Sustained-release polymeric microparticles containing poorly water-soluble drug and method for preparing the same

1. A sustained-release microparticle containing a poorly water-soluble drug, consisting essentially of the poorly water-soluble drug and a multivalent metal ion salt of polylactic acid having at least one terminal carboxyl group or a derivative thereof, wherein the poorly water-soluble drug is entrapped in the multivalent metal ion salt of polylactic acid or a derivative thereof, and

the polylactic acid having at least one terminal carboxyl group or a derivative thereof has an average molecular weight number from 500 to 5,000 daltons.

2. The sustained-release microparticle containing a poorly water-soluble drug according to claim 1 , wherein the polylactic acid having at least one terminal carboxyl group or a derivative thereof is selected from the group consisting of compounds represented by Formulae 1 to 6 below:

RO—CHZ-[A] n -[B] m —COOM  [Formula 1]

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 atom, or acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group, or ethyl group; each of Z and Y independently is hydrogen atom, methyl group or phenyl group; M is independently H, Na, K, or Li; n is an integer of 1 to 30; and m is an integer of 0 to 20;

RO—CHZ—[COO—CHX] p —[COO—CHY′]—COO—CHZ—COOM  [Formula 2]

wherein X is methyl group; Y′ is hydrogen atom or phenyl group; p is an integer of 0 to 25 and q is an integer of 0 to 25 provided that p+q is an integer of 5 to 25; R is hydrogen atom, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group; Z is hydrogen atom, methyl group or phenyl group; and M is independently H, Na, K, or Li;

RO-PAD-COO—W-M′  [Formula 3]

wherein W-M′ is

PAD is selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one; R is hydrogen atom, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group; and M is independently H, Na, K, or Li;

S—O-PAD-COO-Q  [Formula 4]

wherein S is

 L is —NR 1 — or -0- in which R 1 is hydrogen atom or C 1-l0 alkyl; Q is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , or CH 2 C 6 H 5 ; a is an integer of 0 to 4; b is an integer of 1 to 10; M is H, Na, K, or Li; PAD is one or more selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one;

wherein R′ is —PAD-O—C(O)—CH 2 CH 2 —C(O)—OM, in which PAD is selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one, and M is H, Na, K, or Li; and a is an integer of 1 to 4;

YO—[—C(O)—(CHX) a —O—] m —C(O)—R—C(O)—[—O—(CHX′) b —C(O)—] n —OZ  [Formula 6]

wherein each of X and X′ is independently hydrogen, alkyl or aryl; each of Y and Z is independently H, Na, K, or Li; each of m and n is independently an integer of 0 to 95, provided that 5<m+n<100; each of a and b is independently an integer of 1 to 6; R is substituted or unsubstituted —(CH 2 ) k — in which k is an integer of 0 to 10, divalent alkenyl having 2 to 10 carbon atoms, divalent aryl having 6 to 20 carbon atoms, or a combination thereof.

3. The sustained-release microparticle containing a poorly water-soluble drug according to claim 1 , wherein the multivalent metal ion is one or more selected from the group consisting of Ca 2+ , Mg 2+ , Ba 2+ , Cr 3+ , Fe 3+ , Mn 2+ , Ni 2+ , C 11 2+ , Z 11 2+ and Al 3+ .

4. The sustained-release microparticle containing a poorly water-soluble drug according to claim 1 , which has a particle diameter of 1 to 400 μm.

5. The sustained-release microparticle containing a poorly water-soluble drug according to claim 1 , wherein the content of the poorly water-soluble drug is 1 to 50% by weight with respect to the total weight of the microparticle.

6. The sustained-release microparticle containing a poorly water-soluble drug according to claim 1 , wherein the poorly water-soluble drug is one or more selected from the group consisting of olanzapine, risperidone, ziprasidone, rivastigmine, naloxone, naltrexone, sirolimus, tacrolimus, carmustine, progesterone, estrogen, estradiol, levonorgestrel and norethisteron.

7. A method for preparing a sustained-release microparticle containing a poorly water-soluble drug, comprising:

i) preparing a polymer-drug solution containing a monovalent metal salt of polylactic acid having at least one terminal carboxyl group or a derivative thereof and the poorly water-soluble drug in an organic solvent; and

ii) dispersing the polymer-drug solution in an aqueous solution containing a multivalent metal ion and optionally a surfactant to form a microparticle,

wherein the polylactic acid having at least one terminal carboxyl group or a derivative thereof has an average molecular weight number from 500 to 5,000 daltons.

8. The method for preparing a sustained-release microparticle containing a poorly water-soluble drug according to claim 7 , wherein the monovalent metal salt of polylactic acid or a derivative thereof is selected from the group consisting of compounds of Formulae 1 to 6 defined in claim 1 , in which M is Na, K or Li.

9. The method for preparing a sustained-release microparticle containing a poorly water-soluble drug according to claim 7 , wherein the organic solvent is selected from the group consisting of dichloromethane, hexafluoroisopropanol, ethyl acetate, ethanol, methanol, dimethylformamide, acetone, acetonitrile, tetrahydrofuran, acetic acid, dimethyl sulfoxide, chloroform, methyl dichloroacetate, methyl chloroacetate, ethyl chloroacetate, ethyl dichloroacetate, methyl fluoroacetate, methyl difluoroacetate, ethyl fluoroacetate, ethyl difluoroacetate, ethyl acetate, methyl acetate, methyl formate, ethyl formate, isopropyl formate, propyl formate and mixtures thereof.

10. The method for preparing a sustained-release microparticle containing a poorly water-soluble drug according to claim 7 , wherein the multivalent metal ion is one or more selected from the group consisting of Ca 2+ , Mg 2+ , Ba 2+ , Cr 3+ , Fe 3+ , Mn 2+ , Ni 2+ , Cu 2+ , Zn 2+ and Al 3+ .

11. The method for preparing a sustained-release microparticle containing a poorly water-soluble drug according to claim 7 , wherein the poorly water-soluble drug is one or more selected from the group consisting of olanzapine, risperidone, ziprasidone, rivastigmine, naloxone, naltrexone, sirolimus, tacrolimus, carmustine, progesterone, estrogen, estradiol, levonorgestrel and norethisteron.

12. The method for preparing a sustained-release microparticle containing a poorly water-soluble drug according to claim 7 , further comprising:

iii) obtaining the microparticle formed in step ii) and washing it with water.

13. The method for preparing a sustained-release microparticle containing a poorly water-soluble drug according to claim 12 , further comprising:

iv) freeze-drying the microparticle washed in step iii).

14. A sustained-release microparticle containing a poorly water-soluble drug, consisting essentially of the poorly water-soluble drug and a multivalent metal ion salt of polylactic acid having at least one terminal carboxyl group or a derivative thereof, wherein the poorly water-soluble drug is entrapped in the multivalent metal ion salt of polylactic acid or a derivative thereof,

the polylactic acid having at least one terminal carboxyl group or a derivative thereof has an average molecular weight number from 500 to 5,000 daltons,

wherein the multivalent metal ion is one or more selected from the group consisting of Ca 2+ , Mg 2+ , Ba 2+ ,Cr 3 ,Fe 3+ ,Mn 2+ , Ni 2+ , Cu 2+ , Zn 2+ and Al 3+ ,

wherein the polylactic acid having at least one terminal carboxyl group or a derivative thereof is selected from the group consisting of compounds represented by Formulae 1 to 6 below:

RO—CHZ-[A] n -[B] m —COOM  [Formula 1]

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 atom, or acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group, or ethyl group; each of Z and Y independently is hydrogen atom, methyl group or phenyl group; M is independently H, Na, K, or Li; n is an integer of 1 to 30; and m is an integer of 0 to 20;

RO—CHZ—[COO—CHX] p —[COO—CHY′] q —COO—CHZ—COOM  [Formula 2]

wherein X is methyl group; Y′ is hydrogen atom or phenyl group; p is an integer of 0 to 25 and q is an integer of 0 to 25 provided that p+q is an integer of 5 to 25; R is hydrogen atom, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group; Z is hydrogen atom, methyl group or phenyl group; and M is independently H, Na, K, or Li;

RO-PAD-COO—W-M′  [Formula 3]

wherein W-M′ is

 PAD is selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one; R is hydrogen atom, acetyl group, benzoyl group, decanoyl group, palmitoyl group, methyl group or ethyl group; and M is independently H, Na, K, or Li;

S—O-PAD-COO-Q  [Formula 4]

wherein S is

L is —NR 1 — or -0- in which R 1 is hydrogen atom or C 1-10 alkyl; Q is CH 3 , CH 2 CH 3 , CH 2 CH 2 CH 3 , CH 2 CH 2 CH 2 CH 3 , or CH 2 C 6 H 5 ; a is an integer of 0 to 4; b is an integer of 1 to 10; M is H, Na, K, or Li; PAD is one or more selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one;

wherein R′ is -PAD-O—C(O)—CH 2 CH 2 —C(O)—OM, in which PAD is selected from the group consisting of D,L-polylactic acid, D-polylactic acid, polymandelic acid, copolymer of D,L-lactic acid and glycolic acid, copolymer of D,L-lactic acid and mandelic acid, copolymer of D,L-lactic acid and caprolactone, and copolymer of D,L-lactic acid and 1,4-dioxan-2-one, and M is H, Na, K, or Li; and a is an integer of 1 to 4;

YO —[—C(O)—(CHX) a —O—] m ,—C(O)—R—C(O)—[—O—(CHX′ ) b —C(O)—] n —OZ  [Formula 6]

wherein each of X and X′ is independently hydrogen, alkyl or aryl; each of Y and Z is independently H, Na, K, or Li; each of m and n is independently an integer of 0 to 95, provided that 5<m+n<100; each of a and b is independently an integer of 1 to 6; R is substituted or unsubstituted —(CH 2 ) k —in which k is an integer of 0 to 10, divalent alkenyl having 2 to 10 carbon atoms, divalent aryl having 6 to 20 carbon atoms, or a combination thereof,

wherein the multivalent metal ion salt of polylactic acid or a derivative thereof is contained in an amount of 50 to 99% by weight of a total weight of the microparticle, and

wherein the microparticle has an amorphous or spherical shape.

15. The sustained-release microparticle containing a poorly water-soluble drug according to claim 14 , which has a particle diameter of 1 to 400 μm.

16. The sustained-release microparticle containing a poorly water-soluble drug according to claim 14 , wherein the content of the poorly water-soluble drug is 1 to 50% by weight with respect to the total weight of the microparticle.

17. The sustained-release microparticle containing a poorly water-soluble drug according to claim 14 , wherein the poorly water-soluble drug is one or more selected from the group consisting of olanzapine, risperidone, ziprasidone, rivastigmine, naloxone, naltrexone, sirolimus, tacrolimus, carmustine, progesterone, estrogen, estradiol, levonorgestrel and norethisteron.