LONG-ACTING PARATHYROID HORMONE
The invention provides a long-acting parathyroid hormone peptide (PTH) that is retained in a subject's blood serum for periods of time that greatly exceed the natural hormone. The long-acting PTH is conjugated to at the carbon 3 position of a non-hormonal vitamin D via a scaffold of discreet length that facilitates its purification, detection, solubility, and efficacy at the PTH receptor (PTHR). The PTH may be conjugated to the non-hormonal vitamin D via a 36 mer poly(ethylene glycol) moiety (PTH-PEG36-VitD). The invention also provides optimized manufacturing methods and formulations. The PTH-PEG36-VitD has a vastly-improved serum half-life and bioavailability when compared to a non-conjugated PTH peptide. PTH-PEG36-VitD also significantly increases serum calcium, reduces urinary calcium, and reduces serum phosphate.
1 .- 30 . (canceled)
31 . A pharmaceutical composition comprising parathyroid hormone 1-34 (PTH(1-34)) peptides conjugated via a poly(ethylene glycol) (PEG) scaffold to a non-hormonal vitamin D moiety at the carbon 3 position (PTH conjugates); wherein said scaffold is not conjugated to an amine group of said PTH(1-34); wherein said PEG scaffold discreet length is between 34 and 62 PEG subunits; wherein said PTH conjugate consists of an acetate salt of SEQ ID NO: 7; and wherein said composition comprises a pharmaceutically acceptable excipient.
32 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition has a pH of about 4.0 to about 5.5.
33 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition has a pH of about 4.0.
34 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition has a pH of about 5.5.
35 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition further comprises mannitol.
36 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition further comprises Polysorbate 80 (PS80).
37 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition further comprises methionine at a concentration of between about 0 and 40 mM+/−5 mM.
38 . The pharmaceutical composition of claim 31 , wherein said pharmaceutical composition has a pH of about 5.5, and wherein said pharmaceutical composition comprises mannitol and PS80.
39 . The pharmaceutical composition of claim 31 , wherein said PTH conjugates are at a concentration of about 0.4 mg/ml to about 1.0 mg/ml.
40 . The pharmaceutical composition of claim 31 , wherein said PTH conjugates are at a concentration of about 1.0 mg/ml.
41 . The pharmaceutical composition of claim 38 , wherein said PTH conjugates are at a concentration of about 1.0 mg/ml in about 10 mM sodium acetate buffer (+/−10%), about 4.5% mannitol (+/−1.5%), and about 0.25% PS80 (+/−0.25%).
42 . The pharmaceutical composition of claim 31 , comprising 10 mM sodium acetate buffer (+/−10%); 3.0% to 4.5% mannitol; 0% to 0.25% PS80; and 0 mM to 40 mM methionine.
43 . The pharmaceutical composition of claim 41 , further comprising 5 mM to 40 mM methionine (+/−5 mM).
44 . The pharmaceutical composition of claim 41 , further comprising 40 mM methionine (+/−5 mM).
45 . The pharmaceutical composition of claim 40 , wherein said pharmaceutical composition comprises about 2 mM sodium acetate buffer (+/−1 mM), about 4.5% mannitol (+/−1.5%), and about 0.25% PS80 (+/−0.25%).
46 . The pharmaceutical composition of claim 31 , comprising 2 mM sodium acetate buffer (+/−1 mM); 3.0% to 4.5% mannitol; 0% to 0.25% PS80; and 0 mM to 40 mM methionine.
47 . The pharmaceutical composition of claim 46 , wherein said pharmaceutical composition has a pH of about 4.0.
48 . The pharmaceutical composition of claim 47 , further comprising 5 mM to 40 mM methionine (+/−5 mM).
49 . The pharmaceutical composition of claim 47 , further comprising 40 mM methionine (+/−5 mM).
50 . The pharmaceutical composition of claim 48 , wherein said PTH conjugate is at a concentration of about 1.0 mg/ml.
51 . The pharmaceutical composition of claim 31 , comprising 4 mM sodium acetate buffer (+/−2 mM); 3.0% to 4.5% mannitol; 0% to 0.25% PS80; and 0 mM to 40 mM methionine.
52 . The pharmaceutical composition of claim 51 , wherein said pharmaceutical composition has a pH of about 4.0.
53 . The pharmaceutical composition of claim 52 , further comprising 5 mM to 40 mM methionine (+/−5 mM).
54 . The pharmaceutical composition of claim 52 , further comprising 40 mM methionine (+/−5 mM).
55 . The pharmaceutical composition of claim 53 , wherein said PTH conjugate is at a concentration of about 1.0 mg/ml.
56 . The pharmaceutical composition of claim 31 , comprising 6 mM sodium acetate buffer (+/−2 mM); 3.0% to 4.5% mannitol; 0% to 0.25% PS80; and 0 mM to 40 mM methionine.
57 . The pharmaceutical composition of claim 56 , wherein said pharmaceutical composition has a pH of about 4.0.
58 . The pharmaceutical composition of claim 57 , further comprising 5 mM to 40 mM methionine (+/−5 mM).
59 . The pharmaceutical composition of claim 57 , further comprising 40 mM methionine (+/−5 mM).
60 . The pharmaceutical composition of claim 58 , wherein said PTH conjugate is at a concentration of about 1.0 mg/ml.
61 . The pharmaceutical composition of claim 31 , wherein said PTH conjugates have about the same activity on a PTH receptor (PTHR) as an equivalent unconjugated PTH peptide.