Claims for Patent: 10,940,128

Summary for Patent: 10,940,128

Title:	Injectable melphalan compositions comprising a cyclodextrin derivative and methods of making and using the same
Abstract:	The present invention is directed to pharmaceutical compositions comprising melphalan and a cyclodextrin derivative, and methods of making and using the same.
Inventor(s):	Pipkin; James D. (Lawrence, KS), Machatha; Stephen G. (Overland Park, KS)
Assignee:	CYDEX PHARMACEUTICALS, INC. (Lenexa, KS)
Application Number:	14/108,169
Patent Claims:	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.sup.2 to 300 mg/m.sup.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: ##STR00022## wherein n is 4, 5 or 6; wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently a straight-chain or branched -C.sub.1-C.sub.8-(alkylene)-SO.sub.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.sub.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.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 is a hydroxy-substituted-C.sub.3 group. 5. The method of claim 1, wherein the cyclodextrin derivative is a compound of formula II: ##STR00023## wherein R is H or --(CH.sub.2).sub.4-SO.sub.3-Na.sup.+; 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.degree. 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.sub.max in the subject for whom a stem cell transplantation has been indicated that is at least 20% or greater than a melphalan C.sub.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.degree. 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.sup.2 to 300 mg/m.sup.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: ##STR00024## wherein n is 4, 5 or 6; wherein R.sub.1, R.sub.2, R.sub.3, R.sub.4, R.sub.5, R.sub.6, R.sub.7, R.sub.8 and R.sub.9 are independently a straight-chain or branched -C.sub.1-C.sub.8-(alkylene)-SO.sub.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.