SEMI-SOLID DELIVERY VEHICLE AND PHARMACEUTICAL COMPOSITIONS
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 of formula I or formula II
where:
R is a bond, —(CH 2 ) a —, or —(CH 2 ) b —O—(CH 2 ) c —; where a is an integer of 1 to 10, and b and c are independently integers of 1 to 5;
R* is a C 1-4 alkyl;
n is an integer of at least 5; and
A is R 1 , R 2 , R 3 , or R 4 , where
R 1 is:
where:
p is an integer of 1 to 20;
R 5 is hydrogen or C 1-4 alkyl; and
R 6 is:
where:
s is an integer of 0 to 30;
t is an integer of 2 to 200; and
R 7 is hydrogen or C 1-4 alkyl;
R 2 is:
R 3 is:
where:
x is an integer of 0 to 30;
y is an integer of 2 to 200;
R 8 is hydrogen or C 1-4 alkyl;
R 9 and R 10 are independently C 1 -C 12 alkylene;
R 11 is hydrogen or C 1-6 alkyl and R 12 is C 1 -C 6 alkyl; or R 11 and R 12 together are C 3-10 alkylene; and
R 4 is the residue of a diol containing at least one functional group independently selected from amide, imide, urea, and urethane groups;
in which at least 0.01 mol percent of the A units are of the formula R 1 ; and
(ii) a pharmaceutically acceptable, polyorthoester-compatible liquid excipient selected from polyethylene glycol ether derivatives having a molecular weight between 200 and 4000, polyethylene glycol copolymers having a molecular weight between 400 and 4000, mono-, di-, or tri-glycerides of a C 2-19 aliphatic carboxylic acid or a mixture of such acids, alkoxylated tetrahydrofurfuryl alcohols and their C 1-4 alkyl ethers and C 2-19 aliphatic carboxylic acid esters, and biocompatible oils; and
(B) an anesthetic agent.
2 . The semi-solid delivery vehicle of claim 1 where the concentration of the polyorthoester ranges from 1% to 99% by weight.
3 . The semi-solid delivery vehicle of claim 1 where the polyorthoester has a molecular weight between 1,000 and 20,000.
4 . The semi-solid delivery vehicle of claim 1 where the fraction of the A units that are of the formula R 1 is between 1 and 90 mol percent.
5 . The semi-solid delivery vehicle of claim 1 where the polyorthoester is of formula I,
where:
none of the units have A equal to R 2 ;
R 3 is:
where:
x is an integer of 0 to 10;
y is an integer of 2 to 30; and
R 6 is:
where:
s is an integer of 0 to 10;
t is an integer of 2 to 30; and
R 5 , R 7 , and R 8 are independently hydrogen or methyl.
6 . The semi-solid delivery vehicle of claim 5 where:
R 3 and R 6 are both —(CH 2 —CH 2 —O) 2 —(CH 2 —CH 2 )—;
R 5 is methyl; and
p is 1 or 2.
7 . The semi-solid delivery vehicle of claim 5 where:
R 3 and R 6 are both —(CH 2 —CH 2 —O) 9 —(CH 2 —CH 2 )—;
R 5 is methyl; and
p is 1 or 2.
8 . The pharmaceutical composition of claim 1 where the anesthetic agent is selected from the group consisting of bupivacaine, lidocaine, mepivacaine, pyrrocaine and prilocaine.
9 . The pharmaceutical composition of claim 8 , wherein the concentration of the anesthetic agent in the composition is about 1-5 wt. %.
10 . (canceled)
11 . The pharmaceutical composition of claim 1 where the fraction of the anesthetic agent is from 0.1% to 60% by weight of the composition.
12 . The pharmaceutical composition of claim 11 where the fraction of the anesthetic agent is from 0.5 to 40% by weight of the composition.
13 . The pharmaceutical composition of claim 1 where the composition is in topical, syringable, or injectable form.
14 .- 16 . (canceled)
17 . The pharmaceutical composition of claim 1 further comprising a glucocorticosteroid to form a combination composition.
18 .- 19 . (canceled)
20 . A method for the treatment of localized pain in a patient in need thereof, the method comprising administering to the patient the composition of claim 1 via injection.
21 . The method of claim 20 wherein the anesthetic agent is selected from the group consisting of bupivacaine, lidocaine, mepivacaine, pyrrocaine and prilocaine.
22 . The method of claim 20 wherein the patient is a human.
23 . The method of claim 20 wherein the administering comprises applying the composition into a surgical site.
24 . The method of claim 21 , wherein the anesthetic agent is in the form of a free base.
25 .- 31 . (canceled)
32 . A process for the preparation of the delivery vehicle of claim 1 , comprising mixing the components (A) and (B) in the absence of a solvent, at a temperature between about 20 and 150° C.
33 . A process for the preparation of the pharmaceutical composition of claim 1 where the anesthetic agent is in solid form, comprising:
(1) optionally milling the active agent to reduce the particle size of the active agent;
(2) mixing the active agent and the delivery vehicle; and
(3) optionally milling the composition from (2) to reduce the particle size of the active agent in the composition.
34 . (canceled)