Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same

1. A method for conditioning a subject for whom a stem cell transplantation has been indicated, the method comprising:

reconstituting a lyophilized solid consisting of melphalan hydrochloride and a cyclodextrin derivative in an aqueous sodium chloride diluent, wherein the cyclodextrin derivative is present in a ratio of 54:1 (w/w) relative to the melphalan,

then administering the reconstituted lyophilized solid at a melphalan dose of 50 mg/m 2 to 300 mg/m 2 per day to the subject for whom a stem cell transplantation has been indicated, wherein the cyclodextrin derivative consists of a cyclodextrin derivative of formula 1:

wherein n is 4, 5 or 6;

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently a straight-chain or branched -C 1 -C 8 -(alkylene)-SO 3 − group having an average degree of substitution of about 6.5 per cyclodextrin derivative, and the remaining substituents are —H;

wherein the initial pH of the composition is 5; and

wherein the cyclodextrin concentration is about 0.125 M, and wherein the administration is performed via a limb perfusion, and further wherein the administering provides a melphalan AUCo-t in the subject for whom a stem cell transplantation has been indicated that is at least 20% greater than a melphalan AUC o-t provided by a melphalan formulation containing an equivalent dose of melphalan and lacking the cyclodextrin derivative.

2. The method of claim 1 , wherein the administering is for a period of two or more days.

3. The method of claim 1 , wherein the subject in need of the stem cell transplantation is a pediatric subject.

4. The method of claim 1 , wherein at least one of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 is a hydroxy-substituted-C 3 group.

5. The method of claim 1 , wherein the cyclodextrin derivative is a compound of formula II:

wherein R is H or —(CH 2 ) 4 -SO 3− Na + ; and

wherein the pharmaceutical composition comprises about 200 mg of melphalan hydrochloride.

6. The method of claim 1 , wherein the subject for whom a stem cell transplantation has been indicated suffers from a disease or disorder selected from: myeloma, multiple myeloma, a lymphoma, non-Hodgkin lymphoma, leukemia, acute myeloid leukemia, Hodgkin's disease, acute lymphoblastic leukemia, a myelodysplastic syndrome, a myeloproliferative disorder, chronic myelogenous leukemia, neuroblastoma, aplastic anemia, chronic granulocytic leukemia, a neuroblastoma, sickle-cell disease, osteogenic sarcoma, Ewing's sarcoma, a desmoplastic small round cell tumor, plasma cell neoplasm, amyloidosis, scleromyxedema, and combinations thereof.

7. The method of claim 1 , wherein the amount of melphalan in the reconstituted lyophilized solid is 50 mg to 500 mg.

8. The method of claim 1 , wherein the amount of melphalan in the reconstituted lyophilized solid is about 200 mg.

9. The method of claim 1 , wherein the reconstituted lyophilized solid is substantially free of an alcohol.

10. The method of claim 1 , wherein the melphalan reconstituted lyophilized solid degrades by 4% or less at about 25° C. within 10 hours after the reconstitution.

11. The method of claim 1 , wherein the reconstituted lyophilized solid is stored about 0.5 hours to about 12 hours prior to the administering.

12. The method of claim 1 , wherein the administering provides a melphalan C max in the subject for whom a stem cell transplantation has been indicated that is at least 20% or greater than a melphalan C max provided by a melphalan formulation containing an equivalent dose of melphalan and lacking the cyclodextrin derivative.

13. The method of claim 1 , wherein the melphalan in the reconstituted lyophilized solid degrades by 2% or less at about 25° C. within 5 hours after the reconstitution.

14. A method for conditioning a subject for whom a stem cell transplantation has been indicated, the method comprising:

reconstituting a lyophilized solid consisting of melphalan hydrochloride and a cyclodextrin derivative, wherein the cyclodextrin derivative is present in a ratio of 54:1 (w/w) relative to the melphalan, then administering the reconstituted lyophilized solid at a melphalan dose of 50 mg/m 2 to 300 mg/m 2 per day to the subject for whom a stem cell transplantation has been indicated, wherein the melphalan dose is administered in a pharmaceutical composition consisting essentially of sodium chloride, water, melphalan hydrochloride, and a cyclodextrin derivative of formula I:

wherein n is 4, 5 or 6;

wherein R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 and R 9 are independently a straight-chain or branched -C 1 -C 8 -(alkylene)-SO 3 group having an average degree of substitution of about 6.5 per cyclodextrin derivative, and the remaining substituents are —H;

wherein the initial pH of the composition is 5;

wherein the cyclodextrin concentration is about 0.125 M; and

wherein the administering provides a bioavailability of melphalan in the subject for whom a stem cell transplantation has been indicated that is greater than a bioavailability of melphalan provided by a melphalan formulation containing an equivalent dose of melphalan and lacking the cyclodextrin derivative, and wherein the administration is performed via a limb perfusion.