PHARMACEUTICAL COMPOSITIONS OF GHRH ANALOGS AND USES THEREOF
A pharmaceutical composition comprising a GHRH molecule or a pharmaceutically acceptable salt thereof is described, as well as uses thereof and a kit for preparing such a pharmaceutical composition. In an embodiment, GHRH molecule or pharmaceutically acceptable salt thereof is trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof. In an embodiment, a pharmaceutical composition comprising about 1.3 to about 1.5 mg of a GHRH molecule such as trans-3-hexenoyl-GHRH (1-44) -NH 2 at a concentration of about 3.5 mg/mL or more, as well as uses thereof and a kit for preparing such a pharmaceutical composition, are described. Uses of such a pharmaceutical composition to obtain plasmatic levels of e.g., trans-3-hexenoyl-GHRH (1-44) -NH 2 that are bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 at a concentration of 1 mg/mL in a subject are also described.
1 . A pharmaceutical composition comprising (i) about 1.3 to about 1.5 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof at a concentration of about 3.5 mg/mL or more; and (ii) at least one pharmaceutically acceptable excipient.
2 . The pharmaceutical composition of claim 1 , comprising about 1.4 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof.
3 . The pharmaceutical composition of claim 1 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is at a concentration of about 3.8 to about 10 mg/mL.
4 . The pharmaceutical composition of claim 1 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is at a concentration of about 4 to about 8 mg/mL.
5 . The pharmaceutical composition of claim 4 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is at a concentration of about 4 mg/mL.
6 . The pharmaceutical composition of claim 4 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is at a concentration of about 8 mg/mL.
7 . The pharmaceutical composition of claim 1 , wherein the at least one pharmaceutically acceptable excipient comprises a diluent.
8 . The pharmaceutical composition of claim 1 , wherein the at least one pharmaceutically acceptable excipient comprises a bulking agent.
9 . The pharmaceutical composition of claim 8 , wherein the bulking agent is mannitol.
10 . The pharmaceutical composition of claim 1 , wherein the at least one pharmaceutically acceptable excipient comprises a stabilizer.
11 . The pharmaceutical composition of claim 10 , wherein the stabilizer is sucrose.
12 . The pharmaceutical composition of claim 1 , wherein the at least one pharmaceutically acceptable excipient comprises a surfactant.
13 . The pharmaceutical composition of claim 12 , wherein the surfactant is polysorbate 20.
14 . The pharmaceutical composition of claim 1 , wherein the at least one pharmaceutically acceptable excipient comprises a buffering agent.
15 . The pharmaceutical composition of claim 14 , wherein the buffering agent is histidine.
16 . The pharmaceutical composition of claim 1 , wherein the at least one pharmaceutically acceptable excipient comprises a cyclodextrin.
17 . The pharmaceutical composition of claim 16 , wherein the cyclodextiin is a β-cyclodextiin.
18 . The pharmaceutical composition of claim 1 , wherein the pharmaceutically acceptable salt of trans-3-hexenoyl-GHRH (1-44) -NH 2 is an acetate salt.
19 . A method of administering trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof to a subject to obtain plasmatic levels of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof that are bioequivalent to administration of 2 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 at a concentration of 1 mg/mL, the method comprising administering to the subject about 1.3 to about 1.5 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof at a concentration of about 3.5 mg/mL or more.
20 . The method of claim 19 , comprising administering about 1.4 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof.
21 . The method of claim 19 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is at a concentration of about 4 to about 8 mg/mL.
22 . The method of claim 19 , wherein the pharmaceutically acceptable salt of trans-3-hexenoyl-GHRH (1-44) -NH 2 is an acetate salt.
23 . The method of claim 19 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is administered by subcutaneous injection.
24 . The method of claim 19 , further comprising
resuspending lyophilized trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof in a suitable amount of a pharmaceutically acceptable diluent to obtain a trans-3-hexenoyl-GHRH (1-44) -NH 2 or trans-3-hexenoyl-GHRH (1-44) -NH 2 salt solution at a concentration of about 3.5 mg/mL or more;
wherein a suitable volume of the trans-3-hexenoyl-GHRH (1-44) -NH 2 or trans-3-hexenoyl-GHRH (1-44) -NH 2 salt solution is administered so that about 1.3 to about 1.5 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is administered to the subject.
25 . A method of administering trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof to a human subject to obtain:
(i) a maximum plasmatic concentration (C max ) of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof of about 1500 to about 4500 pg/mL in the subject;
(ii) an area under the plasma concentration time curve extrapolated to infinity (AUC 0-∞ ) of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof of about 300 to about 1400 pg·h/mL in the subject;
(iii) a mean plasma concentration-time profile substantially similar to that set forth in FIG. 5 and/or FIG. 6 ; or
(iv) any combination of (i) to (iii);
the method comprising administering to the subject about 1.3 to about 1.5 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof at a concentration of about 3.5 mg/mL or more.
26 . The method of claim 25 , comprising administering about 1.4 mg of trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof.
27 . The method of claim 25 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is at a concentration of about 4 to about 8 mg/mL.
28 . The method of claim 25 , wherein the pharmaceutically acceptable salt of trans-3-hexenoyl-GHRH (1-44) -NH 2 is an acetate salt.
29 . The method of claim 25 , wherein the trans-3-hexenoyl-GHRH (1-44) -NH 2 or pharmaceutically acceptable salt thereof is administered by subcutaneous injection.
30 . A kit comprising:
(a) a first container comprising at least about 1.3 to about 1.5 mg of lyophilized trans-3-hexenoyl-GHRH (1-44) -NH 2 or a pharmaceutically acceptable salt thereof;
(b) a second container comprising a pharmaceutically acceptable diluent;
(c) instructions setting forth the method of claim 26 ; and optionally
(d) at least one syringe.