Mixtures of calcitonin drug-oligomer conjugates comprising polyalkylene glycol, uses thereof, and methods of making same

A mixture of conjugates having a dispersity coefficient (DC) greater than 10,000 where:

• DC = ( ∑ i = 1 n ⁢ N i ⁢ M i ) 2 ∑ i = 1 n ⁢ N i ⁢ M i 2 ⁢ ∑ i = 1 n ⁢ N i - ( ∑ i = 1 n ⁢ N i ⁢ M i ) 2
• wherein:
• n is the number of different molecules in the sample;
• Ni is the number of ith molecules in the sample;
• and
• Mi is the mass of the ith molecule, and
• wherein each conjugate in the mixture comprises salmon calcitonin coupled at Lys11 to a first oligomer and coupled at Lys18 to a second oligomer, and wherein the first oligomer and the second oligomer each have the formula:

A mixture of conjugates having a dispersity coefficient (DC) greater than 10,000 where:

• DC = ( ∑ i = 1 n ⁢ N i ⁢ M i ) 2 ∑ i = 1 n ⁢ N i ⁢ M i 2 ⁢ ∑ i = 1 n ⁢ N i - ( ∑ i = 1 n ⁢ N i ⁢ M i ) 2
• wherein:
• n is the number of different molecules in the sample;
• Ni is the number of ith molecules in the sample;
• and
• Mi is the mass of the ith molecule, and
• wherein each conjugate in the mixture comprises salmon calcitonin coupled at Lys11 to a first oligomer and coupled at Lys18 to a second oligomer, and wherein the first oligomer and the second oligomer each have the formula:

A mixture of conjugates having a dispersity coefficient (DC) greater than 10,000 where:

• DC = ( ∑ i = 1 n ⁢ N i ⁢ M i ) 2 ∑ i = 1 n ⁢ N i ⁢ M i 2 ⁢ ∑ i = 1 n ⁢ N i - ( ∑ i = 1 n ⁢ N i ⁢ M i ) 2
• wherein:
• n is the number of different molecules in the sample;
• Ni is the number of ith molecules in the sample;
• and
• Mi is the mass of the ith molecule, and
• wherein each conjugate in the mixture comprises salmon calcitonin coupled at Lys11 or Lys18 to an oligomer having the formula:

A mixture of conjugates in which each conjugate has the same molecular weight and has the structure:

• Calcitonin Drug-oligomer where the oligomer has the formula:
• [B—Lj—Gk—R—G′m—R′—G″n—T]p (A)
• and wherein:
• the Calcitonin Drug is a salmon calcitonin coupled to the oligomer at Lys11 and Lys18;
• B is a bonding moiety;
• L is a linker moiety;
• G, G′ and G″ are individually selected spacer moieties;
• R is a lipophilic moiety and R′ is a polyalkylene glycol moiety, or R′ is the lipophilic moiety and R is the polyalkylene glycol moiety;
• T is methoxy;
• j, k, m and n are individually 0 or 1;
• and
• p is an integer from 1 to the number of nucleophilic residues on the calcitonin drug.

A mixture of conjugates in which each conjugate has the same molecular weight and has the structure:

• Calcitonin Drug-oligomer where the oligomer has the formula:
• [B—Lj—Gk—R—G′m—R′—G″n—T]p (A)
• and wherein:
• the Calcitonin Drug is coupled to the oligomer at a nucleophilic residue selected from the group consisting of histidine, serine, tyrosine, and combinations thereof;
• B is a bonding moiety;
• L is a linker moiety;
• G, G′ and G″ are individually selected spacer moieties;
• R is a lipophilic moiety and R′ is a polyalkylene glycol moiety, or R′ is the lipophilic moiety and R is the polyalkylene glycol moiety;
• T is methoxy;
• j, k, m and n are individually 0 or 1;
• and
• p is an integer from 1 to the number of nucleophilic residues on the calcitonin drug.

A process for synthesizing a substantially monodispersed mixture of conjugates, each conjugate comprising a calcitonin drug coupled to an oligomer that comprises a polyethylene glycol moiety, said process comprising:

• reacting a substantially monodispersed mixture comprising compounds having the structure of Formula I:
• R1(OC2H4)m—O−X+ (I)
• wherein R1 is H or a lipophilic moiety;
• m is from 1 to 25;
• and X+ is a positive ion, with a substantially monodispersed mixture comprising compounds having the structure of Formula II:
• R2(OC2H4)n—OMs (II)
• wherein R2 is H or a lipophilic moiety;
• and n is from 1 to 25, under conditions sufficient to provide a substantially monodispersed mixture comprising polymers having the structure of Formula III:
• R2(OC2H4)m+n—OR1 (III);
• activating the substantially monodispersed mixture comprising polymers of Formula III to provide a substantially monodispersed mixture of activated polymers capable of reacting with a calcitonin drug;
• and
• reacting the substantially monodispersed mixture of activated polymers with Lys11 and Lys18 of the salmon calcitonin to provide a substantially monodispersed mixture of diconjugates each comprising a salmon calcitonin coupled to two oligomers that each comprise a polyethylene glycol moiety with m+n subunits.