Semi-solid delivery vehicle and pharmaceutical compositions for delivery of granisetron
A semi-solid delivery vehicle contains a polyorthoester and an excipient, and a semi-solid pharmaceutical composition contains an active agent and the delivery vehicle. The pharmaceutical composition may be a topical, syringable, or injectable formulation; and is suitable for local delivery of the active agent. Methods of treatment are also disclosed.
1. A pharmaceutical composition comprising:
(A) semi-solid delivery vehicle, comprising:
(i) a polyorthoester consisting of formula I
where:
R* is ethyl;
n is an integer of 5 to 1000; and
A is R 1 or R 3 where
R 1 is:
where:
p is an integer of 1 to 20;
R 5 is hydrogen; and
R 6 is:
where:
s is an integer of 0 to 10;
R 3 is:
where:
x is an integer of 0 to 30;
in which about 0.05-30 mol percent of the A units are of the formula R 1 ; and
(ii) polyethylene glycol monomethyl ether; and
(B) granisetron in an amount of 1-5 weight % of the composition.
2. The pharmaceutical composition of claim 1 , wherein the polyethylene glycol monomethyl ether has a molecular weight between 200 and 4000.
3. The pharmaceutical composition of claim 2 , comprising polyethylene glycol monomethyl ether 550.
4. The pharmaceutical composition of claim 1 , wherein the total concentration of the polyethylene glycol monomethyl ether is 5-60 weight % of the composition.
5. The pharmaceutical composition of claim 1 , comprising 78.4 weight % polyorthoester, 19.6 weight % polyethylene glycol monomethyl ether and 2 weight % granisetron.
6. The pharmaceutical composition of claim 1 , which provides a controlled release of the granisetron.
7. The pharmaceutical composition of claim 1 , which is suitable for injection.
8. The pharmaceutical composition of claim 7 , which is suitable for subcutaneous injection.
9. The pharmaceutical composition of claim 1 , which is filled into a syringe with a 16-25 gauge needle.
10. The pharmaceutical composition of claim 1 , wherein p is an integer of 1 to 7 in a portion of the units of formula I.
11. The pharmaceutical composition of claim 1 , wherein x is 2 in a portion of the units of formula I.
12. The pharmaceutical composition of claim 1 , wherein s is 2 in a portion of the units of formula I.
13. A pharmaceutical composition comprising (a) a reaction product of 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), triethylene glycol (TEG) and triethylene glycol diglycolide (TEG-diGL) wherein the reaction comprises TEG-diGL in an amount of about 0.05-30 mol percent of total diols; (b) polyethylene glycol monomethyl ether 550 and (c) granisetron in an amount of 1-5 weight % of the composition.
14. A pharmaceutical composition consisting essentially of (a) a reaction product of 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), triethylene glycol (TEG) and triethylene glycol diglycolide (TEG-diGL) wherein the reaction comprises TEG-diGL in an amount of about 0.05-30 mol percent of total diols; (b) polyethylene glycol monomethyl ether 550 and (c) granisetron in an amount of 1-5 weight % of the composition.
15. A pharmaceutical composition comprising:
(A) semi-solid delivery vehicle, comprising:
(i) a polyorthoester which is a reaction product of reagents comprising 3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU), triethylene glycol (TEG) and triethylene glycol diglycolide (TEG-diGL) wherein the reaction comprises TEG-diGL in an amount of about 0.05-30 mol percent of total diols;
(ii) polyethylene glycol monomethyl ether; and
(B) granisetron in an amount of 1-5 weight % of the composition.
16. The pharmaceutical composition of claim 1 , wherein about 0.1-25 mol percent of the A units are of the formula R 1 .
17. The pharmaceutical composition of claim 13 , wherein the reaction comprises TEG-diGL in an amount of about 0.1-25 mol percent of total diols.
18. The pharmaceutical composition of claim 14 , wherein the reaction comprises TEG-diGL in an amount of about 0.1-25 mol percent of total diols.
19. The pharmaceutical composition of claim 15 , wherein the reaction comprises TEG-diGL in an amount of about 0.1-25 mol percent of total diols.