Patient-Centric Long-Acting Injectable and Implantable Platforms─An Industrial Perspective.

The increasing focus on patient centricity in the pharmaceutical industry over the past decade and the changing healthcare landscape, driven by factors such as increased access to information, social media, and evolving patient demands, has necessitated a shift toward greater connectivity and understanding of patients' unique treatment needs. One pharmaceutical technology that has supported these efforts is long acting injectables (LAIs), which lower the administration frequency for the patient's provided convenience, better compliance, and hence better therapeutical treatment for the patients. Furthermore, patients with conditions like the human immunodeficiency virus and schizophrenia have positively expressed the desire for less frequent dosing, such as that obtained through LAI formulations.

Long-Acting Injectable Aqueous Suspensions-Summary From an AAPS Workshop.

Through many years of clinical application of long-acting injectables, there is clear proof that this type of formulation does not just provide the patient with convenience, but more importantly a more effective treatment of the medication provided. The formulation approach therefore contains huge untapped potential to improve the quality of life of many patients with a variety of different diseases. This review provides a summary of some of the central talks provided at the workshop with focus on aqueous suspensions and their use as a long-acting injectable.

Fibrillar pharmacology of functionalized nanocellulose.

Cellulose nanocrystals (CNC) are linear organic nanomaterials derived from an abundant naturally occurring biopolymer resource. Strategic modification of the primary and secondary hydroxyl groups on the CNC introduces amine and iodine group substitution, respectively. The amine groups (0.

A Genomic Profile of Local Immunity in the Melanoma Microenvironment Following Treatment with α Particle-Emitting Ultrasmall Silica Nanoparticles.

An α particle-emitting nanodrug that is a potent and specific antitumor agent and also prompts significant remodeling of local immunity in the tumor microenvironment (TME) has been developed and may impact the treatment of melanoma. Biocompatible ultrasmall fluorescent core-shell silica nanoparticles (C' dots, diameter ∼6.0 nm) have been engineered to target the melanocortin-1 receptor expressed on melanoma through α melanocyte-stimulating hormone peptides attached to the C' dot surface.

Carbon nanotubes exhibit fibrillar pharmacology in primates.

Nanomedicine rests at the nexus of medicine, bioengineering, and biology with great potential for improving health through innovation and development of new drugs and devices. Carbon nanotubes are an example of a fibrillar nanomaterial poised to translate into medical practice. The leading candidate material in this class is ammonium-functionalized carbon nanotubes (fCNT) that exhibits unexpected pharmacological behavior in vivo with important biotechnology applications.

Deconvoluting hepatic processing of carbon nanotubes.

Single-wall carbon nanotubes present unique opportunities for drug delivery, but have not advanced into the clinic. Differential nanotube accretion and clearance from critical organs have been observed, but the mechanism not fully elucidated. The liver has a complex cellular composition that regulates a range of metabolic functions and coincidently accumulates most particulate drugs.

Targeted fibrillar nanocarbon RNAi treatment of acute kidney injury.

RNA interference has tremendous yet unrealized potential to treat a wide range of illnesses. Innovative solutions are needed to protect and selectively deliver small interfering RNA (siRNA) cargo to and within a target cell to fully exploit siRNA as a therapeutic tool in vivo. Herein, we describe ammonium-functionalized carbon nanotube (fCNT)-mediated transport of siRNA selectively and with high efficiency to renal proximal tubule cells in animal models of acute kidney injury (AKI).

Synthesis, pharmacokinetics, and biological use of lysine-modified single-walled carbon nanotubes.

We aimed to create a more robust and more accessible standard for amine-modifying single-walled carbon nanotubes (SWCNTs). A 1,3-cycloaddition was developed using an azomethine ylide, generated by reacting paraformaldehyde and a side-chain-Boc (tert-Butyloxycarbonyl)-protected, lysine-derived alpha-amino acid, H-Lys(Boc)-OH, with purified SWCNT or C60. This cycloaddition and its lysine adduct provides the benefits of dense, covalent modification, ease of purification, commercial availability of reagents, and pH-dependent solubility of the product.

Sodium phosphaethynolate as a building block for heterocycles.

Phosphorus-containing heterocycles have evolved from laboratory curiosities to functional components, such as ligands in catalytically active metal complexes or molecular constituents in electronic devices. The straightforward synthesis of functionalized heterocycles on a larger scale remains a challenge. Herein, we report the use of the phosphaethynolate (OCP)(-) anion as a building block for various sterically unprotected and functionalized hydroxy substituted phosphorus heterocycles.

Carbon nanotubes as vaccine scaffolds.

Carbon nanotubes display characteristics that are potentially useful in their development as scaffolds for vaccine compositions. These features include stability in vivo, lack of intrinsic immunogenicity, low toxicity, and the ability to be appended with multiple copies of antigens. In addition, the particulate nature of carbon nanotubes and their unusual properties of rapid entry into antigen-presenting cells, such as dendritic cells, make them especially useful as carriers of antigens.

Deploying RNA and DNA with Functionalized Carbon Nanotubes.

Carbon nanotubes internalize into cells and are potential molecular platforms for siRNA and DNA delivery. A comprehensive understanding of the identity and stability of ammoniumfunctionalized carbon nanotube (f-CNT)-based nucleic acid constructs is critical to deploying them in vivo as gene delivery vehicles. This work explored the capability of f-CNT to bind single- and double-strand oligonucleotides by determining the thermodynamics and kinetics of assembly and the stoichiometric composition in aqueous solution.

Synthesis and characterization of terminal [Re(XCO)(CO)2(triphos)] (X=N, P): isocyanate versus phosphaethynolate complexes.

The terminal rhenium(I) phosphaethynolate complex [Re(PCO)(CO)(2)(triphos)] has been prepared in a salt metathesis reaction from Na(OCP) and [Re(OTf)(CO)(2)(triphos)]. The analogous isocyanato complex [Re(NCO)(CO)(2)(triphos)] has been likewise prepared for comparison. The structure of both complexes was elucidated by X-ray diffraction studies.

Synthesis and characterization of the copper(II) complexes of new N2S2-donor macrocyclic ligands: synthesis and in vivo evaluation of the (64)Cu complexes.

The aim of this work was to prepare a novel class of (64)Cu(II) labeled complexes with the new macrocyclic ligands 1,10-dithia-4,7-diazacyclododecane-3,8-dicarboxylic acid (NEC-SE, 1), 1,10-dithia-4,7-diazacyclotridecane-3,8-dicarboxylic acid (NEC-SP, 2) and 1,10-dithia-4,7-diazacyclotetradecane-3,8-dicarboxylic acid, (NEC-SB, 3 ) to evaluate the usefulness of these macrocycles for potential utility as (64)Cu(II) chelators. The corresponding non-radioactive complexes [Cu(NEC-SE)] x 3H(2)O (4), [Cu(NEC-SP)] x 3H(2)O (5) and [Cu(NEC-SB)] (6) were prepared and their (64)Cu-analogs, [(64)Cu(NEC-SE)] (7) and [(64)Cu(NEC-SP)] (8) and [(64)Cu(NEC-SB)] (9) were produced in >98% radiochemical purity. Rats were injected with complex 7, 8 or 9 and were euthanized at 1, 4 and 24 h.

Synthesis, in vitro and in vivo characterization of (64)Cu(I) complexes derived from hydrophilic tris(hydroxymethyl)phosphane and 1,3,5-triaza-7-phosphaadamantane ligands.

Four novel (64)Cu complexes ([(64)Cu(thp)(4)](+) (1), [(64)Cu(TPA)(4)](+) (2), [HC(CO(2))(pz(Me2))(2) (64)Cu(thp)(2)] (3) and [HC(CO(2))(tz)(2) (64)Cu(thp)(2)] (4), [where thp is tris(hydroxymethyl)phosphine, TPA is 1,3,5-triaza-7-phosphaadamantane, pz(Me2) is 3,5-dimethylpyrazole and tz is 1,2,4-triazole] were successfully synthesized and characterized. The complexes were produced in high radiochemical purity and yield (more than 98%) without the need for further purification. Their logP values and serum stabilities were measured and in vitro behavior was observed in cultured EMT-6 cells.

Silver(I)-organophosphane complexes of electron withdrawing CF3- or NO2-substituted scorpionate ligands.

New silver(I) complexes have been synthesized from the reaction of AgNO(3), monodentate tertiary phosphanes PR(3) (PR(3) = P(C(6)H(5))(3), P(o-C(6)H(4)CH(3))(3), P(m-C(6)H(4)CH(3))(3), P(p-C(6)H(4)CH(3))(3), PCH(3)(C(6)H(5))(2)) and two novel electron withdrawing ligands: potassium dihydrobis(3-nitropyrazol-1-yl)borate and potassium dihydrobis(3-trifluoromethylpyrazol-1-yl)borate. These compounds have been characterized by elemental analyses, FT-IR, ESI-MS and multinuclear ((1)H, (19)F and (31)P) NMR spectroscopy. Solid state structures of the potassium salts K[H(2)B(3-(NO(2))pz)(2)] and K[H(2)B(3-(CF(3))pz)(2)] have been reported.

Small scorpionate ligands: silver(I)-organophosphane complexes of 5-CF(3)-substituted scorpionate ligand combining a B-H...Ag coordination motif.

The first 5-substituted trihydro(azolyl)borate system, the sodium trihydro(5-CF3-pyrazol-1-yl)borate, Na[H3B(5-(CF3)pz)], has been synthesized by the reaction of 3-trifuoromethyl-pyrazole with NaBH4 in high yield. Na[H3B(5-(CF3)pz)] reacts with AgNO3 in the presence of monodentate tertiary phosphanes PR3 (PR3=P(C6H5)3, P(p-C6H4CH3)3, P(m-C6H4CH3)3, P(o-C6H4CH3)3, or PCH3(C6H5)2) to afford silver(I) bis(phosphane) adducts. These compounds have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H, 19F, and 31P) NMR spectroscopy.

Synthesis, characterization, and in vitro antitumor properties of tris(hydroxymethyl)phosphine copper(I) complexes containing the new bis(1,2,4-triazol-1-yl)acetate ligand.

The new sodium bis(1,2,4-triazol-1-yl)acetate ligand, Na[HC(CO(2))(tz)(2)], has been prepared in methanol solution by using 1,2,4-triazole, dibromoacetic acid, and NaOH. Treatment of the [Cu(CH(3)CN)(4)][PF(6)] acceptor with Na[HC(CO(2))(tz)(2)] or Na[HC(CO(2))[(pz(Me2))(2)] in the presence of the tris(hydroxymethyl)phosphine coligand in methanol/acetonitrile solutions produced unprecedented mononuclear copper(I) complexes of the [L(n)]Cu[P(CH(2)OH)(3)](2) (L(1), 2; L(2), 3) [(CH(3)CN)(2)Cu(P(CH(2)OH)(3))(2)]PF(6), 4. These compounds have been characterized by elemental analyses, FTIR, ESI-MS, and multinuclear (1H and 31P) NMR spectral data.

New copper(I) phosphane complexes of dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand showing cytotoxic activity.

New copper(I) complexes of the type [H(2)B(tz(NO2))(2)]Cu[PR(3)](2) (1-5), [H(2)B (tz(NO2))(2)]Cu[dppe] (6) and [H(2)B(tz(NO2))(2)]Cu[PR(3)] (7, 8) have been synthesized from the reaction of CuCl, potassium dihydrobis(3-nitro-1,2,4-triazol-1-yl)borate, K[H(2)B (tz(NO2))(2)], and mono- or bi-dentate tertiary phosphanes. The complexes obtained have been characterized by elemental analyses and FT-IR in the solid state, and by NMR ((1)H and (31)P{(1)H}) spectroscopy in solution. Selected complexes 1, 3 and 5 have also been tested against a panel of several human tumor cell lines in order to evaluate their cytotoxic activity.

The first nitro-substituted heteroscorpionate ligand.

The new dihydridobis(3-nitro-1,2,4-triazolyl)borate ligand, [H2B(tzNO2)2]-, has been synthesized in dimethylacetamide solution, using 3-nitro-1,2,4-triazole and KBH4 through careful temperature control, and characterized as its potassium salt. The zinc(II) and cadmium(II) complexes, {M[H2B(tzNO2)2]Cl(H2O)2}, have been prepared by metathesis of [H2B(tzNO2)2]K with ZnCl2 and CdCl2, respectively. The complexes likely contain a metal core in which the ligand is coordinated to the metal ions in the K2-N,N' or K4-N,N',O,O' fashion.