US 2009/0022683 A1Published application

Biodegradable and Thermosensitive Poly(Organophosphazene) Hydrogel, Preparation Method Thereof and Use Thereof

AssigneeKist

InventorsSoo-Chang Song, Sun-Mi Lee, Chang-Won Kim, Mi-Ran Park

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Abstract

The present invention relates to a biodegradable and thermosensitive poly(organophosphazene) with a functional group, a preparation method thereof, and a use thereof for delivery of bioactive substances. According to the present invention, poly(organophosphazene) is a phosphagen-based polymer showing biodegradability, thermosensitivity, and sol-gel phase transition depending on temperature change, whereby when administered into a living body with bioactive substances such as drugs, the poly(organophosphazene) forms a gel-phase at body temperature to be capable of controlled release of the bioactive substances. Further, the poly(organophosphazene) has functional groups to chemically bind with bioactive substances through an ionic bond, covalent bond, or coordinate covalent bond to be capable of a sustained release of the bioactive substances due to its good binding property. Therefore, the poly(organophosphazene) is useful as a delivery material for bioactive substances.

Claims57

Dependent claims

A poly(organophosphazene) represented by the following Chemical Formula 1:

wherein,
p is an integer between 7 and 50;
R1 is selected from the group consisting of H, HCH2, CH3, CH2SH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, CH2C2H2C6H4, OCOC4N+H9, CO2C2H5, CH2CO2C2H5, (CH2)2CO2C2H5, and HCONHCH(CH2C6H5),
R2 is selected from the group consisting of CH3, C3H7, C4H9, C2H5, CH2C6H5, and CH2CHCH2;
R3 is CH(W),
R4 is selected from the group consisting of CO2, CO2CH2CO2, CO2CH(CH3)CO2, and CONHCH(X)CO2,
R5 is selected from the group consisting of H, CH3, and C2H5,
W and X are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, OCOC4N+H9, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH;
R6 is CH(Y),
R7 is selected from the group consisting of C2H4, C3H6, C4H8, CH2C6H, CH2CO2, O, CONHCH(Z)O, CO, CO2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO2,
R8 is selected from the group consisting of OH, SH, H, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, and protecting groups as defined in Table 2 described in the detailed description of the present invention,
Y and Z are independently selected from the group consisting of H, HCH2, CH3, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, OCOC4N+H9, CO2C2H5, (CH2)2CO2C2H5, CH2OH, CH(CH3)OH, CH2C6H OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH,
R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)rH, [NHCH(C4H8NH2)CO]rOH, [NHCH[(CH2)3C(═NH)(NH2)]CO]rOH, and protamines,
q is an integer between 1 and 20,
r is an integer between 1 and 18000;
a1, a2, b, c, d, and e respectively represent the content of each substituent, wherein a1, a2, b, and d are independently from 0.01 to 1.9, c and e are independently from 0 to 1.9, and a1+a2+b+c+d+e=2.0;
and
n is from 5 to 100000.

15 more elements

A poly(organophosphazene) hydrogel containing poly(organophosphazene) of the following Chemical Formula 1-1 dissolved in one or more solvents and showing sol-gel phase transition depending on temperature change:

wherein p is an integer between 7 and 50;
R1 is selected from the group consisting of H, HCH2, CH3, CH2SH, CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C6H4OH, CH2C2H2C6H4, OCOC4N+H9, CO2C2H5, CH2CO2C2H5, (CH2)2CO2C2H5 and HCONHCH(CH2C6H5),
R2 is selected from the group consisting of CH3, C3H7, C4H9, C2H5, CH2C6H5, and CH2CHCH2;
R3 is CH(W),
R4 is selected from the group consisting of CO2, CO2CH2CO2, CO2CH(CH3)CO2, and CONHCH(X)CO2,
R5 is selected from the group consisting of H, CH3 and C2H5,
W and X are independently selected from the group consisting of H, HCH2, CH3 CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, OCOC4N+H9, CO2C2H5, (CH2)2CO2C2H5CH2OH, CH(CH3)OH, CH2C6 OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH;
R6 is CH(Y),
R7 is selected from the group consisting of C2H4, C3H6, C4H8, CH2C6H4, CH2CO2, O, CONHCH(Z)O, CO, CO2, S, CONHCH(Z)S, N, CONHCH(Z)N, CON, COCHNH(Z)CON, CONHCH(Z)CO, and CONHCH(Z)CO2,
R8 is selected from the group consisting of OH, SH, H, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, and protecting groups as defined in Table 2 described in the detailed description of the present invention,
Y and Z are independently selected from the group consisting of H, HCH2, CH3 CH(CH3)2, CH2CH(CH3)2, CH(CH3)C2H5, CH2CH2SCH3, CH2C6H5, CH2C2H2C6H4, OCOC4N+H9, CO2C2H5, (CH2)2CO2C2H5CH2OH, CH(CH3)OH, CH2C6 OH, CH2COOH, CH2CH2COOH, CH2CONH2, C4H8NH2, C3H6NHC(═NH)NH2, CH2C3N2H3, and CH2SH,
R9 is selected from the group consisting of OH, SH, H, NH2, CH3, C2H5, C3H7, C4H9, CH2C6H5, CH2CHCH2, NHCH(SH)CO2H, NH(CH2)qSH, NH(CH2CH2NH)rH, [NHCH(C4H8NH2)CO]rOH, [NHCH[(CH2)3C(═NH)(NH2)]CO]rOH, and protamines,
q is an integer between 1 and 20,
r is an integer between 1 and 18000;
a1, a2, b, c, d, and e respectively represent the content of each substituent, wherein a1, a2, and b are independently from 0.01 to 1.9, c, d, and e are independently from 0 to 1.9, and a1+a2+b+c+d+e=2.0;
and
n is from 5 to 100000.

14 more elements

A bioactive substance delivery system containing the biodegradable polymer or a polymer hydrogel containing the biodegradable polymer, a bioactive substance, and one or more additives,

wherein the biodegradable polymer forms a gel-phase at body temperature, and
the polymer hydrogel is biodegradable and forms a gel-phase at body temperature and contains the polymer dissolved in a solvent selected from the group consisting of water, buffer solution, acid solution, basic solution, salt solution, saline solution, water for injection, and glucose salt solution with the concentration of 1 to 50 wt %.

Dependencies are inferred from the claim text.

Facts

Application: 11/568,851Filed 3 Nov 2006
Priority: KR 10-2006-000557918 Jan 2006
Published: 22 Jan 2009
Term ends: Not estimatedThe source records don’t support an estimate.

Classification10 codes

A61K 9/06
Medicinal preparations characterised by special physical form: ointments; Bases therefor; Other semi-solid forms, e.g. creams, sticks, gels
A61K 9/0024
Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in…
A61K 9/08
Medicinal preparations characterised by special physical form: solutions
A61K 47/34
Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates: macromolecular compounds obtained otherwise than by reactions only…