Compounds and compositions for delivering active agents

• US 5,866,536 A
• Filed: 02/06/1997
• Issued: 02/02/1999
• Est. Priority Date: 03/31/1995
• Status: Expired due to Term

• Current Assignee: NOVO Nordisk North America Operations A/S (Novo Nordisk A/S)
• Original Assignee: Emisphere Technologies, Inc. (Novo Nordisk A/S)
• Inventors: Ho, Koc-Kan, Leone-Bay, Andrea, Sarubbi, Donald J., Milstein, Sam J.
• Primary Examiner(s): Russel, Jeffrey E.
• Application Number:
  US08/798,033
• Time in Patent Office: 726 Days
• Field of Search: 424/85.1, 424/85.2, 424/85.4, 424/141.1, 424/184.1, 514/2.3, 514/8, 514/11, 514/12, 514/21, 514/56, 514/456, 514/616, 514/558, 514/559, 514/563, 514/784, 554/111, 562/444
• US Class Current: 424/85.2
• CPC Class Codes: A61K 38/212 IFN-alpha
• CPC Class Codes: A61K 38/23 Calcitonins
• CPC Class Codes: A61K 38/27 Growth hormone [GH], i.e. somatotropin
• CPC Class Codes: A61K 38/29 Parathyroid hormone, i.e. parathormone; Parathyroid hormone-related peptides
• CPC Class Codes: A61K 47/18 Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
• CPC Class Codes: A61K 47/183 Amino acids, e.g. glycine, EDTA or aspartame
• CPC Class Codes: A61K 47/20 containing sulfur, e.g. dimethyl sulfoxide [DMSO], docusate, sodium lauryl sulfate or aminosulfonic acids
• CPC Class Codes: A61K 47/22 Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
• CPC Class Codes: A61K 47/541 Organic ions forming an ion pair complex with the pharmacologically or therapeutically active agent
• CPC Class Codes: A61K 9/0019 Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner non-active ingredients are additionally classified in A61K47/00
• CPC Class Codes: A61K 9/0043 Nose
• CPC Class Codes: A61K 9/0056 Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• CPC Class Codes: A61K 9/1617 Organic compounds, e.g. phospholipids, fats
• CPC Class Codes: A61K 9/4858 Organic compounds
• CPC Class Codes: C07C 233/34 having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by amino groups
• CPC Class Codes: C07C 233/47 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/48 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 233/51 having the carbon atom of the carboxamide group bound to an acyclic carbon atom of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 233/52 with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 233/54 having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of a saturated carbon skeleton
• CPC Class Codes: C07C 233/55 : having the carbon atom of the carboxamide group bound to a carbon atom of an unsaturated carbon skeleton
• CPC Class Codes: C07C 233/63 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/81 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 233/83 : of an acyclic saturated carbon skeleton
• CPC Class Codes: C07C 233/84 : of a saturated carbon skeleton containing rings
• CPC Class Codes: C07C 233/87 : of a carbon skeleton containing six-membered aromatic rings
• CPC Class Codes: C07C 235/24 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/34 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/38 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/40 : having carbon atoms of carboxamide groups bound to carbon atoms of rings other than six-membered aromatic rings and singly-bound oxygen atoms bound to the same carbon skeleton
• CPC Class Codes: C07C 235/52 : having the nitrogen atom of at least one of the carboxamide groups bound to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07C 235/60 : having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 235/64 : having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 235/82 : with the carbon atom of at least one of the carboxamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
• CPC Class Codes: C07C 237/22 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated peptides C07K
• CPC Class Codes: C07C 237/40 : having the nitrogen atom of the carboxamide group bound to a carbon atom of a six-membered aromatic ring
• CPC Class Codes: C07C 237/42 : having nitrogen atoms of amino groups bound to the carbon skeleton of the acid part, further acylated
• CPC Class Codes: C07C 259/06 : having carbon atoms of hydroxamic groups bound to hydrogen atoms or to acyclic carbon atoms
• CPC Class Codes: C07C 2601/14 : The ring being saturated
• CPC Class Codes: C07C 2601/18 : with a ring being at least seven-membered
• CPC Class Codes: C07C 2603/74 : Adamantanes
• CPC Class Codes: C07C 271/22 : to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
• CPC Class Codes: C07C 309/59 : Nitrogen analogues of carboxyl groups
• CPC Class Codes: C07C 311/19 : to an acyclic carbon atom of a hydrocarbon radical substituted by carboxyl groups
• CPC Class Codes: C07D 207/34 : with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
• CPC Class Codes: C07D 213/81 : Amides; Imides
• CPC Class Codes: C07D 295/215 : Radicals derived from nitrogen analogues of carbonic acid
• CPC Class Codes: C07D 317/68 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
• CPC Class Codes: C07D 333/38 : Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

Abstract

Carrier compounds, compositions, and dosage unit forms therefor which are useful in the delivery of active agents are provided. The present invention provides a compound having the formula: ##STR1## or a salt thereof, wherein the compound may be used in a composition or dosage unit form for delivery of at least one active agent, including a peptide, mucopolysaccharide, carbohydrate, or a lipid. Methods of administration and preparation of the compounds and compositions of the invention are provided as well, including oral administration. Further, the compositions of the invention may be prepared by mixing at least one active agent, at least one carrier compound, and, optionally, a dosing vehicle.

Claims

1. A composition comprising:

(A) at least one active agent; and

(B) a compound having the following formula ##STR68## or a salt thereof.

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

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

4. A composition as defined in claim 2, wherein said biologically active agent comprises heparin.

5. A composition as defined in claim 2, wherein said biologically active agent comprises low molecular weight heparin.

8. A dosage unit form comprising:

(A) a composition as defined in claim 1; and

(B) (a) an excipient

(b) a diluent,

(c) a disintegrant,

(d) a lubricant,

(e) a plasticizer,

(f) a colorant,

(g) a dosing vehicle, or

(h) any combination thereof.

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

10. A dosage unit form as defined in claim 9, wherein said active agent is selected from the group consisting of at least one peptide, mucopolysaccharide, carbohydrate, and a combination thereof.

11. A dosage unit form as defined in claim 9 wherein said biologically active agent comprises heparin.

12. A dosage unit form as defined in claim 9 wherein said biologically active agent comprises low molecular weight heparin.

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

14. A dosage unit form as defined in claim 13, wherein said dosing vehicle is selected from the group consisting of water, 1,2-diol, ethanol, and any combination thereof.

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

18. The composition as defined in claim 3, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), and any combination thereof.

19. A composition as defined in claim 18, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, or combinations thereof.

20. A composition as defined in claim 2, wherein said biologically active agent comprises recombinant human growth hormone.

21. The dosage unit form as defined in claim 10, wherein said biologically active agent is selected from the group consisting of human growth hormone, bovine growth hormone, growth hormone-releasing hormone, an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, erythropoietin, atrial naturetic factor, an antigen, a monoclonal antibody, somatostatin, adrenocorticotropin, gonadotropin releasing hormone, oxytocin, vasopressin, cromolyn sodium, vancomycin, desferrioxamine (DFO), and any combination thereof.

22. A dosage unit form as defined in claim 21, wherein said biologically active agent comprises an interferon, interleukin-II, insulin, heparin, low molecular weight heparin, calcitonin, oxytocin, vasopressin, vancomycin, DFO, or combinations thereof.

23. A dosage unit form as defined in claim 9, wherein said biologically active agent comprises recombinant human growth hormone.

6. A composition comprising:

(a) at least one active agent; and

(b) a carrier comprising a compound having the following formula;

##STR69## or a salt thereof, wherein said carrier is selected from the group consisting of a poly(amino acid) and a polypeptide.

7. A composition as defined in claim 6, wherein said carrier comprises a polypeptide.

16. A compound having the formula ##STR70## or a salt thereof.

17. A method for preparing a composition, said method comprising mixing:

(A) at least one active agent;

(B) at least one compound as defined in claim 16; and

(C) optionally, a dosing vehicle.