Solid oral dosage forms
Inventors
Vrettos, John • Daggs, Thomas • Shields, Paul • Claudio, Raymundo
Assignees
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Publication Number
US-9833411-B2
Publication Date
2017-12-05
Expiration Date
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.
Core Innovation
The invention relates to modified release solid oral compositions that provide a pharmacokinetic profile for an active pharmaceutical ingredient. The active pharmaceutical ingredient is a peptide, a peptidomimetic, a small molecule, or a combination thereof. The composition includes a core and an enteric coating surrounding the core.
The core comprises coated acid particles, where the acid particles are coated with a water soluble coat and the acid of the coated acid particles is a pH lowering agent. The core further includes an absorption enhancer and a filler comprising a hydrogel-forming polymer with a specified viscosity for a 2% solution at 20° C. The core has very low disintegrant, and the active pharmaceutical ingredient, the coated acid particles, the absorption enhancer, the filler, and the less than 0.01% disintegrant are intermixed.
The composition provides a pharmacokinetic profile characterized by a Tlag greater than 1.0 h and less than 16 h post-administration, and a Tmax greater than (Tlag + 0.5 h) and less than 20 h post-administration. In addition, when added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, the pH of the solution is lowered to no higher than 5.5. The enteric coating surrounds the core at about 5 mg/cm2 to about 25 mg/cm2.
The documented description emphasizes tuning release timing beyond the upper GI region, with pharmacokinetic release configured to deliver the pharmaceutical active ingredient to the jejunum, the ileum, or both. The background problem being solved is improving oral bioavailability of peptides and small molecules while minimizing undesired release in the stomach/duodenum and reducing variability by controlling pharmacokinetic timing.
Claims Coverage
The relevant independent claims are clm-00001, clm-00015, and clm-00016. Across these claims, the inventive concept is a modified release solid oral core with coated acid particles, an absorption enhancer, and a hydrogel-forming polymer filler, combined with an enteric coating and constrained pharmacokinetic timing together with a defined pH lowering behavior in a sodium bicarbonate test.
Modified release solid oral composition with core and enteric coating
A modified release solid oral composition comprising a core comprising an active pharmaceutical ingredient, coated acid particles with a water soluble coat where the acid is a pH lowering agent, an absorption enhancer, a filler comprising a hydrogel-forming polymer with a specified viscosity, and less than 0.01% by weight of disintegrant, where the active pharmaceutical ingredient, the coated acid particles, the absorption enhancer, the filler and the disintegrant are intermixed; and about 5 mg/cm2 to about 25 mg/cm2 of an enteric coating surrounding the core.
Pharmacokinetic timing and pH lowering constraint
The composition provides a pharmacokinetic profile with a Tlag greater than 1.0 h and less than 16 h post-administration and a Tmax greater than (Tlag + 0.5 h) and less than 20 h post-administration, and if added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, the pH of the solution is lowered to no higher than 5.5.
Modified release solid oral composition free of disintegrant
A modified release solid oral composition comprising a core comprising an active pharmaceutical ingredient, coated acid particles with a water soluble coat where the acid is a pH lowering agent, an absorption enhancer, and a filler comprising a hydrogel-forming polymer with a specified viscosity, wherein the core is free of disintegrant, and wherein the active pharmaceutical ingredient, the coated acid particles, the absorption enhancer, and the filler are intermixed; and about 5 mg/cm2 to about 25 mg/cm2 of an enteric coating surrounding the core.
Oral administration with pharmacokinetic timing and pH lowering constraint
A method of treating a patient comprising providing the solid oral dosage form having the defined core and about 5 mg/cm2 to about 25 mg/cm2 of enteric coating, and orally administering the solid oral dosage form to provide a pharmacokinetic profile with a Tlag greater than 1.0 h and less than 16 h post-administration and a Tmax greater than (Tlag + 0.5 h) and less than 20 h post-administration, wherein if the composition was added to ten milliliters of 0.1 M aqueous sodium bicarbonate solution, the pH of the solution is lowered to no higher than 5.5.
Across the independent claims, protection is directed to modified release solid oral dosage forms for peptide, peptidomimetic, or small molecule actives in which a core containing coated pH-lowering acid particles, an absorption enhancer, and a hydrogel-forming polymer filler of specified viscosity, with very low disintegrant or no disintegrant, is surrounded by a defined amount of enteric coating. The dosage form is further characterized by constrained pharmacokinetic timing and by a sodium bicarbonate test pH lowering requirement.
Stated Advantages
Improved oral bioavailability of peptides and small molecules by controlling modified-release timing and minimizing release in the stomach/duodenum.
Reduced variability in oral performance by modulating dissolution/enteric coat and core design to shift Tlag and Tmax into the claimed ranges.
Documented Applications
A method of treating a patient by orally administering the claimed modified release solid oral dosage form for an active pharmaceutical ingredient that is a peptide, a peptidomimetic, a small molecule, or a combination thereof.
Pharmacokinetic release configured to deliver the pharmaceutical active ingredient to the jejunum, the ileum, or both.
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