PTH compounds with low peak-to-trough ratios
The present invention relates to a pharmaceutical composition comprising a PTH compound, wherein after subcutaneous administration the pharmacokinetic profile of the PTH compound exhibits a peak to trough ratio of less than 4 within one injection interval.
1. A pharmaceutical composition comprising a parathyroid hormone (PTH) compound, wherein the pharmaceutical composition is suitable for subcutaneous administration, and wherein after subcutaneous administration to a mammal the PTH compound has a pharmacokinetic profile exhibiting a peak to trough ratio of free PTH of less than 4 in plasma within one daily injection interval at steady state;
wherein the PTH compound is a water-soluble controlled-release PTH compound of formula (Ia) or a pharmaceutically acceptable salt thereof
wherein
-D is a PTH moiety, which has the sequence of SEQ ID NO:51;
-L 2 -L 1 - has the formula:
wherein the unmarked dashed line indicates the attachment to a nitrogen of -D by an amide bond; and the dashed line marked with an asterisk indicates attachment to —Z;
—Z comprises a polyethylene glycol polymer of about 40 kDa;
x is 1; and
the PTH moiety is released with a release half-life of at least 12 hours.
2. The pharmaceutical composition of claim 1 , wherein the subcutaneous administration is via subcutaneous injection.
3. The pharmaceutical composition of claim 1 , wherein the subcutaneous administration occurs with a pen device.
4. The pharmaceutical composition of claim 1 , wherein the peak to trough ratio is less than 3.
5. The pharmaceutical composition of claim 1 , wherein the administration is to a non-human primate.
6. The pharmaceutical composition of claim 5 , wherein the non-human primate is a cynomolgus monkey.
7. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has a pH ranging from and including pH 3 to pH 8.
8. The pharmaceutical composition of claim 1 , wherein the pharmaceutical composition has a pH ranging from and including pH 4 to pH 5.
9. The pharmaceutical composition of claim 1 , wherein the mammal is a human.
10. The pharmaceutical composition of claim 1 , wherein —Z comprises a branched polyethylene glycol polymer.
11. The pharmaceutical composition of claim 1 , wherein —Z has one branching point.
12. The pharmaceutical composition of claim 10 , wherein -L 2 -L 1 is attached to the N-terminal amine functional group of -D.