Advancing liposome technology for innovative strategies against malaria.

This review discusses the potential of liposomes as drug delivery systems for antimalarial therapies. Malaria continues to be a significant cause of mortality and morbidity, particularly among children and pregnant women. Drug resistance due to patient non-compliance and troublesome side effects remains a significant challenge in antimalarial treatment. Liposomes, as targeted and efficient drug carriers, have garnered attention owing to their ability to address these issues. Liposomes encapsulate hydrophilic and/or hydrophobic drugs, thus providing comprehensive and suitable therapeutic drug delivery. Moreover, the potential of passive and active drug delivery enables drug concentration in specific target tissues while reducing adverse effects. However, successful liposome formulation is influenced by various factors, including drug physicochemical characteristics and physiological barriers encountered during drug delivery. To overcome these challenges, researchers have explored modifications in liposome nanocarriers to achieve efficient drug loading, controlled release, and system stability. Computational approaches have also been adopted to predict liposome system stability, membrane integrity, and drug-liposome interactions, improving formulation development efficiency. By leveraging computational methods, optimizing liposomal drug delivery systems holds promise for enhancing treatment efficacy and minimizing side effects in malaria therapy. This review consolidates the current understanding and highlights the potential of liposome strategies against malaria.

The effect of chitosan addition on cellular uptake and cytotoxicity of ursolic acid niosomes.

This study evaluated the cellular uptake and cytotoxicity of low permeable Ursolic acid (UA) on cancer cells using niosomes composed of span 60 and cholesterol. The results showed that the addition of chitosan increased particle sizes and ζ-potentials. The UA niosomes with chitosan layers had higher cytotoxicity in HeLa cells than without chitosan, however, there was no improvement observed for Huh7it cells. Moreover, chitosan layers improved the cellular uptake, which clathrin-mediated endocytosis may determine the cellular transport of UA niosomes. In conclusion, the addition of chitosan improved cellular uptake and cytotoxicity of UA niosomes in the HeLa cells.

Cellulose- and Saccharide-Based Orally Dispersible Thin Films Transform the Solid States and Dissolution Characteristics of Poorly Soluble Curcumin.

This study aimed at developing and optimizing the orally dispersible thin film (ODTF) containing a plant-derived drug-curcumin (CUR). CUR belongs to a biopharmaceutical classification system (BCS) class IV compound that requires improving its water solubility and tissue permeability preceding formulation. An ODTF was applied to produce a solid dispersion matrix for CUR to resolve such solubility and permeability problems. The film-forming polymers used in the study were cellulose-based (hydroxypropyl methylcellulose/HPMC and carboxymethylcellulose/CMC) and saccharide-based maltodextrin (MDX). Poloxamer (POL) was also employed as surfactant and solubilizer. The solvent casting technique was applied to produce the films. The ethanolic solution of CUR was mixed with an aqueous solution of POLs and then incorporated into different film-forming polymers prior to casting. The processing of the CUR with POL solution was intended to aid in the even dispersion of the drug in the polymeric matrices and enhance the wettability of the films. The physical state and properties of the films were characterized in terms of their morphology, crystallinity of the drug, and phase miscibility of the mixtures. The dissolution profile of the films was also evaluated in terms of dissolution rate and dissolution efficiency. The obtained ODTF products were smooth and flat-surfaced. Physical characterization also indicated that the CUR was homogeneously dispersed in the ODTFs and no longer existed as crystalline material as revealed by X-ray diffraction (XRD). The CUR was also not phase-separated from the films as disclosed by differential scanning calorimetry (DSC). Such dispersion was achieved through the solubilizing effect of POLs and compact polymeric film matrices that prevented the CUR from recrystallization. Furthermore, the ODTFs also improved the dissolution of CUR by 3.2-fold higher than the raw CUR. Overall, cellulose-based films had favorable physical properties compared with saccharide-based films.

Self-medication profiles in school-age adolescents in Surabaya city, Indonesia.

Background: It has been reported that children are already practicing self-medication. Indeed, at the children's age, they are not allowed to self-medicate due to limited knowledge regarding self-medication, leading to inappropriate drug therapy or self-toxicity becoming problems in public health. Objective: This study aimed to determine how school-age adolescents carry out self-medication behavior. Methods: The study was designed as a cross-sectional in which data were collected using questionnaire methods. There were 195 students recruited in this study, consisting of SDN Keputih-245 Elementary School students, SMPN 19 Surabaya Junior High School, and SMAN 11 Surabaya Senior High School. Results: The results showed that most of the students had purchased medicine independently without a doctor's prescription. The primary source of information regarding self-medication by school students is family. Although most of the respondents stated they always inform their parents or doctors, it has been found that the practice of self-medication by school-age teenagers without informing their parents or doctors exists. Moreover, less than 50% of student respondents believe that self-medication is safe. Conclusion: The role of pharmacists is urgently needed to provide proper education related to drug information and self-medication to increase school-age students' knowledge.

Formulation Design and Cell Cytotoxicity of Curcumin-Loaded Liposomal Solid Gels for Anti-Hepatitis C Virus.

Backgrounds: Curcumin (CUR) is a low-molecular-weight polyphenolic substance obtained from the tuber part of Curcuma species. Anti-inflammatory and anti-hepatitis C virus (HCV) activities have been associated with CUR. However, its poor aqueous solubility and low systemic bioavailability have been the challenges in improving the therapeutic efficacy of curcumin. Aim: The study aimed to produce CUR-loaded liposomal solid gels as anti-HCV delivery systems. Parameters including the physical characteristics and the cell cytotoxicity properties were evaluated. Methods: The freeze-drying technique was applied to manufacture the CUR-loaded liposomal solid gels. Scanning electron microscopy (SEM), X-ray diffractometry (XRD), and differential thermal analysis (DTA) were involved to reveal the characteristics of the solid gels. Such characteristics were as follows: the morphology and the microscopic structure of the solid gels, the crystallinity structure of the curcumin, and the thermal properties of the mixtures. Furthermore, their cell cytotoxicity was investigated using a Huh7it cell line. Results: The SEM images confirmed that curcumin liposomes were intact and trapped in the solid gel matrix. The XRD data showed flat patterns diffractograms of the formulations, confirming the transformation of CUR from crystalline to amorphous form. The DTA thermograms showed a single melting endothermic peak at a higher temperature around 200°C, indicating a single-phase transition of the mixtures. The XRD and DTA data revealed the molecular dispersion of CUR in the developed formulations. The cytotoxicity data provided as cell cytotoxicity 50 (CC50) for all formulations were ≥25 mg. These data confirmed that the developed liposomal solid gels were not cytotoxic to Huh7it cell line, indicating that the anti-HCV activity would be through a specific pathway and not by its toxicity. Conclusion: The CUR-loaded liposomal solid gels exhibited the potential and offered an alternative dosage form to improve the therapeutic efficacy of curcumin as an anti-HCV.

The effectiveness of ursolic acid niosomes with chitosan coating for prevention of liver damage in mice induced by n-nitrosodiethylamine.

Ursolic acid (UA) is a pentacyclic triterpene carboxylic acid which produces various effects, including anti-cancer, hepatoprotective, antioxidant and anti-inflammatory. However, UA demonstrates poor water solubility and permeability. Niosomes have been reported to improve the bioavailability of low water-soluble drugs. This study aimed to investigate the protective action of UA-niosomes with chitosan layers against liver damage induced by N-Nitrosodiethylamine (NDEA). UA niosomes were prepared using a thin layer hydration method, with chitosan being added by vortexing the mixtures. For the induction of liver damage, the mice were administered NDEA intraperitoneally (25 mg/kgBW). They were given niosomes orally (11 mg UA/kgBW) seven and three days prior to NDEA induction and subsequently once a week with NDEA induction for four weeks. The results showed that chitosan layers increased the particle sizes, PDI, and ζ-potentials of UA niosomes. UA niosomes with chitosan coating reduced the SGOT and SGPT level. The histopathological evaluation of liver tissue showed an improvement with reduced bile duct inflammation and decreasing pleomorphism and enlargement of hepatocyte cell nuclei in UA niosomes with the chitosan coating treated group. It can be concluded that UA niosomes with chitosan coating improved the efficacy of preventive UA therapy in liver-damaged mice induced with NDEA.

The stability and irritability study of the chitosan-Aloe vera spray gel as wound healing.

OBJECTIVES: Chitosan is a natural polysaccharide widely used in various clinical applications including regeneration of skin tissue. Aloe vera has properties in healing burns on the skin, anti-inflammatory effect, and leaves a protective layer on the skin after drying so it provides protection to the wound. The spray gel of chitosan-A. vera was developed as a wound healing that has combined of effect of both component and easy to use. The purpose of this study was to determine the physical stability and irritability of chitosan-A. vera spray gel. METHODS: The spray gel stability test was conducted using thermal cycling and centrifugation methods. The organoleptic, viscosity, and pH of the spray were evaluated. The irritation test was performed by Draize Rabbit Test method. RESULTS: Chitosan (0.5%)-A. vera (1%) spray gel characteristics has a weak yellow color, clear, and a strong A. vera odor. The pH of the spray gel was 4.88 ± 0.01; and the viscosity was 36.50 ± 0.23 cps. The result from the chitosan (0.5%)-A. vera (1%) spray gel stability test using thermal cycling method showed a decrease of viscosity, but remained stable when evaluated using centrifugation method. There was no difference in the pH and organoleptic observation from both tests. Based on the scoring and analysis of the reaction in rabbit skin, the Primary Irritation Index (PII) obtained was 0.56. CONCLUSIONS: The spray gel of chitosan (0.5%)-A. vera (1%) was stable and according to response category from the acute dermal irritation test, it can be concluded that chitosan (0.5%)-A. vera (1%) spray gel had a slightly irritating effect.

The effect of chitosan type and drug-chitosan ratio on physical characteristics and release profile of ketoprofen microparticles prepared by spray drying.

OBJECTIVES: In order to minimize gastrointestinal irritation and to extend the absorption of ketoprofen, microparticles prepared with chitosan have been developed. In this study, chitosan type and drug-chitosan ratio were investigated to prepare microparticles of ketoprofen and evaluated for physical characteristics and drug release profiles. METHODS: Microparticles were prepared by using ionic gelation methods with chitosan, which has two different viscosities i.e., 19 and 50 cPs, cross-linked with tripolyphosphate, and dried by spray drying method. The microparticles were made with a drug-chitosan ratio of 5:15 and 6:15. RESULTS: The results showed that the microparticles had spherical shapes. Increasing the amount of ketoprofen improved the drug content and entrapment efficiency. Evaluation of drug release in simulated intestinal fluid (pH 6.8) showed that the microparticles prepared with chitosan 19 cPs had the slowest release rate than those of chitosan 50 cPs, while that of the microparticles prepared with chitosan 50 cPs with the ratio of drug/polymer 6:15 was the fastest, as shown by its slope value. The release rate of microparticles with chitosan 19 cPs was slower than those microparticles with chitosan 50 cPs. CONCLUSIONS: It could be suggested that by increasing the amount of ketoprofen, it improved the entrapment efficiency and the release rate of microparticles.

Nanoparticles use for Delivering Ursolic Acid in Cancer Therapy: A Scoping Review.

Ursolic acid is a natural pentacyclic triterpenoid that exerts a potent anticancer effect. Furthermore, it is classified as a BCS class IV compound possessing low permeability and water solubility, consequently demonstrating limited bioavailability in addition to low therapeutic effectiveness. Nanoparticles are developed to modify the physical characteristics of drug and can often be produced in the range of 30-200 nm, providing highly effective cancer therapy due to the Enhanced Permeation and Retention (EPR) Effect. This study aims to provide a review of the efficacy and safety of various types of Ursolic Acid-loading nanoparticles within the setting of preclinical and clinical anticancer studies. This literature study used scoping review method, where the extracted data must comply with the journal inclusion criteria of within years of 2010-2020. The identification stage produced 237 suitable articles. Duplicate screening was then conducted followed by the initial selection of 18 articles that had been reviewed and extracted for data analysis. Based on this review, the use of nanoparticles can be seen to increase the anticancer efficacy of Ursolic Acid in terms of several parameters including pharmacokinetic data, survival rates and inhibition rates, as well as the absence of serious toxicity in preclinical and clinical trials in terms of several parameters including body weight, blood clinical chemistry, and organ histipathology. Based on this review, the use of nanoparticles has been able to increase the anticancer efficacy of Ursolic Acid, as well as show the absence of serious toxicity in preclinical and clinical trials. Evenmore, the liposome carrier provides development data that has reached the clinical trial phase I. The use of nanoparticle provides high potential for Ursolic Acid delivery in cancer therapy.

N-nitrosodiethylamine induces inflammation of liver in mice.

OBJECTIVES: For designing early treatment for liver cancer, it is important to prepare an animal model to evaluate cancer prevention treatment by using inflammation disease. The hepatocarcinogenic N-Nitrosodiethylamine (NDEA) has been reportedly able to produce free radicals that cause liver inflammation leading to liver carcinoma. This study aimed to evaluate the inflammation disease model of mice induced with hepatocarcinogenic NDEA for five weeks induction. METHODS: The BALB-c mice were induced with NDEA 25 mg/kg of body weight once a week for five weeks intraperitonially and it was then evaluated for the body weight during study periods. The mice were then sacrificed and excised for evaluating their organs including physical and morphological appearances and histopathology evaluations. RESULTS: The results showed a significant decrease of body weight of mice after five times induction of 25 mg NDEA/kgBW per week intraperitonially. Different morphological appearances and weight of mice organs specifically for liver and spleen had also been observed. The histopathology examination showed that there were hepatic lipidosis and steatohepatitis observed in liver and spleen, respectively that might indicate the hepatocellular injury. CONCLUSIONS: It can be concluded that inducing mice with NDEA intraperitonially resulted in fatty liver disease leading to progress of cancer disease.

Cocrystal formation of loratadine-succinic acid and its improved solubility.

OBJECTIVES: Loratadine belongs to Class II compound of biopharmaceutics classification system (BCS) due its low solubility and high membrane permeability. Cocrystal is a system of multicomponent crystalline that mostly employed to improve solubility. Succinic acid is one of common coformer in cocrystal modification. This research aims to investigate cocrystal formation between loratadine and succinic acid and its effect on solubility property of loratadine. METHODS: Cocrystal of loratadine-succinic acid was prepared by solution method using methanol as the solvent. Cocrystal formation was identified under observation of polarization microscope and analysis of the binary phase diagram. The cocrystal phase was characterized by differential thermal analysis (DTA), powder X-ray diffraction (PXRD), Fourier transform infrared (FTIR), and scanning electron microscopy (SEM). Solubility study was conducted in phosphate-citrate buffer pH 7.0 ± 0.5 at 30 ± 0.5 °C. RESULTS: Loratadine is known to form cocrystal with succinic acid in 1:1 M ratio. Cocrystal phase has lower melting point at 110.9 °C. Powder diffractograms exhibited new diffraction peaks at 2θ of 5.28, 10.09, 12.06, 15.74, 21.89, and 28.59° for cocrystal phase. IR spectra showed that there was a shift in C=O and O-H vibration, indicating intermolecular hydrogen bond between loratadine and succinic acid. SEM microphotographs showed different morphology for cocrystal phase. Loratadine solubility in cocrystal phase was increased up to 2-fold compared to loratadine alone. CONCLUSIONS: Cocrystal of loratadine and succinic acid is formed by stoichiometry of 1:1 via C=O and H-O interaction. Cocrystal phase shows different physicochemical properties and responding to those properties, it shows improved loratadine solubility as well.

Interactions of primaquine and chloroquine with PEGylated phosphatidylcholine liposomes.

This study aimed to analyze the interaction of primaquine (PQ), chloroquine (CQ), and liposomes to support the design of optimal liposomal delivery for hepatic stage malaria infectious disease. The liposomes were composed of hydrogenated soybean phosphatidylcholine, cholesterol, and distearoyl-sn-glycero-3-phosphoethanolamine-N-(methoxy[polyethyleneglycol]-2000), prepared by thin film method, then evaluated for physicochemical and spectrospic characteristics. The calcein release was further evaluated to determine the effect of drug co-loading on liposomal membrane integrity. The results showed that loading PQ and CQ into liposomes produced changes in the infrared spectra of the diester phosphate and carbonyl ester located in the polar part of the phospholipid, in addition to the alkyl group (CH2) in the nonpolar portion. Moreover, the thermogram revealed the loss of the endothermic peak of liposomes dually loaded with PQ and CQ at 186.6 °C, which is identical to that of the phospholipid. However, no crystallinity changes were detected through powder X-ray diffraction analysis. Moreover, PQ, with either single or dual loading, produced the higher calcein release profiles from the liposomes than that of CQ. The dual loading of PQ and CQ tends to interact with the polar head group of the phosphatidylcholine bilayer membrane resulted in an increase in water permeability of the liposomes.

Characterization and distribution of niosomes containing ursolic acid coated with chitosan layer.

BACKGROUND AND PURPOSE: Ursolic acid (UA) exhibits anti-hepatocarcinoma and hepatoprotective activities, thus promising as an effective oral cancer therapy. However, its poor solubility and permeability lead to low oral bioavailability. In this study, we evaluated the effect of different ratios of Span® 60-cholesterol-UA and also chitosan addition on physical characteristics and stability of niosomes to improve oral biodistribution. EXPERIMENTAL APPROACH: UA niosomes (Nio-UA) were composed of Span® 60-cholesterol-UA at different molar ratios and prepared by using thin layer hydration method, and then chitosan solution was added into the Nio-UA to prepare Nio-CS-UA. FINDINGS/RESULTS: The results showed that increasing the UA amount increased the particle size of Nio-UA. However, the higher the UA amount added to niosomes, the lower the encapsulation efficiency. The highest physical stability was achieved by preparing niosomes at a molar ratio of 3:2:10 for Span® 60, cholesterol, and UA, respectively, with a zeta-potential value of -41.99 mV. The addition of chitosan increased the particle size from 255 nm to 439 nm, as well as the zeta-potential value which increased from -46 mV to -21 mV. Moreover, Nio-UA-CS had relatively higher drug release in PBS pH 6.8 and 7.4 than Nio-UA. In the in vivo study, the addition of chitosan produced higher intensities of coumarin-6-labeled Nio-UA-CS in the liver than Nio-UA. CONCLUSION AND IMPLICATIONS: It can be concluded that the ratio of Span® 60-cholesterol-UA highly affected niosomes physical properties. Moreover, the addition of chitosan improved the stability and drug release as well as oral biodistribution of Nio-UA.

Improving solubility and dissolution of meloxicam by solid dispersion using hydroxypropyl methylcellulose 2910 3 cps and nicotinamide.

Background Solid dispersion (SD) represents a good method for enhancing the solubility of poorly water-soluble drugs. Meloxicam (MLX), a nonsteroidal anti-inflammatory drug has poor solubility in water. Hydroxypropyl methylcellulose (HPMC) 2910 3 cps, a hydrophilic carrier and nicotinamide (NC), a hydrotropic agent can be used as matrix of SD. The aim of this study is to investigate the effect of HPMC 2910 3 cps and NC as SD matrix on the solubility and dissolution rate of MLX. Methods The SD of MLX was prepared by solvent evaporation method using methanol as solvent. The SD formulations composed of HPMC and NC in different ratios (1:1:1, 1:1:2, 1:2:1, 1:2:2). The physical state of MLX SD were characterized by Differential Thermal Analyzer (DTA), Fourier Transform Infrared Spectroscopy, powder X-ray diffractometer (PXRD), Scanning Electron Microscopy (SEM). The solubility and dissolution of the MLX SD were also evaluated. Results The results of differential thermal analysis (DTA) showed that the melting point of MLX SD was lower than MLX further the X-ray diffractogram showed a decrease of the crystallinity of MLX in SD. Those indicated that MLX was dispersed molecularly in SD. The SD showed a widening transmission peak at 3000-3500 cm-1 which resembled the peak of pure MLX transmission. It indicated that intermolecular hydrogen bonds were formed between MLX, HPMC, and NC. The solubility and the dissolution efficiency (ED60) of SD with MLX-HPMC 2910 3 cps-NC = 1:2:1 increased 3.59 times and 1.50 times higher then MLX substance. Conclusions MLX-HPMC-NC SD system increased the solubility and dissolution of MLX. The SD with MLX-HPMC 2910 3 cps-NC ratio of 1:2:1 had the highest solubility and ED60 compared to the other SD formulas.

Development of Andrographolide-Carboxymethyl Chitosan Nanoparticles: Characterization, in vitro Release and in vivo Antimalarial Activity Study.

OBJECTIVES: The purpose of this study was to investigate the effect of andrographolide-carboxymethyl chitosan nanoparticles formation on the physical characteristics, in vitro release profile and in vivo antimalarial activity of andrographolide. MATERIALS AND METHODS: Nanoparticles were prepared by ionic gelation method-spray drying using CaCl2 as the crosslinker with a composition of drug: polymer: CaCl2=40: 250: 100. The obtained particles were evaluated for its size and morphology; physical state, drug content, in vitro drug release and in vivo antimalarial activity on Plasmodium berghei infected mice. RESULTS: The results of DTA and XRD showed that nanoparticle systems had a lower melting point and lower crystallinity degree. The drug dissolved from the nanoparticles was increased up to 6.5 times and the in vivo antimalarial activity was 1.65 times higher compared to andrographolide. CONCLUSION: The formation andrographolide-carboxymethyl chitosan nanoparticles affected the physical characte-ristics of andrographolide. The decrease crystallinity of andrographolide resulted in a lower melting point of andrographolide. Such changes provided a positive impact to the drug dissolution and then its activity.

Physicochemical Characterization and In Vitro Dissolution Test of Quercetin-Succinic Acid Co-crystals Prepared Using Solvent Evaporation.

OBJECTIVES: Quercetin is one of the flavonoids with a polyhydroxyaromatic structure. Quercetin has been proposed to exhibit a bioWactivity against oxidative stress. However, quercetin has poor solubility in aqueous media. The purpose of this study was to investigate the physicochemical properties and dissolution rates of quercetin-succinic acid co-crystals. MATERIALS AND METHODS: The quercetin-succinic acid co-crystals were prepared in 1:1 molar ratio using solvent evaporation. X-ray diffraction, differential thermal analysis, infrared spectroscopy, and scanning electron microscopy were performed to determine the physicochemical properties of quercetin-succinic acid co-crystals. Dissolution was studied in medium citrate buffer with 2% SLS for 60 min using USP II (paddle) apparatus at 100 rpm and 37°C. RESULTS: Based on diffractogram, thermogram, infrared spectrum, and microscopic capture, the physicochemical properties of quercetin-succinic acid co-crystals showed difference to those of quercetin. In addition, the in vitro dissolution test showed that the dissolution profile of co-crystals was significantly higher than pure quercetin. CONCLUSION: This study suggests that the formation of quercetin-succinic acid co-crystals using solvent evaporation enhanced the physicochemical properties and dissolution rate of quercetin.