Engineering 5-flourouracil and leucovorin-loaded vesicular systems for possible colon specific delivery: In vitro evaluation and real time cell assay against HCT-116 colon cell lines.

5-flourouracil (5-FU) is typically modulated with leucovorin (LEU) in clinical practice to improve clinical efficacy and patient survival rates. However, this combination has undesirable side effects and makes 5-FU more toxic. Hence, integrating a vesicular system (proniosomes) with another delivery vehicle may improve drug targeting, while resolving the aforementioned drawbacks. This study aimed to engineer 5-FU/LEU proniosomes for possible delivery to the colon. The modified slurry approach was used to create drug-loaded proniosomes (150 mg/9 g of carrier) using both water-soluble (dextrin (DEX) and lactose (LAC)) and insoluble (Neusilin FH2 (NEU)) carriers. The powdered formulations were filled into Eudragit S100 (10 %)-coated capsules or Eudragit FS 30D capsules for enteric- or colon-specific delivery. In vitro evaluations (flow properties, powder X-ray diffractometry (XRD) analysis, particle size analysis, entrapment efficiency, drug release, scanning electron microscopy (SEM), polydispersity index, Fourier transform infrared spectroscopy (FTIR), and stability studies) were performed on the formulations. An in vitro cytotoxicity test [real-time cell assay (RTCA)] against HCT-116 colon cancer cell lines was performed using the optimized formulation. In vitro evaluations showed that the nanoparticles had good physicochemical properties. RTCA studies showed sustained cell death with the formulations compared to the pure drug and placebo. The sequential drug release of the colon-targeted capsules containing 5-FU and LEU- loaded proniosomes showed negligible drug release in SGF (pH 1.2) and phosphate buffer solution (pH 6.8) (approximately 11 %) but profound drug release (>80 %) at pH 7.4. Drug-loaded proniosomes engineered for colon targeting (Eudragit S100 (10 %) capsules or Eudragit FS 30D capsules) showed good colon-specific targeting and favorable in vitro cytotoxicity profiles.

Formulation and Evaluation of Cola acuminata Gum-based Mucoadhesive Sustained-release Matrix Tablets of Diclofenac Sodium.

OBJECTIVE: This study aimed to evaluate Cola acuminata gum (CAG) for the formulation of mucoadhesive sustained-release matrix tablets of diclofenac sodium. METHODS: Different batches of granules containing CAG and 100 mg of DS in ratios 0.5:1, 1:1, 2:1, and 3:1 were prepared, compressed into tablets, and evaluated for mucoadhesive strength, swelling index, and drug release in SGF (pH 1.2) and SIF (pH 7.4). RESULTS: Swelling indices and mucoadhesive strengths of the tablets were pH-dependent. Swelling indices of 56 ± 2.03 to 121 ± 2.19% and mucoadhesive strengths of 7.25 ± 1.45 to 15.43 ± 2.71 g/cm2 obtained at pH 7.4 were significantly higher (p<0.05) than swelling indices of 25 ± 2.43 to 47 ± 3.15% and mucoadhesive strengths of 5.52 ± 0.76 to 9.22 ± 1.95 g/cm2 obtained at pH 1.2. The percentage release of DS from the matrix tablets at pH 1.2 after 2 h (T2h) was insignificant. However, the percentage of drug release at pH 7.4 was significant for all the batches and dependent on the CAG concentration. The drug release was in the order of batches containing 3 g (80.44 ± 7.75) < 2 g (86.35 ± 5.65) < 1 g (90.08 ± 6.14) < 0.5 g (99.70 ± 3.90). The time for maximum drug release was 7 h (T7h) for CAG containing 0.5 g and 10 h (T10h) for other batches. CONCLUSION: This study showed that CAG could be useful for mucoadhesive sustained drug delivery.

Nanoparticle-based delivery systems as emerging therapy in retinoblastoma: recent advances, challenges and prospects.

Retinoblastoma is the most common intraocular malignancy in children. The treatment of this rare disease is still challenging in developing countries due to delayed diagnosis. The current therapies comprise mainly surgery, radiotherapy and chemotherapy. The adverse effects of radiation and chemotherapeutic drugs have been reported to contribute to the high mortality rate and affect patients' quality of life. The systemic side effects resulting from the distribution of chemotherapeutic drugs to non-cancerous cells are enormous and have been recognized as one of the reasons why most potent anticancer compounds fail in clinical trials. Nanoparticulate delivery systems have the potential to revolutionize cancer treatment by offering targeted delivery, enhanced penetration and retention effects, increased bioavailability, and an improved toxicity profile. Notwithstanding the plethora of evidence on the beneficial effects of nanoparticles in retinoblastoma, the clinical translation of this carrier is yet to be given the needed attention. This paper reviews the current and emerging treatment options for retinoblastoma, with emphasis on recent investigations on the use of various classes of nanoparticles in diagnosing and treating retinoblastoma. It also presents the use of ligand-conjugated and smart nanoparticles in the active targeting of anticancer and imaging agents to the tumour cells. In addition, this review discusses the prospects and challenges in translating this nanocarrier into clinical use for retinoblastoma therapy. This review may provide new insight for formulation scientists to explore in order to facilitate the development of more effective and safer medicines for children suffering from retinoblastoma.

Nanotechnology based drug delivery systems for the treatment of anterior segment eye diseases.

Diseases affecting the anterior segment of the eye are the primary causes of vision impairment and blindness globally. Drug administration through the topical ocular route is widely accepted because of its user/patient friendliness - ease of administration and convenience. However, it remains a significant challenge to efficiently deliver drugs to the eye through this route because of various structural and physiological constraints that restrict the distribution of therapeutic molecules into the ocular tissues. The bioavailability of topically applied ocular medications such as eye drops is typically less than 5%. Developing novel delivery systems to increase the retention time on the ocular surfaces and permeation through the cornea is one of the approaches adopted to boost the bioavailability of topically administered medications. Drug delivery systems based on nanotechnology such as micelles, nanosuspensions, nanoparticles, nanoemulsions, liposomes, dendrimers, niosomes, cubosomes and nanowafers have been investigated as effective alternatives to conventional ocular delivery systems in treating diseases of the anterior segment of the eye. This review discussed different nanotechnology-based delivery systems that are currently investigated for treating and managing diseases affecting the anterior ocular tissues. We also looked at the challenges in translating these systems into clinical use and the prospects of nanocarriers as a vehicle for the delivery of phytoactive compounds to the anterior segment of the eye.

Assessment of the Anti-Malarial Properties of Dihydroartemisinin- Piperaquine Phosphate Solid Lipid-Based Tablets.

BACKGROUND: Artemisininbased combination therapies (ACTs) typified by dihydroartemisinin- piperaquine phosphate are first-line drugs used in the treatment of Plasmodium falciparum malaria. However, the emergence of drug resistance to ACTs shows the necessity to develop novel sustained release treatments in order to ensure maximum bioavailability. OBJECTIVES: To formulate dihydroartemisinin (DHA)-piperaquine phosphate (PQ) sustained release tablets based on solidified reverse micellar solutions (SRMS). METHODS: The SRMS was prepared by fusion using varying ratios of Phospholipon® 90H and Softisan® 154 and characterised. The tablets were prepared by using an in-house made and validated mould. The formulations were tested for uniformity of weight, hardness, friability, softening time, erosion time and in vitro-in vivo dissolution rate. Antimalarial properties were studied using modified Peter's 4-days suppressive test in mice. One-way analysis of variance (ANOVA) was used in the analysis of results. RESULTS: Smooth caplets, with average weight of 1300 ± 0.06 mg to 1312 ± 0.11 mg, drug content of 61 mg for DHA and t 450 mg for PQ. Tablet hardness ranged from 7.1 to 9.0 Kgf and softening time of 29.50 ± 1.90 min. Erosion time of 62.00 ± 2.58 to 152.00 ± 1.89 min were obtained for tablets formulated with Poloxamer 188 (Batches R2, S2 and T2) which significantly reduced the softening and erosion time (p < 0.05). In vitro release showed that the optimized formulations had a maximum release at 12 h. Formulations exhibited significantly higher parasitaemia clearance and in vivo absorption compared to marketed formulations at day 7 (p < 0.05). CONCLUSION: DHA-PQ tablets based on SRMS were much easier and relatively cheaper to produce than compressed tablets. They also showed exceptionally better treatment of malaria owing to their sustained release properties and improved bioavailability and are recommended to Pharmaceutical companies for further studies.

Formulation Development of Azadirachta indica Extract as Nanosuppository to Improve its Intrarectal Delivery for the Treatment of Malaria.

BACKGROUND: Previous folkloric and experimental reports have demonstrated the antimalarial efficacy of Azadirachta indica (AZA) extracts. However, one of the major challenges facing its application for the clinical treatment of malaria is the design of an acceptable dosage form. OBJECTIVE: Consequently, we developed AZA extract-loaded nanostructured lipid carriers (NLC) for the formulation of suppositories, denoted as nanosuppositories, for intrarectal treatment of malaria. METHODS: Various batches of NLC-bearing AZA extract were formulated based on lipid matrices prepared using graded concentrations of Softisan®154 and Tetracarpidium conophorum or walnut oil. NLC was investigated by size and differential scanning calorimetry (DSC). Suppository bearing AZA extract-loaded NLC was developed using cocoa butter or theobroma oil, and their physicochemical properties were profiled. In vitro drug release and in vivo antimalarial activity (using Plasmodium berghei-infected mice) were investigated. RESULTS: NLCs exhibited sizes in nanometers ranging from 329.5 - 806.0 nm, and were amorphized as shown by DSC thermograms. Nanosuppositories were torpedo- or bullet- shaped, weighing 138 - 368 mg, softened/liquefied between 4.10 - 6.92 min, and had controlled release behaviour. In vivo antimalarial study revealed excellent antimalarial efficacy of the nanosuppositories comparable with a commercial brand (Plasmotrim®) and better than the placebo (unloaded nanosuppository), and without toxic alterations of hepatic and renal biochemical factors. CONCLUSION: Thus, AZA extract could be rationally loaded in nanostructured lipid carriers (NLC) for further development as nanosuppository and deployed as an effective alternative with optimum convenience for intrarectal treatment of malaria.

Potential enhancement of metformin hydrochloride in solidified reverse micellar solution-based PEGylated lipid nanoparticles targeting therapeutic efficacy in diabetes treatment.

Metformin hydrochloride (MH) is a widely used oral biguanide antihyperglycemic (antidiabetic) drug with poor bioavailability which necessitates the development of novel drug delivery systems such as PEGylated solid lipid nanoparticles for improving its therapeutic activity. The aim of this study was to formulate, characterize and evaluate in vitro and in vivo pharmacodynamic properties of metformin-loaded PEGylated solid lipid nanoparticles (PEG-SLN) for improved delivery of MH. The lipid matrices (non-PEGylated lipid matrix and PEGylated lipid matrices) used in the formulation of both non-PEGylated (J0) and PEGylated SLNs (J10, J20, J40) were prepared by fusion using beeswax and Phospholipon ® 90H at 7:3 ratio with or without polyethylene glycol (PEG) 4000 (0, 10, 20 and 40% w/w), respectively. Representative lipid matrices (LM and PEG-LM) were loaded with MH by fusion and then characterized by differential scanning calorimetry (DSC) and Fourier transform infrared (FT-IR) spectroscopy. The PEG-SLNs were prepared by high shear hot homogenization using the lipid matrices (5% w/w), drug (MH) (1.0% w/w), sorbitol (4% w/w) (cryoprotectant), Tween ® 80 (2% w/w) (surfactant) and distilled water (q.s to 100% w/w) (vehicle). The non-PEGylated and PEGylated SLNs (J0, J10, J20, J40)) were characterized with respect to encapsulation efficiency (EE%), loading capacity (LC), morphology by scanning electron microscopy (SEM), mean particle size (Zav) and polydispersity indices (PDI) by photon correlation spectroscopy (PCS), compatibility by FT-IR spectroscopy and in vitro drug release in biorelevant medium. Thereafter, in vivo antidiabetic study was carried out in alloxanized rats' model and compared with controls (pure sample of MH and commercial MH- Glucophage®)). Solid state characterizations indicated the amorphous nature of MH in the drug loaded-lipid matrices. The PEG-SLNs were mostly smooth and spherical nanoformulations with Zav and PDI of 350.00 nm and 0.54, respectively, for non-PEGylated SLNs, and in the range of 386.80-783.10 nm and 0.592 to 0.752, respectively, for PEGylated SLNs. The highest EE% and LC were noted in batch J20 and were 99.28% and 16.57, respectively. There was no strong chemical interaction between the drug and excipients used in the preparation of the formulations. The PEGylated SLN (batch J40) exhibited the highest percentage drug released (60%) at 8 h. The PEGylated SLNs showed greater hyperglycemic control than the marketed formulation (Glucophage ®) after 24 h. This study has shown that metformin-loaded PEGylated solid lipid nanoparticles could be employed as a potential approach to improve the delivery of MH in oral diabetic management, thus encouraging further development of the formulations.

Enhanced circulation longevity and pharmacodynamics of metformin from surface-modified nanostructured lipid carriers based on solidified reverse micellar solutions.

Metformin hydrochloride (MTH) has been associated with poor/incomplete absorption (50-60%), low bioavailability, short half-life (0.4-0.5 h), high dosage and dose-related side effects. To overcome these barriers and improve oral bioavailability and efficacy of MTH, surface-modified nanostructured lipid carriers (NLCs) were developed. Lipid matrices composed of rational blends of beeswax and Phospholipon® 90H (as solid lipids) and Capryol-PGE 860 (as liquid lipid) were prepared by fusion, and the resultant lipid matrices were PEGylated to give 10, 20 and 40% PEGylated lipid matrices. MTH-loaded non-PEGylated and PEGylated NLCs were prepared via high-shear hot homogenization and characterized regarding particle properties and physicochemical performance. The encapsulation efficiencies (EE%) and loading capacities (LC) of the MTH-loaded NLCs were determined while the in vitro drug release was evaluated in phosphate buffered saline (PBS, pH 7.4). Antidiabetic and pharmacokinetics properties of the NLCs were ascertained in an alloxan-induced diabetic rats model after oral administration. The MTH-loaded NLCs were nanomeric (particle size: 184.8-882.50 nm) with low polydispersity index (0.368-0.687) and zeta potential (26.5-34.2 mV), irregular shape, amorphous nature with reduced crystallinity. The EE% and LC were >90 % and 16%, respectively. The formulations showed >65 % release over 12 h in a greater sustained manner than marketed MTH formulation (Glucophage®) as well as enhanced pharmacokinetics properties and sustained blood glucose lowering effect, even at reduced doses with PEGylated NLCs than Glucophage®. Thus, PEGylated NLC is a promising approach for improved delivery and oral bioavailability of MTH thus encouraging further development of the formulation.

Systematic review on the application of machine learning to quantitative structure-activity relationship modeling against Plasmodium falciparum.

Malaria accounts for over two million deaths globally. To flatten this curve, there is a need to develop new and high potent drugs against Plasmodium falciparum. Some major challenges include the dearth of suitable animal models for anti-P. falciparum assays, resistance to first-line drugs, lack of vaccines and the complex life cycle of Plasmodium. Gladly, newer approaches to antimalarial drug discovery have emerged due to the release of large datasets by pharmaceutical companies. This review provides insights into these new approaches to drug discovery covering different machine learning tools, which enhance the development of new compounds. It provides a systematic review on the use and prospects of machine learning in predicting, classifying and clustering IC50 values of bioactive compounds against P. falciparum. The authors identified many machine learning tools yet to be applied for this purpose. However, Random Forest and Support Vector Machines have been extensively applied though on a limited dataset of compounds.

Recent and advanced nano-technological strategies for COVID-19 vaccine development.

The outbreak of the COVID-19 pandemic in 2019 has been one of the greatest challenges modern medicine and science has ever faced. It has affected millions of people around the world and altered human life and activities as we once knew. The high prevalence as well as an extended period of incubations which usually does not present with symptoms have played a formidable role in the transmission and infection of millions. A lot of research has been carried out on developing suitable treatment and effective preventive measures for the control of the pandemic. Preventive strategies which include social distancing, use of masks, washing of hands, and contact tracing have been effective in slowing the spread of the virus; however, the infectious nature of the SARS-COV-2 has made these strategies unable to eradicate its spread. In addition, the continuous increase in the number of cases and death, as well as the appearance of several variants of the virus, has necessitated the development of effective and safe vaccines in a bid to ensure that human activities can return to normalcy. Nanotechnology has been of great benefit in the design of vaccines as nano-sized materials have been known to aid the safe and effective delivery of antigens as well as serve as suitable adjuvants to potentiate responses to vaccines. There are only four vaccine candidates currently approved for use in humans while many other candidates are at various levels of development. This review seeks to provide updated information on the current nano-technological strategies employed in the development of COVID-19 vaccines.

Profiling the physicochemical and solid state properties of edible Tetracarpidium conophorum oil and its admixtures for drug delivery

Abstract The study is aimed at investigating the functional physicochemical and solid state characteristics of food-grade Tetracarpidium conophorum (T. conophorum) oil for possible application in the pharmaceutical industry for drug delivery. The oil was obtained by cold hexane extraction and its physicochemical properties including viscosity, pH, peroxide, acid, and thiobarbituric acid values, nutrient content, and fatty acid profile were determined. Admixtures of the oil with Softisan®154, a hydrogenated solid lipid from palm oil, were prepared to obtain matrices which were evaluated by differential scanning calorimetry, fourier-transform infrared spectroscopy, and x-ray diffractometry. Data from the study showed that T. conophorum oil had Newtonian flow behaviour, acidic pH, insignificant presence of hyperperoxides and malondialdehyde, contains minerals including calcium, magnesium, zinc, copper, manganese, iron, selenium, and potassium, vitamins including niacin (B3), thiamine (B1), cyanocobalamine (B12), ascorbic acid (C), and tocopherol (E), and long-chain saturated and unsaturated fatty acids including n-hexadecanoic acid, 9(Z)-octadecenoic acid, and cis-13-octadecenoic acid. The lipid matrices had low crystallinity and enthalpy values with increased amorphicity, and showed no destructive intermolecular interaction or incompatibility between T. conophorum oil and Softisan® 154. In conclusion, the results have shown that, in addition to T. conophorum oil being useful as food, it will also be an important excipient for the development of novel, safe, and effective lipid-based drug delivery systems.

Development of lipid-based microsuspensions for improved ophthalmic delivery of gentamicin sulphate.

Aim: Anterior eye segment disorders are treated with eye drops and ointments, which have low ocular bioavailability necessitating the need for improved alternatives. Lipid microsuspension of gentamicin sulphate was developed for the treatment of susceptible eye diseases. Materials & methods: Lipid microsuspensions encapsulating gentamicin sulphate were produced by hot homogenization and evaluated. Ex vivo permeation and ocular irritancy tests were also conducted. Results & conclusion: Stable microsuspensions with high entrapment efficiency and satisfactory osmolarities were obtained. Release studies achieved 49-88% in vitro release at 12 h with sustained permeability of gentamicin compared with conventional gentamicin eye drop (Evril®). No irritation was observed following Draize's test. The microsuspensions have great potential as ocular delivery system of gentamicin sulphate.

Intranasal artesunate-loaded nanostructured lipid carriers: A convenient alternative to parenteral formulations for the treatment of severe and cerebral malaria.

Early treatment with parenteral antimalarials is key in preventing deaths and complications associated with severe and cerebral malaria. This can be challenging in 'hard-to-reach' areas in Africa where transit time to hospitals with facilities to administer drugs parenterally can be more than 6 h. Consequently, the World Health Organization has recommended the use of artesunate (ATS) suppositories for emergency treatment of patients, however, this treatment is only for children under 6 years. The intranasal route (INR) can provide a safe and effective alternative to parenteral and rectal routes for patients of all ages; thus, reducing delays to the initiation of treatment. Hence, we designed ATS-loaded nanostructured lipid carriers (NLCs) for intranasal administration. ATS-NLCs were formulated using varying concentrations of lipid matrices made up of solidified reverse micellar solutions (SRMS) comprising a 1:2 ratio of Phospholipon ® 90H and lipids (Softisan ® 154 or Compritol ®). ATS-NLCs were spherical, and the small sizes of ATS-NLCs obtained for some formulations (76.56 ± 1.04 nm) is an indication that ATS-NLCs can pass through the nasal mucosa and reach the brain or systemic circulation. Encapsulation efficiency of ATS in NLCs was ≥70% for all formulations. ATS-NLCs achieved up to 40% in vitro drug release in 1 h, while ex vivo permeation studies revealed that formulating ATS as NLCs enhanced permeation through pig nasal mucosa better than drug solution. Most importantly, the activity and reduction in parasitaemia [in mice infected with Plasmodium berghei ANKA in a murine cerebral malaria model] by ATS-NLCs administered through the INR (54.70%, 33.28%) was comparable to intramuscular administration (58.80%, 42.18%), respectively. Therefore, intranasal administration of NLCs of ATS has great potentials to serve as a satisfactory alternative to parenteral administration for the treatment of severe and cerebral malaria in both adults and children in remote areas of sub-Saharan Africa.

Improved antimalarial activity of caprol-based nanostructured lipid carriers encapsulating artemether-lumefantrine for oral administration.

BACKGROUND: Artemether and lumefantrine display low aqueous solubility leading to poor release profile; hence the need for the use of lipid-based systems to improve their oral bioavailability so as to improve their therapeutic efficacy. AIM AND OBJECTIVE: The objective of this work was to utilize potentials of nanostructured lipid carriers (NLCs) for improvement of the oral bioavailability of artemether and lumefantrine combination and to evaluate its efficacy in the treatment of malaria. This study reports a method of formulation, characterization and evaluation of the therapeutic efficacies of caprol-based NLC delivery systems with artemether and lumefantrine. METHOD: The artemether-lumefantrine co-loaded NLCs were prepared using the lipid matrix (5% w/w) (containing beeswax and Phospholipon® 90H and Caprol-PGE 860), artemether (0.1%w/w) and lumefantrine (0.6%w/w), sorbitol (4%w/w), Tween® 80(2%w/w as surfactant) and distilled water (q.s to 100%) by high shear homogenization and evaluated for physicochemical performance. The in vivo antimalarial activities of the NLC were tested in chloroquine-sensitive strains of Plasmodium berghei (NK-65) using Peter´s 4-day suppressive protocol in mice and compared with controls. Histopathological studies were also carried out on major organs implicated in malaria. RESULTS: The NLC showed fairly polydispersed nano-sized formulation (z-average:188.6 nm; polydispersity index, PDI=0.462) with no major interaction occurring between the components while the in vivo study showed a gradual but sustained drug release from the NLC compared with that seen with chloroquine sulphate and Coartem®. Results of histopathological investigations also revealed more organ damage with the untreated groups than groups treated with the formulations. CONCLUSION: This study has shown the potential of caprol-based NLCs for significant improvement in oral bioavailability and hence antimalarial activity of poorly soluble artemether and lumefantrine. Importantly, this would improve patient compliance due to decrease in dosing frequency as a sustained release formulation.

Novel Intravaginal Drug Delivery System Based on Molecularly PEGylated Lipid Matrices for Improved Antifungal Activity of Miconazole Nitrate.

The aim of this study was to investigate the potential of microparticles based on biocompatible phytolipids [Softisan® 154 (SF) (hydrogenated palm oil) and super-refined sunseed oil (SO)] and polyethylene glycol- (PEG-) 4000 to improve intravaginal delivery of miconazole nitrate (MN) for effective treatment of vulvovaginal candidiasis (VVC). Lipid matrices (LMs) consisting of rational blends of SF and SO with or without PEG-4000 were prepared by fusion and characterized and employed to formulate MN-loaded solid lipid microparticles (SLMs) by melt-homogenization. The SLMs were characterized for physicochemical properties, anticandidal activity, and stability. Spherical discrete microparticles with good physicochemical properties and mean diameters suitable for vaginal drug delivery were obtained. Formulations based on SO:SF (1:9) and containing highest concentrations of PEG-4000 (4 %w/w) and MN (3.0 %w/w) were stable and gave highest encapsulation efficiency (83.05-87.75%) and inhibition zone diameter (25.87±0.94-26.33±0.94 mm) and significantly (p<0.05) faster and more powerful fungicidal activity regarding killing rate constant values (7.10 x 10-3-1.09 x 10-2 min-1) than commercial topical solution of MN (Fungusol®) (8.00 x 10-3 min-1) and pure MN sample (5.160 x 10-3 min-1). This study has shown that MN-loaded SLMs based on molecularly PEGylated lipid matrices could provide a better option to deal with VVC.

Novel solidified reverse micellar solution-based mucoadhesive nano lipid gels encapsulating miconazole nitrate-loaded nanoparticles for improved treatment of oropharyngeal candidiasis.

OBJECTIVE: To develop and evaluate solidified-reverse-micellar-solution (SRMS)-based oromucosal nano lipid gels for improved localised delivery of miconazole nitrate (MN). METHODS: Phospholipon® 90G and Softisan® 154 (3:7) were used to prepare SRMS by fusion. Solid lipid nanoparticles (SLNs, 0.25-1.0% w/w MN) formulated with the SRMS by high shear homogenisation were employed to prepare mucoadhesive nano lipid gels. Physicochemical characterisation, drug release in simulated salivary fluid (SSF) (pH 6.8) and anti-candidal activity were carried out. RESULTS: The SLNs were spherical nanoparticles, had mean size of 133.8 ± 6.4 to 393.2 ± 14.5 nm, low polydispersity indices, good encapsulation efficiency (EE) (51.96 ± 2.33-67.12 ± 1.65%) and drug loading (DL) (19.05 ± 2.44-24.93 ± 1.98%). The nano lipid gels were stable, spreadable, pseudoplastic viscoelastic mucoadhesive systems that exhibited better prolonged release and anti-candidal properties than marketed formulation (Daktarin® oral gel) (p < 0.05). CONCLUSION: This study has shown that SRMS-based nano lipid gels could be employed to prolong localised oromucosal delivery of MN.

Sustained-release liquisolid compact tablets containing artemether-lumefantrine as alternate-day regimen for malaria treatment to improve patient compliance.

The present study aimed to develop low-dose liquisolid tablets of two antimalarial drugs artemether-lumefantrine (AL) from a nanostructured lipid carrier (NLC) of lumefantrine (LUM) and estimate the potential of AL as an oral delivery system in malariogenic Wistar mice. LUM-NLCs were prepared by hot homogenization using Precirol® ATO 5/Transcutol® HP and tallow fat/Transcutol® HP optimized systems containing 3:1 ratios of the lipids, respectively, as the matrices. LUM-NLC characteristics, including morphology, particle size, zeta potential, encapsulation efficiency, yield, pH-dependent stability, and interaction studies, were investigated. Optimized LUM-NLCs were mixed with artemether powder and other dry ingredients and the resultant powder evaluated for micromeritics. Subsequent AL liquisolid tablets were tested for in vitro drug release and in vivo antiplasmodial activity in mice infected with Plasmodium berghei berghei (NK 65). Results showed that optimized LUM-NLC were stable, spherical, polydispersed but nanometric. Percentage yield and encapsulation efficiency were ~92% and 93% for Precirol® ATO 5/Transcutol® HP batch, then 81% and 95% for tallow fat/Transcutol® HP batch while LUM was amorphous in NLC matrix. In vitro AL release from liquisolid compacts revealed initial burst release and subsequent sustained release. Liquisolid tablet compacts formulated with Precirol® ATO 5/Transcutol® HP-AL4 achieved higher LUM release in simulated intestinal fluid (84.32%) than tallow fat/Transcutol® HP-BL3 (77.9%). Non-Fickian (anomalous) diffusion and super case II transport were the predominant mechanisms of drug release. Equal parasitemia reduction was observed for both batches of tablet compacts (~92%), superior to the reduction obtained with commercial antimalarial formulations: Coartem® tablets (86%) and chloroquine phosphate tablets (66%). No significant difference (P<0.05) in parasite reduction between double (4/24 mg/kg) and single (2/12 mg/kg) strength doses of AL compacts was observed. Our result highlights that AL could be formulated in much lower doses (4/24 mg/kg), for once-in-two days oral administration to improve patient compliance, which is currently not obtainable with conventional AL dosage forms.

Azadirachta indica extract-artesunic acid combination produces an increased cure rate of Plasmodium berghei-infected mice.

CONTEXT: Available artemisinin-combination therapies (ACTs) are expensive. Various traditional herbal remedies for malaria involve plants, proven scientifically to have antiplasmodial effects, e.g., Azadirachta indica A. Juss. (Meliaceae). OBJECTIVE: Combination of an artemisinin-based compound and a medicinal herb extract will provide an indigenous alternative/herb-based ACT. MATERIALS AND METHODS: The in vivo schizontocidal activity of the crude aqueous extract of 100, 500, and 1000 mg/kg of A. indica fresh leaves (NCE) and 6, 15, and 20 mg/kg of artesunic acid were determined, alone and in combination, while keeping the dose of artesunic acid constant at 15 mg/kg, using the Peter's 4-day suppressive test and Swiss albino mice. The ED50 was calculated from the dose-response relationships. Percentage survival and cure were also determined. RESULTS: The average yield of two extractions of NCE was 8.33 ± 1.67%. Combination of 1000 mg/kg of NCE and 15 mg/kg of artesunic acid, produced a significant reduction of parasitemia (96.87%), compared to 20 mg/kg of artesunic acid alone (68.14%). The combination had an ED50 of 0.58 mg/kg while that of artesunic acid alone was 8.814 mg/kg. The combinations of NCE with artesunic acid produced a cure, although the artesunic acid did not produce a cure in 30 d. DISCUSSION: NCE increased the activity of artesunic acid in terms of reduction in parasitemia, and increased survival time and cure rate. CONCLUSION: The combination of an artemisinin and aqueous extract of neem leaf is possible, providing a potentiated reduction of parasitemia, and increased cure rate.

Sustained-release diclofenac potassium-loaded solid lipid microparticle based on solidified reverse micellar solution: in vitro and in vivo evaluation.

OBJECTIVE: To formulate sustained-release diclofenac potassium-loaded solid lipid microparticles (SLMs) based on solidified reverse micellar solution (SRMS) and to evaluate the in vitro and in vivo properties. METHODS: SRMS consisting of mixtures of Phospholipon® 90H and Softisan® 154 were used to formulate diclofenac potassium-loaded SLMs. Characterization based on the particle size and morphology, stability and encapsulation efficiency (EE%) were carried out on the SLMs. In vitro release was carried out in simulated intestinal fluid (pH 7.5). Anti-inflammatory and ulcerogenic properties were studied using rats. RESULTS: Maximum EE% of 95%, 94% and 93% were obtained for SLMs formulated with SRMS 1:1, 2:1 and 1:2, respectively. In vitro release showed about 85-90% drug release at 13 h. Diclofenac potassium-loaded SLMs showed good anti-inflammatory and gastro-protective properties. CONCLUSION: Diclofenac potassium-loaded SLMs based on SRMS could be used orally or parenterally under controlled conditions, for once daily administration.

Mucuna gum microspheres for oral delivery of glibenclamide: In vitro evaluation.

An investigation into the suitability of mucuna gum microspheres for oral delivery of glibenclamide is presented. Mucuna gum microspheres were formulated under different conditions of polymer concentration and crosslinking time at constant speed. The formulated microspheres were thereafter loaded with glibenclamide by the remote loading process. The microspheres were evaluated according to particle size, yield, loading efficiency and swelling. In vitro release of glibenclamide from the microspheres was studied in simulated intestinal fluid (SIF, pH 7.4). The release data was fitted into two release models to investigate the mechanism of glibenclamide release from the microspheres. All the microspheres showed good swelling characteristics in distilled water. The investigation revealed that the microspheres produced with 5% (m/V) mucuna gum with a crosslinking time of 5 h had the optimum prolonged release pattern. The microspheres produced using 10% (m/V) mucuna gum with a crosslinking time of 1 h had the highest delayed release of the incorporated drug, whereas those without crosslinking had the fastest release. The Ritger-Peppas case I transport model appeared to have adequately described the release process as about 54% of the batches of microspheres conformed to this model. This implies that a formulation of glibenclamide-loaded mucuna gum microspheres is likely to offer a reliable means of delivering glibenclamide by the oral route.