Browsing by Author "Kalombo, Lonji"

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Design and formulation of nano-sized spray dried efavirenz-part I: influence of formulation parameters
(Springer Nature Switzerland AG., 2012-10-25) Katata, Lebogang; Tshweu, Lesego; Naidoo, Saloshnee; Kalombo, Lonji; Swai, Hulda
Efavirenz (EFV) is one of the first-line antiretroviral drugs recommended by the World Health Organisation for treating HIV. It is a hydrophobic drug that suffers from low aqueous solubility (4 μg/mL), which leads to a limited oral absorption and low bioavailability. In order to improve its oral bioavailability, nano-sized polymeric delivery systems are suggested. Spray dried polycaprolactone-efavirenz (PCL-EFV) nanoparticles were prepared by the double emulsion method. The Taguchi method, a statistical design with an L8 orthogonal array, was implemented to optimise the formulation parameters of PCL-EFV nanoparticles. The types of sugar (lactose or trehalose), surfactant concentration and solvent (dichloromethane and ethyl acetate) were chosen as significant parameters affecting the particle size and polydispersity index (PDI). Small nanoparticles with an average particle size of less than 254 ± 0.95 nm in the case of ethyl acetate as organic solvent were obtained as compared to more than 360 ± 19.96 nm for dichloromethane. In this study, the type of solvent and sugar were the most influencing parameters of the particle size and PDI. Taguchi method proved to be a quick, valuable tool in optimising the particle size and PDI of PCL-EFV nanoparticles. The optimised experimental values for the nanoparticle size and PDI were 217 ± 2.48 nm and 0.093 ± 0.02.
Development, characterization and antimalarial efficacy of dihydroartemisinin loaded solid lipid nanoparticles.
(Elsevier, 2016-04-01) Omwoyo, Wesley; Melariri, Paula; Gathirwa, Jeremiah; Oloo, Florence; Mahanga, Geoffrey; Kalombo, Lonji; Ogutu, Bernhards; Swai, Hulda
Effective use of dihydroartemisinin (DHA) is limited by poor water-solubility, poor pharmacokinetic profile and unsatisfactory clinical outcome especially in monotherapy. To reduce such limitations, we reformulated DHA into solid lipid nanoparticles (SLNs) as a nanomedicine drug delivery system. DHA-SLNs were characterized for physical parameters and evaluated for in vitro and in vivo antimalarial efficacy. DHA-SLNs showed desirable particle characteristics including particle size (240.7 nm), particle surface charge (+ 17.0 mV), drug loadings (13.9 wt %), encapsulation efficacy (62.3%), polydispersity index (0.16) and a spherical appearance. Storage stability up to 90 days and sustained release of drug over 20 h was achieved. Enhanced in vitro (IC50 0.25 ng/ml) and in vivo (97.24% chemosuppression at 2 mg/kg/day) antimalarial activity was observed. Enhancement in efficacy was 24% when compared to free DHA. These encouraging results show potential of using the described formulation for DHA drug delivery for clinical application.
Effects of protein binding on the biodistribution of PEGylated PLGA nanoparticles post oral administration
(Elsevier B.V., 2012-03-15) Semete, Boitumelo; Booysen, Laetitia; Kalombo, Lonji; Ramalapa, Bathabile; Hayeshi, Rose; Swai, Hulda
The surface of nanoparticles is often functionalised with polymeric surfactants, in order to increase systemic circulation time. This has been investigated mainly for intravenously administered nanoparticles. This study aims to elucidate the effect of surface coating with various concentrations of polymeric surfactants (PEG and Pluronics F127) on the in vitro protein binding as well as the tissue biodistribution, post oral administration, of PLGA nanoparticles. The in vitro protein binding varied depending on the polymeric surfactant used. However, in vivo, 1% PEG and 1% Pluronics F127 coated particles presented similar biodistribution profiles in various tissues over seven days. Furthermore, the percentage of PEG and Pluronics coated particles detected in plasma was higher than that of uncoated PLGA particles, indicating that systemic circulation time can also be increased with oral formulations. The difference in the in vitro protein binding as a result of the different poloxamers used versus similar in vivo profiles of these particles indicates that in vitro observations for nanoparticles cannot represent or be correlated to the in vivo behaviour of the nanoparticles. Our results therefore suggest that more studies have to be conducted for oral formulations to give a better understanding of the kinetics of the particles.
Effects of spray-drying on w/o/w multiple emulsions prepared from a stearic acid matrix
(2014-01-01) Mlalila, Nichrous; Swai, Hulda; Kalombo, Lonji; Hilonga, Askwar
The goal of this study was to explore the effects of spray-drying on w/o/w double emulsions of methyltestosterone (MT) loaded in a stearic acid matrix. MT-loaded nanoparticles were formulated by a water-in-oil-in-water emulsion technique using 50, 75, and 100 mg of stearic acid, 2% and 3% w/v polyvinyl alcohol, 5% w/v lactose, and 0.2% w/v chitosan. The emulsions were immediately spray-dried based on an optimized model of inlet temperature and pump rate, and characterized for optimized responses with regard to particle size, polydispersity index, and zeta potential, for both emulsion and powder samples. Dynamic light scattering analysis shown that the nanoparticles increased in size with increasing concentrations of polyvinyl alcohol and stearic acid. Scanning electron microscopy indicated that the MT-loaded nanoparticles were spherical in shape, had a smooth surface, and were in an amorphous state, which was confirmed by differential scanning calorimetry. These MT-loaded nanoparticles are a promising candidate carrier for the delivery of MT; however, further studies are needed in order to establish the stability of the system and the cargo release profile under normal conditions of use.
Enhanced oral bioavailability of the antiretroviral efavirenz encapsulated in poly(epsilon-caprolactone) nanoparticles by a spray-drying method.
(NANOMEDICINE, 2014-10-17) Tshweu, Lesego; Katata, Lebogang; Kalombo, Lonji; Chiappetta, Diego; Hocht, Christian; Sosnik, Alejandro; Swai, Hulda
Aim: To encapsulate efavirenz (EFV) within poly(epsilon-caprolactone) (PCL) nanoparticles (NPs) and compare the oral pharmacokinetics with that of EFV-loaded micelles and pure EFV NPs. Materials & methods: EFV-loaded PCL NPs were produced by a double-emulsion/spray-drying method. Results: NPs displayed a hydrodynamic diameter of 200–250 nm. The encapsulation efficiency was 86–93% and the mass recovery was above 60%. X-ray diffraction indicated that drug and PCL underwent amorphization during the spray-drying process. Encapsulation within NPs significantly increased the maximum concentration in plasma and the bioavailability. Conclusion: EFV-loaded PCL NPs represent a promising platform to develop scalable pharmaceuticals with improved (bio)pharmaceutic performance.
Human food safety and environmental hazards associated with the use of methyltestosterone and other steroids in production of all-male tilapia
(Springer, 2015-04) Mlalila, Nichrous; Mahika, Charles; Kalombo, Lonji; Swai, Hulda; Hilonga, Askwar
In recent years, all-male cultures of Nile tilapia (Oreochromis niloticus) have been the most preferred mode of production in aquaculture industry. All-male individuals achieve higher somatic growth rate and shut high energy losses associated with gonadal development and reproduction. The economic advantages of culturing all-male tilapia have led to the development of procedures for producing unisex cultures, using 17α-methyltestosterone (MT). Despite widespread use of the MT in tilapia farming, the implications of hormone treatment in relation to human health and the environment have raised a number of concerns in the scientific community. In this review, the hormonal application processes, economic and ecological significance of MT, food safety and residual MT, comparative uses of steroids in aquaculture, animal husbandry, and medicine have been briefly reviewed for regulatory guidelines, and finally, future research perspectives have been addressed. The review can be used as policy-making guidelines in aquaculture framework development as can be emphasized in African continent, among others. The most important conclusion to draw is that the quantity of MT used in conventional practice is large compared to the actual dose required for sex reversal, fish produced are safe for human consumptions, and the environmental hazards should be further emphasized.
In vivo evaluation of the biodistribution and safety of PLGA nanoparticles as drug delivery systems
(Elsevier Inc., 2010-10) Semete, Boitumelo; Booysen, Laetitia; Lemmer, Yolandy; Kalombo, Lonji; Katata, Lebogang; Verschoor, Jan
The remarkable physicochemical properties of particles in the nanometer range have been proven to address many challenges in the field of science. However, the possible toxic effects of these particles have raised some concerns. The aim of this article is to evaluate the effects of poly(lactide-co-glycolide) (PLGA) nanoparticles in vitro and in vivo compared to industrial nanoparticles of a similar size range such as zinc oxide, ferrous oxide, and fumed silica. An in vitro cytotoxicity study was conducted to assess the cell viability following exposure to PLGA nanoparticles. Viability was determined by means of a WST assay, wherein cell viability of greater than 75% was observed for both PLGA and amorphous fumed silica particles and ferrous oxide, but was significantly reduced for zinc oxide particles. In vivo toxicity assays were performed via histopathological evaluation, and no specific anatomical pathological changes or tissue damage was observed in the tissues of Balb/C mice. The extent of tissue distribution and retention following oral administration of PLGA particles was analyzed for 7 days. After 7 days, the particles remained detectable in the brain, heart, kidney, liver, lungs, and spleen. The results show that a mean percentage (40.04%) of the particles were localized in the liver, 25.97% in the kidney, and 12.86% in the brain. The lowest percentage was observed in the spleen. Thus, based on these assays, it can be concluded that the toxic effects observed with various industrial nanoparticles will not be observed with particles made of synthetic polymers such as PLGA when applied in the field of nanomedicine. Furthermore, the biodistribution of the particles warrants surface modification of the particles to avoid higher particle localization in the liver. From the clinical editor: The aim of this study was to evaluate the effects of poly(lactide-co-glycolide) (PLGA) nanoparticles in vitro and in vivo compared to industrial nanoparticles including zinc oxide, ferrous oxide, and fumed silica. The authors concluded that the toxic effects observed with various industrial nanoparticles is unlikely to be observed with particles made of PLGA. The biodistribution of these particles warrants surface modification to avoid particle accumulation in the liver.
In vivo/in vitro pharmacokinetic and pharmacodynamic study of spray-dried poly-(dl-lactic-co-glycolic) acid nanoparticles encapsulating rifampicin and isoniazid.
(Elsevier B.V., 2013-02-28) Booysen, Laetitia; Kalombo, Lonji; Brooks, Elizabeth; Hansen, Ryan; Gilliland, Janet; Gruppo, Veronica; Lungenhofer, Paul; Semete-Makokotlela, Boitumelo; Swai, Hulda; Kotzé, Awie; Lenaerts, Anne; du Plessis, Lissinda
Poly-(dl-lactic-co-glycolic) acid (PLGA) nanoparticles were prepared by a double emulsion solvent evaporation spray-drying technique and coated with polyethylene glycol (PEG 1% v/v). The PLGA nanoparticles had a small size (229±7.6 to 382±23.9nm), uniform size distribution and positive zeta potential (+12.45±4.53mV). In vitro/in vivo assays were performed to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) performance of these nanoparticles following nanoencapsulation of the anti-tuberculosis drugs rifampicin (RIF) and isoniazid (INH). The results demonstrated the potential for the reduction in protein binding of these drugs by protection in the polymer core. Furthermore, in vitro efficacy was demonstrated using Mycobacterium tuberculosis (M. tb.) (strain H37Rv). Sustained drug release over seven days were observed for these drugs following once-off oral administration in mice with subsequent drug distribution of up to 10 days in the liver and lungs for RIF and INH, respectively. It was concluded by these studies combined with our previous reports that spray-dried PLGA nanoparticles demonstrate potential for the improvement of tuberculosis chemotherapy by nanoencapsulation of anti-tuberculosis drugs.
Mycolic acids, a promising mycobacterial ligand for targeting of nanoencapsulated drugs in tuberculosis
(Elsevier, 2015-06-06) Lemmer, Yolandy; Kalombo, Lonji; Pietersen, Ray-Dean; Jones, Arwyn T.; Semete-Makokotlela, Boitumelo; Van Wyngaardt, Sandra; Ramalapa, Bathabile; Stoltz, Anton C.; Baker, Bienyameen; Verschoor, Jan A.; Swai, Hulda; de Chastellier, Chantal
The appearance of drug-resistant strains of Mycobacterium tuberculosis (Mtb) poses a great challenge to the development of novel treatment programmes to combat tuberculosis. Since innovative nanotechnologiesmight alleviate the limitations of current therapies, we have designed a new nanoformulation for use as an anti-TB drug delivery system. It consists of incorporating mycobacterial cellwallmycolic acids (MA) as targeting ligands into a drug-encapsulating Poly DL-lactic-co-glycolic acid polymer (PLGA), via a double emulsion solvent evaporation technique. Bonemarrow-derivedmousemacrophages, either uninfected or infectedwith differentmycobacterial strains (Mycobacterium avium, Mycobacterium bovis BCG or Mtb), were exposed to encapsulated isoniazid-PLGA nanoparticles (NPs) using MA as a targeting ligand. The fate of the NPs was monitored by electron microscopy. Our study showed that i) the inclusion of MA in the nanoformulations resulted in their expression on the outer surface and a significant increase in phagocytic uptake of the NPs; ii) nanoparticle-containing phagosomes were rapidly processed into phagolysosomes, whether MA had been included or not; and iii) nanoparticlecontaining phagolysosomes did not fuse with non-matured mycobacterium-containing phagosomes, but fusion events with mycobacterium-containing phagolysosomes were clearly observed.
Nanoencapsulation of water-soluble drug, lamivudine, using a double emulsion spray-drying technique for improving HIV treatment
(Springer Nature Switzerland AG., 2013-10-22) Tshweu, Lesego; Katata, Lebogang; Kalombo, Lonji; Swai, Hulda
Current treatments available for human immunodeficiency virus, namely antiretrovirals, do not completely eradicate the virus from the body, leading to life-time commitment. Many antiretrovirals suffer drawbacks from toxicity and unpleasant side effects, causing patience noncompliance. To minimize challenges associated with the antiretrovirals, biodegradable nanoparticles used as drug delivery systems hold tremendous potential to enhance patience compliance. The main objective of this work was to load lamivudine (LAM) into poly(epsiloncaprolactone) (PCL) nanoparticles. LAM is a hydrophilic drug with low plasma half-life of 5–7 h and several unpleasant side effects. LAM was nanoencapsulated into PCL polymer via the double emulsion spray-drying method. Formulation parameters such as the effect of solvent, excipient and drug concentration were optimized for the synthesis of the nanoparticles. Spherical nanoparticles with an average size of 215 ± 3 nm and polydispersity index (PDI) of 0.227 ± 0.01 were obtained, when ethyl acetate and lactose were used in the preparation. However, dichloromethane presented sizes larger than 454 ± 11 nm with PDI of more than 0.4 ± 0.05, irrespective of whether lactose or trehalose was used in the preparation. Some of the nanoparticles prepared with trehalose resulted in crystal formation. UV spectroscopy showed encapsulation efficiency ranging from 68 ± 4 to 78 ± 4 % for LAM depending on the starting drug concentration. Fourier transform infrared spectroscopy and X-ray diffraction confirmed the possibility of preparing amorphous PCL nanoparticles containing LAM. Drug release extended for 4 days in pH 1.3, pH 4.5 and pH 6.8. These results indicated that LAM-loaded PCL nanoparticles show promise for controlled delivery.
Oral lipid-based nanoformulation of tafenoquine enhanced bioavailability and blood stage antimalarial efficacy and led to a reduction in human red blood cell loss in mice
(Dovepress, 2015-02-20) Melariri, Paula; Kalombo, Lonji; Nkuna, Patric; Dube, Admire; Hayeshi, Rose; Ogutu, Benhards; Gibhard, Liezl; deKock, Carmen; Smith, Peter; Wiesner, Lubbe; Swai, Hulda
: Tafenoquine (TQ), a new synthetic analog of primaquine, has relatively poor bioavailability and associated toxicity in glucose-6-phosphate dehydrogenase (G6PD)-deficient individuals. A microemulsion formulation of TQ (MTQ) with sizes 20 nm improved the solubility of TQ and enhanced the oral bioavailability from 55% to 99% in healthy mice (area under the curve 0 to infinity: 11,368±1,232 and 23,842±872 min⋅µmol/L) for reference TQ and MTQ, respectively. Average parasitemia in Plasmodium berghei-infected mice was four- to tenfold lower in the MTQ-treated group. In vitro antiplasmodial activities against chloroquinesensitive and chloroquine-resistant strains of Plasmodium falciparum indicated no change in half maximal inhibitory concentration, suggesting that the microemulsion did not affect the inherent activity of TQ. In a humanized mouse model of G6PD deficiency, we observed reduction in toxicity of TQ as delivered by MTQ at low but efficacious concentrations of TQ. We hereby report an enhancement in the solubility, bioavailibility, and efficacy of TQ against blood stages of Plasmodium parasites without a corresponding increase in toxicity.
Potential of treating tuberculosis with a polymeric nano-drug delivery system
(Elsevier, 2008-12-18) Swai, Hulda; Semete, B.; Kalombo, Lonji; Chelule, P.
An effective therapeutic regimen is available for the treatment of tuberculosis (TB), however in developing countries; patient non-compliance due to high dose frequency and the lengthy duration of treatment, presents a major challenge, thus resulting in treatment failure. To address this challenge, the project seeks to develop a nano-drug delivery system whereby anti-TB drugs can be administered in a single dose that maintains an active level of the drug for at least one week.
Preparation of rifampicin/lactose microparticle composites by a supercritical antisolvent-drug excipient mixing technique for inhalation delivery
(Elsevier, 2013-02) Ober, Courtney A.; Kalombo, Lonji; Swai, Hulda; Gupta, Ram B.
Rifampicin (RIF) is precipitated in the presence of inhalable lactose particles using a supercritical antisolvent-drug excipient mixing (SAS-DEM) technique to create RIF/lactose microparticle composites intended to improve the effectiveness of pulmonary tuberculosis treatments by increasing the respirable fraction of RIF. These RIF/lactose microparticle composites are prepared by dissolving RIF in a liquid solvent and spraying the solution into a high pressure vessel containing supercritical CO2 and suspended lactose particles. As the CO2 extracts the liquid solvent, RIF microparticles precipitate to form a microparticle composite mixture with the lactose particles. The effects of solvent, RIF concentration, and RIF to lactose loading are examined. The RIF/lactose microparticle composites are characterized for composition, particle size and surface morphology, crystallinity, thermal behavior, and physicochemical properties. By placing 1000 mg of lactose microfine in the vessel and varying the spraying time of 1 mg/mL and 5 mg/mL RIF in methanol solutions, RIF/lactose microparticle composites of 1.2%, 7.2%, 14.0%, and 25.7% RIF with relative standard deviations of 5.7%, 4.5%, 5.2%, and 2.3%, respectively, are prepared. Based on scanning electron microscopy, homogeneous RIF/lactose composites consisting of spherical particles less than 8 μm in diameter are produced. X-ray diffraction reveals that the SAS precipitation of RIF form I from methanol produces a polymorphic mixture of RIF form I and RIF dihydrate, due to trace water content in the solvent, while both RIF and lactose retain their individual crystalline structures during SAS-DEM processing. Based on differential scanning calorimetry RIF dihydrate converts to amorphous RIF upon heating. Fourier transform infrared spectroscopy demonstrates the absence of chemical interactions between the RIF and lactose proving a physical composite of the two is produced by the SAS-DEM process, and indicating that the therapeutic effectiveness of the drug should be unaffected.
Preparation, characterization, and optimization of primaquine-loaded solid lipid nanoparticles
(Dovepress, 2014-08-11) Omwoyo, Wesley; Ogutu, Bernhards; Oloo, Florence; Swai, Hulda; Kalombo, Lonji; Melariri, Paula; Mahanga, Geoffrey; Gathirwa, Jeremiah
Primaquine (PQ) is one of the most widely used antimalarial drugs and is the only available drug that combats the relapsing form of malaria. PQ use in higher doses is limited by severe tissue toxicity including hematological- and gastrointestinal-related side effects. Nanoformulation of drugs in an appropriate drug carrier system has been extensively studied and shown to have the potential to improve bioavailability, thereby enhancing activity, reducing dose frequency, and subsequently reducing toxicity. The aim of this work was to design, synthesize, and characterize PQ-loaded solid lipid nanoparticles (SLNs) (PQ-SLNs) as a potential drug-delivery system. SLNs were prepared by a modified solvent emulsification evaporation method based on a water-in-oil-in-water (w/o/w) double emulsion. The mean particle size, zeta potential, drug loading, and encapsulation efficiency of the PQ-SLNs were 236 nm, +23 mV, 14%, and 75%, respectively. The zeta potential of the SLNs changed dramatically, from −6.54 mV to +23.0 mV, by binding positively charged chitosan as surface modifier. A spherical morphology of PQ-SLNs was seen by scanning electron microscope. In vitro, release profile depicted a steady drug release over 72 hours. Differential scanning calorimeter thermograms demonstrated presence of drug in drug-loaded nanoparticles along with disappearance of decomposition exotherms, suggesting increased physical stability of drug in prepared formulations. Negligible changes in characteristic peaks of drug in Fourier transform infrared spectra indicated absence of any interaction among the various components entrapped in the nanoparticle formulation. The nanoformulated PQ was 20% more effective as compared with conventional oral dose when tested in Plasmodium berghei-infected Swiss albino mice. This study demonstrated an efficient method of forming a nanomedicine delivery system for antimalarial drugs.
Spray-Dried, Nanoencapsulated, Multi-Drug Anti-Tuberculosis Therapy Aimed at OnceWeekly Administration for the Duration of Treatment
(MDPI, 2019-08-15) Kalombo, Lonji; Lemmer, Yolandy; Semete-Makokotlela, Boitumelo; Ramalapa, Bathabile; Nkuna, Patric; Booysen, Laetitia; Naidoo, Saloshnee; Hayeshi, Rose; Verschoor, Jan; Swai, Hulda
Aiming to improve the treatment outcomes of current daily tuberculosis (TB) chemotherapy over several months, we investigated whether nanoencapsulation of existing drugs would allow decreasing the treatment frequency to weekly, thereby ultimately improving patient compliance. Nanoencapsulation of three first-line anti-TB drugs was achieved by a unique, scalable spray-drying technology forming free-flowing powders in the nanometer range with encapsulation e ciencies of 82, 75, and 62% respectively for rifampicin, pyrazinamide, and isoniazid. In a pre-clinical study on TB infected mice, we demonstrate that the encapsulated drugs, administered once weekly for nine weeks, showed comparable e cacy to daily treatment with free drugs over the same experimental period. Both treatment approaches had equivalent outcomes for resolution of inflammation associated with the infection of lungs and spleens. These results demonstrate how scalable technology could be used to manufacture nanoencapsulated drugs. The formulations may be used to reduce the oral dose frequency from daily to once weekly in order to treat uncomplicated TB.
State of the art and future directions in nanomedicine for tuberculosis.
(Expert Opinion on Drug Delivery, 2013-12-01) Dube, Admire; Lemmer, Yolandy; Hayeshi, Rose; Balogun, Mohammed; Labuschagne, Philip; Swai, Hulda; Kalombo, Lonji
Introduction: Tuberculosis (TB) ranks the second leading cause of death from an infectious disease worldwide. However, treatment of TB is affected by poor patient compliance due to the requirement for daily drug administration, for lengthy periods of time, often with severe drug-induced side effects. Nanomedicines have the potential to improve treatment outcomes by providing therapies with reduced drug doses, administered less frequently, under shortened treatment durations. Areas covered: In this article, we present the pathophysiology of the disease, focusing on pulmonary TB and the characteristics of drugs used in treatment and discuss the application of nanomedicines within this scope. We also discuss new formulation approaches for TB nanomedicines and directions for future research. Expert opinion: Nanomedicines have the potential to improve TB treatment outcomes. New approaches such as nanoparticle systems able to impact the immune response of macrophages and deliver drug intracellularly, as well as the use of polymer–drug conjugates for drug delivery, are likely to play an important role in TB nanomedicines in future. However, further research is required before TB nanomedicines can be translated to the clinic.