Oral Dosage Forms of Bendamustine and Therapeutic Use Thereof

Abstract

In the present invention there is provided a pharmaceutical composition for oral administration which comprises bendamustine or a pharmaceutically acceptable, ester, salt or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient and which shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes, as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5, and wherein the pharmaceutically acceptable excipient is either a pharmaceutically acceptable non-ionic surfactant, selected from the group consisting of a polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide and propylene oxide or a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1:1-5. The invention further relates to the above pharmaceutical composition for use for the oral treatment of a medical condition which is selected from chronic lymphocytic leukemia, acute lymphocytic leukaemia, chronic myelocytic leukaemia, acute myelocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer and non-small cell lung cancer. The invention moreover relates to the above pharmaceutical composition for the above use wherein the dosage regimen comprises at least the administration of a dose of 100 to 600 mg/m2/per person of bendamustine on day 1 and day 2, optionally a dose of 50 to 150 mg/m 2 i.v. or orally of a corticosteroid on days 1 to 5, and optionally a suitable dose of a further active agent selected from the group consisting of an antibody specific for CD20, an anthracyclin derivative, a vinca alkaloid or a platin derivative; and the repetition of said dosage regimen 4 to 15 times after intervals of two to four weeks.

1 . A pharmaceutical composition for oral administration which comprises bendamustine or a pharmaceutically acceptable, ester, salt or solvate thereof as an active ingredient, and a pharmaceutically acceptable excipient and which shows a dissolution of the bendamustine of at least 60% in 20 minutes, 70% in 40 minutes and 80% in 60 minutes, as measured with a paddle apparatus at 50 rpm according to the European Pharmacopoeia in 500 ml of a dissolution medium at a pH of 1.5, and wherein the pharmaceutically acceptable excipient is either a pharmaceutically acceptable non-ionic surfactant, selected from the group consisting of a polyethoxylated castor oil or derivative thereof and a block copolymer of ethylene oxide and propylene oxide or a pharmaceutically acceptable saccharide selected from the group consisting of one or more of a monosaccharide, a disaccharide, an oligosaccharide, a cyclic oligosaccharide, a polysaccharide and a saccharide alcohol, wherein the ratio by weight of the active ingredient to the saccharide excipient(s) is in the range of 1:1-5. 
     
     
         2 . The pharmaceutical composition according to  claim 1 , characterised in that the active ingredient is bendamustine hydrochloride. 
     
     
         3 . The pharmaceutical composition according to  claim 1 , characterised in that it comprises 10 to 1000 mg, preferably 25 to 600 mg, more preferably 50 to 200 mg and most preferably about 100 mg of the active ingredient. 
     
     
         4 . The pharmaceutical composition according to  claim 1 , characterised in that the polyoxyethylated castor oil or derivative thereof is macrogol glycerol hydroxystearate. 
     
     
         5 . The pharmaceutical composition according to  claim 1 , characterised in that the polyoxyethylated castor oil or derivative thereof is polyoxyl-35 castor oil. 
     
     
         6 . The pharmaceutical composition according to  claim 1 , characterised in that the block copolymer of ethylene oxide and propylene oxide is ethylene oxide/propylene oxide block copolymer (Pluronic® L44 NF or Poloxamer® 124). 
     
     
         7 . The pharmaceutical composition according to  claim 1 , characterised in that the pharmaceutically acceptable excipient is a pharmaceutically acceptable non-ionic surfactant and that it further comprises colloidal silicon dioxide. 
     
     
         8 . The pharmaceutical composition according to  claim 1 , characterised in that it further comprises lauroyl macrogol glycerides (Gelucire® 44/14). 
     
     
         9 . The pharmaceutical composition according to  claim 1 , characterised in that the excipient is a pharmaceutically acceptable non-ionic surfactant and the composition is in a hard gelatine capsule. 
     
     
         10 . The pharmaceutical composition of  claim 1 , wherein the excipient is a pharmaceutically acceptable saccharide and the composition is in a solid dosage form. 
     
     
         11 . The pharmaceutical composition of  claim 10 , wherein the ratio by weight of the active ingredient to the saccharide is 1:2-5. 
     
     
         12 . The pharmaceutical composition according to  claim 10 , which is in the form of a tablet, a granulate, or a pill. 
     
     
         13 . The pharmaceutical composition according to  claim 10 , wherein the tablet or tablet granules, the granulate or the pill are provided with a coating. 
     
     
         14 . The pharmaceutical composition according to  claim 10 , which comprises 10 to 1000 mg of the active ingredient and 30 to 5000 mg of the saccharide excipient. 
     
     
         15 . The pharmaceutical composition according to  claim 10 , wherein the saccharide excipient is selected from mannitol, maltitol, erythritol, xylitol, lactose, sucrose, glucose, sorbitol, maltose, trehalose, lactitol, dextrose and fructose. 
     
     
         16 . The pharmaceutical composition according to  claim 10 , wherein the saccharide excipient is selected from dextrose anhydrous, dextrose monohydrate, lactitol monohydrate, trehalose, sorbitol, erythritol, maltose monohydrate, mannitol, lactose anhydrous, lactose monohydrate, maltitol, xylitol, sucrose, sucrose 97%+maltodextrin 3%, β-cyclodextrin, D-raffinose pentahydrate, D-melezitose monohydrate and microcrystalline cellulose. 
     
     
         17 . The pharmaceutical composition according to  claim 10 , which further comprises a pharmaceutically acceptable lubricant, filler and/or disintegrant. 
     
     
         18 . A method of oral treatment of a medical condition which is selected from chronic lymphocytic leukemia, acute lymphocytic leukaemia, chronic myelocytic leukaemia, acute myelocytic leukaemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, breast cancer, ovarian cancer, small cell lung cancer and non-small cell lung cancer in a person comprising oral administration of the pharmaceutical composition of  claim 1  to the person. 
     
     
         19 . The method according to  claim 18  wherein the pharmaceutical composition is administered in combination with at least one further active agent, wherein said at least one further active agent is administered prior, concurrently, or subsequently to the pharmaceutical composition and is selected from the group consisting of an antibody specific for CD20, an anthracyclin derivative, a vinca alkaloid or a platin derivative. 
     
     
         20 . The method according to  claim 19 , characterised in that the antibody specific for CD20 is rituximab; the anthracyclin derivative is doxorubicin or daunorubicin; the vinca alkaloid is vincristine and the platin derivative is cisplatin or carboplatin. 
     
     
         21 . The method according to  claim 18  wherein the pharmaceutical composition is administered in combination with at least one corticosteroid, wherein said use of the corticosteroid is prior, concurrently, or subsequently to the use of the pharmaceutical composition. 
     
     
         22 . The method according to  claim 21 , characterised in that the corticosteroid is prednisone or prednisolone. 
     
     
         23 . The method according to  claim 18 , wherein the active ingredient is administered in a dose between 50 mg to 1000 mg/m 2 /per person per therapeutic cycle. 
     
     
         24 . The method according to  claim 18  wherein the dosage regimen comprises at least the administration of
 a dose of 100 to 600 mg/m 2 /per person of bendamustine on day 1 and day 2, 
 optionally a dose of 50 to 150 mg/m 2  i.v. or orally of a corticosteroid on days 1 to 5, and 
 optionally a suitable dose of a further active agent selected from the group consisting of an antibody specific for CD20, an anthracyclin derivative, a vinca alkaloid or a platin derivative; and the repetition of said dosage regimen 4 to 15 times after intervals of two to four weeks. 
 
     
     
         25 . The method according to  claim 18 , wherein the active ingredient bendamustine is administered in a dosage regimen selected from
 200-300 mg on day 1 and day 2, optionally followed by a maintenance dose of 50 mg once a day,   50 mg each day from day 1 up till and including day 14, or   150 mg once a week for 3 weeks.   
     
     
         26 . The method according to  claim 18 , wherein the person is one having non-Hodgkin's lymphoma and the dosage regimen comprises administering a total amount of 200 mg/person/day of active ingredient bendamustine on days 1 to 5, 2 mg i.v. of vincristine on day 1 and 100 mg/m 2  i.v. of prednisone on days 1 to 5 and repeating said treatment every three weeks until the non-Hodgkin's lymphoma has improved. 
     
     
         27 . The method according to  claim 18 , wherein the person is one having multiple myeloma and the dosage regimen comprises administering an amount of 100-250, preferably 174 to 217 mg/m 2  body surface area bendamustine hydrochloride on days 1 and 2, 60 mg/m 2  i.v. or orally of prednisone on days 1 to 4 and repeating said treatment every four weeks until the multiple myeloma has improved. 
     
     
         28 . The method according to  claim 18 , wherein the person is one having chronic lymphocytic leukaemia and the dosage regimen comprises administering an amount of 100 to 200, preferably 145 mg/m 2  body surface area bendamustine hydrochloride on days 1 and 2 and 60 mg/m 2  i.v. or orally of prednisone on days 1 to 4 and repeating said treatment every four weeks until the chronic lymphocytic leukaemia has improved. 
     
     
         29 . The method according to  claim 18 , wherein the person is one having follicular, indolent or mantle cell lymphoma and the dosage regimen comprises administering a dose of 375 mg/m 2  rituximab on day 1 plus 100 to 200, preferably 130 mg/m 2  oral bendamustine on days 1 and 2 every 28 days until the respective lymphoma has improved.