Composition

Abstract

Pharmaceutical compositions and methods for the treatment of neoplastic disease and comprising the combination of a taxane, such as docetaxel, with a CYP3A4 inhibitor, such as ritonavir. Methods of treatment of neoplastic disease incorporating the administration of a taxane and the administration of a CYP3A4 inhibitor, either simultaneously or separately, are also included. Further, kits for carrying out the methods are included. Solid pharmaceutical taxane compositions for oral administration comprising a substantially amorphous taxane, a carrier and a surfactant are also included.

1 . A composition, which is:
 (a) a solid pharmaceutical composition comprising a substantially amorphous taxane, a hydrophilic carrier, and a surfactant;   (b) a pharmaceutical composition for oral administration, comprising a substantially amorphous taxane and a carrier wherein the substantially amorphous taxane is prepared by lyophilisation; or   (c) a composition comprising a taxane and a CYP3A4 inhibitor together with one or more pharmaceutically acceptable excipients.   
     
     
         2 . The composition of  claim 1  which is the solid pharmaceutical composition comprising the substantially amorphous taxane, the hydrophilic carrier, and the surfactant, wherein:
 (a) the taxane and the carrier are in the form of a solid dispersion; 
 (b) the taxane, the carrier and the surfactant are in the form of a solid dispersion; 
 (c) the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof; 
 (d) the taxane is selected from docetaxel, paclitaxel, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof; 
 (e) the carrier is PVP; 
 (f) the carrier is PVP and the PVP is selected from PVP-K12, PVP-K15, PVP-K17, PVP-K25, PVP-K30, PVP-K60 and PVP-K90; 
 (g) the carrier is PVP and the PVP is selected from PVP-K30, PVP-K60 and PVP-K90; 
 (h) the surfactant is selected from sodium dodecyl sulphate (SDS), sorbitan esters (sorbitan fatty acid esters), polyoxyethylene stearates, polyoxyethylene sorbitan fatty acid esters, polyoxyethylene castor oil derivatives, polyoxyethylene alkyl ethers, poloxamer, glyceryl monooleate, docusate sodium, cetrimide, benzyl bezoate, benzalkonium chloride, benzethonium chloride, hypromellose, non-ionic emulsifying wax, anionic emulsifying wax and triethyl citrate; 
 (i) the surfactant is SDS; 
 (j) the taxane to carrier weight ratio is between about 0.01:99.99 w/w and about 75:25 w/w; 
 (k) the taxane to carrier weight ratio is between about 0.01:99.99 w/w and about 30:70 w/w; 
 (l) the weight ratio of surfactant, to taxane and carrier combined, is between about 1:99 w/w and about 50:50 w/w; 
 (m) the weight ratio of surfactant, to taxane and carrier combined, is between about 2:98 w/w and about 17:83 w/w; 
 (n) the substantially amorphous taxane is prepared by lyophilisation; or 
 (o) the substantially amorphous taxane is prepared by lyophilisation of a taxane solution in a capsule for oral administration. 
 
     
     
         3 . The composition of  claim 1  which is the solid pharmaceutical composition comprising the substantially amorphous taxane, the hydrophilic carrier, and the surfactant, further comprising:
 (a) one or more additional pharmaceutically active ingredients; 
 (b) one or more additional pharmaceutically active ingredients, wherein the one or more additional pharmaceutically active ingredients comprises a CYP3A4 inhibitor; 
 (c) one or more additional pharmaceutically active ingredients, wherein the one or more additional pharmaceutically active ingredients comprises a CYP3A4 inhibitor, wherein the CYP3A4 inhibitor is ritonavir. 
 
     
     
         4 . The composition of  claim 1  which comprises the taxane and the CYP3A4 inhibitor together with one or more pharmaceutically acceptable excipients, wherein:
 (a) the CYP3A4 inhibitor is ritonavir; 
 (b) the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof; 
 (c) the taxane is docetaxel, a functional derivative thereof or a pharmaceutically acceptable salt or ester thereof; 
 (d) the composition comprises between about 0.1 mg and about 1000 mg of the taxane; 
 (e) the composition is intended for weekly administration and comprises between about 30 mg and about 500 mg of the taxane; 
 (f) the composition is intended for daily administration and comprises between about 0.1 mg and about 100 mg of the taxane; 
 (g) which comprises between about 0.1 mg and about 1200 mg of ritonavir; 
 (h) the composition is intended for weekly administration and comprises between about 50 mg and 1200 mg of ritonavir; 
 (i) the composition is intended for daily administration and comprises between about 50 mg and 1200 mg of ritonavir; or 
 (j) the composition is intended for weekly administration and comprises about 100 mg of the taxane and about 100 mg of ritonavir. 
 
     
     
         5 . A method selected from the group consisting of:
 (a) a method of treating a neoplastic disease, comprising administering to a subject in need thereof an effective amount of the composition according to  claim 1 ;   (b) a method of treating a neoplastic disease, comprising administering to a subject in need thereof an effective amount of a taxane and a CYP3A4 inhibitor;   (c) a method of treating a neoplastic disease, comprising administering a composition comprising a taxane and one or more pharmaceutically acceptable excipients to a subject receiving a CYP3A4 inhibitor simultaneously, separately or sequentially with the taxane;   (d) a method of treating a neoplastic disease, comprising administering a composition comprising a CYP3A4 inhibitor and one or more pharmaceutically acceptable excipients to a subject receiving a taxane simultaneously, separately, or sequentially with the CYP3A4 inhibitor; and   (e) of preparing the composition of  claim 1 , comprising dissolving the taxane, the hydrophilic carrier and the surfactant in a solvent; and lyophilising the solution to form the composition.   
     
     
         6 . The method of  claim 5 , wherein the method is the method of treating a neoplastic disease, comprising administering to a subject in need thereof an effective amount of a taxane and a CYP3A4 inhibitor, wherein:
 (a) the CYP3A4 inhibitor is ritonavir;   (b) the taxane is selected from docetaxel, paclitaxel, BMS-275183, functional derivatives thereof and pharmaceutically acceptable salts or esters thereof;   (c) the taxane is docetaxel, a functional derivative thereof or a pharmaceutically acceptable salt or ester thereof;   (d) the taxane is administered substantially simultaneously with the CYP3A4 inhibitor;   (e) the CYP3A4 inhibitor is administered approximately 60 minutes before the taxane;   (f) the taxane is administered at weekly intervals in a dose of between about 30 mg and 500 mg;   (g) the taxane is administered at daily intervals in a dose of between about 0.1 mg and 100 mg;   (h) the CYP3A4 inhibitor is ritonavir and the ritonavir is administered at weekly intervals in a dose of between about 50 mg and 1200 mg;   (i) the CYP3A4 inhibitor is ritonavir and the ritonavir is administered at daily intervals in a dose of between about 50 mg and 1200 mg;   (j) the CYP3A4 inhibitor is ritonavir and the taxane and ritonavir are administered at weekly intervals in a dose of about 100 mg of the taxane and about 100 mg of ritonavir;   (k) the neoplastic disease is a solid tumour;   (l) the neoplastic disease is a solid tumour, and the solid tumour is selected from breast, lung, gastric, colorectal, head & neck, oesophagus, liver, renal, pancreatic, bladder, prostate, testicular, cervical, endometrial, ovarian cancer and NHL;   (m) the neoplastic disease is a solid tumour, and the solid tumour is selected from breast, ovarian, prostate, gastric, head & neck and non-small cell lung cancer;   (n) the subject is human;   (o) the method further comprises the administration of a booster dose of CYP3A4 inhibitor a predetermined period of time after the administration of the first dose of CYP3A4 inhibitor;   (p) the method further comprises the administration of a booster dose of CYP3A4 inhibitor a predetermined period of time after the administration of the first dose of CYP3A4 inhibitor and the booster dose of CYP3A4 inhibitor is ritonavir; or   (q) the method further comprises the administration of a booster dose of CYP3A4 inhibitor a predetermined period of time after the administration of the first dose of CYP3A4 inhibitor and the booster dose of CYP3A4 inhibitor is ritonavir, wherein the booster dose of ritonavir is about 100 mg.   
     
     
         7 . The method of  claim 5 , wherein the method is the method of treating a neoplastic disease comprising administering to a subject in need thereof a composition comprising a taxane and one or more pharmaceutically acceptable excipients to a subject receiving a CYP3A4 inhibitor simultaneously, separately or sequentially with the taxane, wherein:
 (a) the CYP3A4 inhibitor is ritonavir; or   (b) the composition comprising a taxane is a composition comprising a substantially amorphous taxane, a hydrophilic carrier, and a surfactant.   
     
     
         8 . The method of  claim 5 , which is the method of treating a neoplastic disease comprising administering a composition comprising a CYP3A4 inhibitor and one or more pharmaceutically acceptable excipients, to a subject receiving a taxane simultaneously, separately or sequentially with the CYP3A4 inhibitor, wherein:
 (a) the CYP3A4 inhibitor is ritonavir.   (b) taxane being received by the subject is in the form of a composition of  claim 1 .