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Pharmaceutics Feb 2024This review provides a comprehensive overview of additive manufacturing (AM) or 3D-printing (3DP) applications in the pharmaceutical industry, with a particular focus on... (Review)
Review
This review provides a comprehensive overview of additive manufacturing (AM) or 3D-printing (3DP) applications in the pharmaceutical industry, with a particular focus on the critical role of polymer selection. By providing insights into how material properties influence the 3DP process and the quality of the final product, this review aims to contribute to a better understanding of the interplay between polymers and pharmaceutical 3DP. As 3DP technologies are increasingly integrated into pharmaceutical sciences, this review contributes insights into the nuanced process of polymer selection, serving mainly as a foundational guide for researchers and formulators new to the subject seeking to harness the full potential of pharmaceutical 3DP by understanding the physicochemical properties, roles, and functions of used polymers in 3D-printed dosage forms and medical devices.
PubMed: 38543211
DOI: 10.3390/pharmaceutics16030317 -
Journal of Virology Jul 2023Experimental simian immunodeficiency virus (SIV) infection of Asian macaques is an excellent model for HIV disease progression and therapeutic development. Recent...
Experimental simian immunodeficiency virus (SIV) infection of Asian macaques is an excellent model for HIV disease progression and therapeutic development. Recent coformulations of nucleoside analogs and an integrase inhibitor have been used for parenteral antiretroviral (ARV) administration in SIV-infected macaques, successfully resulting in undetectable plasma SIV RNA. In a cohort of SIVmac239-infected macaques, we recently observed that administration of coformulated ARVs resulted in an unexpected increase in plasma levels of soluble CD14 (sCD14), associated with stimulation of myeloid cells. We hypothesized that the coformulation solubilizing agent Kleptose (2-hydroxypropyl-β-cyclodextrin [HPβCD]) may induce inflammation with myeloid cell activation and the release of sCD14. Herein, we stimulated peripheral blood mononuclear cells (PBMCs) from healthy macaques with HPβCD from different commercial sources and evaluated inflammatory cytokine production . Treatment of PBMCs resulted in increased sCD14 release and myeloid cell interleukin-1β (IL-1β) production-with stimulation varying significantly by HPβCD source-and destabilized lymphocyte CCR5 surface expression. We further treated healthy macaques with Kleptose alone. , we observed modestly increased myeloid cell activation in response to Kleptose treatment without significant perturbation of the immunological transcriptome or epigenome. Our results demonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical coformulations. SIV infection of nonhuman primates is the principal model system for assessing HIV disease progression and therapeutic development. HPβCD has recently been incorporated as a solubilizing agent in coformulations of ARVs in SIV-infected nonhuman primates. Although HPβCD has historically been considered inert, recent findings suggest that HPβCD may contribute to inflammation. Herein, we investigate the contribution of HPβCD to healthy macaque inflammation and We observe that HPβCD causes an induction of sCD14 and IL-1β from myeloid cells and demonstrate that HPβCD stimulatory capacity varies by commercial source. , we observe modest myeloid cell activation in blood and bronchoalveolar lavage specimens absent systemic immune activation. From our findings, it is unclear whether HPβCD stimulation may improve or diminish immune reconstitution in ARV-treated lentiviral infections. Our results demonstrate a need for vehicle-only controls and highlight immunological perturbations that can occur when using HPβCD in pharmaceutical coformulations.
Topics: Animals; 2-Hydroxypropyl-beta-cyclodextrin; Disease Progression; Inflammation; Leukocytes, Mononuclear; Lipopolysaccharide Receptors; Macaca mulatta; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Viral Load
PubMed: 37338342
DOI: 10.1128/jvi.00600-23 -
Briefings in Bioinformatics Nov 2023Today, pharmaceutical industry faces great pressure to employ more efficient and systematic ways in drug discovery and development process. However, conventional...
Today, pharmaceutical industry faces great pressure to employ more efficient and systematic ways in drug discovery and development process. However, conventional formulation studies still strongly rely on personal experiences by trial-and-error experiments, resulting in a labor-consuming, tedious and costly pipeline. Thus, it is highly required to develop intelligent and efficient methods for formulation development to keep pace with the progress of the pharmaceutical industry. Here, we developed a comprehensive web-based platform (FormulationAI) for in silico formulation design. First, the most comprehensive datasets of six widely used drug formulation systems in the pharmaceutical industry were collected over 10 years, including cyclodextrin formulation, solid dispersion, phospholipid complex, nanocrystals, self-emulsifying and liposome systems. Then, intelligent prediction and evaluation of 16 important properties from the six systems were investigated and implemented by systematic study and comparison of different AI algorithms and molecular representations. Finally, an efficient prediction platform was established and validated, which enables the formulation design just by inputting basic information of drugs and excipients. FormulationAI is the first freely available comprehensive web-based platform, which provides a powerful solution to assist the formulation design in pharmaceutical industry. It is available at https://formulationai.computpharm.org/.
Topics: Artificial Intelligence; Drug Compounding; Algorithms; Drug Design; Internet
PubMed: 37991246
DOI: 10.1093/bib/bbad419 -
Pharmaceutics Aug 2023Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to... (Review)
Review
Intranasal delivery of drugs offers several potential benefits related to ease of delivery, rapid onset, and patient experience, which may be of particular relevance to patients with central nervous system (CNS) conditions who experience acute events. Intranasal formulations must be adapted to address anatomical and physiological characteristics of the nasal cavity, including restricted dose volume, limited surface area, and barriers to mucosal absorption, in addition to constraints on the absorption window due to mucociliary clearance. Development of an effective formulation may utilize strategies including the addition of excipients to address the physicochemical properties of the drug within the constraints of nasal delivery. Dodecyl maltoside (DDM) and tetradecyl maltoside are alkylsaccharide permeation enhancers with well-established safety profiles, and studies have demonstrated transiently improved absorption and favorable bioavailability of several compounds in preclinical and clinical trials. Dodecyl maltoside is a component of three US Food and Drug Administration (FDA)-approved intranasal medications: diazepam for the treatment of seizure cluster in epilepsy, nalmefene for the treatment of acute opioid overdose, and sumatriptan for the treatment of migraine. Another drug product with DDM as an excipient is currently under FDA review, and numerous investigational drugs are in early-stage development. Here, we review factors related to the delivery of intranasal drugs and the role of alkylsaccharide permeation enhancers in the context of approved and future intranasal formulations of drugs for CNS conditions.
PubMed: 37631332
DOI: 10.3390/pharmaceutics15082119 -
Micron (Oxford, England : 1993) Nov 2023Micro-computed tomography (micro-CT) provides valuable data for studying soft tissue, though it is often affected by sample movement during scans and low contrast in...
Micro-computed tomography (micro-CT) provides valuable data for studying soft tissue, though it is often affected by sample movement during scans and low contrast in X-ray absorption. This can result in lower image quality and geometric inaccuracies, collectively known as 'artefacts'. To mitigate these issues, samples can be embedded in hydrogels and enriched with heavy metals for contrast enhancement. However, the long-term durability of these enhancements remains largely unexplored. In this study, we examine the effects of two contrast enhancement agents - iodine and phosphotungstic acid (PTA) - and two hydrogels - agarose and Poloxamer 407 - over a 14-day period. We used Drosophila melanogaster as a test model for our investigation. Our findings reveal that PTA and agarose are highly durable, while iodine and poloxamer hydrogel exhibits higher leakage rates. These observations lay the foundation for estimating contrast stabilities in contrast-enhanced micro-CT with hydrogel embedding and serve to inform future research in this field.
Topics: Animals; Hydrogels; X-Ray Microtomography; Drosophila melanogaster; Sepharose; Iodine; Phosphotungstic Acid; Poloxamer
PubMed: 37660476
DOI: 10.1016/j.micron.2023.103533 -
Antiviral Research May 2024Currently, there are two approved vaccine regimens designed to prevent Ebola virus (EBOV) disease (EVD). Both are virus-vectored, and concerns about cold-chain storage...
Currently, there are two approved vaccine regimens designed to prevent Ebola virus (EBOV) disease (EVD). Both are virus-vectored, and concerns about cold-chain storage and pre-existing immunity to the vectors warrant investigating additional vaccine strategies. Here, we have explored the utility of adjuvanted recombinant glycoproteins (GPs) from ebolaviruses Zaire (EBOV), Sudan (SUDV), and Bundibugyo (BDBV) for inducing antibody (Ab) and T cell cross-reactivity. Glycoproteins expressed in insect cells were administered to C57BL/6 mice as free protein or bound to the surface of liposomes, and formulated with toll-like receptor agonists CpG and MPLA (agonists for TLR 9 and 4, respectively), with or without the emulsions AddaVax or TiterMax. The magnitude of Ab cross-reactivity in binding and neutralization assays, and T cell cross-reactivity in antigen recall assays, correlated with phylogenetic relatedness. While most adjuvants screened induced IgG responses, a combination of CpG, MPLA and AddaVax emulsion ("IVAX-1") was the most potent and polarized in an IgG2c (Th1) direction. Breadth was also achieved by combining GPs into a trivalent (Tri-GP) cocktail with IVAX-1, which did not compromise antibody responses to individual components in binding and neutralizing assays. Th1 signature cytokines in T cell recall assays were undetectable after Tri-GP/IVAX-1 administration, despite a robust IgG2c response, although administration of Tri-GP on lipid nanoparticles in IVAX-1 elevated Th1 cytokines to detectable levels. Overall, the data indicate an adjuvanted trivalent recombinant GP approach may represent a path toward a broadly reactive, deployable vaccine against EVD.
Topics: Animals; Mice; Ebolavirus; Hemorrhagic Fever, Ebola; Antibodies, Viral; Sudan; Phylogeny; Antibodies, Neutralizing; Mice, Inbred C57BL; Glycoproteins; Adjuvants, Immunologic; Ebola Vaccines; T-Lymphocytes; Cytokines; Polysorbates; Squalene
PubMed: 38458540
DOI: 10.1016/j.antiviral.2024.105851 -
Nutrients Dec 2023The incidence of Inborn Error of Intermediary Metabolism (IEiM) diseases may be low, yet collectively, they impact approximately 6-10% of the global population,... (Review)
Review
The incidence of Inborn Error of Intermediary Metabolism (IEiM) diseases may be low, yet collectively, they impact approximately 6-10% of the global population, primarily affecting children. Precise treatment doses and strict adherence to prescribed diet and pharmacological treatment regimens are imperative to avert metabolic disturbances in patients. However, the existing dietary and pharmacological products suffer from poor palatability, posing challenges to patient adherence. Furthermore, frequent dose adjustments contingent on age and drug blood levels further complicate treatment. Semi-solid extrusion (SSE) 3D printing technology is currently under assessment as a pioneering method for crafting customized chewable dosage forms, surmounting the primary limitations prevalent in present therapies. This method offers a spectrum of advantages, including the flexibility to tailor patient-specific doses, excipients, and organoleptic properties. These elements are pivotal in ensuring the treatment's efficacy, safety, and adherence. This comprehensive review presents the current landscape of available dietary products, diagnostic methods, therapeutic monitoring, and the latest advancements in SSE technology. It highlights the rationale underpinning their adoption while addressing regulatory aspects imperative for their seamless integration into clinical practice.
Topics: Child; Humans; Printing, Three-Dimensional; Technology; Excipients; Patient Compliance; Sensation
PubMed: 38201891
DOI: 10.3390/nu16010061 -
Human Vaccines & Immunotherapeutics Dec 2023MF59-adjuvanted H5N1, cell culture-derived inactivated influenza vaccine (aH5N1c, AUDENZ®, Seqirus) is available for persons 6 months of age and older. During a...
MF59-adjuvanted H5N1, cell culture-derived inactivated influenza vaccine (aH5N1c, AUDENZ®, Seqirus) is available for persons 6 months of age and older. During a pandemic, lack of preexisting immunity to novel influenza strains increases morbidity and mortality. This study examined the potential for an adjuvanted vaccine to provide cross-protection to novel viruses. Two similarly designed studies involving separate cohorts aged 18-64 and ≥65 y assessed immune responses to five heterologous H5N1 influenza strains elicited by two 7.5 μg doses of aH5N1c given 3 weeks apart. Geometric mean titers (GMT) on Days 1 and 43 and Day 43/Day 1 geometric mean ratios (GMRs) were determined with hemagglutination inhibition (HI) and microneutralization (MN). Rates of seroconversion (SC) and percentages of subjects with HI and MN ≥ 1:40 were determined. Significant increases in GMTs were observed on Day 43 after vaccination for all 5 heterologous strains in all ages tested. SC rates were 28-55% and 17-46% among those aged 18-64 and ≥65 y, respectively. MN ≥ 1:40 was observed in 38-100% of younger and 37-97% of older subjects, and HI ≥ 1:40 was achieved by 28-64% of subjects aged 18-64 y and by 17-57% of subjects aged ≥65 y. A SC rate ≥40% (97.5% CI) was met for two heterologous strains tested in adults aged 18-64 y. In adults aged 18-64 and ≥65 y, two 7.5 μg doses of aH5N1c demonstrated increased immunogenicity from baseline against five heterologous H5N1 strains, illustrating the potential for aH5N1c to provide cross-protection against other H5N1 strains.
Topics: Humans; Aged; Influenza Vaccines; Influenza, Human; Influenza A Virus, H5N1 Subtype; Antibody Formation; Antibodies, Viral; Polysorbates; Squalene; Adjuvants, Immunologic; Hemagglutination Inhibition Tests; Cell Culture Techniques; HIV Seropositivity
PubMed: 37057755
DOI: 10.1080/21645515.2023.2193119 -
Communications Chemistry Feb 2024Protein solubility and stability depend on the co-solutes present. There is little theoretical basis for selection of suitable co-solutes. Some guidance is provided by...
Protein solubility and stability depend on the co-solutes present. There is little theoretical basis for selection of suitable co-solutes. Some guidance is provided by the Hofmeister series, an empirical ordering of anions according to their effect on solubility and stability; and by osmolytes, which are small organic molecules produced by cells to allow them to function in stressful environments. Here, NMR titrations of the protein barnase with Hofmeister anions and osmolytes are used to measure and locate binding, and thus to separate binding and bulk solvent effects. We describe a rationalisation of Hofmeister (and inverse Hofmeister) effects, which is similar to the traditional chaotrope/kosmotrope idea but based on solvent fluctuation rather than water withdrawal, and characterise how co-solutes affect protein stability and solubility, based on solvent fluctuations. This provides a coherent explanation for solute effects, and points towards a more rational basis for choice of excipients.
PubMed: 38418894
DOI: 10.1038/s42004-024-01127-0 -
Asian Pacific Journal of Allergy and... Sep 2023Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse... (Review)
Review
BACKGROUND
Erythropoiesis-stimulating agents (ESA) are commonly used in clinical practice to improve anaemia. Despite a number of patients successfully treated without adverse events, the complications have been previously reported.
OBJECTIVE
To report and review the characteristics and management of ESA hypersensitivities.
METHODS
Case reports and related articles associated with ESA use, published between January 1999 and December 2018, were retrieved through Electronic databases (MEDLINE® and PubMed®).
RESULTS
Forty-seven ESA patients with various immediate and delayed hypersensitivity reactions caused by epoetin and pharmaceutical excipients were identified from nineteen studies and one case report in this paper. Fatal hypersensitivity to ESA and ESA-allergic cross-reactivities have been documented. Desensitization or change of EPO molecular structure has been reported as successful methods of re-introducing the drug.
CONCLUSIONS
ESA hypersensitivity in the various allergic reactions and cross-reactivity have been documented. Desensitization and Epoetin structural changes could be successful methods to re-introduce the drug.
Topics: Humans; Epoetin Alfa; Darbepoetin alfa; Hematinics; Anemia; Pruritus; Recombinant Proteins
PubMed: 32563229
DOI: 10.12932/AP-040719-0592