Industrial update.

The current industry update covers the period 1-31 August 2014, with the information largely based on company press releases, and news from regulatory agencies, patents and various news websites. On the product approval front, Genzyme, The Medicines Company, Merck, Sharpe & Dohme Corporation, Genentech/Roche, and Boehringer Ingelheim-Eli Lilly reported approval of new products. There was promising news on the clinical trial front for the experimental vaccine to prevent the mosquito-borne viral disease 'chikungunya'. The recent multibillion-dollar deal in the pharma sector is the acquisition of InterMune Inc., a California-based biotech firm, by Roche Holding AG. Also, Cilag GmbH International has announced acquisition of Covagen AG, a privately-held biopharmaceutical company.

Chitosan-zinc-insulin complex incorporated thermosensitive polymer for controlled delivery of basal insulin in vivo.

Thermosensitive polymeric delivery system (PLA-PEG-PLA) loaded with chitosan-zinc-insulin complex was designed for continuous in vivo insulin delivery at basal level for prolonged period after a single subcutaneous injection. Chitosan-zinc-insulin complex was optimized to restrict the diffusion of insulin from the delivery system by forming large complexes and thereby reducing the initial burst release. The in vivo absorption and bioactivity of insulin released from the delivery systems were studied in streptozotocin-induced diabetic rat model. The amount of insulin released in vivo was quantified using the Enzyme Linked Immunosorbent Assay (ELISA), and its bioactivity was determined by its ability to reduce the blood glucose levels in diabetic rats. An indirect ELISA was performed to determine the immunogenic potential of insulin released from the formulations. Furthermore, the in vitro and in vivo biocompatibility of the delivery system was studied using an MTT assay, and by studying the histology of skin samples, respectively. Chitosan-zinc-insulin complex significantly (P<0.05) reduced the initial burst release of insulin from the polymeric delivery system in comparison to zinc-insulin or insulin alone. The delivery system released insulin for ~3 months in biologically active form with corresponding reduction in blood glucose levels in diabetic rats. The insulin released from the delivery systems did not provoke any immune response. The delivery systems demonstrated excellent biocompatibility both in vitro and in vivo and were non-toxic. The results indicate that the chitosan-zinc-insulin complex incorporated in the thermosensitive polymeric delivery system can be used as an alternative to the conventional daily basal insulin therapy.

Controlled delivery of basal level of insulin from chitosan-zinc-insulin-complex-loaded thermosensitive copolymer.

Present study was aimed at developing a delivery system for controlled release of insulin, based on chitosan-zinc-insulin complex incorporated into poly(lactic acid)-poly(ethylene glycol)-poly(lactic acid) (4500 Da) thermosensitive polymer. In vitro release of insulin from the delivery system was studied in phosphate-buffered saline (pH 7.4). The effect of zinc and chitosan on the stability of insulin in the delivery systems during release and storage at 4°C and 37°C was investigated. Circular dichroism, calorimetry, polyacrylamide gel electrophoresis (PAGE), high-performance liquid chromatography, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry were used to determine the stability of insulin released and extracted from the gel. A significant decrease (p < 0.05) in the initial burst was observed from the formulation containing chitosan-zinc-insulin complex, compared with all other formulations. The formulations containing chitosan-zinc-insulin complex showed a long-term controlled release (∼ 84 days) of insulin. Insulin released and extracted from the gel was conformationally and structurally stable. Bands at 12 kDa were observed in native PAGE, but sodium dodecyl sulfate-PAGE indicated noncovalent nature of insulin aggregates. Thus, the chitosan-zinc-insulin complex significantly reduced the initial burst release and prolonged the release of insulin. It also improved the stability of insulin in the delivery system and protected insulin from aggregation during the entire release period and storage.

Basal level insulin delivery: in vitro release, stability, biocompatibility, and in vivo absorption from thermosensitive triblock copolymers.

The major goal of this study was to develop the biodegradable and biocompatible thermosensitive polylactic acid-polyethylene glycol-polylactic acid triblock copolymer-based delivery systems for controlled release of basal level insulin for a longer duration after single subcutaneous injection. Insulin was dispersed into aqueous copolymer solutions to prepare the delivery system. The in vitro release profile of insulin from delivery systems was studied at 37°C in phosphate-buffered saline. Stability of released insulin was investigated using circular dichroism, differential scanning calorimetry, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry. A 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and skin histology were used to determine the in vitro and in vivo biocompatibility of the delivery systems, respectively. Streptozotocin-induced diabetic rat model was used to study the in vivo absorption and bioactivity of insulin. In vitro release studies indicated that the delivery systems released insulin over 3 months in structurally stable form. The delivery systems were biocompatible in vitro and in vivo. In vivo absorption and bioactivity studies demonstrated elevated insulin level and corresponding decreased blood glucose level in diabetic rats. Thus, the delivery systems released insulin at a controlled rate in vitro in conformationally and chemically stable form and in vivo in biologically active form up to 3 months.

Controlled delivery of basal insulin from phase-sensitive polymeric systems after subcutaneous administration: in vitro release, stability, biocompatibility, in vivo absorption, and bioactivity of insulin.

The purpose of this study was to investigate the phase-sensitive delivery systems (D,L-polylactide in triacetin) for controlled delivery of insulin at basal level. The effect of varying concentration of zinc, polymer, and insulin on the in vitro release of insulin was evaluated. Stability of released insulin was investigated by differential scanning calorimetry, circular dichroism, and matrix-assisted laser desorption/ionization time of flight mass spectrometry. In Vivo insulin absorption and bioactivity were studied in diabetic rats. In vitro and In Vivo biocompatibility of delivery systems were evaluated by 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide assay and skin histology, respectively. Extended release profiles of insulin for 2, 4, and 8 weeks from delivery systems containing 20%, 30%, and 40% (w/v) polymer concentration was observed. A ratio of 1:5 insulin hexamer to zinc was shown to be optimum. Physical and chemical stability of released insulin was greatly conserved. In Vivo studies demonstrated controlled release of insulin with reduction in blood glucose for approximately 1 month. In vitro and In Vivo studies demonstrated that the delivery system was biocompatible and controlled the delivery of insulin for longer durations after single subcutaneous injection.

In vivo absorption of steroidal hormones from smart polymer based delivery systems.

The purpose of this study was to develop smart polymer based controlled delivery systems to deliver steroidal hormones after single subcutaneous (s.c.) injection at predetermined rates over extended period of time. In vivo absorption and pharmacokinetics of levonorgestrel (LNG) and testosterone (TSN) were investigated from the thermosensitive and phase sensitive polymeric controlled delivery systems. A selective, reliable, and rapid method for determination of serum LNG concentration was developed using high-performance liquid chromatography-tandom mass spectrometry with atmospheric pressure chemical ionization interface (HPLC-MS-MS with APCI), while TSN in serum samples was detected and quantified by a competitive immunoassay. The delivery systems controlled the absorption of LNG in rabbits up to 6 weeks from thermosensitive and approximately 4 weeks from phase sensitive polymeric delivery systems. In vivo study of TSN delivery systems in castrated rabbits controlled the release of TSN for at least 2 months from both thermosensitive and phase sensitive polymers. Thermosensitive and phase sensitive polymer formulations significantly (p < 0.05) increased relative bioavailability of steroidal hormones compared to control. In conclusion, thermosensitive and phase sensitive polymer based delivery systems controlled the release in vivo in rabbits for longer duration after single s.c. injection.