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 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 gastrointestinal 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

[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 weight heparin; calcitonin; erythropoietin; atrial naturetic factor; 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. 1 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  218-221c 35 65.5 7.90 4.78 65.37 8.00 4.66   96-97C 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 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. Nos. 60/017,902, filed Mar. 29, 1996; 08/414,654, filed Mar. 31, 1995; 08/335,148, filed Oct. 25, 1994; and 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: 2

[0042] Derivatives of these compounds are disclosed in U.S. Pat. No. 5,206,384. Actinonin derivatives have the formula: 3

[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

[0046] Carrier Preparation

[0047] General Preparations of Carriers.

[0048] 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.

[0049] Preparation of Compound 79. Method A.

[0050] 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%).

[0051] 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.

[0052] Preparation of Compound 79. Method B.

[0053] 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%).

[0054] Compounds 18, 32, 37, 41, 168, 175, and 183 were also prepared by this process.

[0055] Preparation of Compound 79. Method C.

[0056] 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%).

[0057] 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.

[0058] Preparation of Compound 35.

[0059] 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.

[0060] Preparation of Compound 49.

[0061] 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%).

[0062] Preparation of Compound 167.

[0063] 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%).

[0064] Preparation of Compound 171.

[0065] 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 1N 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%).

[0066] Preparation of Compound 120.

[0067] 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.

[0068] Compounds 104-106 were also prepared by this procedure.

[0069] Preparation of Compound 133.

[0070] 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.

[0071] Preparation of Compound 138.

[0072] 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.

[0073] Preparation of Compound 140.

[0074] 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.

[0075] Compound 150 was also prepared by this procedure.

[0076] Preparation of Compound 145.

[0077] 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 TMSCl. 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.

[0078] Compound 153 was also prepared by this procedure.

[0079] Preparation of Compound 154. 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

[0081] Parathyroid Hormone Dosing Solutions

[0082] Intracolonic (“IC”) dosing compositions containing 100 mg/kg of carrier and 25 &mgr;g/kg of parathyroid hormone in 25% aqueous propylene glycol or oral gavage “PO”) dosing solution containing 400 mg/kg of carrier and 100 &mgr;g/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

[0083] Parathyroid Hormone Dosing Solutions

[0084] An intracolonic dosing composition containing 100 mg/kg of a carrier having the formula 4

[0085] 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

[0086] In vivo Parathyroid Hormone Delivery

[0087] 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.

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

Comparative Example 3A

[0089] In vivo Parathyroid Hormone Delivery

[0090] 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

[0091] In vivo Parathyroid Hormone Delivery

[0092] The procedure of Example 3 was followed with a dosing solution (at a dose of 25 &mgr;g/kg of parathyroid hormone (intra-colonic) or 100 &mgr;g/kg of parathyroid hormone (oral)), P-A-DS, that omitted the carrier.

[0093] Results are illustrated in Table 2, below. 2 TABLE 2 In vivo 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-ØA-DS 11 ± 2 (PO), 27 ± 27 (IC)

EXAMPLES 4

[0094] Recombinant Human Growth Hormone Dosing Solutions

[0095] 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.

[0096] The dosing solutions are designated R- carrier number—DS.

Comparative Example 4A

[0097] Recombinant Human Growth Hormone Dosing Solutions

[0098] An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula 5

[0099] for the carrier. This dosing solution is designated as R-35A-DS.

Comparative Example 4B

[0100] Recombinant Human Growth Hormone Dosing Solutions

[0101] An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula 6

[0102] for the carrier. This dosing solution is designated as R-35B-DS.

Comparative Example 4C

[0103] Recombinant Human Growth Hormone Dosing Solutions

[0104] An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula 7

[0105] for the carrier. This dosing solution is designated as R-9A-DS.

EXAMPLE 5

[0106] In Vivo Recombinant Human Growth Hormone Delivery

[0107] 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.

[0108] Results are illustrated in Table 3, below.

Comparative Example 5A

[0109] In Vivo Recombinant Human Growth Hormone Delivery

[0110] The procedure of Example 5 was followed, substituting the dosing solutions of Comparative Examples 3A-3C for the dosing solutions.

[0111] Results are illustrated in Table 3, below.

Comparative Example 5B

[0112] In Vivo Recombinant Human Growth Hormone Delivery

[0113] 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-D-DS and R-E-DS, respectively. Results are illustrated in Table 3, below. 3 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-ØD-DS 0 ± 0 (IC) R-ØE-DS 0 ± 0 (IC)

EXAMPLE 6

[0114] In Vivo Interferon Delivery

[0115] An intracolonic dosing composition containing 50 mg/kg of carrier 9 and 250 &mgr;g/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 a from Biosource, Inc. Mean peak serum interferon concentration was 2611±695.

Comparative Example 6A

[0116] In Vivo Interferon Delivery

[0117] 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

[0118] Heparin Dosing Solutions

[0119] 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

[0120] Heparin Dosing Solutions

[0121] Comparative intracolonic dosing compositions were prepared according to the procedure of Example 7, substituting the following carriers for the carrier. 8

[0122] These dosing solutions are designated H-35A-DS, H-35B-DS, and H-109A-DS, respectively.

EXAMPLES 8

[0123] In Vivo Evaluation of Heparin in Rats

[0124] The dosing solutions of Example 7 were administered to fasted rats either by oral gavage or intracolonic instillation.

[0125] 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).

[0126] Results are in illustrated in Table 4, below.

Comparative Examples 8A

[0127] In Vivo Evaluation of Heparin in Rats

[0128] 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.

[0129] Results are illustrated in Table 4, below.

Comparative Example 8B

[0130] In Vivo Evaluation of Heparin in Rats

[0131] 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-A-DS and H-B-DS, respectively.

[0132] Blood samples were collected, and heparin activity was determined by the methods of Example 8.

[0133] Results are illustrated in Table 4, below. 4 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-ØA-DS 23 ± 2 (PO) H-ØB-DS 33 ± 6 (IC)

[0134] The above mentioned patents, applications, test methods, and publications are hereby incorporated by reference in their entirety.

[0135] 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

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

and 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

6 189 1 6-N-(3,5-dichloro-2-hydroxybenzoyl)aminocaproic acid 190 2 8(2-aminobenzoylamino)caprylic acid 191 3 8(2-trifluoromethoxy)benzoylamino caprylic acid 192 4 N-(2-hydroxybenzoyl)isonipecotic acid 193 5 4-[4-(2-aminobenzoylamino)phenyl]butyrylhydroxamic acid 194 6 4-(4-pentafluorobenzoyl)aminophenyl)butyric acid 195 7 4-(4-(3-anisoyl)aminophenyl)butyric acid 196 8 8-(3-anisoyl)aminocaprylic acid 197 10 4-(4-(2-nitrobenzenesulfonyl)aminophenyl)butyric acid 198 11 8-(2-nitrobenzenesulfonyl)aminocaprylic acid 199 12 6-(4-salicyloyl)aminophenyl)hexanoic acid 200 13 8-(2-methoxylbenzoyl)amino caprylic acid 201 14 2-[4-Salicyloylamino)phenyl]ethyl methyl sulfone 202 15 1-Salicyloyl-2-succinyl hydrazide 203 16 3-(4-(2,5-dimethoxycinnamoyl)aminophenyl)propionic acid 204 17 4-(4-(2,5-dimethoxycinnamoyl)aminophenyl)butyric acid 205 18 1-salicyloyl-2-glutaryl hydrazide 206 19 Succinyl-4-aminosalicylic acid 207 20 8-(Phenoxyacetylamino)caprylic acid 208 21 8-(2-pyrazinecarbonyl)aminocaprylic acid 209 22 4-(4-(2-pyrazinecarbonyl)aminophenyl)butyric acid 210 23 6-(4-(N-2-Nitrobenzoyl)aminophenyl)hexanoic acid 211 24 6-(4-(N-2-aminobenzoyl)aminophenyl)hexanoic acid 212 25 4-(4-(2-(3-carboxyl)pyrazinecarboxyl)aminophenyl)butyric acid 213 26 4(2-Nitrobenzoyl)aminophenylsuccinic acid 214 27 8-(2-trifluoromethoxy)benzoyl)aminocaprylic acid 215 28 216 29 8-(Benzylcarbonylamino)caprylic acid 217 30 8-(phenylcarbonylamino)caprylic acid 218 31 2-[4-(2-Methoxybenzoylamino)phenyl]ethyl H2PO4 219 32 1-salicyloyl-2-suberyl hydrazide 220 33 4-(4-benzyloxycarbonylaminophenyl)butyric acid 221 34 4-(4-(2-hydroxynicotinoyl)aminophenyl)butyric acid 222 36 4-(4-phenyloxycarbonylaminophenyl)butyric acid 223 37 3-(2-methoxybenzoylamino)-1-propanol 224 38 8-(2-Hydroxynicotinoyl)aminocaprylic acid 225 39 6-(2-methoxybenzoyl)amino nicotinic acid 226 40 salicyloylglycine 227 41 4-(1-(2-pyrimidyl)piperazinoyl)butyric acid 228 42 8-(chromone-3-carbonyl)aminocaprylic acid 229 43 8-(vinylbenzoyl)aminocaprylic acid 230 44 4-(4-(chromone-3-carbonyl)aminophenyl)butyric acid 231 45 8-cinnamoylaminocaprylic acid 232 46 5-(N-salicyloylamino)valeric acid 233 47 9-(2-hydroxybenzamido)nonanic acid 234 48 N-(4-salicyloylamino)-6-caproic acid 235 49 4′-flavonic acid 236 50 11-cinnamoylaminoundecanoic acid 237 51 4-octanoylamino-3-hydroxybenzoic acid 238 52 (3Phenyl2,3dihydroxypropanoyl)8aminocaprylic acid 239 53 8-[N-(3-coumarincarbonyl)]aminocaprylic acid 240 54 8-[N-(4-chlorobenzoyl)]aminocaprylic acid 241 55 8-[N-3-fluorobenzoyl)]aminocaprylic acid 242 56 8-(N-2,5-Dihydroxybenzoyl)aminocaprylic acid 243 57 8-(N-2,3-Dimethoxybenzoyl)aminocaprylic acid 244 58 8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid 245 59 8-(N-2,5-Dimethoxybenzoyl)aminocaprylic acid 246 60 8-(N-3,5-Diacetyloxybenzoyl)aminocaprylic acid 247 61 8-(N-4-Hydroxybenzoyl)aminocaprylic acid (dimer) 248 62 8-(N-2,4-Dihydroxybenzoyl)aminocaprylic acid 249 63 10-(N-2-Methoxyanilino)sebalic acid 250 65 2-Methoxybenzenaminodecanoic acid 251 66 8-(N-benzoyl)aminocaprylic acid 252 68 8-[N-(4-fluorobenzoyl)]aminocaprylic acid 253 69 8-[N-(3-bromobenzoyl)]aminocaprylic acid 254 70 8-(4-(1,2-dihydroxyethyl)benzoyl)aminocaprylic acid 255 71 8-[N-(4-bromobenzoyl)]aminocaprylic acid 256 72 8-[N-(4-iodobenzoyl)]aminocaprylic acid 257 73 4-{4-[N-(2-iodobenzoyl)aminophenyl]}butyric acid 258 74 4-{4-[N-(1-hydroxy-2-naphthoyl)aminophenyl]}butyric acid 259 75 4-(4-(2,4-dimethoxylbenzoyl)aminophenyl)butyric acid 260 76 4-(o-anisoyl)aminophenylacetic acid 261 77 3-[4-(2,4-dimethoxybenzoyl) aminophenyl] propionic acid 262 78 4-{4-[N-(4-iodobenzoyl)] aminophenyl} butyric acid 263 80 4-{4-[N-2-bromobenzoyl)] aminophenyl} butyric acid 264 81 4{4-[N-3-bromobenzoyl) aminophenyl]} butyric acid 265 82 8-(N-3,5 Dihydroxybenzoyl)aminocaprylic acid 266 83 8-(N-3,5-Dimethoxy 4-hydroxybenzoyl)aminocaprylic acid 267 84 8-(N-2-6-Dimethoxybenzoyl)aminocaprylic acid 268 85 4-{[N-(4-bromobenzoyl)aminophenyl]}butyric acid 269 86 8-(2-hydroxy-4-chlorobenzoyl)aminocaprylic acid 270 87 8-(N-2,6-Dihydroxybenzoyl)aminocaprylic acid 271 88 8-(N-2-Hydroxy6-methoxybenzoyl)aminocaprylic acid 272 89 8-(5-chloro-o-anisoyl)aminocaprylic acid 273 90 4-(2-(2,3-dimethoxybenzoyl)aminophenyl)butyric acid 274 91 4-(4-(5-chloro-o-anisoyl)aminophenyl)butyric acid 275 92 4-(4-(4-chloro-o-anisoyl)aminophenyl)butyric acid 276 93 8-(4-chloro-o-anisoyl)aminocaprylic acid 277 94 3-(4-(2,5-dimethoxybenzoyl)aminophenyl)propionic acid 278 95 4-{N-[4-(3-iodobenzoyl)aminophenyl]}butyric acid 279 96 7-cinnamoylaminoheptanoic acid 280 97 8-N-(3-iodobenzoyl)aminocaprylic acid 281 98 8-N-(4-methoxy-3-nitrobenzoyl)aminocaprylic acid 282 99 8-N-(2-methoxy-4-nitrobenzoyl)aminocaprylic acid 283 100 4-{N-[4-(2-methoxy-4-nitrobenzoyl)aminophenyl]}butyric acid 284 101 4-(4-(2,5-dimethoxybenzoyl)aminophenyl)butyric acid 285 104 286 105 287 106 288 107 4-(4-(2,6-dimethoxybenzoyl)aminophenylbutyric acid 289 108 4-[4-N-(4-methoxy-3-nitrobenzoyl)aminophenyl]butyric acid 290 110 8-(N-2-hydroxy-5-iodobenzoyl)aminocaprylic acid 291 112 8-(N-2-hydroxy-4-nitrobenzoyl)aminocaprylic acid 292 113 4-[-N-(2-hydroxy-4-bromobenzoyl)aminophenyl]butyric acid 293 114 8-(N-2,3-Dihydroxybenzoyl)aminocaprylic acid 294 115 8-(N-3-methylsalicyloyl)aminocaprylic acid 295 116 8-(N-5-methylsalicyloyl)aminocaprylic acid 296 118 4-(4-(2-chloro-5-nitrobenzoyl)aminophenyl)butyric acid 297 119 4-{-[N-(2-hydroxy-5-iodobenzoyl)]aminophenyl}butyric acid 298 120 N-2-nitrophenyl-N′-(8-octanoic acid) urea 299 121 N-(2-methoxy-5-nitrophenyl) sebecoyl amide acid 300 123 8-[N-(2-acetoxy-3,5-dibromobenzoyl)]aminocaprylic acid 301 124 8-N-(2-chloro-6-fluorobenzoyl)aminocaprylic acid 302 125 303 126 8-N-(4-hydroxy-3-nitrobenzoyl)caprylic acid 304 127 4-(4-Salicyloylaminophenyl)-4-oxobutyric acid 305 128 12-cinnamoyldodecanoic acid 306 129 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}butyric acid 307 130 8-(4-chloro-3-nitrobenzoyl)aminocaprylic acid 308 131 8-(2-chloronicotinoyl)aminocaprylic acid 309 132 8-(2-chloro-5-nitrobenzoyl)aminocaprylic acid 310 133 4-(4-phthalimidophenyl)butyric acid 311 134 4-{4-[N-(3-hydroxy-2-napthoyl)aminophenyl]}propanoic acid 312 135 3-(4-(2,6-dimethoxybenzoyl)aminophenyl)propionic acid 313 137 8-(N-2-chloro-4-fluorobenzoyl)aminocaprylic acid 314 138 8-(2-(1,2-dihydroisoindole-1-one))octanoic acid 315 139 8-(N-1-hydroxy-2-naphthoyl)aminocaprylic acid 316 140 8-(phthalimido)caprylic acid 317 142 6-(anisoyl)aminocaproic acid 318 143 4-(4-(4-chloro-3-nitrobenzoyl)aminophenyl)butyric acid 319 144 11-N-(1-hydroxy-2-naphthoyl)aminoundecanoic acid 320 145 Bis(N-2carboxylphenyl-N-(N′-8-octanoic acid)ureal)oxalyl diamide 321 146 2-[2-N-(2-chlorobenzoyl)aminoethoxy]ethanol 322 147 2-[2-N-(4-chlorobenzoyl)aminoethoxy]ethanol 323 148 4-(2-methoxybenzoyl)amino 3-carboxysulfoxide 324 149 4-(2-methoxybenzoyl)amino 3-carboxypropylsulfone 325 150 4-(4-(3-hydroxyphthalimido)phenyl)butyric acid 326 151 2-[2-N-(2-methoxybenzoyl)aminoethoxy)]ethanol 327 152 2-[2-N-(3-chlorobenzoyl)aminoethoxy)]ethanol 328 153 Bis(N-2-carboxyphenyl-N-(N′-3(4-aminophenyl)propionic acid)ureal)oxaylyl diamide 329 154 trans-4-(2-aminobenzamidomethyl)cyclohexamecarboxylic acid 330 155 11-N-(3,5-dichloro-2-hydroxybenzoyl)aminoundecanoic acid 331 156 2-[N-(2-bromobenzoyl)aminoethoxy]ethanol 332 157 7-N-(3,5-dichloro-2-hydroxybenzoyl)aminoheptanoic acid 333 158 N-[3,5-dichloro-2-hydroxybenzoyl-4(4-aminophenyl)]butyric acid 334 159 trans-4-(N-salicyloylaminomethyl)cyclohexane carboxylic acid 335 160 N-[3,5-dichloro-2-hydroxybenzoyl-3-(4-aminophenyl)]propionic acid 336 161 12-N-(3,5-dichloro-2-hydroxybenzoyl)aminododecanoic acid 337 162 N-(2-hydroxy-4-carboxy)-6-heptenamide 338 163 N-(2-bromobenzoyl)morpholine 339 164 8-N-cyclohexanoylaminocaprylic acid 340 165 2-[N-(2-iodobenzoyl)aminoethoxy]ethanol 341 166 5-(4-chloro-2-hydroxyanilinocarbonyl)valeric acid 342 167 8-(2-hydroxyphenoxy)-aminocaprylic acid 343 168 N-Salicoyl-5-(3-aminophenyl)valeric acid 344 169 4-(4-(2-ethoxylbenzoyl)aminophenyl)butyric acid 345 170 9-[2-(3-hydroxy)pyridylaminocarbonyl] nonanic acid 346 171 7-(2-hydroxyphenoxyacetyl)aminocaprylic acid 347 172 2-[N-(2-hydroxybenzoylamino)ethoxy]ethanol 348 173 4-[N-(3,5-dichloro-2-hydroxybenzoyl)]aminophenylacetic acid 349 174 8-(2-hydroxy-5-chloroanilinocarbonyl)octanoic acid 350 175 N-salicoyl-5-(4-aminophenyl)valeric acid 351 176 9-(2-hydroxy-5-methylanilinocarbonyl)nonanoic acid 352 177 5-(2-hydroxy-5-methylanilinocarbonyl)valeric acid 353 178 8-(pentafluorobenzoyl)aminocaprylic acid 354 179 3-(3-(salicyloyl)aminophenyl)propionic acid 355 180 8-(2-ethoxybenzoyl)aminocaprylic acid 356 181 4-(4-(2-Dimethylamino benzoic)aminophenyl)butyric acid 357 182 8-(3-Phenoxylpropionylamino)caprylic acid 358 183 4-(Salicyloyl)aminophenylethyltetrazole 359 184 8(-(4(N-Saliciloyl-4aminophenyl)butyric)aminocaprylic acid [sic] 360 185 4-(4-(N-(2-Fluorocinnamoyl))aminophenyl) butyric 361 186 4-(4-(N-8(N-Salicyloyl)aminocaprylic)aminophenyl)butyric acid 362 187 8-(p-anisoyl)aminocaprylic acid 363 188 8-(4-Hydroxybenzoyl)aminocaprylic acid 364 189 8-(3-Hydroxybenzoyl)aminocaprylic acid 365 190 8-(3,4,5-Trimethoxybenzoyl)aminocaprylic acid 366 191 8-(N-4-Methylsalicyloyl)aminocaprillic acid [sic] 367 192 N-10-(2-hydroxy-5-nitroanilino)decanoic acid 368 193 4-(4-(2-chloronicotinoyl)aminophenyl)butyric acid

and a salt of any of the foregoing.

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.