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Chemotherapeutic potential of alginate-chitosan microspheres as anti-tubercular drug carriers
... Microparticles can be obtained using one of the methods: ionotropic gelation of alginate with calcium ions in the presence of chitosan, tripolyphosphate cross-linking method or both of them. Using fi rst method were obtained alginatechitosan microsystems with antimicrobial compounds like: amoxicillin [48,49], nitrofurantoin [50], metronidazole [51], polymyxin B [52], cefaclor [53], rifampicin, isoniazid, pirazinamid [54,56] (Figure 3). By the use of the tripolyphosphate cross-linking method were obtained alginate-chitosan microcapsules with metronidazole [57]. ...
... Encapsulation of amoxicillin in alginate-chitosan mucoadhesive microcapsules as gastroretentive delivery system, resulted in enhanced stability [48] and controlled release of antimicrobial drug in the simulated gastric fl uid, compared to amoxicillin plain drug. [48,49] Reducing approximately two times and more of concentration of used chitosan (0.5% w/v and lower) to obtain antimicrobial alginate-chitosan microparticles resulted in selective sustainedrelease of active principle (nitrofurantoin [50], polymyxin B [52], rifampicin, isoniazid and pyrazinamide [54,56]) in simulated intestinal fl uid, while the release in simulated gastric fl uid was very slow. Cefaclor release from alginatechitosan microparticles in simulated gastric fl uid is intensifying with increasing of alginate concentration up to 7% w/v (chitosan concentration -0.5% w/v) [53]. ...
... Alginate-chitosan beads with metronidazole were obtained; due to high contents of chitosan (5% w/v) fl oat on gastric juice and consequently are retained in the stomach where they gradually release antibiotic compound [51]. In vivo studies have shown that the encapsulation of rifampicin, isoniazid and pyrazinamide in alginate-chitosan microcapsules resulted in an increase of about 13-15 times in their biological half-life compared to non-encapsulated substances, leading to an increased duration of action of the antituberculous compounds [56]. ...
Natural polysaccharides alginate and chitosan have been used extensively, separately or in mixtures (systems), in manufacturing of pharmaceutical products (antimicrobial) and not only. Alginates usually serve as basis for antimicrobial systems, while chitosan, in certain proportions, enhances their physicochemical and antimicrobial properties. Focusing on the recent literature (mostly since 2000), this review outlines the main synthetic approaches for the preparation of systems based on both polymers as well as identify potential areas of their application as antimicrobial agents. Various techniques used for systems preparation like microparticles, films, fibers, nanoparticles, sponges, applications and usefulness of these systems as carriers of antimicrobial compounds will also be discussed.
... One possible solution to the problems associated with anti-malarial pharmaceutical is the use of nanomaterial. The use of colloidal drug carriers (liposomes and micro/nanoparticles) provide versatility in site specific or targeted drug delivery along with controlled optimal drug release [7,8]. Nanoparticles have added advantages over microparticles such as bioavailability, the ability to improve drug encapsulation, pharmacokinetics, and therapeutic therapy [9]. ...
... Nanoparticles are particulate dispersions or solid colloidal structures ranging from 1 -1000 nm in diameter [10]. They are composed of synthetic, semi-synthetic and natural polymers in which the active therapeutic molecule has the capability of being entrapped, encapsulated, dissolved, absorbed, or chemically attached [8,11]. Due to their biodegradability, biocompatibility, and versatility in application, natural hydrophilic polymers have also been extensively investigated [7,12]. ...
... Nanosuspensions are biphasic systems composed of submicronsized drug particles dispersed in an aqueous solution. There are two methods for formulating nanosuspensions which are "bottom-up" and "top-down" technology [8]. In the bottom-up technology, nanoparticles are formed through precipitation, chemical synthesis, and emulsion methods. ...
Despite the many advances that have occurred recently in the treatment of infectious diseases the morbidity and mortality associated with malaria remain major burdens. Children in tropical and subtropical climates are the most affected by this disease, especially those in Africa. Nanotechnology has taken the route of improving accepted formulations of therapeutics by increasing the active range of the treatments as well as decreasing the negative side effects. In this review we examine the efforts and advancements that have been made in the treatment of malaria that are based on nanomaterials.
... Nanoparticles are particulate dispersions or solid colloidal structures ranging from 1 -1000 nm in diameter (20). They are composed of synthetic, semi-synthetic and natural polymers in which the active therapeutic molecule has the capability of being entrapped, encapsulated, dissolved, absorbed, or chemically attached (21,22,23). Due to their biodegradability, biocompatibility, and versatility in application, natural hydrophilic polymers have also been extensively investigated (24). ...
... This was then centrifuged at 10,000 rpm for 15mins and the supernatant discarded. The pellet was washed thrice with distilled water, to remove unbound chitosan and alginates (22). ...
Malaria is a parasitic disease that occurs in tropical and subtropical regions of the world. About 500 million cases of malaria occur every year, and one million people, mostly children living in sub-Saharan Africa, die as a result. This study was conducted to determine the lipid and antioxidant status of chitosan bound ethylacetate fraction of cocos nucifera husk fiber in p. berghei infected mice. Swiss albino mice were innoculated with Plasmodium berghei. The forty five mice were randomly assigned into nine groups, of 5 mice each. Administration of the Therapeutic Dose (TD) (80mg/kg) and Sub Therapeutic Dose (STD) (20mg/kg) (gotten from preliminary studies) of ethylacetate extract fraction of Cocos nucifera husk fibre coupled with chitosan and chitosan/alginate was done orally for four days post-inoculation and 0.2ml of the extract was administered. Group A served as positive control (not infected), Group B received appropriate volume of distilled water, Group C received 5mg/kg. Chloroquine (infected), Group D received80mg/kg of extract (therapeutic dose), Group E received20mg/kg of extract ( sub-therapeutic dose, infected), Group F received80mg/kg of extract + Chitosan + infected, Group G received20mg/kg of extract + Chitosan + infected, Group H received80mg/kg of extract + Chitosan/ Alginate + infected, Group I received20mg/kg of extract + Chitosan/Alginate + infected. At the end of the experimental period, selected tissues was collected, isolated and homogenized. Antioxidant (MDA, GSH and GST) and lipid profile activities (Cholesterol, HDL and LDL) were determined. The results reveal that, there was a significantly decreased in the level of the non-treated groups as compared to other treated groups and control in cholesterol, HDL and LDL level while there was significant increase in triacylglyeride level in non – treated groups compared to other test groups and control after the administered ethylacetate fraction of cocos nucifera bound to chitosan microparticles. In present study reduced glutathione (GSH), GST and lipid peroxidation product malondialdehyde (MDA) were increased significantly compared to test groups and control. These results suggest that ethylacetate fraction of Cocos nucifera husk fibre bound to chitosan microparticles may boost body’s antioxidant systems, which neutralizes the effects of free radicals and also able to reverse the change in serum lipid profile caused by malaria infection.
Keywords: Chitosan, Antioxidant, Lipid, Ethylacetate and plasmodium berghei
... [35,36] These delivery systems show a series of advantages, including an increase in bioavailability of the encapsulated compounds, a delay in the erosion of the formed particles, and sustained release of actives. [37] In one example, conventional alginate NPs have been coated with multiple layers of chitosan. This not only allowed for NP stabilization, but can also help maintain better control of the porosity of the alginate NPs generating sustained release of the encapsulated substance. ...
... This not only allowed for NP stabilization, but can also help maintain better control of the porosity of the alginate NPs generating sustained release of the encapsulated substance. [37] PROTEIN AND PEPTIDE-COATED AMINO ACID-CORE NANOPARTICLES As mentioned above, the recent increase in the number of new active macromolecules highlights the need for novel means for protein and peptide drug delivery. [38] While conventional injectable formulation of these molecules is the most common starting point, the growth of the field is leading current and future research efforts toward alternative delivery routes. ...
This entry details recent developments in surface-modified nanoparticles used as delivery systems for a variety of active molecules. Biopolymeric nanocapsules are first described as carriers for poor water-soluble drugs. Biopolymeric nanoparticles are then addressed for their potential as carriers for macromolecular actives such as antigens. The fabrication of protein-coated nanoparticles and their application in enabling solid dosage forms for transmucosal drug delivery is then described. Finally, the potential of gold nanopar-ticles coated with targeting ligands to improve their spatial localization is reviewed.
... Anal and Stevens [52] stated that alginate and chitosan increased the encapsulation efficiency for complexation, while also improving the properties of controlled release of drugs. Isoniazid, pyrazinamide, and rifampicin containing alginate-chitosan microspheres were prepared by Pandey and Khuller [53] in a similar study. Chitosan acts as a reinforcing polymer by retarding the erosion of alginate microspheres, resulting in slow, but sustained in vitro drug release. ...
... Pandey and Khuller showed that in guinea pigs receiving trice blank alginate/chitosan microparticles (125 mg/ kg each dose), there were no toxic effects showed as no difference in serum level of bilirubin, ALT or AST 84 . Also, nanoparticles based on chitosan/poly-γ-glutamic acid were not toxic after per os administration of 100 mg/kg, daily for 14 days as showed by the lack of histopathological signs in the liver, kidney and in intestine and no alteration of ALT and AST. ...
Gram‑negative spiral‑shaped Helicobacter pylori (Hp) bacteria induce the development of differentgastric disorders. The growing resistance of Hp to antibiotics prompts to search for new therapeuticformulations. A promising candidate is Mycobacterium bovis BCG (BCG) with immunomodulatoryproperties. Biodegradable mucoadhesive chitosan is a good carrier for delivering BCG mycobacteria tothe gastric mucosal environment. This study aimed to show whether BCG bacilli are able to increasethe phagocytic activity of Cavia porcellus—guinea pig macrophages derived from the bone marrowtowards fluorescently labeled Escherichia coli. Furthermore, to encapsulate live BCG bacilli, in spray‑dried chitosan microparticles (CHI‑MPs), and assess the pH‑dependent release of mycobacteria inpH conditions mimicking gastric (acidic) or gut (alkaline) milieu. Microparticles (MPs) were made ofchitosan and coated with Pluronic F‑127‑(Plur) or N‑Acetyl‑d‑Glucosamine‑(GlcNAc) to increase theMPs resistance to low pH or to increase anti‑Hp effect, respectively. Spray‑drying method was used formicroencapsulation of live BCG. The biosafety of tested CHI‑MPs has been confirmed using cell modelsin vitro and the model of guinea pig in vivo. The CHI‑MPs loaded with BCG released live mycobacteriaat pH 3.0 (CHI‑GlcNAc‑MPs) or pH 8.0. (CHI‑Plur‑MPs). The CHI‑MPs loaded with live BCG can beused for per os inoculation of Cavia porcellus to check the effectiveness of delivered mycobacteria inincreasing anti‑H. pylori host response.
... Nanoparticles could, in fact, address many of the needs associated with paediatric medications, this is due to their ability to: 1) modify drug properties 2) taste masking which makes the taste of drugs more palatable to young patients 3) simplify drug administration 4) to achieve an extended drug release, reducing the number of doses required and improving both patient and parental compliance; 5) when targeting drugs; 6) to make it simple to adjust dosages as children grow; 7) and to make it possible to combine more medications in one formulation (González et al., 2021). Because of the stability and controlled delivery of the drugs from nanoparticles, oral administration is made possible (Pandey and Khuller, 2004). ...
Paediatric Tuberculosis (TB) continues to be a major global cause of morbidity and mortality. Children are more prone to contracting TB, which can spread quickly to extrapulmonary infection sites. Although the pathophysiology of the disease, drug pharmacokinetics, and the therapeutic window in children differ from those of adults, the same drugs used to treat adult TB have long been utilised to treat paediatric TB infections. Since many current formulations such as tablets are unsuitable for children due to difficulty swallowing and risk of choking, adult medications are frequently used by breaking or crushing tablets to obtain a paediatric dose. This can result in inaccurate dosing due to pharmacokinetic differences in children which could subsequently lead to sub-therapeutic or toxic systemic concentrations. In addition, many of the medications used in the treatment of TB and most medicines in general, have a profoundly unpleasant taste to children causing them to reject and spit out medication which contributes to challenges with adherence, ultimately leading to treatment failure. The aforementioned demonstrates a huge need for the development of novel drug delivery formulations that are paediatric-friendly and address the limitations of current dosage forms. This review discusses the currently available oral paediatric formulations, recent developments of novel oral drug delivery systems studied to overcome the current problems associated with the treatment of tuberculosis in paediatrics and provides potential direction for future research through nanotechnology by using a SWOT analysis.
... Prescribed dosages of MS administered over a 10-day period to guinea pigs infected with Mycobacterium TB H37Rv resulted in the elimination of the bacteria, within 10 days, comparable to the standard 6-week treatment. Thus, the dosage of drugs is reduced by half when using MS [108]. In another trial, CMs carrying cefradine grafted ethyl cellulose retained their drug's plasma level consistently for 24 h, helping in enhanced drug absorption in the intestine [109]. ...
Chitosan is a natural biodegradable polymer that is recovered from marine shell wastes. It has been widely employed in anticancer, antioxidant, and antibacterial applications due to its outstanding qualities, including biological compatibility, muco-adhesivity, hemocompatibility, and biodegradability. The contributions of this polymer have established it with respect to biomedical applications. The distinct morphologies of chitosan, such as in nanoparticulate and microparticulate for MS and as derivatives and composites have extended its visages even beyond biomedicine. This review specifically summarizes the biomedical highlights of chitosan-based MS. Special attention has been focused on the antimicrobial accomplishments of chitosan-based MS. The impact of chitosan MS against bacteria, fungi and viruses has been reviewed. The gaps in its usage for antimicrobial investigations have been addressed. The lack of significant contribution from chitosan MS towards antifungal and antiviral applications has been explicitly highlighted. Future recommendations and the scope for expansion have been suggested.
... Numerous groups have reported compelling evidence using various kinds of polymeric nanoparticles and microparticles encapsulating various medications against mycobacteria in a variety of different animal TB model systems. Most of these experiments used the polymer poly (lactic-co-glycolic) acid (PLGA), with a few using chitosan or alginate [160,161]. Moreover, the most surprising findings in the realm of tuberculosis are statistics directly comparing traditionally delivered anti-M. ...
Tuberculosis (TB), one of the deadliest contagious diseases, is a major concern worldwide. Long-term treatment, a high pill burden, limited compliance, and strict administration schedules are all variables that contribute to the development of MDR and XDR tuberculosis patients. The rise of multidrug-resistant strains and a scarcity of anti-TB medications pose a threat to TB control in the future. As a result, a strong and effective system is required to overcome technological limitations and improve the efficacy of therapeutic medications, which is still a huge problem for pharmacological technology. Nanotechnology offers an interesting opportunity for accurate identification of mycobacterial strains and improved medication treatment possibilities for tuberculosis. Nanomedicine in tuberculosis is an emerging research field that provides the possibility of efficient medication delivery using nanoparticles and a decrease in drug dosages and adverse effects to boost patient compliance with therapy and recovery. Due to their fascinating characteristics, this strategy is useful in overcoming the abnormalities associated with traditional therapy and leads to some optimization of the therapeutic impact. It also decreases the dosing frequency and eliminates the problem of low compliance. To develop modern diagnosis techniques, upgraded treatment, and possible prevention of tuberculosis , the nanoparticle-based tests have demonstrated considerable advances. The literature search was conducted using Scopus, PubMed, Google Scholar, and Elsevier databases only. This article examines the possibility of employing nanotechnology for TB diagnosis, nanotechnology-based medicine delivery systems, and prevention for the successful elimination of TB illnesses.
... Previous literature reported deionized water (DI) as the solvent for solubilization and preparation of chitosanbased microsphere formulations [33]. Other studies reported the distilled water (DW) solvent for the preparation of microsphere formulations [34]. However, our preliminary solubility studies revealed poor solubility of chitosan in DI or DW, resulting in precipitation of chitosan from DI and DW during formulation. ...
Objective: Chitosan-based pregabalin microsphere (CBPM) formulation was prepared to improve in vitro mucoadhesion and absorption of pregabalin via intranasal administration. Methods: The CBPM formulations were prepared using the inotropic gelation method and optimized using the Box-behnken design. The optimized CBPM formulation was physico-chemically characterized using scanning electron microscopy, thermal analysis, Fourier transform infrared spectrometry and powder x-ray diffraction. Additionally, the CBPM formulation was characterized for functional parameters such as in vitro mucoadhesion, in vitro drug release, ex vivo permeability across the sheep nasal mucosa and in vivo anticonvulsant activity in pentylenetetrazol (PTZ)-induced seizures model in mice. Results: The design-optimized CBPM exhibited a 91.45 % inclusion efficiency of pregabalin in the microspheres. The Physico-chemical analysis of the individual components and the optimized formulation confirmed the formation of CBPM. The in vitro mucoadhesion study revealed ~80% mucoadhesive of the CBPM to the sheep nasal mucosa. The in vitro dissolution profiles of CBPM was significantly higher (~97%) than that of pure pregabalin (~70%). The CBPM displayed a higher rate and extent of permeability (~90%) than pure pregabalin (~76%) across the sheep nasal mucosa. The in vivo anticonvulsant activity showed that intranasal administration of CBPM resulted in significant (P<0.01) protection against PTZ-induced convulsions in mice. Conclusion: The chitosan-based microsphere intranasal formulation could be employed as promising delivery for rapid pregabalin absorption.
... The complexation of drug-loaded Ca-alginate microspheres with chitosan could reduce burst release and improve sustained release of drugs. For example, Pandey et al. used chitosan-Caalginate microspheres to carry anti-tuberculosis drugs, which was shown to maintain the therapeutic concentration of drugs in vivo (Pandey & Khuller, 2004). The effects of the size of microspheres as well as chitosan complexation on the in vitro release of acetaminophen were investigated. ...
We developed a miniature gas-liquid coaxial flow device using glass capillaries, aiming to produce sub-100-μm Ca-alginate microspheres. Depending on collecting distance and the flow rates of nitrogen gas and alginate solution, however, Ca-alginate microparticles of different shapes were obtained. Spherical, monodisperse microparticles (microspheres) could only be obtained at certain gas flow rates and within a corresponding range of collecting distance. The result suggests that, for particles of this size, the gas flow rate and collecting distance are crucial for the formation of the spherical shape. We evaluated, as an example of its applications, the microsphere as a drug carrier using acetaminophen as a model drug. Large (~150 μm) and small (~70 μm) drug-loaded microspheres were prepared using two respective devices. Specifically, the drug-loaded microspheres were complexed with chitosan of different molecular weights. The dependence of in vitro drug release on the microsphere size and the chitosan molecular weight was examined.
... Digestion method was used to determine TS content in the prepared microspheres (Pandey, Khuller, 2004) and the experiments were carried out in triplicate. One hundred micrograms of TS microspheres were crushed carefully in a glass mortar and a definite weight was transferred to a 100 mL volumetric flask using phosphate buffer pH 7.4 and completed to the volume using phosphate buffer pH 7.4. ...
Article Tolmetin sodium (TS) is a powerful non-steroidal mitigating drug for the treatment of rheumatoid joint inflammation, osteoarthritis, and adolescent rheumatoid joint pain. In addition to its gastrointestinal (GIT) problems, TS has a short biological half-life (1 hr). In a trial to overcome these side effects and control the rate of (TS) release, chitosan coated alginate microspheres are recommended. A Box-Behnken experimental design was employed to produce controlled release microspheres of TS in the sodium alginate and chitosan copolymers (Alg-Ch) by emulsification internal gelation methodology. The effect of critical formulation variables namely, drug to polymer ratio (D:P ratio), speed of rotation and span 80% on drug encapsulation efficiency (% EE), drug release at the end of 2 hours (Rel 2) and drug release at the end of 8 hours (Rel 8) were analyzed using response surface modeling. The parameters were assessed using the F test and mathematical models containing only the significant terms were generated for each parameter using multiple linear regression analysis. The produced microspheres were spherical in shape with extensive pores at D:P ratio 1:1 and small pores at a drug to polymer ratio (D:P ratio) 1:3. Differential scanning calorimetry (DSC) affirmed the steady character of TS in microspheres and revealed their crystalline form. All formulation variables examined exerted a significant influence on the drug release, whereas the speed emerged as a lone factor significantly influencing % EE. Increasing the D: P ratio decreases the release of the drug after two and 8 hours. The increase in speed results in an increase in drug release after two and eight hours. The drug release from the microspheres followed zero order kinetics. TS Alg-Ch microspheres exhibited a significant anti-inflammatory effect on incited rat paw edema after eight hours. These results revealed that the internal gelation technique is a promising method to control TS release and eradicate GIT side effects using Alg-Ch copolymers.
... The crosslinked polymer network can be altered to tune the mechanical properties, degradation ability, stimuli-responsive nature, and functionalization with drugs and ligands (macromolecules, proteins, bioactive compounds). Several polymers were widely used to prepare hydrogels such as PLGA, PCL, alginate, poly(ethylene-glycol)-cl-polyethyleneimine, chitosan, and dextrins [114][115][116]. A PMAA-based nanogel loaded with rifampicin and isoniazid showed a sustained release via oral administration. ...
The Mycobacterium tuberculosis bacterium causes pulmonary tuberculosis (TB), and it is the second-deadliest infectious agent after HIV. Several antitubercular drugs are used for treatment. The frequent utilization of various drugs and their combination action is the reason for the development of drug-resistant tuberculosis. So there is a need for an effective drug-delivery system to control drug-resistant strains while also reducing the treatment regimen and side effects. A nano drug-delivery regimen is more effective at controlling TB while also being a promising delivery system for drug administration in various routes. It also controlled the release, reduced the dosage, increased the half-life, had a higher drug concentration at target sites, reduced toxicity, and lessened side effects. This chapter emphasizes various nanotechnology-based therapies that can be used for antitubercular drug delivery.
... (i) lonotropic gelation with an oppositely charged polyelectrolyte, such as sodium tripolyphosphate (Mi et a l, 1999a), calcium alginate (Pandey and Khuller, 2004). ...
The research described in this thesis was undertaken to formulate chitosan hydrogels and microspheres and to investigate the in vitro and in vivo electro-responsive drug release from the hydrogels and microspheres. Hydrogels of medium molecular weight and high molecular weight chitosan were prepared by N-acetylation of chitosan. The gels were homogeneous, clear and transparent. Swelling ratios and loading efficiencies (for the two model drugs, diclofenac sodium and metformin hydrochloride) of medium and high molecular weight hydrogels were similar. The hydrogels stimulated with pulses of 0.4 mA electrical electric current (30 min on and 30 min off; 6 cycles) released more drugs compared to unstimulated gels. More drug was released during the pulse 'on' periods than during the pulse 'off’. However, a definite 'on-off’ release was not evident from the in vitro release study. The high molecular weight hydrogels were generally found to be more sensitive to electric current than medium molecular weight gels and released more drugs. In addition, the higher the drug concentration in the gels, the greater the release. Thus for the in vivo release studies in male Wistar rats, high molecular weight gels loaded with the higher concentration of diclofenac sodium was used. The subcutaneously implanted hydrogels stimulated with 0.4 mA electric pulses released more drug during electric application compared to the electric 'off' periods, though it was not statistically significant. Microspheres of low molecular weight chitosan were prepared by crosslinking with various concentrations of glutaraldehyde and subsequently spray drying the solution. The particles obtained were 2-5 μm in diameter and had surface charge of 35-42 mV. Compared to the higher crosslinked particles, lower crosslinked microspheres had higher entrapment efficiencies for the model drugs and released more drugs when electro-stimulated. As for hydrogels, the electro-stimulated microspheres release more drug than the control microspheres in both in vitro and in vivo experiments. Drug diffusion out of the microspheres along a concentration gradient which occurred under passive conditions meant that a definite 'on-off’ release profile was not obtained. Further work must be conducted to optimise the hint of pulsatile release observed in the experiments.
... Development of carrier/delivery systems that release drugs in a sustained manner at therapeutic concentration over a period of time can ensure patient compliance in terms of reducing dosing frequency, and may also minimize the risk of emergence of drug resistant mutants and potential toxicity. Various carrier systems such as liposomes and microspheres have been developed for the sustained delivery of anti-TB drugs with better chemotherapeutic efficacy [5][6][7] . However, these formulations have to be injected either subcutaneously or intravenously, which, in general, is not acceptable [8] . ...
Objective: Inter polyelectrolyte complexes (IPECs) are an emerging biocompatible polymeric carrier system to transport active substances at target sites. The aim of this study was to evaluate the use of hydrophobic waxy retardant polymer glyceryl monooleate in hydrophilic inter polyelectrolyte matrix system containing three principal anti-tubercular drugs (ATDs). Sustained release polymeric matrix system was prepared by melt granulation technique, which allowed for the manufacture of the multi-layered tablets for segregated delivery of rifampicin, isoniazid and pyrazinamide. Material and methods: The matrix system consisting of hydrophilic IPEC of chitosan and carboxymethyl guar gum in combination with hydrophobic waxy retardant polymer, prepared by melt granulation technique was found to achieve segregated delivery of rifampicin, isoniazid and pyrazinamide. The applicability of piperine, an organic alkaloid as bio enhancer and rifampicin-sodium lauryl sulphate (SLS) complex was tested for improvement in bioavailability of antituberculosis fixed dose combination (FDC), lowering dosage levels and shortening the treatment course. Results: There was no incompatability observed between drug and excipeints based upon FTIR, DSC and X-RD studies. The optimized tablet (composition IPEC 46 % w/w (275mg), glyceryl monooleate 2 % w/w (11.5mg), piperine 1 % w/w (5 mg), pyrazinamide (150mg), isoniazid (50mg) and rifampicin-SLS complex (95.2mg) sustained the delivery of drugs for 12 h. IPECs alone lack sufficient mucoadhesion hence, suitable combination of polymeric blends along with IPEC played a key role in controlling the initial burst release pattern, desired bioadhesion (14.25g) and swelling index (1248.8%). Conclusion: This biocompatible, biodegradable and naturally renewable polymeric matrix system could be successfully utilized in a FDC to maximally release ATDs in a sustained manner achieving complete dissolution.
... Moreover, intratracheal administration of alginate-chitosan carrier caused some haptic toxicity. This contradicts previous reports where oral administration of the same carrier in Guinea pigs did not cause any hepatic abnormalities [57]. This could be attributed to differences in studied species (rats versus Guinea pigs), route of administration (intratracheal versus oral), or the alginate-chitosan carrier preparation technique (supercritical fluid technology versus chemical crosslinking using calcium chloride). ...
This study aims to prepare hybrid chitosan-alginate aerogel microparticles without using
additional ionic crosslinker as a possible pulmonary drug delivery system. The microparticles were prepared using the emulsion gelation method. The effect of the mixing order of the biopolymer within the emulsion and the surfactant used on final particle properties were investigated. Physicochemical characterizations were performed to evaluate particle size, density, morphology, surface area, surface charge, and the crystallinity of the preparation. The developed preparation was evaluated for its acute toxicity in adult male Sprague-Dawley rats. Measurements of zeta potential suggest that the surface charge depends mainly on the surfactant type while the order of biopolymer
mixing has less impact on the surface charge. Chitosan amphiphilic properties changed the hydrophilic-lipophilic balance (HLB) of the emulsifying agents. The specific surface area of the prepared microparticles was in the range of (29.36–86.20) m2/g with a mesoporous pore size of (12.48–13.38) nm and pore volume of (0.09–0.29) cm3/g. The calculated aerodynamic diameter of the prepared particles was in the range of (0.17–2.29 μm). Toxicity studies showed that alginate-chitosan carrier developed herein caused mild lung inflammation with some renal and hepatic toxicities.
... Implants or microparticles can promote a reduction in dosing frequency as an aid to patient compliance (du Toit et al. 2006). Nanoparticles are under investigation as oral, inhalation, and intravenous dosage forms (Gelperina et al. 2005) and microspheres with a payload o f anti-TB drugs have shown an increased bioavailability, long half-life, and high stability (Pandey & Khuller 2004). Use o f these systems may reduce dosing frequency and improve treatment options. ...
Background: The development of new treatments for tuberculosis is a public health priority. We have shown that a South African native remedy for respiratory ailments, based on extracts of Pelargonium reniforme and P. sidoides, contain fatty acids with antimycobacterial activity. In order to further assess their potential as a supplement to conventional therapy, we examined root extracts of these plants for the capacity to stimulate the uptake and intracellular killing of mycobacteria by macrophages. Methods: Murine peritoneal macrophages were obtained by lavage and incubated with Mycobacterium fortuitum. Extract-mediated stimulation of bacterial uptake was determined by enumeration of stained intracellular bacteria; the effect of extracts on intracellular killing was evaluated by spread plate counting of bacteria within macrophages. Bioactive extracts, obtained by sequential extraction with solvents of increasing polarity, were subjected to bioassay-guided fractionation using size exclusion and ion exchange chromatography. HPLC, NMR and mass spectroscopy were used to identify compounds of interest. Active compounds were examined for their capacity to stimulate macrophage uptake of M. tuberculosis. Results: Root powders were sequentially extracted with hexane, ethyl acetate, ethanol, 50% ethanol/water and water; aqueous fractions had a greater capacity to stimulate uptake and killing of M. fortuitum compared to other fractions. P. reniforme extracts possessed significantly greater stimulating activity than P. sidoides extracts. Fractions obtained by bioassay-guided fractionation of P. reniforme aqueous extracts contained a small number of chemically distinct structures, the most prominent being gallic acid, methyl gallate, myricetin and quercetin 3-D-glucoside. Highly pure preparations of these compounds (2-25 μg/ml) stimulated macrophage killing of M fortuitum and M tuberculosis. Conclusion: Representatives of the plant genus Pelargonium elaborate metabolites that increase the capacity of mice peritoneal macrophages to internalize and kill mycobacteria, including M. tuberculosis.
... Though, this previously reported study did not report histopathological examination and was conducted on a different animal species. Moreover, the intratracheal route was used in our study as opposed to the oral route in the previous report (52). Also, intratracheal administration of drug-free hyaluronic acid was reported before to result in milder inflammation as compared to that from treatment with cisplatin-loaded hyaluronic acid-based carrier (34). ...
Polysaccharide-based aerogels are promising drug carriers. Being nanoporous with a high specific surface area allows their use as a drug vehicle for various delivery routes. Intratracheal and intravenous administration of free cisplatin causes toxicity in the rat liver, lungs, and kidneys. In this work, microspherical particles based on alginate-chitosan without a traditional crosslinker were evaluated for targeted delivery of cisplatin by intratracheal administration. The aerogel particles were prepared using the emulsion gelation method, followed by supercritical carbon dioxide extraction. Loading of cisplatin on the prepared porous particles was performed by impregnation using supercritical fluid technology. The prepared carrier and the loaded drug were evaluated for drug content, release, and in vivo acute and subacute toxicity. Cisplatin was successfully loaded (percent drug loading > 76%) on the prepared carrier (particle size = 0.433 ± 0.091 μm) without chemically interacting with the carrier and without losing its crystal form. Sixty percent of cisplatin was released within 2 h, and the rest was loaded inside the polymer pores and had a sustained first-order release over 6 h. Loading cisplatin on the carrier developed herein reduced the cisplatin lung toxicity but increased the liver toxicity after intratracheal administration with nephrotoxicity being proportional to cisplatin dose in case of carrier-loaded cisplatin. Moreover, loading cisplatin on the carrier significantly reduced mortality rate and prevented weight loss in rats as compared to free cisplatin in subacute studies after intratracheal administration. Thus, the developed carrier showed high potential for targeted delivery of cisplatin for lung cancer treatment by inhalation.
Graphical abstract
... The preparation of beads/microspheres/microparticles by this method result in low entrapment efficiency of drug due to the release of drug during curing in calcium chloride solution, and also give the unextended release of drug, especially for soluble and low molecular weight of drugs. [8][9][10][11] In the present research, a new method without immersion the matrices in calcium chloride was performed to obtain the high entrapment efficiency and to produce extended release of drug. The product was called " Alg-Ch matrices". ...
Alginate (Alg) is a polyanionic polymer whereas chitosan (Ch) is a polycationic polymer. The purpose of this study was to compare the swelling, mucoadhesive, and release of ranitidine HCl (RH) from the spherical matrices of Alg, Ch, Alg-Ch and calcium alginate-chitosan (Ca Alg-Ch). The spherical matrices containing RH were prepared by incorporating RH with sodium Alg and/or Ch with the aid of starch mucilage to form a compact mass. This compact mass was then molded to form spherical matrices with diameter of 8.8 mm. For the preparation of Ca Alg-Ch matrices, the Alg-Ch matrices were then immersed in calcium chloride solution. The release of RH and swelling of matrices were measured by using the USP paddle method in simulated gastric fluid (SGF). RH concentrations were determined spectrophotometrically at the wavelength of 224.6 nm. The mucoadhesive force was measured in rabbits stomachs using DuNouy tensiometer. The results showed that the release of RH from Alg-Ch matrices gave the most extended release, followed by matrices of Ca Alg-Ch and then Alg matrices, while Ch matrices did not give extended release of the drug. The Higuchi plot of the release of RH from spherical matrices of Alg, Ch, Alg-Ch, and Ca Alg-Ch showed stright line with regressions coefficient (R 2) of 0.9470, 0.9638, 0.9932, and 0.9837, respectively. The drug release mechanism is anomalous or non-Fickian type. Alg-Ch matrices exhibited the greatest degree of swelling followed by Ca Alg-Ch and then Alg matrices, but Ch matrices eroded in SGF. Alg-Ch matrices showed the strongest mucoadhesive property followed by Ca Alg-Ch, Alg, and Ch matrices. It is concluded that the spherical of Alg-Ch matrices possess the highest swelling degree and mucoadhesive strength, and give the most extended of drug release in SGF than other matrices tested.
... Metformine represent drug of diabetes mellitus that is consumed by goodness patient of type diabetes 1 and also type 2 [1.2]. Metformine is permeated by digestive system better and has biologist bill time is short is around 2-5 hours [3]. Biologist bill time drug is short because patients have to consume drug of continuously. ...
... The properties like biocompatibility, biodegradability and non-toxicity of Sodium alginate made it suitable for its use in the field of drug delivery. The United States Food and Drug Administration has recommended Sodium alginate (SA) for oral use [7][8] and is enriched with the property of hydrophilicity (which protect it from fast uptake by the reticuloendothelial system). It is a natural polysaccharide, rich in carboxyl group and is easy to bind with positive charge cations such as Ca 2+ . ...
Fabrication and evaluation of the Isoniazid loaded sodium alginate nanoparticles (NPs) was main objective of current investigation. These NPs were engineered using ionotropic gelation technique. The NPs fabricated, were evaluated for average particle size, encapsulation efficiency, drug loading, and FTIR spectroscopy along with in vitro drug release. The particle size, drug loading and encapsulation efficiency of fabricated nanoparticles were ranging from 230.7 to 532.1 nm, 5.88% to 11.37% and 30.29% to 59.70% respectively. Amongst all batches studied formulation F-8 showed the best sustained release of drug at the end of 24 hours.
... Chitosan, which is sourced from crustaceans, exists as a cationic polysaccharide at low pH and can complex with negative polyions to produce polyelectrolytes useful as carriers for drug delivery (Hamman J.H., 2010;Nagpal K. et al., 2010;Pandey R. and Khuller G.K., 2004). Chitosan nanoparticles have been explored for various vaccines (Illum L. et al., 2001), including Mycobacterium tuberculosis (MTB) (Feng G. et al., 2013), diphtheria (van der Lubben I.M. et al., 2003), pertussis (Jabbal-Gill I. et al., 1998) influenza (Amidi M. et al., 2007;Sawaengsak C. et al., 2014), and pneumococcal diseases (Xu J. et al., 2011). ...
Immunization can be traced back to classical China. Modern immunization reduces the risk of infection by attenuating or killing the pathogen or using non-infectious antigens to elicit the immune response. The challenge of immunization is to raise a robust protective response without infecting the individual or overstimulating the immune response, and this can be achieved by using nanoparticle delivery systems to specifically target the innate immune system with known antigens and where necessary include an adjuvant to enhance the efficacy. These systems can be targeted to mucosal sites that are located throughout the body with the nasal and pulmonary routes of administration allowing ease of access. Macrophages are the first line of defense of the innate immune system and are the host cell for primary intracellular infection by several respiratory pathogens notably mycobacteria and streptococci. The breadth of nanoparticle technology available to deliver vaccines has been explored and consideration of its value in nasal and pulmonary delivery is addressed specifically.
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... 50 days administration of these formulation to mice substantially cleared bacteria from different organs 2003b [99] PLG RIF, INH, PZA Only a single subcutaneous dose of microparticle was sufficient to maintain drug plasma, lungs and spleen over more than one month. In addition chemotherapeutic efficacy was found to be more efficient than daily dose of free drugs leading to clearance of bacterial count from several organs 2004 [100] PLG RIF, INH, PZA PLG microparticle ligant bound with wheat germ agglutinin loaded with these three drugs and three doses were administered fore-nightly for 45 days which was able to produce sterilizing effects in lungs and spleen 2004 [84] PLG RIF, INH, PZA Studied to evaluate chemotherapeutic efficacy of these three anti-tubercular drugs loaded in PLG NP at sub-therapeutic dose (2/3 rd of therapeutic dose) by administering orally to guinea pigs. Single dose given resulted into sustained release of the drug for 7-12 days in plasma and 11-14 days in the organs with pronounced improvement in mean residence time and bioavailability. ...
In spite of advances in tuberculosis (TB) chemotherapy, TB is still air-born deadly disorder as major issue of health concern worldwide today. Extensive researches have been focused to develop novel drug delivery systems to shorten the lengthy therapy approaches, prevention of relapses, reducing dose related toxicities and to rectify technological related drawbacks of anti-tubercular drugs. Moreover, rapid emergence of drug resistance, poor patient compliance due to negative therapeutic outcomes and intracellular survival of Mycobacterium highlighted to develop carrier with optimum effectiveness of the anti-tubercular drugs. This could be achieved by targeting and concentrating the drug to the infection reservoir of Mycobacterium. In this article, we briefly compiled the general aspects of Mycobacterium pathogenesis, disease treatment along with progressive updates in novel drug delivery carrier system to enhance therapeutic effectiveness of drug and the high level of patient compliance. Recently developed several vaccines might be shortly available as reported by WHO.
... Particularly useful in the controlled release of polar peptide drugs or even vaccines (a specimen of biological origin containing antigens that may include live, weakened virulence/attenuated or killed microorganism, as well as other fragments of its structure or metabolites) through oral and nasal delivery are chitosan's microspheres. Microspheres are obtained in the process of complexation of cationic chitosans with anionic tripolyphosphate or alginates [148,149]. "As active substances introduced into the microspheres, various drugs and vaccines were used" [150,151]. It was found that in such a form, the loaded active substances are protected in the digestive tract and are released and adsorbed on the epithelial layer [152]. ...
Derived from chitin, chitosan is a natural polycationic linear polysaccharide being the second most abundant polymer next to cellulose. The main obstacle in the wide use of chitosan is its almost complete lack of solubility in water and alkaline solutions. To break this obstacle, the structure of chitosan is subjected to modification, improving its physic-chemical properties and facilitating application as components of composites or hydrogels. Derivatives of chitosan are biomaterials useful for different purposes because of their lack of toxicity, low allergenicity, biocompatibility and biodegradability. This review presents the methods of chemical modifications of chitosan which allow to obtain tailor- made properties required for a variety of biomedical applications. Selected pharmaceutical and biomedical applications of chitosan derivatives are also highlighted. Possibility to manage waste from arthropod and crab processing is also emphasized.
... In the nanoparticulate system, drug starts releasing after administration and then moves into the infected cells in a controlled manner (11). The polymer poly (lactic-coglycolic acid) (PLGA) gained the attention of researchers because of its desirable drug delivery (12). PLGA is one of the most useful biodegradable polymer which produces two metabolic monomer units, i.e., lactic acid and glycolic acid after hydrolysis. ...
Enhancement of the aqueous solubility of rifampicin (RMP) via HPMA (N-2-hydroxypropylmethacrylamide)-PLGA based polymeric nanoparticulate system to manage Tuberculosis.
... In the nanoparticulate system, drug starts releasing after administration and then moves into the infected cells in a controlled manner (11). The polymer poly (lactic-coglycolic acid) (PLGA) gained the attention of researchers because of its desirable drug delivery (12). PLGA is one of the most useful biodegradable polymer which produces two metabolic monomer units, i.e., lactic acid and glycolic acid after hydrolysis. ...
Purpose
Tuberculosis (TB) chemotherapy witnesses some major challenges such as poor water-solubility and bioavailability of drugs that frequently delay the treatment. In the present study, an attempt to enhance the aqueous solubility of rifampicin (RMP) was made via co-polymeric nanoparticles approach. HPMA (N-2-hydroxypropylmethacrylamide)-PLGA based polymeric nanoparticulate system were prepared and evaluated against Mycobacterium tuberculosis (MTB) for sustained release and bioavailability of RMP to achieve better delivery.
Methodology
HPMA-PLGA nanoparticles (HP-NPs) were prepared by modified nanoprecipitation technique, RMP was loaded in the prepared NPs. Characterization for particle size, zeta potential, and drug-loading capacity was performed. Release was studied using membrane dialysis method.
Results
The average particles size, zeta potential, polydispersity index of RMP loaded HPMA-PLGA-NPs (HPR-NPs) were 260.3 ± 2.21 nm, −6.63 ± 1.28 mV, and 0.303 ± 0.22, respectively. TEM images showed spherical shaped NPs with uniform distribution without any cluster formation. Entrapment efficiency and drug loading efficiency of HPR-NPs were found to be 76.25 ± 1.28%, and 26.19 ± 2.24%, respectively. Kinetic models of drug release including Higuchi and Korsmeyer-peppas demonstrated sustained release pattern. Interaction studies with human RBCs confirmed that RMP loaded HP-NPs are less toxic in this model than pure RMP with (p < 0.05).
Conclusions
The pathogen inhibition studies revealed that developed HPR-NPs were approximately four times more effective with (p < 0.05) than pure drug against sensitive Mycobacterium tuberculosis (MTB) stain. It may be concluded that HPR-NPs holds promising potential for increasing solubility and bioavailability of RMP.
... Caffeine is the most widely consumed psychoactive or central nervous system (CNS) stimulant in the world [25]. Once ingested it is rapidly absorbed into the blood stream and immediately affects CNS leading to increased alertness, reduced drowsiness and boosted energy level. ...
One of the major challenges with microencapsulation and delivery of low molecular weight bioactive compounds is their diffusional loss during storage and process conditions as well as under gastric conditions. In an attempt to slow down the release rate of core material, electrospray fabricated calcium alginate microhydrogels were coated with low molecular weight and high molecular weight chitosans. Caffeine as a hydrophilic model compound was used due to its several advantages on human behavior especially increasing consciousness. Mathematical modeling of the caffeine release by fitting the data with Korsmeyer-Peppas model showed that Fick's diffusion law could be the prevalent mechanism of the release. Electrostatic interaction between alginate and chitosan (particularly in the presence of 1% low molecular weight chitosan) provided an effective barrier against caffeine release and significantly reduced swelling of particles compared to control samples. The results of this study demonstrated that calcium alginate microhydrogels coated by chitosan could be used for encapsulation of low molecular compounds. However, more complementary research must be done in this field. In addition, electrospray, by producing monodisperse particles, would be as an alternative method for fabrication of microparticles based on natural polymers.
... 28,29 Many natural occurring proteins and polymers such as the plant protein zein, the collagen degradation product gelatin, as well as plant derived alginate and chitosan have been explored as biodegradable, biocompatible slow release mechanisms for anti-TB drug delivery. 30,31 Oral nanoparticle formulations consisting of carriers derived from these agents have demonstrated sustained therapeutic plasma drug concentrations of INH/RIF/PZA/EMB for up to 5-7 days in single dose animal models. 32 More recently, the field of TB drug delivery has migrated toward nano-particle formulations, summarized by Pandey et al. 33 Using the LEAP modelling core, computational simulations were utilized to simulate potential LA administration strategies for four anti-TB agents. ...
Long-acting/extended-release drug formulations have proved very successful in diverse areas of medicine, including contraception, psychiatry and, most recently, human immunodeficiency virus (HIV) disease. Though challenging, application of this technology to antituberculosis treatment could have substantial impact. The duration of treatment required for all forms of tuberculosis (TB) put existing regimens at risk of failure because of early discontinuations and treatment loss to follow-up. Long-acting injections, for example, administered every month, could improve patient adherence and treatment outcomes. We review the state of the science for potential long-acting formulations of existing tuberculosis drugs, and propose a target product profile for new formulations to treat latent tuberculous infection (LTBI). The physicochemical properties of some anti-tuberculosis drugs make them unsuitable for long-acting formulation, but there are promising candidates that have been identified through modeling and simulation, as well as other novel agents and formulations in preclinical testing. An efficacious long-acting treatment for LTBI, particularly for those co-infected with HIV, and if coupled with a biomarker to target those at highest risk for disease progression, would be an important tool to accelerate progress towards TB elimination.
... The use of synthetic polymers is commonly associated with two main limitations: need to use organic solvents in the development process, and high cost of polymers. On the other hand, natural polymers (e.g., alginate and chitosan) have a low cost production, and require a minimal use of organic solvents (Pandey and Khuller, 2004;Tonnesen and Karlsen, 2002). Chitosan is a natural polymer, being one of the most studied polysaccharides. ...
Current estimates indicate that tuberculosis (TB) is the leading cause of death worldwide, alongside the infection by the human immunodeficiency virus (HIV). The current treatment is effective, but is associated with severe adverse effects, and noncompliance to prescribed regimens. Recent advances and emerging technologies in nanoscale systems, particularly nanoparticles, have the potential to encapsulating antituberculosis (anti-TB) drugs efficiently, eliciting controlled drug release, and to overcome the need to administer the anti-TB drugs at high and frequent doses; this would assist in improving patient compliance, and circumvent the drugs’ side-effects. Up to this point, several nanodelivery systems for the oral administration of anti-TB drugs have been intensively studied, and their utility as an alternative to the classical TB treatment has been suggested. In this context, a comprehensive analysis of recent progress in nanodelivery systems for the oral administration of anti-TB drugs will be provided in this chapter. Research using different types of nanoparticles, and the advantages of the noninvasive oral route, will also be discussed. Lastly, the future of this growing field and its potential impact will be reviewed.
... The estimated amount of RIF per embryo was approximately 14.4 ng. This concentration was chosen as a result of previous successful therapy against tuberculosis in a mouse model (Pandey & Khuller 2004). The concentration of RIF and OXA in NLC preparations was 14.6 and 7.4 mg ml −1 , respectively. ...
We tested the efficiency of two different antibiotics, rifampicin and oxolinic acid, against an established infection caused by fish pathogen Francisella noatunensis ssp. orientalis (F.n.o.) in zebrafish. The drugs were tested in the free form as well as encapsulated into biodegradable nanoparticles, either polylactic-co-glycolic acid (PLGA) nanoparticles or nanostructured lipid carriers. The most promising therapies were PLGA-rifampicin nanoparticles and free oxolinic acid; the PLGA nanoparticles significantly delayed embryo mortality while free oxolinic acid prevented it. Encapsulation of rifampicin in both PLGA and nanostructured lipid carriers enhanced its efficiency against F.n.o. infection relative to the free drug. We propose that the zebrafish model is a robust, rapid system for initial testing of different treatments of bacterial diseases important for aquaculture.
... These consist of (1) aqueous background within the matrix, (2) adhesive interface with intestinal epithelium, (3) drug encapsulation process without the use of organic solvent, (4) high gel porosity permitting high diffusion rate of macromolecules, (5) capacity to control this porosity with easy coating measures using polycations, (6) biodegradation of the system under physiological conditions, (7) sustained drug release, and (8) being nontoxic. For all the rationales mentioned above, alginate is utilized as a carrier for the controlled discharge of several molecules of clinical concern including indomethacin [87], gentamicin [88], insulin [89], anticancer drugs [90], and ATDs [91][92][93]. González-Rodríguez et al. have developed ATD-loaded alginate nanoparticles by means of ionotropic gelation with fairly high encapsulation efficiency ranging between 80 and 90% for rifampicin, 70 and 90% for isoniazid and pyrazinamide, and 88 and 95% for ethambutol [94]. After oral administration of this formulation, drugs were observed in plasma for 7, 9, 11, and 12 days for ETB, RIF, INH, and PYZ, respectively, and in tissues until day 15, in contrast to free drugs which were cleared from blood after 12 to 24 hrs and were detectable in tissues only until day 1 [94]. ...
Tuberculosis, commonly known as TB, is the second most fatal infectious disease after AIDS, caused by bacterium called Mycobacterium tuberculosis . Prolonged treatment, high pill burden, low compliance, and stiff administration schedules are factors that are responsible for emergence of MDR and XDR cases of tuberculosis. Till date, only BCG vaccine is available which is ineffective against adult pulmonary TB, which is the most common form of disease. Various unique antibodies have been developed to overcome drug resistance, reduce the treatment regimen, and elevate the compliance to treatment. Therefore, we need an effective and robust system to subdue technological drawbacks and improve the effectiveness of therapeutic drugs which still remains a major challenge for pharmaceutical technology. Nanoparticle-based ideology has shown convincing treatment and promising outcomes for chronic infectious diseases. Different types of nanocarriers have been evaluated as promising drug delivery systems for various administration routes. Controlled and sustained release of drugs is one of the advantages of nanoparticle-based antituberculosis drugs over free drug. It also reduces the dosage frequency and resolves the difficulty of low poor compliance. This paper reviews various nanotechnology-based therapies which can be used for the treatment of TB.
... A wide range of compounds including aminoglycosides [6], antiviral drugs [7], b-lactam antibiotics [8], antifungals [9], and ATDs [10] have been successfully formulated into natural carrier systems. As far as ATDs are concerned, lipid-based formulations [11] as well as polymer-based formulations such as alginate (ALG) [12,13] have been developed with proven therapeutic efficacy in experimental TB. ...
p>ABSTRACT
Objective: To prepare Nanoparticulate dosage form having improved drug bioavailability and reduced dosing frequency of antitubercular drugs
which will helps in improving patient compliance in the treatment of multi-drug resistant tuberculosis (MDR-TB).
Methods: Ionotropic gelation method was used to prepare D-cycloserine (D-CS)-loaded alginate-chitosan nanoparticles, and the particles are
characterized by their particle size and morphology using particle size analyzer and scanning electron microscopy (SEM). X-ray diffraction (XRD),
differential scanning calorimetry (DSC), and Fourier-transformed infrared (FTIR) studies were used to determine drug-polymer interactions and drug
entrapment. Entrapment efficiency, drug loading (DL), particle size, and zeta potential of nanoparticles were also studied. The 2
factorial designs of
experiments by Design-Expert
®
V9 were used to optimize the particle size and entrapment efficiency of nanoparticles.
Results: The optimized batch had shown the entrapment efficiency of 98.10±0.24% and DL of 69.32±0.44% with particle size and zeta potential
as 344±5 nm and −42±11.40 mV, respectively. DSC, FTIR, and XRD studies confirmed the drug entrapment within nanoparticle matrix. SEM results
showed spherical-shaped particles. Sustained release of drug from the nanoparticles was observed for 24 hrs period. Respirable fraction up to
52.37±0.7% demonstrates the formulation suitability for deep lung delivery. Lung inflammatory study showed a less inflammatory response.
Conclusion: Ionotropic gelation method can be used to prepare biocompatible particles with a high entrapment efficiency, DL, optimum particle size,
and controlled release characteristics, which can serve as a convenient delivery system for D-CS and could be a potential alternative to the existing
conventional therapy in MDR-TB.
Keywords: Nanoparticles, Alginate, Chitosan, Inhalation, Sustained release, Tuberculosis.
3</p
... Calcium alginate has been used as a biodegradable support for water decontamination reagents ( Benhouria, Islam, Zaghouane-Boudiaf, Boutahala & Hameed, 2015;Jain, Garg, Kadirvelu & Sillanpää, 2015;Kuang et al., 2015) as well as scaffold for cell cultures ( Cuadros, Erices & Aguilera, 2015). For instance, calcium alginate has also been used for drug delivery such as the parenteral delivery of chemotherapeutics ( Pandey & Khuller, 2004) and topical drug applications such as wound healing dressings ( Pankongadisak, Ruktanonchai, Supaphol & Suwantong, 2015). Calcium alginate is also used in the preparation of sustained release oral delivery systems such as floating ( Nayak, Jain & Pandey, 2011), mucoadhesive ( Adebisi, Laity & Conway, 2015) and colon targeted formulations ( Bansal, Gulbake, Tiwari & Jain, 2016). ...
The ability to engineer biocompatible polymers with controllable properties is highly desirable. One such approach is to cross-link carbohydrate polymers using ionotropic gelation (IG). Previous studies have investigated the effect of curing time on alginate cross-linking. Herein, we discuss a novel study detailing the effect of IG residence time (IGRT) on the cross-linking of alginate with calcium ions (Ca²⁺) along with water migration (syneresis) and their subsequent impact on the pharmaceutical properties of alginate particles. IGRT was shown to have a significant effect on particle size, porosity, density, mechanical strength and swelling of calcium alginate particles as well as drug release mechanism. Furthermore, we describe a novel application of electron dispersive spectroscopy (EDS), in conjunction with Fourier Transform- infra red (FT-IR) spectroscopy, to analyze and monitor the changes in Ca²⁺ concentration during cross-linking. A simple procedure to determine the concentration and distribution of the surface and internal Ca²⁺ involved in alginate cross-linking was successfully developed.
... The main of the cur- and dextrins [135,136]. Some of these polymers were already used 827 to produce nanosystems for anti-TB drug delivery [137][138][139][140], but the 828 potential use of nanogel for TB treatment is poorly studied. The swelling property of this nanogel was pH-dependent. ...
Recent estimates indicate that tuberculosis (TB) is the leading cause of death worldwide, alongside the human immunodeficiency virus (HIV) infection. The current treatment is effective, but is associated with severe adverse-effects and noncompliance to prescribed regimens. An alternative route of drug delivery may improve the performance of existing drugs, which may have a key importance in TB control and eradication. Recent advances and emerging technologies in nanoscale systems, particularly nanoparticles (NPs), have the potential to transform such approach to human health and disease. Until now, several nanodelivery systems for the pulmonary administration of anti-TB drugs have been intensively studied and their utility as an alternative to the classical TB treatment has been suggested. In this context, this review provides a comprehensive analysis of recent progress in nanodelivery systems for pulmonary administration of anti-TB drugs. Additionally, more convenient and cost-effective alternatives for the lung delivery, different types of NPs for oral and topical are also being considered, and summarized in this review. Lastly, the future of this growing field and its potential impact will be discussed.
... Microspheres are submicron size polymeric drug carrier systems in which the therapeutic agents are loaded inside the polymeric matrix or encapsulated or physically absorbed or chemically coupled on to the surface. The size range of these colloidal particles is from 1-1000 micro meter .These particles consist of core material ,which is the drug and a coating material [1].The coat material can be of various types ranging from natural polymers such as albumin, gelatin [2], chitosan [3] and synthetic such as poly(vinyl alcohol) [4], poly(lactate-co-glycolide) [5] and combination of two polymers such chitosan sodium CMC [6] and alginate -chitosan [7] etc. The microspheres are characteristically free flowing powders consist of proteins or synthetic polymers that are biodegradable in nature [8], and ideally having a particle size less than 200 micro meter .Solid biodegradable microspheres incorporating a drug dispersed or dissolved throughout particle matrix have the potential for the controlled release of drug [9]. ...
Microspheres are sub-micron size polymeric drug carrier systems in which the therapeutic agents are loaded micrometer. These particles consist of core material, which is the drug, and a coating material. Microspheres are considered as a very promising controlled and targeted drug delivery system. The formulation and clinical application of microspheres is based on the physicochemical pharmacokinetic and pharmacological properties of drugs. Cefdinir is a beta-lactam antibiotic and is mainly bactericidal. Cefdinir inhibits the third and final stage of bacterial cell wall synthesis by preferentially binding to specific penicillin binding proteins; those are located inside the bacterial cell wall. Cefdinir is the third generation antibiotic used for the treatment of community-acquired pneumonia, acute bacterial otitis media and uncompleted skin and skin structure infections in adult and pediatric patient. Incorporation of Cefdinir in polymeric microspheres can successfully increase the biological half-life and reduce the therapeutic dose of their drug, thereby minimizing the adverse drug reaction. Cefdinir microspheres were formulated by emulsion solvent evaporation method using ethyl cellulose polymer. All the above studies reveal that the microsphere can serve as an ideal drug delivery system for Cefdinir. Further studies can be done on the stability of cefdinir-loaded microspheres and the improvement in therapeutic efficacy due to the targeting effect on to the specific receptor sites.
... Chitosanul ºi alginatul, polimeri polizaharidici naturali ºi relativ simplu de procesat, sunt cei mai utilizaþi pentru realizarea de suporturi biocompatibile [2] pe care se pot imobiliza substanþe active diverse care sunt ulterior eliberate controlat [3,4]. Suporturile pe bazã de chitosan, alginat sau amestecuri din cei doi polimeri pot fi obþinute sub forma de pelicule sau microparticule [5]. ...
This study focuses on the preparation and characterization of the microparticles and films from chitosan,alginate and alginate/chitosan in relation to their application as supports for the urease immobilization. These enzymes are imobilized by using the following adsorbtion on solid supports methods: direct immersion of the support into enzymatic solutions; direct attachment of the carbodiimide derivate or sodium citrate activated supports. Carbodiimide activated supports have proved to be the most appropriate imobilization procedure. In this case the immobilization yields exceed 70%.
Aim: Inhalable microspheres made of polymers as a targeted drug delivery system have been developed to overcome the limitation of current treatments in Tuberculosis. Materials & methods: Isoniazid inhalable microspheres were created using a gelation ionotropic method with sodium alginate, carrageenan and calcium chloride in four different formulations. Result: The particle morphology has smooth surfaces and round spherical shapes with sizes below 5 μm; good flowability. The drug loading and entrapment efficiency values ranged from 1.69 to 2.75% and 62.44 to 85.30%, respectively. The microspheres drug release followed the Korsmeyer-Peppas model, indicating Fickian diffusion. Conclusion: Isoniazid inhalable microspheres achieved as targeted lung delivery for tuberculosis treatment.
Interpolymer Complexes (IPC) of Carboxymethylated Xanthan gum (CMXtG) and chitosan (CH) were prepared by mixing polymeric solutions of different concentrations ratio. The complexes formed were used as coating polymer to coat metronidazole. Core tablet of metronidazole coated by optimized IPC solution to achieved different percent weight gain (7.5%, 10%, and 12.5%) of core tablet. The release of the drug was measured in vitro, along with the measurement of degree of substitution, viscosity of modified gum, DSC, SEM study. Maximum yield of IPC was observed in ratio of 40:60 of CH/ CMXtG. The IPC showed lower release of metronidazole in 0.1 N HCl as compared to phosphate buffer (pH 6.8). As Increasing percent weight gain of tablets coated by IPC led to more decrease in drug release. However, in vitro % drug release was performed in both the with and without rat caecal content. Formulations were evaluated for their Preformulation parameters and found within the specified limit. Formulation code B1 and C1 were the optimized batches with an in vitro release in rat caecal was of 99.1 % and 90.7% respectively.IPC coated tablet successful deliver the metronidazole especially to colon region.
It was examined the behavior of systems which contain surfactants and biopolymers is considered by the example of cationic surfactants and sodium alginate. The rheological and surface-active properties of the systems have been experimentally investigated. It was found that the presence of oppositely charged surfactants in the solution significantly affects the properties of sodium alginate, due to the fact that associates or polymer-colloidal complexes are formed in the solution. Their formation significantly affects the solubilizing ability in relation to non-polar liquids. Hydrodynamic parameters of macromolecules of sodium alginate in comparison with macromolecules of chitosan correspond to the conformation of the loose ball. The state of the SN is determined by the pH of the medium and temperature. The increase in temperature leads to a violation of the structure of the chain, its destruction and a subsequent decrease in viscosity. At a temperature of 293K, the macromolecule is in a more ordered state. In the alkaline environment there is a change in the conformation of the macromolecule. As a result of this change, the viscosity naturally increases. This is explained by the fact that in an alkaline environment, the macromolecule acquires an excess negative charge, there is a repulsion of the carboxyl groups of the same name in the chain links. The macromolecule acquires an expanded configuration. The viscosity increases. In acidic environment, sodium alginate has almost zero charge as a result of protonation of carboxyl groups. The molecule acquires the conformation of a loose ball with the lowest value of viscosity. The isoelectric state of the alginate macromolecule is observed in the pH range of 5.5 to 6.0. The described state of the macromolecule in solution is confirmed by our calculations. The interaction of surface-active cations with carboxyl groups of SN leads first to the formation of associates, then to polymer-colloidal complexes. The association as a result of electrostatic interaction of active groups is enhanced by the hydrophobic interaction of hydrocarbon fragments of surfactant molecules with each other and with the alginate matrix. The association ends with the formation of a polymer-colloidal complex.
Deve dikeni (Silybum marianum) tohumuna çözücü ile ekstraksiyon yöntemi uygulanarak %7,3 verimle silimarin tozu elde edilmiştir. Ekstrakte tozun %57,8 silimarin içerdiği bulunmuştur. Silimarin içeriği dikkate alınarak silybum marianum tohumunun silimarin içeriği %4,21 olarak bulunmuştur. Ekstrakt ve orjinal silimarin, Fourier dönüşümlü kızıl ötesi spektroskopisi (FTIR), Optik Mikroskop, X-ışını kırınımı (XRD) ve taramalı elektron mikroskobu (SEM) ile karakterize edilmiştir. Püskürtme ve enjeksiyon yöntemleri ile ekstrakt ve orjinal silimarin tozları aljinat ile enkapsüle edilmiştir. Silimarin enkapsülasyonu sonrasında mikrokapsüllerin tutuklama verimleri %83,14-%91,27 aralığında bulunmuştur. Simule mide (0,1N HCl) ortamında kümülatif silimarin salımı %13-%71 aralığında, simule bağırsak (PBS) ortamında kümülatif silimarin salımı %28,3-%82 aralığında hesaplanmıştır. Tüm örneklerde simule bağırsak (PBS) ortamında daha yüksek silimarın salımı gözlenmiştir. Salım deneyleri sonrasında örneklerin fonksiyonel gruplarındaki değişikler FTIR ile belirlenmiştir.
Nanosized natural polymers have attained considerable attention in drug delivery applications due to their high encapsulation efficiency, non-toxic nature, sustained and targeted drug delivery. Here we have synthesized Rifampicin loaded alginate nanoparticles by green method. Physicochemical characterization of the nanoparticles was assessed using Transmission electron microscopy, Fourier transform infrared spectroscopy, Dynamic light scattering and X-ray diffraction technique. The swelling and in vitro drug release showed that the framework experiences pH-dependent swelling and release of Rifampicin. Rifampicin has lower release in acid medium and higher release in intestinal condition. Moreover, in view of the drug release results, the release kinetics and transport mechanisms were investigated and discussed. In vitro cytotoxicity assay demonstrated that the nanoparticles were non-toxic in nature. The acute oral toxicity study of the synthesized nanoparticles was done in Wistar albino rats. No systemic toxicity was observed after oral administration of nanoparticles. The present study demonstrated the potential of using alginate nanoparticles synthesized by a green method for drug delivery applications.
Nanoparticle-based delivery systems represent a promising nano medications to deliver a therapeutic agent, selectively and effectively, to a specific tissue or organ in the body; thus treating chronic diseases such as tuberculosis. The delivery of first-line and second-line antituberculosis drugs, using synthetic or natural polymeric carriers, has been extensively reported as a potential intermittent chemotherapy. In addition to the prolonged drug release, this delivery system can enhance the therapeutic efficacy, reduce dosing frequency and side effects, and increase the possibility of selecting different routes of chemotherapy and targeting the site of infection. The choice of carrier, system stability, toxicity and production capacity are the main considerations during the development of such system. Regardless of the obstacles, the nano drug delivery have systems shown a promising effectiveness in treating TB.
Background
Diosmin showed poor water solubility and low bioavailability. Poly(d,l-lactide-co-glycolide) (PLGA) nanoparticles were successfully used to improve the drugs solubility and bioavailability. Coating of PLGA nanoparticles with chitosan can ameliorate their gastric retention and cellular uptake.
Methodology
PLGA nanoparticles of diosmin were prepared using different drug and polymer amounts. Nanoparticles were selected based on entrapment efficiency% (EE%) and particle size measurements to be coated with chitosan. The selected nanoparticles either uncoated or coated were evaluated regarding morphology, ζ-potential, solid-state characterization, in vitro release, storage stability, and mucoadhesion. The anti-ulcer activity (AA) against ethanol-induced ulcer in rats was assessed through macroscopical evaluation, histopathological examination, immunohistochemical localization of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and transmission electron microscopic examination of gastric tissues compared to free diosmin (100 mg/kg) and positive control.
Results
Based on EE% and particle size measurements, the selected nanoparticles, either uncoated or coated with 0.1% w/v chitosan, were based on 1:15 drug-PLGA weight ratio and 20 mg diosmin employing methylene chloride as an organic phase. Examination by scanning electron microscopy (SEM) and transmission electron microscopy (TEM) revealed nanoscopic spherical particles. Drug encapsulation within the selected nanoparticles was suggested by Fourier transform-infrared, differential scanning calorimetry (DSC) and X-ray diffractometry results. Chitosan-coated nanoparticles were more stable against size enlargement probably due to the higher ζ-potential. Only coated nanoparticles showed gastric retention as revealed by SEM examination of stomach and duodenum. The superior AA of coated nanoparticles was confirmed by significant reduction in average mucosal damage, the majority of histopathological changes and NF-κB expression in gastric tissue when compared to positive control, diosmin and uncoated nanoparticles as well as insignificant difference relative to normal control. Coated nanoparticles preserved the normal ultrastructure of the gastric mucosa as revealed by TEM examination.
Conclusion
The optimized chitosan-coated PLGA nanoparticles can be represented as a potential oral drug delivery system of diosmin.
Nanotechnology refers to the control, manipulation, study and manufacture of structures and devices at the nanometer size range. The small size, customized surface, improved solubility and multi-functionality of nanoparticles will continue to create new biomedical applications, as nanoparticles allow to dominate stability, solubility and bioavailability, as well controlled release of drugs. The type of nanoparticle, and its related chemical, physical and morphological properties, influences their interaction with living cells, as well as determine the route of clearance and possible toxic effects. This field requires cross-disciplinary research and gives opportunities to design and develop multifunctional devices, which allow the diagnosis and treatment of devastating diseases. Over the past few decades, biodegradable polymers have been studied for the fabrication of drug delivery systems. There was an extensively development of biodegradable polymeric nanoparticles for drug delivery and tissue engineering, in view of their applications in controlling the release of drugs, stabilizing labile molecules from degradation and site-specific drug targeting. The primary aim is to reduce dosing frequency and prolong the therapeutic outcomes. For this purpose, inert excipients should be selected, being biopolymers, e.g. sodium alginate, commonly used in controlled drug delivery. Nanoparticles composed of alginate (known as anionic polysaccharide widely distributed in the cell walls of brown algae which, when in contact with water, forms a viscous gum) have emerged as one of the most extensively characterized biomaterials used for drug delivery and targeting for a set of administration routes. Their advantages include not only the versatile physicochemical properties, which allow chemical modifications for site-specific targeting but also their biocompatibility and biodegradation profiles, as well as mucoadhesiveness. Furthermore, mechanical strength, gelation, and cell affinity can be modulated by combining alginate nanoparticle with other polymers, surface tailoring using specific targeting moieties and chemical or physical cross-linking. However, for every physicochemical modification in the macromolecule/nanoparticles, a new toxicological profile may be obtained. In this paper, the different aspects related to the use of alginate nanoparticles for drug delivery and targeting have been revised, as well as how their toxicological profile will determine the therapeutic outcome of the drug delivery system.
The direct delivery of antibiotics to the lung has been considered an effective approach to treat pulmonary tuberculosis, which represents approximately 80% of total cases. In this sense, this work aimed at producing inhalable chitosan microparticles simultaneously associating isoniazid and rifabutin, for an application in pulmonary tuberculosis therapy. Spray-dried chitosan microparticles were obtained with adequate flow properties for deep lung delivery (aerodynamic diameter of 4 µm) and high drug association efficiencies (93% for isoniazid and 99% for rifabutin). The highest concentration of microparticles that was tested (1 mg/mL) decreased the viability of macrophage-differentiated THP-1 cells to around 60% after 24 h exposure, although no deleterious effect was observed in human alveolar epithelial (A549) cells. The release of LDH was, however, increased in both cells. Chitosan microparticles further evidenced capacity to activate macrophage-like cells, inducing cytokine secretion well above basal levels. Moreover, the propensity of macrophages to internalise microparticles was demonstrated, with uptake levels over 90%. Chitosan microparticles also inhibited bacterial growth by 96%, demonstrating that the microencapsulation preserved drug antibacterial activity in vitro. Overall, the obtained data suggest the potential of chitosan microparticles systems for inhalable lung tuberculosis therapy.
The development of systems for targeted delivery of anti-tuberculosis drugs is a challenge of modern biotechnology. Currently, these drugs are encapsulated in a variety of carriers such as liposomes, polymers, emulsions and so on. Despite successful in vitro testing of these systems, virtually no success was achieved in vivo, because of low accessibility of the foci of infection located in alveolar macrophage cells. A promising strategy for increasing the efficiency of therapeutic action of anti-tuberculosis drugs is to encapsulate the agents into mannosylated carriers targeting the mannose receptors of alveolar macrophages. The review addresses the methods for modification of drug substance carriers, such as liposomes and biodegradable polymers, with mannose residues. The use of mannosylated carriers to deliver anti-tuberculosis agents increases the drug circulation time in the blood stream and increases the drug concentration in alveolar macrophage cells.
The bibliography includes 113 references.
Lecithin-polysorbate 80-lipid-core nanocapsules (LNC) or chitosan-coated LNC (LNC-CS) containing or not dapsone (DAP) were prepared and characterized. Particle size varied from 126 to 130 nm (laser diffraction) and from 114 to 125 nm (z-average diameter by dynamic light scattering). The pH values ranged from 4.15 to 4.57 and zeta potential inverted from −15 (LNC) to +23 mV (LNC-CS) and from −13 (DAP-LNC) to +21 mV (DAP-LNC-CS). Transmission electron microscopy analysis evidenced four layers of micellar structures coating LNC, constituting a hydrophilic corona. For the first time, a sequence of spherical to cylindrical micellar transformation was observed at the nanocapsule corona. Biological assays demonstrated that DAP-LNC, LNC-CS and DAP-LNC-CS act as growth inhibitors of five clinical isolates of Staphylococcus aureus, which exhibited multidrug-resistance to ciprofloxacin, clindamycin, erythromycin, gentamicin, oxacillin and penicillin G, and six strains of three filamentous fungi species: Aspergillus fumigatus, Aspergillus flavus and Aspergillus niger. The nanoencapsulation of dapsone improved the inhibitory activity of the drug in both assays. In addition, the presence of chitosan in the formulations provided a better performance of the formulation in the case of S. aureus, while the influence of the nanoencapsulated drug was more pronounced in the antifungal activity.
Tuberculosis therapy remains a challenge even today, mainly due to the problems of bacterial resistance, side effects and low patient compliance, associated with anti-tubercular drugs. A bioenhancer is an agent capable of enhancing bioavailability and bioefficacy of a particular drug with which it is combined, without any typical pharmacological activity of its own at the dose used. Microspheres are one of the multiparticulate drug delivery systems prepared to obtain prolonged drug delivery, to improve its bioavailability or stability and to target drug to specific sites. Rifampicin is an important component of fixed dose combination used in first line therapy of tuberculosis. In the present study, we attempted an innovative approach to overcome the above-mentioned problems of tuberculosis therapy by combining both these approaches of microspheres and bioenhancers. Small amount of herbal extract of Piper nigrum were incorporated as a bioenhancer in variable amount for each dose of rifampicin. The drug loading efficiency and in-vitro release behavior of loaded microspheres were found to be satisfactory. Prolonged release of the drug from the microspheres was demonstrated in a simulated intestinal fluid. In-vitro release of rifampicin from the microspheres containing variable fractions of bioenhancer showed significant increase in release profile i.e. 80.24 and 86.16% in formulation containing bioenhancer against 44.54% for the formulation without bioenhancer prepared by complex coacervation method.
The natural polymers alginate and chitosan were used for the preparation of controlled release nicardipine HCl gel microparticles. The effect of the mannuronic/guluronic acid content and the alginate viscosity on the prolonged action of the microparticles, which were prepared with different types of alginates, were investigated. The mean particle sizes and the swelling ratios of the microparticles were also determined. The in vitro release studies were carried out with a flow-through cell apparatus in different media (pH 1.2, 2.5, 4.5, 7 and 7.5 buffer solutions). The release of nicardipine was extended with the alginate gel microparticles prepared with guluronic acid rich alginate. After the determination of the most appropriate alginate type, the effect of alginate-chitosan complex formation was studied on the release pattern of drug incorporated. It was observed that the alginate-chitosan complex formation reduced the erosion of the alginate-chitosan matrix at pH 7-7.5. The release of drug from the chitosan-alginate gel microparticles took place by both diffusion through the swollen matrix and relaxation of the polymer at pH 1.2-4.5.
Previously, we reported on the use of rifampin-loaded microspheres to effectively treat Mycobacterium tuberculosis-infected macrophages and mice. Using similar biocompatible polymeric excipients of lactide and glycolide copolymers, we have increased the rifampin loading of small microsphere formulations (1 to 10 microm) by fourfold. Improved formulations were evaluated individually and in combination with oral regimens of isoniazid for the treatment of Mycobacterium tuberculosis H37Rv-infected mice. Groups (10 mice per group) consisted of mice that received (i) oral dosages of isoniazid (25 to 0.19 mg/kg of body weight/day), (ii) two intraperitoneal injections of rifampin-loaded microspheres on days 0 and 7, (iii) a combination of small rifampin-loaded microspheres on days 0 and 7 and isoniazid orally for 25 days (12.5 to 0.39 mg/kg/day), (iv) placebo injections, and (v) no treatment. Treatment with rifampin-loaded microspheres alone resulted in significant reductions in the numbers of CFU in the lungs and spleens by day 26. A bioassay revealed that plasma rifampin levels from the microspheres exceeded the MICs by more than twofold throughout the 26-day experimental period. Susceptibility testing demonstrated continued sensitivity to rifampin during the treatment period. Whereas isoniazid alone significantly reduced the numbers of CFU for dosages ranging from 12.5 to 1.56 mg/kg, combination therapy with rifampin-loaded microspheres increased the effective range to 0.39 mg/kg. In many cases, complete elimination of CFU was obtained with the combination therapy, something not achieved with most of the single therapies. These results demonstrate the ability to use small microsphere formulations alone to achieve significant results in a murine tuberculosis model and also the ability to use them safely in combination with another antimycobacterial agent.
Alginate microparticles were developed as oral sustained delivery carriers for antitubercular drugs in order to improve patient compliance. In the present study, pharmacokinetics and therapeutic effects of alginate microparticle encapsulated antitubercular drugs, i.e. isoniazid, rifampicin and pyrazinamide were examined in guinea pigs. Alginate microparticles containing antitubercular drugs were evaluated for in vitro and in vivo release profiles. These microparticles exhibited sustained release of isoniazid, rifampicin and pyrazinamide for 3-5 days in plasma and up to 9 days in organs. Peak plasma concentration (Cmax), Tmax, elimination half-life (t1/2e) and AUC0- infinity of alginate drugs were significantly higher than those of free drugs. The encapsulation of drug in alginate microparticles resulted in up to a nine-fold increase in relative bioavailability compared with free drugs. Chemotherapeutic efficacy of alginate drug microspheres against experimental tuberculosis showed no detectable cfu values at 1:100 and 1:1000 dilutions of spleen and lung homogenates. Histopathological studies further substantiated these observations, thus suggesting that application of alginate-encapsulated drugs could be useful in the effective treatment of tuberculosis.
Poly(lactide-co-glycolide) (PLG) microspheres (diameter, less than 3 μm) containing isoniazid, rifampin, and pyrazinamide
were used in a sustained oral drug delivery system to treat murine tuberculosis. Drug levels above the MIC were observed up
to 72 h in plasma and for 9 days in various organs. Relative bioavailability of encapsulated drugs was greater than that of
free drugs. Chemotherapy results showed better or equivalent clearance of bacilli in the PLG-drug-administered group (weekly)
than with free drugs (daily).
A protein-free filtrate of serum was treated with salicylaldehyde to give a hydrazone of INH. Excess salicylaldehyde was removed with bisulfite. The hydrazone in the presence of reducing agents gave an isobutanol-soluble, highly fluorescent compound of unknown structure. The method developed will measure as little as 0.01 μg INH per milliliter of serum.
An oral formulation based on poly (dl-lactide-co-glycolide) (PLG) microparticles was developed for delivery of antituberculous drugs. PLG entrapped antitubercular drugs when administered orally, were found to release the drugs in a sustained manner. This formulation was found to be stable in the acidic environment of gastric fluid whereas, in the intestinal fluid the drug release was obtained up to 20 days as indicated by in vitro studies. Pharmacokinetic analysis of the data revealed changes in Cmax; AUCo–α; t1/2 (a) and t1/2 (e) when drugs were given entrapped in PLG microparticles. Higher peak concentration, area under the concentration time curve and delayed elimination rate of entrapped drugs indicated the potential of PLG for effective treatment of tuberculosis. Further, work is being carried out to evaluate the chemotherapeutic efficacy of the antitubercular drugs encapsulated in PLG microspheres.
The method herein described for separation of INH by means of an ion-exchange column and subsequent measurement of the fluorescent compound formed by H2O2 and heat is quantitative for the measurement of INH in serum in concentrations of 0.05 to 10 μg ING/ml of serum. Neither AINH nor INA interfere and any possible interference of NAM is eliminated by means of a serum blank. IPINH may also be determined by this method; thus, the presence of IPINH in serum or tissues will interfere with INH determination. A distinct advantage of the method is that no special purification of chemicals or solvents is needed, and that it involves no losses in solvent extraction procedures.Several other pyridine derivatives yield highly fluorescent products when treated with H2O2 and heat. The conditions necessary for their reaction and the properties of the fluorescent compounds formed are described.
Liposome-entrapped rifampin (RFP) was examined for therapeutic efficacy against experimental infection induced in mice by
the Mycobacterium avium complex. Intraperitoneal injections (once daily, six times weekly) of liposome-entrapped RFP led to
a greater reduction in bacterial growth in the lungs and spleen of infected mice than did free RFP alone. Liposome-entrapped
RFP given to mice via the intramuscular or subcutaneous route failed to show such an increased therapeutic efficacy. RFP entrapped
in the lipid layer of liposomal vesicles exhibited a level of therapeutic activity similar to that seen with RFP encapsulated
in the inner solute of the vesicles. Entrapment of RFP in liposomal vesicles increased incorporation of the drug into host
peritoneal macrophages and increased the activity of the agent against M. avium complex phagocytosed into the macrophages.
Methods for the estimation of pyrazinamide in serum and of pyrazinamide and pyrazinoic acid in urine using an anion-exchange resin (Dowex-1) have been described. Recoveries were quantitative, and the sensitivity was 5 μg/ml for all 3 estimations. In serum, pyrazinoic acid at a concentration of 50 μg/ml did not interfere with the estimation of pyrazinamide. In urine, pyrazinamide and pyrazinoic acid could be separated from each other and estimated even when the 2 compounds were present together at concentrations of 2000 μg/ml each.
Although, the drug delivery system (DDS) concept is not new, great progress has recently been made in the treatment of a variety of diseases. Targeting delivery of drugs to the diseased lesions is one of the most important aspects of DDS. To convey a sufficient dose of drug to the lesion, suitable carriers of drugs are needed. Nano and microparticle carriers have important potential applications for the administration of therapeutic molecules. The research in this area is being carried out all over the world at a great pace. Research areas cover novel properties that have been developed increased efficiency of drug delivery, improved release profiles and drug targeting. The purpose of this review is to take a closer look at nano/microparticles as drug delivery devices.
Monodisperse Ca-alginate microspheres were prepared using the membrane emulsification method. Three ionic types of drugs (anionic, cationic and non-ionic) were incorporated into the microspheres, and the effects of sodium alginate concentration and the pressure applied during the dispersing process on the properties of the microspheres were examined. Monodisperse microspheres were obtained when the concentration of alginate solution was 2 wt% and the pressure applied was 0.4 x 10(5) Pa. The mean size of microspheres was approximately 4 microm. Lidocaine x HCl (cationic), sodium salicylate (anionic) and 4-acetamidophenol (non-ionic) were selected as ionic model drugs and included in the alginate microspheres. Lidocaine x HCl (cationic drug) release was more retarded than that of the anionic drug, because of the electrostatic attraction between the negative charge of the ionized carboxyl group in the alginate chain and the positive charge of the cationic drug. In acidic release medium, a slow release was observed due to the low swelling characteristic and the increased viscosity of alginate, regardless of ionic type of drug.
Alginate/chitosan particles were prepared by ionic gelation (Ca2+ and Al3+) for the sodium diclofenac release. The systems were characterized by electron microscopy and differential scanning calorimetry. The ability to release the active substance was examined as a function of some technological parameters and pH of dissolution medium. The release of sodium diclofenac is prevented at acidic pH, while is complete in a few minutes when pH is raised up to 6.4 and 7.2. The alginate/chitosan ratio and the nature of the gelifying cation allow a control of the release rate of the drug. The release mechanism was briefly discussed.
Alginates are established among the most versatile biopolymers, used in a wide range of applications. The conventional use of alginate as an excipient in drug products generally depends on the thickening, gel-forming, and stabilizing properties. A need for prolonged and better control of drug administration has increased the demand for tailor-made polymers. Hydrocolloids like alginate can play a significant role in the design of a controlled-release product. At low pH hydration of alginic acid leads to the formation of a high-viscosity "acid gel." Alginate is also easily gelled in the presence of a divalent cation as the calcium ion. Dried sodium alginate beads reswell, creating a diffusion barrier decreasing the migration of small molecules (e.g., drugs). The ability of alginate to form two types of gel dependent on pH, i.e., an acid gel and an ionotropic gel, gives the polymer unique properties compared to neutral macromolecules. The molecule can be tailor-made for a number of applications. So far more than 200 different alginate grades and a number of alginate salts are manufactured. The potential use of the various qualities as pharmaceutical excipients has not been evaluated fully, but alginate is likely to make an important contribution in the development of polymeric delivery systems. This natural polymer is adopted by Ph.Eur. It can be obtained in an ultrapure form suitable for implants. This review discusses the present use and future possibilities of alginate as a tool in drug formulation.
Isoniazid was encapsulated into microspheres of alginate-chitosan by means of a complex coacervation method in an emulsion system. Since the encapsulation of isoniazid tends to be limited by its hydrophilic characteristics, this study proposes its microencapsulation by adsorption. The particles were prepared in three steps: (1) preparation of a W/O emulsion; (2) phase separation; and (3) adsorption of the drug. The isolated particles were placed in a solution of the drug under stirring to allow adsorption. The morphology and particle size were analysed by scanning electron microscopy (SEM). The isoniazid content was determined by extraction in 1 M phosphate buffer pH 7.5 under stirring for 4 h. Finally, the samples were filtered and analysed in an UV/VIS spectrophotometer at 260 nm. In vitro release tests were carried out in 0.05 M phosphate buffer pH 7.5. The results showed that microspheres of alginate-chitosan obtained were of spherical shape. The emulsion used for microparticle formation allows the preparation of particles with a narrow size distribution. The adsorption observed is probably of chemical nature, i.e. there is an ionic interaction between the drug and the surface of the particles.
Chitosan, a natural polymer obtained by alkaline deacetylation of chitin, is non-toxic, biocompatible, and biodegradable. These properties make chitosan a good candidate for the development of conventional and novel gastrointestinal (GI) drug and gene delivery systems. The objective of this review is to summarize the recent applications of chitosan in oral and/or buccal delivery, stomach-specific drug delivery, intestinal delivery, and colon-specific drug delivery. The use of chitosan for targeting of drugs to each of these sites in the GI tract is illustrated by examples supported by in vivo studies. Chitosan appears to be a promising material for GI drug and gene delivery applications as many derivatives and formulations are being examined.
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