Chondroitin Sulphate: An emerging therapeutic multidimensional proteoglycan in colon cancer.

Chondroitin sulfate (CS) is a sulfated glycosaminoglycan (GAG) that has captured massive attention in the field of drug delivery. As the colon is considered the preferred site for local and systemic delivery of bioactive agents for the treatment of various diseases, colon-targeted drug delivery rose to the surface of research. Amid several tactics to attain colon-targeted drug release, the exploitation of polymers degraded by colonic bacteria holds great promise. Chondroitin sulfate as a biodegradable, biocompatible mucopolysaccharide is known for its anti-inflammatory, anti-osteoarthritis, anti-atherosclerotic, anti-oxidant, and anti-coagulant effects. Besides these therapeutic functions, CS thrived to play a major role in nanocarriers as a matrix material, coat, and targeting ligand. This review focuses on the role of CS in nanocarriers as a matrix material or as a targeting moiety for colon cancer therapy, relating the present applications to future perspectives.

The battle of lipid-based nanocarriers against blood-brain barrier: a critical review.

Central nervous system integrity is the state of brain functioning across sensory, cognitive, emotional-social behaviors, and motor domains, allowing a person to realise his full potential. Thus, brain disorders seriously affect patients' quality of life. Efficient drug delivery to treat brain disorders remains a crucial challenge due to numerous brain barriers, particularly the blood-brain barrier (BBB), which greatly impacts the ultimate drug therapeutic efficacy. Lately, nanocarrier technology has made huge progress in overcoming these barriers by improving drug solubility, ameliorating its retention, reducing its toxicity, and targeting the encapsulated agents to different brain tissues. The current review primarily offers an overview of the different components of BBB and the progress, strategies, and contemporary applications of the nanocarriers, specifically lipid-based nanocarriers (LBNs), in treating various brain disorders.

Lipid-based nanocarriers challenging the ocular biological barriers: Current paradigm and future perspectives.

Eye is the most specialized and sensory body organ and treating eye diseases efficiently is necessary. Despite various attempts, the design of a consummate ophthalmic drug delivery system remains unsolved because of anatomical and physiological barriers that hinder drug transport into the desired ocular tissues. It is important to advance new platforms to manage ocular disorders, whether they exist in the anterior or posterior cavities. Nanotechnology has piqued the interest of formulation scientists because of its capability to augment ocular bioavailability, control drug release, and minimize inefficacious drug absorption, with special attention to lipid-based nanocarriers (LBNs) because of their cellular safety profiles. LBNs have greatly improved medication availability at the targeted ocular site in the required concentration while causing minimal adverse effects on the eye tissues. Nevertheless, the exact mechanisms by which lipid-based nanocarriers can bypass different ocular barriers are still unclear and have not been discussed. Thus, to bridge this gap, the current work aims to highlight the applications of LBNs in the ocular drug delivery exploring the different ocular barriers and the mechanisms viz. adhesion, fusion, endocytosis, and lipid exchange, through which these platforms can overcome the barrier characteristics challenges.

Propranolol-Loaded Limonene-Based Microemulsion Thermo-Responsive Mucoadhesive Nasal Nanogel: Design, In Vitro Assessment, Ex Vivo Permeation, and Brain Biodistribution.

Propranolol is the first-line drug for managing migraine attacks. D-limonene is a citrus oil known for its neuroprotective mechanism. Thus, the current work aims to design a thermo-responsive intranasal limonene-based microemulsion mucoadhesive nanogel to improve propranolol efficacy. Microemulsion was fabricated using limonene and Gelucire® as the oily phase, Labrasol®, Labrafil®, and deionized water as the aqueous phase, and was characterized regarding its physicochemical features. The microemulsion was loaded in thermo-responsive nanogel and evaluated regarding its physical and chemical properties, in vitro release, and ex vivo permeability through sheep nasal tissues. Its safety profile was assessed via histopathological examination, and its capability to deliver propranolol effectively to rats' brains was examined using brain biodistribution analysis. Limonene-based microemulsion was of 133.7 ± 0.513 nm diametric size with unimodal size distribution and spheroidal shape. The nanogel showed ideal characteristics with good mucoadhesive properties and in vitro controlled release with 1.43-fold enhancement in ex vivo nasal permeability compared with the control gel. Furthermore, it displayed a safe profile as elucidated by the nasal histopathological features. The nanogel was able to improve propranolol brain availability with Cmax 970.3 ± 43.94 ng/g significantly higher than the control group (277.7 ± 29.71 ng/g) and with 382.4 % relative central availability, which confirms its potential for migraine management.

Application of Box-Behnken Design in the Preparation, Optimization, and In-Vivo Pharmacokinetic Evaluation of Oral Tadalafil-Loaded Niosomal Film.

Benign prostatic hyperplasia (BPH) affects about 90% of men whose ages are over 65. Tadalafil, a selective PDE-5 inhibitor, was approved by FDA for BPH, however, its poor aqueous solubility and bioavailability are considered major drawbacks. This work intended to develop and evaluate oral fast dissolving film containing tadalafil-loaded niosomes for those who cannot receive the oral dosage form. Niosomes were statistically optimized by Box-Behnken experimental design and loaded into a polymeric oral film. Niosomes were assessed for their vesicular size, uniformity, and zeta potential. The thickness, content uniformity, folding endurance, tensile strength, disintegration time, and surface morphology were evaluated for the prepared polymeric film. The optimized niosomes revealed high entrapment efficiency (99.78 ± 2.132%) and the film was smooth with good flexibility and convenient thickness (110 ± 10 µm). A fast release of tadalafil was achieved within 5 min significantly faster than the niosomes-free drug film. The in-vivo bioavailability in rats established that the optimized niosomal film enhanced tadalafil systemic absorption, with higher peak concentration (Cmax = 0.63 ± 0.03 µg/mL), shorter Tmax value (0.66-fold), and relative bioavailability of 118.4% compared to the marketed tablet. These results propose that the oral film of tadalafil-loaded niosomes is a suitable therapeutic application that can be passed with ease to geriatric patients who suffer from BPH.

Freeze-drying: A flourishing strategy to fabricate stable pharmaceutical and biological products.

Freeze-drying (FD) of nanoparticles, microorganisms, genes, and vaccines is an auspicious technique used to enhance long-term stability and facilitate transportation mainly for products that require specific conditions like cold chains. Although freeze-drying is considered a delicate drying process, it can cause numerous stresses that induce chemical and physical instabilities. Subsequently, the inclusion of suitable excipients along with optimizing the process parameters is crucial to attain stable lyophilizates with high-quality attributes. The current review highlights the state of the art of the freeze-drying process applications in nanoparticulate systems, microorganisms, genes, and vaccine formulations. Moreover, the work focuses on the different stresses facing these systems during FD cycle and the strategies which are utilized for their stabilizations during lyophilization and storage.

Role of lignin-based nanoparticles in anticancer drug delivery and bioimaging: An up-to-date review.

Lignin, an aromatic biopolymer, is the second most abundant naturally occurring one after cellulose that has drawn a great deal of interest over the years for its potential uses owing to the presence of high content of phenolic compounds, ecofriendly feature and cost-efficiency in comparison to the synthetic polymers. Nevertheless, with the intention of advancing its development, several efforts have been performed in the direction of utilizing lignin on the nanoscale due to its inimitable properties. The notable absorption capacity, fluorescence emission, biodegradability and non-toxicity of lignin nanoparticles permit its appropriateness as a vehicle for drugs and as a bioimaging material. Moreover, lignin nanoparticles have shown plausible therapeutic effects, such as anticancer, antimicrobial, and antioxidant. The current review sheds light on the recent development in the formulation and anticancer applications of lignin nanoparticles as a drug carrier and as a diagnostic tool. The surface properties of the nanomaterial affect the end product characteristics, hence, factors namely; lignin source, isolation technique, purification and quantitation methods, are discussed in this review. This study represents original work that has not been published elsewhere and that has not been submitted simultaneously for publication elsewhere. The manuscript has been read, revised, and approved by the authors.

Recent advances in freeze-drying: variables, cycle optimization, and innovative techniques.

Freeze-drying (FD) is the most substantial drying technique utilized in the pharmaceutical and biopharmaceutical industries. It is a drying process where the solvent is crystallized at low temperatures and then sublimed from the solid-state directly into the vapor phase. Although FD possesses several merits as its suitability for thermolabile materials and its ability to produce dry products with high-quality attributes, it is a complex and prolonged process that requires optimization of both; process and formulation variables. This review attains to disassemble FD complications through a detailed explanation of the lyophilization concept, stages, the factors influencing the process including controlled ice nucleation, and the modified and innovative FD technologies proposed in recent years to overcome the shortage of traditional FD. In addition, this work points out the quality by design (QbD), critical quality of attributes (CQAs), limitations, and drawbacks of lyophilization.HIGHLIGHTSLyophilization is a propitious drying technique for thermolabile materials.Optimizing the lyophilization cycle requires controlling the process parameters.The formulation excipients and the dispersion medium play crucial roles in designing a successful process.Numerous approaches were developed to ameliorate the lyophilization performance.

Superiority of microemulsion-based hydrogel for non-steroidal anti-inflammatory drug transdermal delivery: a comparative safety and anti-nociceptive efficacy study.

Non-steroidal anti-inflammatory drugs (NSAIDs) represent the foundation of pain management caused by inflammatory disorders. Nevertheless, their oral administration induces several side effects exemplified by gastric ulceration, thus, delivering NSAIDs via skin has become an attractive alternative. Herein, microemulsion-based hydrogel (MBH), proliposomal, and cubosomal gels were fabricated, loaded with diclofenac, and physicochemically characterized. The size, charge, surface morphology, and the state of diclofenac within the reconstituted gels were also addressed. The ex-vivo permeation study using Franz cells was performed via the rat abdominal skin. The formulations were assessed in-vivo on mice skin for their irritation effect and their anti-nociceptive efficacy through tail-flick test. Biosafety study of the optimal gel was also pointed out. The gels and their dispersion forms displayed accepted physicochemical properties. Diclofenac was released in a prolonged manner from the prepared gels. MBH revealed a significantly higher skin permeation and the foremost results regarding in-vivo assessment where no skin irritation or altered histopathological features were observed. MBH further induced a significant anti-nociceptive effect during the tail-flick test with a lower tendency to evoke systemic toxicity. Therefore, limonene-containing microemulsion hydrogel is a promising lipid-based vehicle to treat pain with superior safety and therapeutic efficacy.

siRNA nanohybrid systems: false hope or feasible answer in cancer management.

Finding out predisposition and makeup alterations in cancer cells has prompted the exploration of exogenous small interference RNA (siRNA) as a therapeutic agent to deal with cancer. siRNA is subjected to many limitations that hinder its cellular uptake. Various nanocarriers have been loaded with siRNA to improve their cellular transportation and have moved to clinical trials. However, many restrictions as low encapsulation efficiency, nanocarrier cytotoxicity and premature release of siRNA have impeded the single nanocarrier use. The realm of nanohybrid systems has emerged to overcome these limitations and to synergize the criteria of two or more nanocarriers. Different nanohybrid systems that were developed as cellular pathfinders for the exogenous siRNA to target cancer will be illustrated in this review.

Smart Stimuli-Responsive Liposomal Nanohybrid Systems: A Critical Review of Theranostic Behavior in Cancer.

The epoch of nanotechnology has authorized novel investigation strategies in the area of drug delivery. Liposomes are attractive biomimetic nanocarriers characterized by their biocompatibility, high loading capacity, and their ability to reduce encapsulated drug toxicity. Nevertheless, various limitations including physical instability, lack of site specificity, and low targeting abilities have impeded the use of solo liposomes. Metal nanocarriers are emerging moieties that can enhance the therapeutic activity of many drugs with improved release and targeted potential, yet numerous barriers, such as colloidal instability, cellular toxicity, and poor cellular uptake, restrain their applicability in vivo. The empire of nanohybrid systems has shelled to overcome these curbs and to combine the criteria of liposomes and metal nanocarriers for successful theranostic delivery. Metallic moieties can be embedded or functionalized on the liposomal systems. The current review sheds light on different liposomal-metal nanohybrid systems that were designed as cellular bearers for therapeutic agents, delivering them to their targeted terminus to combat one of the most widely recognized diseases, cancer.

Tailored Limonene-Based Nanosized Microemulsion: Formulation, Physicochemical Characterization and In Vivo Skin Irritation Assessment.

Purpose: Microemulsion (ME) achieved progressing consequences on both the research and industry levels due to their distinctive properties. ME based-limonene system is considered as a surrogate to the traditional microemulsion composed of conventional oils. Thus, a novel microemulsion based on D-limonene and Gelucire® 44/12 had been designed and evaluated with assessing the factors affecting its physicochemical characteristics and in vivo skin irritation. Methods: The impact of microemulsion components and ratios on the isotropic region of the pseudo-ternary phase diagram was investigated. The optimal formula was evaluated in terms of percentage transmittance, average globule size, size distribution, zeta potential, microscopical morphology, stability under different storage conditions and its effect on the mice ear skin. Results: The results demonstrated that Labrasol® and Labrafil® M 1944 CS had been selected as surfactant and co-surfactant, respectively, due to their emulsifying abilities. The largest isotropic area in the pseudo-ternary phase diagram was at a weight ratio of 4:1 for Labrasol® and Labrafil® M 1944 CS. The optimized microemulsion with 25% w/w of the lipid phase and 58.3% w/w of the aqueous phase displayed an optical transparency of 96.5±0.88 %, average globule size of 125±0.123 nm, polydispersity index of 0.272±0.009, zeta potential of -18.9± 2.79 mV with rounded globules morphology and high stability. The in vivo skin irritation and the histopathological evaluation of microemulsion elucidated its safety profile when applied on the skin. Conclusion: The formulated microemulsion is a prospective aid for an essential oil to minimize its volatility, enhance its stability, and mask its dermal irritant.

Collagen-based scaffolds: An auspicious tool to support repair, recovery, and regeneration post spinal cord injury.

Spinal cord injury (SCI) is a perplexing traumatic disease that habitually gives ride to permanent disability, motor, and sensory impairment. Despite the existence of several therapeutic approaches for the injured motor or sensory neurons, they can't promote axonal regeneration. Whether prepared by conventional or rapid prototyping techniques, scaffolds can be applied to refurbish the continuity of the injured site, by creating a suitable environment for tissue repair, axonal regeneration, and vascularization. Collagen is a multi-sourced protein, found in animals skin, tendons, cartilage, bones, and human placenta, in addition to marine biomass. Collagen is highly abundant in the extracellular matrix and is known for its biocompatibility, biodegradability, porous structure, good permeability, low immunogenicity and thus is extensively applied in the pharmaceutical, cosmetic, and food industries as well as the tissue engineering field. Collagen in scaffolds is usually functionalized with different ligands and factors such as, stem cells, embryonic or human cells to augment its binding specificity and activity. The review summarizes the significance of collagen-based scaffolds and their influence on regeneration, repair and recovery of spinal cord injuries.

Formulation and Applications of Lipid-Based Nanovehicles: Spotlight on Self-emulsifying Systems.

The drug delivery investigation field is continuously widened and adapted to overcome many factors such as poor drug solubility, absorption, rapid metabolism, the variability of drug plasma levels, cellular efflux and many others. Due to resemblance to body constituents and their biocompatibility, lipids offer a promising scheme for poorly water-soluble and lipophilic drugs. Various nanoparticles including vesicular systems, lipid particulate systems, and emulsion systems provide some unique benefits as pharmaceutical carriers in drug and biomolecules delivery systems. Nowadays synthesis is directed toward simple, costless techniques, therefore, self-emulsifying systems have gained superiority over the other carriers. Self nano-emulsifying systems composed of oil, surfactant, and co-surfactant emulsified upon contact with an aqueous medium, has been widely exploited. This review attempts to provide a comprehensive interpretation of different types of lipid-based carriers emphasizing on the self-nanoemulsifying system, why it is gaining interest, formulation, composition, and applications.

Tadalafil-Loaded Limonene-Based Orodispersible Tablets: Formulation, in vitro Characterization and in vivo Appraisal of Gastroprotective Activity.

BACKGROUND: Gastric ulcer is a prevalent disease with various etiologies, including non-steroidal anti-inflammatory drugs and alcohol consumption. This study aimed to explore the dual gastric protection effect of tadalafil and limonene as a self-nanoemulsifying system (SNES)-based orodispersible tablets. METHODS: Tadalafil-loaded limonene-based SNES was prepared, and the optimum formula was characterized in terms of particle size (PS), polydispersity index (PDI), and zeta potential (ZP) then loaded on various porous carriers to formulate lyophilized orodispersible tablets (ODTs). The ODTs were evaluated via determining hardness, friability, content uniformity, wetting, and disintegration time. The selected ODT was examined for its gastric ulcer protective effect against alcohol-induced ulcers in rat model. Ulcer score and ulcer index were computed for rats stomachs that were inspected macroscopically and histopathologically. RESULTS: The prepared SNES had droplet size of 104 nm, polydispersity index of 0.2, and zeta potential of -15.4 mV. From the different ODTs formulated, the formula with superior wetting time: 23.67 s, outstanding disintegration time: 28 s, accepted hardness value: 3.11 kg/cm2 and friability: 0.6% was designated. A significant gastroprotective effect of the unloaded and tadalafil-loaded ODTs was recognized compared to the omeprazole pre-treated group. Moreover, the histopathological analysis displayed very mild inflammation in the limonene-based ODTs group and intact structure in the tadalafil-loaded pre-treated animals. CONCLUSION: Limonene gastroprotective effect functioned along with tadalafil in the form of SNES-incorporated ODTs could serve as a promising revenue for better efficacy in gastric ulcer prevention.

Anticancer Activity of Thymoquinone Cubic Phase Nanoparticles Against Human Breast Cancer: Formulation, Cytotoxicity and Subcellular Localization.

INTRODUCTION: Triple negative breast cancer is an aggressive disorder which accounts for at least 15% of breast cancer diagnosis and a high percentage of breast cancer morbidity, hence intensive research efforts are focused on the development of effective therapies to overcome the disease. Thymoquinone (TQ), the bioactive constituent of Nigella sativa, exhibits anticancer activity, yet its translation to the clinic is hindered by its poor bioavailability and lack of quantification method in blood and tissues. To overcome these limitations, cubosomes were utilized for the encapsulation and delivery of this anticancer molecule. METHODS: Thymoquinone loaded cubosomes were prepared through the emulsification homogenization method. The physicochemical characteristics, including particle size, zeta potential, morphology and entrapment efficiency, were studied. Moreover, the in vitro antitumor activity was tested on breast cancer cell lines (MCF-7 and MDA-MB-231) and compared to non-tumorigenic cell line (MCF-10A). Subcellular localization, cellular uptake and apoptotic effects of the formulations were assessed. RESULTS: The results revealed that the TQ loaded cubosomal formulation exhibited a mean particle size of 98.0 ± 4.10 nm with narrow unimodal distribution. The high entrapment efficiency (96.60 ± 3.58%) and zeta potential (31.50 ±4.20 mV) conceived the effectiveness of this nanosystem for TQ encapsulation. Cell viability in both breast cancer cell lines demonstrated a dose-dependent decrease in response to treatment with free TQ or TQ-loaded cubosomes, with enhanced antitumor activity upon treating with the latter formulation. A significant increase in apoptotic bodies and cleaved caspase 3 was observed upon treatment of MDA-MB-231 cells with either TQ or TQ-loaded cubosomes. Localization and trafficking studies unveiled that cubosomes accumulate in the cytoplasm of the studied breast cancer cell lines. DISCUSSION: Our results show that thymoquinone encapsulation in cubosomal nanoparticles provides a promising anticancer drug delivery system with the ability to label, detect and subsequently trace it within the human cells.

Levofloxacin-loaded naturally occurring monoterpene-based nanoemulgel: a feasible efficient system to circumvent MRSA ocular infections.

Staphylococcus aureus is a leading cause of ocular keratitis worldwide, and the upsurge of Methicillin-resistant Staphylococcus Aureus (MRSA) strains necessitated the development of new antimicrobial agents. D-limonene is the major constituent of oil extracted from citrus peel, which has been utilized for its gastroprotective, antifungal, antitumor, and antibacterial effects. The present study aimed to develop an effective in-situ ocular limonene-based nanoemulgel to enhance the efficacy of fluoroquinolones against MRSA associated ocular biofilm infection. The nanoemulsion composed of limonene, Tween®80, propylene glycol at a ratio of 5:4:1 loaded with levofloxacin. The formulated levofloxacin-loaded limonene-based nanoemulsion physiochemical properties namely; droplet size, polydispersity index, zeta potential, and in-vitro drug release were studied and stability over three months was assessed. Furthermore, in-vitro antimicrobial susceptibility was investigated on biofilm-forming MRSA strain through kinetics of killing and biofilm assay. The in-situ nanoemulgel ocular irritation was studied by HET-CAM test. The results demonstrated that levofloxacin-loaded limonene-based nanoemulsion had a particle size of 119 ± 0.321 nm with improved eradicating efficacy of MRSA biofilm, where the MIC of the loaded nanoemulgel was 3.12 mg/ml significantly less than that of drug alone (6.25 mg/ml). HET-CAM test showed no signs of hemorrhage, coagulation, or lysis for the loaded nanoemulgel same as sodium chloride solution (negative control) where its irritation score was zero compared to 9.87 for the positive irritant group (1%w/v sodium lauryl sulfate). In conclusion, the current investigation provided a strong foundation for further studies of limonene nanoemulgel as a potential complementary therapeutic agent against resistant bacterial strains.

Updated but not outdated "Gliadin": A plant protein in advanced pharmaceutical nanotechnologies.

For many years, natural products have been considered as the backbone of medical therapy. Recently, different extracted active moieties of these botanical plants were employed as innovative drug delivery vehicles. Protein-based nanocarriers have acquired great engrossment as colloidal vehicles for delivering different therapeutic agents, anticancer, anti-inflammatory, vitamins, or even biomedical devices. Gliadin is a natural protein, accounts for 80-85% of the total wheat protein, and forms a vital part in the quality and nutritional value of flour. Gliadin is not just a dietary protein, its properties created a novel and surprising applications in medical fields, pharmaceutical, biomedical devices, and drug delivery. Gliadin is safe, biocompatible, and superior over synthetic proteins. The current review highlights the nature, characteristics, quantitation, and extraction of gliadin moreover sheds the light on its different applications. The high bioadhesive ability endorsed its interaction with gastric mucosa facilitating the delivery of various drug molecules, its structure, and the disulfide bonds expanded the encapsulation of lipophilic molecules, vitamins, and enzymes. Add on this its antimicrobial film capability and its flexibility as fibers. Gliadin is applied extensively in food and its safety to the patient with celiac disease, and cytotoxicity to normal cells has not been fully elaborated.

A novel multifaceted approach for wound healing: Optimization and in vivo evaluation of spray dried tadalafil loaded pro-nanoliposomal powder.

The topical delivery of nanotherapeutics at the injury site for skin regeneration has received increasing attention as a strategy for wound treatment. This study aimed to investigate the preparation of spray dried tadalafil loaded pro-nanoliposomes powder as a novel system to accelerate wound healing process. The optimization was carried out employing 32 factorial design based on phospholipid and cholesterol concentrations. The physicochemical characterizations, in vitro cellular assessment and in vivo performance were evaluated. The results obtained pointed out that phospholipid concentration presented a positive effect on the entrapment efficacy and particle size, while cholesterol hindered the entrapment efficacy yet presented a prominent influence on particle size. Moreover, the optimized formulation showed a sustained release, high zeta potential and uniform spherical particles indicating entrapment of tadalafil in its amorphous state as demonstrated by FTIR and XPRD results. Cell viability and in vitro scratch assay demonstrated no cytotoxicity on human fibroblast cell lines and the ability of the drug and optimized formulation to promote cell migration. In vivo wound healing studies revealed significantly higher wound closure rates for areas treated with optimized loaded-formulation (65.95±6.47%) compared to unloaded formulation (29.78±9.65%), free drug (38.87±11.44%) and sham group (10.22±5.11%). In the in vivo study, histopathological specimens supported the previous results with presentation of cascade of healing elements via the angiogenetic activity of tadalafil. These outcomes provide an insight of a novel and emerging therapeutic drug system for wound treatment in clinical practice.

Rifampicin-Carbohydrate Spray-Dried Nanocomposite: A Futuristic Multiparticulate Platform For Pulmonary Delivery.

PURPOSE: Rifampicin, a first-line anti-tuberculosis drug, was loaded into a carbohydrate-based spray-dried nanocomposite with the aim to design a dry powder inhalation formulation. This strategy can enable efficient distribution of rifampicin within the lungs, localizing its action, enhancing its bioavailability and reducing its systemic exposure consequently side effects. METHODS: The respirable nanocomposite was developed utilizing spray drying of rifampicin nanosuspension employing a combination of mannitol, maltodextrin and leucine as microparticles matrix formers. Detailed physicochemical characterization and in-vitro inhalation properties of the nanocomposite particles were investigated. Compatibility studies were carried out using differential scanning calorimetry and Infrared spectroscopy techniques. Moreover, pulmonary in-vitro cytotoxicity on alveolar basal epithelial cells was performed and evaluated. RESULTS: Nanocomposite-based rifampicin-loaded dry inhalable powder containing maltodextrin, mannitol and leucine at a ratio of 2:1:1 was successfully formulated. Rifampicin loading efficiency into the carbohydrate nanocomposite was in the range of 89.3% to 99.2% w/w with a suitable particle size (3.47-6.80 µm) and unimodal size distribution. Inhalation efficiency of the spray-dried nanosuspension was significantly improved after transforming into an inhalable carbohydrate composite. Specifically, mannitol-based powder had higher respirable fraction (49.91%) relative to the corresponding formulation of maltodextrin. Additionally, IC50 value of rifampicin nanocomposite was statistically significantly higher than that of free drug thus providing superior safety profile on lung tissues. CONCLUSION: The obtained results suggested that spray drying of rifampicin nanosuspension utilizing carbohydrates as matrix formers can enhance drug inhalation performance and reduce cellular toxicity. Thus, representing an effective safer pulmonary delivery of anti-tuberculosis drugs.