Review of machine learning for lipid nanoparticle formulation and process development.

Lipid nanoparticles (LNPs) are a subset of pharmaceutical nanoparticulate formulations designed to encapsulate, stabilize, and deliver nucleic acid cargoes in vivo. Applications for LNPs include new interventions for genetic disorders, novel classes of vaccines, and alternate modes of intracellular delivery for therapeutic proteins. In the pharmaceutical industry, establishing a robust formulation and process to achieve target product performance is a critical component of drug development.

Injectable liposome-containing click hydrogel microparticles for release of macromolecular cargos.

Hydrogel microparticles ranging from 0.1-100 μm, referred to as microgels, are attractive for biological applications afforded by their injectability and modularity, which allows facile delivery of mixed populations for tailored combinations of therapeutics. Significant efforts have been made to broaden methods for microgel production including the materials and chemistries by which they are made.

Molecular Mechanism of Antimicrobial Excipient-Induced Aggregation in Parenteral Formulations of Peptide Therapeutics.

Antimicrobial preservatives are used as functional excipients in multidose formulations of biological therapeutics to destroy or inhibit the growth of microbial contaminants, which may be introduced by repeatedly administering doses. Antimicrobial agents can also induce the biophysical instability of proteins and peptides, which presents a challenge in optimizing the drug product formulation. Elucidating the structural basis for aggregation aids in understanding the underlying mechanism and can offer valuable knowledge and rationale for designing drug substances and drug products; however, this remains largely unexplored due to the lack of high-resolution characterization.

Inhibition of N-Nitrosamine Formation in Drug Products: A Model Study.

Nitrosamines, in the absence of toxicological data, are regarded as potential mutagens and need to be controlled at nanogram levels in drug products. Recent high profile product withdrawals have increased regulatory scrutiny of nitrosamine formation assessments for marketed products and for new drug applications. Formation of nitrosamine in drug product is possible when nitrite and vulnerable amines are present.

Antimicrobial Excipient-Induced Reversible Association of Therapeutic Peptides in Parenteral Formulations.

New classes of therapeutic peptides are being developed to prosecute biological targets which have been inaccessible to other modalities. Higher potency and longer half-life peptides have given rise to multiuse injectable formulations that enable convenient, low volume, and self-administered dosing; however, inclusion of antimicrobial preservatives to meet bactericidal requirements can impact other attributes of peptide formulations. Peptide-preservative interactions influencing solution-phase self-association of a non-insulin, linear, palmitoylated 31 amino acid peptide and two structurally similar peptides were assessed via turbidity, intrinsic fluorescence shifts and quenching, isothermal titration calorimetry, and H NMR.

In Situ Characterization of Pharmaceutical Formulations by Dynamic Nuclear Polarization Enhanced MAS NMR.

A principal advantage of magic angle spinning (MAS) NMR spectroscopy lies in its ability to determine molecular structure in a noninvasive and quantitative manner. Accordingly, MAS should be widely applicable to studies of the structure of active pharmaceutical ingredients (API) and formulations. However, the low sensitivity encountered in spectroscopy of natural abundance APIs present at low concentration has limited the success of MAS experiments.

Determining drug release rates of hydrophobic compounds from nanocarriers.

Obtaining meaningful drug release profiles for drug formulations is essential prior to in vivo testing and for ensuring consistent quality. The release kinetics of hydrophobic drugs from nanocarriers (NCs) are not well understood because the standard protocols for maintaining sink conditions and sampling are not valid owing to mass transfer and solubility limitations. In this work, a new in vitroassay protocol based on 'lipid sinks' and magnetic separation produces release conditions that mimic the concentrations of lipid membranes and lipoproteins in vivo, facilitates separation, and thus allows determination of intrinsic release rates of drugs from NCs.

Antitubercular Nanocarrier Combination Therapy: Formulation Strategies and in Vitro Efficacy for Rifampicin and SQ641.

Tuberculosis (TB) remains a major global health concern, and new therapies are needed to overcome the problems associated with dosing frequency, patient compliance, and drug resistance. To reduce side effects associated with systemic drug distribution and improve drug concentration at the target site, stable therapeutic nanocarriers (NCs) were prepared and evaluated for efficacy in vitro in Mycobacterium tuberculosis-infected macrophages. Rifampicin (RIF), a current, broad-spectrum antibiotic used in TB therapy, was conjugated by degradable ester bonds to form hydrophobic prodrugs.

Aerosol delivery of nanoparticles in uniform mannitol carriers formulated by ultrasonic spray freeze drying.

Purpose: While most examples of nanoparticle therapeutics have involved parenteral or IV administration, pulmonary delivery is an attractive alternative, especially to target and treat local infections and diseases of the lungs. We describe a successful dry powder formulation which is capable of delivering nanoparticles to the lungs with good aerosolization properties, high loadings of nanoparticles, and limited irreversible aggregation.

Methods: Aerosolizable mannitol carrier particles that encapsulate nanoparticles with dense PEG coatings were prepared by a combination of ultrasonic atomization and spray freeze drying.

Optimization of cell receptor-specific targeting through multivalent surface decoration of polymeric nanocarriers.

Treatment of tuberculosis is impaired by poor drug bioavailability, systemic side effects, patient non-compliance, and pathogen resistance to existing therapies. The mannose receptor (MR) is known to be involved in the recognition and internalization of Mycobacterium tuberculosis. We present a new assembly process to produce nanocarriers with variable surface densities of mannose targeting ligands in a single step, using kinetically-controlled, block copolymer-directed assembly.

Effects of block copolymer properties on nanocarrier protection from in vivo clearance.

Drug nanocarrier clearance by the immune system must be minimized to achieve targeted delivery to pathological tissues. There is considerable interest in finding in vitro tests that can predict in vivo clearance outcomes. In this work, we produce nanocarriers with dense PEG layers resulting from block copolymer-directed assembly during rapid precipitation.

Constant size, variable density aerosol particles by ultrasonic spray freeze drying.

This work provides a new understanding of critical process parameters involved in the production of inhalation aerosol particles by ultrasonic spray freeze drying to enable precise control over particle size and aerodynamic properties. A series of highly porous mannitol, lysozyme, and bovine serum albumin (BSA) particles were produced, varying only the solute concentration in the liquid feed, c(s), from 1 to 5 wt%. The particle sizes of mannitol, BSA, and lysozyme powders were independent of solute concentration, and depend only on the drop size produced by atomization.

Controlling drug nanoparticle formation by rapid precipitation.

Nanoparticles are a drug delivery platform that can enhance the efficacy of active pharmaceutical ingredients, including poorly-water soluble compounds, ionic drugs, proteins, peptides, siRNA and DNA therapeutics. To realize the potential of these nano-sized carriers, manufacturing processes must be capable of providing reproducible, scalable and stable formulations. Antisolvent precipitation to form drug nanoparticles has been demonstrated as one such robust and scalable process.

Novel method for concentrating and drying polymeric nanoparticles: hydrogen bonding coacervate precipitation.

Nanoparticles have significant potential in therapeutic applications to improve the bioavailability and efficacy of active drug compounds. However, the retention of nanometer sizes during concentrating or drying steps presents a significant problem. We report on a new concentrating and drying process for poly(ethylene glycol) (PEG) stabilized nanoparticles, which relies upon the unique pH sensitive hydrogen bonding interaction between PEG and polyacid species.

Protected peptide nanoparticles: experiments and brownian dynamics simulations of the energetics of assembly.

Soluble peptides, susceptible to degradation and clearance in therapeutic applications, have been formulated into protected nanoparticles for the first time through the process of kinetically controlled, block copolymer directed rapid precipitation using Flash NanoPrecipitation. Complementary Brownian dynamics simulations qualitatively model the nanoparticle formation process. The simulations corroborate the hypothesis that the size of nanoparticles decreases with increasing supersaturation.

Novel methods of targeted drug delivery: the potential of multifunctional nanoparticles.

Nanomaterials have been demonstrated as useful tools for molecular imaging, molecular diagnosis and targeted therapy in biomedical research. The main advantages of such nanomaterials are improved circulation times, precise targeting, enhancement of dissolution rates and enhanced contrast. A challenge and opportunity for nanotechnological strategies is that multiple functionalities, such as therapeutics, targeting, imaging and stimuli responsiveness can be achieved within one nanoparticle.