The anatomical site of subcutaneous injection influences the rate of absorption and bioavailability of rituximab in rats. Saturable binding may be a major determinant of the nonlinear absorptive transport of monoclonal antibodies.

Biotherapeutics is a rapidly growing drug class, and over 200 biotherapeutics have already obtained approval, with about 50 of these being approved in 2015 and 2016 alone. Several hundred protein therapeutic products are still in the pipeline, including interesting new approaches to treatment. Owing to patients' convenience of at home administration and reduced number of hospital visits as well as the reduction in treatment costs, subcutaneous (SC) administration of biologics is of increasing interest. Although several avenues for treatment using biotherapeutics are being explored, there is still a sufficient gap in knowledge regarding the interplay of formulation conditions, immunogenicity, and pharmacokinetics (PK) of the absorption of these compounds when they are given SC. This review seeks to highlight the major concerns and important factors governing this route of administration and suggest a holistic approach for effective SC delivery.

Subcutaneous administration of biologics is highly desirable; however, incomplete bioavailability after sc administration remains a major challenge. In this work we investigated the effects of excipient dependent hyper-osmolarity on lymphatic uptake and plasma exposure of rituximab as a model protein. Using Swiss Webster (SW) mice as our animal model, we compared the effects of NaCl, mannitol and, O-Phospho-L-Serine (OPLS) on plasma concentration of rituximab over 5 days after sc administration. We observed an increase in plasma concentrations in animals administered rituximab in hypertonic buffer solutions, as compared to isotonic buffer. Bioavailability, as estimated by our pharmacokinetic model, increased from 29% in isotonic buffer to 54% in hypertonic buffer containing NaCl, to almost complete bioavailability in hypertonic buffers containing high dose OPLS or mannitol. This improvement in plasma exposure is due to improved lymphatic trafficking as evident from the increase in the fraction of dose trafficked through the lymph node in the presence of hypertonic buffers. The fraction of the dose trafficked through the lymphatic, as estimated by the model, increased from 0.05 % in isotonic buffer to 13% in hyper-tonic buffer containing NaCl to about 30% for hypertonic buffers containing high dose OPLS and mannitol. Our data suggests that hypertonic solutions may be a viable option to improve sc bioavailability.

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Indoles having an ester functionality in the 3-position were prepared from 2-(2-nitrophenyl)propenoic acid derivatives via a palladium-catalyzed reductive N-heteroannulation using carbon monoxide as the ultimate reducing agent. The starting materials were prepared either by a Stille coupling of 2-halo-1-nitrobenzenes with ethyl 2-(tributylstannyl)-2-propenoate or by vicarious nucleophilic substitution of nitrobenzenes followed by a Knoevenageltype condensation with an aldehyde. Synthesis of an example of a 3-nitrile-and a 3-sulfone-substituted indole is also described using the same type of methodologies.