pH responsive biodegradable polylactic acid derivatives forming polymeric micelles and uses thereof for poorly water soluble drug delivery
Polylactic acid derivatives capable of forming micelles in an aqueous solution with a pH of 4 or above, having one terminal carboxyl group. The polylactic acid derivatives may be applied as a drug delivery system in various forms since poorly water soluble drugs can be entrapped inside the micelles.
1. A micellar composition comprising a di- or poly-lactic acid derivative in an aqueous solution with a pH of 4 or higher, said di- or poly-lactic acid derivative can be represented by formula (I):
RO—CHZ-[A] n -[B] m -COOM (I)
wherein A is —COO—CHZ; B is —COO—CHY—, —COO—CH 2 CH 2 CH 2 CH 2 CH 2 —, or —COO—CH 2 CH 2 OCH 2 —; R is hydrogen, an acetyl, benzoyl, decanoyl, methyl, or ethyl group; Z and Y are hydrogen, methyl, or phenyl groups; M is sodium, potassium, or lithium; n is an integer from 5 to 30; and m is an integer from 0 to 20, and
wherein the di- or poly-lactic acid derivative has a number average molecular weight of 500 to 2,000 Daltons.
2. The micellar composition according to claim 1 , wherein the di- or poly-lactic acid derivative is a member selected from the group consisting of D,L-polylactic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxane-2-one.
3. The micellar composition according to claim 1 , wherein M is sodium, or potassium.
4. The micellar composition according to claim 1 , wherein the di- or poly-lactic acid derivative of formula (I) is made from a process comprising:
1) polycondensing monomers of a di- or poly-lactic acid derivative at an elevated temperature under a reduced pressure;
2) adding distilled water to the product of step 1 to precipitate the di- or poly-lactic acid derivative and thereby removing a low-molecular weight oligomer;
3) adding the di- or poly-lactic acid derivative to a neutral or alkaline aqueous solution to dissolve the di- or poly-lactic acid derivative;
4) isolating the di- or poly-lactic acid derivative from the solution of step 3; and
5) adding an alkali metal salt to the di- or poly-lactic acid derivative obtained in step 4.
5. The micellar composition according to claim 4 , wherein isolating the di- or poly-lactic acid derivative in step 4 is conducted by adding acid to the aqueous solution of step 3 and adjusting pH to 1.5˜2.5 to precipitate the di- or poly-lactic acid derivative.
6. The micellar composition according to claim 4 , wherein isolation of the di- or poly-lactic acid derivative in step 4 is conducted by adding an organic solvent to the aqueous solution of step 3 to extract the di- or poly-lactic acid derivative.
7. The micellar composition according to claim 4 , wherein the alkali metal salt in step 5 is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and lithium carbonate.
8. The micellar composition according to claim 1 , wherein R is an acetyl, benzoyl, decanoyl, methyl, or ethyl group and the di- or poly-lactic acid derivative is prepared from a process comprising the steps of:
1) polycondensing a monomer of a di- or poly-lactic acid derivative at an elevated temperature and under a reduced pressure;
2) adding distilled water to the product of step 1 to a precipitate a di- or poly-lactic acid derivative and thereby removing low-molecular weight oligomers;
3) adding the di- or poly-lactic acid derivative to a neutral or alkaline aqueous solution to dissolve the di- or poly-lactic acid derivative;
4) isolating the di- or poly-lactic acid derivative from the solution of step 3;
5) reacting the di- or poly-lactic acid derivative obtained in step 4 with acetic anhydride, acetyl chloride, benzoyl chloride, decanoyl chloride, methyl iodide, or ethyl iodide to substitute the di- or poly-lactic acid derivative; and
6) adding an alkali metal salt to the substituted di- or poly-lactic acid derivative.
9. The micellar composition according to the claim 8 , wherein the step of isolating the di- or poly-lactic acid derivative in step 4 is conducted by adding acid to the aqueous solution of step 3 and adjusting pH to 1.5˜2.5 to precipitate the di- or poly-lactic acid derivative.
10. The micellar composition according to the claim 8 , wherein the step of isolating the di- or poly-lactic acid derivative in step 4 is conducted by adding an organic solvent to the aqueous solution of step 3 to extract the di- or poly-lactic acid derivative.
11. The micellar composition according to the claim 8 , wherein the alkali metal salt in step 5 is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and lithium carbonate.
12. A pharmaceutical composition, wherein a poorly water soluble drug is entrapped in polymeric micelles of a micellar composition comprising a di- or poly-lactic acid derivative in an aqueous solution with a pH of 4 or higher, said di- or poly-lactic acid derivative can be represented by the following formula:
RO—CHZ-[A] n -[B] m -COOM
wherein A is —COO—CHZ; B is —COO—CHY—, —COO—CH 2 CH 2 CH 2 CH 2 CH 2 — or —COO—CH 2 CH 2 OCH 2 —; R is hydrogen, an acetyl, benzoyl, decanoyl, methyl, or ethyl group; Z and Y are hydrogen, methyl, or phenyl groups; M is sodium, potassium, or lithium; n is an integer from 1 to 30; and m is an integer from 0 to 20, and
wherein the di- or poly-lactic acid derivative has a number average molecular weight of 500 to 2,000 Daltons.
13. The pharmaceutical composition according to claim 12 , wherein the di- or poly-lactic acid derivative is a member selected from the group consisting of D,L-polylactic acid, a copolymer of D,L-lactic acid and mandelic acid, a copolymer of D,L-lactic acid and glycolic acid, a copolymer of D,L-lactic acid and caprolactone, and a copolymer of D,L-lactic acid and 1,4-dioxane-2-one.
14. The pharmaceutical composition according to claim 12 , wherein M is sodium, or potassium.
15. The pharmaceutical composition according to claim 12 , wherein the di- or poly-lactic acid derivative of said formula is made from a process comprising:
1) polycondensing monomers of a di- or poly-lactic acid derivative at an elevated temperature under a reduced pressure;
2) adding distilled water to the product of step 1 to precipitate the di- or poly-lactic acid derivative and thereby removing a low-molecular weight oligomer;
3) adding the di- or poly-lactic acid derivative to a neutral or alkaline aqueous solution to dissolve the di- or poly-lactic acid derivative;
4) isolating the di- or poly-lactic acid derivative from the solution of step 3; and
5) adding an alkali metal salt to the di- or poly-lactic acid derivative obtained in step 4.
16. The pharmaceutical composition according to claim 15 , wherein isolating the di- or poly-lactic acid derivative in step 4 is conducted by adding acid to the aqueous solution of step 3 and adjusting pH to 1.5˜2.5 to precipitate the di- or poly-lactic acid derivative.
17. The pharmaceutical composition according to claim 15 , wherein isolation of the di- or poly-lactic acid derivative in step 4 is conducted by adding an organic solvent to the aqueous solution of step 3 to extract the di- or poly-lactic acid derivative.
18. The pharmaceutical composition according to claim 15 , wherein the alkali metal salt in step 5 is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate and lithium carbonate.
19. The pharmaceutical composition according to claim 12 , wherein R is an acetyl, benzoyl, decanoyl, methyl, or ethyl group and the di- or poly-lactic acid derivative is prepared from a process comprising the steps of:
1) polycondensing a monomer of a di- or poly-lactic acid derivative at an elevated temperature and under a reduced pressure;
2) adding distilled water to the product of step 1 to a precipitate a di- or poly-lactic acid derivative and thereby removing low-molecular weight oligomers;
3) adding the di- or poly-lactic acid derivative to a neutral or alkaline aqueous solution to dissolve the di- or poly-lactic acid derivative;
4) isolating the di- or poly-lactic acid derivative from the solution of step 3;
5) reacting the di- or poly-lactic acid derivative obtained in step 4 with acetic anhydride, acetyl chloride, benzoyl chloride, decanoyl chloride, methyl iodide, or ethyl iodide to substitute the di- or poly-lactic acid derivative; and
6) adding an alkali metal salt to the substituted di- or poly-lactic acid derivative.
20. The pharmaceutical composition according to claim 19 , wherein the step of isolating the di- or poly-lactic acid derivative in step 4 is conducted by adding acid to the aqueous solution of step 3 and adjusting pH to 1.5˜2.5 to precipitate the di- or poly-lactic acid derivative.
21. The pharmaceutical composition according to claim 19 , wherein the step of isolating the di- or poly-lactic acid derivative in step 4 is conducted by adding an organic solvent to the aqueous solution of step 3 to extract the di- or poly-lactic acid derivative.
22. The pharmaceutical composition according to claim 19 , wherein the alkali metal salt in step 5 is selected from the group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, and lithium carbonate.