Recently we discovered that two of the peptides currently used in commercial PLGA long-acting release depots (LARs), leuprolide and octreotide, long known to bind to the surface of uncapped PLGA (PLGA-COOH), can in fact be absorbed rapidly into the polymer phase of PLGA-COOH at high drug content with peptide desorption slow enough for potential long-term controlled release 9. Mechanistic analysis of peptide/PLGA interactions revealed a plausible solution to many of the above difficulties. This combination creates a number of undesirable issues: (a) the peptide-loaded microspheres most often cannot be terminally sterilized, thus requiring expensive aseptic processing with organic solvents and numerous unit operations (b) the API is expensive, and therefore it is undesired to discard poorly formed drug-polymer microspheres (tiny fines, large aggregated microspheres, or debris on mixing equipment) and yields can be far less than 100% (c) the complexity of unit operations and components necessary to form microspheres can be problematic to scale-up to large-scale manufacturing (d) some products have one or more residual organic solvents, which pose challenges to storage stability of the final products 5 (e) there is little opportunity to manipulate the polymer structure once the peptide-PLGA matrix is formed, limiting the ability to engineer release kinetics 6, 7 and (f) mixing organic solvent/water mixtures in the presence of peptides, particularly with higher-order structure, can be detrimental to drug stability 8. In each of these methods, the API is combined with PLGA dissolved in an organic solvent before forming microspheres. Microencapsulation has the advantages of much longer intervals between injections (>weeks to months) and no new active pharmaceutical ingredient (API) needs to be developed, thus reducing regulatory obstacles.Ĭonventional microencapsulation approaches to manufacture PLGA microspheres include solvent evaporation, coacervation, and spray-drying. Two common methods to improve systemic exposure and minimize injections of peptides include half-life extension via covalent modification and microencapsulation in biodegradable PLGA systems 3, 4. Once beyond a few amino acids peptides are often difficult to deliver to the body owing to poor bioavailability by noninvasive routes of drug administration and short serum half-lives 2. Peptide drugs with molecular weights from a few hundred to a few thousand Daltons form a unique class of drugs with both unique mechanisms of the pharmacological action and physical-chemical properties 1. Remote absorption encapsulation further removes the need for a critical organic solvent removal step after encapsulation, allowing for simple and cost-effective sterilization of the drug-free microspheres before encapsulation of the peptide. In certain cases, in vitro and in vivo performance of remote-loaded PLGA microspheres exceeded that relative to marketed products.
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The technique is generalizable to encapsulate a number of net cationic peptides of various size, including octreotide, with competitive loading and encapsulation efficiencies to traditional methods.
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Leuprolide encapsulated by this approach in low-molecular-weight PLGA 75/25 microspheres slowly and continuously released peptide for over 56 days in vitro and suppressed testosterone production in rats in an equivalent manner as the 1-month Lupron Depot®. We describe efficient organic-solvent-free remote encapsulation based on the capacity of common uncapped PLGA to bind and absorb into the polymer phase net positively charged peptides from aqueous solution after short exposure at modest temperature. Poly(lactic-co-glycolic acid) (PLGA) long-acting release depots are effective for extending the duration of action of peptide drugs.