MXPA01000924A - Compounds and compositions for delivering active agents - Google Patents

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

COMPOUNDS AND COMPOSITIONS TO ADMINISTER ACTIVE AGENTS Field of the Invention The present invention relates to compounds for administering active agents, and particularly biologically or chemically active agents. These compounds are used as carriers to facilitate the administration of an active agent towards a target. Carrier compounds are well suited to form non-covalent mixtures with biologically active agents for pulmonary, oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, rectal, vaginal, mucosal, transdermal, intradermal, parenteral administration, intravenous, and intramuscular in animals, as well as to cross the blood barrier of the brain. Methods for the preparation and administration of these compositions are also described.

Ref: 126502 Background of the Invention Conventional methods for administering active agents are commonly severely limited by biological, chemical, and physical barriers. Typically, these barriers are imposed by the environment through which the administration occurs, the target environment for its supply, or the objective itself. Biologically or chemically active agents are particularly vulnerable to these barriers. For example, in the delivery to animals of therapeutic and pharmacological agents that are biologically active or chemically active, barriers are imposed by the body. Examples of physical barriers are the skin and various membranes of the organs that must pass through before reaching the target. Chemical barriers include, but are not limited to, pH and lipid bilayer variations, and degrading enzymes. These barriers are of particular significance in the design of drug delivery systems. For example, oral administration of various biologically or chemically active agents is the alternate route of choice for administration in animals if it were not for biological, chemical and physical barriers such as pH variation in the gastrointestinal membranes. Among the various agents that are not typically suitable for 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 rapidly become ineffective or are destroyed in the gastrointestinal tract by acid hydrolysis, enzymes, and the like. In addition, the size and structure of macromolecular drugs can prohibit their absorption. The fact of crossing the cerebral blood barrier, as well as oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, mucosal, transdermal or pulmonary administration to the circulatory system for various biologically active agents can be the route of choice for administration in animals if it were not for physical barriers such as skin, lipid bilayers, and various organic membranes that are relatively impervious to certain biologically active agents, but one or more of these must be crossed before the agent administered through these routes can reach the circulatory system. In addition, the administration of such OOID, for example sublingual administration can be impeded by chemical barriers such as variable pH in the gastrointestinal tract (Gl) and the presence of powerful digestive enzymes. The above methods for oral administration of vulnerable pharmacological agents have relied on co-administration. of adjuvants (for example, resorcinols and nonionic surfactants such as polyoxyethylene oleyl ether and n-hexadecyl polyethylene ether) to artificially increase the permeability of intestinal walls, as well as the co-administration of enzyme inhibitors (for example, inhibitors) of pancreatic trypsin, diisopropylfluorophosphate (DFF) and trasilol) to inhibit enzymatic degradation. Liposomes have also been described as drug delivery systems for insulin and heparin. See, for example, Patent No. E.U.A. 4,239,754; Patel et al. (1976), FEBS Letters, Vol. 62, page 60; and Hashimoto et al. (1979), Endocrinology Japan, Vol. 26, page 337. However, the broad spectrum of use of these drug delivery systems is impeded due to: (1) that the systems require toxic amounts of adjuvants or inhibitors; (2) that adequate charges of low molecular weight, ie active agents, are not available; (3) that the systems exhibit poor stability and inadequate shelf life; (4) that the systems are difficult to manufacture; (5) that the systems can not protect the active agent (load); (6) that the systems adversely alter the active agent; or (7) that 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 to deliver the pharmaceutical agents. For example, Patent U.S. Patent No. 4,925,673 discloses the proteinoid carriers of microspheres containing the drugs as well as methods for their preparation and use. These proteinoid microspheres are useful for the preparation of a variety of active agents. However, there is still a need for simple and inexpensive administration systems that are easily prepared and that can administer a wide range of active agents through various routes.

Brief Description of the Invention The present invention provides the compounds having the formula and you come out of this. These compounds are useful for the administration of active agents. Another embodiment of the invention is a composition comprising: (A) at least one active agent; and (B) a carrier comprising a compound having the formula or salts of this. Unitary dosage forms comprising the above composition and an excipient, a diluent, a disintegrating agent, a lubricant, a plasticizer, a colorant, a dosing vehicle, or any combination thereof are also provided. Methods for administering a biologically active agent to an animal in need of the agent via the pulmonary, oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, rectal, mucosal, transdermal, intradermal, parenteral, intravenous route , or intramuscular or to cross the blood barrier of the brain with the compositions of the present invention, are also provided.

Brief Description of the Figures Figure 1 is a graphic illustration of blood glucose levels after pulmonary administration of insulin. Figure 2 is a graphic illustration of blood glucose levels after pulmonary administration of insulin.

Detailed Description of the Invention A group of compositions of the present invention includes an active agent and a carrier that includes the compound 2- (4-N-salicyloyl) aminophenyl) propionic acid or salts thereof, such as the sodium salt thereof ( 2- (4-N-salicyloyl) aminophenyl) propionate) sodium. These compositions can be used to administer various active agents through the various biological, chemical and physical barriers and are particularly suitable for administering active agents that are subject to environmental degradation.

The subject compositions of the invention are particularly useful for administering or delivering biologically or chemically active agents to any animal such as birds, including but not limited to chickens, mammals, such as primates, and particularly in humans; and insects. Other advantages of the present invention include the use of inexpensive raw material. The compositions and methods of formulation of the present invention are cost-effective, simple to carry out and pleasing to the industrial scale for commercial production. The pulmonary, oral, subcutaneous, intranasal, sublingual, buccal, ocular, intracolonic, intraduodenal, rectal, vaginal, mucosal, transdermal, intradermal, parenteral, intravenous, and intramuscular administration of an active agent such as, for example, the hormone recombinant human growth (rhGH); salmon calcitonin; insulin; heparin, including but not limited to, low molecular weight heparin and very low molecular weight heparin; parathyroid hormone (PTH); and compounds of the compositions as described herein result in an increased bioavailability of the active agent as compared to the administration of the active agent alone.

Active Agents Active agents suitable for use in the present invention are biologically and chemically active agents including, but not limited to, cosmetics, pesticides, pharmacological agents, and therapeutic agents. For example, biologically or chemically active agents for use in the present invention include, but are not limited to, proteins; polypeptides; peptides, and particularly small peptides; hormones, and particularly hormones that in themselves do not pass or only a fraction of them pass through the gastrointestinal mucosa and / or are so susceptible to chemical cleavage by the acids and enzymes in the gastrointestinal tract; polysaccharides, and particularly mixtures of mucopolysaccharides; carbohydrates; lipids; and other organic compounds; or any combination of these. Other examples include, but are not limited to, the following; including synthetic, natural or recombinant sources of these: growth hormones, including human growth hormones (hGH), recombinant human growth hormones (rhGH), bovine growth hormone, and porcine growth hormone; hormones releasing growth hormone; interferons, including α, β and β; interleukin-1; Interleukin-II; insulin; insulin-like growth factor, including IGF-1; heparin, including unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, and ultra low molecular weight heparin; calcitonin, including salmon, eel and human; erythropoietin (EPO); atrial naturético factor; antigens; monoclonal antibodies; somatostatin; protease inhibitors; adrenocorticotropin, gonadotropin-releasing hormone; oxytocin; luteinizing hormone-releasing hormone; follicle stimulating hormone; glucocerebrosidase; thrombopoietin; filgrastima; prostaglandins; cyclosporin; vasopressin; cromolyn sodium (cromolyn sodium or disodium); vancomycin; desferrioxamine (DFO); parathyroid hormone (PTH), including its fragments; antimicrobials, including antifungal agents; analogs, fragments, mimetics or modified derivatives of the polyethylene glycol (PEG) of these compounds; or any combination of these.

Carriers Carrier compounds of the present invention include 2- (4-N-salicyloyl) aminophenyl) propionic acid and its salts. Salts of the compound include, but are not limited to, organic and inorganic salts, such as the sodium salt: 2- (4-N-salicyloyl) aminophenyl) propionate sodium In addition, the carriers of the present invention include the polyamino acids and peptides comprising one or more of the carrier compounds of the present invention. These carrier compounds, polyamino acids, and peptides can be used to administer active agents including, but not limited to, biologically or chemically active agents, such as, for example, pharmacological and therapeutic agents. An amino acid is a carboxylic acid having at least one free amine group and includes natural and synthetic amino acids.

The polyamino acids are either peptides or two or more amino acids linked via a bond that is formed by other groups that may be linked, for example, an ester, anhydride, or an anhydride linkage. The peptides are two or more amino acids joined by a peptide bond. The peptides may vary in length from the dipeptides with two amino acids to the polypeptides with several hundred amino acids. See Chambers Biological Dictionary, editor Peter M. B. Waiker, Cambridge, England: Chambers Cambridge, 1989, page 215. Special mention is made of the dipeptides, tripeptides, tetrapeptides, and pentapeptides. The carriers described herein can be derived from amino acids and can be readily prepared from amino acids by methods within the skill of those in the art based on the present disclosure and methods described in WO96 / 30036, WO97 / 36480, US 5,643,957 and US 5,650,386. For example, the compounds can be prepared by reacting a single amino acid, mixtures of two or more amino acids, or amino acid esters with the appropriate acylating agent or amine modifier, which reacts with an amino-free portion present in the amino acid to form the amides. The protecting groups can be used to avoid undesired side reactions as known to those skilled in the art. With respect to protecting groups, reference is made to T. W. Greene, Protecting Groups in Organic Synthesis, Wiley, New York (1981), the description is incorporated herein for reference. Suitable examples, but not limiting, of the acylating agents useful for preparing the acylated amino acids include the acid chloride acylating agents having the formula wherein R1 is a group appropriate for the modified amino acid being prepared, such as, for example, but not limited to, alkyl, alkenyl, cycloalkyl, or an aromatic group, and particularly methyl, ethyl, cyclohexyl, cyclophenyl, phenyl, or benzyl, and X is a residual group. Typical residual groups include, but are not limited to, halogens such as chlorine, bromine and iodine.

Examples of acylating agents include, but are not limited to, acyl halides including, but not limited to, acetyl chloride, propyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride, benzoyl chloride, hipuryl, and the like, and anhydrides, such as acetic anhydride, propyl anhydride, cyclohexanoic anhydride, benzoic anhydride, hippuric anhydride, and the like. Preferred acylating agents include benzoyl chloride, hipuryl chloride, acetyl chloride, cyclohexanoyl chloride, cyclopentanoyl chloride, and cycloheptanoyl chloride. Amino groups can also be modified by the reaction of the carboxylic acid with coupling agents such as the carbodiimide derivatives of the amino acids, particularly hydrophilic amino acids such as phenylalanine, tryptophan, and tyrosine. Other examples include dicyclohexylcarbodiimide and the like. If the amino acid is multifunctional, ie, having more than one group -OH, -NH, or -SH, then it can be acylated optionally in one or more of its functional groups to form, for example, an ester, amide bond , or thioester. For example, in the preparation of many acylated amino acids, the amino acids are dissolved in an aqueous alkaline solution of a metal hydroxide, for example, sodium or potassium hydroxide and then the acylating agent is added. The reaction time may range from about one hour to about 4 hours, preferably about 2 to about 2.5 hours. The temperature of the mixture is maintained at a temperature generally ranging from about 5 ° C to about 70 ° C, preferably between about 10 ° C and about 50 ° C. The amount of alkali that is employed per equivalence of NH groups, in amino acids generally ranges from about 1.25 moles to about 3 moles, and is preferable between about 1.5 moles and about 2.25 moles per equivalence of NH2. The pH of the reaction solution generally ranges from about pH 8 to about pH 13, and is preferable between about pH 10 and about pH 12. The amount of amino-modifying agent used in relation to the amount of amino acids is based on the moles of the total amount of free NH, in the amino acids. In general, the amino modifying agent is employed in an amount ranging from about 0.5 to about 2.5 molar equivalents, preferably from about 0.75 to about 1.25 equivalents, per molar equivalent of the total NH groups in the amino acids. The reaction for formation of the modified amino acids is typically quenched by adjusting the pH of the mixture with a suitable acid, for example, concentrated hydrochloric acid, until the pH reaches between about 2 and about 3. The mixture is separated by remaining at room temperature to form a transparent topcoat and a white or off-white precipitate. The upper layer is discarded from the modified amino acids are collected by filtration or decanting. The crude modified amino acids are then mixed with water. The insoluble materials are removed by filtration, and the filtrate is dried in a vacuum. The production of modified amino acids generally ranges from about 60%, and usually about 45%. The present invention also contemplates amino acids that have been modified by a multiple acylation, for example diacylation or triacylation, etc. If the amino acid esters or amides are the raw material, they are dissolved in a suitable organic solvent such as dimethylformamide or pyridine, and reacted with the amino modifying agent at a temperature ranging from about 5 ° C to about 70 ° C. C, preferably at about 25 ° C, for a period of time ranging from about 7 to about 24 hours. The amount of the amino modifying agents that are used in relation to the amino acid esters are the same as described above for amino acids. In the following, the reaction solvent is removed under a negative pressure, and optionally, the ester or amide functionality can be removed by hydrolysing the modified amino acid ester with a suitable alkaline solution, for example 1 N sodium hydroxide, at a temperature encompassing between about 50 ° C, about 80 C, preferably about 70 ° C, for a period of time sufficient to hydrolyze the ester group and form the modified amino acid having a free carboxyl group. The hydrolysis mixture is then cooled to room temperature and acidified, for example, with an aqueous solution of 25% hydrochloric acid, at a pH ranging from about 2 to about 2.5. The modified amino acids are precipitated out of the solution and recovered by conventional methods such as filtration or decantation. The modified amino acids can be modified by acid precipitation, recrystallization, or fractionation in one or more solid chromatographic supports, alone or in series. Suitable systems of recrystallization solvents include, but are not limited to, acetonitrile, methanol and tetrahydrofuran. The fractionation can be carried out in a suitable chromatographic support such as silica gel or alumina, by using mixtures of solvents such as methanol / n-propanol or acetic acid / butanol / water mixtures as the mobile phase. The reversible phase column supports utilize trifluoroacetic acid / acetonitrile as mixtures in the manner of the mobile phase, and an ion exchange chromatography which uses the water as the mobile phase. When anion exchange chromatography is carried out, a gradient of 0-500 mM sodium chloride is preferably used. The modified amino acids are also purified by extraction with a lower alcohol such as methanol, butanol or isopropanol to remove impurities such as inorganic salts. Modified amino acids are generally soluble in an alkaline aqueous solution (pH >; 9.0); partially soluble in ethanol, n-butanol and 1: 1 (v / v) in a toluene / ethanol solution, and are insoluble in neutral water. The alkali metal salts, for example the sodium salts of the modified amino acids are generally soluble in water at a pH of about 6-8. In the polyamino acids or peptides, one or more of the amino acids can be modified, acylated and / or sulfonated. The polyamino acids and polypeptides may include one or more acylated amino acids. Although the linearly modified polyamino acids and also the peptides generally include only one acylated amino acid, other configurations of polyamino acids and peptides may include more than one acylated amino acid. The polyamino acids and peptides can be polymerized with the acylated amino acids or can be acylated after the polymerization.

Administration Systems The compositions of the present invention can include one or more active agents. In one embodiment, the above compounds or the salts of these compounds or the polyamino acids or peptides that include at least one of these compounds or salts can be used directly as a carrier of administration simply by mixing one or more compounds or salts , polyamino acids or peptides with the active agent before its administration.

The administration mixtures are prepared by mixing an aqueous solution of the carrier with an aqueous solution of the active ingredient, just before its 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 the phosphate buffered salts, citric acid, acetic acid, gelatin, and acacia gum. Stabilizing additives can be incorporated into the carrier solution. With some drugs, the presence of these additives promote the stability and ease of dispersion of the agent in a solution. Stabilizing additives can be used at a concentration ranging between approximately 0.1 and 5% (w / v), preferably, in approximately 0.5% (w / v).

Suitable but not limiting examples of the stabilizing additives include acacia gum, gelatin, methylcellulose, polyethylene glycol, carboxylic acids and salts thereof, and polylysine. The preferred stabilizing additives are acacia gum, gelatin, and methylcellulose. The amount of the active agent is an amount effective to achieve the purpose of the active agent in particular for the indication of the target. The amount of the active agent and the compositions is typically a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount may be less than the amount pharmacologically, biologically, therapeutically, or chemically effective when the composition is used in a unit dosage form, such as a capsule, a tablet, a powder, a liquid because the form unit dosage may contain a variety of biologically or chemically active carrier / agent compositions which may contain a pharmacologically, biologically, therapeutically, or chemically effective and divided amount. The effective total amount can then be administered in cumulative units containing, in total, pharmacologically, biologically, therapeutically, or chemically active amounts of the biologically or pharmacologically active agent. The total amount of the active agent and particularly the 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 described carriers provides an extremely efficient administration, particularly in the systems of oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic administration systems. , rectal, vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous, intramuscular and ocular, as well as to cross the blood barrier of the brain. Therefore, lower amounts of the biologically or chemically active agents than those used in the above unit dosage forms or in the delivery systems can be administered in a subject, while still achieving the same blood levels and effects. therapeutic The amount of the carrier in the present compositions is an effective amount for administration and can be determined for any biologically or chemically active carrier or agent in particular by methods known to those skilled in the art. The effective amounts of the active agent and the carrier in the composition can vary over a considerable range and are age dependent, weight, sex, sensitivity, medical history and similar of the individual. Clearly, it is necessary to take in the nature of the active agent and the carrier, the specific activity of the agent (units of bioactivity / mass), and its rate of absorption in the gastrointestinal tract, all of which contribute to the determination of the therapeutically effective dose. After administration, the active agent present in the composition or in the unit dosage form is rapidly absorbed into the circulation. The bioavailability of the ingested agent is easily assessed by quantifying a known pharmacological activity in the blood, for example an increase in blood coagulation time caused by heparin, or a decrease in circulating calcium levels caused by calcitonin. The unit dosage forms may also include any of the excipients, diluents, disintegrating agents, lubricants, plasticizers, colorants, flavorants, taste masking agents, sugars, sweeteners, salts, and dosage vehicles, including, but not limited to, the water, 1,2-propanediol, ethanol, olive oil, or any combination of these. The administration compositions of the present invention may also include one or more enzyme inhibitors. These enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof. Derivatives of these compounds are described in U.S. Patent No. 5,206,384, of which the disclosure is incorporated herein by reference. Other enzyme inhibitors include, but are limited to, aprotinin (Trasylol) and the Bowman-Birk inhibitor. The system is particularly advantageous for administering chemically or biologically active agents that are otherwise destroyed or made less effective by the conditions encountered before the active agent reaches its target zone (i.e. the area in which the active agent of the administration composition has to be released) and into the body of the animal to which they are administered. Particularly, the present invention is useful in the pulmonary administration, such as by an inhaler, of the active agents, especially those that can not be administered ordinarily by that route or those for which an improved administration is desired. The improved administration may be faster administration or greater administration in a given period of time.

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

Example 1 - Preparation of 2- (4-N-salicyloyl) aminophenyl) propionic acid A slurry of 58.6 g (0.355 mol) of 2- (4-aminophenyl) propionic acid and 500 ml of methylene chloride is subjected to treatment with 90.11 ml (77.13 g, 0-710 mol) of trimethylsilyl chloride and heated to reflux for 120 minutes. The reaction mixture is cooled to 0 ° C and treated with 184.44 ml (107.77 g, 1.065 mol) of triethylamine. After stirring for 5 minutes, the mixture is subjected to treatment with a solution of 70.45 g (0.355 mol) of 0-acetylsalicyloyl chloride and 150 ml of methylene chloride. The reaction mixture is heated to 25 ° C and stirred for 64 hours. The volatile products are removed in a vacuum. The residue is stirred in 2 N of aqueous sodium chloride for one hour and acidified with 2 M aqueous sulfuric acid. The solid is recrystallized twice from ethanol / water to give a light brown solid. Isolation by filtration yields 53.05 g of (52% yield) of 2- (4- (N-salicyloyl) aminophenyl) propionic acid. Properties Solubility: 200 mg / ml: 200 mg + 350 μl 2N NaOH + 650 μl H20 - pH - 7.67. / Analysis calculated for - C: 67.36, H: 5.3, N: 4.91. It was found - C: 67.05, H: 5.25, N: 4.72.

Example 2 - Preparation of sodium 2- (4- (N-salicyloyl) aminophenyl) propionate A solution of 53.05 g (0.186 mol) of 2- (4- (N-salicyloyl) aminophenyl) propionic acid and 300 ml of ethanol are subjected to a treatment with 7.59 g (0.190 mol) of? aOH dissolved in 22 ml of water. The reaction mixture is stirred for 30 minutes at 25 ° C and for 30 minutes at 0 ° C. The resulting pale yellow solid is isolated by filtration to give 52.61 g of 2- (4- (N-salicyloyl) aminophenyl) propionate sodium. Properties Solubility: 200 mg / ml of a clear solution, pH = 6.85. Analysis calculated for - C: 60.45, H: 5.45, N: 3.92, Na: 4.63. It was found - C: 60.84, H: 5.87, N: 3.85, Na: 6.43. Melting temperature 236-238 ° C.

Example 3 A composition for a dosage of pulmonary administration of 0.1 mg / kg of porcine insulin and 7.5 mg / kg of Example 2 in water is prepared. A dose of 0.3 ml / kg of the pulmonary dosing composition at pH 7.3-7.6 is administered to 5 normal rats without fasting by the following procedure. Feeding needles are inserted by V-i Popper and Songs probe approximately a few centimeters below the throat of the animals. The tip of the needle is manipulated towards the ventral sides of the animals where the needle can fall into a bag and then with further manipulation in the trachea. Once the needle is in the trachea, the dosing solution is administered through the needle. Periodic blood samples are collected through the caudal artery, blood glucose levels are quantified using the EktachemDT slides (Johnson &Johnson Clinical Diagnostics, Inc., Rochester N.Y. ). The results are illustrated in Figure 1.

Comparative Example 3 A The procedure of Example 3 is followed, substituting a dosage composition of 0.1 mg / kg of porcine insulin and water for the dosage composition. The results are illustrated in Figure 1.

Comparative Example 3B The procedure of Example 3 is followed, substituting a dosage composition of 7.5 mg / kg of the compound prepared in Example 1 in water for the dosage solution.

The results are illustrated in Figure 1 Example 4 The procedure of Example 3 is followed, substituting a dosage composition of 0.5 mg / kg of porcine insulin and 7.5 mg / kg of the compound prepared in Example 2, in water for the dosage composition at a pH of 6.6 -6.9. The results are illustrated in Figure 2. Comparative Example 4 A The procedure of Example 4 is followed, substituting a dosage composition of 0.5 mg / kg porcine insulin in water for the composition of the dosage. The results are illustrated in Figure 2.

Comparative Example 4 B The procedure of Example 4 is followed, substituting a dosage composition of 7.5 mg / kg of the compound prepared in Example 2 in water for the dosage solution. The results are illustrated in Figure 2.

Example 5 A dosage composition of 300 mg / kg of the compound prepared in Example 2, and 3 mg / kg of human insulin in water at a pH of 7.02 is prepared. The channeled "strept" rats are dosed by oral feeding by probe with 1 ml / kg of the dosage composition. Blood glucose levels (mg / dL) are quantified. The results are quantified in Table 1 below.

Table 1 Time (hrs): 0 0.5 1 2 3 4 Rating: 0 -44.9 -42.59 -37.58 36.62 -29.88 SD: 0 13.88 28.53 30.87 26.27 18.61 Example 6 A dosage composition of 300 mg / kg of the compound that is prepared in Example 1 and 100 mg / kg of the N-terminal fragment of parathyroid hormone (amino acids 1-34) in water at a pH of 8.13, is prepared. Normal rats are dosed by oral administration by gavage with 1 ml / kg of the dosage composition. Serum levels of parathyroid hormone (pg / mL) are quantified. The results are illustrated in Table 2 below.

Example 7 A dosage composition of 100 mg / kg of the compound prepared in Example 1 and 200 ug / kg of the N-terminal fragment of parathyroid hormone is prepared (amino acids 1-34) in water at a pH of 7.65. Normal rats are dosed by oral gavage with 1 mg / kg of the dosage composition. Serum levels of parathyroid hormone (pg / mL) are quantified. The results are illustrated in Table 3 below.

Example 8 The method of Example 7 is followed but the pH of the dosage composition is 7.5. The results are illustrated in Table 4 below.

Table 4 Example 9 - Pulmonary Insulin Administration The carrier compound which is 2- (4- (N-salicyloyl) aminophenyl) propionic acid is analyzed as follows. Each rat is weighed and identified using an indelible marker and anesthetized by an intramuscular injection of torazine (3 mg / kg) and ketamine (44 mg / kg).

An endotracheal tube (spray instillator from Penn Century of Philadelphia, PA) with a syringe (Hamilton syringe) attached to the endotracheal tube is inserted when using a fiber optic laryngoscope. The syringe (^ Hamilton syringe) of the instillator is used to instill insulin (0.03 mg / kg) and a carrier compound (16 mg / kg) into the inner portions of the airway.The endotracheal tube is removed after administration , and the respiration rate is monitored throughout the rest of the study.The blood samples are extracted at 0, 5, 15, 30, 60 and 120 minutes by means of the caudal artery and evaluated with an Insulin Reagent Kit. DSL # 10-600 after the procedure specified in the kit of reagents.The value Cmax with the carrier is 44.6 ± 10.0.The value Cma? Without the carrier is 19.4 ± 4.3.

Example 10 - Human Recombinant Hormone Growth Hormone Administration (rhGH) Oral tube (PO) dosing solutions containing 200 mg / kg of the carrier compound 2- (4- (N-salicyloyl) aminophenyl) propionic acid and 3 mg / kg rhGH in 100% phosphate buffer are prepared by mixing. The pH of the solutions ranges from about 7.67 to about 8.09. Male Sprague-Dawley rats weighing 200-250 g are fasted for 24 hours and given ketamine (44 mg / kg) and chlorpromazine (1.5 mg / kg) for 15 minutes before dosing. The rats are administered 1 ml / kg of the dosing solution by PO. Blood samples are collected parenterally from the caudal artery to determine serum concentrations of rHGH. Serum concentrations of rHGH are quantified by a kit of immunoassay analysis reagents for rHGH (Reagent Kit No. K1F4015 from Genzyme Corporation Inc., Cambridge, MA). The serum concentration of the main peak for rhGH is 93 ± 74 ng / ml.

Example 11 Oral Administration of the Erythropoietin (EPO) Dosing solutions by oral gavage (PO) containing 200 mg / kg of the carrier compound 2- (4- (N-salicyloyl) aminophenyl) propionic acid and 1 mg / kg cutantin of human erythropoietin IUD in 100 % water are prepared when mixed. The pH of the solutions ranges from about 6.9 to about 7.9. Male Sprague-Dawley rats weighing 200-250 g are fasted for 24 hours and given ketamine (44 mg / kg) and chlorpromazine (1.5 mg / kg) for 15 minutes before dosing. The rats are administered 1 ml / kg of the dosing solution by PO. Blood samples are collected parenterally from the caudal artery to determine serum EPO concentrations. The serum concentrations of EPO are quantified by a set of reagents for an analysis of the Elisa titre (Reagent Kit No. DEPOO from R &D Systems, Minneapolis, MN). The serum concentration of the mean EPO peak is 163 ± 136 mU / ml. The procedure is repeated without the carrier compound. The serum concentration of the average EPO peak is 0 mU / ml. The aforementioned patents, applications, methods of analysis, and publications are incorporated herein by reference and in their entirety.

Various variations of the present invention suggest themselves to those skilled in the art in light of the above detailed description. All obvious variations are within the intended full scope of the appended claims.

It is noted that in relation to this date, the best known method for the applicant to carry out the aforementioned invention, is the conventional one for the manufacture of the objects or products to which it refers.

Claims (27)

CLAIMS Having described the invention as above, the content of the following claims is claimed as property:

1 . A compound characterized in that it has the formula or a salt of this,

2 . A composition characterized in that it comprises: (A) at least one active agent; and (B) a carrier comprising a compound having the formula or a salt thereof.

3. A composition as defined in claim 2, 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.

4. A composition as defined according to claim 3, characterized in that the biologically active agent comprises at least one protein, polypeptide, peptide, small peptide, hormone, polysaccharide, mucopolysaccharide, carbohydrate, lipid, organic compound, or any combination of these .

5. A composition as defined in claim 3, characterized in that the biologically active agent is selected from the group consisting of growth hormones, human growth hormone (hGH), recombinant human growth hormones (rhGH), bovine hormone. of growth, porcine growth hormones, growth hormone releasing hormones, interferons, α-interferon, β-interferon, β-interferon, interleukin-1, interleukin-II, insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin (EPO), atrioventricular factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotropin, gonadotropin-releasing hormone, oxytocin, luteinizing hormone-releasing hormone, follicle-stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim , prostaglandins, cyclosporine, vasopressin, sodium cromoglycate, disodium cromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), PTH fragments, antimicrobials, antifungal agents, analogues, fragments, mimetics and modified polyethylene glycol (PEG) derivatives of these compounds; and any combination of these.

6. A composition as defined in claim 3, characterized in that the biologically active agent is selected from the group consisting of human growth hormone (hGH), bovine growth hormone, growth hormone releasing hormone, interferons, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, very low molecular weight heparin, calcitonin, erythropoietin (EPO), atrioventricular factor, antigens, monoclonal antibodies, somatostatin, adrenocorticotropin, gonadotropin-releasing hormone , oxytocin, vasopressin, sodium cromoglycate, disodium cromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), antimicrobials, antifungal agents, and any combination of these.

7. A composition as defined according to claim 3, characterized in that the biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, very low molecular weight heparin, calcitonin, parathyroid hormone (PTH) , erythropoietin (EPO), human growth hormone (hGH), oxytocin, vasopressin, vancomycin, desferrioxamine (DFO), parathyroid hormone, and combinations of these.

8. A composition as defined according to claim 3, characterized in that the biologically active agent comprises unfractionated heparin, ultra low molecular weight heparin, and combinations thereof.

9. A composition as defined according to claim 3, characterized in that the biologically active agent comprises insulin.

10. A composition as defined according to claim 3, characterized in that the biologically active agent comprises the parathyroid hormone.

11. A composition as defined according to claim 3, characterized in that the biologically active agent comprises human growth hormone.

12. A composition as defined in accordance with claim 3, characterized in that the biologically active agent comprises erythropoietin.

13. A composition as defined according to claim 2, characterized in that the carrier comprises a poly (amino acid) or a polypeptide.

14. A unit dosage form characterized in that it comprises: (A) a composition as defined in accordance with claim 2; and (B) (a) an excipient (b) a diluent, (c) a disintegrating agent, (d) a lubricating agent, (e) a plasticizing agent, (f) a dye, (g) a dosage vehicle, or (h) any combination of these.

15. 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 any combination thereof.

16. A unit dosage form as defined according to claim 14, characterized in that the biologically active agent comprises at least one protein, polypeptide, peptide, small peptide, hormone, polysaccharide, müccpolysaccharide, carixhydrate, lipid, organic compound, or any combination of these.

17. A unit dosage form as defined in claim 14, characterized in that the biologically active agent is selected from the group consisting of growth hormones, human growth hormones (hGH), recombinant human growth hormone (rhGH) , bovine growth hormone, porcine growth hormone, growth hormone releasing hormones, interferons, α-interferon, β-interferon, β-interferon, interleukin-1, interleukin-II, insulin, insulin-like growth factor (IGF), IGF-1, heparin, unfractionated heparin, heparinoids, dermatans, chondroitins, low molecular weight heparin, very low molecular weight heparin, ultra low molecular weight heparin, calcitonin, salmon calcitonin, eel calcitonin, human calcitonin, erythropoietin (EPO), atrioventricular factor, antigens, monoclonal antibodies, somatostatin, protease inhibitors, adrenocorticotro pineapple, gonadotropin-releasing hormone, oxytocin, luteinizing hormone-releasing hormone, follicle-stimulating hormone, glucocerebrosidase, thrombopoietin, filgrastim, prostaglandins, cyclosporine, vasopressin, sodium cromoglycate, disodium cromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH) ), PTH fragments, antimicrobials, antifungal agents, analogues, fragments, mimetics and modified polyethylene glycol (PEG) derivatives of these compounds; and any combination of these.

18. A unit dosage form as defined in claim 14, characterized in that the biologically active agent is selected from the group consisting of human growth hormone (hGH), bovine growth hormone, growth hormone releasing hormone. , interferons, interleukin-1, interleukin-II, insulin, heparin, low molecular weight heparin, very low molecular weight heparin, calcitonin, erythropoietin (EPO), atrial factor, antigen, monoclonal antibodies, somatostatin, adrenocorticotropin, releasing hormone of gonadotropin, oxytocin, vasopressin, sodium cromoglycate, disodium cromoglycate, vancomycin, desferrioxamine (DFO), parathyroid hormone (PTH), antimicrobials, antifungal agents, and any combination of these.

19. A unit dosage form as defined according to claim 14, characterized in that the biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, very low molecular weight heparin, calcitonin, parathyroid hormone (PTH), erythropoietin (EPO), human growth hormone (hGH), oxytocin, vasopressin, vancomycin, desferrioxamine (DFO), parathyroid hormone, and any combination of these.

20. A unit dosage form as defined in claim 14, characterized in that the biologically active agent comprises unfractionated heparin, ultra low molecular weight heparin, and combinations thereof.

21. A unit dosage form as defined according to claim 14, characterized in that the biologically active agent comprises insulin.

22. A unit dosage form as defined according to claim 14, characterized in that the biologically active agent comprises the parathyroid hormone.

23. A unit dosage form as defined according to claim 14, characterized in that the biologically active agent comprises the human growth hormone.

24. A unit dosage form as defined according to claim 14, characterized in that the biologically active agent comprises erythropoietin.

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

26. The use of a composition as defined in accordance with claim 3, for the preparation of a medicament for oral administration.

27. A method for preparing a composition characterized in that it comprises mixing: (A) at least one active agent; (B) the compound according to claim 1; and (C) optionally, a dosing vehicle.