Compositions comprising alprazolam for treating primary insomnia and insomnia associate with anxiety states and process for preparing them

Abstract

Disclosed is a composition comprising alprazolam for treating primary insomnia and insomnia associated with anxiety states and the corresponding use and method comprising the administration of alprazolam sublingual tablets having a disintegration time lower than 30 seconds and having the alprazolam preferably in non-crystalline or partially crystalline form according to the X-ray diffraction crystallography expanded for the position delta 9-12.5 (2 theta), to a patient suffering from said disorder. There is also disclosed a method for preparing a composition according to the invention, where the alprazolam is solved in a pharmaceutical acceptable solvent and a binder, preferably polyvinylpyrrolidone, is incorporated to the solution. A pre-made mixture of part of the cross-linked carboxymethyl-cellulose and the rest of the ingredients of the composition is impregnated with the solution and is dried and grinded, and is added to the rest of the cross-linked carboxymethyl-cellulose and the flavoring additives, being then mixed and compressed.

1 . A method for treating primary insomnia by sublingual administration of alprazolam. 
     
     
         2 . A method for treating primary insomnia by sublingual administration of a composition of alprazolam. 
     
     
         3 . The method of  claim 2  characterised in that said composition comprises a combination of alprazolam and a binder having mucoadhesive properties and wherein the ratio of alprazolam to the binder is in the range between 0.3:1 and 3:1. 
     
     
         4 . The method of  claim 3  characterised in that the binder is polyvinylpyrrolidone. 
     
     
         5 . (canceled) 
     
     
         6 . The method of  claim 2 , wherein said composition is in the form of tablets which provide a disintegration time lower than 1 minute, in vitro when measured in a USP apparatus in medium water without discs according to the United States Pharmacopoeia. 
     
     
         7 . The method of  claim 2  wherein the medicament comprises the alprazolam active principle in a non-crystalline or partially crystalline form, according to an X-ray diffraction crystallography expanded for the position delta 9-12.5 (2 theta). 
     
     
         8 . The method of  claim 2  wherein said composition is prepared in tablets, wherein each tablet comprises between 0, 1 and 2 mg alprazolam. 
     
     
         9 . The method of  claim 8  characterised in that each sublingual tablet comprises 0.5 mg of alprazolam. 
     
     
         10 . The method of  claim 8  characterised in that each sublingual tablet comprises 1.0 mg of alprazolam. 
     
     
         11 . The method of  claim 2 , wherein:
 an improvement higher than 90% in quality of sleep is obtained in patients treated when they go to bed;   the latency period to reach a sleeping state for patients suffering from primary insomnia decreases in a statistically significant fashion;   the decrease in the latency period to reach a sleeping status may mean a shorter period of time up to 80% in relation to the treatment with oral standard tablets including the same contents of alprazolam; and   the degree of preference for alprazolam in sublingual tablets may be as high as 70%; as measured by Abbreviated Pittsburgh Sleep Quality Questionnaire (PSQI).   
     
     
         12 . A pharmaceutical composition in the form of sublingual tablets for treating primary insomnia comprising a combination of alprazolam and a binder having mucoadhesive properties; wherein the ratio of alprazolam to the binder is in the range between 0.3:1 and 3:1. 
     
     
         13 . The pharmaceutical composition of  claim 12 , wherein said composition has a disintegration time lower than 30 seconds, in vitro when measured in a standard USP apparatus in medium water without discs according to the United States Pharmacopoeia and wherein the alprazolam is in a non-crystalline or partially crystalline form according to an X-ray diffraction crystallography expanded for the position delta 9-12.5 (2 theta). 
     
     
         14 . The pharmaceutical composition of  claim 12  wherein the binder is polyvinylpyrrolidone. 
     
     
         15 . The pharmaceutical composition of  claim 14  wherein each tablet comprises between 0, 1 and 2 mg alprazolam per tablet. 
     
     
         16 . The pharmaceutical composition according to  claim 15  characterised in that each sublingual tablet comprises 0.5 mg of alprazolam. 
     
     
         17 . The pharmaceutical composition according to  claim 15  characterised in that each sublingual tablet comprises 1.0 mg of alprazolam. 
     
     
         18 . The pharmaceutical composition according to  claim 12 , wherein the sublingual tablets have a weight of no more than 40 mg. 
     
     
         19 . The pharmaceutical composition according to  claim 18 , wherein the weight of the sublingual tablet is 35 mg. 
     
     
         20 . A process for preparing a pharmaceutical composition, wherein said preparation procedure comprises the following steps:
 dissolving alprazolam and a binder in a pharmaceutically acceptable solvent to form a solution;   providing a mixture comprising a first portion of cross-linked carboxymethyl cellulose;   impregnating said mixture with said solution so as to form a granular mass;   drying the above granular mass and grinding until uniform granulometry is achieved so as to produce a dried mass;   adding a second portion of cross-linked carboxymethyl-cellulose and flavoring additives to the dry mass, then mixing and compressing.   
     
     
         21 . The process according to  claim 20 , wherein the binder is polyvinylpyrrolidone. 
     
     
         22 . A process according to  claim 21 , wherein alprazolam is not significantly detected in its crystalline form according to X-ray diffraction crystallography on the tablets according to an X-ray diffraction crystallography expanded for the position delta 9-12.5 (2 theta). 
     
     
         23 . (canceled)