Roflumilast formulations with an improved pharmacokinetic profile

Abstract

An improved a method of treating a patient having a disorder responsive to PDE-4 inhibition by administering roflumilast. The improvement involves administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a PDE4-inhibiting amount of roflumilast. Such disorders include inflammatory disorders such as inflammatory dermatoses, including psoriasis, atopic dermatitis and seborrheic dermatitis. Such disorders also include inflammatory diseases in a variety of organs, especially the lungs (asthma, COPD). Because of reduced side effects with topical administration due to the improved pharmacokinetics (PK) characteristics, it may be possible to provide higher systemic exposures (AUCs) with topical administration, resulting in greater therapeutic efficacy than with the oral route of administration.

1 . A method of treating a patient having a disorder responsive to phosphodiesterase-4 inhibition by administering a therapeutically effective phosphodiesterase-4-inhibiting amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a therapeutically effective phosphodiesterase-4-inhibiting amount of roflumilast in an oral composition marketed under the trademark DALIRESP®.   
     
     
         2 . The method of  claim 1 , wherein said composition comprises 0.1-0.5% w/w of roflumilast. 
     
     
         3 . The method of  claim 1 , wherein said release profile produces in the patient a delayed Tmax relative to oral administration of a phosphodiesterase-4-inhibiting amount of roflumilast in an oral composition marketed under the trademark DALIRESP®. 
     
     
         4 . The method of  claim 1 , wherein the composition is in the form of a cream or foam. 
     
     
         5 . The method according to  claim 1 , wherein said method produces a higher area under the curve (AUC) relative to oral administration of an inflammatory disease-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®. 
     
     
         6 . The method according to  claim 1 , wherein said disorder responsive to phosphodiesterase-4 inhibition is asthma or chronic obstructive pulmonary disease COPD. 
     
     
         7 . A method of treating a patient suffering from an inflammatory dermatosis with an inflammatory dermatosis-treating effective amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of an inflammatory dermatosis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®.   
     
     
         8 . The method of  claim 5 , wherein said composition comprises 0.1-0.5% w/w of roflumilast. 
     
     
         9 . The method of  claim 5 , wherein said release profile produces in the patient a delayed Tmax relative to oral administration of an inflammatory dermatoses-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®. 
     
     
         10 . The method of  claim 5 , wherein the composition is in the form of a cream or foam. 
     
     
         11 . A method of treating a patient suffering from psoriasis with a psoriasis-treating effective amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a psoriasis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®.   
     
     
         12 . The method of  claim 11 , wherein said composition comprises 0.1-0.5% w/w of roflumilast. 
     
     
         13 . The method of  claim 11 , wherein said release profile produces in the patient a delayed Tmax relative to oral administration of a psoriasis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®. 
     
     
         14 . The method of  claim 11 , wherein the composition is in the form of a cream or foam. 
     
     
         15 . The method according to  claim 11 , wherein said method is suitable for the treatment of psoriasis patients as young as 2 years old. 
     
     
         16 . A method of treating a patient suffering from atopic dermatitis with an atopic dermatitis-treating effective amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of an atopic dermatitis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®   
     
     
         17 . The method of  claim 16 , wherein said composition comprises 0.1-0.5% w/w of roflumilast. 
     
     
         18 . The method of  claim 16 , wherein said release profile produces in the patient a delayed Tmax relative to oral administration of an atopic dermatitis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®. 
     
     
         19 . The method of  claim 16 , wherein the composition is in the form of a cream or foam. 
     
     
         20 . The method according to  claim 16 , wherein said method is suitable for the treatment of atopic dermatitis patients as young as 3 months. 
     
     
         21 . A method of treating a patient suffering from seborrheic dermatitis with a seborrheic dermatitis-treating effective amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of an atopic dermatitis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®.   
     
     
         22 . The method of  claim 21 , wherein said composition comprises 0.1-0.5% w/w of roflumilast. 
     
     
         23 . The method of  claim 21 , wherein said release profile produces in the patient a delayed Tmax relative to oral administration of an atopic dermatitis-treating effective amount of roflumilast in an oral composition marketed under the trademark DALIRESP®. 
     
     
         24 . The method of  claim 21 , wherein the composition is in the form of a cream or foam. 
     
     
         25 . A method of treating a patient having a disorder responsive to phosphodiesterase-4 inhibition by administering a phosphodiesterase-4-inhibiting amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that produces in the patient a flattened plasma concentration time curve and a reduced Cmax relative to oral administration of a phosphodiesterase-4-inhibiting amount of roflumilast marketed under the trademark DALIRESP®, wherein the phosphodiesterase-4-inhibiting amount of roflumilast is sufficient to reduce the severity, duration and/or recurrence of said disorder.   
     
     
         26 . A method of treating a patient having a disorder responsive to phosphodiesterase-4 inhibition by administering a therapeutically effective amount of roflumilast, wherein the improvement comprises:
 administering the roflumilast topically in a composition having a roflumilast release profile that results in reduced psychiatric adverse reactions and weight loss relative to oral administration of a therapeutically effective amount of roflumilast marketed under the trademark DALIRESP®.