonanic acid
48  48
N-(4-salicyloylamino)-6-caproic acid
49  49
4′-flavonic acid
50  50
11-cinnamoylaminoundecanoic acid
51  51
4-octanoylamino-3-hydroxybenzoic acid
52  52
(3Phenyl2,3-dihydroxypropanoyl)8aminocaprylic acid
53  53
8-[N-(3-coumarincarbonyl)]aminocaprylic acid
54  54
8-[N-(4-chlorobenzoyl)]aminocaprylic acid
55  55
8-[N-3-fluorobenzoyl)]aminocaprylic acid
56  56
8-(N-2,5-Dihydroxybenzoyl)amninocaprylic acid
57  57
8-(N-2,3-Dimethoxybenzoyl)aminocaprylic acid
58  58
8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid
59  59
8-(N-2,5-Dimethoxybenzoyl)aminocaprylic acid
60  60
8-(N-3,5-Diacetyloxybenzoyl)aminocaprylic acid
61  61
8-(N-4-Hydroxylbenzoyl)aminocaprylic acid (dimer)
62  62
8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid
63  63
10-(N-2-Methoxyanilino)sebalic acid
64  64
10(N-2-Methoxyanilino)sebacic acid
65  65
2-Methoxybenzeneaminodecanoic acid
66  66
8-(N-benzoyl)aminocaprylic acid
67  67
8-(N-2-Hydroxy-4-methoxybenzoyl)aminocaprylic acid
68  68
8-[N-(4-fluorobenzoyl)]aminocaprylic acid
69  69
8-[N-(3-bromobenzoyl)]aminocaprylic acid
70  70
8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid
71  71
8-[N-(4-bromobenzoyl)]aminocaprylic acid
72  72
8-[N-(4-iodobenzoyl)]aminopcaprylic acid
73  73
4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid
74  74
4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid
75  75
4-{4-(2,4-dimethoxylbenzoyl)aminophenyl)butyric acid
76  76
4-(o-anisoyl)aminophenylacetic acid
77  77
3-[4-(2,4-dimethoxybenzoyl)aminophenyl]propionic acid
78  78
4-{4-[N-(4-iodobenzoyl)]aminophenyl}butyric acid
79  79
3-[4-(2,3-dimethoxybenzoyl)aminophenyl]propionic acid
80  80
4{4-[N-2-bromobenzoyl)]aminophenyl}butyric acid
81  81
4{4-[N-3-bromobenzoyl)aminophenyl)}butyric acid
82  82
8-(N-3,5-Dihydroxybenzoyl)aminocaprylic acid
83  83
8-(N-3,5-Dimethoxy 4-hydroxybenzoyl)aminocaprylic acid
84  84
8-(N-2-6-Dimethoxybenzoyl)amino caprylic acid
85  85
4-{4-[N-(4-bromobenzoyl)aminophenyl]}butyric acid
86  86
8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid
87  87
8-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid
88  88
8-(N-2-Hydroxy6-methoxybenzoyl)aminocaprylic acid
89  89
8-(5-chloro-o-anisoyl)aminocaprylic acid
90  90
4-(4-(2,3-dimethoxybenzoyl)aminophenyl)butyric acid
91  91
4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid
92  92
4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid
93  93
8-(4-chloro-o-anisoyl)aminocaprylic acid
94  94
3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid
95  95
4-{N-[4-(3-iodobenzoyl)aminophenyl]}butyric acid
96  96
7-cinnamoylaminoheptanoic acid
97  97
8-N-(3-iodobenzoyl)aminocaprylic acid
98  98
8-N-(4-methoxy-3-nitrobenzoyl)aminocaprylic acid
99  99
8-N-(2-methoxy-4-nitrobenzoyl)aminocaprylic acid
100 100
4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid
101 101
4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid
102 102
8-(N-2-hydroxy-5-bromobenzoyl)aminocaprylic acid
103 103
3-Indolebutyric acid
104 104
105 105
106 106
107 107
4-(4-(2,6-dimthoxybenzoyl)aminophenylbutyric acid
108 108
4-[4-N-(4-methoxy-3-nitrobenzoyl)aminophenyl]butyric acid
109 109
8-(N-2-hydroxy-5-chlorobenzoyl)aminocaprylic acid
110 110
8-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid
111 111
8-(3-hydroxy-2-naphthoyl)aminocaprylic acid
112 112
8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid
113 113
4-[-N-(2-hydroxy-4-bromobenzoyl)aminophenyl]butyric acid
114 114
8-(N-2,3-Dihydroxybenzoyl)aminocaprylic acid
115 115
8-(N-3-methylsalicyloyl)aminocaprylic acid
116 116
8-(N-5-methylsalicyloyl)aminocaprylic acid
117 117
9-(cinnamoylamino)nonanionic acid
118 118
4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid
119 119
4-{-[N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid
120 120
N-2-nitrophenyl-N′-(8-octanoic acid)urea
121 121
N-(2-methoxy-5-nitrophenyl)sebacoyl amide acid
122 122
8-[N-(2-acetoxy-3,5-dichlorobenzoyl)]aminocaprylic acid
123 123
8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid
124 124
8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid
125 125
126 126
8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid
127 127
4-(4-Salicyloylaminophenyl)-4-oxobutyric acid
128 128
12-cinnamoyldodecanoic acid
129 129
4-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}butyric acid
130 130
8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid
131 131
8-(2-chloronicotinoyl)aminocaprylic acid
132 132
8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid
133 133
4-(4-phthalimidophenyl)butyric acid
134 134
4-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}propanoic acid
135 135
3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid
136 136
8-(N-2-hydroxy-3,5-diiodobenzoyl)aminocaprylic acid
137 137
8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid
138 138
8-(2-(1,2-dihydroisoindole-1-one)octanoic acid
139 139
8-(N-1-hydroxy-2-naphthoyl)aminocaprylic acid
140 140
8-(phthalimido)caprylic acid
141 141
10(4-chloro-2-hydroxyanilino)sebaic acid monoamide
142 142
6-(anisoyl)aminocaproic acid
143 143
4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid
144 144
11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid
145 145
Bis(N-2carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide
146 146
2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol
147 147
2-[2-N-(4-chlorobenzoyl)aminoethoxy]ethanol
148 148
4-(2-methoxybenzoyl)amino 3-carboxysulfoxide
149 149
4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone
150 150
4-(4-(3-hydroxyphthalimido)phenyl)butyric acid
151 151
2-[2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol
152 152
2-[2-N-(3-chlorobenzoyl)aminoethoxy)]ethanol
153 153
Bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxalyl diamide
154 154
trans-4-(2-aminobenzamidomethyl)cyclohexamecarboxylic acid
155 155
11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid
156 156
2-[N-(2-bromobenzoyl)aminoethoxy]ethanol
157 157
7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid
158 158
N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid
159 159
trans-4-(N-salicyloylaminomethyl)cyclohexane carboxylic acid
160 160
N-[3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid
161 161
12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid
162 162
N-(2-hydroxy-4-carboxy)-6-heptenamide
163 163
N-(2-bromobenzoyl)morpholine
164 164
8-N-cyclohexanoylaminocaprylic acid
165 165
2-[N-(2-iodobenzoyl)aminoethoxy]ethanol
166 166
5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid
167 167
8-(2-hydroxyphenoxy)-aminocaprylic acid
168 168
N-Salicyloyl-5-(3-aminophenyl)valeric acid
169 169
4-(4-(2-ethoxybenzoyl)aminophenyl)butyric acid
170 170
9-[2-(3-hydroxy)pyridylaminocarbonyl]nonanic acid
171 171
7-(2-hydroxyphenoxyacetyl)aminocaprylic acid
172 172
2-[N-(2-hydroxybenzoylamino)ethoxy]ethanol
173 173
4-[N-(3,5-dichloro-2-hydroxybenzoyl)]aminophenylacetic acid
174 174
8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid
175 175
N-salicyloyl-5-(4-aminophenyl)valeric acid
176 176
9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid
177 177
5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid
178 178
8-(pentafluorobenzoyl)aminocaprylic acid
179 179
3-(3-(salicyloyl)aminophenyl)propionic acid
180 180
8-(2-ethoxybenzoyl)aminocaprylic acid
181 181
4-(4-(2-Diethylaminobenzoic)aminophenyl)butyric acid
182 182
8-(3-Phenoxy)propionylamino)caprylic acid
183 183
4-(Salicyloyl)aminophenylethyltetrazole
184 184
8(-(4(N-Salicyloyl-4aminophenyl)butyric)aminocaprylic acid
185 185
4-(4-(N-(2-Fluorocinnamoyl))aminophenyl)butyric
186 186
4-(4-(N-8(N-Salicyloyl)aminocaprylic)aminophenyl)butyric acid
187 187
8-(p-anisoyl)aminocaprylic acid
188 188
8-(4-Hydroxybenzoyl)aminocaprylic acid
189 189
8-(3-Hydroxybenzoyl)aminocaprylic acid
190 190
8-(3,4,5-Trimethoxybenzoyl)aminocaprylic acid
191 191
8-(N-4-Methylsalicyloyl)aminocaprillic acid [sic]
192 192
N-10-(2-hydroxy-5-nitroanilino)decanoic acid
193 193
4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid

[0011] Compositions comprising the carrier compounds discussed above and active agents are effective in delivering active agents to selected biological systems.

DETAILED DESCRIPTION OF THE INVENTION

[0012] The specific compositions of the present invention include an active agent and a carrier. These compositions may be used to deliver various active agents through various biological, chemical, and physical barriers and are particularly suited for delivering active agents which are subject to environmental degradation. The compositions of the subject invention are particularly useful for delivering or administering biologically or chemically active agents to any animals such as birds including, but not limited to, chickens; mammals, such as primates and particularly humans; and insects.

[0013] 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.

[0014] Subcutaneous, sublingual, and intranasal coadministration of an active agent, such as, for example, recombinant human growth hormone (rhGH); salmon calcitonin; heparin, including, but not limited to, low molecular weight heparin; parathyroid hormone; and compounds in compositions as described herein result in an increased bioavailability of the active agent compared to administration of the active agent alone.

[0015] Active Agents

[0016] Active agents suitable for use in the present invention include biologically or chemically active agents, chemically active agents, including, but not limited to, fragrances, as well as other active agents such as, for example, cosmetics.

[0017] Biologically or chemically active agents include, but are not limited to, pesticides, pharmacological agents, and therapeutic agents. For example, biologically or chemically active agents suitable for use in the present invention include, but are not limited to, peptides, and particularly small peptides; hormones, and particularly hormones which by themselves do not or only a fraction of the administered dose passes through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro-intestinal tract; polysaccharides, and particularly mixtures of muco-polysaccharides; carbohydrates; lipids; or any combination thereof. Further examples include, but are not limited to, human growth hormones; bovine growth hormones; growth releasing hormones; interferons; interleukin-1; insulin; heparin, and particularly low molecular weightheparin; calcitonin; erythropoietin; atrial natureticfactor; antigens; monoclonal antibodies; somatostatin; adrenocorticotropin, gonadotropin releasing hormone; oxytocin; vasopressin; cromolyn sodium (sodium or disodium chromoglycate); vancomycin; desferrioxamine (DFO); parathyroid hormone anti-microbials, including, but not limited to anti-fungal agents; or any combination thereof.

[0018] Carriers

[0019] Although compounds 1-193 above have been found to act as carriers for the oral delivery of biologically or chemically active agents, special mention is made of compounds 9, 35, 64, 67, 79, 102, 109, 111, 117, 122, 136, and 141, above.

[0020] Properties of compounds 1-193 are listed in Table 1, below.

TABLE 1
Carrier Properties
	Anal. Calculated For	Found	Melting
Compound	C	H	N	S	C	H	N	S	Point (° C.)
1	48.8	4.70	4.40		48.81	4.64	4.39
2	64.73	7.97	10.06		64.54	7.81	10.19
3	55.33	5.80	4.03		55.40	5.79	3.96		69-71
4	62.64	6.06	5.62		62.75	6.08	5.51		151-154
5	65.16	6.11	13.40		65.29	6.03	13.29		144-145
6	54.70	3.24	3.75		54.29	3.24	3.54		165-169
7	69.00	6.11	4.47		69.09	6.24	4.43		126-129
8	65.51	7.90	4.78		65.60	8.25	4.83		89-90
9	68.99	6.11	4.47		69.01	6.08	4.47		104-107
10	52.74	4.42	7.69		52.91	4.45	7.49		142-145
11	48.83	5.85	8.14		48.95	5.89	8.02		120-122
12	69.71	6.47	4.28		69.56	6.47	4.38		144-146
13	65.51	7.90	4.77		65.23	7.88	4.72		72.5-74.5
14	60.17	5.36	4.39	10.04	60.09	5.36	4.35	9.99	155-156
15	52.38	4.79	11.11		52.45	4.94	11.08		220-222
16	67.60	5.95	3.94		67.34	6.01	3.91		219-222
17	68.09	6.53	3.78		67.77	6.24	3.81		130-133
18	54.13	5.30	10.52		54.12	5.24	10.54		192.5-195.5
19	55.26	4.21	7.16		54.48	4.32	6.86		>280 dec
20	65.51	7.90	4.77		65.52	7.90	4.77		75-80
21	58.85	7.21	15.84		58.86	7.16	15.69		120-122
22	63.15	5.30	14.73		63.30	5.43	14.18		197-201
23	64.04	5.66	7.86		64.17	5.67	7.75		188-190
24	69.91	6.88	8.46		69.98	6.79	8.58		131-134
25	58.36	4.56	12.76		58.20	4.63	12.61		138-141
26	56.98	3.94	7.82		56.39	3.92	7.74		221-223
27	55.33	5.80	4.03		55.47	6.10	4.04		70-72
28
29	65.74	7.58	4.79		65.51	7.89	4.78		52-55
30	64.50	7.57	5.02		64.07	7.81	5.40		70-74
31	54.70	5.17	3.99		54.50	4.99	3.95		173-174
32	58.63	5.94	9.12		58.73	6.20	10.34		125-129
33	69.00	6.10	4.47		69.18	6.08	4.54		100-102
34	63.99	5.37	9.33		63.46	5.35	9.06		218-221 C.
35	65.5	7.90	4.78		65.37	8.00	4.66		96-97 C.
36	68.22	5.72	4.68		67.88	5.65	4.55		134-137
37	63.14	7.23	6.69		63.15	7.29	6.58		53.5-56
38	60.00	7.14	10.00		59.78	7.31	9.94		135-138
39	61.67	4.41	10.29		61.69	4.41	10.12		>225
40	55.39	4.65	7.18		55.52	4.77	7.30		162.5-166
41	56.10	6.52	20.14		55.66	6.71	19.69		129-131
42	65.24	6.39	4.23		65.42	6.16	3.78		130-133.5
43	70.59	7.96	4.84		70.35	8.13	4.79		111-113
44	68.37	4.88	3.99		68.61	4.89	3.79		120-123
45	70.59	7.96	4.84		70.48	7.97	4.71		108-110
46	60.75	6.37	5.90		60.97	6.18	5.80		100.5-103
47	64.50	7.57	5.02		64.42	7.58	5.01		97-100
48	64.86	5.98	7.56		64.50	6.01	7.52		165-169
49	72.18	3.76	0.00		72.13	3.84	0.00		>225
50	72.51	8.76	4.23		72.39	8.84	4.12		120-122
51	64.50	7.58	5.01		64.75	7.65	4.69		200.5-204
52		7.74	4.33			7.82	4.30		88-89
53	65.24	6.39	4.23		65.15	6.46	4.23		93-97
54	60.49	6.77	4.70		60.54	6.76	4.65		114-116
55	64.04	7.17	4.98		63.90	7.11	4.93		105-106
56	61.00	7.17	4.74		60.49	6.92	4.65		146-148
57	63.14	7.79	4.33		63.22	7.82	4.36		59-61
58	63.14	7.79	4.33		63.17	7.86	4.26		102-104
59	63.14	7.79	4.33		63.35	7.68	4.20		89-90
60	60.15	6.64	3.69		59.84	6.66	3.64		112-113
61	65.53	8.85	6.65		65.34	8.73	6.67		89-92
62	61.00	7.17	4.74		60.94	7.12	4.49		104-108
63	66.43	8.20	4.56		66.29	8.23	4.36		77-78
64	65.51	7.90	4.77		65.52	8.06	4.54		97-98
65	69.59	9.28	4.77		69.64	9.35	4.86		62-65
66	68.41	8.04	5.32		68.41	8.06	5.28		88-89
67	62.12	7.49	4.53		61.94	7.45	4.43		98-99
68	64.04	7.17	4.98		64.07	7.16	4.95		106-107
69	52.64	5.89	4.09		52.63	5.85	4.03		109-110
70	63.15	7.74	4.33		63.26	7.90	4.14		97-100
71	52.64	5.89	4.09		52.67	5.99	3.97		114-115
72	46.31	5.18	3.61		46.25	4.86	3.52		143-144
73	49.89	3.94	3.42		49.92	3.85	3.39		170-171
74	72.19	5.48	4.01		71.51	5.33	3.75		180
75	66.46	6.16	4.08		66.47	6.26	4.06		168.5-171
76	67.37	5.26	4.91		67.31	5.25	5.07		130-133
77	65.65	5.78	4.26		65.49	6.04	4.26		179-183
78	49.89	3.94	3.42		49.8	3.71	3.29		237-238
79	65.65	5.78	4.26		65.21	6.05	4.24		156-158
80	56.38	4.45	3.87		56.4	4.21	3.91		130-131
81	56.38	4.45	3.87		56.46	4.5	3.84		197-198
82	56.6	7.49	4.4		56.3	7.49	4.14		58-62
83	57.03	8.2	3.91		57.17	7.8	3.7		138-140
84	57.58	7.11	3.95		57.52	7.7	3.94
85	56.38	4.45	3.87		56.31	4.25	3.64		230-231
86	57.42	6.42	4.46		57.14	6.45	4.2		116-117
87	61	7.17	4.74		61.18	7.05	4.65		108-109
88	62.12	7.49	4.53		62.34	7.21	4.39		107-109
89	58.63	6.76	4.27		58.53	6.81	4.2		117-118
90	66.46	6.16	4.08		66.18	6.15	3.84		100-104
91	62.16	5.21	4.03		61.93	4.97	3.86		183-185
92	62.16	5.21	4.03		62.2	5.14	3.98		167-170
93	58.63	6.76	4.27		58.64	6.83	4.19		106-108
94	65.65	5.81	4.25		65.56	5.64	4.2		153-156
95	49.89	3.94	3.42		49.9	3.81	3.18		216-217
96	69.82	7.64	5.09		69.91	7.66	5.02		129-131
97	46.31	5.18	3.61		46.54	4.95	3.64		122-123
98	56.8	6.55	8.28		56.69	6.67	8.1
99	56.8	6.55	8.28		57.37	6.57	8.33		117:118
100	60.33	5.06	7.82		59.98	4.97	7.67		207-209
101	66.46	6.16	4.08		66.37	6.32	3.96		126-128
102	50.29	5.63	3.91		50.14	5.7	3.76		129-131
103	70.93	5.95	6.89		70.94	6.44	6.89
104	65.84	6.14	8.53		65.94	6.19	8.54		228-231
105	64.96	5.77	8.91		64.89	5.82	8.82
106	66.65	6.48	8.18		66.39	6.49	8.05		140-142
107	66.47	6.12	4.07		66.5	6.26	4.08		140-142
108	60.33	5.06	7.82		60.32	4.99	7.78		150-151
109	57.41	6.42	4.46		57.07	6.44	4.39		121-123
110	44.46	4.97	3.46						133-135
111	69.28	7.03	4.25		68.86	7.07	4.11		147-149
112	55.55	6.22	8.64		55.27	5.99	8.5		120-121
113	53.99	4.26	3.7		53.98	4.25	3.63		210 decom
114	57.49	7.39	4.74		57.72	7.57	4.43		80-83
115	65.5	7.9	4.77		64.97	7.79	4.75		90-92
116	65.5	7.9	4.77		65.11	8.03	4.71		125-127
117	71.26	8.3	4.2		70.6	7.89	4.83		94-96
118	56.29	4.17	7.72		56.23	4.01	7.6		173-175
119	47.89	3.81	3.29		47.52	3.71	3.16		236-237
120	55.7	6.55	13		55.71	6.58	13.05		123-5
121	57.98	5.81	7.95		57.9	7.11	7.82		131-133
122	51.74	5.5	4.02		51.41	5.43	3.61		118-119.5
123	41.22	4.38	3.2		41.45	4.36	2.94		143-144.5
124	57.06	6.06	4.44		57.02	6.12	4.35		57-58
125	61.18	4.83	4.2		60.71	4.76	3.89		214 decom
126	55.55	6.22	8.64		55.4	6.24	8.53		150-151
127	65.17	4.83	4.47		65.27	4.87	4.48		208-209
128	73.03	8.99	4.06		72.92	9.36	4.1		99-101
129	72.25	5.44	4		72.14	5.24	4.01		216-217
130	52.56	5.58	8.17		52.66	5.44	8.21		96-100
131	56.28	6.41	9.38		56.32	6.42	9.28		98-100
132	52.56	5.58	8.17		52.46	5.65	7.86		150-153
133	69.89	4.89	4.53		69.64	5	4.54		136-9
134	71.68	5.2	4.2		71.24	5.1	4.13		251-253
135	65.64	5.78	4.25		65.3	5.91	4.04		79-83
136	33.92	3.61	2.64		34.48	3.84	2.48		164-165
137	57.06	6.06	4.44		57.09	6.17	4.45		88-89
138	69.79	7.69	5.09		69.68	7.78	5.08		102-3
139	69.28	7.04	4.25		68.99	7	4.1		107-108
140	66.42	6.62	4.84		66.2	6.49	4.81		88-9
141	58.62	6.76	4.27		58.66	6.93	4.18		134-135
142	63.38	7.21	5.28		63.22	7.28	5.24		71-73
143	56.29	4.17	7.72		56.19	4.04	7.65		156-160
144	71.13	7.88	3.77		70.39	7.91	3.64		95-97
145	58.44	6.06	8.02		58.25	6.38	7.84		165-8
146	54.22	5.79	5.75		54.26	5.65	5.69		77-78.5
147	54.22	5.79	5.75		54.21	5.85	5.61		80-81
148	58.78	4.93	40.3		58.64	4.89	3.97		172-173
149	56.19	4.72	3.85		56.31	4.67	3.86		177
150	66.46	4.65	4.31		66.41	4.56	4.23		158-160
151	58.61	7.24	5.69		58.79	7.35	5.66
152	54.22	5.79	5.75		54.21	5.72	5.62		54-55
153	60.85	4.25	7.89		60.27	4.37	7.89		>260
154	62.5	7.3	10.14		64.77	7.27	9.9		187-190
155	55.4	6.5	3.6		55.56	6.51	3.5		114-116
156	45.85	4.9	4.86		46.06	4.78	4.71		67-68
156	48.8	4.7	4.4		48.81	4.64	4.39		144-146
157	50.3	5.1	4.2		50.25	5.12	3.99		141-143
158	55.5	4.1	3.8		55.55	3.88	3.75		190-192
159	64.97	6.9	5.05		64.7	6.82	5.02		171-174
160	54.3	3.7	4		54.31	3.58	3.83		222-224
161	56.4	6.7	3.5		56.69	6.98	3.11		76-78
162	63.63	6.47	5.3		64.76	6.84	4.74		188-191
163	48.91	4.48	5.19		48.89	4.31	5.10		88.5-90
164	66.66	10.04	5.18		66.69	10.77	5.16		67.5-70.5
165	39.42	4.21	4.18		39.19	4.35	3.88		oil
166	53.05	5.19	5.16		53.06	5.03	4.86		151-152
167	65.53	7.85	4.78		65.4	7.84	4.57		85-89
168	68.99	6.11	4.47		68.62	5.87	4.49		162-6
169	69.71	6.47	4.28		69.67	6.58	4.50		132.5-135
170	61.21	7.53	9.52		61.21	7.68	9.46		134-135
171	62.14	7.44	4.53		61.96	7.52	4.57		101-104
172	58.63	6.71	6.22		58.15	6.83	6.04
173	52.96	3.26	4.12		52.96	3.28	4.02		225-227
174	57.42	6.42	4.46		57.3	6.38	4.39		119-120
175	68.99	6.11	4.47		68.84	6.08	4.51		131-4
176	66.43	8.2	4.56		66.42	8.16	4.51		109-110
177	62.14	6.82	5.57		61.96	6.66	5.52		127-128
178	51.00	4.56	3.97		51.09	4.61	3.93
179	67.36	5.30	4.90		67.26	5.24	4.91		185-186
180	66.43	8.20	4.56		66.32	8.60	5.12		51.5-55
181	69.92	6.79	8.58		67.02	6.93	8.20		81-84
182	66.46	8.14	4.56		66.43	8.34	4.47		82-84
183	62.13	4.89	22.64		62.05	4.88	22.45		271-272
184	68.16	7.32	6.36		67.73	7.44	6.70		114-117
185	71.30	5.98	5.73		71.10	5.97	5.74		146-149
186	68.16	7.32	6.36		67.94	7.31	6.41		105-108
187	65.51	7.90	4.77		65.35	7.63	4.59		102-103
188	64.50	7.58	5.01		64.19	7.69	4.83		133-134
189	64.5	7.58	5.01		64.5	7.57	4.90		116-118
190	61.15	7.71	3.97		61.27	7.79	4.08		124-127
191	65.5	7.9	4.77		65.32	7.94	4.7		114-115
192	56.77	6.51	8.28		56.83	6.76	8.21		141-143
193	60.29	4.74	8.79		60.17	4.58	8.74		202-205
194	48.8	4.7	4.4		48.81	4.64	4.39		144-146

[0021] These carrier compounds or poly amino acids, and peptides, including the amino acids, may be used to deliver active agents including, but not limited to, biologically or chemically active agents such as for example, pharmacological and therapeutic agents.

[0022] An amino acid is any carboxylic acid having at least one free amine group and includes naturally occurring and synthetic amino acids.

[0023] 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.

[0024] 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.

[0025] Salts such as, for example, sodium salt of these carrier compounds can be used as well.

[0026] Many of the compounds described herein are derived from amino acids.

[0027] Many of the compounds of the present invention can be readily prepared from amino acids including, but not limited to, aminocaprylic acid, butyrylhydroxaminic acid, aminophenylbutyric acid, aminophenylhexanoic acid, aminophenylpropionic acid, amino salicylic acid, aminophenylsuccinic acid, aminononanic acid, aminonicotinic acid, amino valenic acid, aminophenylacetic acid, aminocaproic acid, aminoundecanoic acid, aminoheptanoic acid, aminohydroxybenzoic acid, and aminodecanoic acid by methods within the skill of those in the art based upon the present disclosure and the methods described in U.S. patent application Ser. No. 60/017,902, filed Mar. 29, 1996; Ser. No. 08/414,654, filed Mar. 31, 1995; Ser. No. 08/335,148, filed Oct. 25, 1994; and No. 60/003,111, filed Sep. 1, 1995.

[0028] For example, these compounds may be prepared by reacting the single acid with the appropriate agent which reacts with free amino moiety present in the amino acids to form amides. Protecting groups may be used to avoid unwanted side reactions as would be known to those skilled in the art.

[0029] The carrier compound may be purified by recrystallization or by fractionation on solid column supports. Suitable recrystallization solvent systems include acetonitrile, methanol and tetrahydrofuran. Fractionation may be performed on a suitable solid column supports such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase column supports using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. When anion exchange chromatography is performed, preferably a subsequent 0-500 mM sodium chloride gradient is employed.

[0030] Delivery Systems

[0031] The compositions of the present invention may include one or more active agents.

[0032] In one embodiment, compounds or salts of compounds 1-193 or poly amino acids or peptides that include at least one of these compounds or salts may be used directly as a delivery carrier by simply mixing one or more compound or salt, poly amino acid or peptide with the active agent prior to administration.

[0033] The administration mixtures are prepared by mixing an aqueous solution of the carrier with an aqueous solution of the active ingredient, just prior to administration. Alternatively, the carrier and the biologically or chemically active ingredient can be admixed during the manufacturing process. The solutions may optionally contain additives such as phosphate buffer salts, citric acid, acetic acid, gelatin, and gum acacia.

[0034] Stabilizing additives may be incorporated into the carrier solution. With some drugs, the presence of such additives promotes the stability and dispersibility of the agent in solution.

[0035] The stabilizing additives may be employed at a concentration ranging between about 0.1 and 5% (W/V), preferably about 0.5% (W/V). Suitable, but non-limiting, examples of stabilizing additives include gum acacia, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are gum acacia, gelatin and methyl cellulose.

[0036] The amount of active agent is an amount effective to accomplish the purpose of the particular active agent. The amount in the composition typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than a pharmacologically, biologically, therapeutically, or chemically effective amount when the composition is used in a dosage unit form, such as a capsule, a tablet or a liquid, because the dosage unit form may contain a multiplicity of carrier/biologically or chemically active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount. The total effective amounts can then be administered in cumulative units containing, in total, pharmacologically, biologically, therapeutically or chemically active amounts of biologically or pharmacologically active agent.

[0037] The total amount of active agent, and particularly biologically or chemically active agent, to be used can be determined by those skilled in the art. However, it has surprisingly been found that with some biologically or chemically active agents, the use of the presently disclosed carriers provides extremely efficient delivery, particularly in oral, intranasal, sublingual, intraduodenal, or subcutaneous systems. Therefore, lower amounts of biologically or chemically active agent than those used in prior dosage unit forms or delivery systems can be administered to the subject, while still achieving the same blood levels and therapeutic effects.

[0038] The amount of carrier in the present composition is a delivery effective amount and can be determined for any particular carrier or biologically or chemically active agent by methods known to those skilled in the art.

[0039] Dosage unit forms can also include any of excipients; diluents; disintegrants; lubricants; plasticizers; colorants; and dosing vehicles, including, but not limited to water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.

[0040] Administration of the present compositions or dosage unit forms preferably is oral or by intraduodenal injection.

[0041] The delivery compositions of the present invention may also include one or more enzyme inhibitors. Such enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof. These compounds have the formulas below: 194

[0042] Derivatives of these compounds are disclosed in U.S. Pat. No. 5,206,384. Actinonin derivatives have the formula: 195

[0043] wherein R5 is sulfoxymethyl or carboxyl or a substituted carboxy group selected from carboxamide, hydroxyaminocarbonyl and alkoxycarbonyl groups; and R6 is hydroxyl, alkoxy, hydroxyamino or sulfoxyamino group. Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.

[0044] The compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals such as birds; mammals, such as primates and particularly humans; and insects. The system is particularly advantageous for delivering chemically or biologically or chemically active agents which would otherwise be destroyed or rendered less effective by conditions encountered before the active agent its target zone (i.e. the area in which the active agent of the delivery composition are to be released) and within the body of the animal to which they are administered. Particularly, the compounds and compositions of the present invention are useful in orally administering active agents, especially those which are not ordinarily orally deliverable.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0045] The following examples illustrate the invention without limitation. All parts are given by weight unless otherwise indicated.

EXAMPLE 1

Carrier Preparation

[0046] General Preparations of Carriers.

[0047] The following procedures were used to prepare the compounds described herein. Many of the compounds were prepared by reaction of the appropriate amino acid with the appropriate acid chloride. The preparation of compound 79 is given as a representative example of the compounds prepared in this manner.

[0048] Preparation of Compound 79. Method A.

[0049] A 1 L round bottom flask fitted with a magnetic stirrer was charged with 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) and 2 M aqueous sodium hydroxide (300 mL). 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) was added portionwise over 1 h to the stirred solution. After the addition, the reaction was stirred for 2.5 h at ambient temperature, and the pH of the solution was kept at ca 10 by the addition of 10 M sodium hydroxide. The solution was then acidified with 1 M hydrochloric acid (3×100 mL), water (100 mL), and air dried. It was redissolved in boiling acetone (ca 500 mL), decolorized with activated charcoal (3 g), and filtered. Water (1.5 L) was added to the filtrate to induce the formation of a brown oil. The brown oil solidified upon stirring at room temperature for 10 min. The crude solid was collected by filtration and recrystallized from 70% methanol-water (v/v) to afford compound 79 as a tan solid (39.5) g, 50%).

[0050] Compounds 1, 5, 30, 31, 33, 36, 53-66, 68, 69, 71-74, 78, 80-88, 95, 97-99, 102, 108-110, 112-115, 119, 121-126, 136, 137, 139, 141, 144, 146, 147, 151, 152, 155-158, 160, 161, 163, 165, 166, 170, 172-174, 176, 177, 184-186, 188, 189, 191 and 192 were also prepared by this process.

[0051] Preparation of Compound 79. Method B.

[0052] A 2 L three-neck round bottom flask was fitted with a magnetic stirrer and two addition funnels under an argon atmosphere. A suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in ethyl acetate (700 mL) was added to the flask. A solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv.) in ethyl acetate (250 mL) was charged to one of the addition funnels and added dropwise over 1 h. Triethylamine (28.20 g, 0.28 moles, 1.00 equiv.) was subsequently charged to the second funnel and added dropwise over 15 min. The reaction was stirred at ambient temperature for 3 h, and the solvent was evaporated in vacuo giving a residual brown oil. Water (600 mL) was added to the residue followed by sodium hydroxide (2 M, 500 mL), and the mixture was stirred at ambient temperature for 3 hours. The resultant brown solution was acidified with 2 M hydrochloric acid (ca 1 L). After cooling the mixture in an ice bath for 1 h, a yellow solid formed and was collected by filtration. The solid was washed with water (3×1.5 L) and recrystallized from 50% ethanol-water (v/v) to give compound 79 as a tan solid (59.2 g, 68%).

[0053] Compounds 18, 32, 37, 41, 168, 175, and 183 were also prepared by this process.

[0054] Preparation of Compound 79. Method C.

[0055] A 2 L round bottom flask equipped with a magnetic stirrer and a reflux condenser was charged with a suspension of 3-(4-aminophenyl)propionic acid (46.3 g, 0.28 moles, 1.17 equiv.) in dichloromethane (560 mL). Chlorotrimethylsilane (62.36 g, 0.57 moles, 2.05 equiv.) was added in one portion, and the mixture was heated to reflux for 1 h under argon. The reaction was allowed to cool to room temperature and was placed in an ice bath (internal temperature <10° C.). The reflux condenser was replaced with an addition funnel containing triethylamine (42.50 g, 0.42 moles, 1.50 equiv.). The triethylamine was added dropwise over 15 min, and a yellow solid formed during the addition. The funnel was replaced by another addition funnel containing a solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equiv. in dichloromethane (100 mL). The solution was added dropwise over 30 min. The reaction was stirred in the ice bath for another 30 min and at ambient temperature for 1 h. The dichloromethane was evaporated in vacuo to give a brown oil. The brown oil was cooled in an ice bath, and an ice-cold solution of 2 M sodium hydroxide (700 mL) was added. The ice bath was removed, and the reaction was stirred for 2 h to afford a clear brown solution. The solution was acidified with 2 M sulfuric acid (400 mL) and stored at ca 5° C. for 1 hour. A yellow solid formed and was collected by filtration. The solid was washed with water (3×100 mL) and recrystallized from 50% ethanol-water (v/v) to afford compound 79 as tan needles (64.7 g, 82%).

[0056] Compounds 2-4, 6-17, 19-29, 34, 38-40, 42-48, 50-52, 67, 70, 75-77, 89-94, 96, 100, 101, 107, 111, 116-118, 127-132, 134, 135, 193, 142, 143, 148, 149, 159, 162, 164, 169, 178-182, 187, and 190 were also prepared by this process.

[0057] Preparation of Compound 35.

[0058] A solution of O-acetylsalicyloyl chloride (24.68 g, 124 mmol, 1 equiv) in tetrahydrofuran (300 mL) was cooled in an ice bath. Triethylamine (25 g, 249 mmol, 2 equiv) was added dropwise via an additional funnel. The methyl 9-aminononanoate hydrochloride was dissolved in DMF (190 mL, slightly warm to dissolve), charged to an addition funnel and added dropwise to the above mixture. The reaction was stirred in the ice-bath for 20 min and at room temperature for 2 h. Evaporation of the THF under reduced pressure gave a pink DMF solution. The pink solution was cooled in an ice-bath, and 2 M aqueous sodium hydroxide (300 mL) was added. After being stirred at room temperature for 12 h, the mixture was acidified with 2 M hydrochloric acid (500 mL). The solution was cooled in an ice-bath, and a solid formed. The solid was collected by filtration and was recrystallized from 50% ethanol/water to give compound 35 (32 g, 87%) as an off-white solid.

[0059] Preparation of Compound 49.

[0060] 1-(2-hydroxyphenyl)-3-(4-methyl benzoate)-1,3-propane dione (3.00 g, 0.0101 mil.) is placed in a 100 ml round bottomed flask fitted with argon purge, magnetic stir bar and cold water condenser. Glacial acetic acid (20 mls) and concentrated sulfuric acid (5 mls) were added, and heating of the reaction mixture was initiated. The reaction mixture was allowed to heat at reflux for 6 h before heating was discontinued. The reaction mixture was allowed to come to room temperature, and then was poured into 100 mls of ice/water. This was stirred for approximately ½ h before the mixture was filtered, and a brown solid was isolated. The brown solid was recrystallized twice from acetic acid, yielding compound 49 as a tan solid (1.44 g, 53.8%).

[0061] Preparation of Compound 167.

[0062] 2-coumaranone (4.21 g, 0.0314 mol) was dissolved, with stirring, in acetonitrile (75 mls) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser. Triethylamine (3.18 g, 0.0314 mol) and 8-aminocaprylic acid (5.00 g, 0.0314 mol) were added, and a tan slurry was formed. Heating was started, and the reaction mixture was allowed to reflux overnight. After heating overnight, thin layer chromatography of the reaction mixture (50% ethyl acetate/50% hexane) indicated that the reaction had gone to completion. Heating was stopped, the reaction mixture was allowed to cool to room temperature, and was concentrated in vacuo. The resulting residue was taken up in methylene chloride, and was washed with two, 100 ml portions of 1N hydrochloric acid solution. The methylene chloride layer was dried with sodium sulfate and was concentrated in vacuo. The resulting tan solid was allowed to dry in vacuo overnight, yielding compound 167 as a tan solid (8.35 g, 70.4%).

[0063] Preparation of Compound 171.

[0064] 1,4-benzodioxan-2-one (3.93 g, 0.0262 mol) was dissolved, with stirring, in acetonitrile (70 mls) in a 250 ml round bottomed flask fitted with a magnetic stir bar, argon purge and cold water condenser. Triethylamine (2.64 g, 0.0262 mol) and 8-aminocaprylic acid (500 g, 0.0262 mol) were added and a tan slurry was formed. Heating was started, and the reaction mixture was allowed to reflux for approximately 3 hours. At this time, thin layer chromatography of the reaction mixture (50% ethyl acetate /50% hexane) indicated that the reaction had gone to completion. Heating was discontinued, and the reaction mixture was allowed to cool to room temperature and was concentrated in vacuo. The resulting residue was taken up in methylene chloride and was washed with a 100 ml portion of 1 N hydrochloric acid solution. At this time, a tan solid was noted to precipitate, and it was isolated by filtration. This tan solid was washed further with an additional 100 ml portion of 1 N hydrochloric acid solution, and then with 100 ml of water. The resulting tan solid was allowed to dry in vacuo overnight yielding Compound 171 as a tan solid (7.73 g, 95.6%).

[0065] Preparation of Compound 120.

[0066] A solution of 3.00 g (18.3 mmol) of 2-nitrophenylisocyanate and 5 mL of tetrahydrofuran was dropwise over 10 min to an ice bath-cooled solution of 2.08 g (13.1 mmol) of 8-aminocaprylic acid, 1.40 mL of 10 N NaOH and 40 mL of water. The reaction mixture was stirred an additional 30 min, warmed to 25° C. and treated with 3% HCl solution until the pH was 5. The yellow precipitate was filtered off and rinsed with 100 ml of water. The yellow solid was recrystallized in 2-propanol and water to give 3.7 g of compound 120 as pale yellow crystals.

[0067] Compounds 104-106 were also prepared by this procedure.

[0068] Preparation of Compound 133.

[0069] A suspension of 2.40 g (16.3 mmol) and 2.80 g (15.6 mmol) of 4-(4aminophenyl)butyric acid in 20 mL of propylene glycol, 2.40 mL (1.74 g, 17.3 mmol) of triethylamine and 10 mg (0.08 mmol) of dimethylaminopyridine was heated to 140° C. The mixture became a clear solution after 5 min at 140° C. After stirring for 330 min, the reaction mixture was cooled to 25° C. and diluted with 20 mL of water. The solid phthalimide which had formed was filtered off. The filtrate was acidified with 3% HCl solution. The resulting solid was filtered off and was recrystallized from 2-propanol and water to give 0.62 g of compound 133 as a tan solid.

[0070] Preparation of Compound 138.

[0071] A solution of 1.73 g (12.9 mmol) of phthalic dialdehyde, 2.04 g 8-aminocaprylic acid and 20 mL of acetic acid was heated to reflux for 10 min. The reaction mixture was cooled to 40° C., diluted with water and extracted with CH2Cl2 (2×20 mL). The organic phase was washed with water and brine, dried over Na2SO4 and evaporated. The residue was dissolved in ether and extracted with 2N NaOH. The layers were separated. The aqueous layer was made acidic with 3% HCl and extracted with CH2Cl2. The organic phase was dried over Na2SO4 and evaporated. The yellow residue was crystallized from acetonitrile and water to give 1.25 g of compound 138 as a yellow solid.

[0072] Preparation of Compound 140.

[0073] A mixture of 1.40 g (9.48 mmol) of phthalic anhydride and 1.51 g (9.48 mmol) of 8-aminocaprylic acid was heated to 150° C. for 5 min. Upon cooling, 2.61 g of solid compound 140 was received.

[0074] Compound 150 was also prepared by this procedure.

[0075] Preparation of Compound 145.

[0076] A suspension of 2.11 g (10.1 mmol) ethyl carbamoylanthranilic acid and 5 mL of CH2Cl2 was treated with 2.20 mL of oxalyl chloride. After stirring for 1 h the volatiles were stripped off. At that same time, a suspension of 1.60 g (10.1 mmol) of 8-aminocaprylic acid and 15 mL of CH2Cl2 was treated with 2.60 mL (2.23 g, 20.5 mmol) of TMSCI. This mixture was heated to reflux for 90 min, cooled in an ice bath and treated with 4.30 mL (3.12 g, 30.9 mmol) of triethylamine. Five min later, a slurry of the residue from the oxalyl chloride reaction in 20 mL of CH2Cl2 was added. The reaction mixture was warmed to 25° C. and stirred overnight. Upon acidification of the mixture with 3% HCl, a white solid formed. The solid was filtered off and recrystallized from EtOH and water to give 1.88 g of compound 145.

[0077] Compound 153 was also prepared by this procedure.

[0078] Preparation of Compound 154.

[0079] A suspension of 4.02 g(25.6 mmol) of trans-4-aminomethylcyclohexane-carboxylic acid, 4.18 g (25.6 mmol) of isatoic anhydride, 20 mL of CH2Cl2, 20 mL of dioxane, and 4 mL of water was heated to reflux for 12 h. The solution was cooled to 25° C. and extracted with ether (4×20 mL). The organic layer was dried over Na2SO4 and concentrated. The resulting solid was recrystallized from EtOH and water to give 4.95 g of compound 154.

[0080] Compound 103 is available from Aldrich Chemical Company, Inc., Milwaukee, Wis.

EXAMPLE 2

Parathyroid Hormone Dosing Solutions

[0081] Intracolonic (“IC”) dosing compositions containing 100 mg/kg of carrier and 25 μg/kg of parathyroid hormone in 25% aqueous propylene glycol or oral gavage “PO”) dosing solution containing 400 mg/kg of carrier and 100 μg/kg of parathyroid hormone in water, were prepared with carriers 9, 33, 35, 77, 79, 109, 110, 123, 136, 141, and 169. The dosing solutions are designated P-carrier number-DS.

COMPARATIVE EXAMPLE 2A

Parathyroid Hormone Dosing Solutions

[0082] An intracolonic dosing composition containing 100 mg/kg of a carrier having the formula 196

[0083] and 25 ug/kg of parathyroid hormone in 25% aqueous propylene glycol was prepared. The dosing solution is identified as P-9A-DS.

EXAMPLES 3

In vivo Parathyroid Hormone Delivery

[0084] Male Sprague-Dawley rats weighing between 200-250 g were fasted for 24 hours and were administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of dosing solutions P-9-DS, P-33-DS, P-35-DS, P-77-DS, P-79-DS, and P-141-DS by oral gavage (“PO”) or intra-colonic instillation (“IC”). Blood samples were collected serially from the tail artery for serum determination of parathyroid hormone concentration. Serum parathyroid hormone concentrations were quantified by a parathyroid hormone immunoaccuracy test host.

[0085] Results are illustrated in Table 2, below.

COMPARATIVE EXAMPLE 3A

In vivo Parathyroid Hormone Delivery

[0086] The procedure of Example 3 was followed substituting dosing solution P-9A-DS for dosing solution P-9-DS. Results are illustrated in Table 2, below.

COMPARATIVE EXAMPLE 3B

In vivo Parathyroid Hormone Delivery

[0087] The procedure of Example 3 was followed with a dosing solution (at a dose of 25 μg/kg of parathyroid hormone (intra-colonic) or 100 μg/kg of parathyroid hormone (oral)), P-ØA-DS, that omitted the carrier.

[0088] Results are illustrated in Table 2, below.

TABLE 2
In viva Parathyroid Hormone Delivery
                Mean Peak Serum [PTH] ±
Dosing Solution Standard Deviation (pg/ml)
P-9-DS          155 ± 105 (IC)
P-33-DS         58 ± 18 (IC)
P-35-DS         50 ± 27 (IC)
P-77-DS         358 ± 274 (PO)
P-79-DS         521 ± 128 (PO)
P-109-DS        128 ± 25 (IC)
P-110-DS        35 ± 11 (IC)
P-123-DS        49 ± 22 (IC)
P-136-DS        106 ± 72 (IC)
P-141-DS        120 ± 120 (PO)
P-169-DS        19 ± 33 (IC)
P-9A-DS         116 ± 48 (IC)
P-0A-DS         11 ± 2 (PO), 27 ± 27 (IC)

EXAMPLES 4

Recombinant Human Growth Hormone Dosing Solutions

[0089] Intracolonic dosing compositions containing 25 mg/kg of carrier and 1 mg/kg of rHGH in phosphate buffer or oral gavage dosing solutions containing 600 mg/kg of carrier and 3 mg/kg of rHGH in phosphate buffer were prepared with carriers 9, 35, 36, 47, 62, 64, 67, 77, 79, 90, 94, 107, 109, 136, and 141.

[0090] The dosing solutions are designated R-carrier number-DS.

COMPARATIVE EXAMPLE 4A

Recombinant Human Growth Hormone Dosing Solutions

[0091] An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula 197

[0092] for the carrier. This dosing solution is designated as R-35A-DS.

COMPARATIVE EXAMPLE 4B

Recombinant Human Growth Hormone Dosing Solutions

[0093] An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula 198

[0094] for the carrier. This dosing solution is designated as R-35B-DS.

COMPARATIVE EXAMPLE 4C

Recombinant Human Growth Hormone Dosing Solutions

[0095] An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula 199

[0096] for the carrier. This dosing solution is designated as R-9A-DS.

EXAMPLE 5

In vivo Recombinant Human Growth Hormone Delivery

[0097] Male Sprague-Dawley rats weighing 200-250 g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing. The rats were administered one of the dosing solutions of Example 3 by either oral gavage or intracolonic instillation. Blood samples were collected serially from the tail artery for determination of serum rHGH concentrations. Serum rHGH concentrations were quantified by an rHGH immunoassay test kit.

[0098] Results are illustrated in Table 3, below.

COMPARATIVE EXAMPLE 5A

In vivo Recombinant Human Growth Hormone Delivery

[0099] The procedure of Example 5 was followed, substituting the dosing solutions of Comparative Examples 3A-3C for the dosing solutions. Results are illustrated in Table 3, below.

COMPARATIVE EXAMPLE 5B

In vivo Recombinant Human Growth Hormone Delivery

[0100] The procedure of Example 5 was followed, with dosing solutions of active agent (at a dose of 1 mg of rHGH/kg (intracolonic) or 3 mg of rHGH/kg (oral) and no carrier. These dosing solutions are designated R-ØD-DS and R-ØE-DS, respectively. Results are illustrated in Table 3, below.

TABLE 3
In Vivo Recombinant Human Growth Hormone Delivery
                Mean Peak Serum [rHGH] ±
Dosing Solution Standard Deviation (ng/ml)
R-9-DS          125 ± 34 (IC)
R-35-DS         41 ± 46 (PO)
                108 ± 56 (IC)
R-36-DS         28 ± 11 (IC)
R-47-DS         0 (IC)
R-62-DS         11 ± 12 (IC)
R-64-DS         72 ± 22 (PO)
R-67-DS         19 ± 22 (PO)
                88 ± 24 (IC)
R-77-DS         34 ± 10 (PO)
R-79-DS         62 ± 51 (PO)
R-90-DS         9 ± 13 (PO)
R-94-DS         39 ± 35 (PO)
R-107-DS        0 ± 0 (PO)
R-109-DS        128 ± 25 (IC)
R-136-DS        106 ± 72 (IC)
R-141-DS        95 ± 14 (IC)
R-35A-DS        17 ± 3 (IC)
R-35B-DS        42 ± 28 (IC)
R-9A-DS         55 ± 17 (IC)
R-0D-DS         0 ± 0 (IC)
R-0E-DS         0 ± 0 (IC)

EXAMPLE 6

In vivo Interferon Delivery

[0101] An intracolonic dosing composition containing 50 mg/kg of carrier 9 and 250 μg/kg of interferon in 50% propylene glycol was prepared. Rats were administered the dosing composition by intracolonic instillation. Delivery was evaluated by use of an ELISA assay for human interferon α from Biosource, Inc. Mean peak serum interferon concentration was 2611±695.

COMPARATIVE EXAMPLE 6A

In vivo Interferon Delivery

[0102] Rats were administered, orally and by intracolonic instillation, dosing solutions of 1 mg/kg of interferon and no carrier. Delivery was evaluated according to the procedure of Example 6. Mean peak serum interferon concentration was 1951±1857 (PO) and 79±100 (IC).

EXAMPLE 7

Heparin Dosing Solutions

[0103] Intracolonic dosing compositions containing 50 mg/kg of carrier and 25 mg/kg of heparin in 25% aqueous propylene glycol or oral gavage dosing solutions containing 300 mg/kg of carrier and 100 mg/kg of heparin in 25% aqueous propylene glycol were prepared with carriers 9, 35, 47, 50, 58, 62, 64, 67, 76, 96, 102, 109, 110, 111, 117, 122, 123, 139, 141, 144, and 169. The dosing solutions are designated H-carrier number-DS.

COMPARATIVE EXAMPLE 7A

Heparin Dosing Solutions

[0104] Comparative intracolonic dosing compositions were prepared according to the procedure of Example 7, substituting the following carriers for the carrier. 200

[0105] These dosing solutions are designated H-35A-DS, H-35B-DS, and H-109A-DS, respectively.

EXAMPLES 8

In vivo Evaluation of Heparin in Rats

[0106] The dosing solutions of Example 7 were administered to fasted rats either by oral gavage or intracolonic instillation.

[0107] Blood samples were collected by cardiac puncture following the administration of ketamine (44 mg/kg). Heparin activity was determined by utilizing the activated partial thromboplastin time (APTT) according to the method of Henry, J. B., Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, Pa.; W. B. Saunders (1979).

[0108] Results are in illustrated in Table 4, below.

COMPARATIVE EXAMPLES 8A

In vivo Evaluation of Heparin in Rats

[0109] The dosing solutions of Comparative Example 7A were administered to fasted rats by intracolonic instillation. Blood samples were collected and heparin activity was determined by the method of Example 8.

[0110] Results are illustrated in Table 4, below.

COMPARATIVE EXAMPLE 8B

In vivo Evaluation of Heparin in Rats

[0111] An intracolonic dosing solution of 25 mg/kg of heparin and an oral gavage dosing solution of 100 mg/kg of heparin were administered to fasted rats. These dosage solutions were designated H-ØA-DS and H-ØB-DS, respectively.

[0112] Blood samples were collected, and heparin activity was determined by the methods of Example 8.

[0113] Results are illustrated in Table 4, below.

TABLE 4
In Vivo Evaluation of Heparin in Rats
Dosing Solution Heparin APTT (sec)
H-9-DS          48 ± 18 (IC)
H-35-DS         54 ± 27 (PO), 177 ± 85 (IC)
H-47-DS         30 ± 14 (IC)
H-50-DS         40 ± 22 (IC)
H-58-DS         24 ± 4 (IC)
H-62-DS         37 ± 13 (IC)
H-64-DS         59 ± 28 (PO), 168 ± 75 (IC)
H-67-DS         76 ± 36 (IC)
H-76-DS         63 ± 27 (PO)
H-96-DS         36 ± 8 (IC)
H-102-DS        111 ± 108 (IC)
H-109-DS        56 ± 28 (IC)
H-110-DS        37 ± 9 (IC)
H-111-DS        71 ± 39 (IC)
H-117-DS        140 ± 128 (IC)
H-122-DS        49 ± 21 (IC), 207 ± 7 (PO)
H-123-DS        42 ± 14 (PO)
H-139-DS        31 ± 11 (IC)
H-141-DS        59 ± 26 (IC)
H-144-DS        26 ± 3 (IC)
H-35A-DS        61 ± 29 (IC)
H-35B-DS        51 ± 30 (IC)
H-169-DS        23 ± 2 (IC)
H-0A-DS         23 ± 2 (PO)
H-0B-DS         33 ± 6 (IC)

[0114] The above mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety.

[0115] Many variations of the present invention will suggest themselves to those skilled in the art in light of the above detailed description. All such obvious variations are within the full intended scope of the appended claims.

Claims

1. A composition comprising: (A) at least one active agent; and (B) at least one carrier selected from the group consisting of 620116-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid20228(2-aminobenzoylamino)caprylic acid20338(2-trifluoromethoxy)benzoylamino caprylic acid2044N-(2-hydroxybenzoyl)isonipecotic acid20554-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid20664-(4-(pentafluorobenzoyl)aminophenyl)butyric acid20774-(4-(3-anisoyl)aminophenyl)butyric acid20888-(3-anisoyl)aminocaprylic acid209104-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid210118-(2-nitrobenzenesulfonyl)aminocaprylic acid211126-(4-salicyloyl)aminophenyl)hexanoic acid212138-(2-methoxybenzoyl)amino caprylic acid213142-[4-Salicyloylamino)phenyl]ethyl methyl sulfone214151-Salicyloyl-2-succinyl hydrazide215163-(4-(2,5-dimethoxycinnamoyl)aminophenyl)propionic acid216174-(4-(2,5-dimethoxycinnamoyl)aminophenyl)butyric acid217181-salicyloyl-2-glutaryl hydrazide21819Succinyl-4-aminosalicylic acid219208-(Phenoxyacetylamino)caprylic acid220218-(2-pyrazinecarbonyl)aminocaprylic acid221224-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid222236-(4-(N-2-Nitrobenzoyl)aminophenyl)hexanoic acid223246-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid224254-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid225264(2-Nitrobenzoyl)aminophenylsuccinic acid226278-(2-(trifluoromethoxy)benzoyl)aminocaprylic acid22728228298-(Benzylcarbonylamino)caprylic acid229308-(phenylcarbonylamino)caprylic acid230312-[4-(2-Methoxybenzoylamino)phenyl]ethyl H2PO4231321-salicyloyl-2-suberyl hydrazide232334-(4-benzyloxycarbonylaminophenyl)butyric acid233344-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid234364-(4-phenyloxycarbonylaminophenyl)butyric acid235373-(2-methoxybenzoylamino)-1-propanol236388-(2-Hydroxynicotinoyl)aminocaprylic acid237396-(2-methoxybenzoyl)amino nicotinic acid23840salicyloylglycine239414-(1-(2-pyrimidyl)piperazinoyl)butyric acid240428-(chromone-3-carbonyl)aminocaprylic acid241438-(vinylbenzoyl)aminocaprylic acid242444-(4-(chromone-3-carbonyl)aminophenyl)butyric acid243458-cinnamoylaminocaprylic acid244465-(N-salicyloylamino)valeric acid245479-(2-hydroxybenzamido)nonanic acid24648N-(4-salicyloylamino)-6-caproic acid247494′-flavonic acid2485011-cinnamoylaminoundecanoic acid249514-octanoylamino-3-hydroxybanzoic acid25052(3Phenyl2,3-dihydroxypropanoyl)8aminocaprylic acid251538-[N-(3-coumarincarbonyl)]aminocaprylic acid252548-[N-(4-chlorobenzoyl)]aminocaprylic acid253558-[N-3-fluorobenzoyl)]aminocaprylic acid254568-(N-2,5-Dihydroxybenzoyl)aminocaprylic acid255578-(N-2,3-Dimethoxybenzopyl)aminocaprylic acid256588-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid257598-(N-2,5-Dimethoxybenzoyl)aminocaprylic acid258608-(N-3,5-Diacetyloxybenzoyl)aminocaprylic acid259618-(N-4-Hydroxybenzoyl)aminocaprylic acid (dimer)260628-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid2616310-(N-2-Methoxyanilino)sebalic acid262652-Methoxybenzeneaminodecanoic acid263668-(N-benzoyl)aminocaprylic acid264688-[N-(4-fluorobenzoyl)]aminocaprylic acid265698-[N-(2-bromobenzoyl)]aminocaprylic acid266708-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid267718-[N-(4-bromobenzoyl)]aminocaprylic acid268728-[N-(4-iodobenzoyl)]aminocaprylic acid269734-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid270744-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid271754-(4-(2,4-dimethoxybenzoyl)aminophenyl)butyric acid272764-(o-anisoyl)aminophenylacetic acid273773-[4-(2,4-dimethoxybenzoyl) aminophenyl] propionic acid274784-{4-[N-(4-iodobenzoyl)] aminophenyl} butyric acid275804{4-[N-2-bromobenzoyl)] aminophenyl} butyric acid276814{4-[N-3-bromobenzoyl) aminophenyl]} butyric acid277828-(N-3,5-Dihydroxybenzoyl)aminocaprylic acid278838-(N-3,5-Dimethoxy 4-hydroxybenzoyl)aminocaprylic acid279848-(N-2-6-Dimethoxybenzoyl)aminocaprylic acid280854-{4-[N-(4-bromobenzoyl)aminophenyl]}butyric acid281868-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid282878-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid283888-(N-Hydroxy6-methoxybenzoyl)aminocaprylic acid284898-(5-chloro-o-anisoyl)aminocaprylic acid285904-(4-(2,3-dimethoxybenzoyl)aminophenyl)butyric acid286914-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid287924-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid288938-(4-chloro-o-anisoyl)aminocaprylic acid289943-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid290954-{N-[4-(3-iodobenzoyl)aminophenyl]}butyric acid291967-cinnamoylaminoheptanoic acid292978-N-(3-iodobenzoyl)aminocaprylic acid293988-N-(4-methoxy-3-nitrobenzoyl)aminocaprylic acid294998-N-(2-methoxy-4-nitrobenzoyl)aminocaprylic acid2951004-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid2961014-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid2971033-Indolebutyric acid2981042991053001063011084-[4-N-(4-methoxy-3-nitrobenzoyl)aminophenyl]butyric acid3021108-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid3031128-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid3041134-[-N-(2-hydroxy-4-bromobenzoyl)aminophenyl]butyric acid3051148-(N-2,3-Dihydroxybenzoyl)aminocaprylic acid3061158-(N-3-methylsalicyloyl)aminocaprylic acid3071168-(N-5-methylsalicyloyl)aminocaprylic acid3081184-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid3091194-{-[N-(2hydroxy-5-iodobenzoyl)]aminopheny;}butyric acid310120N-2-nitrophenyl-N′-(8-octanoic acid) urea311121N-(2-methoxy-5-nitrophenyl) sebecoyl amide acid3121238-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid3131248-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid3141253151268-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid3161274-(4-Salicyloylaminophenyl)-4-oxobutyric acid31712812-cinnamoyldodecanoic acid3181294-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}butyric acid3191308-(4-chloro-3-nitrobenzoyl)aminocaprylic acid3201318-(2-chloronicotinoyl)aminocaprylic acid3211328-(2-chloro-5-nitrobenzoyl)aminocaprylic acid3221334-(4-phthalimidophenyl)butyric acid3231344-{4-[N-(3-hydroxy-2-naphthoyl)aminophenyl]}propanoic acid3241353-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid3251378-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid3261388-(2-(1,2-dihydroisoindole-1-one))octanoic acid3271398-(N-1-hydroxy-2-naphthoyl)aminocaprylic acid3281408-(phthalimido)caprylic acid3291426-(anisoyl)aminocaproic acid3301434-(4-(4-chloro-3-ribobenzoyl)aminophenyl)butyric acid33114411-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid332145Bis(N-2carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide3331462-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol3341472-[2-(4-chlorobenzoyl)aminoethoxy]ethanol3351484-(2-methoxybenzoyl)amino 3-carboxysulfoxide3361494-(2-methoxybenzoyl)amino 3-carboxypropylsulfone3371504-(4-(3-hydroxyphthalimido)phenyl)butyric acid3381512-[2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol3391522-[2-N-(3-chlorobenzoyl)aminoethoxy)]ethanol340153Bis(M-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxalyl diamide341154trans-4-(2-aminobenzamidomethyl)cyclohexamecarboxylic acid34215511-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid3431562-[N-(2-bromobenzoyl)aminoethoxy]ethanol3441577-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid345158N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid346159trans-4-(N-salicyloylaminomethyl)cyclohexane carboxylic acid347160N-[3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid34816112-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid349162N-(2-hydroxy-4-carboxy)-6-heptenamide350163N-(2-bromobenzoyl)morpholine3511648-N-cyclohexanoylaminocaprylic acid3521652-[N-(2-iodobenzoyl)aminoethoxy]ethanol3531665-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid3541678-(2-hydroxyphenoxyl)-aminocaprylic acid355168N-Salicyloyl-5-(3-aminophenyl)valeric acid3561694-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid3571709-[2-(3-hydroxy)pyridylaminocarbonyl] nananic acid3581717-(2-hydroxyphenoxyacetyl)aminocaprylic acid3591722-[N-(2-hydroxybenzoylamino)ethoxy]ethanol3601734-[N-(3,5-dichloro-2-hydroxybenzoyl)]aminophenylacetic acid3611748-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid362175N-salicyloyl-5-(4-aminophenyl)valeric acid3631769-(2-hydroxy-5-methylanilinocarbonyl)nonanionic acid3641775-(2-hydroxy-5-methylanilinocarbonyl)valeric acid3651788-(pentafluorobenzoyl)aminocaprylic acid3661793-(3-(salicyloyl)aminophenyl)propionic acid3671808-(2-ethoxybenzoyl)aminocaprylic acid3681814-(4-(2-Dimethylamino benzoic)aminophenyl)butyric acid3691828-(3-Phenoxypropionylamino)caprylic acid3701834-(Salicyloyl)aminophenylethyltetrazole3711848(-(4(N-salicyloyl-4aminophenyl)butyric)aminocaprylic acid [sic]3721854-(4-(N-(2-Fluorocinnamoyl)aminophenyl) butyric3731864-(4-(N-8(N-Salicyloyl)aminocaprylic)aminophenyl)butyric acid3741878-(p-anisoyl)aminocaprylic acid3751888-(4-Hydroxybenzoyl)aminocaprylic acid3761898-(3-Hydroxybenzoyl)aminocaprylic acid3771908-(3,4,5-Trimethoxybenzoyl)aminocaprylic acid3781918-(N-4-Methylsalicyloyl)aminocaprillic acid [sic]379192N-10-(2-hydroxy-5-nitroanilino)decanoic acid3801934-(4-(2-chloronicotinoyl)aminophenyl)butyric acidand a salt of any of the foregoing.

2. A composition as defined in claim 1, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.

3. A composition as defined in claim 2, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

4. A composition as defined in claim 2, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.

5. A composition as defined in claim 4, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

6. A composition as defined in claim 1, wherein said carrier comprises a poly(amino acid).

7. A composition as defined in claim 1, wherein said carrier comprises a polypeptide.

8. A dosage unit form comprising (A) a composition as defined in claim 1; and (B) (a) an excipient (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or (h) any combination thereof.

9. A composition as defined in claim 8, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.

10. A composition as defined in claim 9, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

11. A composition as defined in claim 9, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.

12. A composition as defined in claim 11, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

13. A dosage unit form comprising (A) a composition as defined in claim 6; and (B) (a) an excipient (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or (h) any combination thereof.

14. A composition as defined in claim 13, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.

15. A composition as defined in claim 14, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

16. A composition as defined in claim 14, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.

17. A composition as defined in claim 16, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

18. A dosage unit form comprising (A) a composition as defined in claim 7; and (B) (a) an excipient (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a dosing vehicle, or (h) any combination thereof.

19. A composition as defined in claim 18, wherein said active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.

20. A composition as defined in claim 19, wherein said biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

21. A composition as defined in claim 19, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, samatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, desferrioxamine (DFO), or any combination thereof.

22. A composition as defined in claim 21, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytosin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

23. A dosage unit form as defined in claim 8, comprising a tablet, a capsule, or a liquid.

24. A dosage unit form as defined in claim 23, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof.

25. A dosage unit form as defined in claim 13, comprising a tablet, a capsule, or a liquid.

26. A dosage unit form as defined in claim 25, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof.

27. A dosage unit form as defined in claim 18, comprising a tablet, a capsule, or a liquid.

28. A dosage unit form as defined in claim 27, wherein said dosing vehicle is selected from the group consisting of water, 1,2-propane diol, ethanol, or any combination thereof.

29. A method for administering a biologically-active agent to an animal in need of said agent, said method comprising administering orally to said animal a composition as defined in claim 2.

30. A compound selected from the group consisting of

31. A method for preparing a composition, said method comprising mixing: (A) at least one active agent; (B) at least one compound as defined in claim 31; and (C) optionally, a dosing vehicle.