Effect of Co-Solvents on the Controlled Release of Calcitonin Polypeptide fromIn SituBiodegradable Polymer Implants

Abstract

The objective of this study was to design an in situ biodegradable polymer implant controlled-release drug delivery system, using novel combinations of co-solvents and a model polypeptide, calcitonin (CT), and to assess the release of drug as a function of these co-solvents. Formulations were prepared by dissolving/ suspending CT polypeptide in poly-(lactic acid) (PLA) polymer solutions/suspensions containing combinations of a hydrophobic (benzyl benzoate, BB) and a hydrophilic (benzyl alcohol, BA) solvent. The CT-PLA mixtures were each injected into test tubes containing phosphate buffered saline solution to form the in situ implant and sampling was conducted over a 28-day period. The samples were analyzed for drug content using a modified Lowry protein assay procedure. Cumulative drug release demonstrated a rank-order correlation depending on the amount of the hydrophobic (BB) and hydrophilic (BA) solvents within each system. Increasing the amounts of the hydrophobic solvent, BB, in formulations demonstrated a 1.2-4.4-fold increase in CT release. Stability studies of all formulations over a 4-month period showed progressive increase in degradation of the CT polypeptide, especially at 37 degrees C, but a slower degradation pattern prevailed at 4 degrees and 20 degrees C. Differential scanning calorimetric studies revealed a homogenous mixture of drug in the polymer matrix. Overall, these studies demonstrated the feasibility of designing controlled release systems capable of releasing a polypeptide drug as a function of influence of different co-solvent combinations.

Cosolvent Effects on the Drug Release and Depot Swelling in Injectable In situ Depot-Forming Systems

“…Benzyl benzoate (BB) as a hydrophobic solvent and benzyl alcohol (BA) as a hydrophilic solvent have been used as the mixed solvents to understand the effect of the characteristics of the mixed solvents on the drug delivery. However, some of the results were conflicting with respect to drug release 21,24. Higher burst drug release was found in formulations containing greater proportion of BA as reported by Singh and Singh,24 whereas the release of the drug was slowed when the hydrophilic component BA was increased as reported by Prabhu et al21 These observations were not rationalized or reconciled sufficiently, in our opinion, primarily due to lack of complementary experimentation.…”

“…The burst release can also be controlled by adjusting solvent characteristics to tune the rate of water migration into the polymer matrix 21. The preferred solvents in an injectable biodegradable drug delivery systems are NMP and dimethyl sulfoxide (DMSO) because of their pharmaceutical precedence13; however, NMP or DMSO, being hydrophilic, dissipates into surrounding aqueous medium quickly after injection upon contact with water and thus causes the polymer solution to exhibit rapid phase inversion associated with a high burst release and formation of a porous, solid depot structure.…”

Thermosensitive Drug Delivery System of Salmon Calcitonin: In Vitro Release, In Vivo Absorption, Bioactivity and Therapeutic Efficacies

“…Duros implant system was reported to sustain the release of sCT over 4 months, but unfortunately, this system requires a surgical implantation and explantation (12). Thereafter, many investigations were carried out to achieve the goal of controlling the release of sCT using poly (D,L lactide-co-glycolide) or poly(D,L-lactide) polymersbased microsphere, poly(ethylene glycol)-terephthalate film, and surface-modified lipid nanoparticles (13)(14)(15)(16)(17). Although the investigations made improvements in the controlled delivery of sCT, these systems are still unsatisfactory because of the short release duration, large burst release, peptide degradation during manufacturing process, and incomplete release.…”

Nanoparticulate delivery of novel drug combination regimens for the chemoprevention of colon cancer

“…Novel modes of delivery methods using microsphere and nanosphere technology (10,11) are receiving wide attention as these have shown superior delivery compared to conventional dosage forms. Despite evidence of benefits of such carrier systems, its application in chemoprevention has never been studied, demonstrating a need for research in this area.…”