MXPA99007290A - Compounds and compositions for delivering active agents - Google Patents

Abstract

Carrier compounds and compositions which are useful in the delivery of active agents are provided. The carrier compound can be an amino acid derivative, and the active agent can be a peptide, mucopolysaccharide, carbohydrate, or lipid. Methods of administration, including oral administration, and preparation are provided as well.

Description

COMPOUNDS AND COMPOSITIONS TO RELEASE ACTIVE AGENTS.

Field of Invention The present invention relates to compounds for releasing active agents, and particularly biologically or chemically active agents. These compounds are used as carriers to facilitate the release of a charge to a target. Carrier compounds are very suitable for forming non-covalent mixtures with biologically active agents for oral administration to animals. The "methods of administration and preparation of such compositions are also described.

Background of the Invention Conventional means for releasing active agents are often severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which the release occurs, the environment of the release goal, or the Ref: 030904 objective itself. Chemically or biologically active agents are particularly vulnerable to such barriers.

For example, in the release for 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 several organic membranes that have to be crossed before reaching the target. Chemical barriers include, but are not limited to, pH variations, lipid bi-layers, and degraded enzymes.

These barriers are of particular significance in the design of oral delivery systems. Oral release of many biologically or chemically active agents may be the route of choice for administration to animals if not for biological, chemical, and physical barriers such as pH variation in the gastrointestinal tract (Gl), powerful digestive enzymes, and tro-intestinal gas membranes impermeable to the active agent. Among the numerous agents that are not typically sensitive for administration. oral are biologically or chemically active peptides, such as calcitonin and insulin; polysaccharides, and in particular mucopol and saccharides including, but not limited to, heparin; heparinoids; antibiotics; and other organic substances. These agents are rapidly fused ineffectively and are destroyed in the final tro-int gas tract by acid hydrolysis, enzymes, or the like.

The first methods for the oral administration of vulnerable pharmacological agents depended on the co-administration of adjuvants (for example, resorcinol and nonionic surfactants such as polyoxyethylether ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of the intestinal walls, as well as the co-administration of enzymatic inhibitors (for example, inhibitors of pancreatic trypsin, diisopropylfluorophosphate (DFF) and trasilol) to inhibit enzymatic degradation.

Liposomes are also described as drug delivery systems for insulin and heparin. See, for example, U.S. Patent No. 4,239,754; Patel et al. (1976), FEBS Le t t ers, Vol. 62, page 60; and Hashimoto et al. (1979), Endocrinol i and Japan, Vol. 26, page 337.

However, the use of broad spectrum of such drug delivery systems is impeded because: (1) the systems require toxic amounts of adjuvants or inhibitors; (2) the appropriate low molecular weight fillers, ie active agents, are not available; (3) the systems exhibit poor stability and inadequate in their shelf life; (4) systems are difficult to manufacture; (5) systems fail to protect the active agent (load); (6) the systems adversely alter the active agent; or (7) the systems fail to allow or promote the absorption of the active agent.

More recently, artificial polymer microspheres of mixed amino acids (proteinoids) have been used for the release of pharmacists. For example, U.S. Patent No. 4,925,673 describes carriers of proteinoid microspheres containing drugs as well as methods for their preparation and use. These proteinoid microspheres are useful for the release of a number of active agents.

There is still a need in the art for cheap delivery systems that are readily prepared and that can release a wide range of active agents.

Description of the invention.

Compounds and compositions that 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.

Aci 8 (2-trifluoromethoxy) benzoylamino caprylic acid N- (2-hydroxybenzoyl) isonipecotic acid Acid Acid 4- (4- (Phenoxyacetyl) aminophenyl) acid 8- (2-nitrobenzenesulfonyl) ammocaprylic acid Acid 6- (4- (salicyloyl) aminophenyl) hexanoic acid 8- (2-methoxybenzoyl) arapycaprilic 2- [(4-salt ? c? l? aminophenyl] ethylmethylsulfone i i i 4- (4- (2-Pyrazinecarbonyl) aminophenyl) butyric acid Acid 6- (? - í -2-nitrofienzoil) ammophenyl, nexanoic 6- (4- (N-2-aminobenzoyl) ammophenyl) hexanoic acid Acid 4 (2-nitrobenzoyl) aminophenylsuccinic acid Acid 8- (Benzyloxycarbonylamino) caprylic acid 8- (Phenoxycarbonylamino) caprylic acid 4- (4- (2-H drox? N? Cotmo? L) aminophenyl) ou i iicco acid Aci Acid 6- (2-methoxybenzoyl) amino nicotinic Aciao 5- (N-salicylolamine) valeric Acid 9- (2- (hydroxybenzamide) non-nico Acid 4-octane? Lam? No-3-hydroxyl benzoic acid (3-phenyl-2,3-dihydroxypropanoyl) -8-aminocaprylic acid 8- [N-3-fluorobenzoyl) aminocaprylic acid Ac Acid 8- (_N-3, _5rdj.a.c.et.c.et.j.-oxybenzoyl) aminocaprylic Acid 8- (8- (4-hydroxenzoyl) armnooctanoyl) aminocaprylic (dimer) - (N-2-methoxyanilino) sebacic acid 10- (N-2-hydroxamino) sebacic acid 2-methoxybenzylaminodecanoic acid Acid 8- [N- (3-bromobenzoyl) 1-aminocaprylic acid 8- (4- (1,2-dihydroxyethyl) benzole 1) ciminocaprylic acid 8- [N- (4-bromobenzoyl)] ammocaprylic acid 8- [ N- (4-iodobenzoyl)] aminocaprylic Acid 4-. { 4- [N- (2-iodobenzoyl) ammophenyl] Ibutyric Acid 4-. { 4- [N- (l-h.?drox?-2-naftoil) aminophenyl] Jbutír co ci o - 4- (2,3-d? methox? benzo? l) am? nofenil] propiónico - - (2-bromobenzo? l)] aminofemljbut ípco Acid 4- Acid 8- (N-3, 5-dihidroxibenzoil) aminocaprylic acid 8- (N-3,5-d-methoxy-4-hydroxybenzoyl) aminocaprylic acid 8- (N-2-6-d? methoxybenzoyl) aminocaprylic acid 4- Acid 8- (2-h? droxi-4-) chlorobenzoyl) ammocaprylic lf 4 (4 Acid 4- (4- (4-chloro-o-an? So? L) ammophene?) Butyric Ac Acid 3- Acid 4- (N- Acid 8-N- (4-methoxy-3-n? Trobenzoyl) ammocaprylic acid 8-N- (2-methox? -4-n? Trobenzo? I) am? Nocapr? Co acid Acid 4- ( 4- (4- (2, 5-dimethoxy? Oenzo? L) aminophenyl) acid ear 8 (N-2-h? drox? -5-bromobenzo? l aminocaprylic 3-indolbutyric acid 104 4- [4- (2,6-d? Methox? Benzoyl) ammophenyl] butyric acid Acid 8- (N-2-hydroxy? -5-chlorobenzoyl) aminocaprylic acid '& - (N-2-hydroxy-5-iodobenzoyl) aminocapric acid Acid 8- (N-2-hydroxy-4-nitrobenzoyl) aminocaprílic Acid 8- lN-5-metilsa? c? ioil) ammccaprilic acid 9- (cinny oylamino) nonanoic acid Acid Acid 4 ) Acid Amide 8 Acid 8- [N- (2-hydroxy-3,5-d-chlorobenzoyl)] aminocaprylic Acid 8-N- (2-chloro-6-fluorobenzoyl) aminocapryl Acid Acid 4-. { 4- [N-í3-h? Drox? -2-naftoil) am? Nofeml]} butí rich 'Acid 4-. { 4- [N- (3-hydrox? -2-naphtho? L) aminofeml] propanoic Acid 3- 8- (N-2-hydroxy-3,5-diiodobenzoyl) aminocaprylic acid 8- (N-2-chloro-4-fluorobenzoyl) aminocaprylic acid Acid 8- 8- (N-l-hydroxy-2-naphthoyl) aminocaprylic acid 8- (phthalamido) caprylic acid 10- (4-chloro-2-hydroxyanilino) sebacic acid mnoamide 4- (4- (4-Chloro-3-nitrobenzoyl) aminopheyl) butyric acid 11-N- (l-hydroxy-2-naphthoyl) aminoundecane acid Diamida de Bis ( 2- 2- [2-N- (4-chlorobenzoii) aminoethoxy] ethanol 4- (2-methox? Enzo? Lam? No) phen? L-2-carbox? Et? L sulphoxide 4- (2-methoxy-benzoylairu.no) phen? L-2-carbox? Et? L sulfone 2- [2- [2-N- (3-chlorobenzoyl) aminoethoxy] ethanol Dia iaa bis- »N-2-carpox? Feml-N- (N '-3 (4-ammophen? L) acid-cprr" j'in? Mur-? Oji, u, r.ea) oxalilc Trans-4- (2-am? Nobenzam? Domet? L) cyclohexanecarboxylic acid 11-N- (3,5-d? Chloro-2-hydro? Benzoyl) ammoundecane? 2- [N- ( 2-orcmoDenzo? L) ammoethoxy] ethane. 7-N- (3, 5-d? Chloro-2-h? Drox? Benzo? L) ammoheptanoic Acid N- [ Acid Acid 12-N- (3, 5-d? Chloro-2-h? Aroxy "berizoyl) ammododecanoicc N- (2-hydrox? -4-carbox? Phen?) -6-heptenapuda 3-N-cyclohexanediaminocaprylic acid - (4-chloro-2-hydroxyanilinocarbonyl) valeric acid Ac Aci 9- [2- (3-hydroxy) pyridylaminocarbonyl] nonar.ico acid Ac 2- [N- (2-hydroxybenzoylamino) ethoxy] ethanol Acid 8- (2 Acid 8- (2-hydroxy-5-chloroanilmocarbonyl) octanoic acid 5- (2-hydroxy-5-methylanilinocarbonyl) valeric Acid 4- (4- (2-d? Met? Lam? Nobenzo? L) aminophenyl) butyric 8- (3-phenoxypropionylamino) caprylic acid 4- (Salicyloyl) aminophenylethyltetrazole 8- (- (4-N-salt? C? Loyl) amnophenyl) butyric) aminocaprylic acid 4- (4-N- (4- (4-N- (2-Fluoro-cyanoamyl) aminophenyl) butyric) aminophenyl) butyric acid 4- (4- (N-8 (N-salicyloyl) aminocaprylic) aminophenyl) butyric acid Acid 8- (3-h roxibenzoil am nocaprílico • (N-4-Methylsal? Cyloyl) aminocaprylic acid 10-N- (2-h? Drox? -5-mtroanilino) -10-oxodecanoic acid 4- (4- (2-Chloronicotinoyl) aminophenylbutyric acid The compositions comprise the carrier compounds discussed above and active agents effective in the release of active agents for selected biological systems.

Detailed description of the invention.

The specific compositions of the present invention include an active agent and a carrier. These compositions can be used to release various active agents through various biological, chemical and physical barriers and are particularly suitable for releasing active agents that are subject to environmental degradation. The compositions of the subject invention are particularly useful for releasing or administering biologically or chemically active agents to any animal such as birds including, but not limited to, chickens, mammals, such as primates and particularly humans; and insects.

Other advantages of the present invention include the use of pure, inexpensive, easy to prepare materials. The compositions and methods of formulation of the present invention are cost-effective, simple to carry out, and sensitive to the industrial scale for commercial production.

The subcutaneous, sublingual, and intranasal co-administration 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, resulting in an increase in the bioavailability of the active agent compared to the administration of the active agent alone.

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

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 that they may by themselves not or only a fraction of the dose administered, pass through the gastrointestinal mucosa and / or be susceptible to chemical cleavage by acids and enzymes in the gastrointestinal tract; polysaccharides, and particularly mixtures of mucopolysacids; carbohydrates; lipids; or any combination thereof. Additional 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; er i t ropeiet ina; atrial nature factor; antigens; monoclonal antibodies; s ornaments t tina; adrenocort i cotropin, hormone of gonadotropin release; oxytocin; vasopressin; cromolyn sodium (sodium cromoglycate or disodium); vancomycin; desferrioxamine (DFO); ant i -microbianos, hormone for t i roidal, including, but not limited to anti-fungal agents; or any combination thereof.

Carriers Although compounds 1-193 above have been found to act as carriers for the oral release of biologically or chemically active agents, special mention is made of the compounds 9, 35, 64, 79, 102, 109, 111, 117 , 122, ml36, and 141, above.

The properties of compounds 1-193 are listed in Table I, below.

These carrier compounds or polyamino acids, and peptides, including amino acids, can be used to release active agents including, but not limited to, biologically or chemically active agents such as, for example, pharmacological and therapeutic agents.

An amino acid is any carboxylic acid that has at least one free amino group and includes synthetic and naturally occurring amino acids.

The polyamino acids are either peptides or two or more amino acids linked by a bond formed by other groups that can be attached, for example, an ester, anhydride, or an anhydride linkage.

The peptides are two or more amino acids joined by a peptide bond. The peptides can vary in length from the dipeptides with two amino acids to polypeptides with several hundred amino acids. See Chambers Biological Dictionary, edited by Peter M. B. alker, Cambridge, England: Chambers Cambridge, 1989, page 215.

Special mention is made of the di-peptides, tri-peptides, tetra-peptides, and penta-peptides.

Salts such as, for example, sodium salt or its carrier compounds can be well used.

Many of the compounds described herein are amino acid derivatives.

Many of the compounds of the present invention can be prepared rapidly. of amino acids including, but not limited to, aminocapric acid, butylhydroxyamine acid, aminophenylbutyroic acid, aminophenylhexanoic acid, aminophenylpropionic acid, amino salicylic acid, aminophenylsuccinic acid, aminononaic acid, aminonicotinic acid, amino vallenic acid, acid lactic aminopheni, aminocaproic acid, aminoundecanoic acid, aminohept anoic acid, aminohydroxybenzoic acid, and aminodecanoic acid by methods within the skill of those in the art, based on the present disclosure and the methods described in the US patent applications series number 60 / 017,902, filed March 29, 1996; 08 / 414,654, filed March 31, 1995; 08 / 335,148, filed on October 25, 1994; and 60 / 003,111, filed September 1, 1995.

For example, these compounds can be prepared by reacting the simple acid with the appropriate agent which reacts with the free amino moiety present in the amino acids to form amides. The protecting groups can be used to avoid unwanted side reactions as known to those skilled in the art.

The carrier compound can be purified by recrystallization or by fractionation on solid column supports. The suitable solvent crystallization system includes acetonitrile, methanol and tetrahydrofuran. The fractionation can be carried out on appropriate solid column supports such as aluminum oxide, using metanol / n-propanol mixtures as the mobile phase; reverse phase column supports using tri-fluoroacetic acid / acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water as the mobile phase. When the ion exchange chromatography is run, a gradient of sodium chloride to subsequent 0-500 mM is preferably employed.

Release Systems The compositions of the present invention can include one or more active agents.

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

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

Stabilizing additives can be incorporated into the carrier solution. With some medications, the presence of such additives promotes the stability and dispersibility of the agent in the solution.

The stabilizing additives can be used at a concentration range between about 0.1 and 5% (W / V), preferably about 0.5% (W / V). Suitably, but not limiting, examples of stabilizing additives include acacia gum, gelatin, methyl cellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are acacia gum, gelatin and methyl cellulose.

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

The total amount of the active agent, and particularly of the biologically or chemically active agent, to be used, can be determined by those skilled in the art. However, it has been surprisingly found that with some biologically or chemically active agents, the use of the presently described carriers provides an extremely efficient release, particularly in oral, intimate, sublingual, intraduodenal, rectal, vaginal, buccal, ophthalmic, oral systems. , or subcutaneous as well as systems to cross the blood / brain barrier. Accordingly, smaller amounts of biologically or chemically active agent such as those used in the previous unit dose forms or delivery systems can be administered to the subject, while still achieving the same blood levels and therapeutic effects.

The amount of carrier in the present composition is an effective amount of release and can be determined by any particular carrier or biologically or chemically active agent by methods known to those skilled in the art.

Unit dosage forms may also include any of the excipients; diluents; disintegrators; lubricants; plasticizers; colorants; and dosing vehicles, including, but not limited to water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.

The administration of the present compositions or dosage unit forms is preferably oral or by intraduodenal injection.

The release compositions of the present invention may also include one or more inhibitory enzymes. Such inhibitory enzymes include, but are not limited to, compounds such as actinonin or epiac t inonine and derivatives thereof. These compounds have the following formula s: Actinonin Epiactinonin Derivatives of these compounds are described in U.S. Patent No. 5,206,384. The actinonin derivatives have the following formula: wherein R is sulfoximeyl or carboxyl or a substituted carboxyl group selected from carboxamide, hydroxy aminocarbonyl and alkoxycarbonyl groups; and R6 is a hydroxyl, alkoxy, hydroxyamino or sulfoxyamino group. Other inhibitory enzymes include, but are not limited to, aprotinin (Trasilol) and Bo man-Bir k inhibitor.

The compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animal such as birds; mammals, such as primates and particularly humans; and insects. The system is particularly advantageous for releasing chemically or biologically active agents that would otherwise be destroyed or contribute to a lower effectiveness by the conditions found before the active agent in its target zone (ie, the area in which the active agent of the release composition are released) and into the body of the animal to which it will be administered. Particularly, the compounds and compositions of the present invention are useful in orally administered active agents, especially those in which they are not ordinarily orally released.

Description of the Preferred Modalities.

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

E j em lo 1 Preparing Carriers General Preparation of Carriers The following procedures were used to prepare the compounds as described herein. Many of the compounds were prepared by reaction of the appropriate amino acid with the appropriate acid chloride. The preparation of compounds 79 was given as a representative example of the compounds prepared in this way.

Preparation of Compound 79. Method A A 1 liter round bottom flask suitable with a magnetic stirrer was charged with 3- (4-aminophenyl) propionic acid (46.3 g, 0.28 moles, 1.17 equivalents) and 2 M aqueous sodium hydroxide (300 mL). 2,3-dimethoxybenzylchloride (48.0 g, 0.24 moles, 1.00 equivalents) was added in portions over 1 hour to the stirred solution. After the addition, the reaction was stirred for 2.5 hours at room temperature, and the pH of the solution was taken care of 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. This was redissolved in boiling acetone (ca 500 mL), decolorized with 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 was solidified on stirring at room temperature for 10 minutes. The crude solid was collected by filtration and recrystallized from 70% methanol-water (v / v) to provide compound 79 as a brown solid (39.5 g, 50%).

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 are also prepared by this process.

Preparation of Compound 79. Method B A 2-liter, three-necked round bottom flask was fitted with a magnetic stirrer and two additional funnels under an argon atmosphere. A suspension of 3- (4-aminophenyl) propionic acid (46.3 g, 0.28 moles, 1.17 equivalents) in ethyl acetate (700 mL) was added to the flask. A solution of 2,3-dimethoxybenzoylchloride (48.0 g, 0.24 moles, 1.00 equivalents) in ethyl acetate (250 mL) was charged to one of the additional funnels and added dropwise during 1 h. Triethylamine was subsequently charged ( 28.20 g, 0.28 moles, 1.00 equivalent) to the second funnel and added dropwise for 15 minutes. The reaction was stirred at room temperature for 3 hours, and the solvent was evaporated in vacuo giving a residual brown oil. Water (600 mL) was added to the residue followed by sodium hydroxide (500 mL, 2 M) and the mixture was stirred at room temperature for 3 hours. The resulting coffee solution was acidified with 2 M hydrochloric acid (ca 1 L). after cooling the mixture in an ice bath for 1 hour, a yellow solid formed and was collected by filtration. The solid was washed with water (3 x 1.5 L) and recrystallized from 50% ethanol-water (v / v) to give compound 79 as a brown solid (59.2 g, 68%).

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

Preparation of Compound 79. Method C A 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 equivalents) in dichloromethane (560 mL). Chlorot t rimet ilsilane (62.36 g, 0.57 moles, 2.05 equivalents) was added in one portion, and the mixture was heated to reflux for 1 hour under argon. The reaction was allowed to cool to room temperature and placed in an ice bath (internal temperature <10 ° C). The reflux condenser was replaced with an additional funnel containing triethylamine (42.50 g, 0.42 mol, 1.50 equivalent). The triethylamine was added dropwise over 15 minutes, and a yellow solid formed during the addition. The funnel was replaced by another additional funnel containing a solution of 2,3-dimethylbenzoylchloride (48.0 g, 0.24 moles, 1.00 equivalents) in dichloromethane (100 riiL). The solution was added dropwise during 30 minutes. The reaction was stirred in an ice bath for another 30 minutes and at room temperature for 1 hour. The dichloromethane was evaporated in vacuo to give a brown oil. The brown oil was cooled in an ice bath, and a 2 M sodium hydroxide solution cooled on ice (700 mL) was added. The ice bath was removed, and the reaction was stirred for 2 hours to provide a light brown solution. The solution was acidified with 2 M sulfuric acid (400 mL) and stored at 5 ° C for 1 hour. A yellow solid formed and was collected by filtration. The solid was washed with water (3 x 100 mL) and recrystallized from 50% ethanol-water (v / v) to provide compound 79 as brown needles (64.7 g, 82%).

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 are also prepared by this process.

Preparation of Compound 35 A solution of O-acetylsiliciloyl chloride (24.68 g, 124 mmol, 1 equivalent) in tetrahydrofuran (300 ml) was cooled in an ice bath. Triethylamine (25 g, 249 mmol, 2 equivalents) was added dropwise by means of an additional funnel. The 9-aminononanoa hydrochloride was dissolved in DMF (190 mL, slightly warm to dissolve), loaded into an additional funnel and added dropwise to the above mixture. The reaction was stirred in an ice bath for 20 minutes and at room temperature for 2 hours. Evaporation of the THF under reduced pressure gave a solution of pink DMF. The pink solution was cooled in an ice bath, and 2 M aqueous sodium hydroxide (300 mL) was added. After stirring was started at room temperature for 12 hours, the mixture was acidified with 2M hydrochloric acid (500 mL). The solution was cooled in an ice bath, and a solid formed. The solid was collected by filtration and recrystallized from 50% ethanol / water to give compound 35 (32 g, 87%) as a white off solid.

Preparation of Compound 49. 1- (2-Hydroxyphenyl) -3- (4-methyl-banzoate) -1,3-propane dione (3.00 g, 0.0101 mol) was placed in a 100 ml round bottom flask fitted with an argon trap , a magnetic stirring bar and a cold water condenser. Glacial acetic acid (20 ml.) And concentrated sulfuric acid (5 ml.) Were added, and heating of the reaction mixture was started. The reaction mixture was allowed to warm to reflux for 6 hours before the heating was discontinued. The reaction mixture was allowed to come to room temperature, and then it was emptied in 100 ml. Ice / water This was stirred for about 1/2 hour before the mixture was filtered, and a brown solid was isolated. The brown solid was recrystallized twice from acetic acid to afford compound 49 as a brown solid (1.44 g, 53.8%).

Preparation of Compound 167 2-Coumaranone (4.21 g, 0.0314 mol) was dissolved, with stirring, in acetonitrile (75 mis) in a 250 ml round bottom flask fitted with a magnetic stir bar, an argon trap and a cold water condenser. Triethylamine (3.18 g, 0.0314 mol) and 8-aminocaprilic acid (5.00 g, 0.0314 mol) were added, and a brown syrup was formed. The 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 was complete. The heating was stopped, the reaction mixture allowed to cool to room temperature, and concentrated in vacuo. The resulting residue was taken up in methylene chloride, and washed with two 100 ml portions of 1 N hydrochloric acid solution. The methylene chloride layer was dried with sodium sulfate and concentrated in vacuo. The resulting brown solid was allowed to dry in va cu or overnight, yielding compound 167 as a brown solid (8.35 g, 70.4%).

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

Preparation of Compound 120 A solution of 3.00 g (18.3 mmoles) of 2-nitrophenyliscyanate and 5 mL of tetrahydrofuran was dripped for 10 minutes into a cooled solution in an ice bath of 2.08 g (13.1 mmoles) of 8-aminocaprylic acid, 1.40 mL of 10 N NaOH and 40 mL of water. The reaction mixture was stirred for an additional 30 minutes, warmed to 25 ° C and treated with a 3% HCl solution until the pH was 5. The yellow precipitate was completely filtered and rinsed with 100 ml of water . The yellow solid was recrystallized from 2-propanol and water to give 3.7 g of compound 120 as pale yellow crystals.

Compounds 104-106 were also prepared by this procedure.

Preparation of Compound 133.

A suspension of 2.40 g (16.3 mmol) and 2.80 g (15.6 mmol) of 4 - (4-aminophenyl) bu tic acid in 20 mL of propylene glycol, 2.40 mL (1.74 g, 17.3 mmol) of trimethylamine and 10 mg (0.08 mmol) of dimethylaminopyridine were heated to 140 ° C. The mixture began to be a clear solution after 5 minutes at 140 ° C. After stirring for 330 minutes, the reaction mixture was cooled to 25 ° C and diluted with 20 mL of water. The solid phthalamide that formed was completely filtered. The filtrate was acidified with a 3% HCl solution. The resulting solid was completely filtered and recrystallized from 2-propanol and water to give 0.62 g of compound 133 as a brown solid, Preparation of Compound 138.

A solution of 1.73 g (12.9 mmol) of dialdehyde italic, 2.04 g of 8-aminocaprylic acid and 20 ml of acetic acid was heated to reflux for 10 minutes. The reaction mixture was cooled to 40 ° C, it was diluted with water and extracted with CH2Cl2 (2 X 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 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.

Preparation of Compound 140.

A mixture of 1.40 g (9.48 mmoles) of italic anhydride and 1.51 g (9.48 mmoles) and 8-aminocaprylic acid was heated at 150 ° C for 5 minutes.

Once cooled, 2.61 g of the solid of compound 140 was received.

Compound 150 was also prepared by this procedure.

Preparation of Compound 145 A suspension of 2.11 g (10.1 mmol) of ethyl carbamoylanthranilic acid and 5 mL of CH2C12 was treated with 2.20 mL of oxalyl chloride. After stirring for 1 hour the volatiles were stripped completely. At the same time, a suspension of 1. 60 g (10.1 mmol) of 8-aminocaprylic acid and 15 mL of CH2C12 was treated with 2.60 mL (2.23 g, 20.5 mmol) of TMSCI. This mixture was refluxed for 90 minutes, cooled in an ice bath and treated with 4.30 mL (3.12 g, 30.9 mmol) of triethylamine. Five minutes later, a syrup of the residue was added from the oxalyl chloride reaction in 20 ml of CH2C12. The reaction mixture was warmed to 25 ° C and stirred overnight. The acidification of the mixture was made with 3% HCl, a white solid formed, the solid was completely filtered and recrystallized from EtOH and water to give 1.88 g of compound 145.

Compound 153 was also prepared by this procedure.

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 iso- zoic anhydride, 20 mL of CH2C12, 20 mL of dioxane, and 4 mL of water was heated to reflux for 12 hours. hours. The solution was cooled to 25 ° C and extracted with ether (4 x 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.

Compound 103 is available from Aldrich Chemical Company, Inc., Milwaukee, Wl.

Example 2 Dosing Solutions of the Parathyroid hormone The doses of intercolonial compositions ("IC") contain 100 mg / kg of the carrier and 25 μg / kg of the parathyroid hormone in 25% of propylene glycol or oral solution of oral feeding ("PO") containing 400 mg / kg of the carrier and 100 μg / kg of the parathyroid hormone in water, were prepared with carriers 9, 33, 35, 77, 79, 109, 110, 123, 136, 141, and 169. The dose solutions they are designated as P- number of 'carrier -DS.

Comparative Example 2A Solutions of Dosage of the parathyroid hormone.

An intracolonic dose composition containing 100 mg / kg of the carrier has the formula and 25 μg / kg of the parathyroid hormone in 25% aqueous propylene glycol was prepared. The dosing solution is identified as P-9A-DS.

Example 3 - Liberation of the parathyroid hormone in vi.

Male Sprague-Dawley rats weighing 200-250 g, were fasted for 24 hours and were administered ketamine (44 mg / kg) and chlorpromazine (1.5 mg / kg) 15 minutes before the dose. The rats were administered one of the dosing solutions P-9-DS, P-33-DS, P-35-DS, P-77-DS, P-79-DS, and P-141-DS by feed through oral probe ("PO") or inst ra-colonic instillation ("IC"). Blood samples were collected in series from the tail artery for serum determination of the parathyroid hormone concentration. Concentrations of serum paratroid hormone were quantified by a parathyroid hormone immunoexact test host.

The results are illustrated in Table 2, below.

Comparative Example 3A - Liberation of Parathyroid Hormone in vi.

The procedure of Example 3 was followed by replacing the P-9A-DS dosing solution with the P-9-DS dosing solution. The results are illustrated in Table 2, below.

Comparative Example 3B Liberation of parathyroid hormone in vi.

The procedure of Example 3 was followed with a dosing solution (at a dose of 25 μg / kg of parathyroid hormone (int ra-colonon) or 100 μg / kg of parathyroid hormone (oral)), P-0A-DS, who omitted the carrier.

The results are illustrated in Table 2 below TABLE 2 - r ón 'viv the Paratiroid H ona Example 4 Recombinant Human Growth Hormone Dosage Solutions.

Composition of internal doses containing 25 mg / kg of carrier and 1 mg / kg of rHGH in phosphate buffer or oral feeding solution 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, 90, 94, 107, 109, 136, and 141.

The dosing solutions are designated as R- carrier number -DS.

Comparative Example 4A Solutions of Dosage of Human Growth Hormone Recombinant An intracolonic dosing solution was prepared in accordance with the procedure of Example 4, substituting a carrier having the formula for the carrier. This dosing solution is designated as R-35A-DS.

Comparative Example 4B Solutions Dosage of Human Growth Hormone Recombinant An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula for the carrier. This dosing solution is designated as R-35B-DS.

Comparative Example 4C Solutions Dosage of Human Growth Hormone Recombinant An intracolonic dosing solution was prepared according to the procedure of Example 4, substituting a carrier having the formula for the carrier. This dosing solution is designated as R-9A-DS.

Example Release of Recombinant Human Growth Hormone in vi vo.

Male Sprague-Dawley rats weighing 200-250 g were fasted for 24 hours and were administered ketamine (44 mg / kg) and chlorpromazine (1.5 mg / kg) 15 minutes before dosing. The rats were administered one of the dosage solutions of Example 3 by either oral tube feeding or intracolonic instillation. Blood samples were collected serially from the tail artery to determine serum rHGH concentrations. Serum rHGH concentrations were quantified by an immunoanalysis test device rHGH.

The results are illustrated in Table 3, below.

Comparative Example 5A Release of Recombinant Human Growth Hormone in vi The procedure of Example 5 was followed, replacing the dosage solutions of Comparative Examples 3A-3C for the dosing solutions.

The results are illustrated in Table 3, below.

Comparative Example 5B - Release of Recombinant Human Growth Hormone in vi.

The procedure of Example 5 was followed, with the dosing solutions of the active agent (at a dose of 1 mg of rHGH / kg (int racolonic) or 3 mg of rHGH / kg (oral) and without carrier. they were designated R0D-DS and R0E-DS, respectively, The results are illustrated in Table 3, below.

Example 6 - Release of Interferon in vi vo An intracolonic dosage composition containing 50 mg / kg of carrier 9 and 250 μg / kg of interferon in 50% propylene glycol was prepared. The rats were administered the dosage composition by intracolonic instillation. The release was evaluated using an ELISA assay for human interferon from Biosource, Inc. The concentration of interferon serum at the significant peaks was 2611 + 695.

Comparative Example 6A - Interferon release in vi vo.

The rats were administered, orally and by intracolonic instillation, dosing solutions of 1 mg / kg of interferon and without carrier. The release was evaluated in accordance with the procedure of Example 6. The concentration of interferon serum at the significant peaks was 1951 + 1857 (PO) and 79 + 100 (IC).

Example 7 Dosing Solutions for Heparin.

The intracolonic dosage compositions containing 50 mg / kg of the carrier and 25 mg / kg of heparin in 25% aqueous propylene glycol or oral feeding solution dosages containing 300 mg / kg of the carrier and 100 mg / kg of heparin in 25% aqueous propylene glycol was 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 were designated as H- carrier number -DS.

Comparative Example 7A Solutions Heparin dosage.

The comparative intracolonic dosing compositions were prepared according to the procedure of Example 7, substituting the following carriers for the carrier.

These dosing solutions were designated H-35A-DS, H-35B-DS, and H-109A-DS, respectively.

Example 8 - Evaluation of the Heparin in Rats.

The dosage solutions of Example 7 were administered to fasted rats either by oral gavage or intracolonic instillation.

Blood samples were collected by cardiac puncture followed by administration of ketamine (44 mg / kg). the activity of heparin was determined using the time t romboplas tino activated partial (APTT) according to the method of Henry, J.B. Clinical Diagnosis and Management by Laboratory Methods; Philadelphia, PA; W.B. Saunders (1979).

The results are illustrated in Table 4, below.

Comparative Example 8A - In vitro evaluation of heparin in rats.

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

The results are illustrated in Table 4, below.

Comparative Example 8B In vi vo evaluation of the Heparin in Rats.

An intracolonic dosing solution of 25 mg / kg of heparin and an oral gavage feeding solution of 100 mg / kg of heparin were administered to fasted rats. These dosing solutions were designated H-0A-DS and H-0B-DS, respectively.

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

The results are illustrated in Table 4, below.

The aforementioned patents, applications, test methods, and publications are incorporated herein completely for reference.

Those skilled in the art can suggest by themselves many variations of the present invention in light of the above detailed description. Such variations will obviously be within the fully attempted scope of the appended claims.

It is noted that in relation to this date, the best method known by the applicants to carry out the aforementioned invention, is that which is clear from the present description of the invention.

Having described the invention as above, the content of the following is claimed as property.

Claims (40)

Revindications.

1. A composition, characterized in that it comprises: (A) at least one active agent; and (B) at least one carrier selected from the group consisting of 4- (4- (phenoxyace il) aminophenyl) butyric acid Acid Aciao 8- (2-n? Trobenzenesulfon? L) ammocapryl Ac Acid 8- (2-methox? Benzo? I) to caprilic 2- [(4-salt? Cyl?) Ammophenyl] ethyl methylsulfone Hydrazide 1 -salicil oil-2-succ. _mlo Ac • do 4- (4- (2, 5-d? Methox? C? Namo? L) aminophenyl) butyric acid 4- < 4- i 4- (4- (2-pyrazomcarbonyl) ammo phenyl) butyric acid Acid Ipcc Acid (2-n? Robenzo? I) aminofeniiSUCCinic acid S-; 2-trifiuorcmethoxy! benzoyl) ammocaprílicc Acid 8- (phenoxycarbo i lamino) caprylic Aci Aci Acid 8- (2-h? Drcx? N? Cct? Nc? I? Aminocapri? C acid 6- (2-methoxybenzo? L) amino nicotinic acid CIO 5- -.N-salicilcilarr.mo, valeric Acid 9- .2-Hydrcx? Benzamido! non nicc 6- (N-4-N-salicyloyl) aminobenzoyl) aminocaproic acid Ll-cinnamoammoniododecanoic acid 4-octanoiiammo-3-hydrox? Benzo? Co-, J- miaroxiDropancí''L.-amir.ccac: do 8- (_N-3_5; dj..3-.etiloxibenz9il) aminocaprilico Acido 8 - (8- (4-H? Droxibenzo? I; ammooctanoil) ammocaprilic (dimer) 10- N-2-h? Arox? Amlmo acid) sebacic acid 2-me-ox? Bencenammoaecar.o: Acid 8- (-Denzoi / ammocaprico Acid 8- '_l-2-hydrox? -4-rretox? Benzo? L) aminccapplico Acid 8- [N- (3-bromooenzo?!! 1-aminocap yic acid.) Rrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrrr: Acid - (- N-aminophenyl) butyric Acid 4- ( Ac Aciao 4- ( -3, 5-d? N? Drox? Benzo? I1 amir.ocapríiico:? Ao 8- (N-3, 5-d? Ethox? -4-h? Drox? Benzo? L) aminocaprílicc (N-2- 6-d? Metox? Ber.zo? Li apunoca.rilico Acid 4-! 4- [N-; 4-Dromooenzo? L) ammofeml] Jbutíri'c Acido 8- (2-n? Drox? -4-ciorobenzo? l) ammocaprilic; gone 3- Aciao .Acido 4- (4- (2, 3-d? Me ox? Benzoii: ammo phenyl) buyric Ac Aciao Aciac 4-. { N- \ 4- i 3-yodcbenzoyl, aminophenyl] (butyric 7-c? Namo? Iammoheptanoico acid Acid 8-N- (4-methox? -3-n? Robenzo? I) am ocaprilico; cx? -4-n? Trocenzoi-, -. Mccapri-ic Acid 4-. { Acid 4-! 4- (2, 5-d? Methox? Zenzo?) Am cfepi. Du iric Acid '> " í 103 4- [4- (2,6-d? Methox? Benzo? L) ammophenyl] butyric acid ; gone 8- (N-2-hydroxy-5-ciorobenzoyl) ammocaprylic acid Ac "do- 8- (N-2-h? dro?? -5-iodobenzoii) ammocapr? ^? co Acid 3- IN-2- n.?c sx? -4 -.irrcbenzoii), ocaprilic Acid 8- (N-2, 3-d?? Drox? Oenzo? I: ammocaprilic Acid 8- (N-3-met? Lsalic? Io? L) ammocaprilic Aciao 9- Icinamoiamino) nonancic Acid Acid 4- (Amide of the 8- [N- (2-h? Drox? -3,5-d? Chlorobenzoyl)] ammocaprylic acid Acid Acid 4-. { 4- [N- (3-h? Drox? -2-naftoyl) aminofeml] (butipcc TO Acid 3 - 4 - 12, -dimecoxybenzoi ammo and i propiomco Acid 8-; N-2 -.-? Drox? -3, 5-d? Iodobenzo? I) aminocaprylic Acid 8- (Acid 8-12- (1, 2-d? H? Dro? Somdol-l-one) octanoicc Acid 8- (Nih? Drox? -2-naftoil) aminocaprííico rtaiamido) cap inco -cnoamide acid 10 - (4-chloro-2-? Droxianií? No) sebacic 4- (4- (4-Chloro-3-n? Trobenzo? I) ammo phenyl) biric Acid ii-N- (i-hydrox? -2-naphtho?) Aminoundecanoic acid Diamida de Bis ( 2- 2- [2-N- (-chlorobenzoyl) aminoethoxy] ethanol > - [2-N- (3-chlorobenzoyl) aminoethoxy] ethanol Dia-iaa cis- .N-2-carcox? Phen? L-N- (N '-3 (4-am? Nophenyl) propionic acid) Trans-4 Acid 11-N- (3, 5-d? Chloro-2? Drox? Benzo? L) am oundecanoic acid Ac: M- [ Acid Acid Ac -. - bormccenzcil morfcli m na 5- (4-Chloro-2-h? Droxianilinocarbonyl) -meric acid Acid 8- (2-hydrox? Fen? Lacet? L) -ammocaprilic acid Acid 9-Í2- (3-hydroxy) pir? Dilaminocarbonil] nondnico Acid (2-K? Drox? Phenoxyacet? L) ammocapryl 2- [N- (2-hydrox? Benzo? Lammo) ethoxy] ethanol Acid 8- - Acid 8- (2-h? Drox? -5 - chlororan? l? nocarboml) octanoic Acid 3-: 2-ethoxy? benzo? l) am ocaprico Acid 4- (4- (2-d? met? lam? noDenzo? l) ammophenyl) butyric Acid 8- (3- fenox? lprop? on? lam o) caprylic 4- isaliciloii) ami.nofenileti1tetrazol Acid 8- (4- (4-N-salt? C? Lo? L) aminofeml) butyric) ammocaprilico 4- (4-N- (4- (4-N- (2-Fluorocmamoyl) aminophenyl) butyric) ammophenyl) butyric acid 4- (4- (N-8 (N-salicyloyl) am ocapryl) am ofhenyl) butyric acid ? - (3-h? Arox? Benzo? L) am ocapríiico 10-N-? 2-hydroxy? -5-n? Troan? L? No) -10-oxodecane? Co Acyl 4- (4- (2-chlorcn? Cotmo? L) ammophenyl) butyric acid and a salt from any of the aforementioned

2. A composition as defined in claim 1, characterized in that the 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, characterized in that the biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

4. A composition as defined in claim 2, characterized in that the 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, erythropoetin, atrial naturético factor an antigen, a monoclonal antibody, tatina sous, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, des ferrioxamine (DFO), or any combination thereof.

5. A composition as defined in claim 4, characterized in that the biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations of the same.

6. A composition as defined in claim 1, characterized in that the carrier comprises a poly i (amino acid).

7. A composition as defined in claim 1, characterized in that the carrier comprises a polypeptide.

8. A unit dosage form, characterized in that it comprises (A) a composition as defined in claim 1; Y B '(to an excipient, £ b a diluent, (c) a disintegrant, (d) a lubricant, a plasticizer, (f) a colorant, (g) a metering vehicle, or (h) any combination thereof

9. A unit dosage form is as defined in claim 8, characterized in that the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination of the same.

10. A unit dosage form as defined in claim 9, characterized in that the biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

11 A unit dosage form as defined in claim 9, characterized in that the 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 naturético factor, an antigen, a monoclonal antibody, tadalafiloma, adrenocortico tropina, gonadotropin release hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, des-erri-oxamine (DFO), or any combination thereof.

12. A unit dosage form cone is defined in rei indication 11, characterized in that the biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone , and combinations thereof.

13. A unit dosage form, characterized in that it comprises [A) a composition as defined in claim 6; Y B) an excipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a metering vehicle, or (h) any combination thereof

14, A unit dosage form as defined in claim 13, characterized in that the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.

15. A unit dosage form as defined in claim 14, characterized in that the biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

16 • A unit dosage form as defined in rei indication 14, characterized in that the biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone releasing hormone, a interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturético factor, an antigen, a monoclonal antibody, soma tos tat ina, adrenocortic cotropine, gonadotropin releasing hormone, oxytocin, vasopressin, cromolino of sodium, vancomycin, parathyroid hormone, des ferrioxamine (DFO), or any combination thereof.

17. A unit dosage form as defined in claim 16, characterized in that the biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

18. A unit dosage form, characterized in that it comprises (A) a composition as defined in claim 7; Y (B) (a) an excipient, (b) a diluent, (c) a disintegrant, (d) a lubricant, (e) a plasticizer, (f) a colorant, (g) a metering vehicle, or (h) any combination of them

19. A unit dosage form as defined in claim 18, characterized in that the active agent is selected from the group consisting of a biologically active agent, a chemically active agent, or a combination thereof.

2 O. A unit dosage form as defined in claim 19, characterized in that the biologically active agent comprises at least one peptide, mucopolysaccharide, carbohydrate, or lipid.

21. A unit dosage form as defined in claim 19, characterized in that the 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 naturético factor, an antigen, a monoclonal antibody, tatina ornaments, adrenocort icot ropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, parathyroid hormone, des ferrioxamine (DFO), or any combination thereof.

22. A unit dosage form as defined in claim 21, characterized in that the biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, parathyroid hormone, and combinations thereof.

23. A unit dosage form as defined in claim 8, characterized in that it comprises a tablet, a capsule, or a liquid.

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

25. A unit dosage form as defined in claim 13, characterized in that it comprises a tablet, a capsule, or a liquid.

26. A unit dosage form as defined in claim 25, characterized in that the dosage vehicle is selected from the group consisting of water, 1,2-propanediol, ethanol, or any combination thereof.

27. A unit dosage form as defined in claim 18, characterized in that it comprises a tablet, a capsule, or a liquid.

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

29. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises orally administering to the animal a composition as defined in claim 2.

30 A compound selected from the group consisting of Acid Acid 8 ', 2-trifluoromethoxy enzo am caprylic acid N- (2-hydroxybenzoyl) isonipecotic Acid Aci 8- '2-methoxybenzoic acid i) ammo caprylic acid 2- [(4-salt? Cyl) ammophenyl] ethyl methylsulfone Acid 4- v4- ( 4- (4- (2-p? Razmcarbonyl) am ofhenyl) butyric acid ?or Ac 4- (4- Acid 4 (2-n? Trobenzo? I! Am ofennylsuccinic acid Acid "3- (benzyloxycarbonylamino) cacrylic Acid 8- (phenoxycarbonylamino) caprylic 1 Acid 8- (2-h? Droxm? Cot? Nc? L) ammocaprilic Acid 6- (2-methoxybenzoyl) ammo nicotinic acid 8-cinnamoylaminocapr acid N'-sal? C? Loi_a ~? R.o) valéruco Acid Acid 11-c? Namo? Lammoundecano? 4-co octane? Lammo-3-? Drox? Benzo? Co Aciac 3-phen? .- 2, 3-a? P? Drox? Propanc? L -3-ammccapr. Acid 8- [N-3-f luorcbenzoií) J ammocappiico acid 8- (? I-2, '' -aimetcxi enzoi) ammocapp ico acid 10- (N-2- idrox? N? I? Not) sebacicc acid 2- methox? bencenaminodecanoioo Acid - (N-2-hydroxy-4-methoxybenzoyl) ammccaprilic acid 8- [N- (3-bromobenzoyl) 1 ammocaprylic acid. , 2-a? .? arcx? er i. oce zcil (aminocapi Aciao 8- [N- (4-iodobenzo? L) j ammocapriiic acid 4- (4- [N- (2-yoaobenzo? I) ammophenyl] 'butycid Acid 4- { 4- [N- (lh.idrox ? -2-naphtho? L) ammofenii] (but rich ci or 3- [4- (2,3-d? methox? benzo? l) am? nofen? i] prop? on? c Aciao 4- i 4- V- 3-DrcmoDenzo? _)] ammophenyl (butyric) Acid 3- M-3, 5-d? ? drox? benzo? í > aminocaprylic iciao 3- (N-3, 5-d? MetOx? -4-h? droxibenzo? l) LOO aminocapplico 8- (N-2-6-d? MetOx? ber.zc? l) aminocaDrilico acid 4- 8 - (2-n? Drox? -4-chlorobenzo?) Aminocapplica Aciao 3- (N-2-h? Drox? -ó-metcx? Ber.zo? L 'ammocaprilicc Acid 8-: 5-cyclo-o-an? Sol) ammocaprilic Acid 4- (4- (2, 3- a? metox? oenzo? i) am ofenil! butyric Acid 4- l4- (5-chloro-o-an? so? í) ammophenyl) butyric acid 4- (4- (-c oro-o-an? so? l) ammophen? l) butyric OO 3- Acid 4-. { N- 4- i -yo or enzo? : am or enyl] (butyric Acid 8-N-? 4-methox? -3-n? Trobenzo? Lj am ocaprilic acid = -N- rcDe.zoi- arr.inccapr .i icido 4-. { Acid 4- (4- (2, 5-d? Mecox? Oenzo? L) ammofemi) buC rico Acid 8- (? ^ V - 29l-h? Drox? -5-bromoDenzoyl) am ocaprilic 101 4- [4- (2, o-d? Methox? Benzo? L) ammophenyl] butyric acid Acid ? Acid: 3- do (? -2-n arcx -4- ücrcbenzoi 1) ammocaprílico acid 8- (N-3-meth isai c what l????) Ammocaprílico I4-2-nitrophenyl '- ( Acic ± 8-octanoic) acid amide urea N- (2-MetOx? -5-nitrophenyl) sebecoi acid 8- [N- (2-h? drox? -3, 5-d? chlorobenzoyl)] aminocaprylic Acid Acid 4-. { 4- [N- (3-h? Drox? -2-naftoyl) aminophenyl] Jbutiri co Acid 8-, 2-cioro-5-n? Tr? Denzo? L) am ocapply Acid 4- (4-phthalimid)? Dutin? Acid 4 3- (Acid 8- (N-2-n? Drox? -3,5-d? Iodobenzoii) aminocaprílic acid 8- (N-2-Cioro-4-fluorobenzoyl) aminocaprylic acid Acid 8- 8- (N-l-hydroxy-2-naphthoyl) aminocaprylic acid cpoapide of 10- (4-chloro-2-h? Droxianilino) sebacic acid 4- (4- (4-Chloro-3-nitrobenzoyl) aminophenyl) butyric acid L-N- (l-hydroxyl-2-naphthyl) aminoundecane acid Bis (2- [2? N-? 2-cyorobenzoii) ammoecoxy] ecanoi [2-N-4-chlorobenzoyl) aminoethoxy] ethanol diamide. 4- (2-methox? Benzo? Lammo) phen? L-2-carbox? Et? L sulfoxide 4- (2-methox? Benzo? Lammo) phen? L-2-carbox? Et? Lsulf ona Acid 4- (4- (3-hyd ox? F talamido) phenyl) ui ric - [2- [2-N- (3-chlorobenzoyl punoethoxy] ethanol Diamase bis-, N-2-carcox? Phen? I-N- (N '-3 (4-ammophene) aciao. Pr. Pion? Co) urea) oxal :: o Trans-4 -am? No enzam? Domet? L acid) c? Clohexancarbox? L? 11-N- (3, 5-d? Chloro-2-h? Drox? Benzo? L) am oundecanoic acid 7-M-3, 5-dichloro-2-hydroxybenzoii) aminoheptanoic acid N- [3, 5- dichloro-2-hydrox? benzo? l-4 (4-ammophene?!! butyric Acid gone Acid 12-N- (3, 5-diorioro-2-h? Arox? Derfzo l) am? Nodedecanoic 1 - Ormccenzo? , morf oi a 2- 5- (4-chloro-2-hydrox? An? Linocarbonyl) valeric acid Aci or 4- (- t -eccx? Enzo?, Am ofenii, outirico Acid 9- [2- (3-h? Drox?) Pipdilammocarbonyl] nonar._c Acid "'-? 2-H? Drox? F enoxyacetil) ammocapplic 2- [N- (2-hydroxyDenzo? Lammo) ethoxy] ethanol narox? -5-cyanoan? Imccar:: or.?.) Octanoic Acid 8 - 2-ethoxy? Benzo? L) aminccaprilic acid 4- (4- (2-d? Met? Lam? Nobenzo? L) ammophenyl) butyric Acid 8- (3-phenoxylprop? On? Lammo) capplyc Acid 8- (4- (4-N-salt? C? Lo?) Ammophenyl) butyric) ammocaprylic Acid 4- (4-N- (4- (4-N- (2-Fluoroc? Namo? L) aminophenyl) butyric) aminophenyl) butyric acid 4- (4- (N-3 (N-salicyloxy) ammocapryl) am ofhenyl) butyric ci o - (p-an? so? i) ammocaprilic acid 3- (3-? drcx? benzo? l) ammocaprílicc Acid Acid 10-N- (2-hydroxy-5-nitroaiu.lino) -10-oxodecanoxcs 4- (4- (2-chloron-cotonyl) ammonium) butyric acid and a salt of any of the above mentioned.

31. A method for preparing a composition, the method is characterized in that it comprises mixing: (A) at least one active agent; (B) at least one compound as defined in claim 31; and (C) optionally, a dosing vehicle.

32. A method for administering a biologically active agent to an animal in need of such an agent, the method characterized in that it comprises administering intranas ally to the animal a composition as defined in claim 2.

33. The method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises sublingually administering to the animal a composition as defined in claim 2.

34. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises administering intimately to the animal a composition as defined in claim 2.

35. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises administering subcutaneously to the animal a composition as defined in claim 2.

36. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises rectally administering to the animal a composition as defined in claim 2.

37. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises administering vaginally to the animal a composition as defined in claim 2.

38. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises buccally administering to the animal a composition as defined in claim 2.

39. A method for administering a biologically active agent to an animal in need of the agent, the method is characterized in that it comprises administering ophthalmically to the animal a composition as defined in claim 2.

40. A method for passing a biologically active agent through the blood / brain barrier of an animal in need of the agent, the method is characterized in that it comprises administering to the animal a composition as defined in claim 2.