Orally disintegrating dosage form for administration of avanafil, and associated methods of manufacture and use

Abstract

Formulations are provided for the oral administration of avanafil, a Type V phosphodiesterase inhibitor (“PDE V inhibitor”), and analogs thereof. The formulations are orally disintegrating tablets (ODTs) that rapidly dissolve or disintegrate in the oral cavity. The tablets contain an absorption enhancing composition that increases the duodenal absorption of the active agent, following transfer from the low pH environment of the stomach to the more basic pH of the duodenum. Methods for administering the active agent using the dosage forms are provided. The invention also encompasses a method of selecting components and compositions to incorporate in the formulations which will facilitate increased absorption of the active agent in the duodenum and thus serve as “absorption enhancing compositions” herein. Also provided are methods for manufacturing orally disintegrating tablets to optimize the physical properties of the dosage forms, particularly hardness and disintegration time.

We claim: 
     
         1 . An orally disintegrating tablet, comprising the following:
 a therapeutically effective amount of avanafil;   an absorption enhancing composition comprising a surfactant;   an orally disintegrating composition comprising a disintegrant; and   a porous component in a pharmaceutically acceptable carrier.   
     
     
         2 . The tablet according to  claim 1 , wherein the tablet disintegrates within the oral cavity within about 45 seconds and exhibits a hardness of greater than about 30 N. 
     
     
         3 . The tablet according to  claim 2 , wherein the tablet disintegrates within the oral cavity within about 30 seconds and exhibits a hardness of greater than about 15 N. 
     
     
         4 . The tablet according to  claim 2 , wherein the tablet disintegrates within the oral cavity within about 15 seconds and exhibits a hardness of greater than about 7.5 N. 
     
     
         5 . The tablet according to  claim 1 , wherein the disintegrant is a superdisintegrant. 
     
     
         6 . The tablet according to  claim 1 , wherein the porous component comprises porous mannitol. 
     
     
         7 . The tablet according to  claim 1 , wherein the surfactant comprises a polymeric component that mitigates the precipitation of avanafil in an aqueous medium as pH increases from about 2.5 to about 7.0. 
     
     
         8 . The tablet according to  claim 7 , wherein the polymeric component is nonionic and mitigates the precipitation of avanafil in an aqueous medium as pH increases from about 2.5 to about 7.0 by delaying precipitation, reducing the rate of precipitation, decreasing the extent of precipitation, or any combination of the foregoing. 
     
     
         9 . The tablet of  claim 8 , wherein the polymeric component is comprised of a hydrophilic segment and a hydrophobic segment. 
     
     
         10 . The tablet according to  claim 8 , wherein the polymeric component is comprised of a polyoxyethylene-polyoxypropylene copolymer. 
     
     
         11 . The tablet according to  claim 10 , wherein the polymeric component comprises poloxamer 407. 
     
     
         12 . The tablet according to  claim 1 , wherein the avanafil represents in the range of about 10 wt. % to about 50 wt. % of the tablet. 
     
     
         13 . The tablet according to  claim 12 , wherein the avanafil represents up to about 70 wt. % of the dosage form. 
     
     
         14 . The tablet according to  claim 1  wherein the tablet does not comprise fumaric acid, tartaric acid, succinic acid, malic acid, ascorbic acid or aspartic acid. 
     
     
         15 . A method for administering a PDE V inhibitor to a subject having a PDE V inhibitor-treatable condition selected from erectile dysfunction, hypertension, angina pectoris, myocardial infarction, heart failure, pulmonary arterial hypertension, prostatic hyperplasia, female sexual dysfunction, neurogenesis, neuropathy, Alzheimer's disease, psoriasis, skin necrosis, metastasis, baldness, nutcracker oesophagus, anal fissure, hemorrhoids, insulin resistance syndrome, hypoxic vasoconstriction, and blood pressure stabilization, comprising orally administering the tablet according to  claim 1  to the subject on an as-needed basis. 
     
     
         16 . A method for manufacturing a rapidly disintegrating oral dosage form, comprising:
 (a) preparing active agent granules by (i) blending a pharmacologically active agent in particulate form with a first fraction of a disintegrant and a first fraction of a porous binder, to form an initial mixture, and (ii) granulating the initial mixture for a predetermined time period at a predetermined temperature, to provide the active agent granules;   (b) blending the active agent granules with a lubricant, a second fraction of a disintegrant, and a second fraction of a porous binder, to provide a final formulation mixture; and   (c) compacting the final formulation mixture to prepare the rapidly disintegrating oral dosage form.   
     
     
         17 . The method of  claim 16 , wherein granulating is carried out in a solvent and step (a) further comprises drying the granulation prepared in (ii) prior to step (b). 
     
     
         18 . The method of  claim 16 , wherein the porous binder is selected from porous mannitol, porous lactose, and porous glucose and wherein the disintegrant comprises at least one superdisintegrant. 
     
     
         19 . The method of  claim 17 , wherein the active agent is avanafil and the method further comprises incorporating an absorption enhancing composition into the dosage form, wherein a first fraction of the absorption enhancing composition is incorporated in (a) and a second fraction of the absorption enhancing composition is incorporated in (b). 
     
     
         20 . An orally disintegrating tablet having hardness of 13.5 N or more, which is obtained by a process comprising the following steps:
 (a) preparing active agent granules by (i) blending avanafil in particulate form with a first fraction of a disintegrant and a first fraction of a porous binder, to form an initial mixture, and (ii) granulating the initial mixture for a predetermined time period at a predetermined temperature, to provide the active agent granules, wherein granulating is carried out in a solvent;   (b) drying the active agent granules;   (c) blending the dry active agent granules with a lubricant, a second fraction of the disintegrant, and a second fraction of a porous binder, to provide a final formulation mixture; and   (d) compacting the final formulation mixture to prepare the rapidly disintegrating oral dosage form.