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Advanced Healthcare Materials Apr 2022Poly(lactide-co-glycolide) (PLGA) has been extensively used in making long-acting injectable formulations. The critical factors affecting the PLGA formulation properties...
Poly(lactide-co-glycolide) (PLGA) has been extensively used in making long-acting injectable formulations. The critical factors affecting the PLGA formulation properties have been adjusted to control the drug release kinetics and obtain desirable properties of PLGA-based drug delivery systems. The PLGA microparticle formation begins as soon as the drug/PLGA-dissolved in the organic solvent phase (oil phase) is exposed to the water phase. The initial skin (or shell) formation on the oil droplets occurs very quickly, sometimes in the matter of milliseconds, and studying the process has been difficult. The skin formation on the PLGA emulsion droplet surface that can affect the subsequent hardening steps is examined. PLGA droplets with different compositions are prepared. Using collimated light and a high-speed camera made it possible to detect the diffusion of acetonitrile from the oil phase into the water phase during the oil droplet formation. Although the skin formation is not visible on the surface of the oil phase droplet with the current setup, the droplet shapes, solid strand formation, and the difference in the spreading time suggest that the initial contact time between the oil and water phases in the range of a few seconds is critical to the properties of the skin.
Topics: Drug Liberation; Emulsions; Microspheres; Particle Size; Polyglycolic Acid; Polylactic Acid-Polyglycolic Acid Copolymer
PubMed: 34601826
DOI: 10.1002/adhm.202101427 -
Vaccine Sep 2014Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of... (Review)
Review
Immunotherapeutic vaccines to drugs of abuse, including nicotine, cocaine, heroin, oxycodone, methamphetamine, and others are being developed. The theoretical basis of such vaccines is to induce antibodies that sequester the drug in the blood in the form of antibody-bound drug that cannot cross the blood brain barrier, thereby preventing psychoactive effects. Because the drugs are haptens a successful vaccine relies on development of appropriate hapten-protein carrier conjugates. However, because induction of high and prolonged levels of antibodies is required for an effective vaccine, and because injection of T-independent haptenic drugs of abuse does not induce memory recall responses, the role of adjuvants during immunization plays a critical role. As reviewed herein, preclinical studies often use strong adjuvants such as complete and incomplete Freund's adjuvant and others that cannot be, or in the case of many newer adjuvants, have never been, employed in humans. Balanced against this, the only adjuvant that has been included in candidate vaccines in human clinical trials to nicotine and cocaine has been aluminum hydroxide gel. While aluminum salts have been widely utilized worldwide in numerous licensed vaccines, the experience with human responses to aluminum salt-adjuvanted vaccines to haptenic drugs of abuse has suggested that the immune responses are too weak to allow development of a successful vaccine. What is needed is an adjuvant or combination of adjuvants that are safe, potent, widely available, easily manufactured, and cost-effective. Based on our review of the field we recommend the following adjuvant combinations either for research or for product development for human use: aluminum salt with adsorbed monophosphoryl lipid A (MPLA); liposomes containing MPLA [L(MPLA)]; L(MPLA) adsorbed to aluminum salt; oil-in-water emulsion; or oil-in-water emulsion containing MPLA.
Topics: Adjuvants, Immunologic; Aluminum Compounds; Emulsions; Freund's Adjuvant; Haptens; Humans; Lipid A; Lipids; Liposomes; Substance-Related Disorders; Vaccines
PubMed: 25111169
DOI: 10.1016/j.vaccine.2014.07.085 -
Scientific Reports Sep 2023Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of...
Neuroblastoma, the most common type of pediatric extracranial solid tumor, causes 10% of childhood cancer deaths. Despite intensive multimodal treatment, the outcomes of high-risk neuroblastoma remain poor. We urgently need to develop new therapies with safe long-term toxicity profiles for rapid testing in clinical trials. Drug repurposing is a promising approach to meet these needs. Here, we investigated disulfiram, a safe and successful chronic alcoholism treatment with known anticancer and epigenetic effects. Disulfiram efficiently induced cell cycle arrest and decreased the viability of six human neuroblastoma cell lines at half-maximal inhibitory concentrations up to 20 times lower than its peak clinical plasma level in patients treated for chronic alcoholism. Disulfiram shifted neuroblastoma transcriptome, decreasing MYCN levels and activating neuronal differentiation. Consistently, disulfiram significantly reduced the protein level of lysine acetyltransferase 2A (KAT2A), drastically reducing acetylation of its target residues on histone H3. To investigate disulfiram's anticancer effects in an in vivo model of high-risk neuroblastoma, we developed a disulfiram-loaded emulsion to deliver the highly liposoluble drug. Treatment with the emulsion significantly delayed neuroblastoma progression in mice. These results identify KAT2A as a novel target of disulfiram, which directly impacts neuroblastoma epigenetics and is a promising candidate for repurposing to treat pediatric neuroblastoma.
Topics: Animals; Child; Humans; Mice; Alcohol Deterrents; Cell Line, Tumor; Disulfiram; Down-Regulation; Drug Repositioning; Emulsions; Histone Acetyltransferases; Neuroblastoma
PubMed: 37777587
DOI: 10.1038/s41598-023-43219-2 -
International Journal of Nanomedicine 2023The aim of this study was to develop a liposome gel containing -tetrahydropalmatine (-THP) and evaluate its transdermal properties.
PURPOSE
The aim of this study was to develop a liposome gel containing -tetrahydropalmatine (-THP) and evaluate its transdermal properties.
METHODS
A L (4) orthogonal experiment was conducted to optimize the preparation of -THP liposomes and assess their characterization and stability in a gel. The transdermal features were analyzed through in vivo and in vitro experiments on rats and Strat-M membrane, respectively. The metabolism of -THP in liver and skin S9 fractions was also studied.
RESULTS
The optimization of the orthogonal experiment revealed that the ideal mass ratio of phosphatidylcholine, cholesterol, and -THP during preparation was 10:1:3. The resulting liposome exhibited a particle size of 68 nm, a PDI of 0.27, a drug loading of 4.33%, an encapsulation of 18.79%, and a zeta potential of -41.27 mV. Both the -THP and its liposome-gel formulation were found to be stable for a duration of 45 days at 4 °C and 30 °C. During the in vivo transdermal study, the maximum concentration (C) of -THP from the liposome gel was 0.16 μg/mL, and the time to reach this maximum concentration (t) was 1.2 hours. The relative bioavailability of -THP in the liposome gel was 233.8% compared to the emulsion. The concentration of -THP (prepared in PBS) decreased at a rate of 0.0067 μg/mL/min in the liver S9 fraction and 0.0027 μg/mL/min in the skin S9 fraction, however, this difference was not observed when -THP was encapsulated in liposomes. -THP passed through the Strat-M membrane at a rate of 0.0032 mg/cm/h and 0.002 mg/cm/h for the emulsion and liposome gel, respectively.
CONCLUSION
The optimal process for the preparation of -THP liposomes was obtained. Compared to the emulsion, the liposomes provided greater bioavailability when used transdermally. The liposomes also provided greater stability for -THP during storage.
Topics: Animals; Rats; Liposomes; Emulsions; Skin; Lecithins
PubMed: 37600118
DOI: 10.2147/IJN.S422305 -
Nutrients Jun 2018Intravenous lipid emulsions (ILEs) have been an integral component of parenteral nutrition for more than 50 years. Numerous formulations are available and are based on... (Review)
Review
Intravenous lipid emulsions (ILEs) have been an integral component of parenteral nutrition for more than 50 years. Numerous formulations are available and are based on vegetable (soybean, olive, coconut) and animal (fish) oils. Therefore, each of these formulations has a unique fatty acid composition that offers both benefits and limitations. As clinical experience and our understanding of the effects of fatty acids on various physiological processes has grown, there is evidence to suggest that some ILEs may have benefits compared with others. Current evidence suggests that olive oil-based ILE may preserve immune, hepatobiliary, and endothelial cell function, and may reduce lipid peroxidation and plasma lipid levels. There is good evidence from a large randomized controlled study to support a benefit of olive oil-based ILE over soybean oil-based ILE on reducing infections in critically ill patients. At present there is limited evidence to demonstrate a benefit of olive oil-based ILE over other ILEs on glucose metabolism, and few data exist to demonstrate a benefit on clinical outcomes such as hospital or intensive care unit stay, duration of mechanical ventilation, or mortality. We review the current research and clinical evidence supporting the potential positive biological and clinical aspects of olive oil-based ILE and conclude that olive oil-based ILE is well tolerated and provides effective nutritional support to various PN-requiring patient populations. Olive oil-based ILE appears to support the innate immune system, is associated with fewer infections, induces less lipid peroxidation, and is not associated with increased hepatobiliary or lipid disturbances. These data would suggest that olive oil-based ILE is a valuable option in various PN-requiring patient populations.
Topics: Biomarkers; Fat Emulsions, Intravenous; Humans; Lipid Peroxidation; Lipids; Olive Oil; Parenteral Nutrition
PubMed: 29914122
DOI: 10.3390/nu10060776 -
Medicine Sep 2022Localized senile pruritus is a continued health problem for the elderly. This study aimed to evaluate the efficacy and safety of artemether emulsion on localized senile... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Localized senile pruritus is a continued health problem for the elderly. This study aimed to evaluate the efficacy and safety of artemether emulsion on localized senile pruritus.
METHODS
Sixty patients diagnosed with senile pruritus were randomized into the artemether emulsion (1%) group or emulsion base group in a 1:1 ratio (the artemether group vs the control group). The patients used artemether emulsion or emulsion base for pruritus twice daily for 2 weeks. The pruritus visual analog scale (VAS) and the rate of adverse events were evaluated in week 0 and week 2.
RESULTS
The VAS scores in week 2 after treatment decreased significantly compared with those before treatment in both groups (P < .05). After treatment, patients receiving the artemether emulsion had significantly lower mean VAS scores compared to those who received the emulsion base (1.21 ± 1.64 vs 3.67 ± 2.97, P < .05). When the VAS scores were compared between the 2 groups before treatment, the effective rate of the artemether group was significantly higher than that of the control group (χ2 = 55, P < .05) in week 2 after treatment. Besides, no adverse events occurred in both groups.
CONCLUSIONS
Both artemether emulsion and emulsion base were effective in treating localized senile pruritus, and artemether emulsion was superior to emulsion base.
Topics: Aged; Artemether; Emulsions; Humans; Pilot Projects; Pruritus; Visual Analog Scale
PubMed: 36107571
DOI: 10.1097/MD.0000000000030472 -
Journal For Immunotherapy of Cancer Sep 2022Water-in-oil emulsion incomplete Freund's adjuvant (IFA) has been used as an adjuvant in preventive and therapeutic vaccines since its development. New generation,... (Review)
Review
Water-in-oil emulsion incomplete Freund's adjuvant (IFA) has been used as an adjuvant in preventive and therapeutic vaccines since its development. New generation, highly purified modulations of the adjuvant, Montanide incomplete seppic adjuvant (ISA)-51 and Montanide ISA-720, were developed to reduce toxicity. Montanide adjuvants are generally considered to be safe, with adverse events largely consisting of antigen and adjuvant dose-dependent injection site reactions (ISRs). Peptide vaccines in Montanide ISA-51 or ISA-720 are capable of inducing both high antibody titers and durable effector T cell responses. However, an efficient T cell response depends on the affinity of the peptide to the presenting major histocompatibility complex class I molecule, CD4 T cell help and/or the level of co-stimulation. In fact, in the therapeutic cancer vaccine setting, presence of a CD4 T cell epitope seems crucial to elicit a robust and durable systemic T cell response. Additional inclusion of a Toll-like receptor ligand can further increase the magnitude and durability of the response. Use of extended peptides that need a processing step only accomplished effectively by dendritic cells (DCs) can help to avoid antigen presentation by nucleated cells other than DC. Based on recent clinical trial results, therapeutic peptide-based cancer vaccines using emulsions in adjuvant Montanide ISA-51 can elicit robust antitumor immune responses, provided that sufficient tumor-specific CD4 T cell help is given in addition to CD8 T cell epitopes. Co-treatment with PD-1 T cell checkpoint inhibitor, chemotherapy or other immunomodulatory drugs may address local and systemic immunosuppressive mechanisms, and further enhance efficacy of therapeutic cancer peptide vaccines in IFA and its modern variants. Blinded randomized placebo-controlled trials are critical to definitively prove clinical efficacy. Mineral oil-based adjuvants for preventive vaccines, to tackle spread and severity of infectious disease, induce immune responses, but require more studies to reduce toxicity.
Topics: Humans; Adjuvants, Immunologic; Cancer Vaccines; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Emulsions; Immunotherapy; Neoplasms; Peptides; Vaccines, Subunit
PubMed: 36939214
DOI: 10.1136/jitc-2022-004709 -
Journal of Controlled Release :... Sep 2022Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the...
Two widely applied enabling drug delivery approaches, self-nanoemulsifying drug delivery systems (SNEDDS) and amorphous solid dispersions (ASD), were combined, with the aim of enhancing physical stability, solubilization and absorption of the model drug ritonavir. Ritonavir was loaded at a concentration above its saturation solubility (S) in the SNEDDS (superSNEDDS, 250% of S). An ASD of ritonavir with polyvinylpyrrolidone-vinyl acetate copolymers (Kollidon® VA64) was prepared by ball milling. Relevant control formulations, which include conventional SNEDDS (90% of S), superSNEDDS with a physical mix of Kollidon® VA64 and ritonavir (superSNEDDS+PM) and an aqueous suspension of ritonavir were used. A pharmacokinetic (PK) study in rats was performed to assess the relative bioavailability of ritonavir after oral administration. This was followed by evaluating the formulations in a novel two-step in vitro lipolysis model simulating rat gastric and intestinal conditions. The addition of a ritonavir containing ASD to superSNEDDS increased the degree of supersaturation from 250% to 275% S in the superSNEDDS and the physical stability (absence of drug recrystallization) of the system from 48 h to 1 month under ambient conditions. The PK study in rats displayed significantly higher C and AUC (3-fold increase) and faster T for superSNEDDS+ASD compared to the conventional SNEDDS whilst containing 3 times less lipid than the latter. Furthermore, superSNEDDS+ASD were able to keep the drug solubilised during in vitro lipolysis to the same degree as the conventional SNEDDS. These findings suggest that dissolving an ASD in a superSNEDDS can contribute to the development of novel oral delivery systems with increased bioavailability for poorly water-soluble drugs.
Topics: Administration, Oral; Animals; Biological Availability; Drug Delivery Systems; Emulsions; Lipids; Nanoparticles; Particle Size; Povidone; Rats; Ritonavir; Solubility; Water
PubMed: 35787914
DOI: 10.1016/j.jconrel.2022.06.057 -
Critical Care (London, England) Jul 2014The use of intravenous lipid emulsions (ILEs) as antidote in local anaesthetic systemic toxicity has gained widespread support following convincing data from animal... (Review)
Review
The use of intravenous lipid emulsions (ILEs) as antidote in local anaesthetic systemic toxicity has gained widespread support following convincing data from animal models, and successful case reports in humans. Proposed beneficial mechanisms of action for ILEs include intravascular sequestration of intoxicant and subsequent enhanced redistribution to biologically inert tissues, augmentation of fatty acid utilisation for ATP synthesis in the context of metabolic poisoning, and direct cardiotonic and ion channel effects. The evidence base for use of ILEs in acute drug intoxication is evolving. The present evidence supports use of ILEs only in local anaesthetic systemic toxicity and in lipophilic cardiotoxin intoxication when there is an immediate threat to life, and other therapies have proven ineffective.
Topics: Animals; Fat Emulsions, Intravenous; Humans; Poisoning; Resuscitation
PubMed: 25673255
DOI: 10.1186/s13054-014-0457-5 -
Molecules (Basel, Switzerland) Oct 2023Cannabidiol (CBD) is a promising natural agent for treating psoriasis. CBD activity is attributed to inhibition of NF-kB, IL-1β, IL-6, and IL-17A. The present study...
Cannabidiol (CBD) is a promising natural agent for treating psoriasis. CBD activity is attributed to inhibition of NF-kB, IL-1β, IL-6, and IL-17A. The present study evaluated the anti-psoriatic effect of cannabidiol in lipid-stabilized nanoparticles (LSNs) using an imiquimod (IMQ)-induced psoriasis model in mice. CBD-loaded LSNs were stabilized with three types of lipids, Cetyl alcohol (CA), Lauric acid (LA), and stearic-lauric acids (SALA), and were examined in-vitro using rat skin and in-vivo using the IMQ-model. LSNs loaded with coumarin-6 showed a localized penetration depth of about 100 µm into rat skin. The LSNs were assessed by the IMQ model accompanied by visual (psoriasis area severity index; PASI), histological, and pro-psoriatic IL-17A evaluations. Groups treated with CBD-loaded LSNs were compared to groups treated with CBD-containing emulsion, unloaded LSNs, and clobetasol propionate, and to an untreated group. CBD-loaded LSNs significantly reduced PASI scoring compared to the CBD emulsion, the unloaded LSNs, and the untreated group (negative controls). In addition, SALA- and CA-containing nanoparticles significantly inhibited IL-17A release, showing a differential response: SALA > CA > LA. The data confirms the effectiveness of CBD in psoriasis therapy and underscores LSNs as a promising platform for delivering CBD to the skin.
Topics: Mice; Rats; Animals; Interleukin-17; Cannabidiol; Emulsions; Psoriasis; Skin; Imiquimod; Nanoparticles; Lipids; Disease Models, Animal; Mice, Inbred BALB C
PubMed: 37836750
DOI: 10.3390/molecules28196907