Crystalline insulin-conjugates
The present disclosure provides crystalline insulin-conjugates. The present disclosure also provides formulations, methods of treatment, methods of administering, and methods of making that encompass these crystalline insulin-conjugates.
1. A crystalline insulin-conjugate of formula (I):
wherein:
each occurrence of [( )] represents a potential branch within the conjugate;
each occurrence of ( ) represents a potential repeat within a branch of the conjugate;
each occurrence of is independently a covalent bond, a carbon atom, a heteroatom, or an optionally substituted group selected from the group consisting of acyl, aliphatic, heteroaliphatic, aryl, heteroaryl, and heterocyclic;
each occurrence of T is independently a covalent bond or a bivalent, straight or branched, saturated or unsaturated, optionally substituted C 1-30 hydrocarbon chain wherein one or more methylene units of T are optionally and independently replaced by —O—, —S—, —N(R)—, —C(O)—, —C(O)O—, —OC(O)—, —N(R)C(O)—, —C(O)N(R)—, —S(O)—, —S(O) 2 —, —N(R)SO 2 —, —SO 2 N(R)—, a heterocyclic group, an aryl group, or a heteroaryl group;
each occurrence of R is independently hydrogen, a suitable protecting group, or an acyl moiety, arylalkyl moiety, aliphatic moiety, aryl moiety, heteroaryl moiety, or heteroaliphatic moiety;
—B is -T-L B -X;
each occurrence of X is independently a ligand that includes a saccharide wherein at least one ligand comprises a branched trisaccharide;
each occurrence of L B is independently a covalent bond or a group derived from the covalent conjugation of a T with an X;
-D is -T-L D -W I ;
W I is an insulin molecule;
each occurrence of L D is independently a covalent bond or a group derived from the covalent conjugation of a T with a W I ;
k is an integer from 1 to 12, inclusive;
each occurrence of p is independently an integer from 1 to 5, inclusive; and
each occurrence of n is independently an integer from 0 to 5, inclusive; and
each occurrence of m is independently an integer from 1 to 5, inclusive; and
each occurrence of v is independently an integer from 0 to 5, inclusive, with the proviso that within each k-branch at least one occurrence of n is ≧1 and at least one occurrence of v is ≧1; and, wherein the conjugate when administered to a mammal in the absence of an exogenous multivalent saccharide-binding molecule, has at least one pharmacokinetic or pharmacodynamic property of the conjugate that is sensitive to serum concentration of a second saccharide.
2. The crystalline insulin-conjugate of claim 1 , wherein the conjugate is of formula (IIIa):
3. The crystalline insulin-conjugate of claim 2 , wherein the conjugate is of formula (IIIa-1), (III2-2), or (IIIa-3):
4. The crystalline insulin-conjugate of claim 1 , wherein the conjugate is of formula (IIIb):
5. The crystalline insulin-conjugate of claim 4 , wherein the conjugate is of the formula (IIIb-1), (IIIb-2), (IIIb-3), (IIIb-4), (IIIb-4), (IIIb-6), (IIIb-7):
6. The crystalline insulin-conjugate of claim 1 , wherein the conjugate is of formula (IIIc):
7. The crystalline insulin-conjugate of claim 6 , wherein the conjugate is of formula (IIIc-1) or (IIIc-2):
8. The crystalline insulin-conjugate of claim 1 , wherein the insulin molecule is selected from the group consisting of insulin lispro, insulin aspart and insulin glulisine.
9. The crystalline insulin-conjugate of claim 1 , wherein the insulin molecule is insulin glargine or insulin detemir.
10. The crystalline insulin-conjugate of claim 1 , wherein the insulin molecule is conjugated via the epsilon-amino group of Lys B29 .
11. The crystalline insulin-conjugate of claim 1 , the branched trisaccharide is a branched trimannose.
12. The crystalline insulin-conjugate of claim 1 , wherein each occurrence of X is aminoethyltrimannose (AETM).
13. The crystalline insulin-conjugate of claim 1 , wherein each occurrence of X is aminoethyltrimannose (AETM) conjugated to the conjugate framework via an alpha anomeric carbon; and W I is an insulin molecule conjugated to the conjugate framework via the epsilon amino group of Lys B29 .
14. A crystalline insulin-conjugate of formula (IIIb-3):
wherein:
W I is an insulin molecule; and
each occurrence of —X is
15. A crystalline insulin-conjugate comprising a formula selected from the group consisting of: