Long-acting polymeric delivery systems
View Patent ↗Compositions comprised of a delivery vehicle or delivery system and an active agent dispersed within the delivery vehicle or system, wherein the delivery vehicle or system contains a polyorthoester polymer and a polar aprotic solvent. Also disclosed are low viscosity delivery systems for administration of active agents. The low viscosity delivery systems have a polyorthoester polymer, a polar aprotic solvent and a solvent containing a triglyceride viscosity reducing agent. Compositions described include an amide- or anilide-type local anesthetic of the “caine” classification, and a non-steroidal anti-inflammatory drug (NSAID), along with related methods, e.g., for treatment of post-operative pain or for prophylactic treatment of pain. The compositions are suitable for delivery via, e.g., direct application and instillation, intradermal injection, subcutaneous injection, and nerve block (perineural).
1. A semi-solid composition, comprising: a biodegradable polyorthoester, 1 wt % to 10 wt % bupivacaine, and 0.01 wt % to 1 wt % meloxicam, wherein the polyorthoester is represented by Formula I:
where:
R* is a C 1-4 alkyl,
n is an integer ranging from 5 to 400, and
A is a diol, where A is R 1 and/or R 3 , where the fraction of A units that are of formula R 1 is between 0 and 25 mole percent, where
when A is R 3 , R 3 is
where x is 2; and
when A is R 1 , R 1 is
R 5 is H, and R 6 is
the sum of p and q is, on average, 2 and s is 2,
where the resulting component of the polyorthoester comprises the subunit
2. The composition of claim 1 , further comprising a protic or an aprotic solvent.
3. The composition of claim 1 , further comprising a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms.
4. A method for managing pain in a subject in need thereof, comprising: administering to the subject a composition of claim 1 .
5. A method for prophylactic treatment of pain in a subject, comprising: administering to the subject a composition of claim 1 .
6. The method of claim 4 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
7. The method of claim 6 , wherein the pain is acute pain or chronic pain.
8. A composition, comprising: 1 wt % to 10 wt % bupivacaine, 0.01 wt % to 1 wt % meloxicam, and a delivery vehicle comprised of a polyorthoester, a polar aprotic solvent and a triglyceride viscosity reducing agent, wherein the triglyceride viscosity reducing agent comprises three fatty acid groups each independently comprising between 1-7 carbon atoms, and wherein the polyorthoester is represented by Formula I:
where:
R* is a C 1-4 alkyl,
n is an integer ranging from 5 to 400, and
A is a diol, where A is R 1 and/or R 3 , where the fraction of A units that are of formula R 1 is between 0 and 25 mole percent, where
when A is R 3 , R 3 is
where x is 2; and
when A is R 1 , R 1 is
R 5 is H, and R 6 is
the sum of p and q is, on average, 2 and s is 2,
where the resulting component of the polyorthoester comprises the subunit
9. The composition of claim 8 , wherein the composition has a viscosity ranging from about 2500 mPa-s to 10000 mPa-s when measured at 25° C. using a viscometer.
10. The composition of claim 8 , wherein the viscosity of the composition is 10 to 40-fold lower than the viscosity of the same composition with no triglyceride viscosity reducing agent when measured at 25° C. using a viscometer.
11. The composition of claim 8 , wherein the triglyceride viscosity reducing agent is selected from the group consisting of triacetin and tributyrin.
12. The composition of claim 8 , wherein the polar aprotic solvent is selected from dimethylsulfoxide, N-methyl pyrrolidone and dimethyl acetamide.
13. The composition of claim 8 , wherein the bupivacaine is soluble in the triglyceride viscosity reducing agent, the polar aprotic solvent, or a mixture thereof.
14. The pharmaceutical composition of claim 8 , wherein the bupivacaine is released from the composition over a time period of about 1 day to about 8 weeks.
15. A method of treatment, comprising: administering to a patient in need thereof the pharmaceutical composition according to claim 8 .
16. The method according to claim 15 , wherein the patient is experiencing pain or is in need of prophylactic treatment for pain and the pharmaceutical composition provides pain relief.
17. The method of claim 16 , wherein the pain is acute pain or chronic pain.
18. The method of claim 15 , wherein the administering is intramuscular, subcutaneous, perineural or to a wound.
19. A method for providing pain relief to a patient in need thereof, comprising:
providing a composition according to claim 8 , and
instructing that the composition be administered to the patient to provide pain relief for an extended period.