Hydrogel prodrugs

Patent metadata

Field	Value
Publication number	US-9855340-B2
Application number	US-201314434585-A
Country	US
Kind code	B2
Filing date	Oct 8, 2013
Priority date	Oct 11, 2012
Publication date	Jan 2, 2018
Grant date	Jan 2, 2018

Abstract

The present invention relates to a process for the preparation of a hydrogel and to a hydrogel obtainable by said process. The present invention further relates to a process for the preparation of a hydrogel-spacer conjugate, to a hydrogel-spacer conjugate obtainable by said process, to a process for the preparation of a carrier-linked prodrug and to carrier-linked prodrugs obtainable by said process, in particular to carrier-linked prodrugs that provide for a controlled or sustained release of a drug from a carrier. In addition, the invention relates to the use of the hydrogel for the preparation of a carrier-linked prodrug.

First claim

The invention claimed is:

1. A process for the preparation of a hydrogel comprising the steps of:
(a) providing a mixture comprising:
(a-i) at least one backbone reagent, wherein the at least one backbone reagent has a molecular weight ranging from 1 to 100 kDa, and comprises at least three amines (—NH 2 and/or —NH—);
(a-ii) at least one crosslinker reagent, wherein the at least one crosslinker reagent has a molecular weight ranging from 6 to 40 kDa, the at least one crosslinker reagent comprising:
(i) at least two carbonyloxy groups (—(C═O)—O— or —O—(C═O)—); and
(ii) at least two activated functional end groups selected from the group consisting of activated ester groups, activated carbamate groups, activated carbonate groups and activated thiocarbonate groups;
wherein the at least one crosslinker reagent is PEG-based comprising at least 70% PEG; and

(a-iii) a first solvent and at least a second solvent, which second solvent is immiscible in the first solvent;
wherein a weight ratio of the at least one backbone reagent to the at least one crosslinker reagent is in a range of from 1:99 to 99:1; and

(b) polymerizing the mixture of step (a) in a suspension polymerization to a hydrogel.

2. The process of claim 1 ;
wherein the mixture of step (a) further comprises a detergent.

3. The process of claim 2 ;
wherein the detergent is PEG 30 dipolyhydroxystearate.

4. The process of claim 1 ;
wherein the polymerization in step (b) is initiated by adding a base.

5. The process of claim 4 ;
wherein the base comprises at least one compound selected from the group consisting of N,N,N′,N′-tetramethylethylene diamine (TMEDA), 1,4-dimethylpiperazine, 4-methylmorpholine, 4-ethylmorpholine, 1,4-diazabicydo[2.2.2]octane, 1,1,4,7,10,10-hexamethyltriethylenetetramine, 1,4,7-trimethyl-1,4,7-triazacyclononane, tris[2-(dimethylamino)ethyl]amine, triethylamine, diisopropylethylamine (DIPEA), trimethylamine, N,N-dimethylethylamine, N,N,N′,N′-tetramethyl-1,6-hexanediamine, N,N,N′,N″,N″-pentamethyldiethylenetriamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,5-diazabicyclo[4.3.0]non-5-ene, and hexamethylenetetramine.

6. The process of claim 1 ;
wherein the mixture of step (a) is an emulsion.

7. The process of claim 1 ;
wherein the process further comprises the step of:
(c) working-up the hydrogel.

8. The process of claim 1 ;
wherein the at least one backbone reagent is selected from the group consisting of:
a compound of formula (I):)
B(-(A 0 ) x1 -(SP) x2 -A 1 -P-A 2 -Hyp 1 ) x   (1);

wherein:
B is a branching core;
SP is a spacer moiety selected from the group consisting of C 1-6 alkyl, C 2-6 alkenyl and C 2-6 alkynyl;
P is a PEG-based polymeric chain comprising at least 80% PEG;
Hyp 1 is a moiety comprising an amine (—NH 2 and/or —NH—) or a polyamine comprising at least two amines (—NH 2 and/or —NH—);
x is an integer from 3 to 16;
x1 and x2 are independently of each other 0 or 1, provided that x1 is 0, if x2 is 0;
A 0 , A 1 , and A 2 are independently of each other selected from the group consisting of:

wherein R 1 and R 1a are independently of each other selected from H and C 1 alkyl;

a compound of formula (II):
Hyp 2 -A 3 -P-A 4 -Hyp 3   (II);

wherein:
P is defined as above in the compound of formula (I);
Hyp 2 and Hyp 3 are independently of each other a polyamine comprising at least two amines (—NH 2 and/or —NH—); and
A 3 and A 4 are independently selected from the group consisting of:

wherein R 1 and R 1a are independently of each other selected from H and C 1-6 alkyl;

a compound of formula (III):
P 1 -A 5 -Hyp 4   (III);

wherein
P 1 is a PEG-based polymeric chain comprising at least 80% PEG;
Hyp 4 is a polyamine comprising at least three amines (—NH 2 and/or —NH—); and
A 5 is selected from the group consisting of:

wherein R 1 and R 1a are independently of each other selected from H and C 1-6 alkyl; and

a compound of formula (IV):
T 1 -A 6 -Hyp 5   (IV);

wherein
Hyp 5 is a polyamine comprising at least three amines (—NH 2 and/or —NH), and
A 6 is selected from the group consisting of:

wherein R 1 and R 1a are independently of each other selected from H and C 1-6 alkyl; and

T 1 is selected from the group consisting of C 1-50 alkyl, C 2-50 alkenyl or C 2-50 alkynyl, which fragment is optionally interrupted by one or more group(s) selected from the group consisting of —NH—, N(C 1-4 alkyl)-, —O—, —S—, —C(O)—, —C(O)NH—, —C(O)N(C, alkyl)-, —O—C(O)—, —S(O)—, —S(O) 2 —, 4-membered to 7-membered heterocyclyl, phenyl, and naphthyl.

9. The process of claim 8 ;
wherein Hyp 1 , Hyp 2 , Hyp 3 , Hyp 4 , and Hyp 5 are selected from the group consisting of:
a moiety of formula (e-i):

wherein:
p1 is an integer from 1 to 5; and
the dashed line indicates attachment to A 2 if the backbone reagent has a structure of formula (I), and to A 3 or A 4 if the backbone reagent has the structure of formula (H);

a moiety of formula (e-ii):

wherein:
p2, p3, and p4 are identical or different and each is independently of the others an integer from 1 to 5; and
the dashed line indicates attachment to A 2 if the backbone reagent has a structure of formula (I), to A 3 or A 4 if the backbone reagent has a structure of formula (H), to A 5 if the backbone reagent has a structure of formula (III), and to A 6 if the backbone reagent has a structure of formula (IV);

a moiety of formula (e-iii):

wherein:
p5 to p11 are identical or different and each is independently of the others an integer from 1 to 5; and
the dashed line indicates attachment to A 2 if the backbone reagent is of formula (I), to A 3 or A 4 if the backbone reagent is of formula (II), to A 5 if the backbone reagent is of formula (III), and to A 6 if the backbone reagent is of formula (IV);

a moiety of formula (e-iv):

wherein:
p12 to p26 are identical or different and each is independently of the others an integer from 1 to 5; and
the dashed line indicates attachment to A 2 if the backbone reagent has a structure of formula (I), to A 3 or A 4 if the backbone reagent has a structure of formula (II), to A 5 if the backbone reagent has a structure of formula (III), and to A 6 if the backbone reagent has a structure of formula (IV);

a moiety of formula (e-v):

wherein:
p27 and p28 are identical or dif

Assignees

• Ascendis Pharma As

Inventors

• Rau Harald
• Voigt Tobias
• Laufer Burkhardt
• Bisek Nicola
• Hahn Franziska
• Knappe Thomas

Classifications

• C08L2203/02

  for biomedical use · CPC title

• A61K47/48784

  Human Necessities · mapped topic

• C08G65/3322

  acyclic · CPC title

• C08J2400/202

  Dendritic macromolecules, e.g. dendrimers or hyperbranched polymers · CPC title

• C08G65/33337

  cyclic · CPC title