Solid Oral Dosage Forms

Abstract

The present invention provides pharmaceutical compositions suitable for oral delivery of active agent, such as peptides and small molecules, and methods for treating subjects in need thereof. The pharmaceutical compositions of the present invention enhance the bioavailability of therapeutic active agents.

1 . A modified release solid oral composition comprising:
 (a) a core comprising: (i) an effective amount of active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a peptide, a peptidomimetic, a small molecule, or a combination thereof, (ii) a pH lowering agent, (iii) an absorption enhancer, (iv) a filler comprising wax, gum, alginic acid or salt thereof or hyaluronic acid, and (v) less than 10% by weight of disintegrant; and   (b) about 5 mg/cm 2  to about 25 mg/cm 2  of an enteric coating surrounding the core, wherein the composition provides a pharmacokinetic profile for the active agent with a T lag  greater than 1.0 h and less than 16 h post-administration.   
     
     
         2 . The composition of  claim 1  wherein the composition provides a pharmacokinetic profile for the active agent with a T max  greater than (T lag +0.5 h) and less than 20 h post-administration. 
     
     
         3 . The composition of  claim 1  further comprising a water soluble barrier beneath the enteric coating. 
     
     
         4 . The composition of  claim 1  wherein the filler further comprises microcrystalline cellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, chitosan or a combination thereof. 
     
     
         5 . The composition of  claim 1  wherein the absorption enhancer comprises a non-ionic surfactant, a cationic surface active agent, an anionic surface active agent or a combination thereof. 
     
     
         6 . The composition of  claim 1  wherein the absorption enhancer comprises a fatty acid derivative of polyethylene glycol. 
     
     
         7 . The composition of  claim 1  wherein the absorption enhancer comprises an alkylsaccharide. 
     
     
         8 . The composition of  claim 5  wherein the cationic surface active agent comprises an acylcarnitine. 
     
     
         9 . The composition of  claim 5  wherein the anionic surface active agent comprises sodium dodecyl sulfate. 
     
     
         10 . The composition of  claim 1  wherein the pH lowering agent comprises citric acid, tartaric acid or a combination thereof. 
     
     
         11 . The composition of  claim 1  wherein the pH lowering agent is in the form of coated acid particles and wherein the acid particles are coated with a water-soluble coating. 
     
     
         12 . The composition of  claim 1  wherein the peptide is one of leuprolide, insulin, vasopressin, calcitonin, calcitonin gene-related peptide, parathyroid hormone, desmopressin, gonadotrophin releasing hormone (GnRH), luteinizing hormone-releasing factor, erythropoietin, tissue plasminogen activators, human growth hormone, adrenocorticotropin, interleukins, enkephalin, glucagon-like peptide-1, desmopressin, 2,6-dimethyltyrosine-D-arginine-phenylalanine-lysine amide, and analogs thereof. 
     
     
         13 . The composition of  claim 1  wherein the small molecule is classified as BCS Class II, BCS Class III or BCS Class IV. 
     
     
         14 . The composition of  claim 1  wherein the small molecule is a glycylcycline-based tetracycline antibiotic. 
     
     
         15 . The composition of  claim 1  wherein the small molecule is one of tigecycline, zanamivir, kanamycin, tobramycin, or fenofibrate. 
     
     
         16 . The composition of  claim 1  wherein the pharmacokinetic release profile targets release of the pharmaceutical active ingredient to the jejunum, the ileum or the jejunum and the ileum. 
     
     
         17 . The composition of  claim 1  wherein the composition is a tablet or a capsule. 
     
     
         18 . The composition of  claim 1  wherein the active pharmaceutical ingredient is calcitonin or amylin. 
     
     
         19 . The composition of  claim 1  wherein the active pharmaceutical ingredient is gonadotrophin releasing hormone, wherein the gonadotrophin releasing hormone is one of triptorelin, leuprorelin and goserelin. 
     
     
         20 . A modified release solid oral composition comprising:
 (a) a core comprising: (i) an effective amount of active pharmaceutical ingredient, wherein the active pharmaceutical ingredient is a peptide, a peptidomimetic, a small molecule, or a combination thereof, (ii) a pH lowering agent, wherein the pH lowering agent is in the form of coated acid particles and wherein the acid particles are coated with a water-soluble coating, (iii) an absorption enhancer, (iv) a filler comprising wax, gum, alginic acid or salt thereof or hyaluronic acid, and (v) less than 10% by weight of disintegrant; and   (b) about 5 mg/cm 2  to about 25 mg/cm 2  of an enteric coating surrounding the core, wherein the composition provides a pharmacokinetic profile for the active agent with a T lag  greater than 1.0 h and less than 16 h post-administration.   
     
     
         21 . A method of treating a patient comprising
 (a) providing a solid oral dosage form comprising (i) a core comprising: an effective amount of active pharmaceutical ingredient, a pH lowering agent, an absorption enhancer, a filler comprising wax, gum, alginic acid or salt thereof or hyaluronic acid, and less than 10% by weight of disintegrant; and (ii) about 5 mg/cm 2  to about 25 mg/cm 2  of an enteric coating surrounding the core,   (b) administering orally to the patient, the solid oral dosage form,   
       wherein the solid oral dosage form provides a pharmacokinetic release profile for the active agent with a T lag  greater than 1.0 h and less than 16 h post-administration.