Systems for stabilizing and delivering active agents
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IPC분류정보
국가/구분
United States(US) Patent
등록
국제특허분류(IPC7판)
A61K-047/64
A61K-031/47
A61K-049/00
A61K-031/00
A61K-047/54
A61K-038/00
C07D-231/12
A61K-031/4745
출원번호
US-0446212
(2017-03-01)
등록번호
US-10172959
(2019-01-08)
발명자
/ 주소
Alhamadsheh, Mamoun M.
Park, Miki S.
Chan, William K.
Li, Xiaoling
Penchala, Sravan C.
Miller, Mark R.
출원인 / 주소
Alhamadsheh, Mamoun M.
대리인 / 주소
Boyer, Brian S.
인용정보
피인용 횟수 :
0인용 특허 :
53
초록▼
A delivery system for active agents, and methods of making and using the systems, are provided. The delivery systems have (i) a ligand that is selective for an endogeneous plasma protein in the serum of a subject; and, (ii) a linker configured for operatively attaching the ligand covalently to an ac
A delivery system for active agents, and methods of making and using the systems, are provided. The delivery systems have (i) a ligand that is selective for an endogeneous plasma protein in the serum of a subject; and, (ii) a linker configured for operatively attaching the ligand covalently to an active agent to increase the half-life of the active agent in the serum.
대표청구항▼
1. A delivery system for an active agent, comprising: a ligand that is selective for transthyretin in the serum of a subject; and,a linker configured for operatively attaching the ligand covalently to an active agent, the linker selected to cause release of the agent from the transthyretin in the su
1. A delivery system for an active agent, comprising: a ligand that is selective for transthyretin in the serum of a subject; and,a linker configured for operatively attaching the ligand covalently to an active agent, the linker selected to cause release of the agent from the transthyretin in the subject as a conjugated drug, wherein the linker ranges from 14-20 angstroms in length;wherein the system has a structure comprising: where, n is 1 to 8;R1 and R3 are independently selected from a short chain alkyl having 1 to 4 carbon atoms;R2 is selected from the group consisting of a hydrogen, a short chain alkyl having 1 to 4 carbon atoms, and an aryl;Xa is C(R4)(R5), O, N—R5, or S; where R4 and R5 are independently selected from hydrogen, an alkyl having 1 to 4 carbon atoms, a substituted alkyl, an alkoxy, hydroxyl, an alkoxycarbonyl, an an amino;Ra is CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, halogen, acyl, substituted acyl, carboxyl, heterocyclic group, sulfonamide, sulfonyl fluoride, thioester, alkoxycarbonyl or substituted alkoxycarbonyl;Rb is the linker and is positioned ortho or meta to Ra, the linker including a CHO, COOH, COOCH3, COOR6, CONR7R8, tetrazolyl, CONHOH, B(OH)2, CONHSO2Ar, CONHCH(R9)COOH, CF3, hydrogen, halogen, alkyl, substituted alkyl, acyl, substituted acyl, carboxyl, heterocyclic group, sulfonamide, sulfonyl fluoride, ester, thioester, ether, thioether, triazolyl, alkoxycarbonyl or substituted alkoxycarbonyl;R6 is alkyl, haloalkyl, cycloalkyl, or heterocyclyl;R7 and R8 are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, or heteroaryl; and,R9 is the side chain of a naturally occurring α-amino carboxylic acid;or, a pharmaceutically acceptable salt, ester, enol ether, enol ester, amide, acetal, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof. 2. The delivery system of claim 1, wherein the ligand has the structure of Compound (VIIIc): or, a pharmaceutically acceptable salt, ester, enol ether, enol ester, acetal, amide, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof; and,the linker is attached to the ligand ortho at C15 to the carboxyl group at C14. 3. The delivery system of claim 1, wherein the ligand has the structure of Compound (VIIIc): or, a pharmaceutically acceptable salt, ester, enol ether, enol ester, acetal, amide, ketal, orthoester, hemiacetal, hemiketal, hydrate, solvate or prodrug thereof; and,the linker is attached to the ligand meta at C16 to the carboxy carbon at C14. 4. A method of increasing the in vivo half-life of an active agent, the method comprising covalently attaching the delivery system of claim 2 to an active agent for release of the agent in the subject as the conjugated drug, the active agent comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof. 5. A method of increasing the in vivo half-life of an active agent, the method comprising covalently attaching the delivery system of claim 3 to an active agent for release of the agent in the subject as the conjugated drug, the active agent comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof. 6. A method of increasing the in vivo half-life of an active agent in blood serum, the method comprising covalently attaching the delivery system of claim 1 to an active agent for release of the agent in the subject as the conjugated drug, the active agent comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof. 7. A method of increasing the in vivo half-life of an active agent in blood serum, the method comprising covalently attaching the delivery system of claim 3 to a drug for release of the agent in the subject as the conjugated drug, the active agent comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof. 8. A method of increasing the in vivo half-life of an active agent in blood serum, the method comprising covalently attaching the delivery system of claim 2 to an active agent for releasing the agent in the subject as the conjugated drug; wherein, the active agent comprises a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof. 9. A method of increasing the in vivo half-life of an active agent in blood serum, the method comprising covalently attaching the delivery system of claim 3 to an active agent for releasing the agent in the subject as the conjugated drug; wherein, the active agent comprises a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof. 10. A method of reducing the immunogenicity of an active agent in vivo, the method comprising: obtaining a delivery system of claim 1;covalently attaching the delivery system to an active agent to create the conjugated drug for the release in the subject; and,releasing the conjugated drug from the transthyretin in the subject;wherein, the active agent comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an imaging agent, and combinations thereof;and, the transthyretin shields the active agent from antibody generation in vivo prior to the releasing of the conjugated drug in the subject. 11. The method of claim 10, wherein the obtaining comprises obtaining the delivery system of claim 3. 12. The method of claim 10, wherein the obtaining comprises obtaining the delivery system of claim 2. 13. The delivery system of claim 1, wherein the linker, Rb, attaches (i) to the ligand through an ether bond and (ii) to the active agent through an amide bond. 14. The delivery system of claim 1, wherein the linker, Rb, attaches (i) to the ligand through an ether bond and (ii) to the active agent through an ester. 15. The delivery system of claim 1, wherein the linker, Rb, attaches (i) to the ligand through an ether bond and (ii) to the active agent through an amide bond or an ester bond;Ra is a carboxy group;R1 is a methyl group;R2 is hydrogen;R3 is a methyl group; and,the active agent is a protein or peptide. 16. A method of administering an active agent to a subject, the method comprising: covalently attaching the delivery system of claim 1 to an active agent to create the conjugated drug for the release in the subject comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof; and,administering the conjugated drug to the subject including releasing the conjugated drug from the transthyretin in the subject. 17. A method of administering an active agent to a subject, the method comprising: covalently attaching the delivery system of claim 2 to a drug to create the conjugated drug for the release in the subject comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof; and,administering the conjugated drug to the subject including releasing the conjugated drug from the transthyretin in the subject. 18. A method of administering an active agent to a subject, the method comprising: covalently attaching the delivery system of claim 3 to a drug to create the conjugated drug comprising a structure selected from the group consisting of a peptide, an oligopeptide, a polypeptide, a protein, an antibody, an oligonucleotide, a polynucleotide, a virus-like particle, a small molecule, an oligosaccharide, an imaging agent, and combinations thereof; and,administering the conjugated drug to the subject including releasing the conjugated drug from the transthyretin in the subject.
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