Preparation of novel shell-ionotropically crosslinked micelles based on hexadecylamine and tripolyphosphate for cancer drug delivery.

AIMS: Micellar systems have the advantage of being easily prepared, cheap, and readily loadable with bioactive molecular cargo. However, their fundamental pitfall is poor stability, particularly under dilution conditions. We propose to use simple quaternary ammonium surfactants, namely, hexadecylamine (HDA) and hexadecylpyridinium (HDAP), together with tripolyphosphate (TPP) anion, to generate ionotropically stabilized micelles capable of drug delivery into cancer cells. METHODS: optimized mixed HDA/HDAP micelles were prepared and stabilized with TPP. Curcumin was used as a loaded model drug. The prepared nanoparticles were characterized by dynamic light scattering, infrared spectroscopy, transmission electron microscopy, and differential scanning calorimetry. Moreover, their cellular uptake was assessed using flow cytometry and confocal fluorescence microscopy. RESULTS: The prepared nanoparticles were found to be stable under dilution and at high temperatures and to have a size range from 139 nm to 580 nm, depending on pH (4.6-7.4), dilution (up to 100 times), and temperature (25 - 80 °C). They were effective at delivering their load into cancer cells. Additionally, flow cytometry indicated the resulting stabilized micellar nanoparticles to be non-cytotoxic. CONCLUSIONS: The described novel stabilized micelles are simple to prepare and viable for cancer delivery.

Content Analysis of US FDA Warning Letters Issued to Compounding Pharmacies Regarding Violations of Current Good Manufacturing Practices Between 2017 and 2022.

Purpose: Assessment of the US FDA-issued WLs content is an educational tool that can be used in the continuous training program of community pharmacists in compounding pharmacies. The study was designed to critically assess FDA warning letters (WLs) issued to compounding pharmacies in 2017-2022 for violations of Current Good Manufacturing Practices (cGMP). Methods: Content analysis was used to evaluate WLs issued concerning (1) type of violations; (2) frequency of violations mentioned in the WLs; (3) specific evaluations of the deviations related to compounded sterile products, and (4) evaluation of corrective measures requested by the US FDA. Results: A total of 141 WLs were evaluated. The main observed violations in the analyzed WLs were adulterated drug products (130), misbranded drugs (103), unapproved new drug products (42), failure to report adverse events (22), and failure to report drugs (11). Other violations were evaluated related to sterile product compounding with emphasis on personnel qualifications, quality control procedures, equipment, etc. Conclusion: The continuous issuance of WLs by the FDA indicates the need for compounding pharmacies become more vigilant to reduce the recurrence of the addressed violations through establishing adequate training/retraining programs. The analysis of issued WLs can serve as a learning tool to help improve compounding procedures, reduce the recurrence of these violations, and enhance patient safeguards. Supplementary Information: The online version contains supplementary material available at 10.1007/s12247-022-09692-4.

Recent advances on chitosan as an adjuvant for vaccine delivery.

Chitosan (CS) is a natural polymer derived from chitin that has wide applications in drugs, vaccines, and antigen delivery. The distinctive mucoadhesive, biocompatibility, biodegradable, and less toxic properties of chitosan compared to the currently used vaccine adjuvants made it a promising candidate for use as an adjuvant/carrier in vaccine delivery. In addition, chitosan exhibits intrinsic immunomodulating properties making it a suitable adjuvant in preparing vaccines delivery systems. Nanoparticles (NPs) of chitosan and its derivatives loaded with antigen have been shown to induce cellular and humoral responses. Versatility in the physicochemical properties of chitosan can provide an excellent opportunity to engineer antigen-specific adjuvant/delivery systems. This review discusses the recent advances of chitosan and its derivatives as adjuvants in vaccine deliveryand the published literature in the last fifteen years. The impact of physicochemical properties of chitosan on vaccine formulation has been described in detail. Applications of chitosan and its derivatives, their physicochemical properties, and mechanisms in enhancing immune responses have been discussed. Finally, challenges and future aspects of chitosan use has been pointed out.

Stable Chitosan-Based Nanoparticles Using Polyphosphoric Acid or Hexametaphosphate for Tandem Ionotropic/Covalent Crosslinking and Subsequent Investigation as Novel Vehicles for Drug Delivery.

Chitosan nanoparticles (NPs) are widely studied as vehicles for drug, protein, and gene delivery. However, lack of sufficient stability, particularly under physiological conditions, render chitosan NPs of limited pharmaceutical utility. The aim of this study is to produce stable chitosan NPs suitable for drug delivery applications. Chitosan was first grafted to phthalic or phenylsuccinic acids. Subsequently, polyphosphoric acid (PPA), hexametaphosphate (HMP), or tripolyphosphate (TPP) were used to achieve tandem ionotropic/covalently crosslinked chitosan NPs in the presence of 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). Thermal and infrared traits confirmed phosphoramide bonds formation tying chitosan with the polyphosphate crosslinkers within NPs matrices. DLS and TEM size analysis indicated spherical NPs with size range of 120 to 350 nm. The generated NPs exhibited excellent stabilities under harsh pH, CaCl2, and 10% FBS conditions. Interestingly, DLS, NPs stability and infrared data suggest HMP to reside within NPs cores, while TPP and PPA to act mainly as NPs surface crosslinkers. Drug loading and release studies using methylene blue (MB) and doxorubicin (DOX) drug models showed covalent PPA- and HMP-based NPs to have superior loading capacities compared to NPs based on unmodified chitosan, generated by ionotropic crosslinking only or covalently crosslinked by TPP. Doxorubicin-loaded NPs were of superior cytotoxic properties against MCF-7 cells compared to free doxorubicin. Specifically, DOX-loaded chitosan-phthalate polyphosphoric acid-crosslinked NPs exhibited 10-folds cytotoxicity enhancement compared to free DOX. The use of PPA and HMP to produce covalently-stabilized chitosan NPs is completely novel.

Degradability of chitosan micro/nanoparticles for pulmonary drug delivery.

Chitosan, a natural carbohydrate polymer, has long been investigated for drug delivery and medical applications due to its biodegradability, biocompatibility and low toxicity. The micro/nanoparticulate forms of chitosan are reported to enhance the efficiency of drug delivery with better physicochemical properties including improved solubility and bioavailability. This polymer is known to be biodegradable and biocompatible; however, crosslinked chitosan particles may not be biodegradable. Crosslinkers (e.g., tripolyphosphate and glutaraldehyde) are needed for efficient micro/nanoparticle formation, but it is not clear whether the resultant particles are biodegradable or able to release the encapsulated drug fully. To date, no studies have conclusively demonstrated the complete biodegradation or elimination of chitosan nanoparticles in vivo. Herein we review the synthesis and degradation mechanisms of chitosan micro/nanoparticles frequently used in drug delivery especially in pulmonary drug delivery to understand whether these nanoparticles are biodegradable.

Novel nanoparticles based on chitosan-dicarboxylate conjugates via tandem ionotropic/covalent crosslinking with tripolyphosphate and subsequent evaluation as drug delivery vehicles.

Chitosan-based nanoparticles prepared by ionotropic gelation are prone to stability issues. The aim of this work is to chemically modify chitosan by grafting to succinate, phthalate, glutarate and phenylsuccinate moieties and to investigate the suitability of the resulting polymers as covalently-crosslinked nanocarriers. Corresponding nanoparticles (NPs) were formulated by ionotropic gelation using tripolyphosphate (TPP) anion then they were covalently crosslinked using 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide (EDC). Infrared and thermal analysis confirmed the formation of phosphoramide bonds within the NPs indicating the involvement of TPP in covalent crosslinking. This is the first time to report phosphormide covalent crosslinking within nanoparticles matrices. The resulting NPs were found to resist drastic pH and calcium ion conditions. Size analysis indicated the NPs to be spherical and less than 500nm in diameter. Loading studies using Safranine O showed enhanced NPs drug loading upon covalent crosslinking compared to ionotropic gelling. Doxorubicin-loaded NPs were of superior cytotoxic properties compared to free doxorubicin.