Novel gastroretentive extended release dosage form

Abstract

A novel orally administrable dosage form including a drug/active layer for loading a therapeutic agent and an extension layer for retaining the API or drug dosage form in the stomach of a subject in need thereof. Also disclosed is a method of treating diseases with the dosage form.

1 . An orally administrable extended release dosage form, comprising:
 (a) an active pharmaceutical ingredient (API) layer comprising a therapeutically effective amount of a first therapeutic agent, and one or more extended release agents providing extended release of the first therapeutic agent from the dosage form over a period of more than 8 hours in a medium, wherein the medium comprises 900 ml of 50 mM pH 4.5 acetate buffer with 2% Tween 80 at 37° C. with sinker in a standard USP rotating paddle apparatus having a paddle rotating speed of 100 rpm, wherein the first therapeutic agent is Tofacitinib or Apremilast;   (b) a retention layer comprising one or more excipients, wherein the one or more excipients are selected to achieve at least one of the following:   i. the dosage form stays afloat for more than 8 hours in the medium;   and   ii. a length and a width in the retention layer of the dosage form both remain equal or greater than 10 mm for more than 8 hours in un-stirred deionized sitting water or in the medium.   
     
     
         2 . The dosage form of  claim 1 , further comprising a third layer comprising a therapeutically effective amount of a second therapeutic agent. 
     
     
         3 . The dosage form of  claim 1 , further comprising a third layer for keeping the dosage form afloat, wherein the API layer is sandwiched between the retention layer and the third layer. 
     
     
         4 . (canceled) 
     
     
         5 . The dosage form of  claim 1 , wherein the first therapeutic agent is amorphous Apremilast. 
     
     
         6 . The dosage form of any one of  claim 1 , wherein the one or more extended release agents in the API layer and the one or more excipients in the retention layer are selected to control the release of the first therapeutic agent in the medium such that
 (a) less than 30% of the first therapeutic agent is released within about 1 hour; and   (b) from about 35% to about 80% of the first therapeutic agent is release within about 8 hours,   wherein the first therapeutic agent is Apremilast.   
     
     
         7 . The dosage form of  claim 1 , wherein more than 70% of the first therapeutic agent is released in 16 hours, and
 wherein:   i. the dosage form remains afloat during the 16 hours in the medium; or   ii. the length and the width in the retention layer of the dosage form both remain equal or greater than 10 mm during the 16 hours in the medium.   
     
     
         8 . (canceled) 
     
     
         9 . The dosage form of  claim 1 , wherein the one or more extended release agents in the API layer and the one or more excipients in the retention layer are selected to control the release of the first therapeutic agent ranging from about 40 mg to about 80 mg such that the dosage form administered QD with food provides an area under curve (AUC) of the first therapeutic agent ranging from about 70% to about 125% of the AUC of the first therapeutic agent in a daily dosage of about 60 mg administered twice a day (BID) as an immediate release formulation, wherein the first therapeutic agent is Apremilast. 
     
     
         10 . The dosage form of  claim 1 , wherein the one or more extended release agents in the API layer and the one or more excipients in the retention layer are selected to control the release of the first therapeutic agent ranging from about 8 mg to about 15 mg such that the dosage form administered QD with food provides an area under curve (AUC) of the first therapeutic agent ranging from about 70% to about 125% of the AUC of the first therapeutic agent in a daily dosage of about 10 mg administered BID as an immediate release formulation, wherein the first therapeutic agent is tofacitinib. 
     
     
         11 . The dosage form of  claim 1 , wherein the one or more extended release agents in the API layer and the one or more excipients in the retention layer are selected to control the release of the first therapeutic agent ranging from about 15 mg to about 25 mg such that the dosage form administered QD with food provides an area under curve (AUC) of the first therapeutic agent ranging from about 70% to about 125% of the AUC of the first therapeutic agent in a daily dosage of about 20 mg administered BID as an immediate release formulation, wherein the first therapeutic agent is tofacitinib. 
     
     
         12 . (canceled) 
     
     
         13 . The dosage form of  claim 1 , wherein the one or more extended release agents in the API layer comprise hypromellose with viscosity higher than 50 mPa·S and glyceryl behenate. 
     
     
         14 . The dosage form of  claim 1 , wherein the glyceryl behenate comprises glyceryl dibehenate in an amount of more than 50% by weight in the glyceryl behenate. 
     
     
         15 . (canceled) 
     
     
         16 . (canceled) 
     
     
         17 . The dosage form of  claim 13 , wherein the hypromellose has a viscosity of higher than 3000 mPa·S, wherein the hypromellose and the glyceryl behenate are in a ratio ranging from about 1:2 to about 2:1, and wherein the hypromellose and the glyceryl behenate independently range from about 5% to about 20% in the API layer. 
     
     
         18 . The dosage form of  claim 1 , wherein the one or more extended release agents comprise at least two types of hypromelloses, wherein one of the at least two types of hypromelloses has viscosity of higher than about 3,000 mPa·S and the other of the at least two types of hypromelloses has viscosity of lower than about 200 mPa·S. 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . (canceled) 
     
     
         22 . The dosage form of  claim 1 , wherein the one or more excipients in the retention layer comprise low density agents selected from the group consisting of cellulose acetate, hydrogenated vegetable oil, glyceryl behenate, ethylcellulose, and wax. 
     
     
         23 . The dosage form of  claim 22 , wherein the one or more excipients in the retention layer comprise one or more swelling agent selected from the group consisting of hypromellose, hydroxypropyl cellulose, polyethylene oxide, carboxymethylcellulose, Croscarmellose Sodium, sodium starch glycolate, cross-linked povidone, and chitosan. 
     
     
         24 . The dosage form of  claim 1 , wherein the one or more excipients in the retention layer comprise polyethylene oxide having MW of no less than 1000 kDa and cellulose acetate in a ratio ranging from about 10:1 to about 1:1. 
     
     
         25 . (canceled) 
     
     
         26 . (canceled) 
     
     
         27 . The dosage form of  claim 1 , further comprising a low viscosity hypromellose in an amount ranging from about 5% to about 50% in the retention layer, wherein the low viscosity hypromellose has a viscosity of less than 150 mPa·S. 
     
     
         28 . The dosage form of  claim 1 , wherein the retention layer further comprises an effervescent agent and an acid source, wherein the total weight of the effervescent agent and the acid source ranges from about 5% to about 20% in the retention layer. 
     
     
         29 . The dosage form of  claim 1 , wherein the one or more extended release agents in the API layer and the one or more excipients in the retention layer are selected to control retention of the dosage form in the stomach such that the dosage form begins to float in less than 30 minutes in the medium. 
     
     
         30 . The dosage form of  claim 1 , wherein the one or more excipients in the retention layer are selected such that the length and the width of the retention layer independently expand from about 10% to about 20% in the medium within about 30 minutes. 
     
     
         31 . The dosage form of  claim 1 , wherein the one or more excipients in the retention layer are selected such that the length and the width of the retention layer independently expands from about 30% to about 50% in the medium within about 8 hours. 
     
     
         32 . The dosage form of  claim 1 , wherein the length exceeds 18 mm and the width exceeds 10 mm within 30 minutes in the medium. 
     
     
         33 . (canceled) 
     
     
         34 . (canceled) 
     
     
         35 . (canceled) 
     
     
         36 . (canceled) 
     
     
         37 . (canceled) 
     
     
         38 . A method of treating a disease in a subject, comprising administering to the subject the dosage form of  claim 1 , wherein the disease is selected from the group consisting of psoriasis, ankylosing spondylitis, Behcet's disease, rheumatoid arthritis, atopic dermatitis, Crohn's disease, and ulcerative colitis. 
     
     
         39 . The method of  claim 38 , wherein the dosage form is administered once daily. 
     
     
         40 . (canceled) 
     
     
         41 . (canceled) 
     
     
         42 . A method of providing in a subject an area under curve (AUC) of a first therapeutic agent ranging from about 70% to about 125% of the AUC of the first therapeutic agent administered BID as an immediate release formulation, comprising administering to the subject once a day the dosage form of  claim 1 , wherein the amount of the first therapeutic agent in the dosage form ranges from about 60% to about 150% of the daily total amount of the first therapeutic agent in the immediate release formulation. 
     
     
         43 . (canceled) 
     
     
         44 . (canceled) 
     
     
         45 . (canceled) 
     
     
         46 . (canceled) 
     
     
         47 . (canceled) 
     
     
         48 . (canceled) 
     
     
         49 . (canceled) 
     
     
         50 . The method of  claim 1 , wherein the dosage form is administered with food. 
     
     
         51 . (canceled) 
     
     
         52 . (canceled)