EP1226109A2 - Composes d'acide phenylamine carboxylique et compositions permettant de distribuer des agents actifs - Google Patents

Composes d'acide phenylamine carboxylique et compositions permettant de distribuer des agents actifs

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Publication number
EP1226109A2
EP1226109A2 EP00989761A EP00989761A EP1226109A2 EP 1226109 A2 EP1226109 A2 EP 1226109A2 EP 00989761 A EP00989761 A EP 00989761A EP 00989761 A EP00989761 A EP 00989761A EP 1226109 A2 EP1226109 A2 EP 1226109A2
Authority
EP
European Patent Office
Prior art keywords
alkyl
active agent
insulin
hormone
molecular weight
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP00989761A
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German (de)
English (en)
Other versions
EP1226109A4 (fr
Inventor
Andrea Leone-Bay
Kelly Kraft
Maria A. P. Boyd
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Emisphere Technologies Inc
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Emisphere Technologies Inc
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Publication date
Application filed by Emisphere Technologies Inc filed Critical Emisphere Technologies Inc
Publication of EP1226109A2 publication Critical patent/EP1226109A2/fr
Publication of EP1226109A4 publication Critical patent/EP1226109A4/fr
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/21—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups
    • C07C65/24—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing ether groups, groups, groups, or groups polycyclic
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/08—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease
    • A61P19/10—Drugs for skeletal disorders for bone diseases, e.g. rachitism, Paget's disease for osteoporosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/10—Drugs for disorders of the endocrine system of the posterior pituitary hormones, e.g. oxytocin, ADH
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/48—Drugs for disorders of the endocrine system of the pancreatic hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/02—Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/02—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C229/04—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
    • C07C229/06—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton
    • C07C229/18—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one amino and one carboxyl group bound to the carbon skeleton the nitrogen atom of the amino group being further bound to carbon atoms of six-membered aromatic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C229/00—Compounds containing amino and carboxyl groups bound to the same carbon skeleton
    • C07C229/52—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton
    • C07C229/54—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring
    • C07C229/56—Compounds containing amino and carboxyl groups bound to the same carbon skeleton having amino and carboxyl groups bound to carbon atoms of six-membered aromatic rings of the same carbon skeleton with amino and carboxyl groups bound to carbon atoms of the same non-condensed six-membered aromatic ring with amino and carboxyl groups bound in ortho-position
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C237/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups
    • C07C237/28—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton
    • C07C237/30—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by amino groups having the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a non-condensed six-membered aromatic ring of the carbon skeleton having the nitrogen atom of the carboxamide group bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/58—Unsaturated compounds containing ether groups, groups, groups, or groups
    • C07C59/64—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings
    • C07C59/66—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings
    • C07C59/68—Unsaturated compounds containing ether groups, groups, groups, or groups containing six-membered aromatic rings the non-carboxylic part of the ether containing six-membered aromatic rings the oxygen atom of the ether group being bound to a non-condensed six-membered aromatic ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/90—Unsaturated compounds containing keto groups containing singly bound oxygen-containing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C59/00—Compounds having carboxyl groups bound to acyclic carbon atoms and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C59/40—Unsaturated compounds
    • C07C59/76—Unsaturated compounds containing keto groups
    • C07C59/92—Unsaturated compounds containing keto groups containing —CHO groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C65/00—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups
    • C07C65/32—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups
    • C07C65/40—Compounds having carboxyl groups bound to carbon atoms of six—membered aromatic rings and containing any of the groups OH, O—metal, —CHO, keto, ether, groups, groups, or groups containing keto groups containing singly bound oxygen-containing groups

Definitions

  • the present invention relates to phenyl amine carboxylic acid compounds for delivering active agents, such as biologically or chemically active agents, to a target. These compounds are well suited for forming non-covalent mixtures with active agents for oral, intracolonic, pulmonary, and other routes of administration to animals. Methods for the preparation and administration of such compositions are also disclosed .
  • barriers are imposed by the body.
  • physical barriers are the skin, lipid bi-layers and various organ membranes that are relatively impermeable to certain active agents but must be traversed before reaching a target, such as the circulatory system.
  • Chemical barriers include, but are not limited to, pH variations m the gastrointestinal (GI) tract and degrading enzymes .
  • enzymatic inhibitors e.g., pancreatic trypsm inhibitors, dnsopropylfluorophosphate (DFF) and trasylol
  • DFF dnsopropylfluorophosphate
  • trasylol trasylol
  • proteinoid microspheres have been used to deliver pharmaceuticals. See, for example, US Patent Nos . 5,401,516; 5,443,841; and Re. 35,862.
  • certain modified amino acids have been used to deliver pharmaceuticals. See, for example, US Patent Nos. 5,629,020; 5,643,957; 5,766,633; 5,776,888; and 5, 866, 536.
  • Delivery agent compounds of the present invention include those having the following formula
  • R 1 , R 2 , R 3 , and R 4 are independently H, -OH, halogen, -OCH 3 , -NR 10 R 1:L or -N + R ⁇ R ⁇ R 12 (R 13 ) " ;
  • R 5 is H, -OH, -N0 2 , -NR 14 R 15 , -N + R 14 R 15 R 16 (R 13 ) ⁇ , amide,
  • R 5 is optionally substituted with -OH, -SH, or -COOH;
  • R 5 is optionally interrupted by 0, N, S, or -C(0)-;
  • R 6 is a C ⁇ C ⁇ 2 alkylene, C ⁇ -C ⁇ 2 alkenylene, or arylene;
  • R 6 is optionally substituted with a C_ . -C alkyl, C 2 -C 4 alkenyl, C ⁇ -C 4 alkoxy, -OH, -SH, halogen, -NH 2 , or -C0 2 R 9 ;
  • R 6 is optionally interrupted by 0 or N;
  • R 7 is a bond or arylene;
  • R 7 is optionally substituted with -OH, halogen, -
  • R 8 is H or C 1 -C 4 alkyl
  • R 9 is H, C ⁇ -C 4 alkyl, or C 2 -C 4 alkenyl;
  • R 10 , R 11 , and R 12 are independently H or C 1 -C 10 alkyl;
  • R 13 is a halide, hydroxide, sulfate, tetraf luoroborate, or phosphate;
  • R 14 , R 15 , and R 16 are independently H, C ⁇ -C 10 alkyl, C 2 - C 12 alkenyl, 0, or -C(0)R 17 ;
  • R 17 is -OH, C 1 -C 1 0 alkyl, or C2-C 12 alkenyl; and R 18 is -OH, C ⁇ -C 6 alkyl, -NR 1 R 15 , -N + R 14 R 15 R 16 (R 13 ) " , with the proviso that when R 5 is 0CH 3 then R 6 is C ⁇ -C 8 or C10-C12 alkyl.
  • R 5 is not -OCH 3 . More preferably, R 5 is not alkoxy. According to another preferred embodiment, R 1 , R 2 , R 3 , and
  • R 4 are hydrogen, R 5 is -COOH, -C(0)NH 2 , -C(0)CH 3 , or -N0 2 , R 6 is -(CH 2 ) 7 -, and R 7 is a bond.
  • R 1 , R 2 , R 3 , and R 4 are hydrogen, R 5 is -C(0)NH 2 , R 6 is -CH 2 -, and R 7 is a para-phenylene .
  • More preferred delivery agent compounds include, but are not limited to, those having the formula
  • R . 2 z 0 is a C 1 -C 12 alkylene or C ⁇ -C ⁇ 2 alkenylene ;
  • R .21 is a bond or arylene
  • R - 22 is H or C ⁇ -C 4 alkyl
  • R 23 is -OH, Cx-Ce alkyl, or -NH 2 .
  • Preferred delivery agent compounds include, but are not limited to, those described in Table 1 below, and salts thereof .
  • the term "para-Ph” represents para-phenylene.
  • the invention also provides a composition comprising at one of the delivery agent compounds of the formula above, including those compounds excluded by proviso, and at least one active agent. These compositions deliver active agents to selected biological systems in increased or improved bioavailability of the active agent compared to administration of the active agent without the delivery agent compound.
  • the dosage unit may be m the form of a liquid or a solid, such as a tablet, capsule or particle, including a powder or sachet.
  • Another embodiment is a method for administering an active agent to an animal in need of the active agent, by administering a composition comprising at one of the delivery agent compounds of the formula above, including those compounds excluded by proviso, and the active agent to the animal.
  • Preferred routes of administration include the oral, mtracolonic and pulmonary routes .
  • Yet another embodiment is a method of treating a disease or for achieving a desired physiological effect in an animal by administering the composition of the present invention.
  • Yet another embodiment is a method of preparing a composition of the present invention by mixing at least one delivery agent compound of the formula above, including those compounds excluded by proviso, and at least one active agent.
  • alkyl and alkenyl as used herein include linear and branched alkyl and alkenyl substituents , respectively .
  • the delivery agent compounds may be in the form of the carboxylic acid or salts thereof.
  • Suitable salts include, but are not limited to, organic and inorganic salts, for example alkali-metal salts, such as sodium, potassium and lithium; alkaline-earth metal salts, such as magnesium, calcium or barium; ammonium salts; basic amino acids, such as lysine or arginine; and organic amines, such as dimethylamine or pyridine .
  • the salts are sodium salts.
  • the salts may be mono- or multi-valent salts, such as monosodium salts and di-sodium salts.
  • the salts may also be solvates, including ethanol solvates, and hydrates.
  • Salts of the delivery agent compounds of the present invention may be prepared by methods known in the art.
  • sodium salts may be prepared by dissolving the delivery agent compound in ethanol and adding aqueous sodium hydroxide .
  • the delivery agent compound may be purified by recrystallization or by fractionation on one or more solid chromatographic supports, alone or linked in tandem.
  • Suitable recrystallization solvent systems include, but are not limited to, acetonitrile, methanol, and tetrahydrofuran .
  • Fractionation may be performed on a suitable chromatographic support such as alumina, using methanol/n-propanol mixtures as the mobile phase; reverse phase chromatography using trifluoroacetic acid/acetonitrile mixtures as the mobile phase; and ion exchange chromatography using water or an appropriate buffer as the mobile phase.
  • anion exchange chromatography preferably a 0-500 mM sodium chloride gradient is employed.
  • Active agents suitable for use in the present invention include biologically active agents and chemically active agents, including, but not limited to, pesticides, pharmacological agents, and therapeutic agents.
  • biologically or chemically active agents suitable for use in the present invention include, but are not limited to, proteins; polypeptides ; peptides; hormones; polysaccharides, and particularly mixtures of muco- polysaccharides; carbohydrates; lipids; small polar organic molecules (i.e. polar organic molecules having a molecular weight of 500 daltons or less); other organic compounds; and particularly compounds which by themselves do not pass (or which pass only a fraction of the administered dose) through the gastro-intestinal mucosa and/or are susceptible to chemical cleavage by acids and enzymes in the gastro- intestinal tract; or any combination thereof.
  • growth hormones including human growth hormones (hGH) , recombinant human growth hormones (rhGH) , bovine growth hormones, and porcine growth hormones; growth hormone- releasing hormones; interferons, including , ⁇ and y; interleukin-1 ; interleukin-2 ; insulin, including porcine, bovine, human, and human recombinant, optionally having counter ions including zinc, sodium, calcium and ammonium; 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, porcine and human; erythropoietin; atrial naturetic factor; antigens;
  • Daptomycin is described by Baltz in Biotechnology of Antibiotics, 2 nc * Ed., ed. W.R. Strohl (New York: Marcel Dekker, Inc.), 1997, pp. 415-435.
  • Daptomycin is a cyclic lipopeptide antibiotic that can be derived from the fermentation of Streptomyces roseosporus .
  • Daptomycin is a member of the factor A-21978CQ type antibiotics of S . roseosporus and comprises a n-decanoyl side chain linked via a three-amino acid chain to the N-terminal tryptophan of a cyclic 10-amino acid peptide.
  • the compound is currently being developed in a variety of formulations to treat serious infections caused by bacteria, including, but not limited to, methicillin resistant Staphylococcus a ureus (MRSA) and vancomycin resistant enterococci (VRE) .
  • MRSA methicillin resistant Staphylococcus a ureus
  • VRE vancomycin resistant enterococci
  • composition of the present invention comprises one or more delivery agent compounds of the present invention, including those excluded by proviso, and one or more active agents.
  • the delivery agent compound and active agent are typically mixed prior to administration to form an administration composition.
  • the administration compositions may be in the form of a liquid.
  • the solution medium may be water (for example, for salmon calcitonin, parathyroid hormone, and erythropoietin) , 25% aqueous propylene glycol (for example, for heparin) and phosphate buffer (for example, for rhGH) .
  • Other dosing vehicles include polyethylene glycol.
  • Dosing solutions may be prepared by mixing a solution of the delivery agent compound with a solution of the active agent, just prior to administration. Alternately, a solution of the delivery agent compound (or active agent) may be mixed with the solid form of the active agent (or delivery agent compound) . The delivery agent compound and the active agent may also be mixed as dry powders. The delivery agent compound and the active agent can also be admixed during the manufacturing process.
  • the dosing solutions may optionally contain additives such as phosphate buffer salts, citric acid, glycols, or other dispersing agents. Stabilizing additives may be incorporated into the solution, preferably at a concentration ranging between about 0.1 and 20% (w/v) .
  • the administration compositions may alternately be in the form of a solid, such as a tablet, capsule or particle, such as a powder or sachet.
  • Solid dosage forms may be prepared by mixing the solid form of the compound with the solid form of the active agent.
  • a solid may be obtained from a solution of compound and active agent by methods known in the art, such as freeze-drying ( lyophilization) , precipitation, crystallization and solid dispersion.
  • the administration compositions of the present invention may also include one or more enzyme inhibitors .
  • enzyme inhibitors include, but are not limited to, compounds such as actinonin or epiactinonin and derivatives thereof.
  • Other enzyme inhibitors include, but are not limited to, aprotinin (Trasylol) and Bowman-Birk inhibitor.
  • the amount of active agent used in an administration composition of the present invention is an amount effective to accomplish the purpose of the particular active agent for the target indication.
  • the amount of active agent in the compositions typically is a pharmacologically, biologically, therapeutically, or chemically effective amount. However, the amount can be less than that amount when the composition is used in a dosage unit form because the dosage unit form may contain a plurality of delivery agent compound/active agent compositions or may contain a divided pharmacologically, biologically, therapeutically, or chemically effective amount.
  • the total effective amount can then be administered in cumulative units containing, in total, an effective amount of the active agent.
  • compositions of the invention may deliver active agents more efficiently than compositions containing the active agent alone, lower amounts of biologically or chemically active agents than those used in prior dosage unit forms or delivery systems can be administered to the subject, while still achieving the same blood levels and/or therapeutic effects.
  • the presently disclosed delivery agent compounds facilitate the delivery of biologically and chemically active agents, particularly in oral, intranasal, sublingual, intraduodenal, subcutaneous, buccal, intracolonic, rectal, vaginal, mucosal, pulmonary, transdermal, intradermal, parenteral, intravenous, intramuscular and ocular systems, as well as traversing the blood-brain barrier.
  • Dosage unit forms can also include any one or combination of excipients, diluents, disintegrants, lubricants, plasticizers , colorants, flavorants, taste-masking agents, sugars, sweeteners, salts, and dosing vehicles, including, but not limited to, water, 1,2-propane diol, ethanol, olive oil, or any combination thereof.
  • the compounds and compositions of the subject invention are useful for administering biologically or chemically active agents to any animals, including but not limited to birds such as chickens; mammals, such as rodents, cows, pigs, dogs, cats, primates, and particularly humans; and insects.
  • the system is particularly advantageous for delivering chemically or biologically active agents that would otherwise be destroyed or rendered less effective by conditions encountered before the active agent reaches its target zone (i.e. the area in which the active agent of the delivery composition is to be released) and within the body of the animal to which they are administered.
  • target zone i.e. the area in which the active agent of the delivery composition is to be released
  • the compounds and compositions of the present invention are useful in orally administering active agents, especially those that are not ordinarily orally deliverable, or those for which improved delivery is desired.
  • compositions comprising the compounds and active agents have utility in the delivery of active agents to selected biological systems and in an increased or improved bioavailability of the active agent compared to administration of the active agent without the delivery agent. Delivery can be improved by delivering more active agent over a period of time, or in delivering active agent in a particular time period (such as to effect quicker or delayed delivery) or over a period of time (such as sustained delivery) .
  • Another embodiment of the present invention is a method for the treatment or prevention of a disease or for achieving a desired physiological effect, such as those listed in the table below, in an animal by administering the composition of the present invention.
  • Specific indications for active agents can be found in the Physicians' Desk Reference (54 th Ed., 2000, Medical Economics Company, Inc., Montvale, NJ) , which is herein incorporated by reference.
  • the active agents in the table below include their analogs, fragments, mimetics, and polyethylene glycol-modified derivatives.
  • one embodiment of the present invention is a method for treating a patient suffering from or susceptible to diabetes by administering insulin and at least one of the delivery agent compounds of the present invention.
  • the active agent present in the composition or dosage unit form is taken up into the circulation.
  • the bioavailability of the agent is readily assessed by measuring a known pharmacological activity in blood, e.g. an increase in blood clotting time caused by heparin, or a decrease in circulating calcium levels caused by calcitonin. Alternately, the circulating levels of the active agent itself can be measured directly.
  • N, N-dimethylacetamide (80 mL) was poured into a 250 mL round bottom flask. To the flask 14.81 g (109.6 mmol) of 2'- hydroxyacetophenone and 7.21 g (52.2 mmol) of potassium carbonate were added. The slurry was stirred and heated to 105°C, at which time 7.01 g (27.9 mmol) of ethyl 8- bromooctanoate in 20 mL of dimethylacetamide was added dropwise over 2 hours. The reaction mixture was heated at 105°C for an additional 2.5 hours, then cooled to room temperature and stirred overnight. The reaction mixture was poured into 150 mL of water, and the aqueous phase was extracted with four 100-mL portions of ethyl acetate. The organic extracts were combined and concentrated in vacuo to give an orange liquid.
  • the crude solid was weighed into a 500 mL round bottom flask and suspended in 200 mL of ethanol.
  • Sodium borohydride (5.73 g, 151.5 mmol) was added to the flask in two portions. Addition of the sodium borohydride caused the reaction to heat to reflux and give off gas.
  • the reaction mixture was cooled to room temperature, and stirred for 18 hours.
  • the opaque, off-white reaction mixture was diluted with 50 mL of water.
  • the resulting yellow-brown solid was removed by filtration.
  • the filtrate was concentrated in vacuo to give a light brown semi-solid, which was then stirred in 80 mL of saturated aqueous sodium bicarbonate for about 3 hours .
  • N,N-dimethylacetamide (100 mL) was poured into a 500 mL round-bottom flask. To the flask, 13.16 g (95.27 mmol) of 2- nitroaniline and 26.41 g (191.1 mmole) of potassium carbonate were added. The mixture was stirred and heated to 105°C, at which time 24.0 g (95.55 mmol) of ethyl 8-bromooctanoate in 90 mL of dimethylacetamide were added dropwise over 1.5 hours. The reaction mixture was heated at 105°C for an additional 3.5 hours, then cooled to room temperature, and stirred overnight.
  • the reaction mixture then was poured into 200 mL of water, and the aqueous phase was extracted with two 200 mL portions of ethyl acetate. The organic extracts were combined and concentrated in vacuo to give an amber-colored liquid. The purity of the product was checked by HPLC (high pressure liquid chromatography) and TLC (thin layer chromatography) and showed that starting material was still present. The product was redissolved in dimethyl sulfoxide (160 mL) . Crushed potassium hydroxide (10.72 g, 191.1 mmol) and ethyl 8- bromooctanoate (24.0 g, 95.55 mmole) were added to the solution subsequently, and the mixture was stirred overnight.
  • the reaction mixture was added to iced water (200 mL) and extracted with ethyl acetate (2 X 200 mL) .
  • the organic extracts were combined and concentrated in vacuo to give an amber-colored liquid.
  • the product was purified by MPLC (medium-pressure liquid chromatography) using 10% ethyl acetate-90% hexanes as the eluent, and isolated 17.63 g (57.18 mmol, 60.0% yield) as a deep orange liquid.
  • the liquid was dissolved in 100 mL of dioxane.
  • Aqueous sodium hydroxide (IN, 80 mL) were added, and the resulting liquid was stirred and heated to 70°C for three hours.
  • the dioxane was removed in vacuo, and the residue was dissolved in water (60 mL) .
  • the crystals were collected, washed generously with water, and dried under vacuum at 40°C overnight to yield 14.15 g of material (50.49 mmol, 88.3% yield). Melting point: 112- 114°C.
  • PO Oral dosing
  • compositions of a delivery agent compound and salmon calcitonin (sCT) in deionized water were prepared as described in Table 2 below. Typically, 450 mg of the delivery agent compound was added to 2.0 ml of water.
  • Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt by stirring the resultant solution and adding one equivalent of sodium hydroxide (1.0 N) and diluting with water.
  • the solution was vortexed, then heated (about 37°C) and sonicated.
  • the pH was adjusted to about 7 (about 6.5 to 8.5) with NaOH or HC1.
  • 90 ⁇ g sCT from a sCT stock solution (2 mg/ml made by adding 1000% pH 4 phosphate buffer to sCT and allowing it to go into solution by sitting for about 10-20 minutes and periodically gently inverting) was added to the solution. Water was then added to bring the total volume to 3.0 ml (varies depending on solubility of the delivery agent compound) .
  • the typical dosing and sampling protocols were as follows. Male Sprague-Dawley rats weighing between 200-250g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions.
  • Oral gavage (PO) dosing solutions of delivery agent compound and rhGH in phosphate buffer were prepared by mixing.
  • a solution of the- delivery agent compound was made either with the sodium salt of the delivery agent compound or by converting the free acid to its sodium salt.
  • a solution of the delivery agent compound was prepared in phosphate buffer and stirred, adding one equivalent of sodium hydroxide (1.0 N) when making the sodium salt.
  • the final dosing solutions were prepared by mixing the delivery agent compound solution with an rhGH stock solution (15 mg rhGH/ml made by mixing as powders 15 mg rhGH, 75 mg D-mannitol, 15 mg glycine and 3.39 mg dibasic sodium phosphate, then diluting with 2% glycerol) and diluting to the desired volume (usually 3.0 ml) .
  • the pH was adjusted, if necessary, to between about 7 and 8.5.
  • the delivery agent compounds and rhGH dose amounts are listed below in Table 3.
  • the typical dosing and sampling protocols were as follows. Male Sprague-Dawley rats weighing 200-250 g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions.
  • An 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which was then wiped dry. The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors . The dosing solution was administered by pressing the syringe plunger .
  • Intracolonic (IC) dosing solutions containing a delivery agent compound and heparin sodium USP were prepared in 25% aqueous propylene glycol. Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt with one equivalent of sodium hydroxide.
  • the delivery agent compound and heparin (about 166-182 IU/mg (typically 166.9 IU/mg) ) were mixed by vortex as dry powders. This dry mixture was dissolved in 25% v/v aqueous propylene glycol, vortexed, and placed in a sonicator (about 37°C) . The pH was adjusted to about 7 ( 6.5 to 8.5) with aqueous NaOH (2N) . The dosing solution was sonicated to produce a clear solution. The final volume was adjusted to about 3.0 ml. The final delivery agent compound dose, heparin dose, and dose volume amounts are listed below in Table 4.
  • the typical dosing and sampling protocols were as follows. Male Sprague-Dawley rats weighing between 275-350g were fasted for 24 hours and were anesthetized with ketamine hydrochloride (88 mg/kg) intramuscularly immediately prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions.
  • IC intracolonic
  • a 7.5cm, 8 fr Rusch catheter was adapted to a 1 ml syringe with a pipette tip. The dosing catheter was inserted into the colon through the anus until the tube was no longer visible. The dosing solution was expressed slowly into the colon by pressing the syringe plunger.
  • Citrated blood samples were collected by cardiac puncture following the administration of ketamine (88 mg/kg), typically at 0.25, 0.5, 1.0 and 1.5 hours after dosing. Heparin absorption was verified by an increase in clotting time measured by the activated partial thromboplastin time (APTT) according to the method of Henry, J.B., Clinical Diagnosis and Management by Laboratory Methods, Philadelphia, PA, W.B. Saunders (1979). Previous studies indicated baseline values of about 20 seconds. Results from the animals in each group were averaged for each time point and the highest of these averages (i.e., mean peak APTT) is reported below in Table 4.
  • APTT activated partial thromboplastin time
  • Intracolonic (IC) compositions containing a delivery agent compound and low molecular weight heparin (LMWH) were prepared in 25% aqueous propylene glycol. Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt with one equivalent of sodium hydroxide.
  • the delivery agent compound and LMWH Parnaparin, 91 IU/mg average molecular weight about 5,000, available from Opocrin, Modena, Italy
  • 90-105 IU/mg, average molecular weight about 5,000 were mixed by vortex as dry powders.
  • This dry mixture was dissolved m 25% v/v aqueous propylene glycol, vortexed, and placed in a sonicator (37°C) to produce a clear solution.
  • the pH was adjusted to about 7 (6.5-8.5) with 2N aqueous NaOH.
  • the dosing solution was sonicated to produce a clear solution.
  • the final volume was adjusted to 3.0 ml.
  • the final delivery agent compound dose, LMWH dose, and dose volume amounts are listed below in Table 5.
  • the typical dosing and sampling protocols were as follows. Male Sprague-Dawley rats weighing between 275-350g were fasted for 24 hours and were anesthetized with ketamine hydrochloride (88 mg/kg) intramuscularly immediately prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions.
  • IC intracolonic
  • a 7.5cm, 8 fr Rusch catheter was adapted to a 1 ml syringe with a pipette tip. The dosing catheter was inserted into the colon through the anus until the tube was no longer visible. The dosing solution was expressed slowly into the colon by pressing the syringe plunger.
  • LMWH absorption was verified by an increase in plasma LMWH measured by the anti-Factor Xa assay CHROMOSTRATETM Heparin ant ⁇ -X a assay (available from Organon Teknika Corporation, Durham, NC) .
  • Plasma LMWH concentrations from the animals in each group were averaged for each time point and these mean plasma LMWH concentrations were plotted against time. The peak of these mean plasma LMWH concentrations is reported below m Table 5. Table 5.
  • Oral dosing (PO) compositions of delivery agent compound and human zinc insulin were prepared in deionized water. Typically, 500 mg of delivery agent compound was added to 1.5 ml of water. The free acid of the delivery agent compound was converted to the sodium salt by stirring the resultant solution and adding one equivalent of sodium hydroxide. The solution was vortexed, then heated (about 37°C) and sonicated. The pH was adjusted to about 7 to 8.5 with NaOH or HCl. Additional NaOH was added, if necessary, to achieve uniform solubility, and the pH re-adjusted to about 7 to 8.5.
  • PO Oral dosing
  • the typical dosing and sampling protocols were as follows. Male Sprague-Dawley rats weighing between about 200- 250g were fasted for 24 hours and administered ketamine (44 mg/kg) and chlorpromazine (1.5 mg/kg) 15 minutes prior to dosing and again as needed to maintain anesthesia. A dosing group of five animals was administered one of the dosing solutions.
  • an 11 cm Rusch 8 French catheter was adapted to a 1 ml syringe with a pipette tip. The syringe was filled with dosing solution by drawing the solution through the catheter, which was then wiped dry. The catheter was placed down the esophagus leaving 1 cm of tubing past the incisors. The dosing solution was administered by pressing the syringe plunger.
  • Serum human insulin concentrations ( ⁇ U/ml) were measured for each time point for each of the five animals in each dosing group. The five values for each time point were averaged and the results plotted as serum insulin concentration versus time. (Previous experiments revealed no measurable levels of human insulin following oral dosing with human insulin alone.) The maximum (peak) is reported below in Table 6.
  • Example 7 Insulin - Pulmonary Delivery
  • compositions of delivery agent compound and human insulin in water were prepared. Typically, to 1.5 mg of delivery agent compound was added deionized water to bring the volume to 1.0 ml, and the solution was vortexed. Either the sodium salt of the delivery agent compound was used or the free acid was converted to the sodium salt by stirring the resultant solution and adding one equivalent of sodium hydroxide (10 N) and diluting with water. The solution was vortexed, then heated (about 37°C) and sonicated. The pH was adjusted to between about 7.0 to 8.5 with NaOH or HCl. 75 ⁇ l human insulin stock solution (2 mg/ml) was added to the solution. (The stock solution was made as follows.
  • ketamine 44 mg/kg
  • chlorpromazine 3.0 mg/kg 15 minutes prior to dosing and again as needed to maintain anesthesia (using the same amount of ketamine and 1.5 mg/kg chlorpromazine) .
  • ketamine 44 mg/kg
  • chlorpromazine 3.0 mg/kg
  • a dosing group of five animals was administered one of the dosing solutions .
  • a control group of five animals was dosed insulin alone.
  • a tracheal instillator for rodents, equipped with light available from Penn Century, Inc., Pittsburgh, PA
  • the dosing solution was administered by pressing the plunger.
  • Serum insulin levels were determined with an Insulin ELISA Test Kit (Kit # DSL-10-1600 from Diagnostic Systems Laboratories, Inc., Webster, TX) , modifying the standard protocol in order to optimize the sensitivity and linear range of the standard curve for the volumes and concentrations of the samples used in the present protocol. Serum insulin concentrations ( ⁇ U/ml) were measured for each time point for each of the five animals in each dosing group.

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Abstract

L'invention concerne des composés d'acide phénylamine carboxylique et des compositions permettant de distribuer des agents actifs. L'invention concerne également des méthodes d'administration et de préparation de ces compositions.
EP00989761A 1999-11-05 2000-11-06 Composes d'acide phenylamine carboxylique et compositions permettant de distribuer des agents actifs Withdrawn EP1226109A4 (fr)

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US237233P 2000-10-02
PCT/US2000/041960 WO2001032130A2 (fr) 1999-11-05 2000-11-06 Composes d'acide phenylamine carboxylique et compositions permettant de distribuer des agents actifs

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CN1384814B (zh) 2015-11-25
AU2622301A (en) 2001-05-14
KR20020060222A (ko) 2002-07-16
AU2005248960B2 (en) 2009-01-29
ATE427925T1 (de) 2009-04-15
WO2001032596A1 (fr) 2001-05-10
WO2001032130A2 (fr) 2001-05-10
CZ20021554A3 (cs) 2002-10-16
BR0015567A (pt) 2002-07-16
EP1226104B1 (fr) 2009-04-08
BRPI0015567B1 (pt) 2016-10-25
JP2003513060A (ja) 2003-04-08
JP5117658B2 (ja) 2013-01-16
IL149337A (en) 2010-04-15
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CZ20021570A3 (cs) 2002-10-16
EP1226104A4 (fr) 2005-05-04
CA2388240C (fr) 2010-04-20
EP1226109A4 (fr) 2005-01-26
CA2390025A1 (fr) 2001-05-10
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CN1384814A (zh) 2002-12-11
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IL195055A (en) 2015-07-30
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WO2001032130A3 (fr) 2002-03-14
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