Mucoadhesive Formulation Research Articles

Development and Characterization of a Tacrolimus/Hydroxypropyl-β-Cyclodextrin Eye Drop.

Uveitis is a vision inflammatory disorder with a high prevalence in developing countries. Currently, marketed treatments remain limited and reformulation is usually performed to obtain a tacrolimus eye drop as a therapeutic alternative in corticosteroid-refractory eye disease. The aim of this work was to develop a mucoadhesive, non-toxic and stable topical ophthalmic formulation that can be safely prepared in hospital pharmacy departments. Four different ophthalmic formulations were prepared based on the tacrolimus/hydroxypropyl-β-cyclodextrin (HPβCD) inclusion complexes’ formation. Phase solubility diagrams, Nuclear Magnetic Resonance (NMR) and molecular modeling studies showed the formation of 1:1 and 1:2 tacrolimus/HPβCD inclusion complexes, being possible to obtain a 0.02% (w/v) tacrolimus concentration by using 40% (w/v) HPβCD aqueous solutions. Formulations also showed good ophthalmic properties in terms of pH, osmolality and safety. Stability studies proved these formulations to be stable for at least 3 months in refrigeration. Ex vivo bioadhesion and in vivo ocular permanence showed good mucoadhesive properties with higher ocular permanence compared to the reference pharmacy compounding used in clinical settings (t1/2 of 86.2 min for the eyedrop elaborated with 40% (w/v) HPβCD and Liquifilm® versus 46.3 min for the reference formulation). Thus, these novel eye drops present high potential as a safe alternative for uveitis treatment, as well as a versatile composition to include new drugs intended for topical ophthalmic administration.

New perspectives on the topical management of recurrent candidiasis.

Candidiasis is a common opportunistic infection caused by fungi of the Candida genus that affects mainly mucocutaneous tissues (e.g., vaginal, oral, and mammary). This condition has been known for a long time; thus, innumerous topical and systemic treatments are already available on the market worldwide. Yet, recurrent superficial candidiasis (RSC) is an expected outcome, still lacking effective and convenient treatments. Although several individual conditions may contribute to disease recurrence, biofilms' presence seems to be the main etiological factor contributing to antifungal resistance. More than proposing novel antifungal agents, current research seems to be focusing on improving the pharmaceutical technology aspects of formulations to address such a challenge. These include extending and improving intimate contact of drug delivery systems with the mucocutaneous tissues, increasing drug loading dose, and enhancing topical drug permeation. This review discusses the current understanding of the RSC and the use of pharmaceutical technology tools in obtaining better results. Even though several drawbacks of conventional formulations have been circumvented with the help of nano- or microencapsulation techniques and with the use of mucoadhesive formulation excipients, many challenges remain. In particular, the need to mask the unpalatable taste of formulations for the treatment of oral candidiasis, and the necessity of formulations with a "dryer" sensorial feeling and improved performances in providing higher bioavailability for the treatment of mammary and vaginal candidiasis.

Efficacy and safety of plant-based therapy on recurrent aphthous stomatitis and oral mucositis in the past decade: a systematic review

Oral mucosal inflammation is one of the oral diseases causing pain and reducing the quality of human life. The types of oral mucosal inflammation that commonly found were recurrent aphthous stomatitis (RAS) and oral mucositis (OM). Anti-inflammatory drugs, both synthetic and plant-based, have been used to treat RAS and OM. Plant-based drugs have been attracted the attention of some researchers to minimize the side effects of synthetic drugs. However, a comprehensive review addressing the use of plant-based drugs for RAS and OM therapy, including drug formulation and species of plant, has not yet been reported. Here, we reported the article review of 9 publications derived from the databases of PubMed, ScienceDirect, Cochrane Library, and other additional relevant works, in order to find the effectiveness and safety of plant-based drugs for RAS and OM therapy. This review was written by following the PRISMA guidelines, and the risk of bias of the articles was evaluated using the Oxford Quality Scoring System. It was found that the effective and safe drugs for RAS therapy contained acemannan from Aloe vera and curcumin from Curcuma longa, both in an oral gel formulation. For OM therapy, drugs contained curcumin from Curcuma longa; licorice from Glycyrrhiza glabra; Aloe vera and black mulberry from Morus nigra, in soft tablet, mouthwash solution or mucoadhesive film formulation. In conclusion, the most effective and safest plant-based therapy for RAS is Acemannan 0.5% in oral gel, whereas for OM is Licorice root extract 0.18 mg in mucoadhesive film.

Mucoadhesive nanostructured lipid carriers as a cannabidiol nasal delivery system for the treatment of neuropathic pain

The therapeutic potential of cannabidiol (CBD) has been explored to treat several pathologies, including those in which pain is prevalent. However, the oral bioavailability of CBD is low owing to its high lipophilicity and extensive first-pass metabolism. Considering the ability of the nasal route to prevent liver metabolism and increase brain bioavailability, we developed nanostructured lipid carriers (NLCs) for the nasal administration of CBD. We prepared particles with a positively charged surface, employing stearic acid, oleic acid, Span 20Ⓡ, and cetylpyridinium chloride to obtain mucoadhesive formulations. Characterisation of the CBD-NLC dispersions showed uniform nano-sized particles with diameters smaller than 200 nm, and high drug encapsulation. The mucoadhesion of cationic particles has been related to interactions with negatively charged mucin. Next, we added in-situ gelling polymers to the CBD-NLC dispersion to obtain a CBD-NLC-gel. A thermo-reversible in-situ forming gel was prepared by the addition of PluronicsⓇ. CBD-NLC-gel was characterised by its gelation temperature, rheological behaviour, and mucoadhesion. Both formulations, CBD-NLC and CBD-NLC-gel, showed high mucoadhesion, as assessed by the flow-through method and similar in vitro drug release profiles. The in vivo evaluation showed that CBD-NLC dispersion (without gel), administered intranasally, produced a more significant and lasting antinociceptive effect in animals with neuropathic pain than the oral or nasal administration of CBD solution. However, the nasal administration of CBD-NLC-gel did not lessen mechanical allodynia. These findings demonstrate that in-situ gelling hydrogels are not suitable vehicles for highly lipophilic drugs such as CBD, while cationic CBD-NLC dispersions are promising formulations for the nasal administration of CBD.

Biological effects of formulation containing curcuminoids and Bidens Pilosa L. in oral carcinoma cell line.

FITOPROT, which contains curcuminoids and Bidens pilosa L. extract, is an innovative mucoadhesive formulation indicated for the topical treatment of chemoradiotherapy-induced oral mucositis (OM) in patients with advanced and visible oral squamous cell carcinoma. The formulation is used as a mouthwash directly on tumor tissue of patients with advanced neoplasms, without triggering cancer cell proliferation or tumor invasiveness. Thus, the aim of this study was to evaluate the biological effects of FITOPROT on an oral squamous cell carcinoma cell line (SCC-4). The viability of SCC-4 cells was assessed after exposure to FITOPROT using MTT reduction assay. The effects of the mucoadhesive formulation on cell cycle progression and cell death parameters were evaluated using flow cytometry. In addition, the inflammatory profile of the tumor cells was evaluated using the cytometric bead array (CBA) assay. FITOPROT promoted a concentration-dependent decrease in cell viability and cell cycle arrest at the G2/M phase (p < 0.05). Mitochondrial membrane potential was also altered after exposure to the formulation (p < 0.05), in parallel with a reduction in VEGF and IL-8 production (p = 0.01 and p = 0.05, respectively). In summary, the results indicate that FITOPROT reduces SCC-4 cell viability, promotes cell cycle arrest, modulates mitochondrial membrane potential, and exhibits antiangiogenic and anti-inflammatory properties, thus indicating its potential for topical use in patients with OM and visible tumors in the mouth.

A polymeric paste-drug formulation for local treatment of upper tract urothelial carcinoma

BackgroundIntravesical instillation of chemo- or immunotherapy is commonly used in bladder cancer. Upper tract urothelial carcinoma (UTUC) shares similar pathological features, but current formulations are not suitable for direct instillation to the upper urinary tract. ObjectiveTo evaluate in vivo applicability, characteristics and toxicity of ST-UC, a mucoadhesive polymeric paste formulation of gemcitabine, for upper urinary tract instillation. Material and methodsThree pigs received 10 ml of ST-UC (100 mg/ml gemcitabine) retrogradely into 1 renal pelvis for pharmacokinetic studies. Four days later, a second injection into the contralateral renal pelvis was followed by serial euthanasia of the pigs and nephroureterectomy after 1, 3, and 6 hours. Adverse effects were monitored. Urine, serum, and tissue gemcitabine concentrations were measured, along with histologic examination of the upper urinary tract. ResultsRetrograde instillation of ST-UC was well tolerated with mild, completely receding hydronephrosis. Urine gemcitabine concentrations were highest in the first 3-hour collection interval. Hundred percent of gemcitabine was recovered in the urine within 24 hours. Serum peak concentrations (cmax) of gemcitabine were low at 5.5 µg/ml compared to the 10 to 30 µg/ml levels observed after a single intravenous dose of 1,000 mg/m2 gemcitabine. The formulation was still traceable after one hour and gemcitabine tissue concentrations are supportive of this extended drug exposure. No major histopathological changes were observed. The main limitation of this study is the lack of antitumor activity data. ConclusionThis preclinical evaluation of ST-UC demonstrated feasible instillation in the renal pelvis, no significant safety concerns, and sustained release of gemcitabine.

Mapping the potential of thiolated pluronic based nanomicelles for the safe and targeted delivery of vancomycin against staphylococcal blepharitis

The present study was performed to develop mucoadhesive vancomycin loaded thiolated pluronic F68 polymeric nanomicelles against staphylococcal blepharitis. The polymeric micelles were intended to be mucoadhesive in nature with prolonged retention at site of infection to address the barriers in topical delivery to eyelids. The mucoadhesive and enhanced retention of polymeric micelles was investigated by synthesis of vancomycin loaded thiolated polymeric micelles of tri block copolymer Pluronic F68. The drug loaded thiolated polymeric micelles were characterized for their zeta potential, particle size, PDI, release profile, animal studies and stability. The FTIR analysis of the thiolated polymeric nanomicelles confirmed successful synthesis of vancomycin loaded thiolated polymeric nanomicelles (Vnc-PF68-Cys) with no interaction between vancomycin and polymer. X-Ray diffraction studies (XRD) showed crystalline nature of vancomycin in the thiolated polymeric nanomicelles. The surface roughness of the developed polymeric nanomicelles was evident from results of AFM (Atomic force microscopy) images. TEM (Tranmission electron microscopy) confirmed spherical shape and unilamelar nature of nanomicelles. Furthermore, Vnc-PF68-Cys nanomicelles were found to be stable regarding particle size, zeta potential and polydispersity index with nanosize, low polydispersity index and negative zeta potential. Thermal stability of the formulation was confirmed by DSC (Differential scanning calorimetry). Visual inspection of the nanoformulation showed particles-free clear solution. Mucoadhesive property was evaluated by rheological behaviour of formulation when mixed with freshly prepared mucin solution in terms of viscosity that showed 2 folds increase in viscosity upon thiolation of formulation due to thiols group in polymer backbone forming disulfide linkage with cysteine groups of mucins. Release profile showed sustained drug release up to 48 h for thiolated formulation with 98% drug released under sink conditions. The prepared thiolated nanomicelles were found non-toxic towards mice. Based on the results, the developed Vnc-PF68-cys polymeric nanomicelles formulation seems to be promising mucoadhesive formulation for ocular deliveryagainst staphylococcal blepharitis.

Intranasal fosphenytoin: The promise of phosphate esters in nose-to-brain delivery of poorly soluble drugs.

Intranasal administration could increase both safety and efficacy of drugs acting on the central nervous system, but low solubility severely limits administration through this route. Phenytoin's prodrug, fosphenytoin, is hydrophilic and freely soluble in water, but less permeable since it is dianionic. We aimed to assess whether this phosphoester prodrug could be a suitable alternative to phenytoin in intranasal delivery. Secondly, we aimed to compare simple formulation strategies in fosphenytoin delivery. Fosphenytoin formulations containing thermosensitive and/or mucoadhesive (hydroxypropyl methylcellulose, HPMC) polymers were developed, guided by viscosity, gelling temperatures, osmolality, and in vitro drug release tests. Then, a pharmacokinetic study was performed, comparing an intravenous fosphenytoin solution, an intranasal fosphenytoin solution, and intranasal fosphenytoin mucoadhesive formulations with or without albumin. Formulations containing HPMC allowed high drug strengths, and had a relatively fast release profile, which was not changed by albumin. Intranasal administration of a formulation with HPMC and albumin prolonged drug concentration over time and led to complete or even increased absolute bioavailability. Moreover, phenytoin's blood levels did not reach the high peak obtained with intravenous administration. In conclusion, the use of phosphate ester prodrugs could be an efficient and safe strategy to increase the intranasal bioavailability of poorly soluble drugs.

Mucoadhesive Formulation Designs for Oral Controlled Drug Release at the Colon

Mucoadhesive formulations have been demonstrated to result in efficient drug delivery systems with advantages over existing systems such as increased local retention and sustained drug release via adhesiveness to mucosal tissues. The controlled release of colon-targeted, orally administered drugs has recently attracted a number of studies investigating mucoadhesive systems. Consequently, substantial designs, from mucoadhesive cores to shells of particles, have been studied with promising applications. This review will provide an overview of specific strategies for developing mucoadhesive systems for colon-targeted oral delivery with controlled drug release, including mucoadhesive matrices, cross-linked mucoadhesive microparticles, coatings and mucoadhesive nanoparticles. The understanding of the basic principle of these designs and advanced formulations throughout will lead to the development of products with efficient drug delivery at the colon for therapies for different diseases.

Development and Evaluation of a Novel Oral Mucoadhesive Ointment Containing Pomegranate Peel Extract as an Adjuvant for Oral Hygiene of Dogs.

Herbal therapies are used worldwide to treat a variety of health conditions, including dental conditions in veterinary medicine. In this context, the use of medicinal plant-based formulations as potential therapeutics and preventatives in veterinary dentistry is worth highlighting. The objective of the present study was to develop a mucoadhesive ointment formulation, named orabase, that contained pomegranate extract for use in the oral cavity of dogs, with the aim of improving their oral hygiene. The hydroalcoholic extracts of pomegranate peels was incorporated into the orabase in 3 different concentrations. The formulations were subjected to in vitro microbiological testing by a modified disc-diffusion method to study the susceptibility of microorganisms collected from the oral cavities of the dogs. The samples were taken from the buccal mucosa of dogs having the same management and diet. The most effective formulation was submitted to physicochemical tests to evaluate the functionality of the product, namely pH, swelling index, spreadability, and mechanical properties (hardness, cohesiveness, and adhesiveness). The formulation containing 25.0% w/w of the extract was considered most suitable for the intended use as it showed antiseptic activity and demonstrated a swelling index of approximately 35% in the first 20 minutes of the test, high spreadability, and suitable mechanical properties. The results suggest that the product obtained from pomegranate peel extract is a viable option for use to improve oral hygiene, helping to reduce the bacterial component of dental plaque in dogs.

Evaluation of zinc sulfate mucoadhesive formulation on recurrent aphthous stomatitis: a randomized double-blind, placebo-controlled clinical trial

BackgroundRecurrent aphthous stomatitis (RAS) is a common lesion that affects the oral mucosa. There are several methods to treat RAS, including systemic and topical formulations. This study was conducted to evaluate the anti-inflammatory effect of topical zinc sulfate and its efficacy in the treatment of RAS.MethodsA double-blind randomized clinical trial was conducted on 46 patients with RAS. They were randomly assigned into two groups to receive a zinc sulfate mucoadhesive tablet or placebo for 7 days. The pain severity was measured at baseline and daily while the diameter of the lesion was measured at baseline and on days 3, 5, and 7. The obtained data were analyzed in SPSS V.16.ResultsThere was no significant difference in the mean diameter of lesions and pain at baseline between the two groups (P = 0.643 and P = 0.842, respectively). However, on the third, fifth, and seventh days of the study, the diameter of the lesion significantly reduced in the intervention group (P = 0.001) and the pain intensity became significantly different between groups from the fourth day of the study (P = 0.001).ConclusionZinc sulfate mucoadhesive tablet was effective in recovery and reducing the pain and diameter of the aphthous lesion and could be considered for the treatment of RAS.Trial registrationEvaluation of the effectiveness of zinc sulfate mucoadhesive tablet in the improvement of recurrent aphthous stomatitis (RAS), IRCT20151109024975N9. Registered August 1, 2018, https://en.irct.ir/trial/32423. This project was registered by the Iranian Registry of Clinical Trials (http://www.irct.ir). The IRCT ID was IRCT20151109024975N9.

Comparative Evaluation of Bromhexine HCl Mucoadhesive Microspheres Prepared by Anionic, Cationic and Nonionic Polymers

The purpose of this study was to formulate and assess the mucoadhesive microspheres of bromhexine hydrochloride, a mucolytic agent, using three different types of polymers to achieve gastric retention for improved solubility and bioavailability of the drug. The mucoadhesive formulation was prepared because it dissolved in the pH range of 1 to 4. The characteristics of the prepared microspheres were evaluated by determining the particle size, percent drug loading, surface morphology, swelling behavior, mucoadhesive bond strength and drug entrapment efficiency. The in vitro dissolution was studied using the USP dissolution apparatus I in 0.1N HCl (pH 1.2) media for 8 hours. The release kinetics were analyzed by using zero order, first order, Higuchi, Korsmeyer-Peppas and Hixon-crowell equations to explain the release mechanism from the microspheres. The microspheres exhibited good swelling index and the drug entrapment efficiency was above 79 % for all the formulations. All the formulations showed drug release above 25%, 35%, 50% and 75% after 2 hrs, 4 hrs, 6 hrs and 8 hrs of dissolution respectively. The mucoadhesive bond was observed up to 8 hrs in acidic media. The surface morphology of the prepared microspheres was studied by Scanning Electron Microscope (SEM) and no interaction was found between drug and polymer from the FTIR study. Bangladesh Pharmaceutical Journal 23(2): 117-124, 2020

Hybrid nanofilms as topical anesthetics for pain-free procedures in dentistry

Topical anesthetics are widely applied in order to relieve the discomfort and anxiety caused by needle insertion and other painful superficial interventions at the oral cavity. So far, there are no commercially available effective topical anesthetic formulations for that purpose, and the most of developments are related to hydrophilic and low mucoadhesive forms. Therefore, we have prepared different hybrid nanofilms composed of biopolymer matrices (chitosan, pectin, and chitosan-pectin) blended with nanostructured lipid carriers (NLC) loading the eutectic mixture of 5% lidocaine–prilocaine (LDC–PLC), in order to fulfill this gap in the market. These dual systems were processed as hybrid nanofilms by the solvent/casting method, and its mucoadhesive, structural and mechanical properties were detailed. The most appropriate hybrid nanofilm combined the advantages of both pectin (PCT) and NLC components. The resultant material presented sustained LDC–PLC release profile for more than 8 h; permeation across porcine buccal mucosa almost twice higher than control and non-cytotoxicity against 3T3 and HACAT cell lines. Then, the in vivo efficacy of PCT/NLC formulation was compared to biopolymer film and commercial drug, exhibiting the longest-lasting anesthetic effect (> 7 h), assessed by tail flick test in mice. These pectin-based hybrid nanofilms open perspectives for clinical trials and applications beyond Dentistry.

Mucoadhesive interactions between synthetic polyaspartamides and porcine gastric mucin on the colloid size scale

Synthetic polyaspartamides with various functional side groups including primary, secondary, tertiary amine or carboxyl groups were designed to explore the effect of chemical composition on polymer-mucin interactions. Since the molecular weight of the polymers and the degree of modification were identical for each derivative, the role of the functional groups could be evaluated. Chitosan was used as a control sample due to its strong interaction with mucin primarily through electrostatic forces. Mucoadhesive interactions of the polymers with the aqueous dispersion of commercially available porcine gastric mucin were probed on the colloid size scale using various methods including turbidimetric titration, dynamic light scattering and zeta potential measurements. Both the charge of the polymers and the type of amine groups had a pronounced effect on the interactions. The interactions were further analysed by partially screening them with either sodium chloride or urea. The results obtained allow us to classify these polymers in terms of in vitro mucoadhesive strength, which can be useful in the design of mucoadhesive formulations.

Mucoadhesive bilayered buccal platform for antifungal drug delivery into the oral cavity.

A drug delivery technology comprising a mucoadhesive bilayered buccally anchored tablet containing natamycin was developed. The concept was to anchor the tablet to the buccal tissue and allow controlled release of the drug through the matrix into the mouth. Carbomer (Carbopol ® 974 P NF) was used to formulate the mucoadhesive layer. Hydroxypropyl methylcellulose (HPMC) (Methocel® K4M) at 10, 15, 20, and 40% w/w was used for the drug-containing layer. Natamycin, an amphoteric macrolide antifungal agent, was incorporated into the formulations. In addition, tablets containing erythrosine as a marker were prepared in order to examine the distribution and retention of the dye in the oral cavity. As expected, the in vitro analysis showed that the concentration of natamycin released decreased with the increasing proportion of HPMC in the formulation. A small volunteer study was conducted using the tablets containing 10% and 20% HPMC to quantitate the patterns of distribution of the drug released into the oral cavity (upper right buccal vestibule, lower right and left buccal vestibules, and sublingual region). The mucoadhesive bilayered buccal tablet formulation provided a unidirectional release of the drug from the tablet into the oral cavity in a prolonged release fashion, maintaining drug concentration above the MIC value (2μg/mL) for Candida albicans. The amount of the drug in the sublingual region was found to be lowest when compared with other regions, which is due to the higher flow of saliva in this region. Graphical abstract.

The Vaginal-PVPA: A Vaginal Mucosa-Mimicking In Vitro Permeation Tool for Evaluation of Mucoadhesive Formulations.

Drug administration to the vaginal site has gained increasing attention in past decades, highlighting the need for reliable in vitro methods to assess the performance of novel formulations. To optimize formulations destined for the vaginal site, it is important to evaluate the drug retention within the vagina as well as its permeation across the mucosa, particularly in the presence of vaginal fluids. Herewith, the vaginal-PVPA (Phospholipid Vesicle-based Permeation Assay) in vitro permeability model was validated as a tool to evaluate the permeation of the anti-inflammatory drug ibuprofen from liposomal formulations (i.e., plain and chitosan-coated liposomes). Drug permeation was assessed in the presence and absence of mucus and simulated vaginal fluid (SVF) at pH conditions mimicking both the healthy vaginal premenopausal conditions and vaginal infection/pre-puberty/post-menopause state. The permeation of ibuprofen proved to depend on the type of formulation (i.e., chitosan-coated liposomes exhibited lower drug permeation), the mucoadhesive formulation properties and pH condition. This study highlights both the importance of mucus and SVF in the vaginal model to better understand and predict the in vivo performance of formulations destined for vaginal administration, and the suitability of the vaginal-PVPA model for such investigations.

Enhancement of Simvastatin ex vivo Permeation from Mucoadhesive Buccal Films Loaded with Dual Drug Release Carriers.

BackgroundSimvastatin (SMV), a hypocholesterolemic agent, suffers from very low bioavailability due to its poor aqueous solubility and extensive first-pass metabolism.MethodsTwo SMV carrier systems, namely, polymeric drug inclusion complex (IC) and mixed micelles (MM) nanoparticles, were developed and loaded into mucoadhesive buccal films to enhance SMV bioavailability. The two carrier systems were characterized and their permeation across human oral epithelial cells (OEC) was studied. The effect of IC to MM ratio (X1) and the mucoadhesive polymer concentration (X2) on the cumulative percent of drug released, elongation percent and the mucoadhesive strength, from the prepared mucoadhesive films, were optimized. Ex vivo permeation across bovine mucosal tissue was investigated. The permeation parameters for the in vitro and ex vivo release data were calculated.ResultsComplexation of SMV with hydroxypropyl beta-cyclodextrin (HP β-CD) was superior to all other polymers as revealed by the equilibrium saturation solubility, stability constant, complexation efficiency and thermodynamic potential. SMV-HP β-CD IC was utilized to develop a saturated polymeric drug solution. Both carrier systems showed enhanced permeation across OEC when compared to pure drug. X1 and X2 were significantly affecting the characteristics of the prepared films. The optimized mucoadhesive buccal film formulation loaded with SMV IC and drug MM nanoparticles demonstrated superior ex vivo permeation when compared to the corresponding pure drug buccal film, and the calculated permeation parameters confirmed this finding.ConclusionMucoadhesive buccal films containing SMV IC and drug MM can be used to improve drug bioavailability; however, additional pharmacokinetic and pharmacodynamic studies are required.

Brain targeted delivery of lurasidone HCl via nasal administration of mucoadhesive nanoemulsion formulation for the potential management of schizophrenia

This investigation aimed to design, develop, and optimize intranasal nanoemulsion for brain targeted delivery of lurasidone hydrochloride for the management and treatment of schizophrenia. The design of experiment supported optimization of high-pressure homogenization (HPH) process was executed for the manufacturing of lurasidone loaded nanoemulsion. The nanoemulsion comprising of lurasidone hydrochloride (10 mg/mL), 20% Oilmix, 25% surfactant and, 55% aqueous phase (w/w) was processed with HPH at optimized conditions to get droplet size in the nano range. The droplet size of optimized nanoemulsion was found to be 48.07 ± 3.29 nm with a polydispersity index of 0.31 ± 0.01. The optimized translucent nanoemulsion (% transmittance of 88.56 ± 2.47) was found to be non-toxic to sheep nasal mucosa and stable for six months. The results of ex vivo diffusion study revealed the improvement in drug diffused by mucoadhesive nanoemulsion (MLNE) (1.41 × 10−4 ± 1.11 × 10−5 cm2/min) as compared to the solution (1.15 × 10−4 ± 1.35 × 10−5 cm2/min). The results of pharmacodynamic studies in mice uncover the highest inhibition of compulsive behavior (64.63%) and spontaneous locomotor activity (60.87%) shown by MLNE. This may be due to increased bioavailability in a brain, and possibly confirms the potential of nanoemulsion in targeting the brain through nasal route in the treatment of schizophrenia.

Topical Melatonin Niosome Gel for the Treatment of 5-FU-Induced Oral Mucositis in Mice.

Oral mucositis, one of the most common complications of 5-Fluorouracil (5-FU) treatment, leads to several problems, including pain, diarrhea and malnutrition, and reduces the quality of life and subsequent treatments. Melatonin, a neurohormone with anti-inflammatory and antioxidant activities, was encapsulated in niosomes and embedded in a mucoadhesive gel formulation as a Melatonin Niosome Gel (MNG) to perform oral mucositis treatment. This study aimed to investigate the effectiveness of MNG for the treatment of 5-FU-induced oral mucositis in mice. Oral mucositis was induced in ICR mice by 5-FU and randomly assigned to receive daily applications of the topical oral MNG, a fluocinolone acetonide gel, a blank niosome gel, or no treatment for 5 days in comparison with a normal group. Average body weights, food consumption, and behaviors of the mice as well as microscopic histopathology, Fourier-Transform Infrared Spectroscopy (FTIR) analysis, proinflammatory cytokine levels, and oxidative stress markers of the tongues were monitored and collected after sacrifice. In comparison to the normal group, the average body weights of the 5-FU-MNG mice did not deviate from that of the normal group, nor was there a significant difference in the time to sleep or licking (p>0.05 for both parameters). In addition, the mice treated with MNG and fluocinolone acetonide did not show significantly different histopathological, FTIR, interleukin-1β or malondialdehyde (MDA) results in the tongues used as the oral tissue samples. Topical MNG potentially inhibits inflammation and lipid oxidative stress in 5-FU-induced oral mucositis.

Advances in the Design of pH-Sensitive Cubosome Liquid Crystalline Nanocarriers for Drug Delivery Applications.

Nanostructure bicontinuous cubic phase self-assembled materials are receiving expanding applications as biocompatible delivery systems in various therapeutic fields. The functionalization of cubosome, spongosome, hexosome and liposome nanocarriers by pH-sensitive lipids and/or pH-sensitive polymer shells offers new opportunities for oral and topical drug delivery towards a new generation of cancer therapies. The electrochemical behavior of drug compounds may favor pH-triggered drug release as well. Here, we highlight recent investigations, which explore the phase behavior of mixed nonlamellar lipid/fatty acid or phospholipid systems for the design of pH-responsive and mucoadhesive drug delivery systems with sustained-release properties. X-ray diffraction and small-angle X-ray scattering (SAXS) techniques are widely used in the development of innovative delivery assemblies through detailed structural analyses of multiple amphiphilic compositions from the lipid/co-lipid/water phase diagrams. pH-responsive nanoscale materials and nanoparticles are required for challenging therapeutic applications such as oral delivery of therapeutic proteins and peptides as well as of poorly water-soluble substances. Perspective nanomedicine developments with smart cubosome nanocarriers may exploit compositions elaborated to overcome the intestinal obstacles, dual-drug loaded pH-sensitive liquid crystalline architectures aiming at enhanced therapeutic efficacy, as well as composite (lipid/polyelectrolyte) types of mucoadhesive controlled release colloidal cubosomal formulations for the improvement of the drugs’ bioavailability.